The condensation of γ-butyrolactone with ethyl acetate

合集下载

WAters31843

Desolvation gas flow liters/hr 200 to 250 250 to 400 250 to 400 400 to 750
Higher desolvation temperatures give increased sensitivity. However, increasing the temperature above the range suggested reduces beam stability. Increasing the gas flow rate higher that the quoted values lead to unnecessary high nitrogen consumption. Avoid operating the desolvation heater for long periods of time without proper gas flow. To do so could damage the source.
©2004 Waters Corporation
MS Troubleshooting Strategy
Try to simplify -assess impact on lab efficiency -inspect the MS or /MS/MS -try to categorize troubleshoot the easiest to fix items first
Mass Spectrometry
Source: ESI APcI Nano-ESI Mass analyzers: magnetic sectors electric sectors time of flight quadrupole ion trap FT-ICR

Microfluidics of nano-drug delivery

Microﬂuidics of nano-drug deliveryClement Kleinstreuer a,b,*,Jie Li a ,Junemo Koo caDepartment of Mechanical and Aerospace Engineering,North Carolina State University,Raleigh,NC 27695-7910,USA bDepartment of Biomedical Engineering,North Carolina State University,Raleigh,NC 27695-7910,USA cDepartment of Mechanical Engineering,Kyung Hee University,Seocheon-dong,Gyeonggi-do 446-701,South Koreaa r t i c l e i n f o Article history:Received 12December 2007Received in revised form 4April 2008Available online 12June 2008Keywords:Bio-MEMS Drug delivery Nanoﬂuids Microﬂuidics Microchannela b s t r a c tAfter a brief review of microﬂuidics,a bio-MEMS application in terms of nanoﬂuid ﬂow in microchannels is presented.Speciﬁcally,the transient 3-D problem of controlled nano-drug delivery in a heated micro-channel has been numerically solved to gain new physical insight and to determine suitable geometric and operational system puter model accuracy was veriﬁed via numerical tests and com-parisons with benchmark experimental data sets.The overall design goals of near-uniform nano-drug concentration at the microchannel exit plane and desired mixture ﬂuid temperature were achieved with computer experiments considering different microchannel lengths,nanoparticle diameters,channel ﬂow rates,wall heat ﬂux areas,and nanoﬂuid supply rates.Such micro-systems,featuring controlled transport processes for optimal nano-drug delivery,are impor-tant in laboratory-testing of predecessors of implantable smart devices as well as for analyzing pharma-ceuticals and performing biomedical precision tasks.Ó2008Elsevier Ltd.All rights reserved.1.IntroductionMicroﬂuidics is the study of transport processes in microchan-nels,i.e.,methods and devices for controlling and manipulating ﬂuid ﬂow and particle transport at the microscale.Microﬂuidic de-vices,consisting in general of reservoirs,channels,pumps,valves,mixers,actuators,ﬁlters and/or heat exchangers,are primary com-ponents of lab-on-a-chip and total analysis systems [1]or function as bio-MEMS for precise drug delivery by implanted or transder-mal rger versions may be used as micro-heat sinks in miniature electronic systems (see Kleinstreuer and Li,[2]).The basics of microﬂuidics are discussed in the books by Tabeling [3]and Nguyen and Wereley [4],while bio-MEMS fundamentals,technologies,and applications for drug delivery have been re-viewed by Tay [5]as well as in selected chapters by Saliterman [6]and Wang and Soper [7].Beebe et al.[8]summarized the phys-ics and applications of microﬂuidics in biology,discussing micro-device components as well as manufacturing methods,such as micromachining,soft lithography,embossing,in situ construction,injection molding,and laser ablation.As Beebe et al.[8]illustrated,the main component in any microﬂuidic device is the channel network.Bio-MEMS can be considered as having at least one system dimension in the submicron or micron range (100nm–200l m)and other dimensions of up to several millimeters [6].With the increasing awareness of microﬂuidic physics and the surface sci-ence of building materials,such as silicon,polymers,glass and ceramics,the traditional fabrication techniques previously im-ported from integrated circuit manufacturing to MEMS have been also applied to bio-MEMS.The central question in microﬂuidics modeling is the validity of the continuum assumption,and if so (as may be the case for standard water ﬂow in microchannels with D h >0.1l m),which are the dominant forces?Important character-istics and phenomena in the microscale environment include lam-inar ﬂow,entrance effects,surface roughness effects,diffusion,wall forces,surface tension,very high surface-area-to-volume ra-tio,and microﬂuidic resistance.For example,some experimental evidence indicates that the Reynolds number for transition from laminar to turbulent ﬂow may be different in microchannels from that predicted by macrochannel-ﬂow theory.Indeed,recent works analyzed by Koo and Kleinstreuer [9]showed that a lot of contro-versy exists between experimental reports on (thermal)microscale ﬂows,explaining that surface roughness and entrance effects may cause early turbulence.In the 1990s most bio-MEMS studies were concentrated in aca-demia,while in recent years commercialization of such devices be-gan.Examples include an electronically activated drug delivery microchip (Shawgo et al.,[10]);a controlled delivery system via integration of silicon and electroactive polymer technologies;a MEMS-based DNA sequencer developed by Cepheid [11];and0017-9310/$-see front matter Ó2008Elsevier Ltd.All rights reserved.doi:10.1016/j.ijheatmasstransfer.2008.04.043*Corresponding author.Address:Department of Mechanical and Aerospace Engineering,North Carolina State University,Raleigh,NC 27695-7910,USA.Tel.:+19195155261;fax:+19195157968.E-mail address:ck@ (C.Kleinstreuer).International Journal of Heat and Mass Transfer 51(2008)5590–5597Contents lists available at ScienceDirectInternational Journal of Heat and Mass Transferjournal homepage:www.else v i e r.c o m /l o ca t e /i j h mtarrays of in-plane and out-of-plane hollow micro-needles for der-mal/transdermal drug delivery (Ovsianikov et al.,[12]and Kimand Lee,[13]among others)as well as nanomedicine applications of nanogels or gold-coated nanoparticles (Labhasetwar and Leslie-Pelecky,[14]).Part of the advanced endeavors in developing inte-grated micro-or nano-drug delivery systems is the interest in eas-ily monitoring and controlling target-cell responses to pharmaceutical stimuli,to understand biological cell activities,or to facilitate drug development processes.While micro-devices allow precise drug delivery by both im-planted and transdermal techniques,conventional drug delivery is characterized by the ‘‘hill-and-valley”phenomenon.It implies that when a drug is dispensed,drug concentration in the blood will increase,peak and then drop as the drug is metabolized,where the cycle is repeated for each drug dose.In nano-drug delivery (ND)systems,controlled drug release occurs over an extended period of time.Hence,the desired drug concentration will remain within the therapeutic window as ually,an integrated ND sys-tem is composed of drug preparation,feeding,sensing (test),and feedback parts.The types and doses of drugs are selected in the drug preparation part,while the feeding system guides drugs and buffer ﬂuids into the test part.Test cells are placed into the test section,where they react to drugs and resulting (electric)response signals are monitored via the feedback part.Of interest here is the optimal delivery of nanoparticles (drugs)in an aqueous solution in terms of predetermined uniform particle concentration and mixture temperature.Such a dilute suspension,called a nanoﬂuid,is conveyed via microchannels to recipient liv-ing cells situated in a well (see Fig.1a ).Controlled dosages of nano-drugs allow for simultaneous testing of living cells and stim-uli responses.Those micro-systems,featuring controlled transport processes for optimal nano-drug delivery,are important in labora-tory-testing of predecessors of implantable smart devices which may offer closed-loop sensing,result interpretation,and automatic nano-drug dispensation.Other applications for this basic microﬂu-idic device include testing of pharmaceuticals and performing efﬁ-cient biomedical analyses.2.TheoryIn the controlled multiple nano-drug-stream system (Fig.1a ),the plenum chamber functions as a reservoir of an aqueous nutri-ent-supply and/or purging ﬂuid.The microchannels can alter the incoming ﬂuid to the test section,i.e.,target-well with living cells,by adjusting the individual inlet pressure or resistance.Nano-drugs can be supplied by setting the supply pressure of the nano-drug solution higher than that of the ﬂuid supply side,while purging ﬂuid can go through the testing section by lowering or eliminating the drug supply pressure.An appropriate wall heat ﬂux beneath the microchannels ensures that delivery of the drug-ﬂuid mixture to the living cells occurs at an optimal temperature,i.e.,37°C.DueMultiple microchannels(Attached to wells with cells)Surface heatingPlenum chamber(Reservoir)Buffer fluid inletVariable nano-drug inlets(Nanofluid)Fig.1a.Nanomedicine delivery system with eight microchannels.Nomenclature A g geometric area A v valid area c concentrationc p speciﬁc heat capacityd diameterD diffusivity coefﬁcient D h hydraulic diameter H channel heightk thermal conductivity L channel length Nu Nusselt number p pressurePo Poiseuille number Pr Prandtl number q 00uniform heat ﬂuxR b interface thermal resistance Re Reynolds number Ttemperaturet timeu ,v velocity components Wchannel widthGreek symbolsaaspect ratiou volume fraction j B Boltzmann constant l dynamic viscosity m kinematic viscosity q density v Reynolds number ratioSubscripts eff effective f base ﬂuid pparticleFig.1b.Representative microchannel with controlled nanoﬂuid injection.C.Kleinstreuer et al./International Journal of Heat and Mass Transfer 51(2008)5590–55975591to the temperature dependentﬂuid properties,i.e.,viscosity,den-sity,diffusivity and thermal conductivity,the heatﬂux was also as-sumed to have an inﬂuence on the drug concentration and velocity distribution.Selecting one representative microchannel,the cho-sen unit has a hydraulic diameter of40l m for the main channel and20l m for the drug inlet branch.The Reynolds number ratio of drug-inlet to main-channelﬂows is deﬁned asv¼Re2=Re1ð1ÞThe associated Reynolds numbers areRe i¼ðuD hÞim ið2Þwith i=1indicating the purging or nutrient-supply channel and i=2denoting the nanoﬂuid channel(see Fig.1b).The drug concentration distribution for different main-channel lengths and inlet Reynolds numbers was analyzed.The effects of the Reynolds number ratio,v,and thermal boundary condition, q wall,were also compared and analyzed.Both the purging/nutri-ent-supplyﬂuid and nano-drug solution were at inlet room tem-perature(T in=293K).2.1.Nanoﬂuid property correlationsTo evaluate the impact of nanoparticles(i.e.,drugs)and wall heatﬂux on the velocityﬁeld as well as temperature and concen-tration proﬁles,the nanoﬂuid properties have to be identiﬁed.Typ-ically,for a very dilute suspension,the effective viscosity,density and speciﬁc heat capacity have the following forms(Xuan and Roetzel,[15]):l eff ¼l f1ð1ÀÞð3Þqeff¼uq pþð1ÀuÞq fð4Þðq c pÞeff¼uðq c pÞpþð1ÀuÞðq c pÞfð5ÞHere,q eff is the nanoﬂuid density,l eff is the nanoﬂuid viscosity,and (q c p)eff is the nanoﬂuid speciﬁc heat capacity.The nanoparticle dif-fusivity follows the Stokes–Einstein equation:D¼j B Tpl pð6Þwhere j B is the Boltzmann constant,T is theﬂuid temperature,and d p is the nanoparticle diameter.Most challenging is the thermal conductivity of nanoﬂuids,for which benchmark experimental data sets show that the thermal conductivity of a nanoﬂuid has strong volume fraction as well as temperature dependences(Das et al.,[16];Li and Peterson,[17]). Some researchers introduced different effective thermal conduc-tivity theories which directly or indirectly considered temperature dependence,e.g.,Koo and Kleinstreuer[18],Prasher et al.[19],and Jang and Choi[20].In comparison studies,Kleinstreuer and Li[21] and Li and Kleinstreuer[22]analyzed the models of Jang and Choi [20]and Prasher et al.[19],and updated their KKL(Koo–Kle-instreuer–Li)model.The KKL model is based on Brownian-mo-tion-induced micro-mixing and achieved good agreements with various experimental data sets.Speciﬁcally,the KKL thermal con-ductivity model,k eff,takes into account the effects of particle size, particle volume fraction and temperature dependence as well as the type of nanoparticle and baseﬂuid combinations in form of (Koo and Kleinstreuer,[9]):k eff¼k staticþk Brownianð7ÞThe static part is from Maxwell’s model and the dynamic part was developed based on kinetic theory together with Stokes’ﬂow of mi-cro-scale convective heat transfer,i.e.,micro-mixing.Hence,k statick f¼1þ3k p;effk fÀ1uk p;effk fþ2Àk p;effk fÀ1uð8Þandk Brownian¼5Â104uq f c p;fﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃjbTqpd psg T;u;d p;q pð9Þwhere q is the density,c p,f isﬂuid thermal capacity,and u is the vol-ume fraction,while the subscripts f and p indicateﬂuid and particle, respectively.The g-function,determined semi-empirically,was introduced to encapsulate the thermo-hydrodynamic interactions among all nanoparticles and affected micro-scaleﬂuid parcels.For Al2O3–water and CuO–water nanoﬂuids,the nonlinear g-function generated r2values of96%and98%,respectively(Li,[23]).The KKL model was employed in the current study.erning equationsAssuming the continuum approach to be valid(i.e.,here D h P20l m)for transient3-D laminar incompressibleﬂow in a microchannel,the continuity,momentum,energy and species transfer equations have to be solved,considering temperature-dependentﬂuid properties(see Section2.1).Continuity equationrÁ½qðTÞ~u ¼0ð10ÞMomentum equationo uo tþð~uÁr~uÞ¼À1q r pþrÁðm r~uÞð11ÞEnergy equationq c p o Tþð~uÁrÞT!