Use of EBSD to characterise high temperature

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Wear-resistant amorphous SiC coatings produced

Surface and Coatings Technology116–119(1999)1024–1028www.elsevier.nl/locate/surfcoat Wear-resistant amorphous SiC coatings producedby plasma-enhanced CVDT.Blum a,*,B.Dresler a,St.Kaßner b,M.Hoﬀmann aa OSTEC Oberﬂa¨chen-und Schichttechnologie GmbH Meißen,Ossietzkystraße37A,D-01662Meißen,Germanyb Fakulta¨t Maschinenbau und Verfahrenstechnik,Lehrstuhl fu¨r Verbundwerkstoﬀe,TU Chemnitz,Straße der Nationen62,D-09111Chemnitz,GermanyAbstractThe use of plasma-enhanced CVD allows the deposition of thinﬁlms with relatively high coating rates at temperatures below 400°C and on substrates with a three-dimensional geometry.In this way,it is possible to deposit amorphous silicon carbide (a-SiC:H)on temperature-sensitive materials for tribological applications to replace ceramic materials that are diﬃcult to process and expensive to manufacture.The aim of this paper is to examine the correlations between the deposition parameters and the resulting layer characteristics,using an excitation frequency of450kHz.©1999Elsevier Science S.A.All rights reserved. Keywords:Amorphous SiC coatings;Plasma-enhanced CVD;Wear resistance1.Introduction authors found that the composition of the layers andtheir properties are inﬂuenced by all deposition parame-ters.The most striking changes were observed when the In recent years,non-oxidic ceramic materials havebeen gaining growing importance because of their excel-methane/silane concentration ratio in the reactive gaswas varied.Meneve et al.[7]observed an optimum lent tribological characteristics.Furthermore,they havebeen used in high-temperature applications and under friction behaviour for the coatings deposited at a meth-ane volume fraction X(CH4)=0.7.corrosive and abrasive conditions.However,the manu-facture and processing of these materials are complicated Conventional CVD of SiC coatings requires depos-ition temperatures of about1000°C.In many cases,this and costly.The application of amorphous ceramic thinﬁlms deposited onto inexpensive substrate materials(e.g.leads to changed properties of temperature-sensitivesubstrates.In contrast,the use of plasma-enhanced CVD steel with suﬃcient strength)would be an alternative tominimize the processing diﬃculties.for depositing a-SiC:H allows a reduction in the depos-ition temperature below400°C.Amorphous silicon carbide(a-SiC:H)thinﬁlms havebeen widely investigated(e.g.[1,2]).Because of its The use of low excitation frequencies results in inten-sive ion bombardment duringﬁlm deposition.A high excellent physical and chemical properties,such as chem-ical stability and high thermal conductivity,SiC com-ion-energyﬂux inﬂuences hardness positively,asobserved by J.Vandentop et al.[9].Ion bombardment pounds produced by PECVD have been applied up tonow mainly for passivation and window layers in optical which leads to the activation of surface reactions is anessential condition for depositing hard adherent coatings and electronical applications[3,4].Moreover,there areother characteristics,such as excellent tribological prop-[10].Therefore,we used an excitation frequency of450kHz,which is in contrast to most other publications. erties,a low friction coeﬃcient[5]and a high hardness,which make a-SiC:H a promising material for tribologi-cal coatings,too.Halverson and Vakerlis[6]carried out experiments2.Experimentalwith PACVD on three-dimensional substrates.TheA series of experiments have been performed toinvestigate the correlation between the deposition *Corresponding author.Tel.:+49-03521-46-35-70;fax:+49-03521-46-35-71.parameters and the resulting layer characteristics.The0257-8972/99/$–see front matter©1999Elsevier Science S.A.All rights reserved.PII:S0257-8972(99)00319-91025T.Blum et al./Surface and Coatings Technology 116–119(1999)1024–1028kept constant at 450kHz.Before deposition,each sub-strate was sputtered with H 2for 2h;in the case of thetemperature series,sputtering was carried out for 1.5h with H 2and for 0.5h with Ar.UV-VIS transmission spectroscopy (Shimadzu 3101)in the range between 400and 2000nm was used to determine the layer thickness and refractive index.Fourier-transformed infra-red spectroscopy (Bio-Rad FTS 175)in the wave number range between 4000and 400cm −1was performed on coated double-sidedpol-ished Si wafers to gain an insight into the established Fig.1.Schematic diagram of the plasma-enhanced CVD system.bonding structure.In order to determine the layer morphology and topography,surfaces and cross sections a-SiC:H coatings were deposited in a hot-wall PECVD were investigated by scanning electron microscopy reactor (Fig.1)on Corning 7059glass,silicon and steel (JSM-840A fabricated by JEOL).Samples (Si wafer)substrates using gas mixtures of silane and methane.were coated with carbon before the investigation was The reactant gases were introduced at a constant total performed.The surface roughness was determined using gas ﬂow rate of 43.5sccm,and the methane volume a commercial proﬁlometer (TK300produced by fraction X (CH 4)was 0.5or 0.7.The substrate temper-Hommelwerke GmbH).In order to determine the hard-ature ranged from 50to 250°C.The r.f.power and ness,the coatings were tested with a Shimadzu HMV-M pressure were varied (P RF:100…990W,p :4…11Pa).using the Vickers procedure with a static load of 0.25N for 10s.Throughout this study,the excitation frequency was(A)(C)(B)Fig.2.SEM micrographs of a-SiC:H coatings.(a)Surface;deposition parameter:p =5.5Pa,T =50°C,P r.f.=100W,X (CH 4)=0.7.(b)Surface;deposition parameter:p =11Pa,T =125°C,P r.f.=500W,X (CH 4)=0.7.(c)Cross-section of (b).1026T.Blum et al./Surface and Coatings Technology 116–119(1999)1024–10283.Results and discussionFrom SEM investigations of coatings produced at various pressures,temperatures and r.f.power levels,it was found that all layers show the same morphological structure.All deposits,including those produced at temperatures lower than 200°C,are dense and regular [Fig.2(a)and (b)].No cracks or holes could be found.This shows that the plasma-enhanced chemical vapor deposition is a suitable technique for coating temper-ature-sensitive materials.The samples that were pretreated in hydrogen and argon plasma before deposition show an intermediate layer beneath the deposited a-SiC:H layer [Fig.2(c)].Fig.4.Deposition rate vs.temperature.This intermediate layer is considered as native silicon oxide,which will be explained later in the text.The investigations of surface roughness were carried out on various substrates (Corning 7059glass,Si wafer,steel ).Even the layers with a ﬁlm thickness of a few microns do not show any ﬂattening of the substrate surface.Hence,the layer roughness is equal to the roughness of the substrate (R A=0.03m m for polishedSi wafer,R A=0.05m m for SiC coated Si wafer).The deposition rate depends almost linearly on the pressure,as can be seen from Fig.3.A similar behaviour was established by Lelogeais and Ducarroir [11].Deposition rates of up to 2.4m m /h have been achieved with a corresponding set of parameters.With increasing temperature,the deposition rate Fig.5.Hardness vs.temperature.decreases from 0.37to 0.18m m /h (see Fig.4).For tem-peratures above 200°C,the deposition rate remains constant.This result conﬁrms the statement of Meneve[8],who observed a similar behaviour.In contrast,the hardness of the coatings slightly increases with increasing substrate temperature (Fig.5).This can be explained by the higher mobility of particles at the growing surface at higher temperatures,which eventually leads to a lower density of defect sites and to changed bonding conﬁgurations which is shown below.The refractive index vs.r.f.power is shown in Fig.6.Fig.6.Refractive index vs.r.f.power at three pressures.For r.f.levels below 300W,the refractive index decreases,between 300and 500W,it increases,and above 500W,it remains constant for r.f.values .The refractive index is independent of temperature (Fig.7).On the contrary,Young and Partlow [12]found a proportional dependence of the refractive index on substrate temperature,using a much higher pressure and an excitation frequency of 13.56MHz.We presume that the higher values of the Fig.3.Deposition rate vs.pressure at two r.f.power levels.refractive index of our layers are caused by an intensive1027T.Blum et al./Surface and Coatings Technology 116–119(1999)1024–1028Fig.7.Refractive index vs.temperature.Fig.9.FTIR spectra of various SiC-coated samples,sputtered with hydrogen and argon before deposition.ion bombardment due to the low excitation frequency.In this case,the substrate temperature has only a smallinﬂuence on the refractive index.In the FTIR spectra of samples pretreated with hydrogen plasma,oxygen could not be detected.However,in the spectrum of the untreated wafer,a band at about 1100cm −1(Si M O M Si stretching vibration)was found (Fig.8).It can be concluded that hydrogen plasma pretreatment is a suitable method to remove an oxide layer from the wafer.Incorporation of oxygen during the deposition could not be detected.All spectra of the temperature series show a clearly recognizable band at about 1100cm −1,also after subtraction of the wafer spectrum (Fig.9).It has already been mentioned that the temperature samples were pretreated ﬁrst with a hydrogen plasma and then with an argon plasma.Thus,Fig.10.(Si M H 2)nbond bending in FTIR spectra of SiC-coatedwe conclude that pretreatment with a hydrogen plasma samples,deposited at various temperatures.has a more favourable inﬂuence regarding the elimination of silicon oxide than pretreatment with an argon plasma.(Fig.11).This can be interpreted as a splitting-o ﬀof The interpretation of FTIR spectra shows a decrease hydrogen from the Si M CH 3bonds at temperaturesin silicon polyhydride (Fig.10)and Si M CH 3in chain-above 50°C.Because the transformation of CH 2groupslike structures with increasing temperature.However,into carbon-bonded silicon already takes place com-the number of Si M C bonds increases with temperatureFig.11.Si M C stretching vibration mode in FTIR spectra of SiC-Fig.8.FTIR spectra of uncoated Si wafer and various SiC coated samples,sputtered with hydrogen before deposition.coated samples,deposited at various temperatures.1028T.Blum et al./Surface and Coatings Technology 116–119(1999)1024–1028pletely at room temperature,the Si M C absorption band Referencesat 740cm −1can also be seen in the spectrum of layers,which were deposited at 50°C [13].[1]M.M.Rahman,C.Y.Yang,D.Sugiarto,A.S.Byrne,M.Ju,K.Tran,K.H.Lui,T.Asano,W.F.Stickle,J.Appl.Phys.67(11)(1990)7064–7070.[2]Y.Tawada,M.Kondo,H.Okamoto,Y.Hamakawa,Journal de4.SummaryPhysique C4,42(10)(1981)471–474.[3]H.Frey,in:Du ¨nnschichttechnologie,VDI,Du ¨sseldorf,1987,It was found that the use of the plasma-enhancedp.531.[4]G.L.Harris,Amorphous and Crystalline Silicon Carbide andchemical vapor deposition enables the deposition of Related Materials,Springer,New York,1987.dense and regular a-SiC:H layers,even at temperatures [5]J.Meneve,R.Jacobs,L.Eersels,J.Smeets,E.Dekempeneer,lower than 200°C.Surf.Coat.Technol.62(1993)577–582.The surface roughness of these layers is equal to the [6]W.Halverson,G.D.Vakerlis,J.Vac.Sci.Technol.A 10(3)roughness of the substrates.(1992)439–443.The deposition rate depends mainly on the pressure [7]J.Meneve,E.Dekempeneer,R.Jacobs,L.Eersels,V.Van DenBergh,J.Smeets,Diamond Relat.Mater.1(1992)553–557.and the substrate temperature.Deposition rates up to [8]J.Meneve,E.Dekempeneer,R.Jacobs,L.Eersels,V.Van Den2.4m m /h have been achieved.Bergh,J.Smeets,Silicates Industriels 7–8(1992)117–122.The interpretation of FTIR spectra shows a decrease [9]G.J.Vandentop,M.Kawasaki,K.Kobayashi,G.A.Somorjai,in silicon polyhydride (Fig.10)and Si M CH 3in chain-J.Vac.Sci.Technol.A 9(3)(1991)1157–1161.like structures with increasing temperature.[10]S.Peter,R.Pintaske,F.Richter,G.Hecht,in:Thin Films,Proc.Joint 4th Int.Symp.Trends and New Appl.Thin Films —TATF ’94and 11th Conf.High Vacuum,Interfaces and Thin Films —HVITF ’94(1994)191–194.Acknowledgement[11]M.Lelogeais,M.Ducarroir,Surf.Coat.Technol.48(1991)121–129.This work was supported by Sa ¨chsisches [12]R.M.Young,W.D.Partlow,Thin Solid Films 213(1992)Staatsministerium fu ¨r Wirtschaft und Arbeit under con-170–175.[13]A.Bolz,thesis,Universita ¨t Erlangen,1991.tract number 2593.。

语言学考研真题

语言学考研真题和答案第一章语言学Fill in the blanks1. Human language is arbitrary. This refers to the fact that there is no logical or intrinsic connection between a particular sound and the _______it is associated with. （人大2007研）meaning 语言有任意性，其所指与形式没有逻辑或内在联系2. Human languages enable their users to symbolize objects, events and concepts which are not present (in time and space) at the moment of communication. This quality is labeled as _______. （北二外2003研）displacement 移位性指人类语言可以让使用者在交际时用语言符号代表时间和空间上不可及的物体、事件和观点3. By duality is meant the property of having two levels of structures, such that units of the _______ level are composed of elements of the __________ level and each of the two levels has its own principles of organization. （北二外2006研）primary, secondary 双重性指拥有两层结构的这种属性，底层结构是上层结构的组成成分，每层都有自身的组合规则4. The features that define our human languages can be called _______ features. （北二外2006）design人类语言区别于其他动物交流系统的特点是语言的区别特征，是人类语言特有的特征。

芯锋胶合材料公司产品说明书

Figure 3CHO-SEAL 1285 and CHO-SIL 1485Sheet Stock Compression-DeflectionCompression-Deflectionspecial shapes.Conductive ElastomersCompression-DeflectionWhile standard test procedures have been established for measuring the deflection of elastomers under compressive loads, the practical use of such data is to provide a qualitative comparison of thedeformability of different elastomeric materials when in the particular configuration of the test sample.Solid (non-foam) elastomers are essentially incompressible materials;i.e., they cannot be squeezed into a smaller volume. When a solid elas-tomer is subject to a compressive load, it yields by deformation of the part as a whole. Because of this behavior, the actual deflection of a gasket under a compressive load depends upon the size and shape of the gasket as well as on its modulus and the magnitude of the load.The design of a seal should be such that it will be subjected to the minimum squeeze sufficient toprovide the required mechanical and electrical performance. The designed deflection of conductive elastomer gaskets should never exceed the maximum deflection limits shown in Table 1.There is an approximate relation-ship between the force required to deflect a pure elastomer a given amount, and the hardness of the elastomer. In general, the harder the elastomer, the greater the force required. In the case of Chomerics’metal particle-filled elastomers, this relationship is much less definite,and in some instances, these materials demonstrate deflection/hardness and deflection/thickness behavior contrary to that which would be anticipated for conventional rubber compounds.The inclusion of metal particles in the elastomer results in a mechanically structured material. This mechanical structure has a marked effect on the deflection of the elastomer under compressive loads, and in some instances, harder materials deflect more than softer materials.Compressive load-deflection data for many popular conductiveelastomer materials and shapes are given in Figures 1-25. (For “linecontact” gaskets, it is more convenient to express the load in terms of pounds per linear inch instead of pounds per square inch).For compression-deflection data on other Chomerics gaskets, contact our Applications Engineering Department.Compression-DeflectionCompression-DeflectionCONTENTS:Compression-Deflection 80Stress Relaxation 83Compression Set 83Shielding Effectiveness 83EMP Survivability 84Vibration Resistance 84Heat Aging 85Outgassing85Volume Resistivity Measurement86Figure 80.125 in. (3.18 mm) Dia. O-Strip Compression-DeflectionDeflection,%Compression-DeflectionCompression-DeflectionL o a d , l b ./i n c hDeflection, %Figure 210.156 in. (3.96 mm) High Hollow D-Strip Compression-DeflectionL o a d , l b ./i n c hDeflection, %Figure 220.312 in. (7.92 mm) High Hollow D-Strip Compression-DeflectionFigure 200.250 in. (6.35 mm) Dia. Hollow O-Strip Compression-DeflectionL o a d , l b ./i n c hDeflection, %L o a d , l b ./i n c hDeflection, %Figure 230.250 in. (6.35 mm) Dia. Hollow P-Strip Compression-DeflectionFigure 240.360 in. (9.14 mm) Dia. Hollow P-Strip Compression-DeflectionL o a d , l b ./i n c hDeflection, %L o a d , l b ./i n c hDeflection,%Figure 190.156 in. (3.96 mm) Dia. Hollow O-Strip Compression-DeflectionL o a d , l b ./i n c hDeflection, %Figure 170.250 in. (6.35 mm) Wide Rectangular Strip Compression-Deflection0.40.81.20.20.61.0C o m p r e s s i o n F o r c e (l b /i n )00.5 1.50.10.2Deflection (inch)1356P/N 10-09-W864-XXXXFigure 250.410 in. (10.41 mm) High V-Strip Compression-DeflectionStress RelaxationAs important as Compression Set and Compression-Deflection, is the Stress Relaxation characteristic of a gasket.If a rubber is subject to a com-pressive load, it will deflect. There is a stress/strain relationship, which for rubbers is generally non-linear except for very small deflections.After the load is applied, a stress decay occurs within the polymer resulting from the internal rearrange-ment of the molecular structure. An approximate rule is that the relaxed stress for cured silicone will finally settle at 70 to 75 percent of the initial stress.There are two ways in which a rubber gasket can be loaded to a desired value. One way is to load it to a point, let it relax, and reapply the load to restore the original stress. The next time it will relax, but not so much.If this is repeated a sufficient number of times, the correct static load on the gasket will reach equilibrium.A more practical way to reach the design value of stress is to load the gasket to 125 percent of its final design value, so that after the relax-ation process is completed the gasket will settle to 100 percent of the design load. This is very reproducible.Figure 26shows a typical stress relaxation curve for Chomerics’conductive elastomers.Compression SetWhen any rubber is deformedfor a period of time, some of the defor-mation is retained permanently even after the load is removed. The amount of permanent deformation, asmeasured by ASTM D395, is termed “Compression Set.” Compression set is measured under conditions of constant deflection (ASTM D395Method B) and is normally expressed as a percentage of the initialdeflection, not as a percentage of the initial height.For gaskets that are used once, or where the gasket/flange periphery relationship is constant (such as a door gasket), compression set is of minor significance if the original load condition and the service temperature are within the design limitations of the gasket material.For gaskets that are randomlyreseated one or more times in normal service life, it is important that the maximum change in gasket thickness does not exceed twice the maximum mismatch between the opposing mating surfaces.Shielding EffectivenessMost shielding effectiveness data given in Table 3 of the Conductive Elastomer section (pages 32-34) is based on a MIL-G-83528B testmethod, with a 24 in. x 24 in. aperture in a rigid enclosure wall and about 100 psi on the gasket. It is a valid and useful way of comparing variousgasket materials, but does not reflect the shielding effectiveness one can expect at seams of typical enclosures.CHO-TM-TP08 is a modified version of the MIL test that provides typical values achieved in actual applications.Since many factors will affect the actual shielding effectiveness of anenclosure seam (flange design,stiffness, flatness, surface resistivity,fastener spacing, enclosuredimensions, closure force, etc.), the only way to determine shielding effectiveness for real enclosures is to test them.Figures 28and 29provide dataon shielding effectiveness for actualFigure 27Formula for Calculation of Compression Setenclosures. The data in Figure 28shows the difference in attenuation between a shelter door closed with no gasket and the same door closed against a CHO-SEAL 1215 hollow D-strip gasket. Instead of single data points at each frequency tested, a range of data is shown for eachfrequency, representing the worst and best readings measured at many points around the door. Figure 29 shows the effects of closure force on shielding effectiveness of an enclosure tested at high frequencies (1-40 GHz) using CHO-SEAL 1215 solid D-strip gaskets.In order to establish reasonable upper limits on gasket resistivity, it is necessary to understand the rela-tionship between flange interface resistance and EMI leakage through the flange. Figure 30presents this relationship for an aluminum enclosure 3 in. x 3 in. x 4 in. deep, measured at 700 MHz. Die-cut gaskets 0.144 in.wide by 0.062 in. thick, in a wide range of resistivities, were clamped between the gold-plated flanges of thisenclosure. Simultaneous measure-ments of flange interface resistance (all attributable to the gaskets) versus RF leakage through the seamproduced a classic S-shaped curve.For the gasket configuration used in this test, the dramatic change in shielding effectiveness occursbetween gasket volume resistivities of 0.01 and 0.4 ohm-cm. Since real enclosures do not have gold-plated flanges, but rather have surfacefinishes (such as MIL-C-5541 Class 3chromate conversion coatings) which also increase in resistance over time, it is recommended that gasket volume resistivity be specified at 0.01 ohm-cm max. for the life of the equipment.Frequency, HzA t t e n u a t i o n (dB )Figure 28Shielding Effectiveness of a Shelter Door Gasket (14 kHz to 10 GHz)kA/inch of gasket (peak-to-peak).Pure silver (1224) and silver-plated-aluminum filled (1285) gaskets have less current carrying capability than silver-plated-copper materials, but are generally acceptable for EMP hardened systems (depending on specific EMP threat levels, gasket cross section dimensions, etc.).Vibration ResistanceCertain conductive elastomers are electrically stable during aircraft-level vibration environments, while others are not. The key factor which deter-mines vibration resistance is theshape and surface texture of the filler particles. Smooth, spherical fillers (such as those used in silver-plated-Figure 32Scanning Electron Microscopy Illustrates EMP Damage Mechanism for Silver/Glass ElastomersL e a k a g e (d B )Vibration (g)Figure 33Effects of Vibration on Shielding Effectiveness of Conductive Elastomer GasketsEMP SurvivabilityIn order for an enclosure to continue providing EMI isolationduring and after an EMP environment,the conductive gaskets at joints and seams must be capable of carrying EMP-induced current pulses without losing their conductivity. Figure 31shows the EMP current response of various types of conductive elastomer gaskets. Note that gaskets based on silver-plated-glass fillers (1350)become nonconductive at low levels of EMP current, and should therefore not be used when EMP is a design consideration. Figure 32is an electron microscope photo which clearly shows the damage mechanism.Silver-plated-copper filled (1215)gaskets have the highest resistance to EMP type currents, showing no loss of conductivity even at 2.50102030405060Shielding Degradation, dBIn t e r f a c e R e s i s t a n c e , m i l l i o h m sFigure 30Interface Resistance vs. Shielding Degradation at a Flange Jointglass materials) tend to move apart during vibration, leading to dramatic increases in resistance and loss of shielding effectiveness (although they normally recover their initial properties after the vibration has ended). Rough, less spherical particles resist vibration with very little electrical degradation. Figure 33shows the effects of vibration on three types of conductive gaskets.Although Chomerics’ silver-plated-copper filled 1215 gasket, with rough,irregular particle agglomerations,exhibits excellent stability during vibration, users of conductive elastomers should be aware that smooth, spherical silver-plated-copper fillers can be almost asunstable as silver-plated-glass fillers.Frequency, GHzA t t e n u a t i o n (dB )Figure 29Effect of Closure Force on Shielding Effectiveness (1 GHz to 40 GHz)Heat AgingThe primary aging mechanism which affects electrical stability of conductive elastomers is the oxidation of filler particles. Formaterials based on pure silver fillers,particle oxidation is not generally a problem because the oxide of silver is relatively soft and reasonably conductive. If the filler particles are non-noble (such as copper, nickel,aluminum, etc.) they will oxidize readily over time and become nonconductive. Even silver-plated base metal powders, such as silver-V o l u m e R e s i s t i v i t y (o h m -c m )Hours at 150°C (Solid Line)Hours at 125°C (Dotted Line)Figure 34Typical heat aging characteristics of Chomerics’ plated-powder-filled conductiveelastomers. Flanged 1000-hr test recommended for qualification. Unflanged 48-hr. test recommended for QC acceptance.plated-copper or silver-plated-aluminum will become non-conductive over time if the plating is not done properly (or if other processingvariables are not properly controlled).These are generally batch control problems, with each batch being potentially good or bad.The most reliable method of predicting whether a batch will be electrically stable is to promote the rate at which poorly plated or processed particles will oxidize, by heat aging in an air circulating oven.For qualification, 1000 hours (42 days)at maximum rated use temperature (with the gasket sample deflected 7-10% between flanges) is the recommended heat aging test for accelerating the effects of long-term aging at normal ambient tempera-tures. A quicker heat aging test,which correlates well with the 1000hour test and is useful for QC acceptance testing, involves a 48hour/150°C oven bake with thegasket sample on an open wire-grid tray (rather than being clamped between flanges). Figure 34shows typical data for volume resistivity versus time for each of these tests.Note:It is essential that no source of free sulfur be placed in the aging oven, as it will cause the material to degrade electrically and mask any oxidation aging tendencies. Common sources of sulfur are neoprenes,most cardboards and other paper products.OutgassingMany spacecraft specifications require that nonmetallic components be virtually free of volatile residues which might outgas in the hard vacuum environment of space. The standard test method for determining outgassing behavior is ASTM E595-93, which provides for measurement of total mass loss (TML) and collected volatile condensable materials (CVCM) in a vacuum environment. Data for a number of Chomerics conductive elastomers,based on ASTM E595-93 testing done by NASA Goddard SpaceflightCenter, is presented in Table 2. The normal specification limits or guide-lines on outgassing for NASA applications are 1% TML max.,and 0.1% CVCM max.。

