OAX001107 MRS Structure Principle ISSUE1.0

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4.thesis structure

BODY: Developing paragraph & transitional paragraph
Support the thesis with specific evidence---an informal outline very helpful
Example: Movie-going is a problem
Concluding paragraph
Summary
Completeness, Unity and Coherence
Coherence: contextual relationship a. from general to specific (usu. Ts at the beginning) b. from specific to general (usu. Details come first, Ts at the end)
Organize and Connect the Specific Evidence
Common methods of organization: time order, emphatic order Transition ( words, phrases, sentences) Other connecting words (repeated words, pronouns, synonyms)
Essay structure
Introductory paragraph
As we know most of the material things in our daily life have to be bought with money. But money is not all powerful. There are many things which money cannot buy such as time and true love.

Picrofuchsin solution acc. to van Gieson - for mic

Intended purposeThis “Picrofuchsin solution acc. to van Gieson - for microscopy” is used for human-medical cell diagnosis and serves the histological investigation of sample material of human origin. It is a ready-to-use staining solution designed to enhance the visibility of target structures (by fixing, embed -ding, staining, counterstaining, mounting) in human-histological specimen materials, for example histological sections of e. g . the heart or the uterus in combination with other in vitro diagnostica from our portfolio.Unstained structures are relatively low in contrast and are extremely diffi -cult to distinguish under the light microscope. The images created using the staining solutions help the authorized and qualified investigator to better define the form and structure in such cases. 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No. 100591, in the van Gieson elastica staining method to detect elastic fibers in histological sections.Sample materialStarting materials are sections of formalin- or Bouin-fixed tissue embeddedin paraffin (3 µm thick paraffin sections).ReagentsCat. No. 1.00199.0500Picrofuchsin solution acc. to van Gieson 500 ml for microscopyAlso required: for nuclei staining:Cat. No. 115973 Weigert’s iron hematoxylin kit 2 x 500 ml for nuclear staining in histology for detection of elastic fibers:Cat. No. 100591 ELASTIN staining solution acc. to Weigert 500 ml for microscopySample preparationThe sampling must be performed by qualified personnel.All samples must be treated using state-of-the-art technology. All samples must be clearly labeled.Suitable instruments must be used for taking samples and their prepara -tion. Follow the manufacturer’s instructions for application / use.When using the corresponding auxiliary reagents, the corresponding in -structions for use must be observed.Deparaffinize and rehydrate sections in the conventional manner .Reagent preparationThe Picrofuchsin solution acc. to van Gieson used for staining is ready-to-use, dilution of the solution is not necessary and merely produces a deterio -ration of the staining result and its stability.In Vitro Diagnostic Medical DeviceWeigert’s iron hematoxylin staining solutionMix reagent 1 and 2 (Weigert’s solution A and Weigert’s solution B of Weigert’s iron hematoxylin kit, Cat. No. 115973) in the ratio 1 + 1.The prepared staining solution remains stable for approx. one working week.The solution must be exchanged as soon as the cell nuclei appear brown.van Gieson’s staining(nuclei staining)ProcedureStaining in the staining cellDeparaffinize histological slides in the conventional manner and rehydrate in a descending alcohol series.The slides should be allowed to drip off well after the individual staining steps, as a measure to avoid any unnecessary cross-contamination of solu -tions.The stated times should be adhered to in order to guarantee an optimal staining result.Slide with histological specimenWeigert’s iron hematoxylin staining solution 5 min Running tap water3 min Picrofuchsin solution acc. to van Gieson 30 sec Distilled water 30 sec Ethanol 96 %30 sec Ethanol 96 %30 sec Ethanol 100 % 1 min Ethanol 100 % 1 min Xylene 5 min Xylene5 minMount the xylene-wet slides with Entellan ® new and cover glass.After dehydration (ascending alcohol series) and clarification with xylene, histological samples can be mounted with the mounting agent Entellan ® new and a cover glass and can then be stored.ResultNuclei black-brown Collagen red Muscle, glia fibrils yellow Colloid, mucus, hyaline,amyloid, cornified epithelium yellow to redTrouble-shooting“Bleeding” of the specimensNon-aqueous mounting agents such as, Neo-Mount ®, Eukitt ® and others may result in the phenomenon of “bleeding” of the specimens.Mounting should hence be performed using Entellan ® or Entellan ® new.Technical notesThe microscope used should meet the requirements of a medical diagnostic laboratory.When using histoprocessors and automatic staining systems, please follow the instructions for use supplied by the supplier of the system and software.DiagnosticsDiagnoses are to be made only by authorized and qualified personnel. Valid nomenclatures must be used.This method can be supplementarily used in human diagnostics.Further tests must be selected and implemented according to recognized methods.Suitable controls should be conducted with each application in order to avoid an incorrect result.StorageStore Picrofuchsin solution acc. to van Gieson - for microscopy at +15 °C to +25 °C.1.00199.0500MicroscopyPicrofuchsin solution acc. to van Giesonfor microscopyFor professional use onlyShelf-lifePicrofuchsin solution acc. to van Gieson - for microscopy can be used up to the stated expiry date.After first opening of the bottle, the contents can be used up to the stated expiry date when stored at +15 °C to +25 °C.The bottles must be kept tightly closed at all times.The prepared Weigert’s iron hematoxylin staining solution remains stable for approx. one working week.The solution must be exchanged as soon as the cell nuclei appear brown.Capacityapprox. 500 stainings / 500 ml.Additional instructionsFor professional use only.In order to avoid errors, the application must be carried out by qualified personnel only.National guidelines for work safety and quality assurance must be followed. Microscopes equipped according to the standard must be used.Protection against infectionEffective measures must be taken to protect against infection in line with laboratory guidelines.Instructions for disposalThe package must be disposed of in accordance with the current disposal guidelines.Used solutions and solutions that are past their shelf-life must be disposed of as special waste in accordance with local guidelines. Information on dis- posal can be obtained under the Quick Link “Hints for Disposal of Microsco-py Products” at . Within the EU the currently applicable REGULATION (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 applies.Auxiliary reagentsCat. No. 100496 Formaldehyde solution 4%, 350 ml andbuffered, pH 6.9 (approx. 10% Formalin 700 ml (insolution) bottle with widefor histology neck), 5 l, 10 l,10 l Titripac®Cat. No. 100591 ELASTIN staining solution acc. 500 mlto Weigertfor microscopyCat. No. 100974 Ethanol denatured with about 1 l, 2.5 l1 % methyl ethyl ketone for analysisEMSURE®Cat. No. 103699 Immersion oil Type N acc. to ISO 8036 100-ml drop-for microscopy ping bottle Cat. No. 103999 Formaldehyde solution min. 37% 1 l, 2.5 l, 25 lfree from acidstabilized with about 10% methanoland calcium carbonatefor histologyCat. No. 104699 Immersion oil 100-ml drop-for microscopy ping bottle,100 ml, 500 ml Cat. No. 107164 Paraffin pastilles 10 kgsolidification point about 56-58°C (4x 2.5 kg)for histologyCat. No. 107961 Entellan® new 100 ml, 500 ml,rapid mounting medium 1 lfor microscopyCat. No. 108298 Xylene (isomeric mixture) 4 lfor histologyCat. No. 111609 Histosec® pastilles 1 kg, 10 kg (4xsolidification point 56-58°C embedding 2.5 kg), 25 kgagent for histologyCat. No. 115161 Histosec® pastilles (without DMSO) 10 kg (4xsolidification point 56-58°C embedding 2.5.kg), 25 kgagent for histologyCat. No. 115973 Weigert’s iron hematoxylin kit 2x 500 mlfor nuclear staining in histologyHazard classificationCat. No. 1.00199.0500Please observe the hazard classification printed on the label and the infor-mation given in the safety data sheet.The safety data sheet is available on the website and on request.Main components of the productCat. No. 1.00199.0500C.I.42685 1 g/lC6H3N3O716.6 g/l Other IVD productsCat. No. 100408 ISOSLIDE® PAS Control Slides 25 testswith reference tissue for the detection ofpolysaccharides in histological tissueCat. No. 102561 ISOSLIDE® Congo Red Control Slides 25 testswith reference tissue for the detection ofamyloid structures in histological tissueCat. No. 105174 Hematoxylin solution modified acc. 500 ml, 1 l,to Gill III 2.5 lfor microscopyCat. No. 132755 ISOSLIDE® EVG Control Slides 25 testswith reference tissue for the detection ofelastic fibers in histological tissueGeneral remarkIf during the use of this device or as a result of its use, a serious incident has occurred, please report it to the manufacturer and/or its authorised representative and to your national authority.Literature1. R omeis - Mikroskopische Technik, Editors: Maria Mulisch, Ulrich Welsch, 2015, Springer Spektrum, 19. Auflage2. W elsch Sobotta - Lehrbuch Histologie, Editor: Ulrich Welsch, 2006,ELSEVIER Urban&Fischer, 2. Auflage3. Histotechnik, Gudrun Lang, 2013 Springer Verlag, 2. Auflage4. T heory and Practice of Histological Techniques, John D Bancroft, MarilynGamble, 2008, Churchill Livingstone ELSEVIER, 6th Edition5. Laboratory Manual of Histochemistry, Linda L. Vacca, 1985, Raven Press6. B asiswissen Histologie und Zytologie, Karl Heinz Stein, Hellmut Flenker,1998, uZv, 2. Auflage7. H istological & Histochemical Methods: Theory & Practice, J. A. Kiernan,1990, Pergamon Press, 2nd Edition8. H istological and Histochemical Methods, Theory and practice, J. A.Kiernan, 2015, Scion Publishing Ltd, 5th Edition9. C onn’s Biological Stains, R.W. Horobin, J.A. Kiernan, 2002, BiologicalStain Commission Publication, 10th EditionConsult instructionsfor useTemperaturelimitationUse byYYYY-MM-DDCaution, consultaccompanying documentsManufacturer Catalog number Batch codeStatus: 2021-Jan-08Merck KGaA, 64271 Darmstadt, Germany,Tel. +49(0)6151 72-2440EMD Millipore Corporation, 400 Summit DriveBurlington MA 01803, USA, Tel. +1-978-715-4321Sigma-Aldrich Canada Co. or Millipore (Canada) Ltd.2149 Winston Park, Dr. Oakville, Ontario, L6H 6J8Phone: +1 800-565-1400。