¼r2ðkTÞþl Uð12ÞwhereU¼o u io x jþo u jo x io uio x jð13ÞMass transfer equationo co tþ~uÁr c¼D r2cð14ÞHere,~u is the velocity vector,D is the nanoparticle diffusivity,and U is the viscous dissipation function.For nanoﬂuidﬂow and pureﬂuid ﬂow,the corresponding physical properties will be chosen,i.e.,the thermal conductivities,k eff and k f,respectively.For the design analysis,uniform inlet velocity conditions and an ambient pressure condition for the outlet were applied.A5% volume fraction of d p=10and500nm nanoparticles in water was selected to enter the drug supply channel in the form of a rectangular pulse function.The cycle,shows as part of Fig.1b,is centered with basically a one-second pulse during the observation time t T=30s.It starts at dimensionless time t*=0.49,which is deﬁned astÃ¼t=t T;06tÃ61ð15Þwhere t T=L max/u1is the pulse period,and t is the real time,whileL max=10mm being the maximum length used,and u1¼m1Re1D h1.A heatﬂux variable in magnitude and extent was applied along part of the bottom wall,starting at z=0.02mm and ending selectively at z=2.5,3,4or5mm(see Fig.1b).5592 C.Kleinstreuer et al./International Journal of Heat and Mass Transfer51(2008)5590–55972.3.Numerical methodThe numerical solution of the Eulerian transport equations were carried out with a user-enhanced,unstructuredﬁnite-volume based program,i.e.,CFX11from Ansys,Inc.(Canonsburg,PA). The mesh size of the computational domain used in this study was reﬁned until acceptable levels of grid independence of the solutions were achieved.Furthermore,both the maximum mass and momentum residuals were less than10À4.3.Results3.1.Model validationsClassical friction factor correlations as well as k eff-comparisons are discussed.Speciﬁcally,for laminar fully-developedﬂow of a pureﬂuid,the Poiseuille number is deﬁned asPo¼fRe¼D pÁD2h2l f uLð16Þwhere Po=16for circular conduits.3.1.1.Friction factorFor rectangular microchannels,the Poiseuille number is a func-tion of aspect ratio(a=channel width/channel height).It can be determined using Eq.(17)from Shah and London[24].Po¼241À1:3553aþ1:9467a2À1:7012a3Àþ0:9564a4À0:2537a5Áð17Þwhere for square ducts,Po=14.23.Fig.2provides a comparison of friction factors at different Reynolds number.Clearly,the computed friction factor is in very good agreement with the theoretical re-sults.With an increase in inlet velocity,the temperature range and average temperature in theﬂuid decreases,i.e.,from304K to 296K,and theﬂuid kinematic viscosity increases.Thus,for thesame velocity,the Reynolds number,Re1¼ðuD h mÞ1is different for water with temperature-dependent properties when compared to constant properties.The reason is that the bottom heatﬂux inﬂu-ences the temperature distribution and,via the changingﬂuid prop-erties,also the velocityﬁeld,especially where the temperature difference is large.The inset plot in Fig.2indicates the friction fac-tor differences between water with temperature-dependent prop-erties and constant properties for the same velocity.Speciﬁcally,e¼f c:pÀf v:pÀÁf c:pð18Þwhere f c.p is the friction factor for water with constant properties, f v.p is the friction factor for water with variable properties,i.e.,tem-perature dependent.In the lower velocity range,the higherﬂuid temperature induced a lower kinematic viscosity for the tempera-ture-dependentﬂuid which introduced a higher Reynolds number and hence a smaller friction factor.As the velocity increases,the friction factor increases because of the decrease in theﬂuid’s aver-age temperature.Fig.3a and b show the axial velocity distribution at the channel outlet for water with temperature-dependent and constant properties,respectively.As Fig.3a indicates,the tempera-ture generated a decrease in viscosity near the bottom surface and as a result lowers the location of the maximum velocity,while for water with constant properties the maximum velocity always ap-pears at the centerline(see Fig.3b).3.1.2.Pressure gradientLi and Kleinstreuer[22]analyzed the inﬂuence of nanoparticle volume fraction on the pressure gradient for fully-developedﬂow. Selecting nanoﬂuids with4%volume fractions of28.6nm CuO–water mixtures,the pressure gradient increased an average13% for a constantﬂow rate,which matched measured data.Fig.4de-picts the pressure gradients at different mean velocities when employing a5%gold-particle-and-water mixture with differentFig.3.Velocity distribution in channel outlet(a)water with temperature dependent properties and(b)water with constant physical properties.C.Kleinstreuer et al./International Journal of Heat and Mass Transfer51(2008)5590–55975593nanoparticle sizes,i.e.,10and500nm(see Labhasetwar&Leslie-Pelecky,[14]).Clearly,nanoparticle size does not inﬂuence the pressure gradient when the same volume fraction is employed (see Eqs.(3)–(5)).The pressure gradient increases by13–18%when employing the5%nanoﬂuids,conﬁrming the results of Li and Kle-instreuer[22].3.1.3.Enhanced thermal conductivityIn Fig.5,the KKL model is compared with experimental data for CuO–water nanoﬂuid at different temperatures(21°C,36°C,51°C) and volume fractions(1–4%).The KKL model compares well with the experimental observations of Das et al.[16].Because of the lack of quantitative information concerning therapeutic nanoparticles, other than their mean diameters,the practical range for k eff/k f was assumed to be1.0–2.5and the g-function was taken to be lin-early dependent on temperature(20–70°C),generating a value range for g of0.3Â10À3to7Â10À3.3.2.Concentration distributions of drug nano-particlesThe distributions of nanoparticle concentrations and tempera-tures at the main microchannel outlets with variable channel lengths were compared for different particle sizes and boundary conditions,i.e.,different Reynolds numbers Re1and Re2and for dif-ferent Reynolds numbers ratios v as well as different heating modes q w.The desired nano-drug particle uniformity at z=L is de-ﬁned asU c¼A v=A gÂ100%ð19Þwhere A v is the valid area,i.e.,the area where the drug particle con-centration is equal or larger than90%of local maximum concentra-tion,and A g is the actual geometric channel-exit area.Fig.6 compares the dimensionless drug concentration distributions (d p=10nm)at different cross sections in the microchannel for dif-ferent paring the U c(t)graphs for the outlet cross section at z=10mm,it is evident that the added heat measurably increases nanoparticle diffusion D¼j B T3pl d pand hence the drug distribution two-fold,i.e.,via the mixture temperature and the reducedﬂuid vis-cosity.At station z=3mm,the nanoparticles are still concentrated in a small part of the channel cross section and hence the drug uni-formity U c is very low.Clearly,nanoparticle(i.e.,drug)mixing develops as the two streams merge,and for z=10mm the desired near-uniform concentration proﬁle is achieved.There,the differ-ence is less than10%between the maximum value and the mini-mum value in the particular cross section.Figs.7a–d and8a–d depict the velocity and dimensionless nano-drug concentration distributions along the center line (À2Â10À56y62Â10À5)at threeﬂow-developing phases (z=0.5mm,5mm and10mm)at different time levels for the case of v=1.69and L=10mm.The dimensionless nano-drug concen-tration is deﬁned as:cÃ¼c=c0ð20Þ5594 C.Kleinstreuer et al./International Journal of Heat and Mass Transfer51(2008)5590–5597here c is the local drug concentration,and c0is the drug concentra-tion at the drug-channel inlet,which is assumed to be unity.The intensity of drug supply measurably inﬂuences the velocity distribution(Fig.7).At t*=0.51,in the middle of nanoﬂuid injec-tion,the main-channel velocity is at a maximum.The velocity down stream of z>0.5mm is somewhat elevated because of the nano-drug inﬂuence(see Fig.8a).For the same reason,at t*=0.68and t*=0.85,the velocity distribution exhibits the lowest values at z=5mm and z=10mm,respectively(Fig.7b and c).At t*=1.0,most of the nano-drug particles supplied have left the delivery microchannel and hence the velocity distributions at the three axial stations(i.e.,z=0.5,5,and10mm)exhibit no differ-ences any more(Fig.7d).At the middle of the one-second nanoﬂuid cycle(i.e.,t*=0.51), the resulting nano-drug pulse is registered near the inlet at z=0.5mm but is not felt further downstream(Fig.8).The nanoparticles diffuse and they are conveyed through the channel leading to highly nonlinear‘‘time-and space-”dependent concen-tration proﬁles(Fig.8a–d).For example,at t*=0.85the nano-drug distribution is almost uniform across the channel exit plane(see Fig.8c).Fig.9compares the uniformity of drug-particle concentration at different Re1numbers and microchannel lengths.With the de-crease of Re1values from0.04to0.004and with an increase of the channel length,which implies much larger diffusion times, the uniformity of drug-particle distribution improves.As expected, at small Reynolds numbers,drug uniformity can be much more rapidly achieved.Fig.10depicts the drug uniformity at channel outlet z=10mm for drugs with a particle diameter of500nm at different Reynolds numbers.It shows that the decrease of Re1can improve drug parison of Figs.10and6shows that smaller drug-par-ticles may greatly beneﬁt the drug concentration uniformity.Figs.11and12summarize the percentage changes in minimum microchannel-length in order to achieve near-uniform exit concen-tration for different Reynolds number ratios and different wall-heat-ﬂux extents,respectively.The‘‘minimum uniformity-length”is deﬁned as the required main-channel length where the drug-particle concentration in the exit area is equal or larger than90% of the local maximum concentration.Selecting v=1.26as the ref-erence ratio,the dimensionless minimum uniformity length change is compared for different Reynolds number ratios in Fig.11,an increase of v measurably decreases the minimum uni-formity length.As Fig.12shows,a decrease of the heated area also decreases the minimum uniformity length.Because theﬂuid tem-perature increase isﬁxed(from room temperature293K to bodyC.Kleinstreuer et al./International Journal of Heat and Mass Transfer51(2008)5590–559755955596 C.Kleinstreuer et al./International Journal of Heat and Mass Transfer51(2008)5590–5597temperature 310K),the effect on the drug diffusivity is not prom-inent by just decreasing the heated area.4.ConclusionsIn the present study a nano-drug-supply system,i.e.,a bio-MEMS,was introduced.Of main interest were the conditions for achieving uniform concentrations at the microchannel exit of the supplied nano-drugs.A heat ﬂux which depends on the levels of nano-ﬂuid and purging ﬂuid velocity was added to en-sure that drug delivery to the living cells occurs at an optimal temperature,i.e.,37°C.The added wall heat ﬂux had also a po-sitive inﬂuence on drug-concentration uniformity.Overall,thenano-drug concentration uniformity is inﬂuenced by channel length,particle diameter and the Reynolds number of both the nanoﬂuid supply and main microchannels.In light of the convec-tion–diffusion controlled transport mechanisms,longer channels,smaller particle diameters as well as lower Reynolds numbers are desirable for best,i.e.,uniform drug delivery.Furthermore,the Reynolds number ratio and the extent of heated area also measurably inﬂuence the minimum microchannel length re-quired for achieving the desired drug-concentration uniformity.Future work will focus on the effects of angled drug-delivery channel and static mixer in the main channel.AcknowledgementThe support of Jie Li via an endowed fellowship created by Joe and Sarah Archie as well as the use of ANSYS-CFX11(Ansys,Inc.,Canonsburg,PA)are gratefully acknowledged.References[1]H.A.Stone, A.D.Stroock, A.Ajdari,Engineering ﬂows in small devices:microﬂuidics toward a lab-on-a-chip,Annu.Rev.Fluid Mech.36(2004)381–411.[2]C.Kleinstreuer,J.Li,in:D.Li (Ed.),Microscale Cooling Devices,Encyclopedia ofMicro and Nanoﬂuidic,Springer-Verlag,Heidelberg,DE,2008.[3]P.Tabeling,Introduction to Microﬂuidics,Oxford University Press,Oxford,UK,New York,2005.[4]N.-T.Nguyen,S.T.Wereley,Fundamentals and Applications of Microﬂuidics,Arten House,Boston,2006.[5]F.E.H.Tay,Microﬂuidics and Biomems Applications,Kluwer AcademicPublishers,Boston,2002.[6]Steven S.Saliterman,Fundamentals of BioMEMS and Medical Microdevices,Wiley-Interscience SPIE PRESS Bellingham,Washington,USA,2006.[7]W.Wang,S.A.Soper,Bio-MEMS:Technologies and Applications,CRC/Taylor &Francis,Boca Raton,2006.[8]D.J.Beebe,G.A.Mensing,G.M.Walker,Physics and applications ofmicroﬂuidics in biology,Annu.Rev.Biomed.Eng.4(2002)261–286.[9]J.Koo, C.Kleinstreuer,Liquid ﬂow in microchannels:experimentalobservations and computational analysis of microﬂuidics effect,J.Micromech.Microeng.13(2003)568–579.[10]R.S.Shawgo,A.C.R.Grayson,Y.Li,M.J.Cima,Bio-MEMS for drug delivery,Curr.Opin.Solid State Mater.Sci.6(2002)329–334.[11]Cepheid,<>,2003.[12]A.Ovsianikov,B.Chichkov,et al.,Two photon polymerization of polymer–ceramic hybrid materials for transdermal drug delivery,Int.J.Ceramic Technol.4(2007)22–29.[13]K.Kim,J.B.Lee,High aspect ratio tapered hollow metallic microneedle arrayswith microﬂuidic interconnector,Microsyst.Technol.13(2007)231–235.[14]bhasetwar, D.L.Leslie-Pelecky,Biomedical Applications ofNanotechnology,Wiley-Interscience,A John Wiley &Son,Inc.,Publication,2007.[15]Y.Xuan,W.Roetzel,Conceptions for heat transfer correlation of nanoﬂuids,Int.J.Heat Mass Transfer 43(2000)3701–3707.[16]S.K.Das,N.Putra,P.Thiesen,W.Roetzel,Temperature dependence of thermalconductivity enhancement for nanoﬂuids,J.Heat Transfer 125(2003)567–574.[17]C.H.Li,G.P.Peterson,Experimental investigation of temperature and volumefraction variations on the effective thermal conductivity of nanoparticle suspensions (nanoﬂuids),J.Appl.Phys.99(2006)084314.[18]J.Koo,C.Kleinstreuer,A new thermal conductivity model for nanoﬂuids,J.Nanoparticle Res.6(2004)577–588.[19]R.S.Prasher,P.Bhattacharya,P.E.Phelan,Brownian motion based convectiveconductive model for the effective thermal conductivity of nanoﬂuids,J.Heat Transfer 128(2006)588–595.[20]S.P.Jang,S.U.S.Choi,Effects of various parameters on nanoﬂuid thermalconductivity,J.Heat transfer 129(2007)617–623.[21]C.Kleinstreuer,J.Li,Analysis of the Jang &Choi k eff -model,ASME J.HeatTransfer 130(2008).[22]J.Li,C.Kleinstreuer,Thermal performance of nanoﬂuid ﬂow in microchannels,Int.J.Heat Fluid Flow,29(2008),in press.[23]J.Li,Computational Analysis of Nanoﬂuid Flow in Microchannels withApplications to Micro-heat Sinks and Bio-MEMS,Ph.D.dissertation,MAE Department,NCSU,Raleigh,NC,2009.[24]S.K.Shah,A.L.London,Laminar Flow Forced Convection in Ducts,Supplement1to Advances in Heat Transfer Academic,New York,1978.C.Kleinstreuer et al./International Journal of Heat and Mass Transfer 51(2008)5590–55975597。