The

1paring two images, or an image and a model, is the fundamental operation for many image processing and computer vision systems. In most systems of interest, a simple pixelby-pixel comparison won’t do: the diﬀerence measurement that we determine must bear some correlation with the perceptual diﬀerence between the two images, or with the diﬀerence between two adequate interpretations of the two images. In order to compute meaningful diﬀerences between images, the ﬁrst step is usually the determination of a suitable set of features which encode the characteristics that we intend to measure. Measuring meaningful image similarity is a dichotomy that rests on two elements: ﬁnding the right set of features and endowing the feature space with the right metric. Since the same feature space can be endowed with an inﬁnity of metrics, the two problems are by no means equivalent, nor does the ﬁrst subsume the second. In this paper we consider the problem of measuring distances in feature spaces. In a number of cases, after having selected the right set of features extracted, and having characterized an

OSHA现场作业手册说明书

DIRECTIVE NUMBER: CPL 02-00-150 EFFECTIVE DATE: April 22, 2011 SUBJECT: Field Operations Manual (FOM)ABSTRACTPurpose: This instruction cancels and replaces OSHA Instruction CPL 02-00-148,Field Operations Manual (FOM), issued November 9, 2009, whichreplaced the September 26, 1994 Instruction that implemented the FieldInspection Reference Manual (FIRM). The FOM is a revision of OSHA’senforcement policies and procedures manual that provides the field officesa reference document for identifying the responsibilities associated withthe majority of their inspection duties. This Instruction also cancels OSHAInstruction FAP 01-00-003 Federal Agency Safety and Health Programs,May 17, 1996 and Chapter 13 of OSHA Instruction CPL 02-00-045,Revised Field Operations Manual, June 15, 1989.Scope: OSHA-wide.References: Title 29 Code of Federal Regulations §1903.6, Advance Notice ofInspections; 29 Code of Federal Regulations §1903.14, Policy RegardingEmployee Rescue Activities; 29 Code of Federal Regulations §1903.19,Abatement Verification; 29 Code of Federal Regulations §1904.39,Reporting Fatalities and Multiple Hospitalizations to OSHA; and Housingfor Agricultural Workers: Final Rule, Federal Register, March 4, 1980 (45FR 14180).Cancellations: OSHA Instruction CPL 02-00-148, Field Operations Manual, November9, 2009.OSHA Instruction FAP 01-00-003, Federal Agency Safety and HealthPrograms, May 17, 1996.Chapter 13 of OSHA Instruction CPL 02-00-045, Revised FieldOperations Manual, June 15, 1989.State Impact: Notice of Intent and Adoption required. See paragraph VI.Action Offices: National, Regional, and Area OfficesOriginating Office: Directorate of Enforcement Programs Contact: Directorate of Enforcement ProgramsOffice of General Industry Enforcement200 Constitution Avenue, NW, N3 119Washington, DC 20210202-693-1850By and Under the Authority ofDavid Michaels, PhD, MPHAssistant SecretaryExecutive SummaryThis instruction cancels and replaces OSHA Instruction CPL 02-00-148, Field Operations Manual (FOM), issued November 9, 2009. The one remaining part of the prior Field Operations Manual, the chapter on Disclosure, will be added at a later date. This Instruction also cancels OSHA Instruction FAP 01-00-003 Federal Agency Safety and Health Programs, May 17, 1996 and Chapter 13 of OSHA Instruction CPL 02-00-045, Revised Field Operations Manual, June 15, 1989. This Instruction constitutes OSHA’s general enforcement policies and procedures manual for use by the field offices in conducting inspections, issuing citations and proposing penalties.Significant Changes∙A new Table of Contents for the entire FOM is added.∙ A new References section for the entire FOM is added∙ A new Cancellations section for the entire FOM is added.∙Adds a Maritime Industry Sector to Section III of Chapter 10, Industry Sectors.∙Revises sections referring to the Enhanced Enforcement Program (EEP) replacing the information with the Severe Violator Enforcement Program (SVEP).∙Adds Chapter 13, Federal Agency Field Activities.∙Cancels OSHA Instruction FAP 01-00-003, Federal Agency Safety and Health Programs, May 17, 1996.DisclaimerThis manual is intended to provide instruction regarding some of the internal operations of the Occupational Safety and Health Administration (OSHA), and is solely for the benefit of the Government. No duties, rights, or benefits, substantive or procedural, are created or implied by this manual. The contents of this manual are not enforceable by any person or entity against the Department of Labor or the United States. Statements which reflect current Occupational Safety and Health Review Commission or court precedents do not necessarily indicate acquiescence with those precedents.Table of ContentsCHAPTER 1INTRODUCTIONI.PURPOSE. ........................................................................................................... 1-1 II.SCOPE. ................................................................................................................ 1-1 III.REFERENCES .................................................................................................... 1-1 IV.CANCELLATIONS............................................................................................. 1-8 V. ACTION INFORMATION ................................................................................. 1-8A.R ESPONSIBLE O FFICE.......................................................................................................................................... 1-8B.A CTION O FFICES. .................................................................................................................... 1-8C. I NFORMATION O FFICES............................................................................................................ 1-8 VI. STATE IMPACT. ................................................................................................ 1-8 VII.SIGNIFICANT CHANGES. ............................................................................... 1-9 VIII.BACKGROUND. ................................................................................................. 1-9 IX. DEFINITIONS AND TERMINOLOGY. ........................................................ 1-10A.T HE A CT................................................................................................................................................................. 1-10B. C OMPLIANCE S AFETY AND H EALTH O FFICER (CSHO). ...........................................................1-10B.H E/S HE AND H IS/H ERS ..................................................................................................................................... 1-10C.P ROFESSIONAL J UDGMENT............................................................................................................................... 1-10E. W ORKPLACE AND W ORKSITE ......................................................................................................................... 1-10CHAPTER 2PROGRAM PLANNINGI.INTRODUCTION ............................................................................................... 2-1 II.AREA OFFICE RESPONSIBILITIES. .............................................................. 2-1A.P ROVIDING A SSISTANCE TO S MALL E MPLOYERS. ...................................................................................... 2-1B.A REA O FFICE O UTREACH P ROGRAM. ............................................................................................................. 2-1C. R ESPONDING TO R EQUESTS FOR A SSISTANCE. ............................................................................................ 2-2 III. OSHA COOPERATIVE PROGRAMS OVERVIEW. ...................................... 2-2A.V OLUNTARY P ROTECTION P ROGRAM (VPP). ........................................................................... 2-2B.O NSITE C ONSULTATION P ROGRAM. ................................................................................................................ 2-2C.S TRATEGIC P ARTNERSHIPS................................................................................................................................. 2-3D.A LLIANCE P ROGRAM ........................................................................................................................................... 2-3 IV. ENFORCEMENT PROGRAM SCHEDULING. ................................................ 2-4A.G ENERAL ................................................................................................................................................................. 2-4B.I NSPECTION P RIORITY C RITERIA. ..................................................................................................................... 2-4C.E FFECT OF C ONTEST ............................................................................................................................................ 2-5D.E NFORCEMENT E XEMPTIONS AND L IMITATIONS. ....................................................................................... 2-6E.P REEMPTION BY A NOTHER F EDERAL A GENCY ........................................................................................... 2-6F.U NITED S TATES P OSTAL S ERVICE. .................................................................................................................. 2-7G.H OME-B ASED W ORKSITES. ................................................................................................................................ 2-8H.I NSPECTION/I NVESTIGATION T YPES. ............................................................................................................... 2-8 V.UNPROGRAMMED ACTIVITY – HAZARD EVALUATION AND INSPECTION SCHEDULING ............................................................................ 2-9 VI.PROGRAMMED INSPECTIONS. ................................................................... 2-10A.S ITE-S PECIFIC T ARGETING (SST) P ROGRAM. ............................................................................................. 2-10B.S CHEDULING FOR C ONSTRUCTION I NSPECTIONS. ..................................................................................... 2-10C.S CHEDULING FOR M ARITIME I NSPECTIONS. ............................................................................. 2-11D.S PECIAL E MPHASIS P ROGRAMS (SEP S). ................................................................................... 2-12E.N ATIONAL E MPHASIS P ROGRAMS (NEP S) ............................................................................... 2-13F.L OCAL E MPHASIS P ROGRAMS (LEP S) AND R EGIONAL E MPHASIS P ROGRAMS (REP S) ............ 2-13G.O THER S PECIAL P ROGRAMS. ............................................................................................................................ 2-13H.I NSPECTION S CHEDULING AND I NTERFACE WITH C OOPERATIVE P ROGRAM P ARTICIPANTS ....... 2-13CHAPTER 3INSPECTION PROCEDURESI.INSPECTION PREPARATION. .......................................................................... 3-1 II.INSPECTION PLANNING. .................................................................................. 3-1A.R EVIEW OF I NSPECTION H ISTORY .................................................................................................................... 3-1B.R EVIEW OF C OOPERATIVE P ROGRAM P ARTICIPATION .............................................................................. 3-1C.OSHA D ATA I NITIATIVE (ODI) D ATA R EVIEW .......................................................................................... 3-2D.S AFETY AND H EALTH I SSUES R ELATING TO CSHO S.................................................................. 3-2E.A DVANCE N OTICE. ................................................................................................................................................ 3-3F.P RE-I NSPECTION C OMPULSORY P ROCESS ...................................................................................................... 3-5G.P ERSONAL S ECURITY C LEARANCE. ................................................................................................................. 3-5H.E XPERT A SSISTANCE. ........................................................................................................................................... 3-5 III. INSPECTION SCOPE. ......................................................................................... 3-6A.C OMPREHENSIVE ................................................................................................................................................... 3-6B.P ARTIAL. ................................................................................................................................................................... 3-6 IV. CONDUCT OF INSPECTION .............................................................................. 3-6A.T IME OF I NSPECTION............................................................................................................................................. 3-6B.P RESENTING C REDENTIALS. ............................................................................................................................... 3-6C.R EFUSAL TO P ERMIT I NSPECTION AND I NTERFERENCE ............................................................................. 3-7D.E MPLOYEE P ARTICIPATION. ............................................................................................................................... 3-9E.R ELEASE FOR E NTRY ............................................................................................................................................ 3-9F.B ANKRUPT OR O UT OF B USINESS. .................................................................................................................... 3-9G.E MPLOYEE R ESPONSIBILITIES. ................................................................................................. 3-10H.S TRIKE OR L ABOR D ISPUTE ............................................................................................................................. 3-10I. V ARIANCES. .......................................................................................................................................................... 3-11 V. OPENING CONFERENCE. ................................................................................ 3-11A.G ENERAL ................................................................................................................................................................ 3-11B.R EVIEW OF A PPROPRIATION A CT E XEMPTIONS AND L IMITATION. ..................................................... 3-13C.R EVIEW S CREENING FOR P ROCESS S AFETY M ANAGEMENT (PSM) C OVERAGE............................. 3-13D.R EVIEW OF V OLUNTARY C OMPLIANCE P ROGRAMS. ................................................................................ 3-14E.D ISRUPTIVE C ONDUCT. ...................................................................................................................................... 3-15F.C LASSIFIED A REAS ............................................................................................................................................. 3-16VI. REVIEW OF RECORDS. ................................................................................... 3-16A.I NJURY AND I LLNESS R ECORDS...................................................................................................................... 3-16B.R ECORDING C RITERIA. ...................................................................................................................................... 3-18C. R ECORDKEEPING D EFICIENCIES. .................................................................................................................. 3-18 VII. WALKAROUND INSPECTION. ....................................................................... 3-19A.W ALKAROUND R EPRESENTATIVES ............................................................................................................... 3-19B.E VALUATION OF S AFETY AND H EALTH M ANAGEMENT S YSTEM. ....................................................... 3-20C.R ECORD A LL F ACTS P ERTINENT TO A V IOLATION. ................................................................................. 3-20D.T ESTIFYING IN H EARINGS ................................................................................................................................ 3-21E.T RADE S ECRETS. ................................................................................................................................................. 3-21F.C OLLECTING S AMPLES. ..................................................................................................................................... 3-22G.P HOTOGRAPHS AND V IDEOTAPES.................................................................................................................. 3-22H.V IOLATIONS OF O THER L AWS. ....................................................................................................................... 3-23I.I NTERVIEWS OF N ON-M ANAGERIAL E MPLOYEES .................................................................................... 3-23J.M ULTI-E MPLOYER W ORKSITES ..................................................................................................................... 3-27 K.A DMINISTRATIVE S UBPOENA.......................................................................................................................... 3-27 L.E MPLOYER A BATEMENT A SSISTANCE. ........................................................................................................ 3-27 VIII. CLOSING CONFERENCE. .............................................................................. 3-28A.P ARTICIPANTS. ..................................................................................................................................................... 3-28B.D ISCUSSION I TEMS. ............................................................................................................................................ 3-28C.A DVICE TO A TTENDEES .................................................................................................................................... 3-29D.P ENALTIES............................................................................................................................................................. 3-30E.F EASIBLE A DMINISTRATIVE, W ORK P RACTICE AND E NGINEERING C ONTROLS. ............................ 3-30F.R EDUCING E MPLOYEE E XPOSURE. ................................................................................................................ 3-32G.A BATEMENT V ERIFICATION. ........................................................................................................................... 3-32H.E MPLOYEE D ISCRIMINATION .......................................................................................................................... 3-33 IX. SPECIAL INSPECTION PROCEDURES. ...................................................... 3-33A.F OLLOW-UP AND M ONITORING I NSPECTIONS............................................................................................ 3-33B.C ONSTRUCTION I NSPECTIONS ......................................................................................................................... 3-34C. F EDERAL A GENCY I NSPECTIONS. ................................................................................................................. 3-35CHAPTER 4VIOLATIONSI. BASIS OF VIOLATIONS ..................................................................................... 4-1A.S TANDARDS AND R EGULATIONS. .................................................................................................................... 4-1B.E MPLOYEE E XPOSURE. ........................................................................................................................................ 4-3C.R EGULATORY R EQUIREMENTS. ........................................................................................................................ 4-6D.H AZARD C OMMUNICATION. .............................................................................................................................. 4-6E. E MPLOYER/E MPLOYEE R ESPONSIBILITIES ................................................................................................... 4-6 II. SERIOUS VIOLATIONS. .................................................................................... 4-8A.S ECTION 17(K). ......................................................................................................................... 4-8B.E STABLISHING S ERIOUS V IOLATIONS ............................................................................................................ 4-8C. F OUR S TEPS TO BE D OCUMENTED. ................................................................................................................... 4-8 III. GENERAL DUTY REQUIREMENTS ............................................................. 4-14A.E VALUATION OF G ENERAL D UTY R EQUIREMENTS ................................................................................. 4-14B.E LEMENTS OF A G ENERAL D UTY R EQUIREMENT V IOLATION.............................................................. 4-14C. U SE OF THE G ENERAL D UTY C LAUSE ........................................................................................................ 4-23D.L IMITATIONS OF U SE OF THE G ENERAL D UTY C LAUSE. ..............................................................E.C LASSIFICATION OF V IOLATIONS C ITED U NDER THE G ENERAL D UTY C LAUSE. ..................F. P ROCEDURES FOR I MPLEMENTATION OF S ECTION 5(A)(1) E NFORCEMENT ............................ 4-25 4-27 4-27IV.OTHER-THAN-SERIOUS VIOLATIONS ............................................... 4-28 V.WILLFUL VIOLATIONS. ......................................................................... 4-28A.I NTENTIONAL D ISREGARD V IOLATIONS. ..........................................................................................4-28B.P LAIN I NDIFFERENCE V IOLATIONS. ...................................................................................................4-29 VI. CRIMINAL/WILLFUL VIOLATIONS. ................................................... 4-30A.A REA D IRECTOR C OORDINATION ....................................................................................................... 4-31B.C RITERIA FOR I NVESTIGATING P OSSIBLE C RIMINAL/W ILLFUL V IOLATIONS ........................ 4-31C. W ILLFUL V IOLATIONS R ELATED TO A F ATALITY .......................................................................... 4-32 VII. REPEATED VIOLATIONS. ...................................................................... 4-32A.F EDERAL AND S TATE P LAN V IOLATIONS. ........................................................................................4-32B.I DENTICAL S TANDARDS. .......................................................................................................................4-32C.D IFFERENT S TANDARDS. .......................................................................................................................4-33D.O BTAINING I NSPECTION H ISTORY. .....................................................................................................4-33E.T IME L IMITATIONS..................................................................................................................................4-34F.R EPEATED V. F AILURE TO A BATE....................................................................................................... 4-34G. A REA D IRECTOR R ESPONSIBILITIES. .............................................................................. 4-35 VIII. DE MINIMIS CONDITIONS. ................................................................... 4-36A.C RITERIA ................................................................................................................................................... 4-36B.P ROFESSIONAL J UDGMENT. ..................................................................................................................4-37C. A REA D IRECTOR R ESPONSIBILITIES. .............................................................................. 4-37 IX. CITING IN THE ALTERNATIVE ............................................................ 4-37 X. COMBINING AND GROUPING VIOLATIONS. ................................... 4-37A.C OMBINING. ..............................................................................................................................................4-37B.G ROUPING. ................................................................................................................................................4-38C. W HEN N OT TO G ROUP OR C OMBINE. ................................................................................................4-38 XI. HEALTH STANDARD VIOLATIONS ....................................................... 4-39A.C ITATION OF V ENTILATION S TANDARDS ......................................................................................... 4-39B.V IOLATIONS OF THE N OISE S TANDARD. ...........................................................................................4-40 XII. VIOLATIONS OF THE RESPIRATORY PROTECTION STANDARD(§1910.134). ....................................................................................................... XIII. VIOLATIONS OF AIR CONTAMINANT STANDARDS (§1910.1000) ... 4-43 4-43A.R EQUIREMENTS UNDER THE STANDARD: .................................................................................................. 4-43B.C LASSIFICATION OF V IOLATIONS OF A IR C ONTAMINANT S TANDARDS. ......................................... 4-43 XIV. CITING IMPROPER PERSONAL HYGIENE PRACTICES. ................... 4-45A.I NGESTION H AZARDS. .................................................................................................................................... 4-45B.A BSORPTION H AZARDS. ................................................................................................................................ 4-46C.W IPE S AMPLING. ............................................................................................................................................. 4-46D.C ITATION P OLICY ............................................................................................................................................ 4-46 XV. BIOLOGICAL MONITORING. ...................................................................... 4-47CHAPTER 5CASE FILE PREPARATION AND DOCUMENTATIONI.INTRODUCTION ............................................................................................... 5-1 II.INSPECTION CONDUCTED, CITATIONS BEING ISSUED. .................... 5-1A.OSHA-1 ................................................................................................................................... 5-1B.OSHA-1A. ............................................................................................................................... 5-1C. OSHA-1B. ................................................................................................................................ 5-2 III.INSPECTION CONDUCTED BUT NO CITATIONS ISSUED .................... 5-5 IV.NO INSPECTION ............................................................................................... 5-5 V. HEALTH INSPECTIONS. ................................................................................. 5-6A.D OCUMENT P OTENTIAL E XPOSURE. ............................................................................................................... 5-6B.E MPLOYER’S O CCUPATIONAL S AFETY AND H EALTH S YSTEM. ............................................................. 5-6 VI. AFFIRMATIVE DEFENSES............................................................................. 5-8A.B URDEN OF P ROOF. .............................................................................................................................................. 5-8B.E XPLANATIONS. ..................................................................................................................................................... 5-8 VII. INTERVIEW STATEMENTS. ........................................................................ 5-10A.G ENERALLY. ......................................................................................................................................................... 5-10B.CSHO S SHALL OBTAIN WRITTEN STATEMENTS WHEN: .......................................................................... 5-10C.L ANGUAGE AND W ORDING OF S TATEMENT. ............................................................................................. 5-11D.R EFUSAL TO S IGN S TATEMENT ...................................................................................................................... 5-11E.V IDEO AND A UDIOTAPED S TATEMENTS. ..................................................................................................... 5-11F.A DMINISTRATIVE D EPOSITIONS. .............................................................................................5-11 VIII. PAPERWORK AND WRITTEN PROGRAM REQUIREMENTS. .......... 5-12 IX.GUIDELINES FOR CASE FILE DOCUMENTATION FOR USE WITH VIDEOTAPES AND AUDIOTAPES .............................................................. 5-12 X.CASE FILE ACTIVITY DIARY SHEET. ..................................................... 5-12 XI. CITATIONS. ..................................................................................................... 5-12A.S TATUTE OF L IMITATIONS. .............................................................................................................................. 5-13B.I SSUING C ITATIONS. ........................................................................................................................................... 5-13C.A MENDING/W ITHDRAWING C ITATIONS AND N OTIFICATION OF P ENALTIES. .................................. 5-13D.P ROCEDURES FOR A MENDING OR W ITHDRAWING C ITATIONS ............................................................ 5-14 XII. INSPECTION RECORDS. ............................................................................... 5-15A.G ENERALLY. ......................................................................................................................................................... 5-15B.R ELEASE OF I NSPECTION I NFORMATION ..................................................................................................... 5-15C. C LASSIFIED AND T RADE S ECRET I NFORMATION ...................................................................................... 5-16。