MRS文献

European Journal of Radiology 67(2008)218–229ReviewThe principles of quantiﬁcation applied toin vivo proton MR spectroscopyGunther Helms ∗MR-Research in Neurology and Psychiatry,Faculty of Medicine,University of G¨o ttingen,D-37075G¨o ttingen,GermanyReceived 27February 2008;accepted 28February 2008AbstractFollowing the identiﬁcation of metabolite signals in the in vivo MR spectrum,quantiﬁcation is the procedure to estimate numerical values oftheir concentrations.The two essential steps are discussed in detail:analysis by ﬁtting a model of prior knowledge,that is,the decomposition of the spectrum into the signals of singular metabolites;then,normalization of these signals to yield concentration estimates.Special attention is given to using the in vivo water signal as internal reference.©2008Elsevier Ireland Ltd.All rights reserved.Keywords:MRS;Brain;Quantiﬁcation;QAContents1.Introduction ............................................................................................................2192.Spectral analysis/decomposition..........................................................................................2192.1.Principles........................................................................................................2192.2.Statistical and systematic ﬁtting errors ..............................................................................2212.3.Examples of analysis software......................................................................................2212.3.1.LCModel ................................................................................................2212.3.2.jMRUI...................................................................................................2213.Signal normalization ....................................................................................................2233.1.Principles........................................................................................................2233.2.Internal referencing and metabolite ratios............................................................................2233.3.External referencing...............................................................................................2233.4.Global transmitter reference........................................................................................2233.5.Local ﬂip angle...................................................................................................2243.6.Coil impedance effects ............................................................................................2243.7.External phantom and local reference ...............................................................................2253.8.Receive only-coils ................................................................................................2253.9.Internal water reference............................................................................................2253.10.Partial volume correction.........................................................................................2264.Calibration .............................................................................................................2275.Discussion..............................................................................................................2286.Experimental ...........................................................................................................2287.Recommendations.......................................................................................................228Acknowledgements .....................................................................................................229References .............................................................................................................229∗Tel.:+495513913132;fax:+495513913243.E-mail address:ghelms@gwdg.de .0720-048X/$–see front matter ©2008Elsevier Ireland Ltd.All rights reserved.doi:10.1016/j.ejrad.2008.02.034G.Helms/European Journal of Radiology67(2008)218–2292191.IntroductionIn vivo MRS is a quantitative technique.This statement is often mentioned in the introduction to clinical MRS studies. However,the quantiﬁcation of signal produced by the MR imag-ing system is a complex and rather technical issue.Inconsistent terminology and scores of different approaches make the prob-lem appear even more complicated,especially for beginners. This article is intended to give a structured introduction to the principles of quantiﬁcation.The associated problems and pos-sible systematic errors(“bias”)are explained to encourage a critical appraisal of published results.Quantiﬁcation is essential for clinical research,less so for adding diagnostic information for which visual inspection often may sufﬁce.Subsequent to the identiﬁcation of metabolites,its foremost rationale is to provide numbers for comparison of spec-tra from different subjects and brain regions;and–ideally–different scanners and sequences.These numbers are then used for evaluation;e.g.statistical comparison of cohorts or correla-tion with clinical parameters.The problem is that the interaction of the radio-frequency(RF)hardware and the dielectric load of the subject’s body may lead to rather large signal variations(up to30%)that may blur systematic relationships to cohorts or clinical parameters.One of the purposes of quantiﬁcation is to reduce such hardware related variation in the numbers.Thus, quantiﬁcation is closely related to quality assurance(QA).In summary,quantiﬁcation is a procedure of data processing. The post-processing scheme may require additional data acqui-sitions or extraction of adjustment parameters from the scanner. The natural order of steps in the procedure is1.acquisition and pre-processing of raw data,reconstruction ofthe spectrum(e.g.averaging and FFT),2.analysis:estimation of the relative signal for each identiﬁedmetabolite(here,proton numbers and linewidth should be taken into account),3.normalization of RF-induced signal variations,4.calibration of signals by performing the quantiﬁcationscheme on a standard of known concentration.In turn,these steps yield the metabolite signals1.for visual inspection of the displayed spectrum on the ppmscale,2.in arbitrary units,from which metabolite ratios can be cal-culated,3.in institutional units(for your individual MR scanner andquantiﬁcation scheme;these numbers are proportional to the concentration),4.in absolute units of concentration(commonly inmM=mmol/l);estimated by comparison to a standard of known concentration.The term quantiﬁcation(or sometimes“quantitation”)is occasionally used to denote singular steps of this process.In this review,it will refer to the whole procedure,and further differ-entiation is made for the sake of clarity.In practice,some these steps may be performed together.Already at this stage it should be made clear that the numbers obtained by“absolute quantiﬁca-tion”are by no means“absolute”but depend on the accuracy and precision of steps1–4.Measurement and reconstruction(step1) must be performed in a consistent way lest additional errors have to be accounted for in individual experiments.Only in theory it should be possible to correct all possible sources of variation;in clinical practice it is generally is too time consum-ing.Yet the more sources of variation are cancelled(starting with the biggest effects)the smaller effects one will be able to detect.Emphasis will be put on the analysis(the models and the automated tools available),the signal normalization(and basic quality assurance issues),and the use of the localized water signal as internal reference.2.Spectral analysis/decomposition2.1.PrinciplesThe in vivo spectrum becomes more complicated with decreasing echo time(TE):next to the singlet resonances and weakly coupled multiplets,signals from strongly coupled metabolites and baseline humps from motion-restricted macro-molecules appear.Contrary to long-TE spectra short-TE spectra should not be evaluated step-by-step and line-by-line.For exam-ple,the left line of the lactate doublet is superposed onto the macromolecular signal at1.4ppm.The total signal at this fre-quency is not of interest but rather the separate contributions of lactate and macromolecules/lipids.Differences between the two whole resonance patterns can be used to separate the metabolites;e.g.the doublet of lactate versus the broad linewidth.In visual inspection,one intuitively uses such‘prior knowledge’about the expected metabolites to discern partly overlying metabolites in a qualitative way.This approach is also used to simplify the problem to automaticallyﬁnd the metabolite resonances to order to evaluate the whole spectrum“in one go”.Comparing the resonance pattern of MR spectra in vivo at highﬁeld and short TE with those of tissue extracts and sin-gle metabolites in vitro at matchedﬁeld strengths hasﬁrmly established our‘prior’knowledge about which metabolites con-tribute to the in vivo MR spectra[1].Next to TE,theﬁeld strength exerts the second biggest inﬂuence on the appearance of in vivo MR spectra.Overlap and degeneration of binomial multiplets due to strong coupling increase at the lowerﬁeld strengths of clinical MR systems(commonly3,2,or1.5T). These effects can be either measured on solutions of single metabolites[2]or simulated fromﬁrst quantum-mechanical principles,once the chemical shifts and coupling constants(J in Hz)of a certain metabolite have been determined at sufﬁ-ciently highﬁeld[3].Motion-restricted‘macromolecules’are subject to rapid relaxation that blurs the coupling pattern(if the linewidth1/πT∗2>J)and hampers the identiﬁcation of speciﬁc compounds.These usually appear as broad‘humps’that form the unresolved baseline of short-TE spectra(Fig.1).These vanish at longer TE(>135ms).The baseline underlying the metabo-220G.Helms /European Journal of Radiology 67(2008)218–229Fig.1.Including lipids/macromolecules into the basis set.Without inclusion of lipids/macromolecules in the basis set (A)the broad “humps”at 1.3and 0.9ppm are ﬁtted by the baseline.Inclusion of lipids/macromolecules (B)resulted in a better ﬁt and a lower baseline between 2.2and 0.6ppm.The SNR improved from 26to 30.The signals at 2.0ppm partly replaced the co-resonating tNAA.The 6%reduction in tNAA was larger than the ﬁtting error (3%).This may illustrate that the ﬁtting error does not account for the bias in the model.LCModel (exp.details:6.1-0;12.5ml VOI in parietal GM,3T,STEAM,TE/TM/TR/avg =20/10/6000/64).lite signals is constituted from all rapidly relaxing signals that have not decayed to zero at the chosen TE (macromolecules and lipids),the “feet”of the residual water signal,plus possible arte-facts (e.g.echo signals from moving spins that were not fully suppressed by gradient selection).The ‘prior knowledge’about which metabolites to detect and how the baseline will look like is used to construct a math-ematical model to describe the spectrum.Selecting the input signals reduces the complexity of the analysis problem.In con-trast to integrating or ﬁtting singlet lines the whole spectrum is evaluated together (“in one go”)by ﬁtting a superposition of metabolite signals and baseline signals.Thus,the in vivo spec-trum is decomposed into the constituents of the model.Without specifying the resonances this is often too complicated to be per-formed successfully,in the sense that an unaccountable number of ‘best’combinations exist.G.Helms/European Journal of Radiology67(2008)218–229221Prior knowledge may be implemented in the metabolite basis set adapting experimental data(like in LCModel[2]),theoretical patterns simulated fromﬁrst principles(QUEST[4]),or purely phenomenological functions like a superposition of Gaussians of different width to model strongly coupled signals and baseline humps alike(AMARES[5]).The least squaresﬁt may be per-formed in either time domain[6]or frequency domain or both [7].For an in-depth discussion of technical details,the reader is referred to a special issue of NMR in Biomedicine(NMR Biomed14[4];2001)dedicated to“quantitation”(in the sense of spectrum analysis)by mathematical methods.2.2.Statistical and systematicﬁtting errorsModelﬁtting yields the contribution of each input signal. Usually Cr´a mer–Rao lower bounds(CLRB)are provided as an estimate for theﬁtting error or the statistical uncertainty of the concentration estimate.These are calculated from the residual error and the Fisher matrix of the partial derivatives of the con-centrations.In the same way,correlations between the input data can be estimated.Overlapping input signals(e.g.from glutamate (Glu)and glutamine(Gln))are inversely correlated.In this case, the sum has a smaller error than the single metabolites.The uncertainties are fairly well proportional to the noise level(both must be given in the same units).The models are always an approximate,but never a com-plete description of the in vivo MR spectrum.Every model thus involves some kind of systematic error or“bias”,in the sense of deviation from the unknown“true”concentration.Contrary to the statistical uncertainty,the bias cannot be assessed within the same model.In particular,the CRLB does not account for the bias.Changes in the model(e.g.,by leaving out a minor metabo-lite)may result in systematic differences that soon become signiﬁcant(by a paired t-test).These are caused by the pro-cess of minimizing the squared residual difference whenﬁtting the same data by two different models.Spurious artefacts or“nuisance signals”that are not included in the model will results in errors that are neither statistical nor systematic.It is also useful to know,that for every non-linear function(as used in MRS)there is a critical signal-to-noise (SNR)threshold for convergence onto meaningful values.2.3.Examples of analysis softwareA number of models and algorithms have been published dur-ing the past15years.A few are available to the public and shared by a considerable number of users.These program packages are generally combined with some automated or interactive pre-processing features,such as correction of frequency offset,zero andﬁrst order,as well as eddy-current induced phase errors.We shall in brief describe the most common programs for analysis of in vivo1H MRS data.2.3.1.LCModelThe Linear Combination Model(LCModel)[2]comes as stand-alone commercial software(/ lcmodel).It comprises automated pre-processing to achieve a high degree of user-independence.An advanced regularization ensures convergence for the vast majority of in vivo spectra.It was theﬁrst program designed toﬁt a basis set(or library)of experimental single metabolite spectra to incorporate maximum information and uniqueness.This means that partly overlap-ping spectra(again such as,Glu and Gln)are discerned by their unique features,but show some residual correlation as mentioned above.Proton numbers are accounted for,even“frac-tional proton numbers”in“pseudo-singlets”(e.g.,the main resonance of mIns).Thus,the ratios provided by LCModel refer to the concentrations rather than proton numbers.The basis set of experimental spectra comprises the prior information on neurochemistry(metabolites)as well as technique(TE,ﬁeld strength,localization technique).The non-analytic line shape is constrained to unit area and capable toﬁt even distorted lines (due to motion or residual eddy currents).The number of knots of the baseline spline increases with the noise level.Thus,the LCModel is a mixture of experimental and phenomenological features.Although the basis spectra are provided in time domain, the evaluation is performed across a speciﬁed ppm interval.LCModel comes with a graphical user interface for routine application.Optionally the water signal may be used as quan-tiﬁcation reference.Recently,lipids and macromolecular signals have been included to allow evaluation of tumour and muscle spectra.An example is shown in Fig.1.LCModel comprises basic signal normalization(see below) according to the global transmitter reference[8]to achieve a consistent scaling of the basis spectra.An in-house acquired basis set can thus be used to estimate absolute concentrations. Imported basis sets are available for a wide range of scanners and measurement protocols,but require a calibration to match the individual sensitivity(signal level)of the MR system[9]. Owing to LCModel’sﬂexibility,the basis set may contain also simulated spectra or an experimentally determined baseline to account for macromolecular signals.Such advanced applica-tions require good theoretical understanding and some practical experience.Care must be taken to maintain consistent scaling when adding new metabolite spectra to an existing basis.This is easiest done by cross-evaluation,that is evaluating a reference peak(e.g.,formate)in spectrum to be included by the singlet of the original basis and correcting to the known value.Caveat:The fact that LCModel converges does not ensure reliability of the estimates;least in absolute units(see Sections 3and4).Systematic difference in SNR may translate into bias via the baseline spline(see Fig.2).The same may be due an inconsistent choice of the boundaries of the ppm interval,partic-ularly next to the water resonance.In particular,with decreasing SNR(lower than4)one may observe more often systematically low or high concentrations.This is likely due to the errors in the feet of the non-analytical line shape,as narrow lines lead to underestimation and broad lines to overestimation.The metabo-lite ratios are still valid,as all model spectra are convoluted by the same lineshape.2.3.2.jMRUIThe java-based MR user interface for the processing of in vivo MR-spectra(jMRUI)is provided without charge222G.Helms /European Journal of Radiology 67(2008)218–229Fig.2.Systematic baseline differences between low and high SNR.Single spectrum from an 1.7ml VOI in white matter of the splenium (A)and the averaged spectra of seven healthy subjects (B).Note how the straight baseline leads to a severe underestimation of all metabolites except mIns.Differences were most prominent for Glu +Gln:3.6mM (43%)in a single subject vs.6.7mM (7%)in the averaged spectrum.(http://www.mrui.uab.es/mrui/mrui Overview.shtml ).It comes with a wide range of pre-processing features and interac-tive graphical software applications,including linear prediction and a powerful water removal by Hankel–Laclosz single value decomposition (HLSVD).In contrast to LCModel,it is designed to support user interaction.Several models for analy-sis/evaluation have been implemented in jMRUI,in particular AMARES [5]and QUEST [4].These focus on time-domain analysis,including line shape conversion,time-domain ﬁlter-ing and eddy-current deconvolution.Note that in the context of jMRUI ‘quantitation’refers to spectrum analysis.The pre-processing steps may exert a systematic inﬂuence on the results of model ﬁtting.jMRUI can handle large data sets as from time-resolved MRS,two-dimensional MRS,and spatially resolved MRS,so-called MR spectroscopic imaging (MRSI)or chemical-shift imaging (CSI).G.Helms/European Journal of Radiology67(2008)218–2292233.Signal normalization3.1.PrinciplesThe signal is provided in arbitrary units of signed integer numbers,similar to MRI,and then converted toﬂoating complex numbers.In addition to scaling along the scanner’s receiver line, the proportionality between signal strength and number of spins per volume is strongly inﬂuenced by interaction of the RF hard-ware and its dielectric and conductive load,the human body.It is the correction of this interaction that forms the non-trivial part of signal normalization.Signal normalization is mainly applied to single-volume MRS,since spatially resolved MRSI poses addi-tional technical problems that are not part of this review.For sake of simplicity we assume homogeneous conditions across the whole volume-of-interest(VOI).Normalization consists of multiplications and divisions that render the signal,S,proportional to the concentration(of spins), C.Regardless whether in time domain(amplitude)or frequency domain(area),the signal is proportional to the size V of the VOI and the receiver gain R.S∼CVR or(1a) S/V/R∼C(1b) Logarithmic(decibel)units of the receiver gain must be con-verted to obtain a linear scaling factor,R.If R can be manually changed,it is advisable to check whether the characteristic of S(R)follows the assumed dependence.If a consistent(often the highest possible)gain used by default for single voxel MRS, one does not have to account for R.Correction of V for partial volume effects is discussed below.The proportionality constant will vary under the inﬂuence of the speciﬁc sample“loading”the RF coil.The properties of a loaded transmit–receive(T/R)coil are traditionally assessed by measuring the amplitude(or width)of a speciﬁc RF pulse,e.g., a180◦rectangular pulse.This strategy may also be pursued in vivo.The signal theory for T/R coils is given in concise form in [10]without use of complex numbers.Here,we develop it by presenting a chronology of strategies of increasing complexity that have been used for in vivo quantiﬁcation.3.2.Internal referencing and metabolite ratiosBy assuming a concentration C int for the signal(S int)of ref-erence substance acquired in the same VOI,one has not to care about the inﬂuence of RF or scanner parameters:SS intC int=C(2)When using the total creatine(tCr)signal,internal referencing is equivalent to converting creatine ratios to absolute units.In early quantiﬁcation work,the resonance of tCr has been assigned to 10mM determined by biochemical methods[11].However,it turned out that the MRS estimates of tCr are about25%lower and show some spatial dependence.In addition,tCr may increase in the presence of gliosis.3.3.External referencingThe most straightforward way is to acquire a reference sig-nal from an external phantom during the subject examination, with C ext being the concentration of the phantom substance [12,13].The reference signal S ext accounts for any changes in the proportionality constant.It may be normalized like the in vivo signal:S(VR)C extS ext/(V ext R ext)=C(3)If,however,the phantom is placed in the fringeﬁeld of the RF receive coil,the associated reduction in S ext will result in an overestimation of C.Care has to be taken to mount the external phantom reproducibly into the RF coil if this bias cannot be corrected otherwise.3.4.Global transmitter referenceAlready in high-ﬁeld MR spectrometers it has been noticed that by coil load the sample inﬂuences both the transmit pulse and the signal:a high load requires a longer RF pulse for a 90◦excitation,which then yields reciprocally less signal from the same number of spins.This is the principle-of-reciprocity (PoR)for transmit/receive(T/R)coils in its most rudimentary form.It has been applied to account for the coil load effect, that is,large heads giving smaller signals than small heads [8].On MRI systems,RF pulses are applied with constant duration and shape.A high load thus requires a higher volt-age U tra(or transmitter gain),as determined during pre-scan calibration.S/V/R∼Ctraor(4a) S U tra/V/R∼C(4b)Of course,U tra must always refer to a pulse of speciﬁc shape, duration andﬂip angle,as used forﬂip angle calibration.On Siemens scanners,the amplitude of a non-selective rectangu-lar pulse(rect)is used.The logarithmic transmitter gain of GE scanners is independent of the RF pulse,but has to be converted from decibel to linear units[9].Normalization by the PoR requires QA at regular intervals,as the proportionality constant in Eqs.((4a)and(4b))may change in time.This may happen gradually while the performance of the RF power ampliﬁer wears down,or suddenly after parts of the RF hardware have been replaced.For this purpose,the MRS protocol is run on a stable QA phantom of high concentration and the concentration estimate C QA(t i)obtained at time point, t i,is used to refer any concentration C back to time point zero byC→C C QA(t0)C QA(t i)(5)An example of serial QA monitoring is given in Fig.3.224G.Helms /European Journal of Radiology 67(2008)218–229Fig.3.QA measurement of temporal variation.Weekly QA performed on stable phantom of 100mM lactate and 100mM acetate from January 1996to June 1996.The standard single-volume protocol and quantiﬁcation procedure (LCModel and global reference)were applied.(A)The mean estimated concentration is shown without additional calibration.The A indicates the state after installation,B a gradual breakdown of the system;the sudden jumps were due to replacement of the pre-ampliﬁer (C and D)or head-coil (E),and retuning of the system (F).Results were used to correct proportionality to obtain longitudinally consistency.(B)The percentage deviation from the preceding measurement in Shewhart’s R-diagram indicates the weeks when quantiﬁcation may not be reliable (data courtesy of Dr.M.Dezortov´a ,IKEM,Prague,Czech Republic).3.5.Local ﬂip angleDanielsen and Hendriksen [10]noted that the PoR is a local relationship,so they used the amplitude of the water suppression pulse,U tra (x ),that had been locally adjusted on the VOI signal.S (x )U tra (x )/V/R ∼C(6)The local transmitter amplitude may also be found be ﬁtting the ﬂip angle dependence of the local signal [14].The example in Fig.4illustrates the consistency of Eq.(6)at the centre (high signal,low voltage)and outside (low signal,high voltage)the volume headcoil.Fig.4.Local veriﬁcation of the principle of reciprocity.Flip angle dependence of the STEAM signal measured at two positions along the axis of a GE birdcage head-coil by varying the transmitter gain (TG).TG was converted from logarith-mic decibel to linear units (linearized TG,corresponding to U tra ).At coil centre (×)and 5cm outside the coil (+)the received signal,S (x ),was proportional to the transmitted RF,here given by 1/lin TG(x )at the signal maximum or 90◦ﬂip angle.Like in large phantoms,there are considerable ﬂip angle devi-ations across the human head as demonstrated at 3T in Fig.5a [15].The local ﬂip angle,α(x ),may be related to the nominal value,αnom ,by α(x )=f (x )αnom(7)The spatially dependent factor is reciprocal to U tra (x ):f (x )∼1/U tra (x ).The ﬂip angle will also alter the local signal.If a local transmitter reference is used,S (x )needs to be corrected for excitation effects.For the ideal 90◦–90◦–90◦STEAM local-ization and 90◦–180◦–180◦PRESS localization in a T/R coil,the signals areS (x )STEAM ∼M tr (x )∼C2f (x )sin 3(f (x )90◦)(8a)S (x )PRESS ∼M tr (x )∼C f (x )sin 5(f (x )90◦)(8b)The dependence of S (x )was simulated for a parabolic RF proﬁle.A constant plateau is observed as the effects of transmission and reception cancel out for higher ﬂip angles in the centre of the head where the VOI is placed.This is the reason why the global ﬂip angle method works even in the presence of ﬂip angle inhomogeneities.Note that the signal drops rapidly for smaller ﬂip angles,i.e.close to the skull.3.6.Coil impedance effectsOlder quantiﬁcation studies were performed on MR systems where the coil impedance Z was matched to 50 [8,10].Since the early 1990s,most volume head coils are of the high Q design and approximately tuned and matched by the RF load of the head and the stray capacitance of the shoulders.The residual variation of the impedance Z will affect the signal by S (x )U tra (x )/V/R ∼CZ(9)G.Helms/European Journal of Radiology67(2008)218–229225Fig.5.Flip angle inhomogeneities across the human brain.(Panel A)T1-w sagittal view showing variation in the RFﬁeld.Flip angles are higher in the centre of the brain.The contours correspond to80–120◦localﬂip angle for a nominal value of90◦.(Panel B)The spatial signal dependence of STEAM and PRESS was simulated for a parabolicﬂip angle distribution with a maximum of115%relative to the global transmitter reference.This resulted in a constant signal obtained from the central regions of the brain,and a rapid decline at the edges.Reﬂection losses due to coil mismatch are symmetric in trans-mission and reception and are thus accounted for by U tra.These are likely to occur with exceptionally large or small persons (infants)or with phantoms of insufﬁcient load.3.7.External phantom and local referenceWhen the impedance is not individually matched to50 , the associated change in proportionality must be monitored by a reference signal.In aqueous phantoms,the water signal can be used as internal reference.For in vivo applications,one may resort to an extra measurement in an external phantom[14].An additionalﬂip angle calibration in the phantom will account for local differences in the RFﬁeld,especially if the phantom is placed in the fringe RFﬁeld:SU tra(x)/(VR)S ext U tra(x ext)/(V ext R ext)C ext=C(10)This is the most comprehensive signal normalization.The com-bination of external reference and localﬂip angle method corrects for all effects in T/R coils.The reference signal accounts for changes in the proportionality,while the localﬂip angle cor-rects for RF inhomogeneity.Note also that systematic errors in S,U tra and V cancel out by division.Calibration of each individual VOI may be sped up by rapid RF mapping in three dimensions.3.8.Receive only-coilsThe SNR of the MRS signal can be increased by using sur-face coils or phased arrays of surface coils.The inhomogeneous receive characteristic cannot be mapped directly.The normaliza-tions discussed above(except Section3.2)cannot be performed directly on the received signal,as the coils are not used for trans-mission.Instead,the localized water signal may be acquired with both the receive coil and the body coil to scale the low SNR metabolite signal to obey the receive characteristics of the T/R body coil[16,17]:S rec met S bodywaterS rec water=S bodymet(11)For use with phased array coils it is essential that the metabolite and water signals are combined using consistent weights,since the low SNR of the water suppressed acquisition is most likely inﬂuenced by noise.3.9.Internal water referenceThe tissue water appears to be the internal reference of choice, due to its high concentration and well established values for water content of tissues(βper volume[18]):SS waterβ55mol/litre=C(12)It should be kept in mind that in vivo water exhibits a wide range of relaxation times,with the main component relaxing consider-able faster than the main metabolites.T2-times range from much shorter(myelin-associated water in white mater T2of15ms)to much longer(CSF,2400ms in bulk down to700ms in sulci with large surface-to-volume ratio).This implies an inﬂuence of TE on the concentration estimates.In addition,relaxation time and water content are subject to change in pathologies.Since the water signal is increasing in most pathologies(by content and relaxation),water referencing tends to give lower concentration estimates in pathologies.Ideally,the water signal should be determined by a multi-componentﬁt of the T2-decay curve[12].An easy but time-consuming way is to increase TE in consecutive fully relaxed single scans.A reliable way to determine the water sig-nal is toﬁt a2nd order polynomial through theﬁrst50ms of the magnitude signal(Fig.6).Thus,determining the amplitude cancels out initial receiver instabilities and avoids lineﬁtting at an ill deﬁned phase.If care is taken to avoid partial saturation by RF leakage from the water suppression pulses,this is consistent with multi-echo measurements using a CPMG MRI sequence [18](Fig.7).。

Apparatuses and methods for accurate structure mar

专利名称：Apparatuses and methods for accuratestructure marking and marking-assistedstructure locating发明人：Navrit Pal Singh申请号：US13925865申请日：20130625公开号：US09789462B2公开日：20171017专利内容由知识产权出版社提供专利附图：摘要：Working equipment includes a tool configured to work a structure at a working location thereon, with the structure having an applied marking at a known location with aknown relationship with the working location. A computer system is configured to determine placement of the structure, and accordingly position the tool into at least partial alignment with the working location, and which in at least one instance, the tool is aligned with a second, offset location. A camera is configured to capture an image of the structure and including the marking, and further including the second location with which the tool is aligned. And the computer system is configured to process the image to locate the working location, reposition the tool from the second location and into greater alignment with the located working location, and control the repositioned tool to work the structure at the located working location.申请人：The Boeing Company地址：Seal Beach CA US国籍：US代理机构：Womble Carlyle Sandridge & Rice LLP更多信息请下载全文后查看。