Antibiotics for FGID

Case Studies of Antibiotic Therapy in the Management of Functional Gastrointestinal DisordersJ a n u a r y 2007e 3, I s s u e 1, S u p p l e m e n t 1w w w.c l i n i c a l a d v a n c e s .c o m V o l u m Commentary by Mark Pimentel, MD Cedars-Sinai Medical Center Los Angeles, CaliforniaSupported through an educational grant from Salix Pharmaceuticals, Inc.FacultyCharles Cattano, MDAnne Arundel Gastroenterology Associates Annapolis, Md .Jennifer Christie, MDMount Sinai School of Medicine New York, NYCharles Loewe, MDSarasota Center for Digestive Diseases Sarasota, Fla.Venkat Mohan, MDNorthwest Gastroenterology AssociatesBellevue, Wash.Th is publication is not intended to oﬀ er an opinion on the advisability of administering XIFAXAN (rifaximin) tablets 200 mg in a manner inconsistent with product labeling. Please consult the accompanying product information for full prescribing details or contact the Salix Medical Aﬀ airs Department (800-508-0024) with any questions.Maria T. Abreu, MDMount Sinai School of Medicine Nezam H. Afdhal, MDBeth Israel DeaconnessMedical CenterHarvard Medical SchoolRobert N. Baldassano, MD Children’s Hospital of Philadelphia University of Pennsylvania Theodore Bayless, MDJohns Hopkins HospitalManoop S. Bhutani, MD University of TexasMedical BranchThomas D. Boyer, MD University of ArizonaJoel V. Brill, MDPredictive Health, LLCRobert S. Brown, Jr., MD, MPH Columbia University Medical Center Stephen Brunton, MD Cabarrus Family Medicine Residency Brooks D. Cash, MDNational Naval Medical CenterLin Chang, MDDavid Geffen School of Medicine University of California,Los AngelesWilliam D. Chey, MD University of MichiganMedical CenterRussell D. Cohen, MD University of ChicagoScott J. Cotler, MDUniversity of Illinois at Chicago Douglas Dieterich, MDMount Sinai Medical CenterJack A. Di Palma, MD University of South Alabama Raymond DuBois, MD Vanderbilt UniversityGary W. Falk, MDCleveland Clinic Foundation Ronnie Fass, MDSouthern Arizona VAHealth Care SystemUniversity of Arizona HealthSciences CenterM. Brian Fennerty, MDOregon Health & ScienceUniversityRobert Gish, MDCalifornia Pacific Medical CenterTarek Hassanein, MDUniversity of California, San DiegoJorge Herrera, MDUniversity of South AlabamaColin W. Howden, MDNorthwestern UniversityFeinberg School of MedicineIra M. Jacobson, MDWeill Medical College ofCornell UniversityLennox J. Jeffers, MDUniversity of MiamiDavid A. Johnson, MDEastern VA Medical SchoolMaureen M. Jonas, MDChildren’s Hospital BostonSunanda V. Kane, MD, MSPHUniversity of ChicagoPhilip O. Katz, MDAlbert Einstein Medical CenterAsher Kornbluth, MDMount Sinai Medical CenterJoshua Korzenik, MDMassachusetts General HospitalBrian E. Lacy, MD, PhDDartmouth Hitchcock Medical CenterBret A. Lashner, MDCleveland Clinic FoundationAnthony J. Lembo, MDBeth Israel DeaconessMedical CenterRichard MacDermott, MDAlbany Medical CenterPhilip B. Miner Jr., MDOklahoma School of MedicineMark Pimentel, MD, FRCP(C)Cedars-Sinai Medical CenterPaul J. Pockros, MDScripps ClinicFred Poordad, MDCedars-Sinai Medical CenterDaniel H. PresentMount Sinai School of MedicineEamonn M. M. Quigley, MDNational University of Ireland, CorkK. Rajender Reddy, MDUniversity of PennsylvaniaDouglas K. Rex, MDIndiana University Medical CenterDavid T. Rubin, MDUniversity of ChicagoPaul Rutgeerts, MDKatholieke Universiteit LeuvenSeymour M. Sabesin, MDRush University Medical CenterRichard E. Sampliner, MDUniversity of ArizonaR. Balfour Sartor, MDUniversity of North Carolina,Chapel HillPhilip S. Schoenfeld, MD, MEd, MScUniversity of MichiganBo Shen, MDThe Cleveland ClinicMitchell Shiffman, MDVirginia CommonwealthUniversityDaniel Shouval, MDHadassah University HospitalJerome H. Siegel, MDBeth Israel Medical CenterMark Sulkowski, MDJohns Hopkins UniversitySchool of MedicineNicholas J. Talley, MD, PhDMayo ClinicNizar Zein, MDCleveland Clinic FoundationEDITORIAL ADVISORY BOARDE d i t o r-i n-C h i e fGary R. Lichtenstein, MDDirector, Inflammatory BowelDisease ProgramProfessor of MedicineUniversity of PennsylvaniaS e c t i o n E d i t o r sJohn Baillie, MB ChB, FRCPProfessor of MedicineDirector of PancreatobiliaryDisorders ServiceWake Forest University HealthSciences CenterStephen B. Hanauer, MDProfessor of Medicineand Clinical PharmacologyDirector, Section ofGastroenterology and NutritionUniversity of ChicagoJoel E. Richter, MD, FACP, MACGProfessor of MedicineChairman, Department of MedicineTemple University School of MedicineEugene R. Schiff, MDProfessor of MedicineChief of the Division of HepatologyDirector of the Center for Liver DiseasesUniversity of Miami School of MedicineDisclaimerFunding for this case study compendium has been provided through an unrestricted educational grant from Salix Pharmaceuticals, Inc., Morrisville, NC. Sponsorship of this supplement does not imply the sponsor’s agreement with the views expressed herein. Every eﬀ ort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Gastro-Hep Communications, the sponsors, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.©2007 Gastro-Hep Communications. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.Introduction: Antibiotics for Functional Gastrointestinal Symptoms4Ciprofloxacin in a Patient With Exacerbation of Functional Gastrointestinal Symptoms After an Episode of Gastroenteritis5Charles Cattano, MDRifaximin Therapy in a Patient With Constipation-predominant IBS6Jennifer Christie, MDRifaximin in a Patient With Relapsing Functional Gastrointestinal Symptoms7Venkat Mohan, MDRifaximin as Acute Therapy and Maintenance Treatment for Functional Gastrointestinal Symptoms9Charles Loewe, MD CommentaryMark Pimentel, MD10Table of ContentsCase Studies of Antibiotic Therapy in the Management of Functional Gastrointestinal DisordersC A S E S T UD IE SIntroduction: Antibiotics for Functional Gastrointestinal SymptomsI rritable bowel syndrome (IBS) is a substantial healthproblem, aﬀ ecting an estimated 10–20% of individuals in the United States.1 Symptoms commonly associated with IBS include bloating, abdominal pain, constipation, diarrhea, and ﬂ atulence.2Th e causes of IBS are not well deﬁ ned but appear to be multifaceted. Underlying factors contributing to IBS pathogenesis include visceral hypersen-sitivity, altered gastrointestinal motility, chronic inﬂ amma-tion, and small intestinal bacterial overgrowth (SIBO).3,4 Th ese factors are not mutually exclusive, and speciﬁ c gastro-intestinal symptoms may vary among patients. For instance, SIBO may account for the increased gas production that occurs in many patients with IBS, and methane production is strongly associated with constipation-predominant IBS.4 Many potential mechanisms have been proposed to explain the pathophysiologic symptoms of IBS, including genetic predisposition; food intolerance; social, environ-mental, or behavioral factors; and previous enteric infec-tion.3 Th e complex nature of IBS pathology makes optimal treatment challenging. T reatment options for IBS include bulking agents, 5-hydroxytryptamine–modifying agents, antidepressants, antispasmodics, antiinﬂ ammatory agents, laxatives, antidiarrheals, antibiotics, and probiotics. Notably, antibiotics have a favorable eﬃ cacy proﬁ le in the treatment of individuals with SIBO.5-9,11Th e cases included in this supplement provide examples of the pathogenic role of bacteria in IBS and suggest that therapeutic approaches that aﬀ ect gut bacteria and the respective host responses to these pathogens might allevi-ate symptoms in patients with functional gastrointestinal symptoms. Th is notion is supported by observations from several open-label investigations as well as randomized, double-blind, controlled studies that have characterized the therapeutic beneﬁ t of antibiotics in the treatment of func-tional gastrointestinal symptoms in patients with or without a diagnosis of IBS.5-12Th e cases described in this supplement also provide real-world examples of antibiotic treatment of functional gastrointestinal symptoms in clinical practice. Although no conclusions about the eﬃ cacy of antibiotics for functional gastrointestinal symptoms can be drawn on the basis of these cases alone, the present observations illustrate the potential applications of antibiotics for the treatment of functional gastrointestinal disorders and suggest areas for further investigation.References1. Saito YA, Schoenfeld P, Locke GR 3rd. Th e epidemiology of irritable bowel syndrome in North America: a systematic review. 2002;97:rol. 2Am J Gastroenterol1910-1915.2. Th ompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut. 1999;45:43-47.3. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.4. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292:852-858.5. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing cor-relates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol6. Di Stefano M, Malservisi S, Veneto G, et al. Rifaximin versus chlortetracycline in the short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Th er. 2000;14:551-556.7. Lauritano EC, Gabrielli M, Lupascu A, et al. Rifaximin dose-ﬁ nding study for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Th er. 2005;22:31-35.8. T respi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin. 1999;19:47-52.9. Corazza GR, Ventrucci M, Strocchi A, et al. T reatment of small intestine bacte-rial overgrowth with rifaximin, a non-absorbable rifamycin. J Int Med Res. 1988;16: 312-316.10. Di Stefano M, Strocchi A, Malservisi S, et al. Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms. Aliment Pharmacol Th er. 2000;14:1001-1008.11. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and ﬂ atulence. Am J . 2006;101:326-333rol. 20Gastroenterol.12. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563.4Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Ciprofloxacin in a Patient With Exacerbationof Functional Gastrointestinal Symptoms Afteran Episode of GastroenteritisDr. Cattano is a partner with Anne Arundel Gastroenterology Associates. A member of Mensa, he is Principal Investigator forMaryland Clinical Trials and is actively engaged in clinical trials involving both functional and inﬂ ammatory bowel disorders. Charles Cattano, MDA 50-year-old white woman presented with a 20-year his-tory of functional gastrointestinal symptoms, manifesting as recurrent abdominal cramps, excessive gas, and stool urgency without hematochezia or nocturnal stooling. Th e patient complained of severe diarrhea and moderate bloating, gas, and abdominal pain. Fatty meals exacerbated symptoms, and abdominal pain and bloating improved following bowel movements. A previous evaluation in 2004 resulted in a diagnosis of Rome II–positive, diarrhea-predominant IBS. Additionally, in August 2005, the patient’s symptoms ﬂ ared after an 8-day episode of acute viral gastroenteritis. Her medi-cal history included a longstanding history of anxiety, but no history of diabetes, thyroid disease, or neurologic issues. Her only surgery was hysterectomy for ﬁ broids, preceded by two uncomplicated childbirths. She denied tobacco use but admitted prior marijuana smoking. She has consumed alcohol socially. Her family history was notable for the pres-ence of “colitis” in her mother and sister, who had similar gastrointestinal symptoms.Current medications included dicyclomine 10 mg daily, which was initiated in June 2004. Previously the patient had been taking alprazolam as needed for restlessness but elected to discontinue use in order to “avoid addiction.” Her response to dicyclomine was rated as “50% better.” Th e patient also received a trial regimen of chlordiazepoxide 5 mg plus clidinium 2.5 mg twice daily (bid) with a reported 60% response, but discontinued the medication after 2 weeks due to oversedation. Th us, the patient was referred for gastroen-terology consultation for further evaluation and treatment.On physical examination, the patient weighed 142 lbs at a height of 5' 4". Her skin was nonicteric and lungs clear to posterior and anterior auscultation bilaterally. Heart sounds revealed S1S2 with a mitral click but no murmur. Her abdomen was scaphoid with mild tenderness in the right and left lower quadrants, without rebound. Bowel sounds were active in all four quadrants. Rectal examination revealed guaiac-negative brown stool and no digital tender-ness. Review of colonoscopic ﬁ ndings from August 2004 indicated diﬀ use spasm, but random biopsy was negative for inﬂ ammation. Results of complete blood count and blood chemistry tests provided by her referring primary care physi-cian were normal, as was the baseline level of serum thyreo-tropic hormone. Stool analysis proved negative for Giardia, enteric pathogens, and leukocytes. No breath test for bacte-rial overgrowth was available within our community.On the basis of her post-infectious symptoms, a diagnosis of SIBO was suspected. She received ciproﬂ oxa-cin 500 mg bid for 10 days. At a follow-up visit in August 2005, 3 weeks after discontinuing ciproﬂ oxacin treatment, her gastrointestinal symptoms were moderately improved and she reported no adverse eﬀ ects related to ciproﬂ oxa-cin treatment.Th e patient was lost to follow-up thereafter, due to a lack of interest in maintenance therapy. She telephoned again 6 months later to report recurrence of diarrhea without bleeding and requested a reﬁ ll of her ciproﬂ oxacin prescrip-tion. Based on available data, the patient was oﬀ ered a 14-day trial regimen of rifaximin 400 mg three times daily, with the expectation of consolidating symptom improve-ment. Her prior history of improvement with ciproﬂ oxacin provided support for a presumption of SIBO; however, formal breath testing was deferred. Tegaserod was initiated concomitantly with low-dose rifaximin 200 mg bid. Within 7 days on the combined regimen of tegaserod and rifaximin, the patient reported signiﬁ cant reduction in diarrhea (from 7 to 2 stools daily), as well as reductions in fecal urgency and abdominal cramping.DiscussionTh e merits of rifaximin treatment in IBS patients are under investigation, and preliminary data discussed else-where herein suggest beneﬁ t. Th e empiric use rifaximin in patients with SIBO symptoms, however, bears consid-eration, even without formal SIBO documentation. As noted in the case above, breath testing is not always readily ordered, and where available the cost of analysis is often substantial. Th erefore, empiric rifaximin treatment in IBS patients may be justiﬁ ed, particularly because, unlike with systemic antibiotics, the GI selectivity of rifaximin permits few side eﬀ ects and little expectation of signiﬁ cant bacterial resistance.1Reference1. Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Th er. 2005;3:201-211.Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20075C A S E S T UD IE SRifaximin Therapy in a Patient With Constipation-predominant IBSDr. Christie is an Assistant Professor and Director of the Womens’ Gastrointestinal Health and Motility Center in the Division of Gastroenterology at the Mount Sinai School of Medicine in New York City.Jennifer Christie, MDA 38-year-old Hispanic woman presented on August 10, 2005, with a 2-year history of postprandial bloating, gas, abdominal pain, and constipation, which was spontane-ous, intermittent, and self-limiting. Her medical history included migraine headaches and cholecystectomy. Medica-tions included sumatriptan as needed. Th e patient denied smoking, drinks alcohol socially, denied extraordinary stress, and had no known history of gastroenteritis and no known drug allergies.Functional gastrointestinal symptoms were refractory to treatment with simethicone (2-month course), alpha-galactosidase (Beano), and dietary modiﬁ cations, which included high-ﬁ ber foods and avoidance of lactose-con-taining products, raw vegetables, and beans. Th e patient reported worsening of gas and bloating. Another IBS drug was prescribed, which resulted in severe diarrhea. Upon presentation to the gastroenterologist, the patient was tak-ing no prescription medications.Upon physical examination, the patient appeared in no acute distress. Abdominal examination revealed mild dis-tention, a right upper quadrant surgical scar, positive bowel signs, mild diﬀ use tenderness, no rebound, and no guard-ing. Based on her symptoms of very severe bloating and gas, abdominal pain, and constipation, she was diagnosed with constipation-predominant IBS. Basic blood work consist-ing of metabolic panel and thyroid-stimulating hormone (TSH) was negative. A glucose breath test was negative for SIBO, based on hydrogen measures only. Despite her negative breath test but because of her symptom proﬁ le, the patient was administered rifaximin 400 mg three times daily for 10 days.T wo weeks later, the patient reported improvement in bloating and gas. However, she still complained of slight constipation. T egaserod 2 mg twice daily was prescribed with resolution of constipation. DiscussionIrritable bowel syndrome is commonly associated with symptoms of gas and bloating. Investigators have found that small bowel gas is found in excess in patients with IBS compared to controls.1Additionally, Pimentel and colleagues2found that treatment with oral antibiotics after a positive lactulose breath test was associated with improvement in IBS symptoms as well as normalization of breath test results. Interestingly, the hydrogen breath test using glucose in this patient was negative, yet the patient’s symptoms improved with empiric rifaximin treatment. Th is may have been due to the elimination of methane-producing intestinal bacteria that were not detected during the hydrogen breath test. In a study measuring methane production during lactulose breath testing, a 100% asso-ciation was found between constipation-predominant IBS and a methane-positive breath test.3 Breath testing may be falsely negative in patients with primarily methanogenic bacteria causing symptoms of IBS. Th erefore, we must consider methane to be an important intestinal gas in the production of gastrointestinal symptoms. References1. Koide A, Yamaguchi T, Odaka T, et al. Quantitative analysis of bowel gas using plain abdominal radiograph in patients with irritable bowel syndrome. Am J Gastro-enterol. 2000;95:1735-1741.2. Pimentel M, Chow E, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, random-ized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol3. Pimentel M, Mayer AG, Park S, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci. 2003;48:86-92.6Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Rifaximin in a Patient With Relapsing Functional Gastrointestinal SymptomsDr. Mohan is a practicing gastroenterologist with Northwest Gastroenterology Associates in Bellevue, Washington, as wellas Clinical Assistant Professor of Medicine at the University of Washington in Seattle. His clinical interests include thetreatment of functional bowel and acid reﬂ ux disorders.Venkat Mohan, MDA 47-year-old white woman presented in December 2004 with a 10-year history of functional gastrointestinal symp-toms, including abdominal discomfort, loose stools, and a 2-year worsening of symptoms manifesting as excessive ﬂ atulence, bloating, and gas, without constipation or diar-rhea. Milk, cheese, and stress exacerbated her symptoms. Th e patient’s medical history indicated abdominal cramps and acid reﬂ ux, with no known history of gastroenteritis, neurologic disease, diabetes, or thyroid disease. Review of symptoms was unremarkable, with no weight loss, blood in the stool, or nausea. Her surgical history included appen-dectomy and hysterectomy. Her psychiatric history was noted for complaints of anxiety. In regard to related familial history, her father had colon cancer and her mother had diverticulosis. Her alcohol intake was reported as a once-weekly glass of wine. She was a nonsmoker.Gastrointestinal symptoms were refractory to dietary changes, which included replacement of dairy intake with soy products; consumption of small, low-fat meals; and avoidance of carbonated beverages, coﬀ ee, and artiﬁ cial sweeteners. Over-the-counter treatment with simethicone or alpha-galactosidase supplements provided only a mini-mal response. No speciﬁ c medications had been prescribed for treatment of her functional gastrointestinal symptoms, and the patient was not receiving medications for other disorders. Because of persistent symptoms, the patient was referred for gastroenterology consultation.On physical examination, the patient could be char-acterized as a pleasant, well-nourished female weighing 157 lbs at 5' 6". Cardiovascular, lung, and abdominal examinations were unremarkable. Results of routine screening laboratory tests for complete blood count, chemistry proﬁ le, TSH, erythrocyte sedimentation rate, and anti-endomysial antibody were normal. Stool test for fecal fat was normal. Breath tests were not performed. Results of a colonoscopy performed in November 2004 were negative. Based on symptom-based clinical data, the patient was diagnosed with functional bowel disorder and SIBO.Th e patient received rifaximin 400 mg twice daily (bid) for 10 days in combination with the probiotic Flora-Q once daily for 2 weeks and tegaserod 6 mg nightly for 2 months. She had a mild increase in loose bowel movements in the initial days of therapy due to the eﬀ ect of tegaserod, which ultimately normalized. At a follow-up visit 4 weeks after initiation of rifaximin adjunct therapy, the patient reported improved symptoms of bloating, gas, and abdominal dis-comfort, as well as normal stool consistency. At a routine follow-up oﬃ ce visit in May 2005, the patient reported that symptoms were greatly improved. No side eﬀ ects attributed to the treatment regimen were reported.No maintenance treatment was prescribed. Th e patient experienced a relapse in August 2005 and received rifaximin 400 mg bid for 2 weeks. Her symptoms of bloating, gas, and abdominal pain markedly improved. She was placed on a course of tegaserod 6 mg nightly for 2 months and currently remains symptom-free.DiscussionEmerging evidence supports the hypothesis that SIBO con-tributes to the pathogenesis of IBS.1 Many individuals with IBS also have SIBO, as indicated by reports of abnormal breath test results in up to 84% of individuals with IBS.2,3 Furthermore, multiple randomized, double-blind, placebo-controlled studies have demonstrated that patients who experienced normalization of breath test results following antibiotic treatment experience greater improvement of functional bowel symptoms.2-5 Speciﬁ cally, the nonsystemic antibiotic rifaximin has been shown to safely and eﬀ ectively eliminate bacterial overgrowth and improve global symp-toms of IBS.5,6Abnormal motility of the phase III “housekeeper” waves of the migrating motor complex in the small intestine may contribute to the development of SIBO in individuals with IBS.7 Th e recurrence of symptoms in this patient may be related to a lack of stimulation of this housekeeper wave. Th e administration of promotility agents such as tegaserodGastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20077C A S E S T UD IE Smay help stimulate the phase III complex and prevent recurrence of SIBO. An additional agent administered to promote normal intestinal motility is oral erythromycin 50 mg daily.References1. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292:852-858.2. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial over-growth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol.2000; 95:3503-3506.3. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing cor-relates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol4. Di Stefano M, Strocchi A, Malservisi S, et al. Non-absorbable antibiotics for man-aging intestinal gas production and gas-related symptoms. Aliment Pharmacol Th er. 2000;14:1001-1008.5. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and ﬂ atulence. Am J . 2006;101:326-333.rol. 20Gastroenterol6. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann . 2006;145:557-563.Med. 20Intern Med7. Pimentel M, Soﬀ er EE, Chow EJ, et al. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci. 2002;47:2639-2643.8Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Rifaximin as Acute Therapy and Maintenance Treatment for Functional Gastrointestinal Symptoms Charles Loewe, MDDr. Loewe has been in private practice in Sarasota, Florida, since 1982 and is the founder of the Sarasota Center for Digestive Diseases.He has performed over 40,000 procedures and maintains a keen interest in advanced endoscopic procedures.A 55-year-old white woman presented with a 10-year history of functional gastrointestinal symptoms, includ-ing mild diarrhea, severe constipation, abdominal pain, bloating, and gas. Symptoms were exacerbated by certain carbohydrates and alleviated only by not eating. A medi-cal consultation in 1998 resulted in a diagnosis of Rome II–positive, alternating-form IBS. Th e patient’s medical history was notable for recurrent episodes of diverticulitis, appendectomy, cholecystectomy, total abdominal hysterec-tomy, and a family history of colorectal cancer. Th e patient had no known history of gastroenteritis, diabetes, thyroid disease, neurologic disorder, or psychiatric problems, and reported no signiﬁ cant weight loss, no tobacco use, and only occasional consumption of alcohol. Symptoms were refractory to previous interventions, including oral dicyclo-mine 20 mg before meals, over-the-counter laxatives, and a high-ﬁ ber diet. Th e patient was referred to a gastroenterolo-gist for recurrent diverticulitis and alternating symptoms of constipation and diarrhea.On physical examination, the patient’s temperature was normal and her pulse rate was 75 bpm with a blood pressure of 120/75 mm Hg. Her height measured 5' 3" and weight 125 lbs. Abdominal examination revealed no hepatosplenomegaly, no abnormal mass, and slight tender-ness in the lower quadrants. Results of all stool studies were negative, with no detection of blood. Results of thyroid studies, complete blood count and C-reactive protein lev-els, and liver proﬁ le studies were normal. A 3-hour lactulose breath test revealed an abnormal hydrogen peak. Results of a colonoscopy performed in August 2004 revealed diver-ticulosis. A CT scan also showed evidence of diverticulosis with muscular hypertrophy.Based on clinical symptoms, the patient was adminis-tered oral rifaximin 400 mg twice daily for 10 days. A lactu-lose breath test administered after initiation of rifaximin treatment was normal. Following completion of rifaximin treatment, probiotic therapy and tegaserod 2 mg daily were administered as maintenance therapy. At her 3-month fol-low-up evaluation, the patient had not experienced symp-tom recurrence.DiscussionIrritable bowel syndrome is a very common chronic medi-cal condition with no known cause. Dr. Douglas Drossman ﬁ rst presented the biopsychosocial model of IBS,1which has gained much acceptance as a pathophysiologic cause, as have the application of symptom-based diagnostic criteria originally put forth by Manning and colleagues2 and further applied in the Rome diagnostic criteria. Research currently focuses on altered motility, neuroenteric signaling, visceral hypersensitivity, and brain-gut dysfunction.Irritable bowel syndrome is a complex gastrointestinal disorder characterized by a heterogeneous pathophysiology.A primary focus of recent research is the role of enteric bacteria in IBS pathogenesis, as demonstrated by the correlation between postinfectious IBS and a previous episode of bacterial gastroenteritis (eg, travelers’ diarrhea). Pimentel and colleagues have utilized the lactulose breath test to identify a subset of IBS patients with SIBO.3 Th eir therapeutic method began with neomycin and has evolved into a rifaximin-based primary treatment to normalize the abnormal breath test and to achieve global improvement of IBS symptoms, including bloating, abdominal discomfort, diarrhea, and constipation.4References1. Drossman DA. Gastrointestinal illness and the biopsychosocial model. J Clin Gas-. 1996;22:252-254.rol. 19troenterol2. Manning AP, Th ompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. . 1978;2:653-654.d J. 19Br Med J3. Lee H-C, Pimentel M. Bacteria and irritable bowel syndrome: the evidence for small intestinal bacterial overgrowth. Curr Gastroenterol Rep. 2006;8:305-311.4. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563.Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20079。