MT8KTF51264HZ-1G6E1

1.35V DDR3L SDRAM SODIMMMT8KTF12864HZ – 1GB MT8KTF25664HZ – 2GB MT8KTF51264HZ – 4GB Features•DDR3L functionality and operations supported as defined in the component data sheet•204-pin, small-outline dual in-line memory module (SODIMM)•Fast data transfer rates: PC3-14900, PC3-12800, or PC3-10600•1GB (128 Meg x 64), 2GB (256 Meg x 64), 4GB (512Meg x 64)•V DD = 1.35V (1.283–1.45V)•V DD = 1.5V (1.425–1.575V)•Backward compatible with standard 1.5V (±0.075V)DDR3 systems •V DDSPD = 3.0–3.6V•Nominal and dynamic on-die termination (ODT) for data, strobe, and mask signals •Single rank•Fixed burst chop (BC) of 4 and burst length (BL) of 8via the mode register set (MRS)•On-board I 2C serial presence-detect (SPD) EEPROM •Gold edge contacts •Halogen-free •Fly-by topology•Terminated control, command, and address bus Figure 1: 204-Pin SODIMM (MO-268 R/C B2, B4)Module height: 30mm (1.181in)OptionsMarking•Operating temperature–Commercial (0°C ≤ T A ≤ +70°C)None •Package–204-pin DIMM (halogen-free)Z •Frequency/CAS latency– 1.07ns @ CL = 13 (DDR3-1866)-1G9– 1.25ns @ CL = 11 (DDR3-1600)-1G6– 1.5ns @ CL = 9 (DDR3-1333)-1G4Table 1: Key Timing ParametersTable 2: AddressingTable 3: Part Numbers and Timing Parameters – 1GB Modules1Table 4: Part Numbers and Timing Parameters – 2GB Modules1Table 5: Part Numbers and Timing Parameters – 4GB Modules1Notes: 1.The data sheet for the base device can be found on Micron’s web site.2.All part numbers end with a two-place code (not shown) that designates component and PCB revisions.Consult factory for current revision codes. Example: MT8KSF51264HZ-1G9P1.Pin AssignmentsTable 6: Pin AssignmentsNotes: 1.Pin 78 is NF for 1GB and 2GB; A15 for 4GB.2.Pin 80 is NF for 1GB; A14 for 2GB and 4GB.Pin DescriptionsThe pin description table below is a comprehensive list of all possible pins for all DDR3modules. All pins listed may not be supported on this module. See Pin Assignments forinformation specific to this module.Table 7: Pin DescriptionsTable 7: Pin Descriptions (Continued)DQ MapsTable 8: Component-to-Module DQ Map, R/C B2 (PCB 1092)Table 9: Component-to-Module DQ Map, R/C B4 (PCB 1348)Functional Block Diagram Figure 2: Functional Block DiagramS0#A[15/14/13:0]RAS#WE#CKE0A[15/14/13:0]: DDR3 SDRAMWE#: DDR3 SDRAMCKE0: DDR3 SDRAMRESET#: DDR3 SDRAMCK0CK0#CK1CK1#V REFCAV SSV DDControl, command,and address terminationV DDSPDV TTV REFDQClock, control, command, and address line terminations:TTV DDNote: 1.The ZQ ball on each DDR3 component is connected to an external 240Ω ±1% resistorthat is tied to ground. It is used for the calibration of the component’s ODT and outputdriver.1GB, 2GB, 4GB (x64, SR) 204-Pin DDR3L SODIMMFunctional Block DiagramGeneral DescriptionDDR3 SDRAM modules are high-speed, CMOS dynamic random access memory mod-ules that use internally configured 8-bank DDR3 SDRAM devices. DDR3 SDRAM mod-ules use DDR architecture to achieve high-speed operation. DDR3 architecture is essen-tially an 8n-prefetch architecture with an interface designed to transfer two data wordsper clock cycle at the I/O pins. A single read or write access for the DDR3 SDRAM mod-ule effectively consists of a single 8n-bit-wide, one-clock-cycle data transfer at the inter-nal DRAM core and eight corresponding n-bit-wide, one-half-clock-cycle data transfersat the I/O pins.DDR3 modules use two sets of differential signals: DQS, DQS# to capture data and CKand CK# to capture commands, addresses, and control signals. Differential clocks anddata strobes ensure exceptional noise immunity for these signals and provide precisecrossing points to capture input signals.Fly-By TopologyDDR3 modules use faster clock speeds than earlier DDR technologies, making signalquality more important than ever. For improved signal quality, the clock, control, com-mand, and address buses have been routed in a fly-by topology, where each clock, con-trol, command, and address pin on each DRAM is connected to a single trace and ter-minated (rather than a tree structure, where the termination is off the module near theconnector). Inherent to fly-by topology, the timing skew between the clock and DQS sig-nals can be easily accounted for by using the write-leveling feature of DDR3.Serial Presence-Detect EEPROM OperationDDR3 SDRAM modules incorporate serial presence-detect. The SPD data is stored in a256-byte EEPROM. The first 128 bytes are programmed by Micron to comply withJEDEC standard JC-45, "Appendix X: Serial Presence Detect (SPD) for DDR3 SDRAMModules." These bytes identify module-specific timing parameters, configuration infor-mation, and physical attributes. The remaining 128 bytes of storage are available for useby the customer. System READ/WRITE operations between the master (system logic)and the slave EEPROM device occur via a standard I2C bus using the DIMM’s SCL(clock) SDA (data), and SA (address) pins. Write protect (WP) is connected to V SS, per-manently disabling hardware write protection. For further information refer to Microntechnical note TN-04-42, "Memory Module Serial Presence-Detect."Electrical SpecificationsStresses greater than those listed may cause permanent damage to the module. This is astress rating only, and functional operation of the module at these or any other condi-tions outside those indicated in each device's data sheet is not implied. Exposure to ab-solute maximum rating conditions for extended periods may adversely affect reliability. Table 10: Absolute Maximum RatingsTable 11: Operating ConditionsNotes: 1.Module is backward-compatible with 1.5V operation. Refer to device specification fordetails and operation guidance.2.V TT termination voltage in excess of the stated limit will adversely affect the commandand address signals’ voltage margin and will reduce timing margins.3.T A and T C are simultaneous requirements.4.For further information, refer to technical note TN-00-08: “Thermal Applications,”available on Micron’s web site.5.The refresh rate is required to double when 85°C < T C≤ 95°C.DRAM Operating ConditionsRecommended AC operating conditions are given in the DDR3 component data sheets.Component specifications are available at . Module speed grades correlatewith component speed grades, as shown below.Table 12: Module and Component Speed GradesDesign ConsiderationsSimulationsMicron memory modules are designed to optimize signal integrity through carefully de-signed terminations, controlled board impedances, routing topologies, trace lengthmatching, and decoupling. However, good signal integrity starts at the system level.Micron encourages designers to simulate the signal characteristics of the system'smemory bus to ensure adequate signal integrity of the entire memory system.PowerOperating voltages are specified at the DRAM, not at the edge connector of the module.Designers must account for any system voltage drops at anticipated power levels to en-sure the required supply voltage is maintained.I DD SpecificationsTable 13: DDR3 I DD Specifications and Conditions – 1GB (Die Revision J)Values are for the MT41K128M8 DDR3L SDRAM only and are computed from values specified in the 1.35V 1GbTable 14: DDR3 I DD Specifications and Conditions – 2GB (Die Revision K)Values are for the MT41K256M8 DDR3L SDRAM only and are computed from values specified in the 1.35V 2GbTable 15: DDR3 I DD Specifications and Conditions – 4GB (Die Revision E)Values are for the MT41K512M8 DDR3L SDRAM only and are computed from values specified in the 1.35V 4GbTable 16: DDR3 I DD Specifications and Conditions – 4GB (Die Revision N)Values are for the MT41K512M8 DDR3L SDRAM only and are computed from values specified in the 1.35V 4GbTable 17: DDR3 I DD Specifications and Conditions – 4GB (Die Revision P)Values are for the MT41K512M8 DDR3L SDRAM only and are computed from values specified in the 1.35V 4GbSerial Presence-Detect EEPROMFor the latest SPD data, refer to Micron's SPD page: /spd .Table 18: Serial Presence-Detect EEPROM DC Operating ConditionsTable 19: Serial Presence-Detect EEPROM AC Operating ConditionsNotes:1.Guaranteed by design and characterization, not necessarily tested.2.To avoid spurious start and stop conditions, a minimum delay is placed between the fall-ing edge of SCL and the falling or rising edge of SDA.3.For a restart condition, or following a WRITE cycle.1GB, 2GB, 4GB (x64, SR) 204-Pin DDR3L SODIMMSerial Presence-Detect EEPROMModule DimensionsFigure 3: 204-Pin DDR3 SODIMM3.8 (0.150)1.8 (0.071)(2X)2.0 (0.079) RFront viewTYP45° 4XNotes:1.All dimensions are in millimeters (inches); MAX/MIN or typical (TYP) where noted.2.The dimensional diagram is for reference only.8000 S. Federal Way, P .O. Box 6, Boise, ID 83707-0006, Tel: 208-368-4000/products/support Sales inquiries: 800-932-4992Micron and the Micron logo are trademarks of Micron Technology, Inc.All other trademarks are the property of their respective owners.This data sheet contains minimum and maximum limits specified over the power supply and temperature range set forth herein.Although considered final, these specifications are subject to change, as further product development and data characterization some-times occur.1GB, 2GB, 4GB (x64, SR) 204-Pin DDR3L SODIMMModule DimensionsMouser ElectronicsAuthorized DistributorClick to View Pricing, Inventory, Delivery & Lifecycle Information:M icron Technology:MT8KTF25664HZ-1G6K1MT8KTF51264HZ-1G6P1MT8KTF51264HZ-1G9P1MT8KTF51264HZ-1G6N1。

Advanced Materials Characterization

Advanced Materials CharacterizationAdvanced materials characterization is a crucial aspect of modern science and technology. It involves the study of the physical, chemical, and structural properties of materials at the atomic and molecular level. The information gained from advanced materials characterization is essential for the development of new materials and for improving the performance of existing materials. In this essay,I will discuss the importance of advanced materials characterization from multiple perspectives. From a scientific perspective, advanced materials characterizationis essential for understanding the fundamental properties of materials. Bystudying the structure and composition of materials at the atomic and molecular level, scientists can gain insights into how materials behave under different conditions. This information is crucial for developing new materials that have specific properties, such as increased strength, improved conductivity, or enhanced durability. Advanced materials characterization also allows scientists to study the behavior of materials under extreme conditions, such as high temperatures or pressures, which can provide insights into the properties of materials in space or on other planets. From an engineering perspective, advanced materials characterization is essential for designing and improving materials that are used in various applications, such as aerospace, automotive, and biomedical engineering. By understanding the structure and properties of materials, engineers can develop materials that are stronger, lighter, and more durable. For example, advanced materials characterization has led to the development of new alloys that are used in the aerospace industry to improve fuel efficiency and reduce emissions. Similarly, advanced materials characterization has led to the development of new materials for biomedical implants that are more compatible with the human body and have a longer lifespan. From an economic perspective, advanced materials characterization is essential for developing new products and technologies thatcan drive economic growth. The development of new materials and technologies can create new industries and jobs, and can lead to the creation of new products and services that improve people's lives. For example, the development of newmaterials for solar panels has led to the growth of the renewable energy industry, which has created new jobs and reduced dependence on fossil fuels. Similarly, thedevelopment of new materials for biomedical implants has led to the growth of the medical device industry, which has improved the quality of life for millions of people around the world. From a societal perspective, advanced materials characterization is essential for addressing global challenges such as climate change, energy security, and healthcare. By developing new materials and technologies, we can reduce our dependence on fossil fuels, improve energy efficiency, and develop new treatments for diseases. For example, the development of new materials for energy storage has the potential to revolutionize the way we store and use energy, which could have a significant impact on reducing greenhouse gas emissions. Similarly, the development of new materials for drug delivery could lead to more effective treatments for diseases such as cancer and Alzheimer's. In conclusion, advanced materials characterization is essential for advancing science, engineering, economics, and society. By studying the physical, chemical, and structural properties of materials at the atomic and molecular level, we can gain insights into how materials behave under different conditions, develop new materials with specific properties, and improve the performance of existing materials. The development of new materials and technologies has the potential to create new industries and jobs, improve energy efficiency, and develop new treatments for diseases. Therefore, it is important to continue investing in advanced materials characterization to address the challenges of the 21st century.。

OSRAM SYLVANIA Sylvania '350BL' Blacklight Fluores

Sylvania brand Fluorescent Lamps, manufactured by OSRAM SYLVANIA Products Inc., are exempted from the requirements of the OSHA Hazard Communication Standard (29 CFR 1910.1200) because they are “articles.” The following information is provided by OSRAM SYLVANIA as a courtesy to its customers. I. PRODUCT IDENTIFICATION-----------------------------------------------------------------------------------------------------------------------------------------------------------Trade Name (as labeled): Sylvania "350BL" Blacklight Fluorescent LampsManufacturer: OSRAM SYLVANIA Products Inc.100 Endicott StreetDanvers, MA 01923(978) 777-1900----------------------------------------------------------------------------------------------------------------------------------------------------------- II. HAZARDOUS INGREDIENTS----------------------------------------------------------------------------------------------------------------------------------------------------------- THERE ARE NO KNOWN HEALTH HAZARDS FROM EXPOSURE TO LAMPS THAT ARE INTACT. If the lamp is broken, the following materials may be released:Chemical Name CAS Number % by wt. Exposure Limits in Air (mg/cubic m) ACGIH (TLV) OSHA (PEL)Glass (Soda-Lime) --- 80-90 10.0 (2) 15.0 (2) (1,4) Mercury 7439-97-6 <0.05 0.025 0.1 Ceiling (1, 3,4) Lead Oxide 1317-36-8 0.2-2.0 0.05 0.05(1) Phosphor 2011, (Barium Mesosilicate: Lead) 12650-28-1 1.5-2.5 --- ---(1, 4) (As Pb) 7439-92-1 <0.05 0.05 0.05(1) These chemicals are subject to the reporting requirements of section 313 of Title III of the Superfund Amendments and Reauthorization Act of 1986 and 40 CFR Part 372.(2) Limits as nuisance particulate.(3) This element is contained in the material as part of its chemical structure; the material is not a mixture.(4) The mercury and lead in this product are substances known to the state of California to cause reproductive toxicity if ingested. [California Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).] ----------------------------------------------------------------------------------------------------------------------------------------------------------- III. PHYSICAL PROPERTIES----------------------------------------------------------------------------------------------------------------------------------------------------------- Not applicable to intact lamp.----------------------------------------------------------------------------------------------------------------------------------------------------------- IV. FIRE & EXPLOSION HAZARDS----------------------------------------------------------------------------------------------------------------------------------------------------------- Flammability: Non-combustible Fire Extinguishing Materials: Use extinguishing agents suitable for surrounding fire. Special Firefighting Procedure: Use a self-contained breathing apparatus to prevent inhalation of dust and/or fumes that may be generated from broken lamps during firefighting activities. Unusual Fire and Explosion Hazards: When exposed to high temperature, toxic fumes may be released from broken lamps. ----------------------------------------------------------------------------------------------------------------------------------------------------------- PRODUCT SAFETY DATA SHEETPSDS No. 1.1.4FLUORESCENT BLACKLIGHT LAMPSV. HEALTH HAZARDS-----------------------------------------------------------------------------------------------------------------------------------------------------------A. OPERATING LAMPSConsult the OSRAM SYLVANIA Product Catalog or relevant technical data sheets for complete warnings,B. LAMP MATERIALSTHERE ARE NO KNOWN HEALTH HAZARDS FROM EXPOSURE TO LAMPS THATARE INTACT. No adverse effects are expected from occasional exposure to broken lamps. As a matterof good practice, avoid prolonged or frequent exposure to broken lamps unless there is adequateventilation. The major hazard from broken lamps is the possibility of sustaining glass cuts.NIOSH/OSHA Occupational Health Guidelines for Chemical Hazards and/or NIOSH Pocket Guide toChemical Hazards lists the following effects of overexposure to the chemicals/materials tabulatedbelow when they are inhaled, ingested, or contacted with skin or eye:Mercury - Exposure to high concentrations of vapors for brief periods can cause acute symptoms such aspneumonitis, chest pains, shortness of breath, coughing, gingivitis, salivation and possibly stomatitis. Maycause redness and irritation as a result of contact with skin and/or eyes.Lead - Ingestion and inhalation of lead dust or fume must be avoided. Irritation of the eyes and respiratorytract may occur. Excessive lead absorption is toxic and may include symptoms such as anemia, weakness,abdominal pain, and kidney disease. However, the chemical inertness and insolubility of this material isexpected to reduce the potential for systemic lead toxicity.Glass - Glass dust is considered to be physiologically inert and as such, has an OSHA exposure limit of 15mg/cubic meter for total dust and 5 mg/cubic meter for respirable dust. The ACGIH TLVs for particulatesnot otherwise classified are 10 mg/cubic meter for total dust and 3 mg/cubic meter for respirable dust.Phosphor - Inhalation of insoluble barium compounds has been reported to cause benign pneumoconiosiswith no specific symptoms and no changes in pulmonary function.EMERGENCY AND FIRST AID PROCEDURES:Glass Cuts: Perform normal first aid procedures. Seek medical attention as required.Inhalation: If discomfort, irritation or symptoms of pulmonary involvement develop, remove from exposure and seek medical attention.Ingestion: In the unlikely event of ingestion of a large quantity of material, seek medical attention.Contact, Skin: Thoroughly wash affected area with mild soap or detergent and water and prevent further contact.Seek medical attention if irritation occurs.Contact, Eye: Wash eyes, including under eyelids, immediately with copious amounts of water for 15 minutes.Seek medical attention.CARCINOGENIC ASSESSMENT (NTP ANNUAL REPORT, IARC MONOGRAPHS, OTHER): None-----------------------------------------------------------------------------------------------------------------------------------------------------------VI. REACTIVITY DATA----------------------------------------------------------------------------------------------------------------------------------------------------------- Stability: StableConditions to avoid: None for intact lamps.Incompatibility (materials to avoid): None for intact lamps.Hazardous decomposition products (including combustion products): None for intact lampsHazardous polymerization products: Will not occur.----------------------------------------------------------------------------------------------------------------------------------------------------------- VII. PROCEDURES FOR DISPOSAL OF BROKEN LAMPS----------------------------------------------------------------------------------------------------------------------------------------------------------- OSRAM SYLVANIA recommends that all mercury-containing lamps be recycled. For a list of lamp recyclers and to obtain state regulatory disposal information, log onto .Ventilate area where breakage occurred. Clean-up with a special mercury vacuum cleaner (not a standard vacuum cleaner) or other suitable means that avoid dust and mercury vapor generation. Take usual precautions for collection of broken glass. Clean-up requires special care due to mercury droplet proliferation. Place materials in closed containers to avoid generating dust.It is the responsibility of the waste generator to ensure proper classification and disposal of waste products. To that end, TCLP tests should be conducted on all waste products, including this one, to determine the ultimate disposition in accordance with applicable federal, state and local regulations. Some states have specific disposal requirements for lamps containing mercury.----------------------------------------------------------------------------------------------------------------------------------------------------------- VIII. SPECIAL HANDLING INFORMATION - FOR BROKEN LAMPS----------------------------------------------------------------------------------------------------------------------------------------------------------- Ventilation: Use adequate general and local exhaust ventilation to maintain exposure levels below the PEL or TLV limits. If such ventilation is unavailable, use respirators as specified below.Respiratory Protection: Use appropriate NIOSH approved respirator if airborne dust concentrations exceed the pertinent PEL or TLV limits. All appropriate requirements set forth in 29 CFR 1910.134 should be met.Eye Protection: OSHA specified safety glasses, goggles or face shield are recommended if lamps are being broken.Protective Clothing: OSHA specified cut and puncture-resistant gloves are recommended for dealing with broken lamps.Hygienic Practices: After handling broken lamps, wash thoroughly before eating, smoking or handling tobacco products, applying cosmetics, or using toilet facilities.Although OSRAM SYLVANIA Products Inc. attempts to provide current and accurate information herein, it makes no representations regarding the accuracy or completeness of the information and assumes no liability for any loss, damage or injury of any kind which may result from, or arise out of, the use of, or reliance on the information by any person.----------------------------------------------------------------------------------------------------------------------------------------------------------- Issue Date: July 19, 2011 Rev C Supercedes: June 08, 2005 Rev B.----------------------------------------------------------------------------------------------------------------------------------------------------------- In case of questions, please call: OSRAM SYLVANIA Products Inc.Product Safety Engineer(978) 777-1900。