Optical properties of self-assembled quantum wires for application in infra-red detection

a rX iv:c ond-ma t/1183v2[c ond-m at.m trl-sci ]9J a n201Optical properties of self-assembled quantum wires for application in infra-red detection Liang-Xin Li,Sophia Sun,and Yia-Chung Chang Department of Physics and Materials Research Laboratory University of Illinois at Urbana-Champaign,Urbana,Illinois 61801(February 1,2008)Abstract We present theoretical studies of optical properties of Ga 1−x In x As self-assembled quantum-wires (QWR’s)made of short-period superlattices with strain-induced lat-eral ordering.Valence-band anisotropy,band mixing,and eﬀects due to local strain distribution at the atomistic level are all taken into ing realistic ma-terial parameters which are experimentally feasible,we perform simulations of the absorption spectra for both inter-subband and inter-band transitions (including the excitonic eﬀect)of this material.It is shown that the self-assembled QWR’s have favorable optical properties for application in infra-red detection with normal inci-dence.The wavelength of detection ranges from 10µm to 20µm with the length of QWR period varying from 150˚A to 300˚A .I.INTRODUCTIONQuantum-well infra-red photodetectors(QWIP’s)have been extensively studied in recent years. The main mechamism used in QWIPs is the inter-subband optical transition,because the wavelengths for these transitions in typical III-V quantum wells can be tailored to match the desired operating wavelength(1-20µm)for infra-red(IR)detection.Due to its narrow band absorption,QWIP’s are complementary to the traditional HgCdTe detectors,which utilize the inter-band absorption, and therfeore are applicable only for broad-band absorption.The main drawback of QWIP’s is the lack of normal-incidence capability,unless some processing is made to create diﬀraction gartings on the surface,which tends to reduce the responsivity of the material to the incident radiation. Because electrons in quantum wells have translational invariance(within the eﬀective-mass model) in the plane normal to the growth axis,the electron inter-subband transitions for normal-incident radiation is zero(or very small even if the coupling with other bands is considered).One way to break the translational invariance is to introduce the surface diﬀraction grating as commonly adopted in many QWIP’s fabricated today.A better(and less expensive)way to break the in-plane translational invariance is to utilize the strain-induced lateral modulation provided in self-assembled nano-structure materials.These nano-structures inculde quantum dots and quantum wires.Because the lateral modelation is formed via self-assembly,the fabrication of this type of materials will be much more eﬃcient once the optimized growth parameters are known.Hence,it will be cost eﬀective to use them for device fabrications.Self-assembled III-V QWR’s via the strain-induced lateral-layer ordering(SILO)process have attracted a great deal of attention recently.[21−23]The self-assembly process occurs during the growth of short-period superlattices(SPS)[e.g.(GaAs)2/(InAs)2.25]along the[001]direction on InP substrate.The excess fractional InAs layer leads to stripe-like islands during the initial MBE growth.[4]The presence of stripes combined with strain leads to natural phase separation as additional layers of GaAs or InAs are deposited and the structure becomes laterally modulated in terms of In/Ga composition.A self-assembled QWR heterostructure can then be created by sandwiching the laterally modulated layer between barrier materials such as Al0.24Ga0.24In0.52As(quarternary),Al0.48In0.52As (ternary),or InP(binary).[4-6]It was found that diﬀerent barrier materials can lead to diﬀerent degree of lateral composition modulation,and the period of lateral modulation ranges from100˚A to 300˚A depending on the growth time and temperature.In this paper,we explore the usefulness of InGaAs quantum wires(QWR’s)grown by the strain-induced lateral ordering(SILO)process for IR detection.Our theoretical modeling inculdes the eﬀects of realistic band structures and microscopic strain distributions by combining the eﬀective bond-orbital model(EBOM)with the valence-force-ﬁeld(VFF)model.One of the major parameters for the IR detectors is the absorption quantum eﬃciency which is directly related to the absorption coeﬃcient byη=1−e−αl whereαis the absorption coeﬃcient and l is the sample length.Thus,to have a realistic accessment of the materials for device application,we need to perform detailed calculations of the absorption coeﬃcient,taking into account the excitonic and band structure eﬀects.Both inter-subband and inter-band transitions are examined systematically for a number of structure parameters (within the experimentally feasible range)chosen to give the desired eﬀect for IR detection.It is found that the wavelengths for the inter-subband transitions of InGaAs self-assembled QWR’s range from10to20µm,while the inter-band transitions are around1.5µm.Thus,the material provides simultaneneous IR detection at two contrasting wavelengths,something desirable for appli-cation in multi-colored IR vedio camera.Several structure models with varying degrees of alloy mixing for lateral modulation are con-sidered.For the inter-band absorption,the excitonic eﬀect is important,since it gives rise a large shift in transition energy and substantial enhancement of the absorption spectrum.To study the excitonic eﬀect on the absorption spectrum for both discrete and contunuum states,we use a large set of basis functions with aﬁnite-mesh sampling in the k-space and diaginalize the exciton Hamilto-nian directly.Emphasis is put on the analysis of line shapes of various peak structures arising from discrete excitonic states of one pair of subbands coupled with the excitonic(discrete and continuum) states associated with other pairs of subbands.Weﬁnd that the excitonic eﬀect enhances theﬁrst absorption peak around1.5times and shifts the peak position by20-30meV.II.THEORETICAL MODELThe QWR structures considered here consist of8pairs of(GaAs)2(InAs)2.25short-period super-lattices(SPS)sandwiched between Al0.24Ga0.24In0.52As barriers.The SPS structure prior to strain induced lateral ordering(SILO)is depicted in Fig.1.With lateral ordering,the structure is modeled by a periodic modulation of alloy composition in layers with fractional monolayer of(In or Ga)in the SPS structure.In layers7and9(starting from the bottom as layer1),we havex In=x m[1−sin(πy′/2b)]/2for y′<b0for b<y′<L/2−bx m{1+sin[π(y′−L/2)/2b]}/2for L/2−b<y′<L/2+bx m for L/2+b<y′<L−bx m{1−sin[π(y′−L)/2b]}/2for y′>L−b,(1)where x m is the maximum In composition in the layer,2b denotes the width of lateral composition grading,and L is the period of the lateral modulation in the[110]direction.The experimental feasible range of L is between100˚A and300˚A.The length of L is controled by the growth time and temperature.In layers3and13,we havex In=0for0<y′<5L/8−bx m{1+sin[π(y′−5L/8)/2b]}/2for5L/8−b<y′<5L/8+b,x m for5L/8+b<y′<7L/8−bx m{1−sin[π(y′−7L/8)/2b]}/2for7L/8−b<y′<7L/8+b0for7L/8+b<y′<L.(2)Similar equation for x Ga in layers5and11can be deduced from the above.By varying the parameters x m and b,we can get diﬀerent degrees of lateral alloy mixing.Typically x m is between0.6and1, and b is between zero and15a[110]≈62˚A.A VFF model[13-15]is used toﬁnd the equilibrium atomic positions in the self-assembled QWR structure by minimizing the lattice energy.The strain tensor at each atomic(In or Ga)site is then obtained by calculating the local distortion of chemical bonds.Once the microscopic strain distribution in the model structure is determined,the energy levels and wave-functions of self-assembled quantum wires are then calculated within the eﬀective bond-orbital model(EBOM).Detailed description of this method can be found in Refs.24,25−26.EBOM used here is a tight-binding-like model in which two s-like conduction bands(including spin)and four valence bands with total angular momentum J=3/2(due to spin-orbit coupling of p-like orbitals with the spinor).Thus,the present model is comparable to the six-band k·p model as adpoted in Ref.?To minimize the computing eﬀort,we express the electron and hole states for the quantum wire structures in terms of eigen-states of a quantum well structure with diﬀerent in-plane wave vectors.The quantum well consists of8pairs of(GaAs)2(InAs)2short-period superlattice(SPS)plus two InAs monolayers(one inserted after the second pair of SPS and the other after the sixth pair of SPS),so the the total In/Ga composition ratio is consistent with the(GaAs)2(InAs)2.25SPS.The whole stack of SPS’s is then sandwiched between two slabs of Al0.24Ga0.24In0.52barriers.Let us denote the quantum well eigen-states as|n,k1,k2 QW where n labels the subband,k1denotes the wave vector along thewire([1¯10])direction and k2labels the wave vector in the[110]direction,which is perpendicular to the wire and the growth axis.Expanding the quantum well states in terms of bond-orbitals,we have |n,k1,k2 QW=1L α,R f n,k1,k2(α,R z)exp(ik2R2)exp(ik1R1)|uα(R) ,where L is the sample length along the wire axis,f n,k1,k2(α,R z)is the eigen-vector for the quantum well Hamiltonian and uα(R)denotes anα-like bond orbital state at site R(α=1,···,6for two s-like conduction-band and four J=3/2valence-band orbitals).Here R runs over all lattice sites within the SPS layer(well region)and AlGaInAs layer(barrier region).We then diagonalize the hamiltonian for the quantum wire(QWR)within a basis which consists of the quantum well states with k2’s separated by reciprocal lattice vectors g m=m(2π/a[110]);m= ly,|i,k1,k2 = n,m C i,k1(n,k2+g m)|n,k1,k2+g m QWwhere C i,k1(n,k2+g m)is the eigen-vector for the quantum-wire hamiltonian matrix for the i−th QWR subband at wave vector(k1,k2).In terms of the bond orbitals,we can rewrite the QWR states as|i,k1,k2 = α,R F i,k1,k2(α,R)|uα(R)whereF i,k1,k2(α,R)=1Ln,mC i,k1(n,k2+g m)f n,k1,k2+g m(α,R z)exp[i(k2+g m)R2]exp(ik1R1)is the QWR envelope function.For the laterally conﬁned states,the dispersion of bands versus k2is negligible;thus,the k2dependence can be ignored.The absorption coeﬃceient for inter-subband transitions between subbands i and j is given by αij(¯hω)=4π2e2¯hwhere n r is the refractive index of the QWR,V is the volume of the QWR sample restricted within the SPS region,f i(f j)is the Fermi-Dirac distribution function for subbnad i(j).The optical matrix elements between QWR subband states are related to those between bond orbitals byi,k1,k2|ˆǫ·p|j,k1,k2 = α,α′,τF∗i,k1,k2(α,R)F j,k1,k2(α′,R) uα(R)|ˆǫ·p|uα′(R+ τ) ,where τruns over on-site or the12nearest-neighbor sites in the fcc lattice.The optical matrix elements between bond orbitals are related to the band parameters by requiring the optical matrix elements between bulk states near the zone ceneter to be identical to those obtained in the k·p theory28.We obtain27langleu s(R)|pαuα′(R) =2a)(E p/Eg−m0/m∗e)τα;α=x,y,z,whereταis theα-th of the lattice vectorτin units of a/2,E p is the inter-band optical matrix element as deﬁned in Ref.28,and m∗e is the electron eﬀective mass.Next,we study the inter-band transitions.For this case,the excitonic eﬀect is important.Here we are only interested in the absorption spectrum near the band edge due to laterally conﬁned states.Thus,the dispersion in the k2direction can be ignored.The exciton states with zero center-of-mass momentum can then be written as linear combinations of products of electron and holes states associated with the same k1(wave vector along the wire direction).We write the electron-hole product state for the i-th conduction subband and j-th valence subband as|i,j;k1 ex=|i,k1 |j,k1≡α,β,R e,R h F i,k1(α,R e)G j,k1(β,R h)|u(α,R e)>|u(β,R h)>.The matrix elements of the exciton Hamiltonian within this basis is given byi,j,k1|H ex|i′,j′,k′1 =[E i(k1)δi,i′−E j(k1)δj,j′]− R e,R h F∗ii′(R e)v(R e−R h)G jj′(R2),(4) where v(R e,R h)=4πe2F ii′(R e)= αF∗i,k1(α,R e)F i′,k1(α,R e)describes the charge density matrix for the electrons.Similarly,G jj′(R h)= βG∗j,k1(β,R h)G j′,k1(β,R h)describes the charge density matrix for the holes.In Eq.(x),we have adopted the approximation u(α,R e)| u(β,R h)|v|u(α′,R′e) |u(β′,R′h) ≈v(R e−R h)δα,α′δβ,β′δR e,R′eδR h,R′h,since the Coulomb potential is a smooth function over the distance of a lattice copnstant,except at the origin,and the bond orbitals are orthonormal to each other.At the origin(R e=R h),the potential is singular,and we replace it by an empirical constant which is adjusted so as to give the same exciton binding energy as obtained in the eﬀective-mass theory for a bulk system.The results are actually insensitive to the on-site Coulomb potential parameter,since the Bohr radius of the exciton is much larger than the lattice constant.After the diagonalization,we obtain the excitonic states as linear combinations of the electron-hole product states,and the inter-band absorption coeﬃcient is computed according to4π2e2¯hαex(¯hω)=m0E p/2is needed,In order to obtain a smooth absorption spectrum,we replace theδfunction in Eq.(1)by a Lorentzian function with a half-widthΓ,δ(E i−E)≈Γ/{π[(E i−E)2+Γ2]}(7)Γis energy width due to imhomogeneous broadening,which is taken to be0.01eV(??).III.RESULTS AND DISCUSSIONSWe have performed calculations of inter-subband and inter-band absorption spectra for the QWR structure depicted in Fig.1with varaying degree of alloy mixing and diﬀerent lengths of period (L)in lateral modulation.Weﬁnd that the inter-subband absorption spectra are sensitive to the length of period(L),but rather insensitive to the degree of of alloying mixing.Thus,we only present results for the case with moderate alloy mixing,which are characterized by parameters b=33˚A and x m=1.0.In all the calculations,the bottom layer atoms of QWR’s are bounded by the InP substrate,while the upper layer atoms and GaAS capping layer atoms are allowed to move freely. This strucure is corresponding to the unclamped struture as indicated in reference10.For diﬀerent period length L of QWR’s,the strain distribtion proﬁles are qualitatively similar as shown in reference10.As L decreases,the hydrostatic strain in rich In region(i.e.right half zone of QWR’s unit)increase,while it decreases in rich Ga region.The bi-axial strain has the opposite change with L.The variation of hydrostatic and bi-axial strains with deducing QWR’s period reﬂects in the potential proﬁles as the diﬀerence of CB and VB band eage increases,which can be seen in Figure2.It can be easily understood that the shear strains increase when L is decuded.The potential proﬁles due to strain-induced lateral ordering seen by an electron in two QWR structures considered here(L=50a[110]and L=40a[110])are shown in Fig.2.more discussions...The conduction subband structures for the self-assembled QWRs with alloying mixing(x m=1.0 and b=8a[110])for(L=50a[110]and L=40a[110])are shown in Fig.3.All subband are grouped in pairs with a weak spin splitting(not resolved on the scale shown).For L=50a[110],the lowest three pairs of subbands are nearly dispersionless along the k2direction,indicating the eﬀect of strong lateral conﬁnement.The inter-subband transition between theﬁrst two pairs give rise to the dominant IR response at photon energy around60meV.For L=40a[110],only the lowest pair of subbands(CB1) is laterally conﬁned(with a weak k2dispersion).The higher subbands corresponding to laterally unconﬁned states(but remain conﬁned along the growth axis)and they have large dispersion versus k2.Weﬁnd three pairs of subbands(CB2-CB4)are closely spaced in energy(within5meV?).State orgion of degeneracry??The valence subband structures for the self-assembled QWRs with alloying mixing(x m=1.0and b=8a[110])for(L=50a[110]and L=40a[110])are shown in Fig.4.more discussions??A.Inter-subband absorptionInter-subband absorption spectrum is the most relavent quantity in determining the usefulness of self-assembled QWR’s for application in IR detection.Fig.5shows the calculated inter-subband absorption spectra of the self-assembled QWR structure(as depicted in Fig.1)for three diﬀerent lengths of period:L=72,50,and40a[110](approximatley300˚A,200˚A,and160˚A,respectively).In the cacluation,we assume that these QWR structures are n-type doped with linear carrier density around1.65×106cm−1(which corresponds to a Fermi level around25meV above the condunction band minimum).For comparison purposes,we show results for polarization vector along both the[110](solid curves)and[001]directions(dashed curves).The results for[1¯10]polarization are zero due to the strict translational invariance imposed in our model calculation.The peak positions for the inter-subband transition with normal incidence(with[110]polarization) are around65meV,75meV,and110meV for the three cases considered here.All these are within the desirable range of IR detection.As expected,the transition energy increases as the length of period decreases due to the increased degree of lateral conﬁnement.However,the transition energy will saturate at around110meV as we further reduce the length of period,since the bound-to-continuum transition is already reached at L=40a[110].The absorption strengths for theﬁrst two cases(L=72a[110]and L=50a[110])are reasonably strong(around400cm−1and200cm−1,respectively).They both correspond to the bound-to-bound transitions.In contrast,the absorption strength for the third case is somewhat weaker(around50 cm−1),since it corresponds to the bound-to-continuum transition.For comparison,the absorption strength for typical III-V QWIPs is around??The inter-subband absorption for the[001]polarization is peaked around??meV.The excited state involved in this transition is a quantum conﬁned state due to the Al0.24Ga0.24In0.52barriers. Thus,it has the same physical origin as the inter-subband transition used in typical QWIP structure. Although this peak is not useful for IR detection with normal incidence,it can be used as the second-color detection if one puts a diﬀraction grating on the surface as typically done in the fabrication of QWIPs.B.Inter-band absorptionThe inter-band optical transitions are important for the characterization of self-assembled QWR’s, since they are readily observable via the Photoluminescence(PL)or optical transimission experiment. For IR-detector application,they oﬀer another absorption peak at mid IR wavelengths,which can be used together with the inter-subband transitions occured at far IR wavelengths for multi-colored detection.Thus,to understand the full capability of the self-assembled QWR material,we also need to analyze the inter-band absorption.Fig.6shows the squared optical matrix elements versus k2for two self-assembled QWR’s con-sidered in the previous section(with L=50and40a[110]).For the case with L=50a[110],the optical matrix elements for both[110]and[1¯10]polarizations are strong with a polarization ratio P[1¯10]/P[110] around2.This is similar to the case with L=72a[110]as reported in Ref.xx.For the case with L=40a[110],the optical matrix elements for both[110]and[1¯10]polarizations are weak.This is due to the fact that the electrons and hole are laterally conﬁned in diﬀerent regions in the QWR,as already indicated in the potential proﬁle as shown in Fig.2(b).Thus,the inter-band absorption for this case will be uninteresting.Fig.7shows the inter-band absorption spectra for SILO QWR’s with L=72and50a[110], including the excitonic eﬀects.The PL properties of the L=72a[110]structure with alloying mixing characterized by x m=0.1and b=8a[110]has been studied in our previous paper.The QWR structure has a gap around0.74eV with a PL polarization ratio(P[1¯10]/P[110])around3.1.The absorption coeﬃcient for this structure has a peak strength around250cm−1.The binding energy for the ground state exciton labeled1-1(derived primarily from the top valence subband and the lowest conduction subband)is around20meV.Thus,the peak position in the absorption spectrum shifts from0.76meV(without the excitonic eﬀect)to0.74meV(with the excitonic eﬀect).The exctionic eﬀect also enhances the peak strength from200cm−1to250cm−1.The other peak structures(labeled 2-2,2-3,...etc.)are derived primarily from the transitions between the lower valence subbands to the higher conduction subbands).For the QWR structure with L=50a[110],we obtain similar absorption spectrum with a peak strength around400cm−1(??).The exciton binding is around40??meV,and the excitonic en-hancement factor of theﬁrst peak is around1.15(??),higer than the case with L=72a[110].This indicates that the case with L=50a[110]has stronger lateral conﬁnement for electrons and holes, which leads larger exciton binding energy and stronger excition oscillator strength(due to the largerprobability that the electron and hole appear at the same position).The secondary peaks due to excitonic states derived from higher subbands are also subtantially stronger than their counterparts in the L=72a[110]case.IV.SUMMARY AND DISCUSSIONSWe have studied the inter-subband and inter-band absorption spectra for self-assembled InGaAs quantum wires for consideration in IR-detector application.Detailed band structures,microscopic strain distributions,and excitonic eﬀects all have been taken into account.A number of realistic structures grown via strain-induced lateral ordering process are examined.Weﬁnd that the self-assembled InGaAs quantum wires are good candidate for multi-colored IR detector materials.They oﬀer two groups of strong IR absorption peaks:one in the far-IR range with wavelengths covering10 -20µm(via the inter-subband transition),the other in the mid-IR range with wavelengths centered around1.5µm(via the inter-band transition).Due the strain induced lateral modulation,the inter-subband transition is strong for normal incident light with polarization along the direction of lateral modulation([110]).This gives the self-assembled InGaAs quantum wires a distinct advantage over the quantum well systems for application in IR detection.The inter-subband absorption is found to be sensitive to the length of period(L)of laterial modulation with the aborption peak position varying from60meV to110meV as the length of period is reduced from300˚A to160˚A.However,further reduction in the length of period does not shift the absorption peak very much,as the excited states become laterally unconﬁned.For the inter-band transition,weﬁnd that the excitonsic eﬀect enhances the absorption peak strength by about10-20%,and shift the peak position by about20-40meV for the structures considered.The reduction in the period length(L)leads to stronger lateral conﬁnement,hence larger exciton binding and stronger absorprtion strength.As conclusion,this paper should give the experiment the realistic guidance in the growth of the IR detector and present the interesting physical thoughts for the theoretists and experimentists.In conclusion,we successfully demonstrated that self-assembled quantum wires are promising IR-detector materials and we provided theoretical modeling for the optical characteristics for realistic QWR structures,which can be used to guide future fabrication of quantum wire infrared detectors.REFERENCES1A.R.Adams,Electron.Lett.22,249(1986).2A.C.Gossard,P.M.Petroﬀ,W.Weigman,R.Dingle,and A.Savage,Appl.Phys.Lett.29,323 (1976);E.E.Mendez,L.L.Chang,C.A.Chang,L.F.Alexander,and L.Esaki,Surf.Sci.142, 215(1984).3Y.C.Chang and J.N.Schulmann,Appl.Phys.Lett.43,536(1983);Phys.Rev.B31,2069(1985).4G.D.Sanders,Y.C.Chang,Phys.Rev.B31,6892(1985);32,4282(1985);35,1300(1987).5R.B.Zhu and K.Huang,Phys.Rev.B36,8102(1987).6R.B.Zhu,Phys.Rev.B37,4689(1988).7Hanyou Chu and Y.C.Chang,Phys.Rev.B39(1989)108618S.T.Chou,K.Y.Cheng,L.J.Chou,and K.C.Hsieh,Appl.Phys.Lett.17,2220(1995);J.Appl. Phys.786270,(1995);J.Vac.Sci.Tech.B13,650(1995);K.Y.Cheng,K.C.Hsien,and J.N. Baillargeon,Appl.Phys.Lett.60,2892(1992).9L.X.Li and Y.C.Chang,J.Appl.Phys.846162,2000.10L.X.Li,S.Sun,and Y.C.Chang,J.Appl.Phys.,2001(in print).11Y.Miyake,H.Hirayama,K.Kudo,S.Tamura,s.Arai,M.Asada,Y.Miyamoto,and Y.Suematsu, J.Quantum electron.QE-29,2123-2131(1993).12E.Kapon,S.Simhony,J.P.Harbison,L.T.Florez,and P.Worland,Appl.Phys.Lett.56,1825-1827(1990)13K.Uomi,M.Mishima and N.Chinone,Appl.Phys.Lett.51,78-80(1987)14Y.Arakawa and A.Yariv,J.Quantum.Electron.QE-22,1887-1899(1986).15D.E.Wohlert,S.T.Chou,A.C Chen,K.Y.Cheng,and K.C.Hsieh,Appl.Phys.Lett.17,2386 (1996).16D.E.Wohlert,and K.Y.Cheng,Appl.Phys.Lett.76,2249(2000).17D.E.Wohlert,and K.Y.Cheng,private communications.18Y.Tang,H.T.Lin,D.H.Rich,P.Colter,and S.M.Vernon,Phys.Rev.B53,R10501(1996). 19Y.Zhang and A.Mascarenhas,Phys.Rev.B57,12245(1998).20L.X.Li and Y.C.Chang,J.Appl.Phys.846162,1998.21S.T.Chou,K.Y.Cheng,L.J.Chou,and K.C.Hsieh,Appl.Phys.Lett.17,2220(1995);J.Appl. Phys.786270,(1995);J.Vac.Sci.Tech.B13,650(1995);K.Y.Cheng,K.C.Hsien,and J.N. Baillargeon,Appl.Phys.Lett.60,2892(1992).22D.E.Wohlert,S.T.Chou,A.C Chen,K.Y.Cheng,and K.C.Hsieh,Appl.Phys.Lett.17,2386 (1996).23D.E.Wohlert,and K.Y.Cheng,Appl.Phys.Lett.76,2247(2000).24Y.C.Chang,Phys.Rev.B37,8215(1988).25J.W.Matthews and A.E.Blakeslee,J.Cryst.Growth27,18(1974).26G.C.Osbourn,Phys.Rev.B27,5126(1983).27D.S.Citrin and Y.C.Chang,Phys.Rev.B43,11703(1991).28E.O.Kane,J.Phys.Chem.Solids1,82(1956).Figure CaptionsFig.1.Schematic sketch of the unit cell of the self-assembled quantum wire for the model structure considered.Each unit cell consists of8pairs of(2/2.25)GaAs/InAs short-period superlattices(SPS). In this structure,four pairs of(2/2.25)SPS(or17diatomic layers)form a period,and the period is repeated twice in the unit cell.Filled and open circles indicate Ga and In rows(each row extends inﬁnitely along the[1¯10]direction).Fig.2.Conduction band and valence band edges for self-assembled QWR structure depicted in Fig. 1for(a)L=50a[110]and(b)L=40a[110].Dashed:without alloy mixing.Solid:with alloy mixing described by x m=1.0and b=8a[110].Fig.3.Conduction subband structure of self-assembled QWR for(a)L=50a[110]and(b)L=40a[110] with x m=1.0and b=8a[110].Fig.4.Valence subband structure of self-assembled QWR for(a)L=50a[110]and(b)L=40a[110] with x m=1.0and b=8a[110].Fig.5.Inter-subband absorption spectra of self-assembled QWR for(a)L=72a[110],(b)L=50a[110], and(c)L=40a[110]with x m=1.0and b=8a[110].Solid:[110]polarization,dashed:[001] polarization.Fig. 6.Inter-band optical matrix elements squared versus k1of self-assembled QWR’s for(a) L=50a[110]and(b)L=40a[110]with x m=1.0and b=8a[110].Fig.7.Inter-band absorption spectra of self-assembled QWR’s for(a)L=72a[110]and(b)L= 50a[110]with x m=1.0and b=8a[110].Solid:[110]polarization with excitonic eﬀect.Dotted:[1¯10] polarization with excitonic eﬀect.Dashed:[110]polarization without excitonic eﬀect.。