J. Label. Compd. Radiopharm. 2004, 47, 821–835.

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALSJ Label Compd Radiopharm2004;47:821–835.Published online in Wiley InterScience().DOI:10.1002/jlcr.870Research ArticleIsotope labeled‘HEA Moiety’in the synthesisof labeled HIV-protease inhibitors–Part1I.Victor Ekhato1,*,Yuan Liao1,2and Mihaela Plesescu1,31Bristol-Myers Squibb Company,Pharmaceutical Research Institute,5Research Parkway,Wallingford,CT06492,USA2Pﬁzer Global Research and Development,Ann Arbor,MI48105,USA3Millennium Pharmaceuticals,Cambridge,MA023139,USASummary[(S)-10-((N-tert-Butyloxycarbonyl)amino)-2S-[2H5]phenyl-ethyl]oxirane11,made from [2H5]-bromobenzene,was transformed into the HIV-protease inhibitors[2H5]-DPH 153893and[2H5]-DPH140662.Both compounds are members of the hydroxyethy-lamine class of protease inhibitors(HIV-PIs).The method of synthesis is applicable to members of this class and the HEE group of HIV-PIs.Copyright#2004John Wiley &Sons,Ltd.Key Words:protease inhibitor;anti-HIV;AIDS;[2H5]-HEA isostereIntroductionDPH153893and DPH140662,like amprenavir1and saquinavir,2are members of the hydroxyethylamine(HEA)isostere class of HIV protease inhibitors(HIV-PIs).3The two compounds are highly potent HIV-aspartyl protease inhibitors with an average IC90of4–8nM against wild-type viruses. Both were selected for pre-clinical evaluation as potential new generation anti-HIV drugs.4Aspects of the studies involved LC-MS analysis and the stable isotope-labeled forms of DPH153893and DPH140662were needed as internal standards.We wanted to make the penta-deuterated DPH153893and DPH 140662molecules in which the[2H5]is situated at the core as the[phenyl ring-2H5]-HEA.We preferred to make the penta-deuterated analog based on the calculation that the molecular weight is suﬃciently increased,such that overlap with other ions due to isotopic mass distribution is avoided.*Correspondence to:I.V.Ekhato,Bristol-Myers Squibb Company,Pharmaceutical Research Institute, 5Research Parkway,Wallingford,CT06492,USA.E-mail:ihoezo.ekhato@Copyright#2004John Wiley&Sons,Ltd.Received15July2003Since both compounds possess the HEA core structure,we planned to prepare DPH153893and DPH140662from a common labeled precursor bearing the elements of the[phenyl ring-2H5]-HEA moiety.We believe that the phenyl group of the HEA sub-unit is metabolically stable,since metabolites have not been reported.5Similarly,these metabolites are absent from our internal study6of DPH153893or DPH140662.As a result,we were encouraged to explore the current synthesis with the prospect that a protease inhibitor containing the[phenyl ring-2H5]-HEA moiety might,in addition to our initial reason for synthesis,be suitable for in vivo investigation.By routine reactions we made the required[2H5]-intermediate from[2H5]-bromobenzene and transformed this compound into[2H5]-DPH153893and[2H5]-DPH 140662.Results and discussionIn the synthetic literature on anti-HIV protease inhibitors,unlabeled(1S,2S)-(1-oxiranyl-2-[2H5]phenylethyl)-carbamic acid tert-butyl ester11is extensively used as an intermediate3,7for synthesis of aspartyl protease inhibitors.We considered11to be an attractive key intermediate from which to make[2H5]-protease pound11,Figure1,has the epoxide functionality from which to build[2H5]-DPH153893and[2H5]-DPH140662.In addition,11 provides the[phenyl ring-2H5]-HEA isostere core of both inhibitors.Unlike previous work,7the present approach does not draw on any chiral pools of reagents,such as optically pure amino acids or derivatives,to construct11. Therefore,constructing the[2H5]-labeled carbon skeleton from[2H5]-bromo-benzene1with the desired1S,2S-conﬁguration in11was a challenging task. To address this point,we implemented a facially selective syn-aldol condensation reaction with S-4-benzyl-(3-[2H5]phenylpropionyl)-oxazolidin-2-one5.[2H5]-Bromobenzene was used to prepare compound5,and theSYNTHESIS OF LABELED HIV-PROTEASE INHIBITORS823 sequence of routine reactions that was employed is shown in Scheme1.Thus, following a lithium-halogen exchange reaction with[2H5]-bromobenzene1, DMF was added and acid workup provided the aldehyde,2.A Wittig-type homologation protocol8with compound2furnished3-[2H5]phenylacrylic acid ethyl ester,3.The carboxylic acid made by the hydrolysis of3was activated as the mixed pivaloyl anhydride,and reacted with(S)-(-)-4-benzyl-N-lithio-2-oxazolidinone,according to a literature procedure,9to form(S)-4-benzyl-3-(3-[2H5]phenylacryloyl)-oxazolidin-2-one,pound4was saturated by subjecting it to Pd/C catalyzed hydrogenation to furnish(S)-4-benzyl-3-(3-[2H5]phenylpropionyl)-oxazolidin-2-one,5.2222Et4Scheme1.Conversion of[2H5]-bromobenzene into the acyl oxazolidinone5to enable the asymmetric synthesis of11To complete the required carbon skeleton and simultaneously achieve the desired(S,S)-conﬁguration,compound5was condensed with(benzyloxy) acetaldehyde,10as shown in Scheme2.The combination of dibutylboron triﬂate and diisopropylethylamine reagent resulted in the highly diastereofa-cially selective syn-aldol condensation reaction yielding6.In the manner described in the literature,11lithium peroxide was used to cleave the amide bond in compound6to obtain(2S,3S)-[(2-[2H5]benzyl-4-(benzyloxy)-3-hydroxybutyric acid,7,in84%pound7was reﬂuxed in a solution of toluene containing diphenylphosphoryl azide and triethylamine to produce 8,an oxazolidinone.Formation of compound8is explained by the intra-molecular cyclization reaction of the intermediate isocyanate with the participation of the neighboring hydroxy group,as described in the literature.10The deprotection of8and the formation of(1S,2S)-1-[N-tert-butyloxycarbonyl)amino]-1-[25H5]benzyl-3-(benzyloxy)propan-2-ol,9,wasachieved in a one-pot pound5was subsequently hydrogenated under Pd/C catalysis to yield10(see Scheme2).The diol grouping in10was converted to the epoxide ring by a modiﬁed literature protocol12to give11(Scheme3).Speciﬁcally,compound10was treated with1-(bromocarbonyl)-1-methylethyl acetate in ethanol-free chloro-form at08C,converting it to an intermediate bromohydrin.The bromohydrin was cyclized by treatment with a solution of sodium methoxide in THF to provide(1S,2S)-(1-oxiranyl-2-[2H5]phenyl-ethyl)-carbamic acid tert-butyl ester,11,in73%yield.From intermediate11we proceeded to make[2H5]-DPH153893and[2H5]-DPH140662.At the second step in the reaction sequence isobutylamine wasreacted with11in hot isopropyl alcohol to pound12is the lastintermediate common to both synthetic targets,i.e.the reaction step after 12is the point of divergence of the reaction sequences to DPH 140662and DPH 153893.In order to make [2H 5]-DPH 140662,compound 12was treated with 4-nitro-benzenesulfonyl chloride in the presence of potassium carbonate as acid scavenger.After removal of the Boc group,13was obtained as the methanesulfonic acid salt in 80%overall yield over the two steps.By a standard coupling method with EDC.HCl,4-methylmorpholine and HOBt 13in DMF,compound 13and Boc-l -tert -leucine formed the Boc protected 14.We found that the stepwise sequence of coupling Boc-l -tert -leucine to make the Boc protected 14,the removal of Boc to yield 14and the coupling reaction of compound 14with IS066(IS066was generously supplied bythe 11into 14via compound 12,a commonintermediate to [2H 6]-DPH 153893and [H 5]-DPH 140662SYNTHESIS OF LABELED HIV-PROTEASE INHIBITORS 825Department of Chemical Process,DuPont Pharmaceuticals Company,Wilmington,DE)to give 15,as shown in Scheme 4,was the best sequence for making [2H 5]-DPH 140662.An alternative single coupling reaction to DPH 140662from 13was complicated by intra-molecular cyclization of the dipeptide reagent under our reaction conditions.Chromatographic puriﬁca-tion was required to obtain 15,and then only in poor yield.The single coupling approach was therefore abandoned.A standard coupling protocol in DMF containing EDC.HCl,HOBt and 4-methylmorpholine as acid scavenger converted 14to compound 15.After Pd/C catalyzed hydrogenation of 15to the 4-aminobenzenesulfonamide,the Boc group was removed with TFA-Et 3SiH and the reaction mixture was neutralized with NaHCO 3to provide [2H 5]-DPH 140662in 61%yield.By substituting 3-nitrobenzenesulfonyl chloride for 4-nitrobenzenesulfonyl chloride in Scheme 3,and following a sequence of reactions analogous to Schemes 3and 4,we accomplished the synthesis of [2H 5]-DPH 153893in comparable yield.ConclusionTwo HIV protease inhibitors were speciﬁcally labeled with [2H 5]at the HEA sub-unit by transforming [2H 5]-bromobenzene into a common intermediate for these agents.The intermediate was made using established reactionsthat 14into [2H 5]-DPH 140662I.V.EKHATO ET AL.826included an asymmetric reaction step.The intermediate was used to create the[phenyl ring-2H 5]labeled HEA core structure of DPH 140662and DPH 153893.Very high deuterium incorporation was achieved by the sequence we have described and the synthetic approach may be applicable,with some modiﬁcations,to other HIV-protease inhibitors.ExperimentalAll reactions were carried out under an atmosphere of argon unless otherwise speciﬁed.Solvents were commercial grade and used without puriﬁcation or drying.Column chromatography was carried out on Merck Kiesegel 60(230m)silica gel.Flash chromatographic separations were on a Biotage Flash System using a pre-packed silica gel cartridge.TLC visualization reagents included (10%iodine plus 10%AcOH)in 40%aqueous KI.1H NMR spectra were recorded at 300,400or 500MHz.Chemical shifts are given in ppm relative to tetramethylsilane (TMS).Only the important IR absorptions (cm À1)and the molecular ion and/or base peaks in MS are given.HPLC columns used include Zorbax Rx C 18,Discovery Amide C 16,and Waters Symmetry C 18columns.4S-Benzyl-3-(3-[2H 5]phenyl-propionyl)-oxazolidin-2-one,%5To a stirred solution of [2H 5]-phenylacrylic acid (10.1g,65.07mmol,see Scheme 1for preparation)and 4-methylmorpholine (7.15ml,65.07mmol)in dry THF (120ml)maintained at À788C with a dry ice-acetone bath was added trimethylacetyl chloride (8.01ml,65.07mmol).After 30min the cold bath was replaced with an ice-water bath and the reaction was stirred for another 45min.The precipitate was removed by ﬁltration,and the ﬁltrate was transferred to a solution of N -lithio-oxazolidinone that was pre-generated as follows.(S)-(-)-4-Benzyl-2-oxazolidinone (11.53g,65.07mmol)in dry THF (120ml)was stirred under argon atmosphere at À788C while BuLi (1.6M solution in hexanes,40.6ml,65.07mmol)was added dropwise.The solution was stirred at À788C for 1.0h and the above ﬁltrate,a solution of mixed anhydride in THF,was added in one portion.The reaction was quenched after 1h with saturated NH 4Cl solution (100ml)and the organic phase was separated.The aqueous portion was further extracted with ethyl acetate (3Â200ml),the combined organic extract was dried and evaporated to dryness to give (S)-4-benzyl-3-(3-[2H 5]phenylacryloyl)-oxazolidin-2-onepound 4was dissolved in ethyl acetate (150ml)and a suspension of 10%Pd/C (1.2g)in ethyl acetate (20ml)was added.After the reaction mixture was degassed,it was stirred under a hydrogen atmosphere for 3h and ﬁltered through a pad of Celite to remove the spent catalyst.The ﬁltrate was evaporated to a product which crystallized from EtOAc-hexane to give 5(17.10g,84%).1H NMR (400MHz)d 2.74(dd,1H),3.03(m,2H),3.28(m,SYNTHESIS OF LABELED HIV-PROTEASE INHIBITORS 8273H),4.16(m,2H),4.65(m,1H),7.17(d,2H)and 7.32(m,3H).13C NMR (75MHz)d 30.30,37.12,37.94,55.17,66.26,127.4,128.0,128.2,129.0,129.5,140.4,153.4and 172.5.IR n max (CHCl 3)2276,1785,1699,1490,1478,1390,1372,and 1202cm À1.4S-Benzyl-3-[(2S-[2H 5]benzyl-4-(benzyloxy)-3S-hydroxy-butyryl)]-oxazoli-din-2-one,%6To a stirred solution 4S-benzyl-3-(3-[2H 5]phenylpropionyl)-oxazolidin-2-one 5(23.68g,75.3mmol)in CH 2Cl 2(140ml)at 08C was added dibutylboron triﬂate (1.0M solution in dichloromethane,98.0ml,98mmol)followed by diisopro-pylethylamine (19.67ml,112.97mmol).After stirring the mixture for 1h at room temperature it was cooled to À788C and a solution of (benzyloxy)ace-taldehyde (20g,133.17mmol)in CH 2Cl 2(30ml)was added.The reaction mixture was stirred for 30min at À788C and warmed to room temperature for 2h.A phosphate buﬀer of pH 7.3(40ml)was added and while the reaction was cooled to 08C,methanol (140ml)was added followed by a mixture of (2:1)MeOH and 30%H 2O 2(180ml).The resulting mixture was stirred for 1h,concentrated to a small volume and extracted with EtOAc (2Â200ml).The organic portions were combined and washed with saturated NaHCO 3(200ml),brine (200ml)and dried over anhydrous magnesium sulfate.Evaporation of the solvent gave the crude product which was puriﬁed by chromatography on silica gel.The column was eluted with 10–25%ethyl in hexane to give 6(25g,71.46%).1H NMR (500MHz)d 2.10(dd,Hz,1H),2.64(brs,1H),2.83(dd,1H),3.08(q,Hz,1H),3.17(q,1H),3.59(m,2H),3.78(tr,1H),3.86(q,1H),4.18(q,1H),4.42(m,1H),4.50(s,2H),4.64(m,1H),6.93(dd,2H),7.20–7.343(m,10H).IR n max (CHCl 3)2274,1778,1694,1496,1386,1210,and 1104cm À1.S-2-[2H 5]Benzyl-4-(benzyloxy)-3S-hydroxy-butyric acid,%7To a stirred solution of 4S-benzyl-3-[(2S-[2H 5]benzyl-4-(benzyloxy)-3S-hydro-xy-butyryl)]-oxazolidin-2-one 6(23.1g,49.72mmol)in 50%aqueous THF (105ml)at 08C were added 30%H 2O 2(25ml,220mmol)and LiOH.H 2O (4.25g,101.2mmol)in succession.The reaction mixture was stirred in an ice bath and monitored by TLC until acyloxazolidinone was consumed in a calculated 6h.Saturated sodium metabisulﬁte (100ml)was added and the mixture was extracted with EtOAc (3Â200ml).After acidiﬁcation of the aqueous portion to pH 2with dilute HCl,it was extracted with EtOAC (2Â120ml).The organic portions were combined,dried over anhydrous Na 2SO 4,ﬁltered and evaporated to an oil.TLC on silica gel (ether:pet.ether:acetic acid,60/40/1v/v/v)showed fast running desired product and slow running oxazolidinone.The mixture was applied to a column of silica gel and I.V.EKHATO ET AL.828eluted with (ether:pet.ether:acetic acid 60/40/1,v/v/v/)to aﬀord crystalline (CH 2Cl 2-hexane)7(12.98g,84%).1H NMR (500MHz)d 2.95(m,1H),3.10(2H),3.49(dd,1H),3.59(dd,1H),4.03(m,1H),4.54(s,2H),7.31–7.36(m,5H).13C NMR (75MHz)d 33.67,50.09,70.38,71.64,73.57,127.9,128.0,128.2,128.3,128.6,137.6,138.6,and 177.9.IR n max (CHCl 3)3254,2275,1728,1454and 1169cm À1.S-4-[2H 5]Benzyl-5S-((benzyloxymethyl)-oxazolidin-2-one,%8A mixture of S-(2-[2H 5]benzyl-4-(benzyloxy)-3S-hydroxy-butyric acid 7(11.0g,36.0mmol),diphenylphosphoryl azide (9.84ml,45.66mmol)and triethylamine (6.68ml,47.92mmol)in toluene (78ml)was reﬂuxed for 4h and cooled to room temperature.Ethyl acetate (250ml)was added and the solution was washed with saturated NaHCO 3(100ml),dried and evaporated to give a residue that was chromatographed on silica gel.The fast running impurities were ﬁrst eluted with 25%EtOAc in hexane,and 35%EtOAc in hexane was used to elute the desired product 8(11.7g,98%).1H NMR (300MHz)d 2.75(dd,1H),2.92(dd,1H),3.797(d,2H),4.12(m,1H),5.62(s,2H),5.8(m,2H)and 7.40(m,5H).