jstd035声学扫描

JOINT INDUSTRY STANDARDAcoustic Microscopy for Non-HermeticEncapsulatedElectronicComponents IPC/JEDEC J-STD-035APRIL1999Supersedes IPC-SM-786 Supersedes IPC-TM-650,2.6.22Notice EIA/JEDEC and IPC Standards and Publications are designed to serve thepublic interest through eliminating misunderstandings between manufacturersand purchasers,facilitating interchangeability and improvement of products,and assisting the purchaser in selecting and obtaining with minimum delaythe proper product for his particular need.Existence of such Standards andPublications shall not in any respect preclude any member or nonmember ofEIA/JEDEC or IPC from manufacturing or selling products not conformingto such Standards and Publications,nor shall the existence of such Standardsand Publications preclude their voluntary use by those other than EIA/JEDECand IPC members,whether the standard is to be used either domestically orinternationally.Recommended Standards and Publications are adopted by EIA/JEDEC andIPC without regard to whether their adoption may involve patents on articles,materials,or processes.By such action,EIA/JEDEC and IPC do not assumeany liability to any patent owner,nor do they assume any obligation whateverto parties adopting the Recommended Standard or ers are alsowholly responsible for protecting themselves against all claims of liabilities forpatent infringement.The material in this joint standard was developed by the EIA/JEDEC JC-14.1Committee on Reliability Test Methods for Packaged Devices and the IPCPlastic Chip Carrier Cracking Task Group(B-10a)The J-STD-035supersedes IPC-TM-650,Test Method2.6.22.For Technical Information Contact:Electronic Industries Alliance/ JEDEC(Joint Electron Device Engineering Council)2500Wilson Boulevard Arlington,V A22201Phone(703)907-7560Fax(703)907-7501IPC2215Sanders Road Northbrook,IL60062-6135 Phone(847)509-9700Fax(847)509-9798Please use the Standard Improvement Form shown at the end of thisdocument.©Copyright1999.The Electronic Industries Alliance,Arlington,Virginia,and IPC,Northbrook,Illinois.All rights reserved under both international and Pan-American copyright conventions.Any copying,scanning or other reproduction of these materials without the prior written consent of the copyright holder is strictly prohibited and constitutes infringement under the Copyright Law of the United States.IPC/JEDEC J-STD-035Acoustic Microscopyfor Non-Hermetic EncapsulatedElectronicComponentsA joint standard developed by the EIA/JEDEC JC-14.1Committee on Reliability Test Methods for Packaged Devices and the B-10a Plastic Chip Carrier Cracking Task Group of IPCUsers of this standard are encouraged to participate in the development of future revisions.Contact:EIA/JEDEC Engineering Department 2500Wilson Boulevard Arlington,V A22201 Phone(703)907-7500 Fax(703)907-7501IPC2215Sanders Road Northbrook,IL60062-6135 Phone(847)509-9700Fax(847)509-9798ASSOCIATION CONNECTINGELECTRONICS INDUSTRIESAcknowledgmentMembers of the Joint IPC-EIA/JEDEC Moisture Classiﬁcation Task Group have worked to develop this document.We would like to thank them for their dedication to this effort.Any Standard involving a complex technology draws material from a vast number of sources.While the principal members of the Joint Moisture Classiﬁcation Working Group are shown below,it is not possible to include all of those who assisted in the evolution of this Standard.To each of them,the mem-bers of the EIA/JEDEC and IPC extend their gratitude.IPC Packaged Electronic Components Committee ChairmanMartin FreedmanAMP,Inc.IPC Plastic Chip Carrier Cracking Task Group,B-10a ChairmanSteven MartellSonoscan,Inc.EIA/JEDEC JC14.1CommitteeChairmanJack McCullenIntel Corp.EIA/JEDEC JC14ChairmanNick LycoudesMotorolaJoint Working Group MembersCharlie Baker,TIChristopher Brigham,Hi/FnRalph Carbone,Hewlett Packard Co. Don Denton,TIMatt Dotty,AmkorMichele J.DiFranza,The Mitre Corp. Leo Feinstein,Allegro Microsystems Inc.Barry Fernelius,Hewlett Packard Co. Chris Fortunko,National Institute of StandardsRobert J.Gregory,CAE Electronics, Inc.Curtis Grosskopf,IBM Corp.Bill Guthrie,IBM Corp.Phil Johnson,Philips Semiconductors Nick Lycoudes,MotorolaSteven R.Martell,Sonoscan Inc. Jack McCullen,Intel Corp.Tom Moore,TIDavid Nicol,Lucent Technologies Inc.Pramod Patel,Advanced Micro Devices Inc.Ramon R.Reglos,XilinxCorazon Reglos,AdaptecGerald Servais,Delphi Delco Electronics SystemsRichard Shook,Lucent Technologies Inc.E.Lon Smith,Lucent Technologies Inc.Randy Walberg,NationalSemiconductor Corp.Charlie Wu,AdaptecEdward Masami Aoki,HewlettPackard LaboratoriesFonda B.Wu,Raytheon Systems Co.Richard W.Boerdner,EJE ResearchVictor J.Brzozowski,NorthropGrumman ES&SDMacushla Chen,Wus Printed CircuitCo.Ltd.Jeffrey C.Colish,Northrop GrummanCorp.Samuel J.Croce,Litton AeroProducts DivisionDerek D-Andrade,Surface MountTechnology CentreRao B.Dayaneni,Hewlett PackardLaboratoriesRodney Dehne,OEM WorldwideJames F.Maguire,Boeing Defense&Space GroupKim Finch,Boeing Defense&SpaceGroupAlelie Funcell,Xilinx Inc.Constantino J.Gonzalez,ACMEMunir Haq,Advanced Micro DevicesInc.Larry A.Hargreaves,DC.ScientiﬁcInc.John T.Hoback,Amoco ChemicalCo.Terence Kern,Axiom Electronics Inc.Connie M.Korth,K-Byte/HibbingManufacturingGabriele Marcantonio,NORTELCharles Martin,Hewlett PackardLaboratoriesRichard W.Max,Alcatel NetworkSystems Inc.Patrick McCluskey,University ofMarylandJames H.Moffitt,Moffitt ConsultingServicesRobert Mulligan,Motorola Inc.James E.Mumby,CibaJohn Northrup,Lockheed MartinCorp.Dominique K.Numakura,LitchﬁeldPrecision ComponentsNitin B.Parekh,Unisys Corp.Bella Poborets,Lucent TechnologiesInc.D.Elaine Pope,Intel Corp.Ray Prasad,Ray Prasad ConsultancyGroupAlbert Puah,Adaptec Inc.William Sepp,Technic Inc.Ralph W.Taylor,Lockheed MartinCorp.Ed R.Tidwell,DSC CommunicationsCorp.Nick Virmani,Naval Research LabKen Warren,Corlund ElectronicsCorp.Yulia B.Zaks,Lucent TechnologiesInc.IPC/JEDEC J-STD-035April1999 iiTable of Contents1SCOPE (1)2DEFINITIONS (1)2.1A-mode (1)2.2B-mode (1)2.3Back-Side Substrate View Area (1)2.4C-mode (1)2.5Through Transmission Mode (2)2.6Die Attach View Area (2)2.7Die Surface View Area (2)2.8Focal Length(FL) (2)2.9Focus Plane (2)2.10Leadframe(L/F)View Area (2)2.11Reﬂective Acoustic Microscope (2)2.12Through Transmission Acoustic Microscope (2)2.13Time-of-Flight(TOF) (3)2.14Top-Side Die Attach Substrate View Area (3)3APPARATUS (3)3.1Reﬂective Acoustic Microscope System (3)3.2Through Transmission AcousticMicroscope System (4)4PROCEDURE (4)4.1Equipment Setup (4)4.2Perform Acoustic Scans..........................................4Appendix A Acoustic Microscopy Defect CheckSheet (6)Appendix B Potential Image Pitfalls (9)Appendix C Some Limitations of AcousticMicroscopy (10)Appendix D Reference Procedure for PresentingApplicable Scanned Data (11)FiguresFigure1Example of A-mode Display (1)Figure2Example of B-mode Display (1)Figure3Example of C-mode Display (2)Figure4Example of Through Transmission Display (2)Figure5Diagram of a Reﬂective Acoustic MicroscopeSystem (3)Figure6Diagram of a Through Transmission AcousticMicroscope System (3)April1999IPC/JEDEC J-STD-035iiiIPC/JEDEC J-STD-035April1999This Page Intentionally Left BlankivApril1999IPC/JEDEC J-STD-035 Acoustic Microscopy for Non-Hermetic EncapsulatedElectronic Components1SCOPEThis test method deﬁnes the procedures for performing acoustic microscopy on non-hermetic encapsulated electronic com-ponents.This method provides users with an acoustic microscopy processﬂow for detecting defects non-destructively in plastic packages while achieving reproducibility.2DEFINITIONS2.1A-mode Acoustic data collected at the smallest X-Y-Z region deﬁned by the limitations of the given acoustic micro-scope.An A-mode display contains amplitude and phase/polarity information as a function of time ofﬂight at a single point in the X-Y plane.See Figure1-Example of A-mode Display.IPC-035-1 Figure1Example of A-mode Display2.2B-mode Acoustic data collected along an X-Z or Y-Z plane versus depth using a reﬂective acoustic microscope.A B-mode scan contains amplitude and phase/polarity information as a function of time ofﬂight at each point along the scan line.A B-mode scan furnishes a two-dimensional(cross-sectional)description along a scan line(X or Y).See Figure2-Example of B-mode Display.IPC-035-2 Figure2Example of B-mode Display(bottom half of picture on left)2.3Back-Side Substrate View Area(Refer to Appendix A,Type IV)The interface between the encapsulant and the back of the substrate within the outer edges of the substrate surface.2.4C-mode Acoustic data collected in an X-Y plane at depth(Z)using a reﬂective acoustic microscope.A C-mode scan contains amplitude and phase/polarity information at each point in the scan plane.A C-mode scan furnishes a two-dimensional(area)image of echoes arising from reﬂections at a particular depth(Z).See Figure3-Example of C-mode Display.1IPC/JEDEC J-STD-035April1999IPC-035-3 Figure3Example of C-mode Display2.5Through Transmission Mode Acoustic data collected in an X-Y plane throughout the depth(Z)using a through trans-mission acoustic microscope.A Through Transmission mode scan contains only amplitude information at each point in the scan plane.A Through Transmission scan furnishes a two-dimensional(area)image of transmitted ultrasound through the complete thickness/depth(Z)of the sample/component.See Figure4-Example of Through Transmission Display.IPC-035-4 Figure4Example of Through Transmission Display2.6Die Attach View Area(Refer to Appendix A,Type II)The interface between the die and the die attach adhesive and/or the die attach adhesive and the die attach substrate.2.7Die Surface View Area(Refer to Appendix A,Type I)The interface between the encapsulant and the active side of the die.2.8Focal Length(FL)The distance in water at which a transducer’s spot size is at a minimum.2.9Focus Plane The X-Y plane at a depth(Z),which the amplitude of the acoustic signal is maximized.2.10Leadframe(L/F)View Area(Refer to Appendix A,Type V)The imaged area which extends from the outer L/F edges of the package to the L/F‘‘tips’’(wedge bond/stitch bond region of the innermost portion of the L/F.)2.11Reflective Acoustic Microscope An acoustic microscope that uses one transducer as both the pulser and receiver. (This is also known as a pulse/echo system.)See Figure5-Diagram of a Reﬂective Acoustic Microscope System.2.12Through Transmission Acoustic Microscope An acoustic microscope that transmits ultrasound completely through the sample from a sending transducer to a receiver on the opposite side.See Figure6-Diagram of a Through Transmis-sion Acoustic Microscope System.2April1999IPC/JEDEC J-STD-0353IPC/JEDEC J-STD-035April1999 3.1.6A broad band acoustic transducer with a center frequency in the range of10to200MHz for subsurface imaging.3.2Through Transmission Acoustic Microscope System(see Figure6)comprised of:3.2.1Items3.1.1to3.1.6above3.2.2Ultrasonic pulser(can be a pulser/receiver as in3.1.1)3.2.3Separate receiving transducer or ultrasonic detection system3.3Reference packages or standards,including packages with delamination and packages without delamination,for use during equipment setup.3.4Sample holder for pre-positioning samples.The holder should keep the samples from moving during the scan and maintain planarity.4PROCEDUREThis procedure is generic to all acoustic microscopes.For operational details related to this procedure that apply to a spe-ciﬁc model of acoustic microscope,consult the manufacturer’s operational manual.4.1Equipment Setup4.1.1Select the transducer with the highest useable ultrasonic frequency,subject to the limitations imposed by the media thickness and acoustic characteristics,package conﬁguration,and transducer availability,to analyze the interfaces of inter-est.The transducer selected should have a low enough frequency to provide a clear signal from the interface of interest.The transducer should have a high enough frequency to delineate the interface of interest.Note:Through transmission mode may require a lower frequency and/or longer focal length than reﬂective mode.Through transmission is effective for the initial inspection of components to determine if defects are present.4.1.2Verify setup with the reference packages or standards(see3.3above)and settings that are appropriate for the trans-ducer chosen in4.1.1to ensure that the critical parameters at the interface of interest correlate to the reference standard uti-lized.4.1.3Place units in the sample holder in the coupling medium such that the upper surface of each unit is parallel with the scanning plane of the acoustic transducer.Sweep air bubbles away from the unit surface and from the bottom of the trans-ducer head.4.1.4At aﬁxed distance(Z),align the transducer and/or stage for the maximum reﬂected amplitude from the top surface of the sample.The transducer must be perpendicular to the sample surface.4.1.5Focus by maximizing the amplitude,in the A-mode display,of the reﬂection from the interface designated for imag-ing.This is done by adjusting the Z-axis distance between the transducer and the sample.4.2Perform Acoustic Scans4.2.1Inspect the acoustic image(s)for any anomalies,verify that the anomaly is a package defect or an artifact of the imaging process,and record the results.(See Appendix A for an example of a check sheet that may be used.)To determine if an anomaly is a package defect or an artifact of the imaging process it is recommended to analyze the A-mode display at the location of the anomaly.4.2.2Consider potential pitfalls in image interpretation listed in,but not limited to,Appendix B and some of the limita-tions of acoustic microscopy listed in,but not limited to,Appendix C.If necessary,make adjustments to the equipment setup to optimize the results and rescan.4April1999IPC/JEDEC J-STD-035 4.2.3Evaluate the acoustic images using the failure criteria speciﬁed in other appropriate documents,such as J-STD-020.4.2.4Record the images and theﬁnal instrument setup parameters for documentation purposes.An example checklist is shown in Appendix D.5IPC/JEDEC J-STD-035April19996April1999IPC/JEDEC J-STD-035Appendix AAcoustic Microscopy Defect Check Sheet(continued)CIRCUIT SIDE SCANImage File Name/PathDelamination(Type I)Die Circuit Surface/Encapsulant Number Affected:Average%Location:Corner Edge Center (Type II)Die/Die Attach Number Affected:Average%Location:Corner Edge Center (Type III)Encapsulant/Substrate Number Affected:Average%Location:Corner Edge Center (Type V)Interconnect tip Number Affected:Average%Interconnect Number Affected:Max.%Length(Type VI)Intra-Laminate Number Affected:Average%Location:Corner Edge Center Comments:CracksAre cracks present:Yes NoIf yes:Do any cracks intersect:bond wire ball bond wedge bond tab bump tab leadDoes crack extend from leadﬁnger to any other internal feature:Yes NoDoes crack extend more than two-thirds the distance from any internal feature to the external surfaceof the package:Yes NoAdditional veriﬁcation required:Yes NoComments:Mold Compound VoidsAre voids present:Yes NoIf yes:Approx.size Location(if multiple voids,use comment section)Do any voids intersect:bond wire ball bond wedge bond tab bump tab lead Additional veriﬁcation required:Yes NoComments:7IPC/JEDEC J-STD-035April1999Appendix AAcoustic Microscopy Defect Check Sheet(continued)NON-CIRCUIT SIDE SCANImage File Name/PathDelamination(Type IV)Encapsulant/Substrate Number Affected:Average%Location:Corner Edge Center (Type II)Substrate/Die Attach Number Affected:Average%Location:Corner Edge Center (Type V)Interconnect Number Affected:Max.%LengthLocation:Corner Edge Center (Type VI)Intra-Laminate Number Affected:Average%Location:Corner Edge Center (Type VII)Heat Spreader Number Affected:Average%Location:Corner Edge Center Additional veriﬁcation required:Yes NoComments:CracksAre cracks present:Yes NoIf yes:Does crack extend more than two-thirds the distance from any internal feature to the external surfaceof the package:Yes NoAdditional veriﬁcation required:Yes NoComments:Mold Compound VoidsAre voids present:Yes NoIf yes:Approx.size Location(if multiple voids,use comment section)Additional veriﬁcation required:Yes NoComments:8Appendix BPotential Image PitfallsOBSERV ATIONS CAUSES/COMMENTSUnexplained loss of front surface signal Gain setting too lowSymbolization on package surfaceEjector pin knockoutsPin1and other mold marksDust,air bubbles,ﬁngerprints,residueScratches,scribe marks,pencil marksCambered package edgeUnexplained loss of subsurface signal Gain setting too lowTransducer frequency too highAcoustically absorbent(rubbery)ﬁllerLarge mold compound voidsPorosity/high concentration of small voidsAngled cracks in package‘‘Dark line boundary’’(phase cancellation)Burned molding compound(ESD/EOS damage)False or spotty indication of delamination Low acoustic impedance coating(polyimide,gel)Focus errorIncorrect delamination gate setupMultilayer interference effectsFalse indication of adhesion Gain set too high(saturation)Incorrect delamination gate setupFocus errorOverlap of front surface and subsurface echoes(transducerfrequency too low)Fluidﬁlling delamination areasApparent voiding around die edge Reﬂection from wire loopsIncorrect setting of void gateGraded intensity Die tilt or lead frame deformation Sample tiltApril1999IPC/JEDEC J-STD-0359Appendix CSome Limitations of Acoustic MicroscopyAcoustic microscopy is an analytical technique that provides a non-destructive method for examining plastic encapsulated components for the existence of delaminations,cracks,and voids.This technique has limitations that include the following: LIMITATION REASONAcoustic microscopy has difficulty inﬁnding small defects if the package is too thick.The ultrasonic signal becomes more attenuated as a function of two factors:the depth into the package and the transducer fre-quency.The greater the depth,the greater the attenuation.Simi-larly,the higher the transducer frequency,the greater the attenu-ation as a function of depth.There are limitations on the Z-axis(axial)resolu-tion.This is a function of the transducer frequency.The higher the transducer frequency,the better the resolution.However,the higher frequency signal becomes attenuated more quickly as a function of depth.There are limitations on the X-Y(lateral)resolu-tion.The X-Y(lateral)resolution is a function of a number of differ-ent variables including:•Transducer characteristics,including frequency,element diam-eter,and focal length•Absorption and scattering of acoustic waves as a function of the sample material•Electromechanical properties of the X-Y stageIrregularly shaped packages are difficult to analyze.The technique requires some kind ofﬂat reference surface.Typically,the upper surface of the package or the die surfacecan be used as references.In some packages,cambered packageedges can cause difficulty in analyzing defects near the edgesand below their surfaces.Edge Effect The edges cause difficulty in analyzing defects near the edge ofany internal features.IPC/JEDEC J-STD-035April1999 10April1999IPC/JEDEC J-STD-035Appendix DReference Procedure for Presenting Applicable Scanned DataMost of the settings described may be captured as a default for the particular supplier/product with speciﬁc changes recorded on a sample or lot basis.Setup Conﬁguration(Digital Setup File Name and Contents)Calibration Procedure and Calibration/Reference Standards usedTransducerManufacturerModelCenter frequencySerial numberElement diameterFocal length in waterScan SetupScan area(X-Y dimensions)Scan step sizeHorizontalVerticalDisplayed resolutionHorizontalVerticalScan speedPulser/Receiver SettingsGainBandwidthPulseEnergyRepetition rateReceiver attenuationDampingFilterEcho amplitudePulse Analyzer SettingsFront surface gate delay relative to trigger pulseSubsurface gate(if used)High passﬁlterDetection threshold for positive oscillation,negative oscillationA/D settingsSampling rateOffset settingPer Sample SettingsSample orientation(top or bottom(ﬂipped)view and location of pin1or some other distinguishing characteristic) Focus(point,depth,interface)Reference planeNon-default parametersSample identiﬁcation information to uniquely distinguish it from others in the same group11IPC/JEDEC J-STD-035April1999Appendix DReference Procedure for Presenting Applicable Scanned Data(continued) Reference Procedure for Presenting Scanned DataImageﬁle types and namesGray scale and color image legend deﬁnitionsSigniﬁcance of colorsIndications or deﬁnition of delaminationImage dimensionsDepth scale of TOFDeviation from true aspect ratioImage type:A-mode,B-mode,C-mode,TOF,Through TransmissionA-mode waveforms should be provided for points of interest,such as delaminated areas.In addition,an A-mode image should be provided for a bonded area as a control.12Standard Improvement FormIPC/JEDEC J-STD-035The purpose of this form is to provide the Technical Committee of IPC with input from the industry regarding usage of the subject standard.Individuals or companies are invited to submit comments to IPC.All comments will be collected and dispersed to the appropriate committee(s).If you can provide input,please complete this form and return to:IPC2215Sanders RoadNorthbrook,IL 60062-6135Fax 847509.97981.I recommend changes to the following:Requirement,paragraph number Test Method number,paragraph numberThe referenced paragraph number has proven to be:Unclear Too RigidInErrorOther2.Recommendations forcorrection:3.Other suggestions for document improvement:Submitted by:Name Telephone Company E-mailAddress City/State/ZipDate ASSOCIATION CONNECTING ELECTRONICS INDUSTRIESASSOCIATION CONNECTINGELECTRONICS INDUSTRIESISBN#1-580982-28-X2215 Sanders Road, Northbrook, IL 60062-6135Tel. 847.509.9700 Fax 847.509.9798。