阅读scientificstructure

阅读scientificstructure
【原创实用版】
目录
1.介绍科学结构的重要性
2.阐述科学结构的定义和特征
3.讨论科学结构的应用领域
4.总结科学结构的价值和未来发展
正文
科学结构是科学知识和信息的组织方式，它反映了科学领域的基本概念、原则和理论。

在当今信息爆炸的时代，科学结构在帮助人们理解和掌握科学知识方面起着至关重要的作用。

首先，科学结构的定义和特征是理解其重要性的基础。

科学结构可以理解为科学知识的分类和组织方式，包括学科、领域、理论和方法等。

其主要特征包括层次性、系统性和动态性。

层次性指的是科学知识从基础到应用的层次结构；系统性指的是科学知识之间的相互联系和影响；动态性指的是科学知识的不断更新和演化。

其次，科学结构在各个应用领域发挥着重要作用。

在教育领域，科学结构可以帮助学生系统地学习和掌握科学知识；在科研领域，科学结构可以帮助科研人员全面了解研究领域的知识体系，从而更好地进行创新研究；在产业领域，科学结构可以帮助企业更好地应用科学知识，提高生产效率和产品质量。

最后，科学结构的价值和未来发展也是我们需要关注的。

随着科学技术的不断发展，科学结构也在不断演化和完善。

如何更好地构建和更新科学结构，以适应时代的发展和科技的进步，是我们需要深入研究和探讨的问题。

总的来说，科学结构作为科学知识和信息的组织方式，对于我们理解和掌握科学知识具有重要价值。

4 ML

目录Chapter 1 Civil Engineering (1)Section A Introduction of CivilEngineering (1)Section B Structural Engineering (4)Section C Careers in Civil Engineering (6)参考译文 (9)Grammar：专业英语的特点(Ⅰ)——文体特点 (12)Chapter 2 New Building Structure (14)Section A Steel Structure (14)Section B High Rise Building (16)Section C Attributes of Structural Steels (18)参考译文 (21)Grammar：专业英语的特点(Ⅱ)——词汇特点 (24)Chapter 3 Structure Materials (25)Section A Civil Engineering Materials (25)Section B Reinforced Concrete (29)Section C Durability of Concrete (32)参考译文 (36)Grammar：专业英语的特点(Ⅲ)——结构特点 (40)Chapter 4 Mechanical Behavior ofMaterials (43)Section A Mechanics of Materials (43)Section B Stress-strain Relationship ofMaterials (47)Section C Prestressed Concrete (50)参考译文 (54)Grammar：专业英语翻译技巧(I)——概述............................................59Chapter 5 Load and Design Process. (61)Section A Principles of Structure Design (61)Section B Earthquake (63)Section C Load Action and Propagation (66)参考译文 (68)Grammar：专业英语翻译技巧(II)——翻译的过程 (71)Chapter 6 Construction Engineering (73)Section A Construction of Concrete Works (73)Section B Construction Equipment (76)Section C Scaffolding (81)参考译文 (84)Grammar：专业英语的翻译技巧(Ⅲ)——词义引申 (89)Chapter 7 Hydraulic Structures (92)Section A Dam (92)Section B Hydraulic Engineering (95)Section C Harbours (100)参考译文 (104)Grammar：专业英语的翻译技巧(Ⅳ)——词量增减 (109)Chapter 8 Bridge Engineering (113)Section A Bridges (113)Section B Substructure of Bridge (117)Section C Bridge Rehabilitation (120)参考译文 (123)Grammar：专业英语的翻译技巧(Ⅴ)——词类转换 (127)Chapter 9 Structure Analysis andComputer Application (130)Section A Structures (130)土木工程专业英语Section B Computer-aided Design (135)Section C Fundamentals of Finite ElementAnalysis (138)参考译文 (142)Grammar：专业英语的翻译技巧(Ⅵ)——成分转换 (147)Chapter 10 Soil Mechanics andFoundation (149)Section A Characteristics of Soils (149)Section B Foundations on Slopes (153)Section C Introduction to PileFoundations (156)参考译文 (160)Grammar：专业英语的翻译技巧(Ⅶ)——重复译法 (165)Chapter 11 Highway Design (167)Section A Highway Engineering (167)Section B Subgrade and Pravement (170)Section C Highway Cross Section (174)参考译文 (177)Grammar：专业英语的翻译技巧(Ⅷ)——长句翻译 (182)Chapter 12 Traffic Engineering and UrbanTransportation Planning (184)Section A Traffic Engineering (184)Section B Traffic Planning (188)Section C Public Transport Priority (191)参考译文 (194)Grammar：专业英语的翻译技巧(Ⅸ)——特殊句型的译法(1) (198)Chapter 13 EnvironmentEngineering (203)Section A Energy and Environment (203)Section B Air Pollution (206)Section C Health Effects of Noise (209)参考译文 (212)Grammar：专业英语的翻译技巧(Ⅸ)——特殊句型的译法(2) (216)Chapter 14 Heating andRefrigeration (221)Section A Introduction of Heating andRefrigeration (221)Section B Radiant Heating on the Ground (224)Section C Solar Energy in Buildings (228)参考译文 (231)Grammar：科技论文的写作(Ⅰ)——论文体例 (235)Chapter 15 Air-conditioning andVentilating (237)Section A Air Conditioning (237)Section B Ventilation (240)Section C Ground-source Heat Pump AirCondition System (243)参考译文 (246)Grammar：科技论文的写作(II)——标题与署名 (249)Chapter 16 Emerging Role of Managementin Civil Engineering (251)Section A Construction SafetyManagement (251)Section B Construction Management (255)Section C Construction QualityManagement (260)参考译文 (264)Grammar：科技论文的写作(III)——摘要与关键词 (271)Chapter 17 Construction Planning andEstimating (274)Section A Construction Planning andSchedule Management (274)IVChapter 1Section B Construction Estimating and CostManagement (278)Section C Construction ContractManagement (282)参考译文 (287)Grammar：科技论文的写作(Ⅳ)——正文的组织与写作 (294)Chapter 18 Real Estate and InternationalConstruction (298)Section A Real Estate (298)Section B International ConstructionManagement (302)Section C Project Risk Management (307)参考译文 (312)Grammar：科技论文的写作(Ⅴ)——结语、致谢和参考文献 (319)附录A 专业英语常用词缀 (322)附录B 土木工程中常用的度量衡和单位换算 (325)附录C 土木工程网址及信息检索 (326)习题参考答案 (331)参考文献 (350)V。

基于系统功能语言学及物性系统对乔布斯的情书的语篇分析

摘要：作为在二十世纪至今大放异彩的系统功能语言学，展现了顽强的生命力和蓬勃生机。

功能语法创立的目的之一即为语篇分析提供一个理论和分析框架。

本文将以元功能中概念功能之及物性系统进行解读苹果之父史蒂夫乔布斯写给爱妻的情书。

关键词：系统功能语言学; 元功能; 及物性系统；乔布斯情诗; 语篇分析1.引言：2011年10月5日，美国痛失一位天才，他的名字将与爱迪生和爱因斯坦一同被铭记，过去的四十年中，他一次又一次预见了未来，并用热情、信念和才识把它付诸实践，使电脑等电子产品简约化、平民化，重塑了现代通讯、娱乐乃至生活的方式。

他是麦金塔计算机、ipad、iphone等风靡全球亿万人的电子产品的缔造者，他就是计算机业界与娱乐业界的标志性人物史蒂夫乔布斯。

10月23日《乔布斯传》的出版，让乔布斯写给爱妻的情书也得以留芳不朽，本文试以韩礼德系统功能语言学元功能中及物性的角度对乔布斯的这首情诗进行功能语篇分析。

2. 系统功能语言学概述作为二十世纪后半叶最具影响力的语言学理论之一，由韩礼德(m. a. k. halliday) 创造的系统功能语法在语言教学，社会语言学，语篇分析，文体学，机器翻译，等与语言相关的一系列领域产成了深远的影响。

学者黄国文（2002）在《功能语篇分析面面观》中指出：“关于语言, 功能语言学是这样认为的：（1.）语言使用是由功能决定的, (2.)语言的功能是用于创造和表达意义,（3.）意义的表达受到特定的社会和文化因素的影响和制约,（4.）使用语言的过程是个符号（semiotic）过程”。

不同于乔姆斯基（noam chomsky）的转换生成语法把理想发话人的语言能力作为研究对象，系统功能语法则把语言的实际运用作为研究的对象。

系统功能语法包括系统语法和功能语法,二者相辅相成，缺一不可。

一方面, 人们使用语言表达某种功能时要从这些系统中选择; 另一方面, 人们在语言系统中的每一次选择都是为了表达某种功能而做出的必要的选择。

organizational structure

organizational structureOrganizational structure refers to the way a company or an organization is structured. It typically identifies the top-level position, often called the Chief Executive Officer (CEO) of the organization and the reporting structure of the organization, including departmental managers and other subordinate positions. All organizations have to establish an organizational structure to assign roles, set and achieve goals and objectives, and to effectively manage resources.To create a successful organization, it is important to identify the mission and goals, the areas of responsibility and possible obstacles. An organizational structure should be designed to support and further the mission of the organization by providing structure and authority to its employees. This structure should also provide guidelines for decision-making, communication, collaboration and resource allocation. Additionally, it should be flexible and allow for growth.Organizational structures are typically divided into categories such as centralized, decentralized and matrix. A centralized structure means that decision-making power is concentrated in the hands of one individual or a few individuals who are ultimately responsible for the overall success of the organization. A decentralized structure gives decision-making power to the employees, or to several department or section heads. The matrix structure combines both centralized and decentralized approaches by providing specific tasks to individuals and teams.Organizational structures can also be further divided into formal and informal structures. A formal organizational structure is characterized by a clear chain of command and defined roles and responsibilities. An informal organizational structure does not have clearly defined roles and responsibilities; rather, it relies on the norms, values and customs that contribute to the shared beliefs and values of the organization.No matter what structure an organization chooses to adopt, it should ensure that it is appropriate for the business, that it supports the mission and goals of the organization, and that it allows for innovation and growth.。

Functionalstructure

Functional structure:A company organized with a functional structure groups people together into functional departments such as purchasing, accounts, production, sales, marketing. These departments would normally have functional heads who may be called managers or directors depending on whether the function is represented at board level.Though titles vary depending on the organization, each unit in a functional structure includes employees who are trained to perform specialized tasks. The top tier of a functional structure may be a company president. The second tier may be comprised of several vice presidents, each positioned in an area of expertise, such as vice president of manufacturing or vice president of sales and marketing. Below each vice president may be one or more directors with abilities in the same specialized area as that particular vice president. The directors might be followed by managers, and the managers followed by assistant managers, all possessing skills in the same area as those preceding them.The larger the organization, the more challenging it is for each specialized group to clarify how individual departments ultimately connect and contribute to the business succeeding as a unified company. For this reason, the functional structure is most successful in organizations that are small to medium in size and only deal with a few product types and servicesStrengths:1) Functional groups are reservoirs of skills and knowledge in their areas of expertise.2) Functional groups’ well-established communication processes and decision-making procedures provide timely and consistent support for the group’s projects.3) Functional groups provide people with a focused and supportive job environment.Weaknesses:1) Because each unit in a functional structure is focused on its own area of specialty, it might be lacking a broad view of the company if there isn't consistent integration of and communication between departments.2) Units may have limited flexibility in problem-solving, making changes or responding quickly to customer demands or needs since the final decision-making authority rests with the top level of management.3) It is not good for innovation since a company is separated into different departments according to their functions.Matrix structure:Definition: a type of organizational management in which people with similar skills are pooled for work assignments. For example, all engineers may be in one engineering department and report to an engineering manager, but these same engineers may be assigned to different projects and report to a different engineering manager or a project manager while working on that project. Therefore, each engineer may have to work under several managers to get their job done.The matrix structure is often viewed as being the most suitable for project work relating to new product development. Many projects are often interdisciplinary and requiring staff and resources from a number of different functional areas, hence a matrix structure would be most suitable.Remember that the matrix structure is a constantly changing form of management. As projects are created and dissolved, workers are redistributed. A matrix structure can be temporary, lasting only as long as a project, or it can be an ongoing approach to the management.Advantages:1) The matrix structure makes it possible to assign specialized resources to projects when needed. For example, Individuals can be chosen according to the needs of the project.2) it is beneficial for information sharing. Because people work on more than one project at a time, they can keep one another informed about the progress in other areas of the company.3) Few people need to be hired because workers are shared among different projects. Disadvantages:1) A conflict of loyalty between line managers and project managers over the allocation of resources.2) Projects can be difficult to monitor if teams have a lot of interdependence.3) Costs can be increased if more managers (project managers) are created through the use of project teams.Line structure:This is the kind of structure that has a very specific line of command. The approvals and orders in this kind of structure come from top to bottom in a line, hence the name line structure. This kind of structure is suitable for smaller organizations like small accounting firms and law offices. This is the sort of structure that allows for easy decision-making and is also very informal in nature. They have fewer departments, which makes the entire organization a very decentralized one.A wide variety of positions exist within a line-and-staff organization. Some positions are primary to the company's mission, whereas others are secondary—in the form of support and indirect contribution. Although positions within a line-and-staff organization can be differentiated in several ways, the simplest approach classifiesthem as being either line or staff.Staff positionJob position within a chain of command of an organization that has the responsibility of providing information and advice to personnel in the line position.Staff positions serve the organization by indirectly supporting line functions. Staff positions consist of staff personnel and staff managers. Staff personnel use their technical expertise to assist line personnel and aid top management in various business activities. Staff managers provide support, advice, and knowledge to other individuals in the chain of command.Line positionJob position within a chain of command of an organization that has the responsibility for decisions involving the use of the organization's resources to generate revenue and to achieve its other objectives.A line position is directly involved in the day-to-day operations of the organization, such as producing or selling a product or service. Line positions are occupied by line personnel and line managers. Line personnel carry out the primary activities of a business and are considered essential to the basic functioning of the organization.Line managers make the majority of the decisions and direct line personnel to achieve company goals. An example of a line manager is a marketing executive. Line authority:Line authority flows down the chain of command. For example, line authority gives a production supervisor the right to direct an employee to operate a particular machine, and it gives the vice president of finance the right to request a certain report from a department head. Therefore, line authority gives an individual a certain degree of power relating to the performance of an organizational task.Staff authority:Staff authority is the right to advise or counsel those with line authority. Decentralization:Delegation of decision-making to the subunits of an organization. It is a matter ofdegree. The lower the level where decisions are made, the greater is the decentralization. Decentralization is most effective in organizations where subunits are autonomous and costs and profits can be independently measured.The benefits of decentralization include:(1) Decisions are made by those who have the most knowledge about local conditions;(2) Greater managerial input in decision- making has a desirable motivational effect;(3) Managers have more control over results.The costs of decentralization include:(1) Managers have a tendency to look at their division and lose sight of overall company goals;(2) There can be costly duplication of services;(3) Costs of obtaining sufficient information increase。