(S)-1-[N-tert-Butyloxycarbonyl)amino]-1-[2H 5]benzyl-3-(benzyloxy)propan-2S-ol,%9S-4-[2H 5]Benzyl-5S-(benzyloxymethyl)-oxazolidin-2-one 8(11.7g,38.74mmol)in 50%aqueous ethanol (40ml)containing KOH (9.0g,160.4mmol)was heated at 708C for 3h and then cooled to room temperature.The solution was adjusted to pH 7with 1.0M HCl and concentrated under reduced pressure.Di-tert -butyl dicarbonate (16.99g,77.84mmol)in CH 2Cl 2(60ml)was added at 08C and the reaction was stirred for 2h at room temperature.Saturated NH 4Cl solution (40ml)was added.The mixture was extracted with CH 2Cl 2(2Â50ml),the combined organic portions were dried and evaporated to yield a solid residue.The crude product was applied to a column of silica gel and the excess di-tert -dibutyl dicarbonate was eluted with 10%EtOAc in hexane.Further elution with 35%EtOAc in hexane gave a solid which crystallized from hexane to aﬀord 9(15.2g,94%).1H NMR (300MHz)d 1.35(s,9H),2.62(brs),2.88(d,2H),3.56(m,2H),3.73(brs,1H),3.93(brs,1H),4.51(s,2H),4.72(d,1H),7.33(m,C 6H 5).13C NMR (75MHz)d 28.34,36.36,54.20,71.72,71.82,73.68,79.53,125.9(tr)127.8,127.9,128.1,128.5,129.1(tr),137.8,137.9and 155.9.IR n max (CHCl 3)1685,2273,1526,and 1172cm À1.S-1-[N-tert-Butyloxycarbonyl)amino]-1-[2H 5]benzyl-propan-2S,3-diol,10To a solution of S-1-[N -tert -butyloxycarbonyl)amino]-1-[2H 5]benzyl-3-(benzy-loxy)-propan-2S-ol 9(14.0g,37.18mmol)in EtOAc (140ml)was added a SYNTHESIS OF LABELED HIV-PROTEASE INHIBITORS 829suspension of 5%Pd/C (1.40g)in ethyl acetate (10ml).The stirred reaction mixture was purged to remove air and stirred under hydrogen atmosphere for 18h.The spent catalyst was ﬁltered oﬀand the ﬁltrate was concentrated to a white solid that crystallized from hexane-ethyl acetate to give 10(10.48g,%100%).1H NMR (500MHz)d 1.37(s,9H),1.59(brs,1H),2.75(d,1H),2.91(dd,1H),3.09(dd,1H),3.33(brs,2H),3.65(m,2H),3.82(m,1H),4.53(d,1H).13C NMR (75MHz)d 28.30,36.55,52.59,63.06,73.27,80.41,126.2(tr),128.2(tr),129.0(tr),137.3,and 157.1.IR n max (CHCl 3)3356,2273,1685,1525,1445,1250,and 1171cm À1.[(S)-10-((N-tert-Butyloxycarbonyl)amino)-2S-[2H 5]phenyl-ethyl]oxirane,111-Bromocarbonyl-1-methylethyl acetate (2.0ml,13.63mmol)was added to a stirred suspension of (S)-1-[N -tert -butyloxycarbonyl)amino]-1-[2H 5]benzyl-propan-2S,3-diol 10(3.0g,10.48mmol)in dry,ethanol free,chloroform (30ml)maintained at 08C in an ice water bath.After 3h at room temperature the reaction was quenched by the addition of saturated NaHCO 3solution (20ml)and extracted with EtOAc (3Â30ml).The organic extract was washed with brine (30ml),dried over anhydrous Na 2SO 4and evaporated to give a solid.The solid was stirred as a solution in dry THF (40ml),cooled to 08C in an ice bath and NaOCH 3(0.92g,17.03mmol)was added.After stirring the reaction mixture at room temperature for 4h,saturated ammonium chloride solution (30ml)was added and the mixture extracted with EtOAc (3Â30ml).The organic extract was dried over anhydrous Na 2SO 4,ﬁltered,and the ﬁltrate was evaporated to a small volume.The material was applied to a column of silica gel and the compound was eluted with 22%EtOAc in hexane to give a white solid 11(2.08g,73%).1H NMR (300MHz)d 1.75(d,J =7.0Hz,3H),2.45(s,3H),4.97(q,J =7.0Hz,1H),7.10–7.27(m,3H),7.32–7.43(m,2H),7.51(d,J =8.2Hz,2H)and 7.75(d,J =7.3Hz,1H).13C NMR (75MHz)d 28.34,37.65,41.61,46.81,53.3,79.71,126.2(tr),128.1(tr),129.1(tr),136.7and 155.3.IR n max (CHCl 3)2275,1679,1523and 1168cm À1.3S-[N-(tert-Butyloxycarbonyl)amino-1-(2-methylpropyl)amino-4-[2H 5]phe-nylbutan-2R-ol,12To a solution of 2S-[10-(S)-((N -tert -butyloxycarbonyl)amino)-2-[2H 5]phenyl-ethyl]-oxirane 11(2.06g,7.20mmol)in isopropanol (6ml)was added isobutylamine (6ml,111.5mmol)and heated at 868C for 4h under argon atmosphere.The solvent was evaporated after cooling to room temperature.The white solid obtained was crystallized from ether-petroleum ether to give 12(2.32g,%100%).1H NMR (500MHz)d 0.89(dd,6H),1.35(s,9H),1.70(m,1H),2.39(d,3H),2.68(d,2H),2.86(dd,1H),2.98(dd,1H),3.44(m,1H),3.79(brs,1H),4.67(d,1H).IR n max (CHCl 3)3365,1648,1521,and 1173cm À1.I.V.EKHATO ET AL.830N-(3S-Amino-2R-hydroxy-4-[2H5]phenyl-butyl)-N-isobutyl-4-nitro-benzene-sulfonamide,13A solution of K2CO3(430mg,3.11mmol)in water(3ml)was added to a solution of3S-[N-(tert-butyloxycarbonyl)amino-1-(2-methylpropyl)amino-4-[2H5]phenylbutan-2R-ol12(575.19mg,1.68mmol)in isopropyl acetate(3ml). The mixture was stirred at568C to attain solution.4-Nitro-benzenesulfonyl chloride(360mg,1.62mmol)in isopropyl acetate(3ml)was added and stirring continued for30min after the addition was completed.A solid product separated upon cooling the reaction to room temperature,and it was collected byﬁltration.This material(Boc protected amine)(885.8mg,1.681mmol)was stirred in isopropyl acetate(18ml)and the temperature was brought to858C under argon atmosphere.Methanesulfonic acid(130.9m l, 2.0mmol)in isopropyl acetate(5ml)was added slowly and the reaction mixture was stirred for another30min.Upon cooling to room temperature a crystalline product separated and it was collected byﬁltration to aﬀord13(722.6mg, 80%).1H NMR(300MHz)(DMSO-d6)d0.89(dd,6H),1.80(m,1H),2.36(s, 3H),2.85(m,2H),3.10(m,3H),3.49(dd,1H),3.95(m,1H),5.58(d,1H),7.80 (brs,2H),8.15(d,1H),8.40(d,1H).2-Amino-N-{1-[2H5]benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl-3,3-dimethylbutyramide,14N-tert-Butyloxycarbonyl tert-butylglycine(Boc-l-tert-leucine)(360.80mg, 1.56mmol),1-hydroxybenzotriazole hydrate(210.8mg,1.56mmol)in anhy-drous DMF(10ml)was treated with4-methylmorpholine(343m l,3.12mmol) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (298.8mg,1.56mmol).Compound13(680mg,1.302mmol)was added and the reaction mixture was stirred under argon atmosphere overnight.The reaction mixture was concentrated to a small volume,partitioned between ethyl acetate(20ml)and water(15ml),and the aqueous portion was separated.The aqueous portion was further extracted with ethyl acetate (3Â20ml)and the combined organic portions were washed sequentially with saturated NH4Cl solution(20ml),saturated K2CO3solution(20ml),brine (20ml)and dried.Theﬁltrate was evaporated to a residue(843mg),and then dissolved in isopropyl acetate(10ml).While the stirred solution was maintained at858C,methanesulfonic acid(102m l,1.85mmol)in isopropyl acetate(3ml)was added dropwise.The reaction mixture was cooled to room temperature after30min,and concentrated to a small volume.Upon the addition of ether,a crystalline solid precipitated,and the material was collected byﬁltration to aﬀord14(708mg,84%).HPLC analysis on a Zorbax Rx C18column4.6Â250mm at aﬂow rate of1.0ml/min under isocratic conditions using40%water in acetonitrile containing0.05%TFA gave aretention time of3.3min.1H NMR(300MHz)(DMSO-d6)d0.75(dd,6H), 0.96(s,9H),1.89(m,1H),2.28(s,3H),2.65(dd,1H),2.82(m,1H),2.96(dd, 1H),3.08(dd,1H),3.40(m,2H),3.65(m,1H),3.85(brs),4.10(m,1H),7.85 (brs,2H),8.10(d,1H),8.38(d,1H).IR n max(CHCl3)2276,1691,1530,1352, 1350,and1150cmÀ1.[{1-{1-[2H5]Benzyl-2-hydroxy-3-[isobutyl-{4-nitro-benzenesulfonyl)-amino]-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl}-methyl](3-ﬂuoro-benzyl)-carbamic acid tert-butyl ester,15To a solution of N-[(tert-butyloxycarbonyl)-(3-ﬂuorobenzyl)]glycine(IS066) (373.95mg,1.32mmol),1-hydroxybenzotriazole hydrate(HOBT),178.38mg,1.32mmol)in anhydrous DMF(5ml)was added4-methylmorpholine(290m l,2.64mmol)followed by EDC.HCl(252.56mg, 1.32mmol).While stirring under an argon atmosphere,14(700mg,1.1mmol)was added.After stirring overnight,the mixture was concentrated under high vacuum to a small volume and partitioned between EtOAc(20ml)and water(15ml).The organic phase was separated and the aqueous portion was further extracted with ethyl acetate(2Â20ml).The combined organic portions were washed with water (20ml),saturated NH4Cl solution(20ml),saturated K2CO3(20ml),brine (20ml)and dried over magnesium sulfate.The solvent was evaporated to givea foamy solid15(880mg,91%).HPLC analysis on a Zorbax Rx C18column4.6Â250mm at aﬂow rate of1.0ml/min under isocratic conditions using40% water in acetonitrile containing0.05%TFA gave a retention time of 11.12min.N-{3-[(4-Amino-benezenesulfonyl)-isobutyl-amino]-1-[2H5]benzyl-2-hydroxy-propyl}-2-[2-(3-ﬂuorobenzylamino)-acetylamino]-3,3-dimethyl-butyramide, [2H5]-DPH140662To a solution of15(700mg,0.869mmol)in methanol(25ml)was added a suspension of10%Pd/C(224mg)in methanol(8ml).The reaction mixture was stirred at room temperature in an atmosphere of hydrogen for3h and thenﬁltered.The solvent was evaporated to yield a foamy solid.Triﬂuor-oacetic acid(2.616ml)and triethylsilane(Et3SiH)(0.4ml)were added successively to a solution of the solid in methylene chloride(18ml).The mixture was stirred at room temperature and the reaction was monitored by TLC(3%MeOH in dichloromethane).After2h the reaction mixture was evaporated to a residue and,EtOAc(20ml),water(15ml),and solid NaHCO3 (1.3g)were added.The mixture was stirred for20min and the organic portion was separated.The aqueous portion was further extracted with ethyl acetate (2Â20ml)and the combined organic extract was dried over MgSO4. The product was puriﬁed by chromatography on silica gel column eluted with8%EtOH in toluene to give an oil.Trituration of the oil with ether gave[2H5]-DPH140662(385mg,61%;D598.9%,D4, 1.1%).[a]20D–15.648 (c=0.41%in MeOH).The product was analyzed by HPLC on a Discovery Amide C16Supelco250Â4.6mm,5m m column.The solvent combination of A (10mmol ammonium formate)and B(acetonitrile)was used under gradient conditions of20–30%B in0–5min,30–50%B in5–18min and20–30%B in 18–20min at aﬂow rate of ml/min.The product peak was detected by UV at a wavelength of254nm and gave>98%chemical purity at a retention time of 14.13min.IR n max(CHCl3)1314,1285,and1143cmÀ1.1H NMR(300MHz, d6-DMSO)d0.85(m,15H),1.82(m,1H),2.52(dd,1H),2.68(m,1H),2.85(m, 2H),2.95(dd,1H),3.05(s),3.22(dd,1H),3.30(s,3H),3.50(s),3.60(m,1H), 3.89(m,1H),4.18(d,1H),4.89(d,1H),5.98(brs,2H),6.60(d,2H),7.12(m, 3H),7.42(m,3H),7.78(d,1H),7.98(d,1H).HRMS(TOF MS ES+;M+1); calcd.675.3762,found675.3766.ESI full ms gave z at675(M+1,100%)and 397(5%),372(15%)and354(2%).N-{1-[2H5]Benzyl-2-hydroxy-3-[isobutyl-(3-nitro-benzenesulfonyl)-amino]-propyl}-2-[2-(3-ﬂuorobenzylamino)-acetylamino]-3,3-dimethyl-butyramide, [2H5]-DPH153893N-[(tert-butyloxycarbonyl)-(3-ﬂuorobenzyl)]glycine(356.0mg, 1.256mmol) was reacted with2-amino-N-{1-[2H5]benzyl-2-hydroxy-3-[isobutyl-(3-nitro-benzenesulfonyl–amino]-propyl-3,3-dimethyl-butyramide methanesulfonic acid salt17(799mg, 1.256mmol)to make[(1{1-[2H5]benzyl-2-hydroxy-3-[isobutyl-(3-nitro-benzenesulfonyl)-amino]-propyl-carbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]–(3-ﬂuorobenzylcarbamic acid tert-butyl ester (902mg,89%)as described under experiment15.Sequential hydrogenolysis and boc deprotection with methanesulfonic acid in isopropyl acetate gave N-{1-[2H5]benzyl-2-hydroxy-3-[isobutyl-(3-nitro-benzenesulfonyl)-amino]pro-pyl}-2-[2-(3-ﬂuorobenzylamino)-acetylamino]-3,3-dimethyl-butyramide[2H5]-DPH153893(947mg, 1.09mmol,98%;D5,98.9%,D4, 1.1%)as the methanesulfonic acid salt.[a]20D–17.848(c=0.43%in MeOH).HPLC analysis on Discovery Amide C16Supelco250Â4.6mm,5m m column with elution solvent combination of A(10mmol ammonium formate)and B(acetonitrile), under the gradient conditions of20–30%B in0–5min,30–50%B in5–18min and20–30%B in18–20min and aﬂow rate of1.0ml/min.The product peak was detected by UV at a wavelength of254nm,and gave>99.6%chemical purity at a retention time of10.7min.HRMS(TOF MS ES+;M+1);calcd. 675.3762,found675.3765.1H NMR(300MHz,d6-DMSO)d0.85(dd,and s, overlapped,15H),1.92(m,1H),2.50(dd,1H overlapped with DMSO),2.80 (m,2H),2.90(m,2H),3.03(s),3.50(s),3.60(m,1H),3.95(m,1H),4.20(d, 1H),4.90(d,1H),5.51(brs),6.70(d,1H),6.80(d,1H),6.90(s,1H),7.10(m, 3H),7.30(m,1H),6.65(d,1H),7.90(d,1H).ESI full MS gave z675(M+1, 100%),397(2%),372(18%),and354(5%).AcknowledgementsThe authors are grateful to Dr Gerald Miwa and Shimoga Prakash (Millennium Pharmaceuticals)for their support.IVE gratefully acknowledges D.R.Schroeder and S.Huang(DAS,BMS Wallingford,CT)for NMR support;Julie Nielsen(DAS,BMS,Wallingford,CT)for the determination of Optical Rotations of Protease Inhibitors and Richard E.Gedamke(ARD, BMS,Lawrenceville,NJ)for the determination of at%D.References1.(a)Kim EE,Baker CT,Dwyer MD,Murcko MA,Rao BG,Tung RD,NaviaMA.J Am Chem Soc1995;117:1181–1182.(b)Tung RD,Murcko MA,Bhissetti GR.Vertex Pharmaceuticals Inc.,1994;WO94/05639.2.(a)Roberts NA,Martin JA,Kinchington D,Broadhurst AV,Craig JC,DuncanIB,Gaplin SA,Handa BA,Kay J,Kroehn A,Lambert RW,Merret JH, Mills JS,Parkes KEB,Redshaw S,Ritchie AJ,Taylor DL,Thomas GJ, Machin PJ.Science1990;248:358.(b)Skinner C,Sedwick A,Bragman K, Pinching AJ,Weber J.Abstracts at the9th International Conference on AIDS,Berlin,1993.(c)Parkes KEB,Bushnell DJ,Crackett PH, Dunsdon SJ,Freeman AC,Gunn MP,Hopkins RA,Lambert RW,Martin JA, Merrett JH,Redshaw S,Spurden WC,Thomas GJ.J Org Chem1994;59: 3656–3664.3.(a)Rich DH,Green J,Toth MV,Marshall GR,Kent SBH.J Med Chem1990;33:1285–1287.(b)Rich DH,Sun CQ,Vara Prasad JVN,Pathiasseril A, Toth MV,Marshall GR,Clara M,Mueller RA,Houseman KJ.J Med Chem 1991;34:1222–1225.(c)Beaulieu PL,Wernic D.J Org Chem1996;61: 3635–3645.4.Kaltenbach III RF,Trainor D,Getman G,Harris S,Diamond M,Saye JJ,Erickson-Viitanen S.Antimicrobial Agents Chemother2001;45:3021–3028.5.Treluyer JM,Bowers G,Cazali N,Sonnier M,Rey E,Pons G,Cresteil T.DrugMetab Dispos2003;31:275–281.6.Solon EG,Yang TD.Dept of Drug Metabolism and Pharmacokinetics,DupontPharmaceutical Company,Newark,DE19714;Personal Communication.7.Albeck A,Persky R.Tetrahedron1994;50:6333–6346.(b)Thottahthil JK,Polniaszek RP.Synlett2000;6:902–904.(c)Rotella DP.Tetrahedron Lett1995;35:5453–5456.(d)Beaulieu PL,Wernic D,Duceppe J-S,Guindon Y.Tetrahedron Lett1995;36:3317–3319.(e)Beier C,Schaumann E,Adiwidjaja G.Synlett1998;1:42–44.8.(a)Lombardo L,Taylor RJK.Synthesis1978;2:131–132.(b)Coutrot P,SnoussiM,Savignac P.Synthesis1978;2:133–134.(c)Monache GD,Di Giovanni MC, Maggio F,Misiti D,Zappia G.Synthesis1995;9:1155–1158.9.Dobarro A,Velasco D.Tetrahedron1996;52:13525–13530.10.(a)Ghosh AK,Hussain KA,Fidanze S.J Org Chem1997;62:6080–6082.(b)Ghosh AK,Fidanze S.J Org Chem1998;63:6146–6152.。