【AP物理C】【真题】解答题C2004

AP® Physics C2004 Free Response QuestionsThe materials included in these files are intended for noncommercial use by AP teachers for course and exam preparation; permission for any other use must be sought from theAdvanced Placement Program®. Teachers may reproduce them, in whole or in part, in limited quantities, for face-to-face teaching purposes but may not mass distributethe materials, electronically or otherwise. This permission does not apply to any third-party copyrights contained herein. These materials and any copies made of themmay not be resold, and the copyright notices must be retained as they appear here.The College Board is a nonprofit membership association whose mission is to connect students to college success and opportunity.Founded in 1900, the association is composed of more than 4,500 schools, colleges, universities, and other educational organizations. Each year, the College Board serves over three million students and their parents, 23,000 high schools, and 3,500 colleges, through major programs and services incollege admissions, guidance, assessment, financial aid, enrollment, and teaching and learning. Among its best-known programs are the SAT®, the PSAT/NMSQT®, and the Advanced Placement Program® (AP®). The College Board is committed to the principles of equity andexcellence, and that commitment is embodied in all of its programs, services, activities, and concerns.For further information, visit College Board, Advanced Placement Program, AP, SAT, and the acorn logo are registered trademarks of the College Entrance Examination Board.2004M1. A rope of length L is attached to a support at point C. A person of mass m1 sits on a ledge at position A holding the other end of the rope so that it is horizontal and taut, as shown above. The person then drops off the ledge and swings down on the rope toward position B on a lower ledge where an object of mass m2 is at rest. At position B the person grabs hold of the object and simultaneously lets go of the rope. The person and object then land together in the lake at point D, which is a vertical distance L below position B. Air resistance and the mass of the rope are negligible. Derive expressions for each of the following in terms of m1, m2, L, and g.a. The speed of the person just before the collision with the objectb. The tension in the rope just before the collision with the objectc. The speed of the person and object just after the collisiond. The ratio of the kinetic energy of the person-object system before the collision to the kinetic energy after thecollisione. The total horizontal displacement x of the person from position A until the person and object land in the water atpoint D.2004M2. A solid disk of unknown mass and known radius R is used as a pulley in a lab experiment, as shown above. A small block of mass m is attached to a string, the other end of which is attached to the pulley and wrapped around it several times. The block of mass m is released from rest and takes a time t to fall the distance D to the floor.a. Calculate the linear acceleration a of the falling block in terms of the given quantities.b. The time t is measured for various heights D and the data are recorded in the following table.i. What quantities should be graphed in order to best determine the acceleration of the block? Explain yourreasoning.ii. On the grid below, plot the quantities determined in (b) i., label the axes, and draw the best-fit line to the data.iii. Use your graph to calculate the magnitude of the acceleration.c. Calculate the rotational inertia of the pulley in terms of m, R, a, and fundamental constants.d. The value of acceleration found in (b)iii, along with numerical values for the given quantities and your answer to (c),can be used to determine the rotational inertia of the pulley. The pulley is removed from its support and its rotational inertia is found to be greater than this value. Give one explanation for this discrepancy.2004M3. A uniform rod of mass M and length L is attached to a pivot of negligible friction as shown above. The pivot is located at a distance L/3 from the left end of the rod. Express all answers in terms of the given quantities and fundamental constants.a. Calculate the rotational inertia of the rod about the pivot.b. The rod is then released from rest from the horizontal position shown above. Calculate the linear speed ofthe bottom end of the rod when the rod passes through the vertical.c. The rod is brought to rest in the vertical position shown above and hangs freely. It is then displaced slightly from thisposition. Calculate the period of oscillation as it swings.2004E1. The figure above left shows a hollow, infinite, cylindrical, uncharged conducting shell of inner radius r1 and outer radius r2. An infinite line charge of linear charge density +λ is parallel to its axis but off center. An enlarged cross section of the cylindrical shell is shown above right.a. On the cross section above right,i. sketch the electric field lines, if any, in each of regions I, II, and III andii. use + and - signs to indicate any charge induced on the conductor.b. In the spaces below, rank the electric potentials at points a, b, c, d, and e from highest to lowest (1 = highestpotential). If two points are at the same potential, give them the same number.____V a ____V b ____V c- ____V d ____V ec. The shell is replaced by another cylindrical shell that has the same dimensions but is nonconducting and carries auniform volume charge density +ρ. The infinite line charge, still of charge density +λ, is located at the center of the shell as shown above. Using Gauss's law, calculate the magnitude of the electric field as a function of the distance r from the center of the shell for each of the following regions. Express your answers in terms of the given quantities and fundamental constants.i. r < r lii. r l≤ r≤ r2iii. r > r22004E2. In the circuit shown above left, the switch S is initially in the open position and the capacitor C is initially uncharged. A voltage probe and a computer (not shown) are used to measure the potential difference across the capacitor as a function of time after the switch is closed. The graph produced by the computer is shown above right. The battery has an emf of 20 V and negligible internal resistance. Resistor R1has a resistance of 15 kΩ and the capacitor C has a capacitance of 20 μF.a. Determine the voltage across resistor R2 immediately after the switch is closed.b. Determine the voltage across resistor R2 a long time after the switch is closed.c. Calculate the value of the resistor R2.d. Calculate the energy stored in the capacitor a long time after the switch is closed.e. On the axes below, graph the current in R2as a function of time from 0 to 15 s. Label the vertical axis withappropriate values.Resistor R2is removed and replaced with another resistor of lesser resistance. Switch S remains closed for a long time.(f) Indicate below whether the energy stored in the capacitor is greater than, less than, or the same as it was withresistor R2in the circuit._____Greater than _____Less than _____The same asExplain your reasoning.2004E3. A rectangular loop of dimensions 3 ℓ and 4 ℓ lies in the plane of the page as shown above. A long straight wire also in the plane of the page carries a current I.a. Calculate the magnetic flux through the rectangular loop in terms of I, ℓ , and fundamental constants. Starting at time t = 0, the current in the long straight wire is given as a function of time t byI (t) = I0e-kt , where I0 and k are constants.b. The current induced in the loop is in which direction?____Clockwise ____CounterclockwiseJustify your answer.The loop has a resistance R. Calculate each of the following in terms of R, I0 , k, ℓ , and fundamental constants.c. The current in the loop as a function of time td. The total energy dissipated in the loop from t = 0 to t=∞Copyright © 2004 by College Entrance Examination Board. All rights reserved.Visit (for AP professionals) and /apstudents (for AP students and parents)。

超声增强的输送的物料进入并通过皮肤翻译

超声增强的输送的物料进入并通过皮肤翻译Ultrasound-enhanced delivery of materials into and through the skinA method for enhancing the permeability of the skin or other biological membrane to a material such as a drug is disclosed. In the method, the drug is delivered in conjunction with ultrasound having a frequency of above about 10 MHz. The method may also be used in conjunction with chemical permeation enhancers and/or with iontophoresis.图片(11)权利要求(21)We claim:1. A method for enhancing the rate of permeation of a drug medium into a selected intact area of an individual's body surface, which method comprises:(a) applying ultrasound having a frequency of above 10 MHz to said selected area, at an intensity and for a period of timeeffective to enhance the permeability of said selected area;(b) contacting the selected area with the drug medium; and(c) effecting passage of said drug medium into and through said selected area by means of iontophoresis.2. The method of claim 1, wherein said ultrasound frequency is in the range of about 15 MHz to 50 MHz.3. The method of claim 2, wherein said ultrasound frequency is in the range of about 15 to 25 MHz.4. The method of claim 1, wherein said period of time is in the range of about 5 to 45 minutes.5. The method of claim 4, wherein said period of time is in the range of about 5 to 30 minutes.6. The method of claim 1, wherein said period of time is less than about 10 minutes.7. The method of claim 1, wherein said intensity of said ultrasound is less than about 5.0W/cm.sup.2.8. The method of claim 7, wherein said intensity of said ultrasound is in the range of about 0.01 to 5.0 W/cm.sup.2.9. The method of claim 8, wherein said intensity of said ultrasound is in the range of about 0.05 to 3.0 W/cm.sup.2.10. The method of claim 1, wherein said area of the stratum corneum is in the range of about 1 to 100 cm.sup.2.11. The method of claim 10, wherein said area of the stratum corneum is in the range of about 5 to 100 cm.sup.2.12. The method of claim 11, wherein said area of the stratum corneum is in the range of about 10 to 50 cm.sup.2.13. The method of claim 1 wherein said drug medium comprises a drug and a coupling agent effective to transfer said ultrasound to the body from an ultrasound source.14. The method of claim 13 wherein said coupling agent is a polymer or a gel.15. The method of claim 13 wherein said coupling agent is selected from the group consisting of glycerin, water, and propylene glycol.16. The method of claim 1 wherein said drug medium further comprises a chemical permeation enhancer.17. The method of claim 1, wherein steps (a) and (b) are carried out approximately simultaneously.18. The method of claim 1, wherein step (b) is carried out before step (a).19. The method of claim 1, wherein step (a) is carried out before step (b).20. The method of claim 1, wherein the ultrasound is applied continuously.21. The method of claim 1, wherein the ultrasound is pulsed.说明This application is a division of application Ser. No. 07/844,732 filed Mar. 2, 1992, now U.S. Pat. No. 5,231,975 which is a divisional of application Ser. No. 07/484,560, now U.S. Pat. No. 5,115,805, filed Feb. 23, 1990.TECHNICAL FIELDThis invention relates generally to the field of drug delivery. More particularly, the invention relates to a method of enhancing the rate of permeation of topically, transmucosally or transdermally applied materials using high frequency ultrasound.BACKGROUNDThe delivery of drugs through the skin ("transdermal drug delivery" or "TDD") provides many advantages; primarily, such a means of delivery is a comfortable, convenient and non-invasiveway of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.Skin is a structurally complex, relatively impermeable membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the stratum corneum, a layer approximately 5-15 micrometers thick over most of the body, which presents the primary barrier to absorption of topical compositions or transdermally administered drugs. It is believed to be the high degree of keratinization within its cells as well as their dense packing and cementation by ordered, semicrystalline lipids which create in many cases a substantially impermeable barrier to drug penetration. Applicability of transdermal drug delivery is thus presently limited, because the skin is such an excellent barrier to the ingress of topically applied materials. For example, many of the new peptides and proteins now produced as a result of the biotechnology revolution cannot be delivered across the skin in sufficient quantities due to their naturally low rates of skin permeability.Various methods have been used to increase skin permeability, and in particular to increase the permeability of thestratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally). The primary focus has been on the use of chemical enhancers, i.e., wherein drug is coadministered with a penetration enhancing agent (or "permeation enhancer"). While such compounds are effective in increasing the rate at which drug is delivered through the skin, there are drawbacks with many permeation enhancers which limit their use. For example, many permeation enhancers are associated with deleterious effects on the skin (e.g., irritation). In addition, control of drug delivery with chemical enhancement can be quite difficult.Iontophoresis has also been used to increase the permeability of skin to drugs, and involves (1) the application of an external electric field, and (2) topical delivery of an ionized form of drug (or of a neutral drug carried with the water flux associated with ion transport, i.e., via "electroosmosis"). While permeation enhancement via iontophoresis has, as with chemical enhancers, been effective, there are problems with control of drug delivery and the degree of irreversible skin damage induced by the transmembrane passage of current.The presently disclosed and claimed method involves the use of ultrasound to decrease the barrier function of the stratum corneum and thus increase the rate at which a drug may be delivered through the skin. "Ultrasound" is defined as mechanical pressure waves with frequencies above 20,000 Hz (see, e.g., H. Lutz et al., Manual of Ultrasound: 1. Basic Physical and Technical Principles (Berlin: Springer-Verlag, 1984)).As discussed by P. Tyle et al. in Pharmaceutical Research 6(5):355-361 (1989), drug penetration achieved via "sonophoresis" (the movement of drugs through skin under theinfluence of an ultrasonic perturbation; see D. M. Skauen and G. M. Zentner, Int. J. Pharmaceutics 20:235-245 (1984)), is believed to result from thermal, mechanical and chemical alteration of biological tissues by the applied ultrasonic waves. Unlike iontophoresis, the risk of skin damage appears to be low.Applications of ultrasound to drug delivery have been discussed in the literature. See, for example: P. Tyle et al., supra (which provides an overview of sonophoresis); S. Miyazaki et al., J. Pharm. Pharmacol. 40:716-717 (1988) (controlled release of insulin from a polymer implant using ultrasound); J. Kost et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater.16(141):294-295 (1989) (overview of the effect of ultrasound on the permeability of human skin and synthetic membranes); H. Benson et al., Physical Therapy 69(2):113-118 (1989) (effect of ultrasound on the percutaneous absorption of benzydamine); E. Novak, Arch. Phys. Medicine & Rehab. 45:231-232 (1964) (enhanced penetration of lidocaine through intact skin using ultrasound); J. E. Griffin et al., Amer. J. Phys. Medicine 44(1):20-25 (1965) (ultrasonic penetration of cortisol into pig tissue); J. E. Griffin et al., J. Amer. Phys. Therapy Assoc.46:18-26 (1966) (overview of the use of ultrasonic energy in drug therapy); J. E. Griffin et al., Phys. Therapy 47(7):594-601 (1967) (ultrasonic penetration of hydrocortisone); J. E. Griffin et al., Phys. Therapy 48(12):1336-1344 (1968) (ultrasonic penetration of cortisol into pig tissue); J. E. Griffin et al., Amer. J. Phys. Medicine 51(2):62-72 (1972) (same); J. C. McElnay, Int. J. Pharmaceutics 40:105-110 (1987) (the effect of ultrasound on the percutaneous absorption of fluocinolone acetonide); and C. Escoffier et al., Bioeng. Skin 2:87-94 (1986) (in vitro study of the velocity of ultrasound in skin).In addition to the aforementioned art, U.S. Pat. Nos. 4,767,402 and 4,780,212 to Kost et al. relate specifically to the use of specific frequencies of ultrasound to enhance the rate of permeation of a drug through human skin or through a synthetic membrane.While the application of ultrasound in conjunction with drug delivery is thus known, results have for the most part been disappointing, i.e., enhancement of skin permeability has been relatively low.SUMMARY OF THE INVENTIONThe present invention provides a novel method for enhancing the rate of permeation of a given material through a selected intact area of an individual's body surface. The method comprises contacting the selected intact area with the material and applying ultrasound to the contacted area. The ultrasound preferably has a frequency of above about 10 MHz, and is continued at an intensity and for a period of time sufficient to enhance the rate of permeation of the material into and through the body surface. The ultrasound can also be used to pretreat the selected area of the body surface in preparation for drug delivery, or for diagnostic purposes, i.e., to enable non-invasive sampling of physiologic material beneath the skin or body surface.In addition to enhancing the rate of permeation of a material, the present invention involves increasing the permeability of a biological membrane such as the stratum corneum by applying ultrasound having a frequency of above about 10 MHz to the membrane at an intensity and for a period of time sufficient to give rise to increased permeability of the membrane. Once the permeability of the membrane has been increased, it is possible to apply a material thereto and obtain an increased rate of flowof the material through the membrane.It is accordingly a primary object of the invention to address the aforementioned deficiencies of the prior art by providing a method of enhancing the permeability of biological membranes and thus allow for an increased rate of delivery of material therethrough.It is another object of the invention to provide such a method which is effective with or without chemical permeation enhancers.It is still another object of the invention to minimize lag time in such a method and provide a relatively short total treatment time.It is yet another object of the invention to provide such a method in which drug delivery is effected using ultrasound.It is a further object of the invention to enable sampling of tissue beneath the skin or other body surface by application of high frequency (>10 MHz) ultrasound thereto.A further feature of the invention is that it preferably involves ultrasound of a frequency greater than about 10 MHz.Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.BRIEF DESCRIPTION OF THE DRAWINGSFIGS. 1A, 1B and 1C are theoretical plots of energy dissipation within the skin barrier versus frequency of applied ultrasound.FIGS. 2, 3 and 4 are graphic representations of the amount of salicylic acid recovered from the stratum corneum after ultrasound treatment at different frequencies.FIGS. 5 and 6 represent the results of experiments similar to those summarized in FIGS. 2, 3 and 4, but with a shorter treatment time.FIGS. 7, 8, 9 and 10 are plots of enhancement versus "tape-strip number," as described in the Example.FIG. 11 illustrates the effect of ultrasound on the systemic availability of salicylic acid following topical application.DETAILED DESCRIPTION OF PREFERRED EMBODIMENTSBefore the present method of enhancing the rate of permeation of a material through a biological membrane and enhancing the permeability of membranes using ultrasound are disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein as such process steps and materials may, of course, vary. It is alto to be understood that the terminology used herein is used for purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.It must be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes mixtures of drugs and their pharmaceutically acceptable salts, reference to "an ultrasound device" includes one or more ultrasound devices of the type necessary for carrying out the present invention, and reference to "the method of administration" includes one or more different methods of administration known to those skilled in the art or which will become known to those skilled in the art upon reading this disclosure.In one aspect of the invention a method is provided forenhancing the permeation of a given material such as a drug, pharmacologically active agent, or diagnostic agent into and/or through a biological membrane on an individual's body surface, which method comprises: (a) contacting the membrane with the chosen material in a pharmacologically acceptable carrier medium; and (b) applying ultrasound of an intensity and for a treatment time effective to produce delivery of the material through the membrane. The material is preferably a drug and it is preferable to obtain a desired blood level of the drug in the individual. The ultrasound is of a frequency and intensity effective to increase the permeability of the selected area to the applied drug over that which would be obtained without ultrasound. The ultrasound preferably has a frequency of more than 10 MHz, and may be applied either continuously or pulsed, preferably continuously. The ultrasound may be applied to the skin either before or after application of the drug medium so long as administration of the ultrasound and the drug medium is relatively simultaneous, i.e., the ultrasound is applied within about 6, more preferably within about 4, most preferably within about 2 minutes of drug application.The invention is useful for achieving transdermal permeation of pharmacologically active agents which otherwise would be quite difficult to deliver through the skin or other body surface. For example, proteinaceous drugs and other high molecular weight pharmacologically active agents are ideal candidates for transdermal, transmucosal or topical delivery using the presently disclosed method. In an alternative embodiment, agents useful for diagnostic purposes may also be delivered into and/or through the body surface using the present method.The invention is also useful as a non-invasive diagnostictechnique, i.e., in enabling the sampling of physiologic material from beneath the skin or other body surface and into a collection (and/or evaluation) chamber.The present invention will employ, unless otherwise indicated, conventional pharmaceutical methodology and more specifically conventional methodology used in connection with transdermal delivery of pharmaceutically active compounds and enhancers.In describing the present invention, the following terminology will be used in accordance with the definitions set out below.A "biological membrane" is intended to mean a membrane material present within a living organism which separates one area of the organism from another and, more specifically, which separates the organism from its outer environment. Skin and mucous membranes are thus included."Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a material such as a pharmacologically active agent, i.e., so as to increase the rate at which the material permeates into and through the skin. The present invention involves enhancement of permeation through the use of ultrasound, and, in particular, through the use of ultrasound having a frequency of greater than 10 MHz."Transdermal" (or "percutaneous") shall mean passage of a material into and through the skin to achieve effective therapeutic blood levels or deep tissue therapeutic levels. While the invention is described herein primarily in terms of "transdermal" administration, it will be appreciated by those skilled in the art that the presently disclosed and claimed methodalso encompasses the "transmucosal" and "topical" administration of drugs using ultrasound. "Transmucosal" is intended to mean passage of any given material through a mucosal membrane of a living organism and more specifically shall refer to the passage of a materialfrom the outside environment of the organism, through a mucous membrane and into the organism. "Transmucosal" administration thus includes delivery of drugs through either nasal or buccal tissue. By "topical" administration is meant local administration of a topical pharmacologically active agent to the skin as in, for example, the treatment of various skin disorders or the administration of a local anaesthetic. "Topical" delivery can involve penetration of a drug into the skin but not through it, i.e., topical administration does not involve actual passage of a drug into the bloodstream."Carriers" or "vehicles" as used herein refer to carrier materials without pharmacological activity which are suitable for administration with other pharmaceutically active materials, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with the drug to be administered in a deleterious manner. Examples of suitable carriers for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.By the term "pharmacologically active agent" or "drug" as used herein is meant any chemical material or compound suitable for transdermal or transmucosal administration which can either (1) have a prophylactic effect on the organism and prevent an undesired biological effect such as preventing aninfection, (2) alleviates a condition caused by a disease such as alleviating pain caused as a result of a disease, or (3) either alleviates or completely eliminates the disease from the organism. The effect of the agent may be local, such as providing for a local anaesthetic effect or it may be systemic. Such substances include the broad classes of compounds normally delivered through body surfaces and membranes, including skin. In general, this includes: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers. By the method of the present invention, both ionized and nonionzed drugs may be delivered, as can drugs of either high or low molecular weight.Proteinaceous and polypeptide drugs represent a preferred class of drugs for use in conjunction with the presently disclosed and claimed invention. Such drugs cannot generally be administered orally in that they Are often destroyed in the G.I.tract or metabolized in the liver. Further, due to the high molecular weight of most polypeptide drugs, conventional transdermal delivery systems are not generally effective. It is also desirable to use the methodof the invention in conjunction with drugs to which the permeability of the skin is relatively low, or which give rise to a long lag-time (application of ultrasound as described herein has been found to significantly reduce the lag-time involved with the transdermal administration of most drugs).By a "therapeutically effective" amount of a pharmacologically active agent is meant a nontoxic but sufficient amount of a compound to provide the desired therapeutic effect. The desired therapeutic effect may be a prophylactic effect, in preventing a disease, an effect which alleviates a system of the disease, or a curative effect which either eliminates or aids in the elimination of the disease.As noted above, the present invention is a method for enhancing the rate of permeation of a drug through an intact area of an individual's body surface, preferably the human skin. The method involves transdermal administration of a selected drug in conjunction with ultrasound. Ultrasound causes thermal, mechanical and chemical alterations of biological tissue, thereby enhancing the rate of permeation of a given material therethrough.While not wishing to be bound by theory, applicants propose that the use of higher frequency ultrasound as disclosed herein specifically enhances the permeation of the drug through the outer layer of skin, i.e., the stratum corneum, by causing momentary and reversible perturbations within (and thus short-term, reversible reduction in the barrier function of) the layer ofthe stratum corneum. It will be appreciated by those skilled in the art of transdermal drug delivery that a number of factors related to the present method will vary with the drug to be administered, the disease or injury to be treated, the age of the selected individual, the location of the skin to which the drug is applied, and the like.As noted above, "ultrasound" is ultrasonic radiation of a frequency above 20,000 Hz. As may be deduced from the literature cited above, ultrasound used for most medical purposes typically employs frequencies ranging from 1.6 to about 10 MHz. The present invention, by contrast, employs ultrasound frequencies of greater than about 10 MHz, preferably in the range of about 15 to 50 MHz, most preferably in the range of about 15 to 25 MHz. It should be emphasized that these ranges are intended to be merely illustrative of the preferred embodiment; in some cases higher or lower frequencies may be used.The ultrasound may be pulsed or continuous, but is preferably continuous when lower frequencies are used. At very high frequencies, pulsed application will generally be preferred so as to enable dissipation of generated heat.The preferred intensity of the applied ultrasound is less than about 5.0 W/cm.sup.2, more preferably is in the range of about 0.01 to 5.0 W/cm.sup.2, and most preferably is in the range of 0.05 to 3.0 W/cm.sup.2. The total treatment time, i.e., the period over which drug and ultrasound are administered, will vary depending on the drug administered, the disease or injury treated, etc., but will generally be on the order of about 30 seconds to 60 minutes, preferably 5 to 45 minutes, more preferably 5 to 30 minutes, and most preferably 5 to 10minutes. It should be noted that the aforementioned ranges represent suggested, or preferred, treatment times, but are not in any way intended to be limiting. Longer or shorter times may be possible and in some cases desirable. Virtually any type of device may be used to administer the ultrasound, providing that the device is callable of producing the higher frequency ultrasonic waves required by the present method. A device will typically have a power source such as a small battery, a transducer, a reservoir in which the drug medium is housed (and which may or may not be refillable), and a means to attach the system to the desired skin site.As ultrasound does not transmit well in air, a liquid medium is generally needed to efficiently and rapidly transmit ultrasound between the ultrasound applicator and the skin. As explained by P. Tyle et al., cited above, the selected drug medium should contain a "coupling" or "contacting" agent typically used in conjunction with ultrasound. The coupling agent should have an absorption coefficient similar to that of water, and furthermore be nonstaining, nonirritating to the skin, and slow drying. It is clearly preferred that the coupling agent retain a paste or gel consistency during the time period of ultrasound administration so that contact is maintained between the ultrasound source and the skin. Examples of preferred coupling agents are mixtures of mineral oil and glycerine and propylene glycol, oil/water emulsions, and a water-based gel. A solid-state, non-crystalline polymeric film having the above-mentioned characteristics may also be used. The drug medium may also contain a carrier or vehicle, as defined alone.A transdermal patch as well known in the art may be used in conjunction with the present invention, i.e., to deliver the drugmedium to the skin. The "patch", however, must have the properties of the coupling agent as described in the preceding paragraph so as to enable transmission of the ultrasound from the applicator, through the patch, to the skin.As noted earlier in this section, virtually any chemical material or compound suitable for transdermal, transmucosal or topical administration may be administered using the present method. Again, the present invention is particularly useful to enhance delivery of proteinaceous and other high molecular weight drugs.The method of the invention is preferably carried out as follows. The drug medium, i.e., containing the selected drug or drugs in conjunction with the coupling agent and optionally a carrier or vehicle material, is applied to an area of intact body surface. Ultrasound preferably having a frequency greater than about 10 MHz may be applied before or after application of the drug medium, but is preferably applied immediately before application of the drug so as to "pretreat" the skin prior to drug administration.It should also be pointed out that the present method may be used in conjunction with a chemical permeation enhancer as known in the art, wherein the ultrasound enables the use of much lower concentrations of permeation enhancer--thus minimizing skin irritation and other problems frequently associated with such compounds--than would be possible in the absence of ultrasound. The permeation enhancer may be incorporated into the drug medium or it maybe applied in a conventional transdermal patch after pretreatment of the body surface with ultrasound.The present invention may also be used in conjunction with。