Electronic structure of LaFe1-xCoxAsO from first principle calculations

Electronic structure of LaFe1-x Co x AsO from first principle calculationsHaiming Li1, Jiong Li1, Shuo Zhang1,2, Wangsheng Chu1, Dongliang Chen1 and Ziyu Wu1,2,3,*1Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, P. R. China2National Synchrotron Radiation Lab, University of Science and Technology of China, Hefei 230026, P. R. China3Theoretical Physics Center for Science Facilities (TPCSF), Chinese Academy of Sciences, Beijing 100049, P. R. ChinaBased on the first-principles calculations, we have investigated the geometry, binding properties, density of states and band structures of the novel superconductor LaFe1-x Co x AsO and its parent compounds with the ZrCuSiAs structure. We demonstrate that La–O bond and TM-As (TM=Fe or Co) bond are both strongly covalent, while the LaO and TMAs layers have an almost ionic interaction through the Bader charge analysis. Partial substitution of iron with cobalt modify the Fermi level from a steep edge to a flat slope, which explains why in this system Co doping suppresses the spin density wave (SDW) transition.PACS numbers: 74.25.Jb, 74.70.-b, 71.20.-b* Electronic address: wuzy@IntroductionFollowing the discovery of high-T c copper oxides 1 and MgB 22, the appearance of superconductivity in quaternary pnictide-oxides triggered new researches and stimulated the entire scientific community. Of this new class of compounds, iron- and nickel-based layered compounds LaFePO and LaNiPO were the first systems that showed superconductivity although with a low transition temperature T 34c : 5 K and 3 K, respectively. In the last months, the superconductivity transition temperature raised first 26 K in the LaFeAsO by a partial substitution of O with F atoms (LaFeAsO 1-x F x ), and 43 K at high pressure . The progress encouraged researchers to look for superconductivity in other FeAs-based materials and other families of FeAs quaternary pnictide-oxides with Ce, Pr, Nd, Sm, Gd replacing La were identified with superconducting temperature higher than 50 K . The quaternary pnictide-oxides LaFeAsO belong to a tetragonal family with the ZrCuSiAs type structure and the space group of P4/nmm . They consist of alternative stacking of FeAs tetrahedral layers and LaO tetrahedral layers along the c-axis. These two layers are supposed to be positively and negatively charged, respectively so that the LaO layer mainly acts as a donor and superconducting pairing is supposed to occur in the FeAs layers. The parent materials without doping undergo a weakly first order structural phase transition from tetragonal (P4/nmm) to orthorhombic (Cmma), and then followed by antiferromagnetic spin density wave (SDW) transition at about 140 K . More recently, it has been reported that other free oxygen FeAs-based compounds: Ba 567-1213141-x K x Fe 2As 215-17, Sr 1-x K x Fe 2As 218, Eu 1-x K x Fe 2As 219, Ca 1-x Na x Fe 2As 220, Li 0.6FeAs may exhibit a similar superconducting behavior as the LaFeAsO 211-x F x , with T c of 38 K, 38 K, 32 K, 20 K and 18 K, respectively. The similar SDW instablity is also observed in these systems. The maximum T c achieved up today is 56 K by with the partial substitution of Gd by Th in the GdFeAsO . At the moment it is not possible to predict if T 22c in FeAs based compounds will continue to grow as rapidly as happened in cuprate superconductors, nevertheless this unexpected discovery will be certainly useful to better understand the physics of high-T c superconductor materials. The suppression of SDW transition is actually believed to be an important prerequisite for the appearance of superconductivity in these doped FeAs-based materials .8, 14, 23, 24In general, superconductors are doped in the donor layers by nonmagnetic atom, as in the case of La 2-x Ba x CuO 41 and Na x CoO 2·yH 2O 25, etc.. Indeed, it was well established that doping by magnetic atoms in a conducting layer generally destroys Cooper pairs and induces large distortion in the layer. However, a new type of FeAs based superconductor: the LaFe 1-x Co x AsO with T c ~ 10 K is just theresult of a real doping by a magnetic atom (cobalt) in the superconducting-active FeAs layer, and the doping system suppress the SDW transition26, 27. In addition, Co-doped SrFe2As228 and BaFe2As229 show also superconductivity at T c ~ 20 K and 22 K, respectively. The evidence of Co-doping inducing superconductivity has challenged our knowledge between superconductivity and magnetic interactions. Additional accurate investigations are then mandatory.Theoretical investigations in the frames of the density functional theory successfully reproduced the slope of the density of states (DOS) near the Fermi level, and gave many reasonable explanations on the interaction of FeAs-based superconductors24, 30-35. In this study, we focus through first principle calculations, to both geometry and electronic structure near the Fermi level of the new iron-pnictide system LaFe1-x Co x AsO, and explain why in this system Co doping suppresses the spin density wave (SDW) transition.Calculating methodThe present calculations have been performed using the first-principles plane-wave Vienna ab initio simulation package (V ASP)36, 37 while the exchange-correlation is described by the Perdew-Burke-Ernzerhof general gradient approximations (GGA)38. The projector augmented wave (PAW) method in its implementation of Kresse and Joubert was used to describe the electron-ion interaction39, 40.The La (5s25p65d16s2), Fe (3d64s2), Co (3d74s2), As (3s23p3), O (2s22p4) are treated as valence states. To ensure an enough convergence, the energy cutoff was chosen to be 600 eV, while the Brillouin zone was sampled with a mesh of 16×16×8 k points generated by the Monkhorst–Pack41 scheme for the pure LaFeAsO and LaCoAsO. Doping was modeled with a supercell of the parent material with Co atoms, with well converged grid k points in calculations. A first-order Methfessel–Paxton method with σ=0.2 eV has been considered for the relaxation42. The crystal cell and the internal parameters were optimized using the conjugate gradient method until the total forces on each ion was less than 0.02 eV/Ǻ. The density of states (DOS) calculations were performed using the tetrahedron method with the Blöchl corrections43.Results and discussionI Pure LaFeAsO and LaCoAsO systemsA. Crystal structureLaFeAsO and LaCoAsO crystallize in a tetragonal structure with the space group P4/nmm. Corresponding Wyckoff positions of the space group for different atoms are La(2c) (0.25, 0.25, z La), Fe or Co(2b) (0.75, 0.25, 0.5), As(2c) (0.25, 0.25, z As), and O(2a) (0.75, 0.25, 0), where z La and z As are both internal coordinates. Partial replacement of Fe with Co atoms in the LaFeAsO structure generates the LaFe1-x Co x AsO whose crystal structure is displayed in Fig. 1.Table 1 reports the calculated lattice constants and the internal coordinates of both LaFeAsO and LaCoAsO together with available experimental data. The experimental determinations are consistent and in good agreement with our calculations. The existing differences among experimental data and calculations may be addressed to the poor description of the exchange-correlation interaction by both LDA and GGA approaches in density functional theory. Both LaFeAsO and LaCoAsO systems are layered structure with alternating stack of LaO and FeAs (CoAs) layers. FeAs (CoAs) layers are conducting layers formed by a square lattice sheet of Fe (Co) ions coordinated by As above and below the plane to form face sharing FeAs4 (CoAs4) tetrahedra24. The Fe (Co) atoms coordinate tetrahedrally with four As atoms with a bond length of 2.34 Ǻ, forming a distorted tetrahedra with two different As-Fe-As (As-Co-As) angles of 118.86˚ and 104.99˚ (119.58˚ and 104.67˚), in agreement with results of Refs. 5, 14, 44. Every Fe (Co) has also four neighboring Fe (Co) atoms within the same layer with a bond length of about 2.85 Ǻ (2.86 Ǻ).B. Electronic structureThe LaTMPnO (Pn=P, As) systems crystallize in quasi two-dimensional structure and the LaO and TMPn layers interact through an ionic interaction. For a deeper understanding of the framework of LaFeAsO and LaCoAsO systems, we performed also a Bader analysis of the charge density45, 46. Table 2 compares the charges of each atom using the Bader analysis with the pure ionic picture. It addresses that the large charge transfer of both La-O bonds and TM-As bonds, which is quite different from the ionic description, are strong chemical bonding. Moreover, the charge transfer between LaO and TMAs layers is considerably smaller, which implies an ionic bonding between layers. Similar conclusions have also addressed in both LaFePO47 and LaNiPO31.The density of states of LaFeAsO and LaCoAsO compound was calculated. Fig. 2 shows that the DOS lineshape of these compounds is quite similar and in the case of LaFeAsO our DOS is in goodagreement with previous reports24, 30, 48.It is well recognized that electrons near the Fermi surface contribute to the superconductivity. From the analysis of Fig. 2 around the Fermi level in the range -3 eV to 2 eV we found Fe 3d states while As 4p and O 2p states appear at lower energies, from -2 eV down to -5 eV. Actually As 4p states may hybridize with Fe 3d near the Fermi surface while the O 2p contribution can be neglected. In the Co doped system, Co2+ (3d7) ions contribute with one more electron respect to Fe2+ (3d6) and the Fermi level is pushed up of about 0.7 eV. We can see that the DOS of LaFeAsO near the Fermi energy is monotonous with the energy, while in the LaCoAsO the Fermi level locates near the t2 peak, and the Fermi level both locate at the steep edge. We may address that the changes near the Fermi level are correlated to the spin density wave transition in the LaFeAsO near 150 K5, 14, 49 and in the LaCoAsO at 66 K44 which make these parent materials out from superconductivity.Both Fe and Co 3d states split by the exchange interaction and the crystal field and, in the ideal TMAs tetragonal structure, the crystal field due to the four nearest neighbor As atoms splits the fivefold degenerate d states of a free TM atom into a doubly degenerate e band (d z2 and d x2-y2) and a triply degenerate t2 band (d xy, d xz and d yz). Similarly, in TM-doped GaN diluted magnetic semiconductor systems, the large interaction among TM t2 states and N 2p states pushes up the t2 band above the e band50-52. However, from the orbital resolved DOS of Fe and Co 3d states in the parent compounds shown in Fig. 3, all the fivefold degenerate d states contributes around the Fermi energy indicating that the hybridization and the crystal field are relatively small in the distorted tetrahedral TMAs system. Moreover, the complex distributions of TM 3d states are influenced by the TM-TM direct interactions with bond length of 2.85 Ǻ in the same layers. The complicate distribution of Fe or Co 3d states is different from CuO2 planes. In a comparison with the copper-oxide superconductor systems, a Cu2+ occupies a planar fourfold square site and the DOS at the Fermi level are mainly correlated with the d x2-y2 orbital, suggesting a different superconductive mechanism between cuprate and new FeAs based superconductors.The band structures of LaFeAsO and LaCoAsO are showed in Fig 4. The band structure of LaFeAsO is in good agreement with previous data24, 48, and the lack of dispersion along both Г-Z and A-M directions suggests a quasi 2-D structure, in consistent with the Bader charge analysis. The band shape of these compounds is quite similar, except at the Fermi energy where it is pushed up about 0.7 eV in the LaCoAsO, in agreement with the DOS data. To clarify the role of electrons at the Fermi surface wecompare in Fig 5 the band structures of LaFeAsO and LaCoAsO in the range -0.6 eV to 0.6 eV. The dispersion near Fermi level between these two parent compounds is greatly different as a result of the Fermi level shift, which may result in different superconductivity mechanics.II LaCo x Fe1-x AsO systemIn the experiment reported by Wang et al.27, Co replaces Fe in a single crystalline phase as shown by XRD. According to our lattice and internal parameter relaxation steps, we claim that the doped system is energetically stable for the partial substitution of cobalt for iron. We find that the two kinds of As-Co-As angels change to 107.41˚ and 113.68˚, trend to less distorted tetrahedral than the parent compounds. The Bader analysis data are very close to the pure phase.As discussed for the parent materials, the Fermi level will push up about 0.7 eV for the replacement of Co for Fe in LaFeAsO. Thus, it is expected that Fermi level would locate at the range in the doping system. In Fig. 6 we compare the total DOS of both LaCo0.125Fe0.875AsO and LaCo0.25Fe0.75AsO and those of the pure LaFeAsO and LaCoAsO compounds. Like for other calculations on Fe-based superconductors such as LaFeAsO24, 30, 48 and LaFePO47, the Fermi energy lies just above a peak in the DOS. Actually, their DOS have a very steep and negative slope near the Fermi level, which drives the system close to a magnetic instability and at the moment no Fe-based parent materials exhibit superconductivity. At higher Co concentration the occupation at Fermi level decreases, i.e., 4.85 for the pure LaFeAsO, 3.25 for LaCo0.125Fe0.875AsO and 1.5 for LaCo0.25Fe0.75AsO, and the DOS near the Fermi level become flat pushing the doped system away from the magnetic instability. Many experiments in other superconductor systems revealed that the appearance of spin density wave transition may destroy superconductivity in Fe-based compounds; however nothing is known for these systems and it is fundamental to explore the relationship between SDW and superconductivity in these Fe-based compounds.ConclusionsWe have investigated the geometry structure, binding properties and electronic structure of LaFe1-x Co x AsO and its parent materials through first principle calculations. We find that FeAs-based ZrCuSiAs structure compounds LaFeAsO, LaCoAsO and the cobalt doping systems have quasi two-dimensional character, with ionic layer-layer interaction. The Fe or Co 3d states mainly contributenear the Fermi level, and the orbit resolved components of 3d states distribute complicate, which reveals an underlying mechanics different from cuprate superconductors. We further compare the DOS near the Fermi energy of LaFeAsO, LaCoAsO and the cobalt doping compounds, and demonstrate that cobalt doping push up the Fermi level of the LaFeAsO from a steep and negative edge towards the flat distribution of doping system, which suppresses the spin density wave transition in LaFe1-x Co x AsO doping systems. It would be interesting to explore the relationship between spin fluctuations and superconductivity for future work.AcknowledgementsThis work is partially supported by the National Outstanding Youth Fund (Project No. 10125523 to Z.W.), by the Knowledge Innovation Program of the Chinese Academy of Sciences (KJCX2-SW-N11), and by Supercomputing Center, CNIC, CAS. We are grateful for discussions with A. Marcelli.Table 1. Comparison of experimental and calculated crystal lattice and internal parameters of LaFeAsO and LaCoAsO compounds.(Ǻ) ( Ǻ) a c La z As z LaFeAsO Calculated 4.026 8.611 0.1451 0.6381 Experiment 5 4.035 8.741 0.1415 0.6512 Experiment 13 4.038 8.754 - - Experiment 14 4.030 8.737 0.1418 0.6507 LaCoAsO Calculated 4.045 8.518 0.1454 0.6382 Experiment 13 4.054 8.472 - -Table 2. Comparison of the electronic charges to different species obtained by the Bader analysis and their pure ionic picture.La TM As O LaO TMAs Bader (LaFeAsO) 9.1009 7.7103 5.8928 7.2960 16.3969 13.6031 Ionic picture (LaFeAsO) 8(La3+) 6(Fe2+) 8(As3-) 8(O2-) 16 14 Bader (LaCoAsO) 9.0957 8.8937 5.7158 7.2947 16.3904 14.6095 Ionic picture (LaCoAsO) 8(La3+) 7(Co2+) 8(As3-) 8(O2-) 16 15Figure 1. Cystal structure of the LaFe1-x Co x AsO. Elements are labeled inside the spheres.Figure 2. Total density of states of LaFeAsO (top) and LaCoAsO (bottom) and their partial density of states within the GGA approximation. The character of Fe (Co), O and As is shown separately. All energies are relative to the Fermi energy.-6-4-2021020D O S (s t a t e s /e V )Energy (eV)LaFeAsO Fe 3d As 4p O 2p-6-4-2021020D O S (s t a t e s /e V )Energy (eV)LaCoAsO Co 3d As 4p O 2pFigure 3. Orbital resolved DOS of Fe 3d states in the LaFeAsO (top) and of Co 3d states in LaCoAsO (bottom).-6-4-20251015D O S (s t a t e s /e V )Energy (eV)51015D O S (s t a t e s /e V )Energy (eV)Figure 4. Calculated band structures of LaFeAsO (top) and LaCoAsO (bottom). All energies are relative to the Fermi energy.-6-4-22ΓE n e r g y (e V )ΓX MZ R A-6-4-22E n e r g y (e V )ΓX M ΓZ R A MFigure 5. Band structures of LaFeAsO (top) and LaCoAsO (bottom) near the Fermi energy from -0.6 eV to +0.6 eV . All energies are relative to the Fermi level.-0.6-0.4-0.20.00.20.40.6ΓE n e r g y (e V )ΓX MZ R AM-0.6-0.4-0.20.00.20.40.6E n e r g y (e V )ΓX M ΓZ R A MFigure 6. Comparison of the total density of states of LaCo x Fe 1-x AsO, LaFeAsO and LaCoAsO. All energies are relative to the Fermi level.-2-10125101520D O S (s t a t e s /e V )Energy (eV)LaFe 0.875Co 0.125AsO LaFe 0.75Co 0.25AsOpure LaFeAsO pure LaCoAsOReferences1 J. G. Bednorz and K. A. 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The structure which possesses change possible magn

专利名称：The structure which possesses changepossible magnetic property发明人：ウィルトシャーマイケルチャールズキーオウ申请号：JP特願2001-566217(P2001-566217)申请日：20010306公开号：JP特表2003-526423(P2003-526423A)A公开日：20030909专利内容由知识产权出版社提供专利附图：摘要： (57)< Abstract > The structure which possesses change possible magnetic property, consists of the array of the capacitive element (44), each capacitive element includes the resistant electric conduction road low, the magnetic component (H) of the electromagnetic emission (12) which exists inside specified frequency zone, turning the aforementioned electric conduction road, the element (44) which it is related the electriccurrent which flows is induced. Size and as for those intervals of the element (44) (a) are selected, the description above responding to the electromagnetic emission (12) which is received, in order to give magnetic permeability (). Each capacitive element (44) consists of the plural lamination plane surface sections (42), each section, at least consists of two concentric spiral conductive members or the track/truck (46 and 48), these components or the track/truck have severed relations mutually electrically. The permittivity change possible material like barium - strontium - chitaneito (BST), is given between thetracks/trucks. Magnetic property of structure is changed by adding dc electric potential between the conductive tracks/trucks.申请人：マルコニオプティカルコンポーネンツリミテッド地址：イギリスロンドンダブリュー1エックス 8エイキューワンブルートンストリート(番地なし)国籍：GB代理人：中村稔 (外9名)更多信息请下载全文后查看。