半导体低维物理讲义之八

Pcoh = P0 exp(−t / T2 )
2T2 ≤ T1
Bloch Oscillation
The motion of a wave packet centered around k in a periodic lattice under the influence of an external force F, e.g., an electric field, neglecting for the moment all scattering processes:
德布罗意波及其与能量德关系
各种长度范围
各种低维结构及其状态密度
量子点的各种制备方法
利用刻蚀方法制备的量子点结构
利用刻蚀方法制备量子点的步骤
采用自组装制备的量子点及其尺寸分布
外延生长的几种主要模式；自组装量子点中的应力分布
自组装量子点的形貌及其荧光谱
高指数面上生长的自组装量子点及其TEM照片
l B = B / 2eE
where B is the width of the band. The periodic motions in real and In momentum space are known as Bloch oscillation. Actually, the carriers in bulk semiconductors have no chance to complete such an orbit because the decoherence time T2 is too short. Condition for the observation of Bloch oscillation:
dk h = F = eE dt
Under the above conditions, the electron will perform a periodic orbit in k space in the direction of E. The duration of one orbit in k-space and the frequency are given by

吸电子基取代苯偶姻的实用合成

吸电子基取代苯偶姻的实用合成杨文领;杨云刚;方丽;张万顺【摘要】The Benzoins condensation reaction by the way of the classical Vitamin B1 is substituted under the protection of inert gases and adds aqueous Na2 S2 O3 and zinc dust after its completion to inhibit product disintegration to make thiamin derivate which is replaced by electron-withdrawing groups depended upon KCN hyper toxic catalyst synthesis.It is supposed that the classical way of Vitamin B1 segregated nothing and electron-deficient benzoins could not be prepared by classical Vitamin B1 -promoted ones might be owing to the synergy between silica gel /alumina and decomposed Vitamin B1 during column chromatography,which could be inhibited by Zn-Na2 S2 O3 .%将经典维生素 B1法安息香缩合反应改进在惰性气体保护下进行，且在反应完成后加入硫代硫酸钠和锌粉抑制产物分解，可制备过去主要依赖 KCN 等剧毒催化剂合成的吸电子基团取代的苯偶姻衍生物。

推测经典维生素 B1法分离不到产物，可能是由于柱层析时硅胶或氧化铝与维生素 B1分解产物的共同作用导致贫电子苯偶姻产物的分解，而 Zn-Na2 S2 O3溶液可以抑制这种作用。

Derwent(德温特)创新索引世界专利数据库

“Setting machine”
描述性的摘要
专利文献原摘要
The present invention relates to capsules encapsulating antibodyproducing cells, and to the use of such capsules and encapsulated cells,
1、Derwe入框检索时间限定
选择检索的数据库类型
数据库类型
• 如果不做指定，系统默认为检索所有数据库如果不做指定， • 可选类型：可选类型：
– Drwent Innovations Index (Chemical Section)；； – Derwent Innovations Index (Electrical & Electronic Section)；； – Derwent Innovations Index (Engineering Section)
Derwent Innovations Index
(德温特创新索引世界专利数据库) 德温特创新索引世界专利数据库)
东北大学图书馆 2010.03
数据库简介
•英国 Derwent（德温特）公司是全球最权威的英国 Derwent（德温特）专利情报和科技情报机构之一，1948年由化学专利情报和科技情报机构之一，1948年由化学在英国创建。家 Monty Hyams 在英国创建。 •德温特公司于 1995年首次建立了专利引文索德温特公司于 1995年首次建立了专利引文索 Index，数据库。引(Patent Citation Index，简称 PCI) 数据库。 1998年德温特公司与美国科学情报研究所 ISI）年德温特公司与美国科学情报研究所（ 1998年德温特公司与美国科学情报研究所（ISI）联合成立一个新的集团—— ——Thomson 联合成立一个新的集团——Thomson Science and Technology(简称TST)，简称TST) Technology(简称TST)，共同开发德温特创新索 Index）简称DII) DII)。引（Derwent Innovations Index）(简称DII)。

Determination of the Surface Fractal Dimension for Porous Media by Capillary Condensation

Determination of the Surface Fractal Dimension for Porous Media by Capillary CondensationFumin Wang and Shaofen Li*Department of Chemical Engineering,Tianjin University,Tianjin300072,People’s Republic of ChinaWe describe several methods of evaluating the surface fractal dimension of porous media.Theseinclude the thermodynamic method and the fractal version of Frenkel-Halsey-Hill theory.Neither method yields accurate estimates of the fractal dimensions of porous solids under thewhole range of experimental scales.We propose a modified thermodynamic method that isrelatively simple but is significantly more accurate than Neimark’s relation from the adsorptionexperiments.Then we use these methods to estimate the surface fractal dimension of severalkinds of porous media.After a concrete analysis of the properties of topology and mercuryporosimetry,N2adsorption,and N2desorption processes for porous media,we conclude that thereal surface fractal dimension should be determined by D abs(from the adsorption isotherm),D des(from the desorption isotherm),and D m(from the mercury porosimetry)jointly as D real)D abs+(D m-D des).IntroductionFractal geometry has been widely used in many areas of modern science.The key quantity in fractal geometry is the fractal dimension D,which is an operative measure of the surface and structural irregularities of a given solid.The fractal dimension should be deter-mined first before we can use the concept and knowledge of fractal geometry to characterize the structure of a given solid.The experimental methods used for the determination of the surface fractal dimension of porous solids have been reviewed by Avnir et al.(1992).The most common techniques are the adsorption and mercury porosimetry methods.In addition,electron microscopy image analy-sis and scattering methods(light,X-rays,neutrons)have also been used to demonstrate surface roughness for porous materials(Martin et al.,1986;Aubert et al., 1986;Freltoft et al.,1986).In this paper we restrict our attention to calculating the surface fractal dimen-sion from adsorption measurements because they are the most commonly used methods to determine the fractal dimension D of solid materials.Perhaps one of the oldest methods of evaluating the surface fractal dimension is that based on the depen-dence of monolayer capacity on the adsorbate size, which was developed by Pfeifer and Avnir(1983). Although this method is simple,the fractal dimensions determined by this method are not always consistent, especially when the orientations of adsorbate molecules on the surface are different.Also,this procedure has some disadvantages related to evaluation of the mono-layer capacity and selection of suitable adsorbates in order to avoid the effects associated with adsorbate-adsorbate interactions(Jaroniec,1995).Moreover,in this method,one needs to evaluate the monolayer capacities of several adsorbates of different molecular sizes,which makes the experiment rather time-consum-ing.Because the molecules adsorbed play the role of the gauges,the range of scales available in this method is limited by the molecular sizes.These problems become particularly important for adsorption on some microporous solids that possess a high degree of surface irregularity(Jaroniec and Madey,1988).Pfeifer et al.(1991)developed an adsorption-based method for surface roughness determination in1991. The principle is to measure the variation in surface area of the material coated with a series of presorbed films. In this method,they assume that every point of the film surface has the same shortest distance z to the solid,so the film area S(z)is related to the film volume V(z)by When the surface of the solid is fractal,with fractal dimension D,V(z)is proportional to z3-D and,therefore, S(z)is proportional to z2-D,so one obtainsFrom eq2,one can get the fractal dimension by measuring the surface area of the adsorbed film with varied film thicknesses of z.However,the equidistance assumption,on which this method is based,is open to doubt.The surface tension wants to make the film-vapor interface as flat as possible,so as to minimize the surface area of the interface.One cannot ignore the effect of the surface tension,especially when the film thickness is large(Pfeifer and Cole,1990).From the simulation results of this method,we can see that the deviations are very large and the corresponding cor-relation coefficient is very small(Pfeifer et al.,1991). Another popular method for evaluating D is that given by the Frenkel-Halsey-Hill(FHH)equation, which in logarithmic form can be expressed as follows (Pfeifer and Cole,1990):where N is the amount adsorbed at the relative pressure P/P0and absolute temperature T andµis the so-called adsorption potential defined asUsing eq3,one can determine D from physical adsorp-tion measurements on the fractal surface.On the other hand,Neimark et al.(1992,1994) proposed the so-called thermodynamic method for cal-culating the fractal dimension D from the adsorption isotherm data.In this model,the fractal surface area*Author to whom correspondence should be addressed.S(z))d V/d z(1)S∝V(2-D)/(3-D)(2)ln(N))const-(3-D)ln(µ)(3)µ)RT ln(P/P)(4)1598Ind.Eng.Chem.Res.1997,36,1598-1602S0888-5885(96)00555-6CCC:$14.00©1997American Chemical Societywas related to the average pore radius as(Neimark,1992):and the surface area of the adsorbed film is calculatedaccording to the Kiselev equation:where X denotes the relative pressure and N max denotesthe amount adsorbed at X tending to unity.Theyardstick is measured in terms of the average radius ofcurvature of the meniscus at the interface betweencondensed adsorbate and gas by the Kelvin equation: The thermodynamic method proposed by Neimark(1992)and the method based on the FHH theoryproposed by Pfeifer and Cole(1990)have been comparedwith one another by Jaroniec(1995).The theoreticalanalysis shows that both methods are essentially equiva-lent.However,the simulation results using Neimark’srelation show that the range of scale in which fractalexists is rather limited,which makes us suspect itsvalidity and robustness.The objective of this work is to develop a more reliablescaling relation to determine surface fractal dimensionof porous materials using the capillary condensationdata.We also show that the new method,based onconcrete analysis of the properties of topology andcapillary condensation processes for porous media,ismuch more accurate than Neimark’s relation and coversa wide range of scales.Then the simulation results willbe compared with those of the references.TheoryMandelbrot(1982)gave a correlation of the area fora fractal surface and the volume circumscribed by thesurface:In case the fractal surface is measured on a Euclideanarea,the above relation can be changed into thesubsequent form by dimensional analysis:where k0is a factor relating surface area with the corresponding volume.Just as illustrated by Neimark(1992),a given fractalsurface can be approximated by its inscribed equicur-vature surface(IES)of varying mean curvature radius(MCR).The decrease of the MCR,r c,causes penetrationof the IES into surface indentations of smaller size.Inother words,with a decrease of r c,the IES repeats allthe peculiarities of the substratum relief.In the limitr c f0,the IES is the fractal surface with the same dimension as the surface fractal dimension of thesubstratum.So,the mean curvature radius of theinscribed equicurvature surfaces can be chosen as ayardstick for measurement of the fractal surface.The practical realization of this method can be provided by using the adsorption experiments.In the process of adsorption of nitrogen in porous media,the equilibrium interface between the liquid film and gas acts as the inscribed equicurvature surface.So, the surface area of the adsorbed film can be calculated according to the Kiselev equation(6).After assuming that the liquid cannot be compressed, one can get the following relation:Substitution of S E and V(X)into eq9by eqs6and10 gives the following expression:LetEquation11will be changed into the ensuring style Accordingly,from the adsorption isotherm of nitrogen in the region of capillary condensation,we can compute a series of A(X)and B(X),where r c(X)can be predicted by the Kelvin equation(7)and then the surface fractal dimension can easily be achieved.Results and DiscussionFor a given porous solid,the desorption isotherm does not always retrace the adsorption isotherm but lies above it over a range pressures,forming a hysteresis loop,before eventually rejoining the adsorption iso-therm.The fractal dimension determined by eq13can be calculated either from the adsorption isotherm or from the desorption isotherm.First,the simulation of surface fractal dimension for several samples has been made by eq13using the nitrogen adsorption and desorption data of the literature(Neimark et al.,1994), so that we can have a comparison with the simulation results by Neimark’s relation.The evaluation of the surface fractal dimension of SiO2(A)using eqs5and13 is illustrated in Figures1and2,respectively,as an example.The obtained results are reported in Table1. This table also includes the range of scale from which the D was calculated.The above calculations and analyses show that the results simulated by means of eq13for several kinds of porous materials totally fall in the range of2<D< 3,which is predicted by fractal geometry,so this method is comparatively reasonable among the methods used to determine the surface fractal dimensions.From these results one can conclude that the method in this work is reliable over a sufficiently wide range of scales from1to250nm.Neimark’s relation,however,is seemingly reasonable only over a rather narrow range of scales.This is caused by the defects in the scaling relation(5).We know,from eq9,that only when theln(S))const-(D-2)ln(r)(5)S(X))RTσ∫N(X)N max ln(X)d N(X)(6) r)-2σVLRT ln(X)(7) S1/D∼V1/3(8)S E (δ))kDδ2-D V D/3(9)V(X))[Nmax-N(X)]VL(10)-∫N(X)N maxln(X)d N(X)rc2(X))kD VLD/3σRT[(N max-N(X))1/3rc(X)]D(11)-∫N(X)N maxln(X)d N(X)rc2(X))A(X)[Nmax-N(X)]1/3rc(X))B(X)(12)ln A(X))const+D ln B(X)(13)Ind.Eng.Chem.Res.,Vol.36,No.5,19971599volume encompassed by the fractal surface remains unchanged in the process can eq 3be rewritten asfrom which eq 5was obtained.But the capillary condensation process cannot satisfy this condition.With the increase of the relative pressure of nitrogen,the volume encompassed by the liquid -gas interface is decreased,so Neimark’s simulation results cannot characterize the real structure of the porous media.However,when the relative pressure of nitrogen X )P/P 0is relatively small,the volume does not change remarkably,so Neimark’s relation shows seemingly reasonable results in this range.In the range of greater relative pressure of nitrogen,especially after the valueof X surpassed 0.8,the volume encompassed by the liquid -gas interface decreased remarkably with an increase of X ,so the experimental data violated the simulated straight line.Neimark cannot find the defects in his scaling law and get to the wrong conclu-sion that the scaling interval for these porous solid is very narrow.So,it is necessary that the scaling relation developed to measure the surface fractal dimension using the capillary condensation data not only conform to the theory of fractal geometry itself but also consort with the concrete process of capillary condensation as well.Obviously,this idea has been considered when the scaling relation of this paper is being deduced.By contrast,the surface fractal dimensions deter-mined by the adsorption data are smaller than those determined by the desorption data;this cannot be thought of as caused by the experimental probable error.The surface morphology is not the only factor that affects the desorption process;the topology of the porous space has a significant influence on this process.In the process of desorption,due to the “shielding”effect of the small pores on the large one,the calculating results of S E (X )are larger than those of S E in reality and thus make the discrepancy between D abs and D des .The quantitative difference between the two indicates the degree of the influence of the shielding effect,so it reflects the topological feature of the porous solid in some degree.Jaroniec (1995)compared the fractal FHH equation (3)and Neimark’s relation (5)and concluded that the two methods are theoretically equivalent.So,the FHH equation meets the same difficulty when being used to evaluate the surface fractal dimension.Sahouli et al.(1996)reexamined the two methods and concluded that the FHH type equation is also sensitive to the mi-croporous structures in contrast to Neimark’s relation,and this causes the disagreement of the results of the two methods for the solids with high surface area.In fact,the disagreement is due to the fact that the two methods were used in two different scale ranges.When being used in the same scale range,these two methods should yield the same results.The method in this work is based on the thermody-namic principle;another thermodynamic method to measure the surface fractal dimensions for the porous materials has been developed by Zhang and Li (1995).These two methods use different experimental data,with Zhang’s method using the mercury porosimetry data and the method in this work developed to use the capillary condensation data,but both are based on the same principle.In order to make a comparison between the two methods,we have done the experiments to get the mercury porosimetry and nitrogen adsorption iso-therm of the same four porous materials.The experi-mental data of mercury porosimetry are measured by means of a J5-70porosimeter made in Shanghai,People’s Republic of China.The range of pressureinFigure 1.Simulation results from eq 13for SiO 2(A).Figure 2.Simulation results from eq 5for SiO 2(A).Table 1.Surface Fractal Dimensions Determined from Equations 13and 5,Respectively,with Capillary Condensation Data in the Literature (Neimark et al.,1994)eq 13eq 5analyzed sample D des D abs a min (nm)a max (nm)D des D abs a min (nm)a max (nm)porous glass 2.52 2.35 1.089.0 2.10 2.14 1.016.0Si300 2.48 2.34 1.553.7 2.20 2.22 1.510.0MgO(A) 2.41 2.33 1.389.0 2.36 2.43 1.422.4cement 2.68 2.63 1.825.1 2.43 2.43 1.87.2MgO(B) 2.51 2.33 1.2251.0 2.54 2.55 2.713.2SiO 2(A) 2.53 2.41 1.5125.0 2.47 2.59 1.512.5O 22.67 2.65 1.179.4 2.76 2.71 1.1 5.5SiO 2(B)2.552.501.139.828.52.882.08.0S E (δ)∼δ2-D1600Ind.Eng.Chem.Res.,Vol.36,No.5,1997the experiment is from0.1to300MPa.The experi-mental data of the nitrogen adsorption isotherm are measured by means of a CHEMBET-3000adsorption apparatus made by Quantachrome Co.,Syosset,NY. The simulation results are demonstrated in Table2. The simulation results show that the surface fractal dimensions determined by mercury porosimetry,D m,are larger than both D abs and D des.In the process of adsorption,before capillary condensation occurs,there has been a nitrogen film adsorbed on the surface of the porous solid.As a result,the interface between the film and the vapor,with which the film is in equilibrium,is no longer a simple replica of the film-solid interface. Due to the effect of the surface tension,the D abs is smaller than the real dimension of the fractal surface. So,the discrepancy between D abs and D real is determined by the competition between the attractive van der Waals gas-solid potential and the repulsive surface free energy of the nitrogen film.The potential wants to make the film-vapor interface follow the ups and downs of the surface as closely as possible,so that the adsorbed molecules get to set as close to the solid surface as possible.The surface tension,on the other hand,wants to make the film-vapor interface as flat as possible,so as to minimize the surface area of the interface;the two effects entangled together make the discrepancy be-tween D abs and D real.These effects,also,act on the determination of D des.On the other hand,the shielding effect makes the surface fractal dimension D m deter-mined by mercury porosimetry larger than the real dimension of the fractal surface,so it is not surprising that D m ofγ-Al2O3(C)is greater than 3.So,the shielding effect of the small pores on the large one and the effect of the surface tension result in D m>D des> D abs,which is proved by this work.From the analysis above,we can see that the discrepancies between D m and D real,D des and D abs show the shielding effect of the small pores on the large one,while the discrepancies between D real and D abs,D m and D des show the effect of the surface tension.So,we can easily get the conclusion that the following relation exists:The real surface fractal dimension of porous media can be determined by D abs,D des,and D m jointly. ConclusionA new method is proposed to determine the surface fractal dimension for a porous solid.The method is based on the approximation of a given fractal surface by inscribed equicurvature surfaces of varying mean curvature radius.The practical realization of this method for determining the surface fractal dimension of real porous materials is provided by analyzing experimental data of capillary condensation.The simulations for several kinds of porous media are fulfilled by analyzing the nitrogen adsorption isotherm and mercury porosimetry from the literature and our own.The results show that D abs,D des,and D m are different and D m>D des>D abs.By analyzing the process of adsorption,desorption of nitrogen,and mer-cury incursion,the author gives a reasonable explana-tion of the results and achieves the conclusion that D real )D abs+(D m-D des))D m-(D des-D abs).So,the real surface fractal dimension cannot be determined by D abs, D des,and D m,respectively,but jointly. AcknowledgmentSupport from funds of Science and Technology of National Education Committee of People’s Republic of China is gratefully acknowledged.Nomenclaturea min)outer cutoff of a finite scaling regimea max)inner cutoff of a finite scaling regimeD)fractal dimension of pore surfacek0)shape factorN)physisorption quantity,molP)current pressure of nitrogen,PaP0)saturation pressure of nitrogen,Par c)mean curvature radius,mS E)fractal area of pore surface in Euclidean space,m2 T)absolute temperature of the adsorption,KV)volume of the space encompassed by the fractal surface,m3V L)molar volume of liquid nitrogen,m3/molGreek Symbolsδ)yardstick size of measurements,mµ)chemical potential energy,J/molσ)surface tension between liquid and gas of nitrogen,J/m Literature CitedAubert,C.;Cannel,D.S.Restructuring of Colloidal Silica Ag-gregates.Phys.Rev.Lett.1986,56,738.Avnir,D.;et al.A Discussion of Some Aspects of Surface Fractality and Its Determination.New J.Chem.1992,16(4),439. Freltoft,T.;et al.Power-law Correlations and Finite-size Effects in Silica Particle Aggregates Studied by Small-angle Neutron Scattering.Phys.Rev.B1986,33(1),269.Jaroniec,M.Evaluation of the Fractal Dimension From a Single Adsorption ngmuir1995,11,2316.Jaroniec,M.;Madey,R.Physical Adsorption on Heterogeneous Solids;Elsevier:Amsterdam,The Netherlands,1988. Mandelbrot,B.B.The Fractal Geometry of Nature;Freeman:New York,1982;p109.Martin,J.E.;et al.Fractal Geometry of Vapor-phase Aggregates.Phys.Rev.A1986,33(5),3540.Table2.Surface Fractal Dimension Determined from Equation13and Zhang’s Relationeq13Zhang’s relation analyzedsample D abs D des a min(nm)a max(nm)D m a min(nm)a max(nm)γ-Al2O3(A) 2.75 1.024.0 2.81 2.025.7 B106 2.72 1.024.0 2.80 2.025.7γ-Al2O3(B) 2.68 1.024.0 2.72 2.025.7γ-Al2O3(C) 2.66 2.75 1.024.0 3.07 2.026.3Dreal )Dabs+(Dm-Ddes))Dm-(Ddes-Dabs)Ind.Eng.Chem.Res.,Vol.36,No.5,19971601Neimark,A.V.A New Approach to the Determination of the Surface Fractal Dimension of Porous Solids.Physica A1992, 191,258.Neimark,A.V.;et al.Determination of the Fractal Dimension for Porous Solids from Adsorption Isotherm of Nitrogen.Z.Phys.Chem.1994,187,265.Pfeifer,P.Structure analysis of Porous Solids From Presorbed ngmuir1991,7,2833.Pfeifer,P.;Avnir,D.Chemistry in Noninteger Dimensions Be-tween Two and Three.J.Chem.Phys.1983,79(7),3558. Pfeifer,P.;Cole,M.W.Fractals in Surface Science:Scattering and Thermodynamics of Adsorbed Films II.New J.Chem.1990,14,221.Zhang,B.;Li,S.Determination of the Surface Fractal Dimension for Porous Media by Mercury Porosimetry.Ind.Eng.Chem.Res.1995,34,1383.Received for review September9,1996 Revised manuscript received January27,1997Accepted February3,1997XIE960555W X Abstract published in Advance ACS Abstracts,March15, 1997.1602Ind.Eng.Chem.Res.,Vol.36,No.5,1997。