海藻酸钠基凝胶球的制备、改性及其食品包装的应用研究进展

杨小叶，马淑凤，王利强. 海藻酸钠基凝胶球的制备、改性及其食品包装的应用研究进展[J]. 食品工业科技，2023，44（24）：376−383. doi: 10.13386/j.issn1002-0306.2023020228YANG Xiaoye, MA Shufeng, WANG Liqiang. Research Progress on Preparation and Modification of Sodium Alginate-based Gel Spheres and Its Application in Food Packaging[J]. Science and Technology of Food Industry, 2023, 44(24): 376−383. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2023020228· 专题综述 ·海藻酸钠基凝胶球的制备、改性及其食品包装的应用研究进展杨小叶1，马淑凤2，王利强1,3,*（1.江南大学机械工程学院，江苏无锡 214122；2.江南大学食品科学与技术学院，江苏无锡 214122；3.江苏省食品先进制造装备技术重点实验室，江苏无锡 214122）摘　要：海藻酸钠是一种天然的多糖材料，具有良好的凝胶特性。

目前利用凝胶特性制备的海藻酸钠基凝胶球主要是作为微胶囊在包封益生菌、细胞与酶的固定、包封精油等方面的应用，但近年来利用海藻酸钠凝胶成球技术包装粘性液体也吸引了众多学者关注，展现出良好的应用前景。

该文概述海藻酸钠凝胶成球形成机理，重点总结海藻酸钠基凝胶球的制备方法及适用范围，包括正向球化法、乳化凝胶法、反向球化法、冷冻反向球化法和同轴挤出法。

由于海藻酸钠基凝胶球的凝胶强度、持水性和包埋率极大影响其应用，故探讨了对海藻酸钠进行复配混合、疏水改性以及对海藻酸钠基凝胶球二次涂膜的改善方法。

Edinburgh, Scotland

This research was supported by SERC grants GR/E78463, GR/H73103 and GR/J07303. research was supported by SERC grants GR/E78463, GR/J07693, a SERC Advanced Fellowship, and the COMPASS Basic Research working group. z This research was supported by SERC grants GR/H76739 and GR/E78463, an ECfunded COST fellowship, and KBN grant PB 1247/P3/93/04.
y This
on foundations and tools. This paper is a report on the current state of this de nition as it nears completion. SML is a widely-used functional programming language. Apart from useful features it shares with a number of similar languages (a exible type system with polymorphic types, function de nition by patterns, etc.) it has two special characteristics which make it very well-suited to the enterprise mentioned above. First, it provides state-of-the-art modularisation facilities for building large software systems by de ning and combining self-contained generic program units. Such facilities seem to be a prerequisite for the use of formal development methods on examples of signi cant size. The main emphasis of EML is on development \in the large", relying heavily on linguistic support from the SML module facilities and incorporating ideas from foundational work on speci cation and formal development of modular systems 37], 33], 30], 36]. Second, the syntax and semantics of SML is formally de ned 22]. This makes it possible (at least in principle) to reason formally about the behaviour of SML programs, as required for proofs of correctness with respect to a speci cation of requirements. The size and complexity of the semantics is such that fully formal use of it, e.g. to prove correctness of an optimizing transformation, would be quite a di cult task. Nevertheless, the semantics is small and elegant enough that such use seems not to be completely out of the question. The idea of building a fully- edged speci cation and formal development framework around a \real" programming language seems to be novel to EML. Somewhat related is work on the Anna language for annotating Ada programs with assertions concerning their intended behaviour 19]; but this is not intended for formal development of software from speci cations (although see 17]), and as far as we are aware there is no formal semantics of Anna nor any intention to formally relate Anna to the semantics of Ada 2]. Similar comments apply to Larch 10], which has been used in connection with various programming languages. Attempts to apply Larch to the speci cation of SML modules have recently begun 39], but this work is still at an early stage and many problems remain to be solved. Real programming languages are inevitably complex, and any serious attempt to give a formal treatment of such a language and a development framework based on it is an ambitious goal bringing a host of problems which do not arise when considering toy programming languages or when considering speci cation and formal development in abstract terms. Another novelty of this work is in its treatment of the speci cation of a number of \di cult" facets of computation, all of which arise in SML. These include polymorphic types, higher-order functions, exceptions and non-termination. In spite of the fact that these are common features of modern programming languages, they are rarely addressed by approaches to speci cation. There have been attempts to treat each of these features in isolation, but not in combination with one another. It is precisely in the interaction between such features that some of the most di cult issues arise. The structure of the paper is as follows. Section 2 gives a short introduction to the main features of SML and EML in order to set the scene for the rest of the paper. We have resisted the temptation to dwell at length on aspects of EML which are not directly relevant to the topic at hand; for more information, see the papers cited in Section 2. Section 3 discusses the way in which EML relates to and extends SML. Section 4 is an overview of the semantics of EML which attempts to give the reader an overall impression of its strucct

液质高通量分析

High-throughput quantitative bioanalysis by LC/MS/MSMohammed Jemal*Bioanalytical Research,Metabolism and Pharmacokinetics,Bristol-Myers Squibb Pharmaceutical Research Institute,New Brunswick,NJ 08903-0191,USAABSTRACT:This review article discusses the most recent signiﬁcant advances in the sample preparation and mass spectrometry aspects of high-throughput bioanalysis by LC/MS/MS for the quantitation of drugs,metabolites and endogenous biomolecules in biological matrices.The introduction and implementation of automated96-well extraction has brought about high-throughput approaches to the biological sample preparation techniques of solid-phase extraction,liquid-liquid extraction and protein precipitation.The fast-ﬂow on-line extraction technique is a different high-throughput approach that has also signiﬁcantly speeded up analysis by LC/MS/MS.The use of pierceable caps for biological tubes further enhances the analysis speed and improves the safety in handling biological samples.The need for adequate chromatographic separation in order to eliminate interferences due to metabolites and/or matrix effects in LC/MS/MS is discussed.To highlight our limited understanding of atmospheric pressure ionization mass spectrometry,results from recent investigations that appear to be counter-intuitive are presented.Looking ahead to the future, multiplexed LC/MS/MS systems and capillary LC are presented as areas that can bring about further improvements in analysis speed and sensitivity to quantitative bioanalysis by LC/MS/MS.Copyright#2000John Wiley&Sons,Ltd.INTRODUCTIONThe ever shortening timelines in drug discovery and development have brought about the need for high-throughput approaches to methods used to quantitate drugs,metabolites and endogenous biomolecules in biological matrices(blood,plasma,serum,urine,and in-vitro biological samples).The timely advent of the technique of liquid chromatography coupled with tandem mass spectrometry(LC/MS/MS)has greatly enabled bioanalysts to rise to this challenge.It has been possible to drastically reduce the chromatographic run time due to the inherent speciﬁcity/sensitivity of this technique compared to bioanalytical LC methods based on tradi-tional detection means,such as UV.The achievement of very short chromatographic run times has in turn brought about the need for high-throughput approaches to biological sample preparation that precede the LC/MS/ MS analyses.This review paper will highlight the most recent signiﬁcant advances in sample preparation and LC/MS/MS.SAMPLE PREPARATIONAutomated96-well extractionThis sample preparation technique is based on the use of 96-well format for extractions such as solid-phase extraction(SPE)and liquid–liquid extraction(LLE), automated using a robotic liquid handling system.This approach automates most of the tedious steps encoun-tered in the traditional manual extraction procedures and eliminates some of the time-consuming steps,such as tube labeling and most of the capping/uncapping steps of individual tubes.The principles and application details of automated96-well SPE have been described in a number of publica-tions(Allanson et al.,1996;Simpson et al.,1998; Hempenius et al.,1998;Harrison and Walker,1998; Jemal et al.,1999a,2000a;Zhang and Henion,1999; Wells,1999a,b).In a typical automated96-well SPE procedure,a96-well SPE plate is conditioned,using a robotic liquid handling system,with an organic solvent followed by an aqueous buffer ing the robotic system,plasma samples are transferred to the96-well SPE plate,internal standard and aqueous buffer solutions are added,and then vacuum is applied.The plate is rinsed by applying organic solvent/aqueous buffer solution robotically.The waste tray is then removed manually and replaced with a collection plate.Elution is performed robotically with an organic solvent.The collection plate is manually placed in an evaporator to evaporate the eluates to dryness.The collection plate is placed back on the robotic system for reconstitution.The96-well plate isBIOMEDICAL CHROMATOGRAPHYBiomed.Chromatogr.14:422–429(2000)*Correspondence to:M.Jemal,Bioanalytical Research,Metabolism and Pharmacokinetics,Bristol-Myers Squibb Pharmaceutical Research Institute,Po Box191,New Brunswick,NJ08903-0191,USA.E-mail:jemalm@Abbreviations used:API,atmospheric pressure ionization;LLE, liquid–liquid extraction;SPE,solid-phase extraction;SRM,selective reaction monitoring;TOF,time-of-ﬂight.REVIEW ARTICLEsealed with a cover mat and placed on the autosampler,ready for injection.If elution can successfully be achieved with an appropriate organic/aqueous mixture,the eluates can be directly injected,obviating the evaporation and reconstitution steps.A few papers have been published in the area of automated 96-well LLE (Jemal et al.,1999a;Zweigen-baum et al.,1999;Steinborner and Henion,1999;Peng et al.,2000;Teitz et al.,2000).In a typical automated 96-well LLE,plasma samples are transferred,using a robotic liquid handling system,into separate wells of a 96-well plate consisting of racked collection microtubes.Then the internal standard solution,the appropriate reagent (a buffer,acid or base solution)and the extracting organic solvent are added using the robotic system.The microtubes are capped with strip caps and then the plate is shaken ofﬂine.The aqueous and the organic layers are then separated by centrifugation.The robot is used to transfer the organic layers from the microtubes to a clean deep 96-well collection plate.The extracts in the 96-well plate are evaporated ofﬂine and then the dried extracts in the 96-well plate are dissolved by adding the reconstitu-tion solution using the robotic system.The 96-well plate is sealed with a cover mat and placed on the autosampler,ready for injection.Using 96-well automation speeds up bioanalysis as measured by both the numbers of samples processed per unit time and by the analyst’s available time for other tasks.For instance,to extract 96samples by manual SPE or LLE,4–6h are required and the bioanalyst is physically occupied for most of this time.On the other hand,it takes only 20–120min to process 96samples by automated SPE or LLE and the bioanalyst is physically occupied for only approximately 10min.Automated SPE has fewer manual steps than automated LLE and has the potential to be signiﬁcantly less time-consuming when the evaporation step of SPE eluates can be eliminated.However,LLE generally tends to give cleaner extracts than SPE,as evidenced by less matrix effect (matrix effect is discussed below)and less tendency for pressure build-up in the LC column as more samples are injected.It is well known that plasma protein precipitation with acids or water miscible organic solvents has been used as a sample clean-up procedure for the analysis of plasma samples by LC/MS/MS.The main attraction to the protein precipitation technique,compared with manual LLE or SPE,has been its speed,simplicity and universality,in that the same basic procedure can be applied to extract almost any analyte.The technique has been made even more attractive by the recent automation using a 96-well format (Biddlecombe and Pleasance,1999;Watt et al.,2000;Teitz D,Khan S,Powell ML,Jemal M.One-pot sample preparation in a 96-well plate combined with LC/MS/MS for a high-throughput analysis of plasma samples,unpublished).With the introduction of the fast-ﬂow on-line extraction (discussed below)and 96-well automation for SPE and LLE,which have reduced the sample preparation time to less than 30s per sample,the advantages of speed,simplicity and universality for the protein precipitation technique is now less obvious.The disadvantage of the protein precipita-tion approach is that the extract is not as clean as that obtained by SPE,LLE or fast-ﬂow on-line extraction,as evidenced by the matrix effect or physical effects such as soiling of the mass spectrometer or the LC components.The result is that the chromatographic run time is normally relatively long in order to cleanse the system and avoid the matrix effect,usually incorporating a gradient scheme.Therefore,automated SPE,automated LLE,and on-line extraction are the preferred approaches to sample preparation,especially at a stage when the drug candidate enters the development phase,where sensitive,accurate,precise and rugged high-throughput methods are required for routine analyses of large batches of clinical samples.Fast-¯ow on-line extractionThis technique is based on direct injection of biological samples,without prior extraction,into an LC/MS/MS system that incorporates a switching valve.There isnoFigure 1.A schematic representation of on-line extraction LC/MS/MS system.Bioanalysis byLC/MS/MSsample preparation except for sample aliquotting,inter-nal standard addition and centrifugation.The unique feature of this new on-line puriﬁcation approach is the use of a narrow-bore LC column (typically1Â50mm)packed with large particles of a stationary phase material(typically30–50m m),with a very highﬂow of the mobile phase(typically3–5mL/ min),which translates to a very fast linear speed of approximately10–17cm/s.The combination of the fast ﬂow and large particle sizes provides the desired chromatographic behavior(turbulentﬂow behavior)that allows for the rapid passage of the large biomolecules of the biological sample with the simultaneous retention of the small-molecule analyte(s)of interest.Because of the narrow i.d.of the column and the large particle sizes,the fast linear speedﬂow,which is a central feature of the direct-injection technique,can be achieved with a manageable volumetricﬂow of3–5mL/min and reason-able column pressure(typically700–1200psi).The principles and application details of fast-ﬂow on-line extraction have been described in a number of publica-tions(Ayrton et al.,19971998,1999;Jemal et al.,1998a 1999b,c,2000b;Zimmer et al.,1999;Ding and Neue, 1999;Wu et al.,2000;Xia et al.,2000;Eeckhout et al., 2000).A simple on-line extraction system is presented in Fig.1.The system is assembled using two pumps,two columns in series,an autosampler and a mass spectro-meter equipped with a six-port switching valve.Theﬁrst column(Oasis1HLB,1Â50mm,30m m)is a specia-lized column that serves as the extraction column.The second column(C18,2.0Â50mm,5m m)is a regular analytical column.A plasma sample fortiﬁed with an internal standard is injected into the extraction column, with a100%aqueous mobile phase at a highﬂow rate(eg 5.0mL/min,to achieve a linear speed of approximately 11cm/s in the extraction column).This sample extraction stage lasts for less than0.5min[Fig.1,conﬁguration(a)]. During the extraction stage,the column efﬂuent is diverted to waste to protect the mass spectrometer.The valve is then switched so that the extraction column is in-line with the analytical column and the mass spectro-meter,using an organic/aqueous mobile phase at aﬂow rate(eg0.5mL/min)compatible with the analytical column and mass spectrometer[Fig.1,conﬁguration(b)]. This is the elution stage.The elution stage is followed by the equilibration stage to recondition the extraction column under the same conditions as the extraction stage,using a100%aqueous mobile phase at the high ﬂow rate[Fig.1,conﬁguration(a)].A typical total run time is only2.0min,with the analyte retention time of about 1.0min.Within this short run time,baseline chromatographic separation between an analyte and another compound can be achieved.Using mass spectrometers and other equipment that already exist in a typical bioanalytical laboratory,the bioanalyst can put together a direct injection LC/MS/MS system using different autosamplers and pumps.The assembled systems are simple but very versatile,capable of accommodating different sample analysis needs.The most complex system that has been assembled in the author’s laboratory utilizes a ternary-column approach, with dual extraction columns used in parallel for puriﬁcation and an analytical column for analysis(Xia et al.,2000).The use of this system allows the equilibration of one extraction column while the analysis is ongoing on the other extraction column.Thus,the equilibration time does not add to the chromatographic run time,thereby shortening the run time and hence increasing the sample throughput.The use of two extraction columns also extends the working life of the system,making it feasible to analyze several hundred samples in a single batch.It should be pointed out that integrated direct-injection systems are also commercially available.A direct-injection system can also be used in conjunction with96-well collection plates using a robotic liquid handling system to aliquot samples,prepare standards and quality control samples and add the internal standard solution into a96-well collection plate. The samples are then injected directly from the96-well plate.For compounds that are not stable in plasma at room temperature,even after a stabilization treatment, such as the adjustment of the sample pH,it is important that the autosamplers used possess temperature control capability for96-well plates.Pierceable capsBiological samples are normally collected and stored in capped tubes until analysis.To obtain aliquots of biological samples for analysis,the sample tubes have to be uncapped and then recapped for further storage. This is one of the tedious and labor intensive steps in the bioanalytical laboratory.Recently,the use of pierceable caps for sample tubes has been investigated in the author’s laboratory with the aim of obviating the uncapping and recapping steps(Teitz et al.,2000).The commercially available sample tube caps are retroﬁtted with pierceable septa.The probes of a robotic liquid handling system are programmed to pierce the septa of the capped sample tubes and aliquot the samples into a 96-well plate.A bioanalytical method was successfully developed and validated using calibration standards and QC samples contained in tubes with pierceable caps.In addition,post-dose samples which were collected and stored in tubes with pierceable caps have been success-fully analyzed.Direct transfer of samples from capped tubes not only protects the analyst from biohazards and repetitive-motion injury but also saves the analyst’s time.424REVIEWARTICLELIQUID CHROMATOGRAPHY±TANDEM MASS SPECTROMETRYThe need for chromatographic separation Biological samples obtained from animals or humans dosed with a drug could contain,in addition to the administered drug,other compounds that arise from the biotransformation of the drug.Thus,in vivo,a lactone drug may hydrolyze to produce the open-ring acid form or,vice versa,an acid drug may conjugate to produce the acylglucuronide,and an amine drug may oxidize to produce the N-oxide metabolite.The presence of a prodrug,which has not been completely converted to the intended drug,can also be present in post-dose samples. The electrospray ionization of the biotransformation product(or the prodrug)may produce,via in-source transformation,an ion that is identical to the parent ion of the drug.Thus,the selected-reaction monitoring(SRM) transition adopted for the quantitative determination of the drug will respond not only to the drug but also to the biotransformation product or the prodrug.Thus,in the absence of adequate chromatography to separate the drug from the biotransformation product,the LC/MS/MS method will not be speciﬁc to the drug,the analyte of interest.This problem may not be apparent during the method development and validation for the drug since,in practice,the biotransformation products of the drug are not known in the very early phase of drug development. However,bioanalysts need to keep in mind the potential for this type of interference when working with post-dose samples arising from the administration of drugs of certain functional groups.A number of examples involving drugs with a variety of functional groups have been reported(Jemal and Xia,1999;Jemal et al., 2000a,b;Naidong et al.,1999).The occurrence of the problematic in-source transfor-mation will depend on the mobile phase compositions and the mass spectrometric parameters,such as heated capillary temperature and capillary and tube lens potentials(these are the Finnigan TSQ-7000mass spectrometer parameters),which affect in-source trans-formation.It will also depend on whether the electrospray is used in the positive or negative ion mode.Clearly,not all lactone/acid pairs,drug/drug-conjugate pairs,drug/ prodrug pairs and amine/N-oxide pairs will have common SRM transitions.Future research in this area should focus on determining conditions that eliminate the occurrence of common SRM transitions.This will allow the use of methods with very short run times without the risk of interference from the drug-related compounds.It should be emphasized that the chromatographic capacity factor,k',required to achieve the desired chromato-graphic separation,will depend on the particular pair of compounds that need to be separated(Jemal and Xia, 1999).Mobile phase optimizationA good understanding of the effects of the LC mobile phase composition on the two atmospheric pressure ionization(API)techniques(APCI and electrospray)is necessary in order to optimally utilize these techniques for analysis of biological samples for analytes that cover a wide scope of chemical structures.The effects of the mobile phase on the two API techniques,especially electrospray,is not well understood and hence the behavior of a compound under a set of LC mobile phase conditions cannot be routinely predicted.However,our practical knowledge base in this area is growing thanks to the active contributions by bioanalytical chemists,as evidenced by the wide coverage of this area in a number of published papers(Oda et al.,1995;Zhou and Hamburger,1995;Schaefer and Dixon,1996;Jemal et al.,1997a,b,1998b;Mansoori et al.,1997;Newby and Mallet,1997;Jemal and Hawthorne,1999;Temesi and Law,1999;Huber and Premstaller,1999;Huber and Krajete,1999;Kamel et al.,1999).The author will brieﬂy present below two observations from the work in his laboratory that appear,at least onﬁrst glance,to be counter-intuitive or not amenable to straightforward explanations.Negative ion electrospray with formic acid in LC mobile phase.The results of an investigation,undertaken to study the effects of varying concentrations of additives in the acetonitrile/water LC mobile phase,especially formic acid and ammonium formate,on the negative ion electrospray response of a carboxylic acid drug candi-date,were very revealing(Jemal et al.,1998b).The best response was achieved with a water/acetonitrile mobile phase that contains no additives.However,under this condition,the retention time of the analyte was not adequately reproducible on repeated injections.Both formic acid and ammonium formate decreased the analyte response,but the ammonium formate caused the more severe decrease.For instance,the sensitivity achieved with a1m M formic acid mobile phase,in which the carboxylic acid was expected to be about10%in the ionized form,was approximately nine times better than the sensitivity achieved with a1m M ammonium formate mobile phase,in which the carboxylic acid was expected to be about99%in the ionized form.Thus,contrary to common perceptions,there is no simple predictable correlation between the response and the pH of the mobile phase vis-a`-vis the p K a of the analyte.Acidiﬁca-tion of the mobile phase with formic acid also had the added beneﬁt of maintaining a reasonably high capacity factor(k')for the analyte even at a relatively high acetonitrile concentration.A concentration of1m M formic acid in the mobile phase was large enough to achieve the reproducible elongated retention time for the analyte,with a loss in the analyte response of about60%Bioanalysis byLC/MS/MSonly.Theﬁnding that a1m M formic acid water/ acetonitrile appears to be the optimum mobile phase to use in the negative ion electrospray LC/MS/MS quantita-tion of a carboxylic acid compound has recently been conﬁrmed in the author’s laboratory with another drug candidate.Methanol vs acetonitrile in LC mobile phase.The dramatic difference in the positive ion electrospray response that was witnessed in the author’s laboratory when acetonitrile was substituted for methanol in the mobile phase during LC/MS method development for a new drug candidate was very surprising(Jemal and Hawthorne,1999).The compound in a water/acetonitrile mobile phase gave only a weak electrospray response in the positive ion mode with formic acid and/or ammonium acetate.The compound in a water/methanol mobile phase,in contrast,gave a signiﬁcantly higher response, approximately25-fold,with formic acid and/or ammo-nium acetate.On the other hand,acetonitrile and methanol mobile phases gave about the same response in the negative ion mode.Another noteworthyﬁnding was that for both methanol and acetonitrile mobile phases,the presence of formic acid and/or ammonium acetate enhanced the negative ion electrospray response. This was contrary to the expectation based on the previous work using the carboxylic acid compound(see above,under‘Negative ion electrospray with formic acid in LC mobile phase’).This difference between the two may be due to the fact that the methyl sulfone group of the second compound,to which the negative ion response is attributed,is a weaker acid compared to the carboxylic acid.It should also be noted that the weakly acidic methyl sulfone group,with the expected p K a of greater than10, gave a good negative ion electrospray response in methanol or acetonitrile mobile phases of neutral and acidic pH in which the compound was not expected to be in the ionized form.This is again contrary to the common perceptions.Matrix effectIn the absence of adequate chromatographic separation in a bioanalytical LC/MS/MS method,the response of the analyte in the biological matrix could be affected by endogenous coeluting components present in the original biological sample,even though those components themselves may not possess mass spectrometric response (Clarke et al.,1996;Buhrman et al.,1996;Fu et al.,1998, Matuszewski et al.,1998;Bonﬁglio et al.,1999).The basis for the matrix effect is thus the modiﬁcation of the ionization of the drug analyte by endogenous matrix components,not arising from the drug administered.The matrix effect can occur with any biological matrix (plasma,serum,blood or urine).The extent of the effect in the same matrix(eg plasma)may vary depending on the source of the matrix(eg plasma specimens from different subjects)and depending on the nature of the compound.Thus,if the internal standard used in a bioanalytical LC/MS/MS method does not behave identically to the analyte in terms of the degree of the matrix effect in the different batches of plasma,then it is conceivable that a method validated using QC samples prepared in one batch of plasma could fail when QC samples prepared in a different batch of plasma are used. The same matrix-effect problem could occur with the post-dose samples since such samples are taken from different subjects and at different time points from the same subject.Therefore,it is very important to evaluate the matrix effect during method development/validation by using different batches of plasma.The use of a stable isotope analog as the internal standard,which is expected to experience the same exact matrix effect as the analyte in any batch of plasma,will not eliminate the matrix effect but will ensure that the accuracy/precision of the method is unaffected by presence of the matrix effect. However,even with the use of a stable isotope analog internal standard,the matrix effect could signiﬁcantly lower the response,affecting the achievable lower limit of quantitation.The probability of the occurrence of the matrix effect can be reduced or eliminated by utilizing a more thorough clean-up procedure of the biological samples,modifying the chromatographic conditions,or allowing longer run times in order to enhance the chromatographic separation between the matrix-effect causing component and the analyte.Generally,a bioanalytical LC/MS/MS method based on electrospray ionization is more likely to experience a matrix effect than that based on APCI(Clarke et al.,1996). Multiplexed LC/MS/MS systemsWith the great advances made in sample preparation through the implementation of fast-ﬂow on-line extrac-tion and96-well automation,the sample preparation time that precedes LC/MS/MS can be reduced to less than30s per sample.So,there is now a renewed impetus to shift the focus to reducing the chromatographic cycle time in order to use the mass spectrometer more efﬁciently.To this effect,LC/MS/MS bioanalytical methods for multi-ple analytes with run times of only30s have recently been reported(Zweigenbaum et al.,1999;Heinig and Henion,1999)using short dwell times to accommodate the fast-eluting chromatographic peaks.However,it should be realized that the chance of getting interference from biotransformation products and drug unrelated coeluting components(matrix effect)tends to increase as the chromatographic separation capability of the system is decreased,as would be the case when the chromatographic run time is greatly reduced.A system that maintains a run time long enough to provide an acceptable chromatographic separation but allows the426REVIEWARTICLEanalysis of more than one sample during the period of a single chromatographic run time would increase the efﬁciency of the use of the mass spectrometer without compromising the chromatographic separation.Such a system has recently been put together in the author’s laboratory with existing equipment,using two integrated LC units(each unit with an autosampler and a pumping component),two analytical columns in parallel(with each connected to its own LC unit)and one mass spectrometer.This system can be used to make two successive sample injections at speciﬁed intervals within a single chromatographic run time,with a mass spectro-meter dataﬁle opened at each injection.Thus,the mass spectrometer collects data from two sample injections within a single chromatographic run time.Therefore, without compromising the chromatographic separation or the mass spectrometer dwell time,the sample throughput is increased by a factor of two.This type of approach has also been demonstrated in other laboratories.A second approach is to use a mass spectrometer equipped with several API spray probes so that each of the analytical columns in parallel will be connected to a separate spray probe and each spray will be sampled in rapid succes-sions for data acquisition by the mass spectrometer,with a separate dataﬁle for each spray.Thus,within a single chromatographic run time several samples can be injected simultaneously onto the parallel columns,one sample per column.Such a system with a four-channel multiplexed electrospray is now commercially available (Biasi,et al.,1999)and has been used with a time-of-ﬂight(TOF)mass spectrometer.Capillary LCUsing a1.0mL volume of plasma,a sensitivity of as low as10–50pg/mL is often achievable using LC/MS/MS. As more potent drugs are discovered,the need to routinely achieve even better sensitivity will become a reality.Another reason for looking into ways of improving sensitivity is to be able to use smaller volumes of plasma for analysis.This would allow less blood to be drawn during pharmacokinetic studies,which is desirable especially for human pediatric studies and for rodent non-clinical studies,allowing several serial bleeds on each animal.After the LC/MS/MS method has been optimized in terms of the composition of the LC mobile phase,mass spectrometric parameters and chromatographic peak efﬁciency,there is normally little that the bioanalyst can do to further improve the sensitivity.One area that is now attracting closer attention for this purpose is the use of capillary LC columns for bioanalytical LC/MS/MS methods(Ayrton et al.,1999;Zell et al.,1997;Abian et al.,1999;Plumb et al.,1999;Fraser et al.,1999;Zhou et al.,2000).For an electrospray mass spectrometer,which tends to behave as if it were a concentration-sensitive detector(Abian et al.,1999),a100-fold increase in the analyte peak concentration in the detector can theoreti-cally be achieved by simply reducing the diameter of the LC column from2mm,which is currently in common use,to a capillary column dimension of0.2mm.To realize this tremendous theoretical gain in on-column sensitivity,a dedicated capillary LC/MS/MS system with minimum dead volume will be required to handle the very lowﬂow-rates associated with capillary LC.To translate the excellent on-column sensitivity to equally excellent concentration sensitivity,there is a need toﬁnd a way to inject larger volumes of samples in a quicker manner than the normally lowﬂow-rates would allow. Thus,it remains to be seen if rugged high-throughput capillary LC/MS/MS bioanalytical methods,with short run times,can be developed and routinely used.REFERENCESAbian,J.,Oosterkamp,A.J.and Gelpi,parison of conventional,narrow-bore and capillary liquid chromatography/ mass spectrometry for electrospray ionization mass spectrometry: practical considerations.Journal of Mass Spectrometry34:244. Allanson,J.P.,Biddlecombe,R.A.,Jones,A.E.and Pleasance,S. 1996.The use of automated solid phase extraction in the‘96well’format for high throughput bioanalysis using liquid chromatography coupled to tandem mass spectrometry.Rapid Communications in Mass Spectrometry10:811.Ayrton,J.,Dear,G.J.,Leavens,W.J.,Mallett,D.N.and Plumb,R.S. 1997.The use of turbulentﬂow chromatography/mass spectrometry for the rapid,direct analysis of a novel pharmaceutical compound in plasma.Rapid Communications in Mass Spectrometry11:1953. Ayrton,J.,Dear,G.J.,Leavens,W.J.,Mallett,D.N.and Plumb,R.S. 1998.Optimisation and routine use of generic ultra-highﬂow-rate liquid chromatography with mass spectrometric detection for the direct on-line analysis of pharmaceuticals in plasma.Journal of Chromatography A828:199.Ayrton,J.,Clare,R.A.,Dear,G.J.,Mallett,D.N.and Plumb,R.S. 1999.Ultra-highﬂow rate capillary liquid chromatography with mass spectrometric detection for the direct analysis of pharmaceu-ticals in plasma at sub-nanogram per millilitre concentrations.Rapid Communications in Mass Spectrometry13:1657.Biasi,V.D.,Haskins,N.,Organ,A.,Bateman,R.,Giles,K.and Jarvis, S.1999.High throughput liquid chromatography/mass spectro-metric analyses using a novel multiplexed electrospray interface. Rapid Communications in Mass Spectrometry13:1165. Biddlecombe,R. A.and Pleasance,S.1999.Automated protein precipitation byﬁltration in the96-well format.Journal of Chromatography B734:257.Bonﬁglio,R.,King,R.C.,Olah,T.V.and Merkle,K.1999.The effects of sample preparation methods on the variability of the electrospray ionization response for model drug compounds.Rapid Commu-nications in Mass Spectrometry13:1175.Buhrman,D.L.,Price,P.I.and Rudewicz,P.J.1996.Quantitation of SR27417in human plasma using electrospray liquid chromatogra-phy-tandem mass spectrometry:a study of ion suppression.Journal of the American Society for Mass Spectrometry7:1099. Clarke,S.D.,Hill,H.M.,Noctor,T.A.G.and Thomas,D.1996. Matrix-related modiﬁcation of ionization in bioanalytical liquid chromatography-atmospheric pressure ionization tandem mass spectrometry.Pharmaceutical Sciences2:203.Ding,J.and Neue,U.D.1999.A new approach to the effective preparation of plasma samples for rapid drug quantitation using on-line solid phase extraction mass spectrometry.Rapid Communica-tions in Mass Spectrometry13:2151.Eeckhout,N.V.,Perez,J.C.,Claereboudt,J.,Vandeputte,R.and Peteghem,C.V.2000.Determination of tetracylines in bovine kidney by liquid chromatography/tandem mass spectrometry withBioanalysis byLC/MS/MS。