A structural basis for mutational inactivation of the tumour suppressor Smad4

the N domain.Other tumour-suppressor mutations,including missense mutations in the C domains of Smad2and Smad4,act by disrupting protein stability or effector function 12.Our ﬁndings reveal a mechanism of tumour suppressor inactivation which instead involves a gain of autoinhibitory function.Antagonists of SMAD autoinhibition might be useful in reversing the effects of thistype of mutation.Ⅺ.........................................................................................................................MethodsConstruction of expression vectors.To generate human Smad4and Smad2mutations,a fragment of the corresponding cDNAs 1,4was ampliﬁed by PCR.The ampliﬁed region was subcloned into full-length Smad4or Smad2in pCMV5for transfection into mammalian cells.The regions ampliﬁed by PCR and the presence of missence mutations were conﬁrmed by sequencing.Yeast two-hybrid system.LexA fusions were created in pBTM 116(ref.21)and GAD fusions within pGAD424(Clontech).Interactions were tested in the strain L40(ref.22).Activation of the LexA operator–HIS3reporter was assayed on medium lacking histidine with increasing concentrations of 3-amino-triazole.Transfection,immunoprecipitation,immunoblot and metabolic labelling.For Smad2/Smad4homo-or hetero-complex analysis,COS cells were transiently transfected with the indicated constructs and stimulated with 200pM TGF-␤1for 1h.Cells were lysed in TNE buffer 3,immunoprecipitated with anti-Flag M2monoclonal antibody (IBI;Eastman Kodak),and interacting proteins detected by immunoblotting with the anti-HA monoclonal antibody 12CA5(Boehringer Mannheim)as described 3.Anti-SMAD rabbit polyclonal antibody was raised against full-length Smad1.To study the interaction between the N and C domains of Smad4or Smad2,transiently transfected COS cells were lysed in LSLD buffer (50mM HEPES,pH 7.4,50mM NaCl,0.1%Tween 20,10%glycerol,1mM DTT)containing protease and phospha-tase inhibitors.Immunopreciptiaiton and immunoblotting were done as described.COS or R-1B/L17cells transfected with the indicated constructs were labelled with 35S-methionine or 32P-orthophosphate and visualized by electrophoresis and autoradiography 23.In vitro binding.The Smad2N domain (amino acids 1–184)fused to GSTand the Smad2C domain (amino acids 248–467)protein were expressed in Escherichia coli and partially puriﬁed by column chromatography.GST fusion proteins were conjugated to glutathione–Sepharose beads (Pharmacia)and incubated with Smad2C domain protein.Smad2C domain protein was detected by western blotting using anti-Smad antibody.Functional assays.For the animal cap assay,RNA (10nl,2ng)was introduced in the animal pole of two-cell Xenopus embryos.Animal caps were explanted at the blastula stage and cultured to the tadpole stage.Total RNA from the explants and control sibling embryos was extracted and was ampliﬁed with reverse transcription by using muscle actin and EF-1a primers 24.In the MDA-MB468cell experiments,the amount of transfected plasmids was adjusted to render the TGF-␤response dependent on both Smad2and Smad4.Luciferase and growth inhibition were assayed as described 3.Received 24March;accepted 6May 1997.1.Hahn,S.A.et al .DPC4,a candidate tumor suppressor gene at human chromosome 18q21.1.Science271,350–353(1996).2.Eppert,K.et al .MADR2maps to 18q21and encodes a TGF-␤-regulated MAD-related protein that isfunctionally mutated in colorectal carcinoma.Cell 86,543–552(1996).gna,G.,Hata,A.,Hemmati-Brivanlou,A.&Massague´,J.Partnership between DPC4and SMAD proteins in TGF-␤signalling pathways.Nature 383,832–836(1996).4.Liu,F.et al .A human Mad protein acting as a BMP-regulated transcriptional activator.Nature 381,620–623(1996).5.Baker,J.&Harland,R.M.A novel mesoderm inducer,mMadr-2,functions in the activin signaltransduction pathway.Genes Dev.10,1880–1889(1996).6.Massague´,J.,Hata,A.&Liu,F.TGF-␤signalling through the Smad pathway.Trends Cell Biol.7,187–192(1997).7.Zhang,Y.,Feng,X.-H.,Wu,R.-Y.&Derynck,R.Receptor-associated Mad homologues synergize aseffectors of the TGF-␤response.Nature 383,168–172(1996).8.Hoodless,P .A.et al .MADR1,a MAD-related protein that functions in BMP2signaling pathways.Cell85,489–500(1996).9.Macı´as-Silva,M.et al .MADR2is a substrate of the TGF ␤receptor and phosphorylation is required for nuclear accumulation and signaling.Cell 87,1215–1224(1996).10.Kretzschmar,M.,Liu,F.,Hata,A.,Doody,J.&Massague´,J.The TGF-␤family mediator Smad1is phosphorylated directly and activated functionally by the BMP receptor kinase.Genes Dev.11,984–995(1997).11.Wu,R.-Y.,Zhang,Y.,Feng,X.-H.&Derynck,R.Heteromeric and homomeric interactions correlatedwith signaling activity and functional cooperativity of Smad3and Smad4/DPC4.Mol.Cell.Biol.17,2521–2528(1997).12.Shi,Y.,Hata,A.,Lo,R.S.,Massague´,J.&Pavletich,N.P .A structural basis for mutational inactivation of the tumour suppressor Smad4.Nature 388,87–93(1997).13.Ca´rcamo,J.et al .Type I receptors specify growth inhibitory and transcriptional responses to TGF-␤and activin.Mol.Cell.Biol.14,3810–3821(1994).14.Schutte,M.et al .DPC4gene in various tumor types.Cancer Res.56,2527–2530(1996).15.Kim,S.K.et al .DPC4,a candidate tumor suppressor gene,is altered infrequently in head and neck squamous cell carcinoma.Cancer Res.56,2519–2521(1996).16.Nagatake,M.et al .Somatic in vivo alterations of the DPC4gene at 18q21in human lung cancers.Cancer Res.56,2718–2720(1996).17.Barrett,M.T.,Schutte,M.,Kern,S.E.&Reid,B.J.Allelic loss and mutational analysis of the DPC4gene in esophageal adenocarcinoma.Cancer Res.56,4351–4353(1996).18.Riggins,G.J.et al .Mad -related genes in the human.Nature Genet.13,347–349(1996).19.Uchida,K.et al .Somatic in vivo alternations of the JV18-1gene at 18q21in human lung cancers.Cancer Res.56,5583–5585(1996).20.Graff,J.M.,Bansal,A.&Melton,D.A.Xenopus Mad proteins transduce distinct subsets of signals for the TGF ␤superfamily.Cell 85,479–487(1996).21.Bartel,P .L.,Chien,C.-T.,Sternglanz,R.&Fields,S.in Cellular Interactions in Development:A Practical Approach (ed.Hartley,D.A.)153(Oxford University Press,Oxford,1993).22.Vojtek,A.B.,Hollenberg,S.M.&Cooper,J.A.Mammalian Ras interacts directly with the serine/threonine kinase Raf.Cell 74,205–214(1993).23.Wrana,J.L.,Attisano,L.,Wieser,R.,Ventura,F.&Massague´,J.Mechanism of activation of the TGF-␤receptor.Nature 370,341–347(1994).24.Hemmati-Brivanlou, A.&Melton, D. A.Inhibition of activin receptor signalling promotes neuralization in Xenopus .Cell 77,273–281(1994).Acknowledgements.We thank Y.Shi for recombinant Smad2proteins,and I.Reynisdo´ttir,J.Doody and S.Lee for advice and technical assistance.G.L.thanks A.Hemmati-Brivanlou for support and advice.This work was supported by NIH Breast Spore and Cancer Center grants.D.W.is the recipient of a postdoctoral fellowship from the Human Frontier Science Program.A.H.is a research associate and J.M.an investigator of the Howard Hughes Medical Institute.Correspondence and requests for materials should be addressed to J.M.(e-mail:j-massague@).A structural basis formutational inactivation of the tumour suppressor Smad4Yigong Shi,Akiko Hata *,Roger S.Lo *,Joan Massague*&Nikola P .PavletichCellular Biochemistry and Biophysics Program,*Cell Biology Program and the Howard Hughes Medical Institute,Memorial Sloan-Kettering Cancer Center,New York,New York 10021,USA.........................................................................................................................The Smad4/DPC4tumour suppressor 1is inactivated in nearly half of pancreatic carcinomas 2and to a lesser extent in a variety of other cancers 2–4.Smad4/DPC4,and the related tumour suppressor Smad2,belong to the SMAD family of proteins that mediate signalling by the TGF-␤/activin/BMP-2/4cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus 5–7.SMAD proteins,which are phosphorylated by the activated receptor,propagate the signal,in part,through homo-and hetero-oligomeric interactions 8–13.Smad4/DPC4plays a cen-tral role as it is the shared hetero-oligomerization partner of the other SMADs.The conserved carboxy-terminal domains of SMADs are sufﬁcient for inducing most of the ligand-speciﬁc effects,and are the primary targets of tumorigenic inactivation.We now describe the crystal structure of the C-terminal domain (CTD)of the Smad4/DPC4tumour suppressor,determined at2.5A˚resolution.The structure reveals that the Smad4/DPC4CTD forms a crystallographic trimer through a conserved protein–protein interface,to which the majority of the tumour-derived missense mutations map.These mutations disrupt homo-oligomerization in vitro and in vivo ,indicating that the trimeric assembly of the Smad4/DPC4CTD is critical for signalling and is disrupted by tumorigenic mutations.The conserved C-terminal domain can mediate many of the biological effects of SMAD proteins,and the conserved N-terminal domain can negatively regulate the SMAD activity 14,15.When over-expressed in a Smad4/DPC4−/−cell line,the Smad4/DPC4CTD can activate the transcription of TGF-␤responsive genes and result inFigure1The structure of the Smad4/DPC4CTD consists of a␤-sandwichwith a three-helix bundle on one end and a collection of three large loopsand an␣-helix on the other.The view is along the edge of the␤-sandwich;the dotted line represents the disordered region between the H3and H4helices.Figures were prepared with the programs MOLSCRIPT26andRASTER3D27.APEYWCSIAYFEMDVQVGETFKVPSS-CPIVTVDGYVDPSGGD--RFCLGQLSNVHRTEAIERARLHIGKGVQLEC-KGEGDV397Smad4/DPC4Smad1Smad2Smad3Smad5MadSma-2Sma-3Sma-4Smad4/DPC4Smad1Smad2Smad3Smad5MadSma-2Sma-3Sma-4Smad4/DPC4Smad1Smad2Smad3Smad5MadSma-2Sma-3Sma-4--KHWCSIVYYELNNRVGEAFHASST---SVLVDGFTDPS-NNKNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYV--GGEV343-A-FWCSIAYYELNQRVGETFHASQP---SLTVDGFTDPS-NS-ERFCLGLLSNVNRNATVEMTRRHIGRGVRLYYI--GGEV345-A-FWCSISYYELNQRVGETFHASQP---SMTVDGFTDPS-NS-ERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYI--GGEV312-PKHWCSIVYYELNNRVGEAFHASST---SVLVDGFTDPS-NNKSRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYV--GGEV343-A-FWASIAYYELNCRVGEVFHCNNN---SVIVDGFTNPS-NNSDRCCLGQLSNVNRNSTIENTRRHIGKGVHLYYV--TGEV333--QFWATVSYYELNTRVGEQVKVSST---TITIDGFTDPC-INGSKISLGLFSNVNRNATIENTRRHIGNGVKLTYVRSNGSL296--KSWAQITYFELNSRVGEVFKLVNL---SITVDGYTNPS-NSNTRICLGQLTNVNRNGTIENTRMHIGKGIQLDNKEDQMHI271L-DNWCSIIYYELDTPIGETFKVSARDHGKVIVDGGMDPHGENEGRLCLGALSNVHRTEASEKARIHIGRGVELTA-HADGNI427WVRCLSDHAVFVQSYYLDREAGRAPGDAVHKIYPS-AYIKVFDLRQCHRQMQQQAATAQAAAAAQAAAVAGNIPGPGSVGGIA479-PSGCSLKIFN-NQEFAQLLAQSVNH----------------------GFE401FAECLSDSAIFVQSPNCNQRYGWHPAT VCK PPGCNLKIFN-NQEFAALLAQSVNQ----------------------GFE403FAECLSDSAIFVQSPNCNQRYGWHPAT VCK-PPGCNLKIFN-NQEFAALLAQSVNQ----------------------GFE360YAECLSDSSIFVQSRNCNFHHGFQSTS VCK-PSSCSLKIFN-NQEFAQLLAQSVNH----------------------GFE401YAECLSDSAIFVQSRNCNYHHGFHPST VCK-391FAQCESDSAIFVQSSNCNYINGFHSTT VVK-354MITNNSDMPVFVQSKNTNLMMNMPLVK VCR-329SIT--SNCKIFVRSGYLDYTHGSEYSSKAHRFTPNESSFTVFDIRWAYMQMLRRSRDSNEAVRAQAAAVAGYAPMS-----VM503PAISLSAAAGIGVDDLRR-LCILRMSFVKGWGPDYPRQSIKETPCWIEIHLHRALQLLDEVLHTMPIAD---PQPLD552VYEL T------465VYQL T-------467VYQL T-------424465455418393570-R441PDPC-4B4H1L1D493HDPC-4B7B8H20 – 60% buried90 – 100% buriedConserved and solvent-exposed residuesFigure2SMAD C-terminal domains are highly conserved and are targeted by tumorigenicand developmental mutations.a,Sequence alignment of C-terminal domains ofﬁve humanSMAD proteins1,8,10(Smad1,2,3,5and Smad4/DPC4)and homologues from Drosophila18(Mad)and C.elegans19(Sma-2,3,4),with the Smad4/DPC4CTD secondary structureelements indicated below the sequences.Residues that are more than40%exposed tosolvent have no signiﬁcant role in the structure and are conserved in at least6out of the9aligned sequences are highlighted in cyan.The14missense mutations shown above thealignment include tumour-derived Smad4/DPC4and Smad2mutations1,2,4,12,17,28(yellow),aswell as mutations from Drosophila and C.elegans genetic screens18,19(developmentalmutations,in green).The residues at which these mutations occur are in bold face andunderlined.b,Mapping of the missense mutations and the highly conserved and solvent-exposed residues identiﬁes the three-helix bundle and the three-loop/helix region asregions likely to be important for the macromolecular recognition that mediates SMADfunction.Colour coding is the same as in a.The amino-acid substitution and the residuenumber of the mutation in SMAD family members other than Smad4/DPC4are shown inparentheses.The three structural mutations(Arg441Pro in Smad4/DPC4,Leu440Arg andPro445H in Smad2)are not shown.Rgrowth arrest in a ligand-independent manner,paralleling the effects of the TGF-␤ligand 9;microinjection of messenger RNAs encoding the CTD of Smad2into Xenopus embryos can induce a mesoderm response that mimics the effects of the full-length protein 16;and the Smad4/DPC4CTD fused to a heterologous DNA-binding domain can activate gene expression from a reporter construct 14.Consistent with the SMAD C-terminal domain being the main effector domain,the majority (10out of 13)of tumorigenic missense mutations in Smad4/DPC4and Smad2,as well as muta-tions isolated from Drosophila and Caenorhabditis elegans genetic screens map to the C-terminal domain.To investigate how the SMAD C-terminal domain functions in mediating TGF-␤signalling and how its mutation in cancer inactivates the pathway,we determined the crystal structure of the 234-amino-acid Smad4/DPC4CTD (residues 319–552)at 2.5A˚resolution (Table 1).The structure consists of a ␤-sandwich with twisted antiparallel ␤-sheets of ﬁve and six strands each (Fig.1).One end of the ␤-sandwich is capped by a three-␣-helix bundle (H3,H4and H5helices)that extends over the plane of the six-stranded ␤-sheet,at a roughly perpendicular angle;the other end of the ␤-sandwich is capped by a group of three large loops and an ␣-helix (L1,L2,L3loops and H1helix;Fig.1).To simplify the presentation,the three large loops and ␣-helix,as well as portions of ␤-strands in their immediate vicinity,will be collectively referred to as the loop/helix region.The three ␣-helices of the bundle pack in an up-down-up orientation primarily through leucine residues.In between the H3and H4helices,a 34-amino-acid sequence that is rich in Ala (39%),Gly and Pro residues and is present only in Smad4/DPC4and its C.elegans homologue Sma-4,is disordered in the crystals (residues 457–491).In the loop/helix region,the L1,L2and L3loops of 7,9and 18residues,respectively,and the H1helix are mostly polar and pack through extended hydrogen-bond networks.These hydrogen bonds are likely to contribute to the rigid structure of this region that is suggested by the well deﬁned electron density.SMAD proteins are highly conserved within the family and across species,with Smad4/DPC4and its C.elegans homologue,Sma-4,representing a somewhat divergent subtype which still retains about 40%identity with other family members 5,7(Fig.2a).Many of the conserved residues have structural roles.These include the hydro-phobic residues that make up the hydrophobic core of the ␤-sandwich and of the three-helix bundle,as well as many of the polar residues that form the hydrogen-bond networks important for the structure of the loop/helix region.Examples of the latter group are the invariant Arg 372and Arg 380residues from the H1helix that make four and three charge-stabilized hydrogen bonds,respectively.Many other highly conserved residues are exposed to solvent and do not appear to stabilize the structure.They are thus candidates for functional residues that may mediate macro-molecular interactions important for the function of SMAD proteins.The structure reveals that these candidate functional residues (highlighted in Fig.2b)have a strong tendency to cluster at the loop/helix region and the three-helix bundle.Another indication that the loop/helix region and the three-helix bundle are functionally important comes from an analysis of nine tumour-derived missense mutations,some occurring several times,in the CTDs of the Smad4/DPC4and Smad2tumour suppressors.Excluding three mutations that map to structural residues,ﬁve of the six tumour-derived missense mutations map to either the loop/helix region or to the three-helix bundle:the Smad4/DPC4muta-tions Asp351His 2,Arg361Cys 17and Val370Asp 17map to the loop/helix region,whereas the Smad4/DPC4mutation Asp493His 1and the Smad2mutation Asp450Glu 12(corresponding to Asp 537of Smad4/DPC4)map to the three-helix bundle.We presume that these mutations deprive the CTD of critical intermolecular contacts.The one mutation that does not map to either region is Arg420His from Smad4/DPC4,which instead maps to the side of the ␤-sandwich (H2helix),a region that is not as well conserved.The remaining three mutations map to structural residues:the Smad2Leu440Arg mutation (corresponding to Ile 527of Smad4/DPC4)in the hydro-phobic core of the ␤-sandwich probably disrupts packing in the hydrophobic core;the Smad4/DPC4Arg441Pro mutation at the three-helix bundle probably disrupts the H3helix because of the introduction of a proline in the middle of the helix;and the Smad2Pro445His mutation (corresponding to Ala 532in Smad4/DPC4),also at the three-helix bundle,probably disrupts the packing between the three-helix bundle and the ␤-sandwich as there is little space for the larger histidine side chain in this part of the hydrophobic core.In support of the functional signiﬁcance of the loop/helix region,mutations in Drosophila and C.elegans in this region produce null or severe developmental phenotypes 18,19.These mutations map to Gly 508(Drosophila Mad,C.elegans Sma-2),Gly 510(Sma-3),and Glu 520(Mad)of the L3loop in the loop/helix region (Fig.2).Thus the location of conserved,solvent-exposed residues and of muta-tions derived from tumours or from Drosophila and C.elegans genetic screens together indicate that the loop/helix region and the three-helix bundle are critical for mediating Smad activity.As SMAD CTDs can mediate most of the effects of the full-length proteins,we tested the Smad4/DPC4CTD for homo-oligomeriza-tion activity.Co-immunoprecipitation using extracts from COSTable 1Statistics from the crystallographic analysisData setNative 1(8ЊC)Native 2(−170ЊC)Thimerosal UO 2(OAc)2*(CH 3)3PbOAc *Resolution (A) 3.0 2.5 3.0 3.0 3.2Observations30,69139,12530,57223,48825,150Unique reﬂections 7,18911,4967,0736,7655,759Data coverage (%)96.896.596.892.894.6R sym (%)†6.53.74.88.510.0MIR analysis (20.0–3.2A):Mean isomorphous difference ‡0.180.140.24Phasing power § 2.541.381.03Reﬁnement statistics:R.m.s.d.#Resolution (A )Reﬂections(|F |Ͼ2␴ÞProtein atoms Waters atoms R -factor k (%)R -free ¶(%)Bonds(A )Angles(Њ)B -factor(A 2)7.0–2.510,3591,52212920.928.60..0101.663.29...................................................................................................................................................................................................................................................................................................................................................................*OAc,acetate.†R sym ¼S h S i |I h ;i ϪI h |=S h S i I h ;i for the intensity (I )of i observations of reﬂection h .‡Mean isomorphous difference ¼S |F PH ϪF P |=S F PH ,where F PH and F P are the derivative and native structure factors,respectively.§Phasing power ¼½ðF H ðcalc ÞÞ2=ðF PH ðobs ÞϪF PH ðcalc ÞÞ2ÿ1=2.k R -factor ¼S |F obs ϪF calc |=S |F obs |,where F obs and F calc are the observed and calculated structure factors,respectively.¶R -free is the R -factor calculated using 5%of the reﬂection data chosen randomly and omitted from the start of reﬁnement.#R.m.s.d.,root-mean-square deviations from ideal geometry and root-mean-square variation in the B -factor of bonded atoms.cells transfected with differentially tagged Smad4/DPC4CTD con-structs showed that the Smad4/DPC4CTD could still form homo-oligomers when overexpressed15(Fig.3d),suggesting that the CTDmay contain a primary homo-oligomerization activity.However,full-length Smad4/DPC4homo-oligomers are more stable thanSmad4/DPC4CTD homo-oligomers in vivo15,indicating thatresidues N-terminal to the Smad4/DPC4CTD may contribute tohomo-oligomerization.To investigate the homo-oligomerization activity of the Smad4/DPC4CTD further,we examined the crystal packing of the Smad4/DPC4CTD molecules and identiﬁed a trimer that formed throughthree identical extended protein–protein interfaces,burying4,800A˚2of surface area(Fig.3a).Each interface forms throughthe interactions of the highly conserved regions of the Smad4/DPC4CTD that contain most of the candidate functional residues:theloop/helix region of one subunit packs extensively with the three-helix bundle from another subunit while making a few additionalcontacts to residues from the␤-sandwich(Fig.3a).The onlyportion of the loop/helix region that does not participate in thisinterface is the L3loop.The trimer interface includes the majority of the conservedresidues and the tumour-derived non-structural missense muta-tions(ﬁve out of six).Most noteworthy is an extended intermole-cular hydrogen-bond network involving,from one subunit,theArg361and Asp351side chains and two backbone amide groups ofthe loop/helix region,and from another subunit,the Asp537sideFigure3In the crystals,the Smad4/DPC4CTD forms a trimer that is disrupted bytumorigenic mutations and is probably important for SMAD function.a,The threemonomers(red,blue and purple)pack across three identical protein–proteininterfaces.Tumour-derived missense mutations map toﬁve amino acids(yellow)that are involved in intermolecular contacts.b,Close-up of an intermolecularhydrogen-bond network involving three residues,all of which have been foundmutated in cancer.Colouring is as in a.c,Close-up showing the intermolecularpacking of Val370,mutated to Asp in colon tumours,against Phe329,Trp524andthe aliphatic portion of Lys519.The subunit in which Val370is shown is in space-ﬁlling representation,whereas the other subunit is shown as a molecular surface(red mesh).Other intermolecular interactions not mentioned in the text include:van der Waals contacts between the L1loop of the loop/helix region and the H4and H5helices of the three-helix bundle(Tyr353,Val354and Pro356wedging inbetween His530,Leu533,Leu536,Leu540and His541);the hydrogen-bondnetworks between Ser368of the L2loop and Arg496,Glu526and His528of the␤-sheet,and between His371of the L2loop and Asp332of the␤-sheet.Theﬁgure was prepared with the program GRASP29.d,In vivo,tumour-derived trimerinterface mutations(D351H,R361C,V730D,D537E)disrupt both homo-andhetero-oligomerization,whereas a developmental mutation in the L3loop(G508S)disrupts only hetero-oligomerization.To assay for homo-oligomerization,mammalian COS-1cells were transiently transfected with Flag-tagged wild-typeSmad4/DPC4CTD and HA-tagged WT or mutant constructs.For hetero-oligomerization,cells were transfected with Flag-tagged Smad2C-terminaldomain and HA-tagged Smad4/DPC4C-terminal domain WT or mutant con-structs together with a constitutively active TGF-␤type I receptor construct.Thecell lysate was immunoprecipitated with anti-Flag antibody and subsequentlyimmunoblotted using anti-HA antibody.Immunoblots indicated that the mutantSmad4/DPC4CTDs were expressed at levels comparable to chose of the wild-type constructs(data not shown).Lower panels,full-length(FL)proteins weretreatedsimilarly.chain of the three-helix bundle(Fig.3b).The Asp351,Arg361,and Asp537residues are essentially invariant,apart from a conservative Arg-to-Lys substitution in Sma2(Fig.2a),and all three are mutated in cancer(Fig.2):Asp351His and Arg361Cys mutations have been found in Smad4/DPC4in ovarian2and colon cancers17,respectively, and the Asp450Glu mutation,corresponding to Asp537of Smad4/ DPC4,has been isolated from Smad2in colon cancer12.These mutations all disrupt the intricate hydrogen-bond network at the interface.Also noteworthy are the intermolecular van der Waals contacts between Val370on the L2loop of the loop/helix and Trp524,Phe329,and the aliphatic portion of the Lys519side chain on the␤-sheet at the base of the three-helix bundle(Fig.3c).The two aromatic residues are invariant,except for a conservative Tyr-to-Phe substitution in Smad4/DPC4(Fig.2a).Also,Val370is mutated to Asp in colon cancer17,causing the hydrophobic portion of the trimer interface to be destabilized by the charged amino acid. The Smad4/DPC4Asp493His mutation found in pancreatic tumours1also maps to the trimer interface(Fig.3a)and may interfere with the electrostatic packing of Asp493of one subunit with Arg496and Arg497of another subunit at the trimer interface. Asp493is near the disordered region of the H4helix and its interaction with the arginine residues is not well deﬁned.Many of the other trimer–interface contacts are also conserved in the SMAD family(Fig.3c legend),suggesting that other SMAD CTDs may form a similar trimeric structure.Not all residues in the Smad4/DPC4CTD trimer interface are conserved in all SMAD,and those that differ may contribute to subtype speciﬁcity.An example is an intermolecular hydrogen-bond contact between His371and Asp332:this pair is conserved in the C.elegans Smad4/DPC4 homologue Sma4,but is an invariant Asn–Asn pair in the path-way-restricted SMADs(Fig.2).If the trimeric Smad4/DPC4CTD assembly in the crystals is part of the in vivo homo-oligomer,then mutations of residues that make intermolecular contacts at the interface,particularly tumour-derived mutations,should disrupt or reduce homo-oligomerization in vivo.Figure3d shows the results of co-immunoprecipitation experiments using extracts from COS cells transfected with differ-entially tagged mutant Smad4/DPC4molecules.All four of the tumorigenic mutations that are imporant at the trimer interface, Asp351,Arg361,Val370and Asp537,disrupt homo-oligomeriza-tion of the Smad4/DPC4CTD and of full-length Smad4/DPC4(Fig. 3d).Conversely,the Drosophila/C.elegans developmental mutation Gly508Ser(Fig.2a)had no effect on homo-oligomerization(Fig.3d).This mutation maps to the L3loop,which is the only portion of the loop/helix region not involved in the trimer interface.If Smad4/DPC4CTD forms a trimer,then so should full-length Smad4/DPC4.Recombinant full-length Smad4/DPC4,puriﬁed to near homogeneity,elutes from a gel-ﬁltration column with an apparent relative molecular mass(M r)ofϳ180K,consistent with the calculated size(181K)of the Smad4/DPC4trimer(Fig.4a).This large M r is probably due to trimerization,because the M r is reduced by a factor ofϳ3in the tumour-derived trimer-interface mutants (Fig.4b).Conversely,the Drosophila/C.elegans developmental mutation Gly508Ser in the L3loop has no effect on the large M r of Smad4/DPC4(Fig.4b).Note that the Smad4/DPC4CTD elutes as a monomer from a gel-ﬁltration column,which is consistent with residues N-terminal to the CTD contributing to homo-oligomerization15.In principle,the full-length Smad4/DPC4protein could assume oligomeric states other than a trimer but have a gel-ﬁltration mobility approximating that of a trimer.However,our in vivo and in vitro results with the trimer-interface mutants,both with the CTD and the full-length proteins,indicates that the trimeric protein–protein interface in the crystals also participates in homo-oligomerization in vivo.The Smad4/DPC4CTD also supports hetero-oligomerization,as shown by the co-immunoprecipitation of overexpressed Smad4/ DPC4CTD and Smad2CTD from COS cells15(Fig.3d),and by their association on electrophoresis in non-denaturing gels(data not shown).Furthermore,both the tumour-derived trimer-interface mutants and the L3-loop mutants abolished hetero-oligomerization between the CTDs of Smad4/DPC4and Smad2(Fig.3d);results were similar with full-length Smad4/DPC4.As the L3-loop develop-mental mutation,which does not signiﬁcantly affect homo-oligomerization,disrupts hetero-oligomer formation,the L3loop may participate in hetero-oligomerization.Also,mutations pre-venting homo-oligomerization that also disrupt hetero-oligomer-ization indicate that the former is a prerequisite for the latter. Although several models of hetero-oligomerization could explain our results,one that is suitable from a structural perspec-tive is the formation of a heterohexamer between Smad4/DPC4 and Smad2trimers.The trimer structure resembles a disk,with the L3loops forming undulations on the face of the disk(Fig.5a), so two disks couldﬁt together face to face through their L3loops (Fig.5b),explaining why L3-loop mutations disrupt hetero-oligomerization.In this model,heterohexamer formationwouldFigure4Size-exclusion chromatography showing that wild-type full-lengthSmad4/DPC4,but not tumour-derived mutants,has an apparent M r consistentwith that of a trimer.a,Recombinant Smad4/DPC4protein,puriﬁed to nearhomogeneity,was applied to a Superdex-200gel-ﬁltration column,and it elutedat M r180K.Fractions were visualized with Coomassie blue staining.b,In vitro,tumour-derived trimer-interface mutations disrupt homo-oligomerization,but adevelopmental mutation in the L3loop does not.Gel-ﬁltration fractions of partiallypuriﬁed wild-type and mutant Smad4/DPC4proteins were analysed by immuno-blotting with anti-Smad4/DPC4antibody.。