grape pomace 葡萄

Invited reviewFunctional components of grape pomace:their composition,biological properties and potential applicationsJianmei Yu 1*&Mohamed Ahmedna 21Department of Family and Consumer Sciences,North Carolina A&T State University,1601East Market Street,Greensboro,NC 27411,USA2Centre for Excellence in Post-Harvest Technologies,North Carolina A&T State University,500Laureate Way,Suite 4222,North Carolina Research Campus,Kannapolis,NC 28081,USA(Received 20April 2012;Accepted in revised form 25July 2012)SummaryThe roles of functional foods on human health have been realised by more and more researchers,food producers and consumers.Functional food ingredients from both plant and animal sources such as die-tary ﬁbre,soy protein isolate,whey protein isolate and omega 3fatty acid have been widely used in func-tional food product development.Many fruit processing by-products such as grape,apple and orange peels are rich in bioactive phytochemicals,dietary ﬁbre and unsaturated fatty acids,hence have potential to serve as functional food ingredients.In this review,we summarise recent advancement of research in grape pomace (GP),the residual of grapes after wine making.The polyphenol proﬁle of GP and their bio-logical,antioxidant and antimicrobial activities,the stability of GP polyphenols in food system,the inter-action between GP polyphenol and other food ingredients,as well as the functionalities of grape seed oil and GP ﬁbre are covered.KeywordsBiological properties,dietary ﬁbre,grape pomace,grape seed oil,grape seed protein,polyphenol composition,thermal stability.Introduction Grape pomace (GP)is a by-product of wine industry.GP consists mainly of peels (skins),seeds and stems and accounts for about 20–25%of the weight of the grape crushed for wine production.Grape seed is rich in extractable phenolic antioxidants such as phenolic acid,ﬂavonoids,procyanidins and resveratrol,while grape skins contain abundant anthocyanins.The health beneﬁts of GP polyphenols have been the great interest of researchers,food industry and nutraceutical industry.In addition to phenolic antioxidants,GPs also contain signiﬁcant amount of lipid,proteins,non-digestible ﬁbre and minerals.Grape seeds contain 13–19%oil,which is rich in essential fatty acids,about 11%protein,60–70%of non-digestible carbohydrates,and non-phenolic antioxidants such as tocopherols and beta-carotene (Rao,1994;Baydar &Akkurt,2001;Bravi et al.,2007;Llobera &Can ellas,2007).This review summarises the recent studies on major components of GP,their important properties and their possible applications that are.Phenolic compounds of GP and their propertiesPolyphenol composition of GPPhenolics are the secondary metabolites of plants.Chemically,phenolics can be deﬁned as substances pos-sessing an aromatic ring bearing one or more hydroxyl groups,including their functional derivatives (Shahidi &Naczk,2004).Polyphenols are compounds that have more than one phenolic hydroxyl group attached to one or more benzene rings (Vermerris &Nicholson,2006).Most food phenolics have more than one hydroxyl group attached on the aromatic ring;therefore,in this review,phenolics and polyphenols are used interchange-ably.In food science research,natural phenolics are generally classiﬁed into classes and sub-classes based on the similarity of their chemical structures,that is,the types of building blocks that appear as repeated units.Four major classes of polyphenols found in foods are phenolic acids,ﬂavonoids,lignans and stilbenes (Spencer et al.,2008).Major stilbenoids found in foods of plant origin are resveratrol and it glycosides.Resveratrol is a phytoalexin produced in the plant in response to pathogen attack.It has a low toxicity in humans and is a naturally occurring fungicide.*Correspondent:Fax:3363347239;e-mail:jyu@International Journal ofFood Science and Technology 2013,48,221–237doi:10.1111/j.1365-2621.2012.03197.x©2012The Authors.International Journal of Food Science and Technology ©2012Institute of Food Science and Technology221Phenolic acids are phenols that possess one carbox-ylic acid functional group and are divided into hydroxycinnamic acids and hydroxybenzoic acids.The hydroxycinnamic acids are more common than hydroxy-benzoic acids,and they mainly include gallic acid,p -coumaric,caﬀeic,chlorogenic acid,ferulic and sinapic acids.These acids are rarely found in the free form,except in food that has undergone freezing,sterilisation or fermentation.The bound forms are glycosylated derivatives or esters of quinic acid,shikimic acid and tartaric acid (Vermerris &Nicholson,2006).The largest and best studied polyphenols are the ﬂavonoids.Based on their molecular structures,ﬂavonoids are divided into seven subclasses:ﬂavones,ﬂavanones,ﬂavonols,isoﬂavones,anthocyanidins/an-thocyanins,ﬂavanols (or catechins and procyanidins)and chalcones (Karakaya,2004).Another group of ﬂavonoids,which are not included in this classiﬁca-tion,are proanthocyanidins,also called,procyanidins,condensed tannins or oligomeric procyanidins (Prior &Gu,2005).Although phenolics are present virtually in all plant foods,some fruits such as grape,apple,blueberry and cranberry are extremely rich in these bioactive com-pounds.In grape berries,the phenolic compounds reside mainly in the skins,seeds and short stems (Rodriguez et al.,2006;Poudel et al.,2008).GP is rich in extractable phenolic antioxidants (10–11%of dry weight)(Makris et al.,2007).Anthocyanins,catechins,procyanidins,ﬂavonol glycosides,phenolic acids and stilbenes are the principal phenolic constituents found in GP (Montealegre et al.,2006).Polyphenol composition of GP is variety dependant.The red varieties are usually rich in anthocyaninins that are neglected in while white varieties.Within the same variety,diﬀerent part has signiﬁcantly diﬀerent polyphenol composition.Cantos et al.(2002)analysed the polyphenol composition of four red and three white table grape varieties by HPLC-ADA-MS and found that anthocyanins were the main phenolics in red grapes ranging from 69(Crimson Seedless)to 151(Flame Seedless)mg kg À1fresh weight of grapes,whereas ﬂavan-3-ols were the most abundant phenolics in the white varieties ranging from 52(Dominga)to 81(Moscatel Italica)mg kg À1fresh weight of grapes.Flavan-3-ols were also detected and were identiﬁed as gallocatechin,procyanidin B1,procyanidin B2,procy-anidin B4,procyanidin C1,catechin and epigallocate-chin.The study of the phenolic compounds content and antioxidant activity of pomace from the viniﬁcation of grape varieties widely produced in Brazil (Cabernet Sauvignon,Merlot,Bordeaux and Isabel)found that catechin was the most abundant non-anthocyanic com-pound identiﬁed in the GP (150.16mg 100g À1)for all varieties;Cabernet Sauvignon pomace had the highest content of total phenolic compounds (75mg g À1),while Bordeaux variety showed the highest content of total anthocyanins (Rockenbach et al.,2011).Phenolic compound distribution in diﬀerent parts of grapes was reviewed by Xia et al.(2010).The grape skins,part of pomace,are proven to be rich sources of anthocyanins,hydroxycinnamic acids,ﬂavanols and ﬂavonol glycosides,whereas gallic acid and ﬂavanols were mainly present in the seed portion (Kammerer et al.,2004;Xia et al.,2010).Thirty-seven anthocya-nins have been separated by McCalluma et al.(2007)from Concord grape skin,and among them twenty-ﬁve were identiﬁed using LC-MS.Among the anthocyanins identiﬁed in GP,ﬁve of them are the 3-O -monogluco-sides of delphinidin,cyaniding,petunidin,peonidin and mavidin;another ﬁve of them are the acetylgluco-sides of the ﬁve anthocyandins.Malvidin 3-O -gluco-side was found to be the predominant anthocyanin.Grape seeds are rich in monomeric phenolic com-pounds,such as (+)-catechins,(À)-epicatechin and (À)-epicatechin-3-Ogallate,and dimeric,trimeric and tet-rameric procyanidins.Anthocyanin content of GP var-ies with wine viniﬁcation method and contact time.The longer the contact time,the lower the anthocyanincontent remains in the pomace (Gomez-Plaza et al.,2006).The phenolic proﬁle of grape skin and seeds of European variety Vitis Vinifera has been intensively studied by scientists all over the world.Montealegre et al.(2006)quantiﬁed many phenolic compounds in seeds and skins of ten V.vinifera grapes grown in the warm climate of Spain,including six white varieties (Chardonnay,Sauvignon blanc,Moscatel,Gewu rztr-aminer,Riesling and Viogner)and four red grape vari-eties (Cencibel,Cabernet Sauvignon,Merlot and Shiraz).They found that the skin of Viogner had the least of total hydroxycinnamates,catechin and procy-anidin dimmers,while that of Moscatel had the most of total hydroxycinnamates and ﬂavonols.Chardon-nay and Gewu rztraminer skins were the richest in cate-chin and procyanidins among white grape varieties.Red grape skin contains higher amount of hydroxycin-namates than white grape skin (31–55mg kg À1fresh grape),but much lower amount of catechins (9.0–18mg kg À1fresh grape),procyanidin dimmers (8.0–18mg kg À1fresh grape)and total ﬂavonols (12–19mg kg À1fresh grape).The polyphenol composition of each part of the GP varies depending on the varieties of grapes and is inﬂu-enced by the growing location,climate,maturity and the time of fermentation (Fuleki &Ricardo da Silva,1997;Kennedy et al.,2000;Shi et al.,2003a;Monteal-egre et al.,2006).The per-berry extractable yield of all polyphenols decreased with maturity and followed sec-ond-order kinetics.The ﬂavan-3-ol monomers decreased most rapidly,followed by the procyanidin extension units and ﬁnally the terminal units.The©2012The AuthorsInternational Journal of Food Science and Technology ©2012Institute of Food Science and TechnologyInternational Journal of Food Science and Technology 2012Functional components of grape pomace J.Yu and M.Ahmedna222relative proportion of procyanidin extension units did not vary with maturity(Kennedy et al.,2000).The phenolic composition of white and red grape seeds is comparable,but catechin,epicatechin and procyanidin B1are higher in white grape seeds.Overall,grape seeds contained lower amount of phenolic acid than grape skin,but rich in catechins and procyandins. Castillo-Mun oz et al.(2010)investigated theﬂavonol proﬁles of white GPs from twenty-one V.vinifera white grape cultivars in Spain and found thatﬂavonol proﬁles of white grapes are dominated by quercetin-typeﬂavonols,but some cultivars(e.g.Pedro Xime nez, Gewu rztraminer,Verdejo,Albillo,and Riesling)were characterised by relatively high and signiﬁcantly diﬀer-ent proportions of isorhamnetin-typeﬂavonols.The phenolic compounds in grape seeds are essen-tially allﬂavonoids,particularly,ﬂavan-3-ols(catechin, epicatechin and epicatechin-3-O-gallate monomers) and their polypmers.Flavan-3-ols easily condenses into oligomeric procyanidins and polymeric com-pounds(condensed tannins).The dimeric procyanidins are often referred as B-series,and the trimeric procy-anidins as C-series.Five diﬀerent dimers(procyanidin B1,B2,B3,B4and B5)and two trimers(C1and C2) were identiﬁed from grape skin and seeds(Shi et al., 2003a).Analysis of procyanidins extracted from both white and red grape seeds by electrospray ionisation–mass spectrometry(ESI-MS and ESI-MS/MS)in the positive mode found protonated molecules of procy-anidin species of nongalloylated and monogalloylated type-A and type-B oligomers,with degree of polymeri-sation2–5,and digalloylated oligomers,with degree of polymerisation2–3(Passos et al.,2007).The native grape variety grown in the United States is Muscadine,which includes the popular cultivars of Carlos,Cowart,Jumbo,Magnolia,Sterling,Nesbitt, Scuppernong and Noble.These grapes have tougher skins and less seeds than V.vinifera grapes.The study conducted in our laboratory demonstrated that Mus-cadine GP had about5%more skin,but8%less seeds than Cabernet GP.The polyphenol composition of Muscadine GP and Cabernet GP was also diﬀerent. The contents of total extractable polyphenol,total anthocyanin and totalﬂavonoid were36.42,0.88and 21.02mg gÀ1DM in Muscadine seeds,19.39,8.15 and4.78mg gÀ1DM in Muscadine skin,respectively (Yu et al.,2011).Ellagic acid,gallic acid,(À)-epicate-chin,(À)-epigallocatechin,catechin,myricetin,querce-tin,and kaempferol and some anthocyanidins including delphinidin,cyanidin,petunidin,peonidin and malvidin were identiﬁed in the extract of Musca-dine pomace extract using the combination of reten-tion time and spectral properties on a reverse-phase HPLC–PDA(Wang et al.,2010).Approximately90% of the total anthocyanins in Muscadine grapes were 3,5-diglucoside of delphinidin,cyanidin and petunidin;the remaining10%were3,5-diglucoside of peonidin and malvidin;purple-skinned muscadine grapes(Jumbo and Cowart)have signiﬁcantly higher levels of anthocy-anins than bronze-skinned muscadine grapes(Carlos and Higgin)(Huang et al.,2009).Resveratrol is another important polyphenol found in grape skins and seeds.Resveratrols are found lar-gely in the skins of red grapes and in other foods such as mulberries and peanuts(Sanders et al.,2000).The trans-resveratrol content was found to be 1.11–12.3 mg per100dry mass in grape skin,8.64±4.5mg per 100dry mass in white grape skin and1.42±0.18mg per100g dry mass in white grape seeds(Kammerer et al.,2004).The resveratrol content in grapes diﬀers according to the variety of grape(Ector et al.,1996) and the grape maturation(Moreno et al.,2008).Mus-cadine grapes and their products were reported to con-tain more resveratrol than any other type of grape (Ector et al.,1996).‘Carlos’and‘Magnolia’Musca-dine cultivars had the greatest skin resveratrol concen-tration of all the Muscadine cultivars evaluated. Except for‘Sweet Jenny’,bronze cultivars had greater skin resveratrol concentration than black skinned culti-vars.