anhydrous for analysis emsure -回复

anhydrous for analysis emsure -回复Anhydrous for Analysis EMSURE: Understanding Its Importance and ApplicationsIntroduction:Anhydrous for Analysis EMSURE is a high-quality reagent widely used in various scientific disciplines and industries. It plays a crucial role in ensuring accurate and reliable analytical results. In this article, we will explore in detail the significance, properties, and applications of Anhydrous for Analysis EMSURE, thereby providing a comprehensive understanding of this essential reagent.1. What is Anhydrous for Analysis EMSURE?Anhydrous for Analysis EMSURE is a term used to describe a broad range of reagents that are completely free from water molecules. These reagents are produced using advanced techniques to remove any moisture content, ensuring maximum stability and purity. Anhydrous for Analysis EMSURE is typically available in ultra-pure forms, meeting the highest quality standards demanded by analytical laboratories.2. Importance of Anhydrous for Analysis EMSURE:2.1. Eliminating Water Interference:Water is a common impurity in many chemicals used in analytical processes. However, the presence of water can interfere with various reactions and measurements, leading to inaccurate results. Anhydrous for Analysis EMSURE eliminates this interference, allowing for precise and reliable analysis.2.2. Enhanced Stability:Water can initiate degradation processes in certain substances, affecting their stability over time. Anhydrous for Analysis EMSURE, being entirely free from water, exhibits superior stability and prolonged shelf life. This property is especially critical for long-term storage of reagents and standards.2.3. Prevention of Hydrate Formation:Certain compounds readily react with water, forming hydrates—a chemically combined form where water molecules are incorporated into the substance's crystal lattice. Anhydrous for Analysis EMSURE prevents hydrate formation, maintaining the integrity of thecompound and ensuring accurate analysis.3. Properties of Anhydrous for Analysis EMSURE:3.1. Low Water Content:Anhydrous for Analysis EMSURE reagents typically have an extremely low moisture content, often in the range of parts per million (ppm) or below. This ensures minimal water-related interference during analytical procedures.3.2. High Purity:To meet the stringent requirements of analytical applications, Anhydrous for Analysis EMSURE reagents are manufactured to possess high purity levels. They undergo rigorous quality control measures, including multiple purification steps, to eliminate impurities that could affect the accuracy of analytical results.3.3. Traceable Certification:Anhydrous for Analysis EMSURE reagents are accompanied by comprehensive certificates of analysis, detailing the quality, purity, and conformity of the product. These certificates provide traceability and help maintain consistency in analytical procedures.4. Applications of Anhydrous for Analysis EMSURE:4.1. Chemical Analysis:Anhydrous for Analysis EMSURE reagents are widely used in various chemical analyses, including titrations, spectrophotometry, chromatography, and atomic absorption spectroscopy. Their water-free nature ensures accurate measurements and consistent results.4.2. Pharmaceutical Industry:In the pharmaceutical industry, Anhydrous for Analysis EMSURE is invaluable for conducting quality control tests, formulation development, and stability studies. It helps ensure the purity and stability of drug substances and excipients, thus contributing to the production of safe and effective medications.4.3. Food and Beverage Industry:Anhydrous for Analysis EMSURE reagents find extensive utility in the food and beverage industry. They are employed for the analysis of food components, additives, and contaminants, ensuring compliance with regulatory standards and ensuring consumersafety.4.4. Environmental Analysis:In environmental analysis, Anhydrous for Analysis EMSURE reagents aid in monitoring pollution levels, assessing the quality of water and air, and investigating the impact of pollutants on the environment. The absence of water interference allows for precise measurements and reliable data.5. Conclusion:Anhydrous for Analysis EMSURE is an indispensable reagent that plays a vital role in ensuring accurate and reliable analysis across various scientific disciplines and industries. Its ability to eliminate water interference, enhance stability, and prevent hydrate formation makes it a preferred choice for a wide range of applications. By understanding the significance and properties of Anhydrous for Analysis EMSURE, researchers and analysts can confidently employ this high-quality reagent to obtain precise and consistent results.。

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Writing an essay in English without plagiarizing requires a combination of creativity, critical thinking,and a thorough understanding of the topic.Here are some steps to ensure your essay is original and wellcrafted:1.Understand the Topic:Begin by thoroughly understanding the topic you are given. This will help you form your own thoughts and arguments,which are essential for original writing.2.Research:Conduct extensive research using various sources such as books,academic journals,and reputable websites.Make sure to take detailed notes and always cite your sources to avoid accidental plagiarism.3.Develop a Thesis Statement:Your thesis statement is the central argument of your essay.It should be clear,concise,and unique to your perspective on the topic.4.Outline Your Essay:Before you start writing,create an outline to organize your thoughts and structure your essay logically.This will help you ensure that your essay flows well and that each paragraph supports your thesis.5.Write in Your Own Words:When writing your essay,always express your ideas in your own words.If you need to quote or paraphrase from a source,make sure to properly cite it to give credit to the original author.e Paraphrasing Techniques:If you need to include information from a source that is not easily rephrased,use paraphrasing techniques to put the information into your own words while maintaining the original meaning.7.Cite All Sources:Proper citation is crucial in avoiding plagiarism.Whether you are quoting,paraphrasing,or summarizing,always provide a citation to the original source.8.Revise and Edit:After writing your first draft,revise your essay to check for clarity, coherence,and consistency.Edit for grammar,punctuation,and spelling errors.e Plagiarism Detection Tools:Before submitting your essay,use plagiarism detection software to ensure that your work is original.These tools can help you identify any unintentional plagiarism.10.Get Feedback:Share your essay with peers,teachers,or mentors to get feedback on its originality and quality.They can provide valuable insights and suggestions for improvement.Remember,the goal is not only to avoid plagiarism but to produce a wellresearched, thoughtful,and original piece of writing that demonstrates your understanding and analysis of the topic.。