principle

driven by external in uences into a steady state far from equilibrium may show the spontaneous creation of patterns in space, in time or both. Standard examples are given by the Benard cells, chemical oscillations, or the creation of waves in active media (like reaction-di usion systems), respectively. The patterns re ect a new dynamical organization of the system which is inscribed neither into the microscopic dynamics nor into the external conditions. So the system may be called to have created this organization "out of nothing" by itself. Although largely di erent in detail, there is a common principle guiding this process of SO. The systems concerned are characterized by (i) observing global symmetries (like the homogeneity and isotropy of a chemical uid) and (ii) the presence of feed-back mechanisms able of amplifying local symmetry breakings caused by uctuations up to macroscopic scales. The patterns are the result of a symmetry breaking arising as the minimal compromise of violating versus conserving the global symmetries of the system. In the language of arti cial intelligence this symmetry breaking scenario is a domain invariant principle. In the above sense the movement of an agent (robot or living being) in a complex external world is a spatio-temporal pattern. Can we nd common, i.e. domain invariant principles which drive the self-organization of such patterns? Little is known here, a notable exception being the principle of homeostasis rst introduced in physiology by Cannon as early as 1939 1]. His aim was to nd a basic understanding of the goal-oriented reactions (behavior) of the body in response to external perturbations. The reactions are produced by the orchestrated action of many interweaved control circuits. According to the principle of homeostasis, the function of the individual circuit is not controlled by the behavior of the system as a whole. Instead all the circuit does is to try to keep itself in a stable stationary state. Of course this is done best if the system is able to react to external disturbancies. Hence the behavoir of the body so to say is a byproduct of this internal drive of the system to uphold its stationary state. This is a very general, unspeci c principle not tailored to any speci c process. However, the principle has not found much applications in practice. In the present paper we argue that it is the focus on the stationary (homeostatic) state of the system which restricts its applicability for the construction of realistic controllers. The principle of homeokinesis to be introduced is the dynamical pendant of homeostasis. Coarsely speaking it means that the internal goal of the agent is not the stabilization of a stationary state but of 2

Parallel Structures

Parallel Construction The Rule:
Sentences, or parts of sentences that are connected by ideas, should be expressed in similar form.
Nouns
Correct: In understanding the importance of learning English, Wanda would pay attention to her listening, writing, reading, and speaking. Not correct: In understanding the importance of learning English, Wanda would pay attention to her listening, writing, reading, and whether she spoke correctly.
Clauses
Correct: Wanda believed that a healthy body was important, that the only way to live was to play hard, and that knowledge was power. Not correct: Wanda believed that a healthy body was important, that the only way to live was to play hard, and gaining power through knowledge.
Parallel Structure
What is parallel construction?

Structures and Grammars

of spring and new life on Easter.
Find differences between usage of “of” and “for”
It is childish of Chen Mingda to steal our vegetables every day, but maybe it is joyful for him to do it to enrich his spare time.
This cat has been staying on our doorway since last night. It must be deserted by its owner. guessing
Mr. Chen is listening to lesson carefully. He ＿＿ be stealing vegetables. ( A. can B. can’t ) C. must D. mustn’t
Something’s feature
necessary, interesting, happy, sad, boring, important, meaningful,
clever, beautiful, cruel, patient, kind, intelliБайду номын сангаасent, brave, graceful, gentle,
It is conscientious of Huijun to be our monitor, so it is deserving for her to receive the awards of “Outstanding
Class Cadre”.
Objective
Subjective Somebody’s nature or character

Structure principles of energy efficient machine tools

Structure principles of energy efﬁcient machine toolsR.Neugebauer a ,b ,M.Wabner a ,H.Rentzsch b ,*,S.Ihlenfeldt aa Fraunhofer Institute for Machine Tools and Forming Technology IWU,Chemnitz,Germany bChemnitz University of Technology,Chemnitz,Germany1.IntroductionHardly any other topic stirs the German,European and worldwide discussion as intensely,as the question for a sustain-able increase of resource efﬁciency.The ambitions for more comfort by industrialized nations,aspiring developing nations and increasing numbers of the overall population are meeting limited resources and growing ambitions to protect the global climate –these facts of a global community will determine the challenges in production engineering for the next 20years.The European Union,the economy and organizations have set the ambitious goal to signiﬁcantly increase the efﬁciency of the used resources in all areas,such as living,transportation,energy production and industry,within the next years.Ecodesign Directive 2005/32/EC is a framework provided by the European Union,which is also relevant for production engineering.The concrete implementation of the policy is currently in progress and will be reﬂected in a concrete need of action in the production engineering industry.Internationally developed approaches and solutions for in-creasing energy efﬁciency in production are manifold.However,we can establish that currently most measures are aimed to either an increase of component efﬁciency factors or the avoidance of ineffective components.These locally focused actions in summa-tion led to a ﬁrst recognisable decrease of energy consumption in production.Great but yet barely considered potential can be seen in the optimisation of complex energetic dependencies between com-ponents in the superior system level.Besides optimising interac-tion this approach offers the chance to detach from the classic function driven structures and to develop new energy-optimised systems.Summarized a methodical approach should give answers to the questions:WHERE (on which development step and system level)is WHAT kind of engineering activity necessary to reach the goals.Thereby a closed systematic for the development of energy efﬁcient production solutions seems very doubtful because of the high number of potential intervention approaches [1].2.Inﬂuencing variables on energy-efﬁcient design of production systems2.1.Energy efﬁciency in the hierarchy of production technologySince system analyses –also in production technology –are complex tasks,structuring and systematisation of aspects relevant for energy efﬁciency is the ﬁrst fundamental action to be carried out.Through subsumption of production systems and their elements in the energetic hierarchy of production clearly deﬁned interfaces and boundaries of energy consumption balancing can be deduced.The development process from product to a corresponding production system with signiﬁcant aspects for decisions relating to energy and resource consumption can be summarized as given in Fig.1.Here,each step determines energy consumption to a certain level,which again sets limits to intervention possibilities in following steps:I.Product deﬁnition :The product or the product range deﬁnes the requirements for the development,conﬁguration or selection ofCIRP Journal of Manufacturing Science and Technology 4(2011)136–147A R T I C L E I N F OArticle history:Available online 6August 2011Keywords:Machine tool Energy Efﬁciency Structures Mobility BionicsRedundancyA B S T R A C TActivities for energy efﬁciency increase of machine tools and production systems can roughly be divided into direct efﬁciency increase on components level and efﬁciency increase by optimised interaction of the components on the respective higher system level.The paper is focused on system level.In the ﬁrst part,inﬂuences on energy consumption in production are structured hierarchically.General aspects of energy efﬁciency of machine tools and production systems will be discussed.In the second part,selected solution approaches for machine tools will be addressed more in detail,especially mobility and miniaturization as well adaptivity through redundancy.ß2011CIRP.*Corresponding author.Tel.:+4937153971392;fax:+49371531837891.E-mail address:hendrik.rentzsch@iwu.fraunhofer.de (H.Rentzsch).Contents lists available at ScienceDirectCIRP Journal of Manufacturing Science and Technologyj ou r n a l h o m e p a g e :w w w.e l s e v i e r .co m /l o c a t e /c i r p j1755-5817/$–see front matter ß2011CIRP.doi:10.1016/j.cirpj.2011.06.017machine tools and production systems.With the product deﬁnition the following resource and energy needs will be substantially deﬁned.Besides primary product properties like function,complexity or life cycle,secondary aspects like material,geometry,accuracy and series volume signiﬁcantly affect the manufacturing technologies and therewith the energy needs in production [2,3].Exemplary,by a lower surface quality resource-intense ﬁne ﬁnishing operations could be substituted by more efﬁcient and productive manufacturing technologies.Reasoned by this,a cooperative development of product and production technolo-gies is generally desirable,such as it is suggested in [3]with the ‘‘Design for Energy Minimisation’’approach.II.Process deﬁnition :Based on product speciﬁcations the necessary processes have to be deﬁned.For evaluating alternative solutions,speciﬁc process energy needs and resource con-sumptions can be used in a ﬁrst approach.For example,hard turning is normally much more efﬁcient than grinding.But for overall effectiveness and efﬁciency two additional aspects have to be considered:The efﬁciency of the machine tool to realize the favoured processes and the degree of material utilization.For that reason a holistic approach is needed as the manufacturing technology not only deﬁnes the primary process energy to a major level but also requires speciﬁcally equipped production systems and therefore entails secondary loads to support the process itself [4].Consequently the choice of certain processes already narrows the margin for efﬁciency measures in the corresponding production systems.Furthermore adequate machining strategies have to be developed to optimise interaction between production system and process not only in terms of productivity,quality and cost effectiveness,but also regarding energy efﬁciency.One way is to optimise combinations of machining parameters as it is carried out by [5].In [6,7]approaches for utilizing ﬂexible work piece arrangement within the machine combined with ade-quate path planning to minimize energy requirements in feed axes are presented.III.Machine tool components :Along with the machining process,machine tool components as energy converters are mainly responsible for energy consumption in production.By its efﬁciency they dissipate energy into anergy.Consequently,efﬁciency increase is the primary task on components level.The development of efﬁcient components is a prior task of suppliers,whereas further potential of minimizing energy consumption exists by increasing the effectiveness of compo-nent application on machine tool level.IV.Machine tools :Functional structuring in kinematics,control andautomation is the core competence of machine tool engineer-ing.Besides the selection of efﬁcient components,two design problems have to be considered,what will be most relevant forthe effectiveness of energy usage.Firstly,an optimal task-dependent arrangement and interaction of machine tool components has to be realized.For example,this will be reached by task-adaptive conﬁguration and the ﬂexibility for re-conﬁguration.Secondly,optimal time-dependent operation modes of components should be guaranteed.V.Production line :Analogously to the components-structure-dependencies summarized above,on this level machine tools are considered as components characterized by its efﬁciencies.Additionally,automation and handling systems have to be considered.With increasing number of energy consumers,aspects of intelligent energy management become relevant.Especially idle energy and power peak management becomes more effective on this level.VI.Factory :This level covers the production relevant aspects.Herethere is a signiﬁcant potential to improve the energetic balance of machine tools or production systems.Besides management of electrical energies,especially the usage of thermal losses,could be effective.But analogously to product design level,a deeper cooperation between machine tool supplier and plant planning is necessary.According to [8,9]implicating interdependencies of production equipment and technical building services is a crucial task for increasing efﬁciency on production plant level.Especially facility equipment which is directly interlinked with production systems (e.g.extract units for exhaust air,supply units for compressed air)is seen to have high potential for improvements through optimised adjustment to production tasks,although the allocation of energy consumption to certain processes is complicated.2.2.Identiﬁcation of consumers and loss originsTo deﬁne energy relevant options of intervention in the structure of production systems,the context and the level of consideration should ﬁrst be deﬁned.Within the hierarchy of production technology,the production system including its components,machine tool and transport device,as well as their components,has thus two energetically relevant interfaces,which are also the boundaries:The factory as energy provider on the input side and the process as a user on the output side (Fig.2).The actual goal of the energy respectively power ﬂow through the system therefore is the realization of the process on the output side.By this,the actual power requirement is determined for a discrete time –hence,the energy requirement is determined over the course of the process at the interface production system –process.This percentage represents the resulting useful energy and is therefore called primary demand:E use ;prim ¼E sha ping þE mastering(1)Fig.1.Energy relevant aspects in production.R.Neugebauer et al./CIRP Journal of Manufacturing Science and Technology 4(2011)136–147137This includes the performance,which has to ﬁt the tool,to use the processing operations (shaping)including all losses on the process side,as well as performances,which are related to process mastering.For the example of 3-axis-milling,the shaping is realized during the work intervention by the mechanical performances F f Áv f of the translational feed motions of the feed drives and M c Áv of the rotational movement of the main drive.The supply of coolant,which the process side requires for process mastering,is providedby the hydraulic performance ˙VÁp at the oriﬁce of the coolant nozzle.Experimental and simulative energy consumption balanc-ing of such a machine were discussed in [10].The secondary demand is determined by those processes in the machine,which do not lead to a modiﬁcation on the work piece and therefore are not attributable to the machining process itself.This includes the ﬁeld of process logistics,in which –among other things –secondary movements,handling and clamping operations,as well as control and measurement processes,are combined.The secondary demand also includes the consumption,which is used to operate the machine itself.This includes the cooling and the lubrication of machine components as well as control,regulation and monitoring.E use ;sec ¼E o peration þE logistics(2)In principle,the secondary demand presents useful energy forthese processes.However,it can be considered a loss for the ‘‘black box’’production system since it is not directly demanded by the process.That means,this is a typical example for ineffective energy usage which has to be minimized by system optimisation.In addition to this,the realization of primary and secondary processes generates energetic losses by inefﬁcient components (friction,damping,electrical losses,ﬂow losses).These ‘‘real losses’’can be divided into base load losses and load-dependent losses and should be minimized either by component improve-ment or by improving the effectiveness of energy usage in secondary processes.On the latter it will be focused in the following sections:E loss ¼E loss ;basic þE loss ;o perate(3)This total demand is the input parameter at the interface of the production system to the factory.It should also be mentioned that the losses of the production system conditional upon the efﬁciency are diffusely emitted as thermal energy to the factory.Circuits to the potential beneﬁt of these energy losses are initially left out of the considerations.Considering these assumptions,the total energy demand of a production system can be calculated byE total ¼E use ;prim þE use ;sec þE loss(4)Based on these assumptions,efﬁciency h can be used as a key ﬁgure for energetic evaluation of a machine tool or a production systemh ¼E use ;prim E total ¼E use ;primE use ;prim þE use ;sec þE loss(5)In actual practice,the percentage of the primary demands for the process is often small in comparison to the total energy demand of machine tools and production systems.Depending on the machining process and accuracy (roughing,ﬁnishing,ﬁne ﬁnish-ing;dry machining,ﬂood machining,etc.),the energy for the process reaches values between 10%(e.g.ﬁne ﬁnishing)and 70%(e.g.roughing)[11,12].From this a high potential for decreasing the energy consumption of machine tools and production systems by improvement of the effectiveness of energy usage on the system level can be derived.General intervention possibilities will be discussed in the ter on selected solution approaches for machine tools,and alternative production scenarios will be addressed more in detail,especially mobility,miniaturization,autonomy and adaptivity.2.3.System inﬂuences on losses in componentsA machine tool may be regarded as a structural order scheme of individual machine components.The distinction of energy demand in load-dependant and load-independent units means that both the internal component properties as well as the interaction of the components in the system are the cause of losses (Fig.3).While load-independent losses occur without the interaction between component and system,load-dependent losses canonlyFig.2.Demands,losses and interfaces on production system level.R.Neugebauer et al./CIRP Journal of Manufacturing Science and Technology 4(2011)136–147138be analysed and inﬂuenced at the system level.Therefore,the knowledge of system inﬂuences (loads)on load-dependent efﬁciencies and power losses of active (e.g.electric motors)and passive (e.g.bearings)energy converter components is a central aspect for the successful development of energy efﬁcient machine structures.A distinction between the losses in machine tools into electric losses,ﬂow losses and damping losses can be made.Due to the signiﬁcantly different variables,the friction losses are treated separately as a subset of the damping losses.In summary,this means that for developing energy efﬁcient machine tools one has to distinguish between component optimisation and system optimisation.With increased efﬁciency factors and the same machine structure the component optimisa-tion leads to a direct increase of the energy efﬁciency of the overall system,where energetically relevant internal component proper-ties are affected.In contrast,the system optimisation leads to an indirect increase in energy efﬁciency,since here,through appropriate measures,the secondary demand (system inﬂuences)itself,as well as the related absolute load-dependent and load-independent losses can be reduced.The improvement of energy efﬁciency on the machine structure level is therefore an optimisation problem,posed by the given characteristics (e.g.efﬁciency factors)of the used machine components,without affecting them directly.The purpose of the design of energy efﬁcient machine structures is,ﬁrst,by appropriate selection and structural arrangement,to minimize the variables affecting the energy converters and to ensure the operation of the components each with best possible efﬁciency range.Second,the secondary energy requirement should be reduced by minimizing the number of necessary secondary systems and their demand-based operation has to be ensured.3.Selected approaches for energy-efﬁcient machine tool structures3.1.General approachesConcrete approaches to improve the energy balance can be derived from the discussion in Section 2.The relevance ofindividual options of intervention can thereby be evaluated from extensive literature,e.g.[13–16].For example,currently support systems,in particular cooling and coolant systems,have the largest share of the overall energetic loss of machine tools.In this section,different functional and geometric layout principles for machine tools with impact on system level are derived from existing analysis and applications.Since an exact quantiﬁcation of the impact each of these aspect has on energy efﬁciency is not possible on a general level,only qualitative effects are analysed in this section.In general the demand of consumers can be divided into primary (ensure the primary demand of energy for the process:main drive,feed drives,coolant system,etc.)and secondary demand (handling,tool changers,component cooling,etc.).The primary loads can be assumed to be applied effectively (i.e.directly for the process).In this case an energy optimisation can be achieved by the increase of efﬁciency.In contrast,secondary loads are not applied effectively,since they do not contribute directly to the realization of the process and therefore are not effective at all,hence treated as loss-makers on the machine tool level.Theoreti-cally,an energetically ideal machine tool no longer has secondary loads.While optimisation approaches on component level,speciﬁcal-ly the improvement of component efﬁciency factors,is a direct approach for efﬁciency,the measures presented here pursue an indirect approach through system optimisation.Overall efﬁciency (cf.Eq.(5))is to be increased by reducing secondary demand (raising effectiveness)and total loads (cf.Section 2.3).Speciﬁc principles and effects of these aspects are:RobustnessThere are different approaches to obtain robust machine structures with various effects on energy efﬁciency.E.g.thermal robustness in machine tools can lead to a decrease of secondary demand for machine operation,since cooling efforts for machine components can be reduced.Active and passive approaches for thermal robust design are presented in various literature [17–19].Regarding static and dynamic stiffness of structural components,a robust design can lead to higherproductivity,Fig.3.System inﬂuences on the energy losses of machine tool components.R.Neugebauer et al./CIRP Journal of Manufacturing Science and Technology 4(2011)136–147139hence less base load share,through increased dynamic proper-ties and the move of critical cutting depths[20].MobilityTwo aspects of mobility can be identiﬁed for machine tools. Firstly,this would be the general transportability of production systems to the site of operation,respectively the work piece. Secondly the placement of the machinery on/at the work piece, instead of placing the work piece inside a machine.Especially the second point leads to new approaches in machine tool design(cf. Section3.2).Both mobility aspects combined can lead to major energy savings in work piece transport,especially for large parts, were a small,lightweight machine can be transported to the part. Examples for applications of mobile machining are presented in [21]and[22].MiniaturizationA general reduction of system size establishes possibilities for smaller dimensioned components due to smaller loads or even the omitting of various supporting consumers.Therewith, absolute losses in components as well as secondary demand for machine operation could be reduced,since smaller systems often require less support systems[23,24].Furthermore minor effects in the overall life cycle balancing result from the decrease of material consumption for machine tool construction.Natu-rally,miniaturization can only be carried out with regard to process and work piece.However,since production systems are often over dimensioned for certain tasks,down-sizing can generate major energy savings.For speciﬁc applications energy requirements up to3magnitudes smaller could be demonstrated [25].AdaptivityAdaptivity can be seen as a short term modulation of machine properties to match production process requirements with the capabilities of the executing system for operation in optimal areas.A plurality of speciﬁc applications on component and system level was already examined.For example in[26]an piezo based actuator is used to vary the pre-load of ball screws,which allows to reduce friction in certain operating states,e.g.while no process loads are applied.Another possibility with high potential for energy savings is demand based operation of devices,hence the reduction of secondary demand[27],and the allocation of tasks to speciﬁc consumers(e.g.redundant drives for highly dynamic and far travel movements,cf.Section3.3).MutabilityCompared to short-term characteristics of adaptivity,muta-bility enables long term modiﬁcations on production systems [28,29].Although the idea of reconﬁgurable machine tools is mainly justiﬁed by the potential to react to uncertain market conditions(e.g.altering product variants and quantities),there are also environmental effects resulting from this approach.Selective and modular substitution of system components allows a higher degree of reuse(life cycle extension)and therefore avoids resource extensive disposal and new construc-tion.Moreover,energetic optimal equipment could be applied,if operating conditions change and a reconﬁguration of the system is practicable[30,31].Multifunctionality/specialisationAs mentioned before,the presented approaches have to be evaluated for every speciﬁc application,which due to cross interferences leads to a multi-criteria optimisation problem. Especially multifunctionality and specialisation are two options that exclude each other and need to be speciﬁcally analysed for every use case.Both approaches have principle advantages in terms of energy efﬁciency in production systems.Especially work pieces with complex geometric features can be machined much faster and more efﬁcient through completemachining on multifunctional machine tools because of elimi-nation of work piece transport between different workstations [32].Furthermore,a lower number of machines involved in machining a work piece may decrease the base-load share per part.On the other hand side,specialised production technology may be provided with processﬁtted equipment,thus ensuring very effective and efﬁcient application of operating devices.Distinctive characteristics between multifunctional and specialised machine tools can apply to functionality itself as well as to other aspects such as capacity.A method for decision making regarding multiple parameters is presented in[33]. Furthermore mutability as an approach to realize both strategies is included.Energetic networking–decrease of losses through secondary usage and reallocation of energyIn practical systems,mechanical and electrical reactive energies are producing energeticﬂow losses.Reactive energy ﬂows have to be minimized,e.g.braking energies by lightweight design.On the other hand,reactive energies can supply other consumers.An example is the active power factor correction in electrical drive systems by direct energetic networking of electric consumers in machine tools,production systems and factory workshops[34].In addition,not avoidable energetic losses (waste heat)in some cases can be used directly for heating or conditioning.Because of components interaction,the addressed aspects typically need considerations on system level.The presented energetically relevant aspects and their general qualitative inﬂuence on the machine structure level with details on the intervention target,the life cycle phase and consumers (according to Fig.2)are summarized in Table1.Subsequently,two structural approaches for energy efﬁcient machine tools using several of the above mentioned aspects are presented in more detail.3.2.Mobility and miniaturization by mobile and autonomous machine tools3.2.1.Potentials of mobile machines regarding energy efﬁciency3.2.1.1.Structure principles.The above mentioned analogies to solutions in nature already provide an obvious approach for introducing the concept of mobility in production technology, especially for the machining of large work pieces.The machining of components with an uncommon high ratio of overall dimension (place requirement inside the machine)to the dimension of the machined geometry(effectively required workspace)results in an inefﬁcient operation of production systems.For conventional machine tools the work piece is placed inside the structure and therefore its overall dimensions determine the size of the workspace and with it also the general size of the complete system,which leads to extreme disproportions between theoreti-cally appropriate and actually needed system size(Fig.4).Consequently,this results in larger inertias of moved compo-nents and therefore,due to larger dimensioned drives,higher absolute energy losses compared to a machine with theoretically ﬁtting dimensions.But it is not only the energy consumption caused by accelerating heavy components that increases.Growing workspace dimensions generally,besides larger frame compo-nents,lead to additional and larger dimensioned backup systems, which,compared to smaller dimensioned systems,cause signiﬁ-cantly higher energy consumptions in ready-for-use condition (basic load)and process load losses–a coherence that can not be resolved(Fig.5).Despite that,higher energy input for theR.Neugebauer et al./CIRP Journal of Manufacturing Science and Technology4(2011)136–147 140production of the machine itself andﬁrst costs can be seen as main drivers of a need for action.In terms of necessary measures conventional machine tools, where the work piece is placed inside the machine and therefore determines workspace and overall machine size through its dimensions,reach their limits due to their basic concept.An approach to solve the problem is to dispose the dogma‘‘work piece inside machine’’in the given case and replace it by the principle ‘‘small machines on large work pieces’’.The basic idea is to use autonomous machining units which are placed locally at the work piece using it as machine base.The dimension of these units and their performance no longer depend on overall dimensions but on the geometry which is to be machined.This approach predominantly follows the principles of miniaturization,mobility and utilization of synergies(cf.Table1).3.2.1.2.Further effects.The concept of mobile machines does not only affect the production system itself,but also higher-level systems in production.The fact that the concept of placing machines at work pieces relies on light and autarkic machining units,results in new approaches in machine and work piece transportation.The transportability of machines,i.e.the capability to relocate the systems,is already an issue in production planning. This relocation can be related to the rearrangement of machines within theﬂow process or a factory or even global cross-plant transportation in the context of rearranging a production network.But especially for maintenance of large machines and facilities small mobile machine structures offer great potentials.The transportation of such components to central service locations demands enormous amounts of resources.This can be avoided by using small machine systems,which can be transported to the facility’s location.With their help the machining can take place on-site and resources can be saved.In addition,the facilities’downtime would be signiﬁcantly reduced because transportation to the service location and possible intermediate storage are no longer necessary.Further potential lies in the machining of built-in components,which makes applications for disassembly and reassembly irrelevant(Fig.6).Table1Classiﬁcation of selected energy-relevant aspects on machine structure level.Target Efﬁciency Efﬁciency/effectivenessLife cycle phase Operating phase Manufact./Disposal Consumer Primary demand Secondary demandMachine operation Process logisticsEnergy relevant aspects on machine structure levelRobustness o+o oMobility o o+oMiniaturization++++Adaptivity+++oMutability++++MultifunctionalityÀÀ+oSpecialisation++ÀoEnergetic networking+oEffect on energy efﬁciency:(+)positive;(À)negative;(o)neutral.Fig.4.Workspace deﬁned by component dimension and by machinedgeometry.Fig.5.Relation of machine size and basic load using the example of the cooling system.R.Neugebauer et al./CIRP Journal of Manufacturing Science and Technology4(2011)136–147141。

Chomsky’scontributiontolinguistics

Chomsky’scontributiontolinguisticsChomsky’s contribution to linguisticsChomsky an linguistics, beginning with his Syntactic Structures, a distillation of his Logical Structure of Linguistic Theory (1955, 75), challenges structural linguistics and introduces transformational grammar. This approach takes utterances (sequences of words) to have a syntax characterized by a formal grammar; in particular, a context-free grammar extended with transformational rules.Perhaps his most influential and time-tested contribution to the field, is the claim that modeling knowledge of language using a formal grammar accounts for the "productivity" or "creativity" of language. In other words, a formal grammar of a language can explain the ability of a hearer-speaker to produce and interpret an infinite number of utterances, including novel ones, with a limited set of grammatical rules and a finite set of terms. He has always acknowledged his debt to Pā?ini for his modern notion of an explicit generative grammar although it is also related to Rationalist ideas of a priori knowledge.It is a popular misconception that Chomsky proved that language is entirely innate and discovered a "universal grammar" (UG). In fact, Chomsky simply observed that while a human baby and a kitten are both capable of inductive reasoning, if they are exposed to exactly the same linguistic data, the human child will always acquire the ability to understand and produce language, while the kitten will never acquire either ability. Chomsky labeled whatever the relevant capacity the human has which the cat lacks the "language acquisition device" (LAD) and suggested that one of the tasks for linguistics should be to figure out what the LADis and what constraints it puts on the range of possible human languages. The universal features that would result from these constraints are often termed "universal grammar" or UG.[36] The Principles and Parameters approach (P&P)—developed in his Pisa 1979 Lectures, later published as Lectures on Government and Binding (LGB)—makes strong claims regarding universal grammar: that the grammatical principles underlying languages are innate and fixed, and the differences among the world's languages can be characterized in terms of parameter settings in the brain (such as the pro-drop parameter, which indicates whether an explicit subject is always required, as in English, or can be optionally dropped, as in Spanish), which are often likened to switches. (Hence the term principles and parameters, often given to this approach.) In this view, a child learning a language need only acquire the necessary lexical items (words, grammatical morphemes, and idioms), and determine the appropriate parameter settings, which can be done based on a few key examples.Proponents of this view argue that the pace at which children learn languages is inexplicably rapid, unless children have an innate ability to learn languages. The similar steps followed by children all across the world when learning languages, and the fact that children make certain characteristic errors as they learn their first language, whereas other seemingly logical kinds of errors never occur (and, according to Chomsky, should be attested if a purely general, rather than language-specific, learning mechanism were being employed), are also pointed to as motivation for innateness.More recently, in his Minimalist Program(1995), while retaining the core concept of "principles and parameters,"Chomsky attempts a major overhaul of the linguistic machinery involved in the LGB model, stripping from it all but the barest necessary elements, while advocating a general approach to the architecture of the human language faculty that emphasizes principles of economy and optimal design, reverting to a derivational approach to generation, in contrast with the largely representational approach of classic P&P.Chomsky's ideas have had a strong influence on researchers of the language acquisition in children, though many researchers in this area such as Elizabeth Bates[37] and Michael T omasello[38] argue very strongly against Chomsky's theories, and instead advocate emergentist or connectionist theories, explaining language with a number of general processing mechanisms in the brain that interact with the extensive and complex social environment in which language is used and learned.His best-known work in phonology is The Sound Pattern of English(1968), written with Morris Halle(and often known as simply SPE). This work has had a great significance for the development in the field. While phonological theory has since moved beyond "SPE phonology" in many important respects, the SPE system is considered the precursor of some of the most influential phonological theories today, including autosegmental phonology, lexical phonology and optimality theory. Chomsky no longer publishes on phonology.Generative grammarThe Chomskyan approach towards syntax, often termed generative grammar, studies grammar as a body of knowledge possessed by language users. Since the 1960s, Chomsky has maintained that much of this knowledge is innate, implying that children need only learn certain parochial features of their nativelanguages.[39] The innate body of linguistic knowledge is often termed Universal Grammar. From Chomsky's perspective, the strongestevidence for the existence of Universal Grammar is simply the fact that children successfully acquire their native languages in so little time. Furthermore, he argues that there is an enormous gap between the linguistic stimuli to which children are exposed and the rich linguistic knowledge they attain (the "poverty of the stimulus" argument). The knowledge of Universal Grammar would serve to bridge that gap.Chomsky's theories have been immensely influential within linguistics, but they have also received criticism. One recurring criticism of the Chomskyan variety of generative grammar is that it is Anglocentric and Eurocentric, and that often linguists working in this tradition have a tendency to base claims about Universal Grammar on a very small sample of languages, sometimes just one. Initially, the Eurocentrism was exhibited in an overemphasis on the study of English. However, hundreds of different languages have now received at least some attention within Chomskyan linguistic analyses.[40][41][42][43][44] In spite of the diversity of languages that have been characterized by UG derivations, critics continue to argue that the formalisms within Chomskyan linguistics are Anglocentric and misrepresent the properties of languages that are different from English.[45][46][47] Thus, Chomsky's approach has been criticized as a form of linguistic imperialism.[48]In addition, Chomskyan linguists rely heavily on the intuitions of native speakers regarding which sentences of their languages are well-formed. This practice has been criticized on general methodological grounds. Some psychologists andpsycholinguists,[who?] though sympathetic to Chomsky's overall program, have argued that Chomskyan linguists pay insufficient attention to experimental data from language processing, with the consequence that their theories are not psychologically plausible. Other critics (see language learning) have questioned whether it is necessary to posit Universal Grammar to explain child language acquisition, arguing that domain-general learning mechanisms are sufficient.Today there are many different branches of generative grammar; one can view grammatical frameworks such as head-driven phrase structure grammar, lexical functional grammar and combinatory categorial grammar as broadly Chomskyan and generative in orientation, but with significant differences in execution.。