液质联用的帮助指南

Protein Identification withinthe Bruker Proteineer LineUsing the HCT for Protein Identification within the Bruker Proteineer LineContents1AUTOMATIC PROCEDURE OF PROTEIN IDENTIFICATION (6)2PEPTIDE SEPARATION AND WORKFLOW CONTROL BY HYSTAR 3.0 (7)3DATA ACQUISITION IN ESQUIRECONTROL 5.2 (22)4DATA PROCESSING IN DATAANALYSIS 3.2 (32)5DATABASE SEARCH (48)APPENDIX (62)CopyrightCopyright 2004Bruker Daltonik GmbHAll Rights ReservedReproduction, adaptation, or translation without prior written permission is prohibited, except as allowed under the copyright laws.Document HistoryProteineer Line Tutorial, Version 1.0 (June 2004)First edition: June 2004Printed in GermanyWarrantyThe information contained in this document is subject to change without notice.Bruker Daltonik GmbH makes no warranty of any kind with regard to this material, including, but not limited to, the implied warranties of merchantability and fitness for a particular purpose.Bruker Daltonik GmbH shall not be liable for errors contained herein or for incidental or consequential damages in connection with the furnishing, performance or use of this material.Bruker Daltonik GmbH assumes no responsibility for the use or reliability of its software on equipment that is not furnished by Bruker Daltonik GmbH.Bruker Daltonik GmbHFahrenheitstrasse 428359 BremenGermanyPhone: +49 (4 21) 22 05-420FAX: +49 (4 21) 22 05-370Email: esi.support@bdal.deInternet: www.bdal.dePreliminary remarksRelated software:Compass 1.0 for esquire / HCT incl. esquireControl 5.2 and DataAnalysis 3.2Hystar 3.0BioTools 2.2ProteinScape 1.2Mascot 1.9MetaboliteTools 1.1This document shows up the Bruker Proteineer line with respect to electrospray LC-MS/MS starting with liquid digest samples from the Bruker digester. It describes sample separation via nano-LC, data acquisition using the HCT, data processing with DataAnalysis and protein identification and results handling in ProteinScape. To guide through the software, a low amount (1 fmol) of tryptically digested enolase was used to show adequate parameters for the whole procedure (Enolase_1fmol_LCA_1-E,4_07_415.d).Table of Contents Copyright (ii)Preliminary remarks (iii)Table of Contents (iv)1AUTOMATIC PROCEDURE OF PROTEIN IDENTIFICATION (6)2PEPTIDE SEPARATION AND WORKFLOW CONTROL BY HYSTAR 3.0 (7)2.1Hardware Setup (7)2.1.1General Hardware Setup Settings (7)2.1.2Hardware Settings for Proteomic Applications (9)2.1.3Overview of Connected Ports (11)2.2Method (11)2.2.1Method Set (12)2.2.2Method Parts (13)2.2.2.1LC Methods (13)2.2.2.2Autosampler Method (16)2.2.2.3MS Acquisition and Processing Method (16)2.2.2.4Switchos Method (16)2.2.2.5BioTools (16)2.3Sample Table (17)2.4Acquisition (20)2.5Connection between Ultimate and Esquire (21)3DATA ACQUISITION IN ESQUIRECONTROL 5.2 (22)3.1New in Esquire 5.2 !! (22)3.1.1Scan Modi (22)3.1.1.1Standard Enhanced Scan (22)3.1.1.2Ultra Scan (22)3.1.1.3Peptide Scan (23)3.1.2Smart Target (23)3.2Optimizing Parameters for a Task (23)3.2.1High Sequence Coverage / High Speed (23)3.2.2Highly Sensitive Measurements / High Dynamic Range (24)3.2.3High Performance MS/MS spectra (24)3.3Data Acquisition Parameters (25)4DATA PROCESSING IN DATAANALYSIS 3.2 (32)4.1New in DataAnalysis 3.2 !! (32)4.2Loading a File (32)4.3Find Compounds and Create Mass List (34)4.3.1General parameters (34)4.3.2Parameters for FindCompounds (34)4.3.3Parameters for creating MS and MS(n) Mass List (36)4.3.4Find Compounds (37)4.3.5Changing the MS and MS(n) Mass List (38)4.4Deconvolution (39)4.5Preparing Export of the Peaklist (43)4.5.1Export options (43)4.5.2MS Charge Limitation for Database Search (43)4.5.2.1Priority 1: Charge Determination by Deconvolution (43)4.5.2.2Priority 2: Charge Limitation set in DataAnalysis (43)4.5.3MS(n) Charge Limitation for Database Search (44)4.5.4Further Export Parameters (44)4.6Use of Automation Scripts in DA (46)5DATABASE SEARCH (48)5.1Preparing BrukerDaltonicsPushDaemon and ProteinScape (48)5.2Connect Project and Database Search Method (49)5.3Mascot Search in ProteinScape (51)5.4Other Search Pathways (52)5.4.1Proteineer Line w/ Hystar and BioTools and w/o ProteinScape (52)5.4.1.1Preparing BioTools (52)5.4.1.2Viewing Results (54)5.4.2Mascot Database Searches starting from DataAnalysis (57)5.4.2.1Using an Automation Script and BioTools (57)5.4.2.2Interactive Processing and Search w/ BioTools (57)5.4.2.3Interactive Processing and Search w/o BioTools (58)APPENDIX (62)1 Automatic Procedure of Protein Identification1 Automatic Procedure ofProtein IdentificationThe following table describes where to find the required information.Steps for Proteineer line Application Manual ProteineerLine part• Software installation:o ProteinScapeo BrukerDaltonicsPushDaemono Hystar (incl. MethodSet“Methodset_Proteineer_ProteinScape.m”)o Esquire incl. DataAnalysiso (BioTools)Software manual• Create a project in ProteinScape 1.2• Spot picking• Sample table setup in DP control• Digest/ MALDI sample preparationI: From gel to digested sample• MALDI MS measurements • MALDI MS/MS measurements IIa: Using the Ultraflex for Protein Identification within the Bruker Proteineer Line• (configuration of the BioTools default method)Present manual: chapter5.4.1.1• Configuration of the hardware setup Present manual: chapter 2.1• Configuration of the BrukerDaltonicsPushDaemonPresent manual: chapter 5.1• Preparing ProteinScape in respect of searchmethodPresent manual: chapter 5.1• Starting Hystar and subsequentlyo Chromatographyo Data acquisitiono Data processingo Export to ProteinScapeo Database searchPresent manual: chapter 2.42 Peptide Separation and Workflow Control by HyStar 3.0 2 Peptide Separation andWorkflow Control byHyStar 3.0HyStar allows to control different LC Systems (single components and complete systems) from different vendors in combination with Bruker Daltonik MS systems. For details please refer to the Hystar manual. This application manual will focus on Hystar cooperating with the Ultimate nanoLC system integrated in the Bruker Proteineer line.The HyStar (or Compass) main menu (Figure 1) shows different modules. They are opened using the LMB. Relevant for proteomic applications are:• Hardware Setup• Method• Sample Table• AcquisitionFigure 1Setup2.1 Hardware2.1.1 General Hardware Setup SettingsBefore starting the measurements all hardware components are defined in HardwareSetup | System (Figure 2).This setup is saved as hss-file. Hardware setup-files located in the default path are listed at the right side of the window (not shown).2 Peptide Separation and Workflow Control by HyStar 3.0requiredFigure 2The following hardware categories are relevant for proteomic applications (please refer to chapter 2.1.3):• In the Solvent Delivery System section, choose the LC pump (Ultimate), configure the port and type the serial number (sticker with “Nr. ...” at the back of the instrument).• In the Sample Introduction section, choose the autosampler (Famos) and configure the port. Some parameters in HardwareSetup | System | SampleIntroduction | Configuration (Figure 3) are essential for the workflow and therefore have to be set correctly. They are not saved in the hardware setup file!o Tray typeo Loop sizeo Syringe height (has to be adapted for this instrument)• In the SeparationDevice/Oven section, select column (for Hystar report, PepMap C18 75 my 15 cm) and configure the oven port for acquiring column pressure data. • In the LC Detectors section choose LC Detector (Ultimate) and configure the port. • In the Mass Spectrometer section, select “esquire series” as mass spectrometer type.2 Peptide Separation and Workflow Control by HyStar 3.0Figure 32.1.2 Hardware Settings for Proteomic Applications In HardwareSetup | System| AuxiliaryDevices| General (Figure 4) select “Switchos” and “Proteineer”. Activate:• 1st HardwareSetup | System| AuxiliaryDevices| Switchos, configure the ports for valves and pump, and set the serial number (sticker with “Nr. ...” at the back of the instrument).• 2nd Proteineer. Activate HardwareSetup | System| AuxiliaryDevices| Proteineer | Settings (Figure 5).In the Proteineer Properties window (Figure 6), configure the port and set the name of the ProteinScape server.o Special case 1: For the Proteineer line without ProteinScape the ProteinScape server is not set. Instead, the location of the ProteineerXML folder is chosen.o Special case 2: For measurements without Proteineer line integration Proteineer is not activated in HardwareSetup | System|AuxiliaryDevices| General (Figure 4).2 Peptide Separation and Workflow Control by HyStar 3.0Figure 4Figure 5Figure 62.1.3 Overview of Connected PortsImportant hint: the port number set in HyStar hardware setup is the Moxa box port number plus the number of serial ports of the computer.Hystar port location Instrument port location Comment HardwareSetup | System |SolventDeliverySystem |LCPump portUltimate Pump RS-232 1HardwareSetup | System | SampleIntroduction | Autosampler port Autosampler communication S2 INHardwareSetup | System | SeparationDevice/Oven | ColumnOven port Ultimate CommunicationSolvent Organizerrequired for columnpressure profileHardwareSetup | System |LCDetector | LCDetectorportLC Detector RS-232 1HardwareSetup | System |AuxiliaryDevices | Switchos| SwitchosPump portSwitchos RS-232 1HardwareSetup | System | AuxiliaryDevices | Switchos | SwitchosValves port Switchos Communication InputHardwareSetup | System | AuxiliaryDevices | Proteineer | Settings | TransponderReader port Transponder Reader not required withoutProteineer line2.2 MethodHystar methods are accessible via Method in the Hystar main menu (Figure 1). When the menu shown in Figure 7 opens a Method Set can be selected, which comprises all Proteineer line methods (please refer to chapter 2.2.1).Figure 7Set2.2.1 MethodIn the Method Set window (Figure 8), which is accessible from the Hystar main menu, some methods can only be selected (e.g. MS acquisition, MS processing), and some can be edited (e.g. LC and Switchos method). Except for Famos default methods (e.g. Advanced Microliter Pickup) autosampler methods can be edited as well. Those are described below in more detail. A default Method Set is provided in the Hystarinstallation CD (Methodset_Proteineer_ProteinScape.m).Figure 82.2.2 Method Parts2.2.2.1 LC MethodsAs part of the Method Set (Figure 8) the LC method can be edited and selected in Hystar. Upon activating Edit the LC Method window opens.In LCMethodPart | General comments not concerning the LC-MS run itself are set (Operator, sample preparation etc.).In LCMethodPart | LCParameters (Figure 9) some parameters have to be set properly for proteomic applications. Those are listed below:General Parameters RecommendationLC pump parameters Punp Runtimegradient lengthPump flow rate To achieve flow rates of about 200 nl/min through thecolumn, the pump flow rate has to be set to 200 ul/min(due 1000:1 splitting ratio). In any case the column flowrate should be measured by connecting a µl-syringe tothe capillary, and it might be necessary to adapt it for thedesired flow.Pressure limitsShould be redueced to about 250 bar to protect thecolumn.Data acquisition Start delay Usually the first few minutes from an LC-run contain no useful data. Omitting them reduces file size.Runtime Can be used to reduce file size.From LCMethodPart | Signals 1-8 (Figure 10) choose chromatograms (BPC, EIC etc, comparable to esquireControl) and wavelengths (up to 4 for the Ultimate detector) which are displayed in Hystar acquisition view.In LCMethodPart | LCTimetable (Figure 11) the solvent gradient is defined via time, function (solvent mix, flow rate, wavelength, autozero, and oven temperature), and the respective value on the left side of the window. In the middle of the window, the gradient profile is displayed, and by moving the pointer underneath (dotted line) the exact solvent composition for any time is shown. For any time, the current solvent composition is displayed. The LC method is saved by activating SaveAs .Figure 9Figure 10Figure 112.2.2.2 AutosamplerMethodAs part of the Method Set (Figure 8) the Autosampler method can be edit ed in Hystar, except for Famos default methods (e.g. Advanced Microliter Pickup), which can only be selected.2.2.2.3 MS Acquisition and Processing MethodAs part of the Method Set (Figure 8) the MS Acquisition and Processing Method can be selected. Editing requires the esquire and DataAnalysis software, respectively.Method2.2.2.4 SwitchosAs part of the Method Set (Figure 8) the Switchos method can be edited in Hystar upon activating Edit. In the SwitchosMethod window a Switchos timetable is set up, which is defined by the solvent composition and the flow rate for each time segment (left side, Figure 12). In the middle of the window, a visual output is shown. The colors are explained in the legend on the right side.Figure 122.2.2.5 BioToolsIn BioTools 2.2 the BioTools default method is used for database search. To start the search automatically the DataAnalysis method “Method_DA_Proteineer_Mascot_BT.m” is required. It contains the automation script with command “Analysis.MascotSearch” activated (unlike Figure 42).Table2.3 SampleFigure 13Upon activating Sample Table in the Hystar main menu the dialogue shown in Figure 13 opens. For Proteineer runs (with and without ProteinScape) the transponder reader detects the transponder code automatically upon activating Autodetection, and the Sample table opens (Figure 14). Then, all the columns described below are automatically shown:• the transponder code in the window header (not shown).• checkboxes. The samples are automatically checked when the respective sample has not been identified by any Bruker mass spectrometer. For exceptions see below. • vial position• Hystar working status• sample ID• injection parameters (accessible in SampleTable | General, Figure 15) including: o number of injections per vialo injection volumeo amount (only required for quantitation experiments)• data path (set in SampleTable | General). The filename of the analysis data will be a combination of sampleID, LC-system, vial number (or XY-position), injection number (from this vial), and a counter, starting at zero when HyStar is installed for the first time. This filename will also be used for the MS data, and a name defined in the esquire control software is ignored.• Method Set if “Use Method Set” is activated (set in SampleTable | Methods, Figure 16).• Result path (data path plus data file name)• Gel code and plate code (shown in SampleTable | Details, Figure 17)For other instrumental setups, the Sample table handling is different:• Special case 1: For the Proteineer line without ProteinScapeo the samples are not automatically checked. This has to be done manually.• Special case 2: For measurements without Proteineer line integration (in addition to above)o the window header shows the data path ando all table parameters have to be set manually.Figure 14Figure 15Figure 16Figure 17If required table entries can be changed by activating the respective row and changing the parameters in the parameter window. To apply changes to a complete column, click the respective field with the RMB and choose ApplyToAll from the mouse menu.After setting all parameters Acquisition used to open the acquisition window. During a sequence run changes in the sample table are possible for unmeasured samples. To be applied the sample table has to be saved.2.4 AcquisitionThe Acquisition window is opened from the Hystar main menu or from the Sample table (Figure 18). It provides the following information:Instrument status section (main figure top)The status of each instrument defined in Hardware Setup is displayed in the top row. Colors indicate the general status (green: OK, red: failure, blue: currently in use by HyStar, yellow: busy with itself). Some instrument parameters can be changed via context menus (RMB).Spectra windows (main figure middle left)The real time displays of line and profile spectra from esquireControl are shown. Chromatogram window (main figure lower left) and chromatogram definition (main figure middle right)Those MS and UV traces are shown which have been defined in LCMethodPart | Signals 1-8 (Figure 10). To display data of different magnitudes in the same diagram, correction factors can be defined in the Additional menu (e.g. 100 for UV-absorption and 0.0001 for MS data). It is also possible to use the stretch button and drag the chromatograms by mouse to a useful size. Pressure traces do not have to be predefined to be shown.Start/Stop sectionThere are two types of start and stop buttons (Figure 18 top):• The start button with the blue rack brings up a selection window. Either the sample which has been activated in the sample table or the the complete sequence, beginning with this sample can be started.• The green triangle is used for starting mesurements without autosampler only.• The red rack stops data acquisition after finishing the gradient of the current sample.• The red square immediately stops data acquisition of the current sample, but not the sequence. The runtime continues which prevents starting a new sample without interactively stopping it.If during data acquisition the runtime predefined in the method appears to be too short to elute all compounds completely, the runtime can be increased via Options | DefineRuntime using the solvent composition defined for the end of the gradient. When the sample sequence is finished the shutdown settings defined in Acquisition | ShutdownSettings will be executed.2 Peptide Separation and Workflow Control by HyStar 3.0Figure 182.5 Connection between Ultimate andEsquireThe esquire is equipped with a Bruker Online Nanospray source using picoTIP needle (New Objective) with inner diameter 10 um at the tip and 20 um at the end.3 Data Acquisition in esquireControl 5.2Acquisitionin3 DataesquireControl 5.23.1 New in Esquire 5.2 !!The esquire 5.2 software controls the esquire HCT, which shows highly useful properties for sophisticated peptide analysis. Those are:• high MS and MS/MS sensitivity• high scan speed• high dynamic range• improved mass resolution• improved mass accuracySome new / changed parameters have to be set correctly for the optimal use of the esquire HCT. They depend on the analytical goals, e.g. mass accuracy or high speed.Modi3.1.1 Scan3.1.1.1 Standard Enhanced Scan• 16 measurement points per mass• scan speed 8100 m/z/sFor acquiring MS spectra this high-resolution mode (set in Mode window of esquireControl, Figure 22) is recommended for any type of analysis (chapter 3.2), and for high-quality MS(n) spectra it is the scan of choice for acquiring high performance spectra, e.g. for de-novo sequencing (chapter 3.2.3). Since most of the interesting peaks in the MS spectrum occur at m/z-values below 1500, a scan range from 300 to 1500 is recommended, which saves time.Scan3.1.1.2 Ultra• 5 measurement points per mass• scan speed 26000 m/z/sThis scan modus is faster than the Standard Enhanced Scan mode. It is recommended for MS(n) spectra required for high sequence coverage, high sensitivity measurements, overlapping compounds and fast gradients (e.g. for monolithic columns or for CE-MS). The scan range is set from 100 to 2800 m/z giving excellent MS/MS data despite the high speed.3 Data Acquisition in esquireControl 5.2Scan3.1.1.3 PeptidePeptide scan is more than just a scan mode: it includes a complete parameter setting for protein digest analysis using AutoMS(n):• It combines an accurate short scan for MS (Standard Enhanced Scan) with a fast, longer scan for MS/MS (Ultra Scan)• It optimizes other Advanced AutoMS(n) parameters (e.g. Exclude Sinlgy Charged Ions, ICC, scan range).Upon selecting “PeptideScan” in the MS(n) window (Figure 27) an intermediate window shows all parameters which are supposed to be changed (Figure 19). Optionally, the user can accept these changes.Figure 193.1.2 Smart TargetWhen ICC (General parameter window, Figure 21) is ON, each acquired spectrum is checked for it’s MS peak distribution. For spectra with the total intensity distributed among many MS peaks the actually set Smart target value is considered. But for spectra with only a few MS peaks the target value is reduced automatically to avoid overlading of the spectrum. Therefore, the actually set value is the highest possible ICC value for this analysis.3.2 Optimizing Parameters for a TaskCoupling LC to MS means that time for MS and MS/MS experiments is limited to peak width. In respect to the task a compromise between data quality and number of fragmented peptides is required.3.2.1 High Sequence Coverage / High SpeedHigh speed measurements are performed e.g. for Protein Sequence Confirmation or other analyses where high sequence coverage is required. They are also required for3 Data Acquisition in esquireControl 5.2analysing protein mixtures in a short time (e.g. using monolithic columns or CE-MS). Several parameters should be optimized in order to achieve this goal:• A small number of averages for MS and MS/MS scans saves time, and more precursor ions can be selected. Even “1” gives good data.• MS data should only be acquired in a small scan range covering all compounds (Standard Enhanced Scan, e.g. 300 – 1500).• MS/MS data should be acquired with high speed (Ultra Scan, 26000 m/z/s, scan range 100 – 3000)• To avoid wasting time on fragmenting solvent clusters, it is useful to select “exclude single charged“ since tryptic peptides in positive ion mode are usually at least doubly charged. Therefore, the information lost by omitting single charged ions is negligible. Furthermore, the number of useless compound mass spectra derived from solvent clusters decreases dramatically.• To save time “Prefer Double Charged Ions” should be OFF.• The maximum accumulation time should be low (e.g. 100 ms).• The number of precursor ions for AutoMS(n) should be high (e.g. 4).3.2.2 Highly Sensitive Measurements / HighDynamic RangeFor measurements at the protein identification limit (incl. measurements over a high dynamic range) a very good statistical distribution is necessary, since the proteins are identified based on only very few peptides (sometimes just one).• High quality MS/MS spectra are required, which are obtained using an increased number of averages (e.g. 4).• The number of MS averages should be 7 - 8.• Duty cycle time can be kept low by acquiring MS data only in a small scan range (e.g. 300 – 1500).• The fragmentation threshold should be low (Figure 27, e.g. 500 for the absolute threshold)• The maximum accumulation time should be set high (300 to 700 ms).• The number of precursor ions should be 1.3.2.3 High Performance MS/MS spectraE.g., de-novo sequencing requires highest quality MS/MS spectra. This can be achieved by:• A high number of MS/MS averages (e.g. 5 - 15)• A high resolution for MS/MS spectra (Standard Enhanced Scan)• Acquisition of MS(3)-data• The maximum accumulation time should be set high (300 to 700 ms).3 Data Acquisition in esquireControl 5.23.3 Data Acquisition ParametersFor acquiring LC-MS/MS data using a HPLC system as described above theparameters are described in the table. The figures show the parameters which were setfor the file Enolase_1fmol_LCA_1-E,4_07_415.d.ParameterRecommendationGeneral (Figure 20;Figure 21)Source NanoESI on-lineIon polarity usually positive (depends on peptide modifications)Ion charge controlONSmart targetAbout 100000 for esquire HCT . Higher values are possible.Max. accu. time esquire HCT : low for high speed measurements (e.g. 100),higher for high sensitivity or high performance (incl.MS(3)) measurements (> 200 ms). This value depends onthe cleanliness of instrument and HPLC.Scan range esquire HCT : This is the MS scan range. Lowering the scanrange to about 300 – 1500 m/z saves time.Averages esquire HCT : 7 - 8 for high sensitive or high performance, 1for high speed measurementsRolling averagesautomatically OFF for LC-MS/MS data acquisitionFigure 203 Data Acquisition in esquireControl 5.2Figure 21ParameterRecommendation Mode (Figure 22) Profile spectra IncludedScan Mode Standard EnhancedDivert valve to Source for Nano-LCMode – Filter (Figure 23) Gauss filter ONWidth Std/ UltraScan 0.1 – 0.2 m/zWidth Std -Enhanced 0.15 m/zWidth Std/ Maximum 0.08 - 0.1 m/zWidth Extended 0.3 m/zAssume unresolved peaks OFF (only ON forannotating unresolvedpeaks)Normalize to Accumulation time OFF (automatically OFF when ICC is ON)Mode – Configure(Figure 24)External start OFFFigure 223 Data Acquisition in esquireControl 5.2Figure 23Figure 243 Data Acquisition in esquireControl 5.2 ParameterRecommendation Tune (Figure 25) Capillary voltage 1500 – 2000 V, depends on sprayNebulizer Automatically OFF for Nano-ESI on-linesourceDry gas 10 l/min. The high flow rate preventsaspirating air.Dry temperature 150 – 200 ºCSkimmer 40 - 60 VCapillary exit not critical for esquire HCT / esquire 3000plus (incontrast to esquire 3000), 180 – 230 VOctopole 1 DC ~ 12 VOctopole 2 DC 2.5 – 3 VTrap drive Depends on peptide massOctopole RF amplitude~ 200 VLens 1 -5 - -10 VLens 2 -60 - -100 VTune – Detector & Block Voltages (Figure 26)Please refer to handbook. The Reference gain should be checked regularly.Figure 253 Data Acquisition in esquireControl 5.2Figure 26ParameterRecommendationMS(n) (Figure 27) AutoMS(n) ONn = 2 (> 3 for high performance MS(n) spectra,e.g. for de-novo sequencing)Include 300 – 1100 /1500Exclude Masses to be excluded are solventdependend and should be set by the user.Precursor Ions 4 for high speed, 1 for high sensitivitymeasurements.Abs. Threshold Above the noise peaks for high amounts, inthe noise for low sample amounts. Lowthreshold (e.g. 500) required for highsensitivity measurements.Rel. Threshold not set if the abs. threshold is setActiveExclusionONExclude after 1 – 2 spectraInclude after depends on width of chromtographic peaksSPS Only recommended for digests which containlarge peptides.MaxRes Scan Only useful to resolve higher charge states (>4). Disadvantage: time consuming.Fragmentationamplitude MS(2)0.7 V – 1 VMS(n) –Fragmentation(Figure 28)Cut-Off selection defaultSmart Frag ON, for best fragmentation resultsAmplitude 50 to 200 %。

Materials Characterization

Materials Characterization Materials characterization is a crucial process that is used to determine the properties of a material. This process involves the use of various techniques to analyze the structure and composition of a material. The information obtained from materials characterization is used to understand the behavior of a material under different conditions and to develop new materials with improved properties. Inthis article, we will discuss the importance of materials characterization, the different techniques used for characterization, and the challenges faced in materials characterization. The importance of materials characterization cannotbe overstated. It is essential for the development of new materials with improved properties. Understanding the structure and composition of a material is crucialfor determining its mechanical, thermal, electrical, and optical properties. This information is used to design materials that can withstand extreme conditions,such as high temperatures, pressure, and radiation. Materials characterization is also used to identify the causes of material failure, which is important for improving the reliability and safety of materials used in various applications. There are several techniques used for materials characterization, each with its advantages and limitations. One of the most commonly used techniques is X-ray diffraction (XRD). XRD is used to determine the crystal structure of a material. This technique involves passing X-rays through a material and measuring the diffraction pattern. The diffraction pattern provides information about the arrangement of atoms in the material. XRD is used in the development of new materials, such as semiconductors and catalysts. Another technique used for materials characterization is scanning electron microscopy (SEM). SEM is used to obtain high-resolution images of the surface of a material. This techniqueinvolves scanning a beam of electrons over the surface of a material and measuring the emitted electrons. The emitted electrons provide information about the surface topography and composition of the material. SEM is used in the analysis of materials used in microelectronics, such as integrated circuits. Transmission electron microscopy (TEM) is another technique used for materials characterization. TEM is used to obtain high-resolution images of the internal structure of a material. This technique involves passing a beam of electrons through a thinsample of a material and measuring the transmitted electrons. The transmitted electrons provide information about the internal structure of the material, such as the arrangement of atoms and defects. TEM is used in the analysis of materials used in nanotechnology, such as nanowires and nanotubes. Despite the importance of materials characterization, there are several challenges faced in this process. One of the main challenges is the complexity of materials. Many materials have complex structures and compositions that are difficult to analyze. This complexity makes it difficult to obtain accurate and reliable results from materials characterization techniques. Another challenge is the cost of materials characterization. Many techniques used for materials characterization require expensive equipment and highly trained personnel, which can be a significant barrier to their widespread use. In conclusion, materials characterization is a crucial process that is used to determine the properties of a material. This process involves the use of various techniques to analyze the structure and composition of a material. The information obtained from materialscharacterization is used to understand the behavior of a material under different conditions and to develop new materials with improved properties. Despite the challenges faced in materials characterization, it remains an essential tool for the development of new materials and the improvement of existing ones.。

材料导论中英文讲稿 (20)

Module 2 Point Defects and Crystal ImpuritesThe crystal lattices we have described so far are idealized, simplified lattices. However, solids are never perfect in their microstructure, such an idealized solid does not exist. Crystalline solids all contain large numbers of various defects or imperfections, ranging from variable amounts of impurities to missing or misplaced atoms or ions. What is a crystalline defect? A crystalline defect refers to anything that disrupts the regular crystalline structure of the solid.译文：我们之前讨论过的晶格点阵都是理想化的、简化的点阵。

然而固体的微观结构从不完美，那种完美的固体并不存在。

晶体总是存在大量的、各种各样的缺陷，包括不同含量的杂质，缺失或错位的原子或离子。

什么是晶体缺陷？晶体缺陷是指任何破坏固体晶体结构规则排布的区域。

Many of the materials’ properties are profoundly sensitive to crystal defects; the influence is not always in a bad way. Some imperfections can improve certain properties; others may degrade some properties.Just like Prof. Sir Colin Humphreys, University of Cambridge, said: “Crystals are like people, it is the defects in them which tend to make them interesting!” Defects, even in very small concentrations, can have a dramatic impact on the properties of a material. Defects bring about the Development of Semiconductor industry, Production of High-carbon steel, Toughness Reduction of Ceramics, etc.译文：材料的许多性能都对晶体的缺陷非常敏感，但是这种影响并不总是负面的。

英国CIE考试物理真题

英国cie考试物理真题道客巴巴
UNIVERSITY OF CAMBRIDGE INTERNATIONAL EXAMINATIONS General Certificate of Education Advanced Subsidiary Level and Advanced Level
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