‘Miss Blanc’Vitis labrusca grape had greater skin resveratrol concentration than all other cultivars (LeBlanc,2006).Resveratrol contents in grape tissues can be modiﬁed by post-harvest technologies.Cold storage alone doubled skin stilbene concentration in ‘Carlos’grape,but UV irradiation did not signiﬁcantly change stilbene levels.In contrast,UV irradiation increased skin stilbene concentration by50%in ‘Noble’grape,but cold storage alone had no eﬀect (LeBlanc,2006).Although certain amount of resvera-trols in grape transfers into wine during grape macera-tion,signiﬁcant amount of resveratrols remains in the pomace(Feijo o et al.,2008).Like other plant materials,GP contains relatively higher amount of non-extractable polyphenols(NEP). Although the total polyphenol content in dry GP is about 4.8–5.4%(Makris et al.,2007),only2%of polyphenols in GP is extractable under mild conditions commonly used to develop polyphenol databases (Bravo&Saura-Calixto,1998).The majority portion of GP polyphenols has been reported to be highly polymerised condensed tannin,and some polyphenols form complex withﬁbre and are non-extractable unless strong acidic treatments are applied(Arranz et al., 2010).Monomeric and oligomeric proanthocyanidins are certainly soluble in the organic solvents usually used for polyphenol extraction,but a major propor-tion of high-molecular-weight proanthocyanidins and polyphenols complexed with protein or cell wall poly-saccharides remain insoluble(Huemmer&Schereier, 2008).The quantiﬁcation of NEP in GP needs hydro-lysis of GP residual to release the bound phenolics from cell wall or protein after soluble polyphenols are©2012The AuthorsInternational Journal of Food Science and Technology©2012Institute of Food Science and Technology International Journal of Food Science and Technology2012Functional components of grape pomace J.Yu and M.Ahmedna223extracted (Ignat et al.,2011).The NEP content of GP can be as high as 67mg g À1DM in red GP (var.Cencibel)and as low as 1.68mg g À1in white GP (var.Thompson,seedless)(Perez-Jime nez et al.,2009).Some food processing methods such as extrusion increased extractable and bioavailable polyphenols (catechin and epicatechin)and reduced the NEP by reducing the degree of polymerisation (Khanal et al.,2009).Similar results were observed for the extractabil-ity of polyphenols in roasted peanut and almond skins (Yu et al.,2005,2006,2007;Garrido et al.(2008).These studies suggest that thermal processing may increase the extractability and bioavailability of some polyphenols while destroying heat sensitive polyphe-nols,in grape skin and seeds.Biological properties of GP polyphenolsNumerous studies have demonstrated that grape seed phenolics,particularly procyanidins,have many health beneﬁts such as antimutagenic and anticarcinogenic activity (Joshi et al.,2000;Carini et al.,2000;Manten-a &Katiyar,2006;Yeh &Yen,2006;Bagchi et al.,2000;de Rezende,et al.,2009),antioxidant and anti-inﬂammatory activities (Prior &Gu,2005;Sartor et al.,2002),prevention and delay of cardiovascular diseases (Brito et al.,2002;Vigna et al.,2003;Bagchi et al.,2003;Karthikeyan et al.,2009;Bradamante et al.,2004;Sano et al.,2005),increase in lifespan and retarded the onset of age-related markers (Valenzano et al.,2006).Some recent studies have also shown that taking grape seed extract (GSE)reduced food intake in rats and energy intake in human (Vogels &Plant-enga,2004).The main bioactive compounds responsi-ble for many reported health beneﬁts of wine and wine by-products consist of antioxidant phenolics such as phenolic acids,anthocyanins,procyanidins and revera-trols (Shrikhande,2000;Yilmaz &Toledo,2004;).Antimutagenic and anticarcinogenic propertiesA study by Bagchi et al.(2000)demonstrated that grape seed procyanidin extract (GSPE)was highly bio-available and provided signiﬁcantly greater protection against free radicals and free radical induced lipid oxi-dation and DNA damage than vitamins C,E or b -car-otene.Cytotoxicity of GSPE towards human breast,lung,gastric adenocarcinoma cells,while enhancing the growth and viability of gastric mucosal cells,was also observed in the same study.GSPE also exhibited protection against skin cancer by inhibiting UV-radia-tion-induced oxidative stress and activation of mito-gen-activated protein kinase and NF-jB signalling in human epidermal keratinocytes (Bagchi et al.,2000;Mantena &Katiyar,2006;White et al.,2006).The study of Kaur et al.(2008)found that irrespective of source,GSE strongly inhibits LoVo,HT29andSW480cell growth,with a G1arrest in LoVo and HT29cells,but an S and/or G2/M arrest in SW480cell cycle progression.GSE also induced Cip/p21levels in all three cell lines.Furthermore,an induction of apoptosis was observed in all three cell lines by GSE.These ﬁndings suggest that GSE could be an eﬀective alternative and complementary medicine against colo-rectal cancer because of its strong growth inhibitory and apoptosis-inducing eﬀects.It also has been reported that phenolics from grape seeds and skin inhibit some matrix proteases,such as leucocyte elastase and gelatinases,associated with inﬂammation and cancer invasion (Sartor et al.,2002).The cell cultural study of Mertens-Talcott et al.(2008)show that the polypenol extracts from both red Musca-dine and Cabernet Sauvignon wine signiﬁcantly inhib-ited the growth of MOLT-4leukaemia cells.Wine extracts reduced cell viability up to 68%and cell num-bers up to 50%after 48h with muscadine extracts being more eﬀective than cabernet sauvignon.These extracts also induced caspase-3activity and cell cycle arrest in the G2/M phase.The roles of anthocyanins in cancer prevention were extensively reviewed by Wang &Stoner (2008)and will not be repeated in this review.Grape seeds are rich in B type procyanidins.Many studies revealed that GSPE can serve as potential ther-apeutic agent for diﬀerent cancers.An in vitro study found that grape seed procyanidins inhibited pancre-atic carcinoma cells MIA PaCa-2and BxPC-3prolifer-ation in a dose-dependent manner and induced G1-phase arrest of the cell cycle in BxPC-3or mito-chondria-mediated apoptosis in MIA PaCa-2.Grape seed procyanidin also inhibited the adhesion and inva-sion potential of both cell lines in a dose-dependent manner through downregulation of MMP-2or MMP-9in pancreatic carcinoma cells (Chung et al.,2012).Grape seed proanthocyanidins also induced apoptosis of non-small cell lung cancer (NSCLC)cells,A549and H1299,in vitro through increased expression of pro-apoptotic protein Bax,decreased expression of antia-poptotic proteins Bcl2and Bcl-xl,disruption of mitochondrial membrane potential and activation of caspases 9,3and poly (ADP-ribose)polymerase (PARP).Further,administration of 50,100or 200mg GSPs kg À1body weight of mice by oral gavage (5days week À1)markedly inhibited the growth of s.c.A549and H1299lung tumour xenografts in athymic nude mice,which was associated with the induction of apoptotic cell death,increased expression of Bax,reduced expression of antiapoptotic proteins and acti-vation of caspase-3in tumour xenograft cells (Singh et al.,2011).Grape seed catechin and procyanidin B 4pretreatment was found to protect cardiomyocytes against doxorubicin-induced toxicity by decreasing reactive oxygen species generation as well as the num-ber of apoptotic cells,preventing DNA fragmentation,©2012The AuthorsInternational Journal of Food Science and Technology ©2012Institute of Food Science and TechnologyInternational Journal of Food Science and Technology 2012Functional components of grape pomace J.Yu and M.Ahmedna224regulating the expression levels of the pro-apoptotic protein Bax-a and the antiapoptotic protein Bcl-2,and inhibiting apoptotic signalling pathways(Du&Lou, 2008).There is growing evidence that resveratrol can pre-vent or delay the onset of various cancers,heart dis-eases,ischaemic and chemically induced injuries, pathological inﬂammation and viral infections.As a chemoprevention agent,resveratrol has been shown to inhibit tumour initiation,promotion and progression (Jang et al.,1997).The review of Shanker et al.(2007) summarises the molecular mechanisms of resveratrol and its clinical beneﬁts for human diseases.Resvera-trol induces apoptosis by upregulating the expression of Bax,Bak,PUMA,Noxa,Bim,p53,TRAIL, TRAIL-R1/DR4and TRAIL-R2/DR5and simulta-neously downregulating the expression of Bcl-2,Bcl-XL, Mcl-1and survivin.Resveratrol also potentiates the apoptotic eﬀects of cytokines,chemotherapeutic agents and gamma-radiation.Pharmacokinetic and pharmaco-dynamic studies demonstrate that the main target organs of resveratrol are liver and kidney,and it is metabolised by hydroxylation,glucuronidation,sulf-ation and hydrogenation(Bishayee et al.,2010).Resve-ratrol(~25l M)potentiated GSE(35l g mLÀ1) induced colon cancer cell apoptosis via the activation of p53-dependent pathways(Radhakrishnan et al., 2011).This discovery suggests the importance of under-standing the potentiating eﬀects of phytonutrients in combination as they would occur in nature rather than individually.The cancer prevention mechanism of food polyphe-nols has been extensively studied.Many potential chemopreventive polyphenols may interrupt or reverse the carcinogenesis process by acting on intracellular signalling network molecules involved in the initiation and/or promotion of cancer(Manson,2003;Surh, 2003).The programmed cell death is considered one of the important targets in a preventive approach against cancer.Reversing the conversion of a normal cell to a malignant one is a complex process that involves active participation of aﬀected cells in a self-destruc-tion cascade.In addition to signal transduction and regulation of proliferation and immune response,die-tary polyphenols readily interact with reactive oxygen species or free radicals to form relatively stable com-pounds,thus prevent cells from oxidative damage and onset of cancer.The major chemoprevention and che-motherapy mechanisms of dietary polyphenols may include(i)alteration of phase-I and phase-II drug-met-abolising enzymes,(ii)antioxidant properties,(iii) inhibition of protein kinases,(iv)blocking of receptor-mediated functions,(v)attenuation of protease activities,(vi)alteration of cell cycle checkpoint controls,transcription factor expression and apoptosis, (vii)inhibition of angiogenesis,invasion and metastasis,and(viii)epigenetic changes in promoter methylation and chromatin remodelling(Dashwood,2007;Kundu &Surh,2008).Prevention of cardiovascular diseasesEpidemiological studies suggest that consumption of wine,grape products and other foods containing polyphenols is associated with decreased risk of car-diovascular disease.Cardiovascular disease is associ-ated with modiﬁcations in fatty acid metabolism and excessive lipid peroxidation of LDL.These oxidation products are also implicated in the formation of thromboxane,which leadsﬁrst to enhanced platelet aggregation,then to artery blockage andﬁnally to thrombosis.The accumulation of lipid oxidation prod-ucts from LDL can be attributed to the low levels of plasma antioxidants.A rat study showed that a15%GP in cholesterol diet(0.3%)produced a signiﬁcant reduction in choles-terol and triacylglycerols in the liver and serum.The diet contains15%GP reduced VLDL and LDL by50 and60–70%,respectively,while increase HDL level by 26%(Bobek,1999).Grape seed polyphenols reduce the risk of heart disease by inhibiting the oxidation of LDL(Shi et al.,2003a,b).Intravenous and oral administration of grape seed procyanidins was found to signiﬁcantly inhibit laser-induced thrombus forma-tion in the carotid artery of mice(Sano et al.,2005). Protection against myocardial ischaemia-reperfusion and myocardial injury in rats was reported by Bagchi et al.(2000)and Karthikeyan et al.(2009).GSEs rich in polyphenols exhibited higher eﬀectiveness in reduc-tion in platelet adhesion,aggregation and generation of superoxide anion than pure resveratrol(Olas et al., 2008).Experimental studies indicate that grape polyphenols could reduce atherosclerosis by a number of mechanisms,including inhibition of oxidation of LDL and other favourable eﬀects on cellular redox state,improvement in endothelial function,lowering blood pressure,inhibition of platelet aggregation, reducing inﬂammation and activating novel proteins that prevent cell senescence(Dohadwala&Vita, 2009).Procyanidins from GP inhibit human endothelial NADPH oxidase,the enzyme responsible for the increased production of reactive oxygen species, regardless of their polymerisation degree and galloyla-tion percentage.The procyanidin fractions even blocked NADPH oxidase activity in intact HUVEC, inhibiting ROS production at both extra-and intracel-lular levels.Therefore,grape procyanidins are suitable NADPH oxidase inhibitors,which could serve as models for therapeutic alternatives for cardiovascular diseases(A lvarez et al.,2012).Supplementation with the high dose of mixture of cathechin,caﬀeic acid and resveratrol signiﬁcantly reduced the presence of©2012The AuthorsInternational Journal of Food Science and Technology©2012Institute of Food Science and Technology International Journal of Food Science and Technology2012Functional components of grape pomace J.Yu and M.Ahmedna225atherosclerotic plaque by 40and 36%in the aortic sinus and in the ascending aorta,respectively Norata et al.(2007).Resveratrol alone also showed signiﬁcant antiatherogenic and anti-inﬂammatory eﬀects in an animal model of rabbits fed a hypercholesterolemic diet (1%cholesterol)Matos et al.(2012).CVD pre-ventative activities of anthocyanins,including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mecha-nisms of action,were reviewed by Wallace (2011)and will not be repeated in this review.Antilipogenic propertiesVogels &Plantenga (2004)reported that GSE reduced food intake in rats and energy intake in humans.In an in vitro study by Moreno et al.(2003),GSE was found to signiﬁcantly inhibit pancreatic lipase,lipoprotein lipase and hormone sensitive lipase that responsible for the fat digestion and metabolism in human body.A study with rats fed high-fat diet shows that GSPE rectiﬁes dyslipidemia associated with a high-fat diet in rats and repress genes controlling lipogenesis and VLDL assembling in liver (Baiges et al.,2010).Low-dose (25mg per kg body weight per day)GSPE treat-ment of high-fat-diet (HFD)fed rats signiﬁcantly reduced the adiposity index and the weight of all the white adipose tissue depots and reversed the increase in plasma phospholipids induced by the HFD feeding (Caimari et al.,2012).Chronic consumption of grape phenolics has shown to reduce obesity development and related metabolic pathways including adipokinesecretion and oxidative stress in a rat model (Decorde et al.,2009).These studies suggest that grape seed polyphenols may play a role in body-weight management.Antiageing activitiesGrape seed extract has been shown to have a modula-tory role on age-related oxidative DNA damage and lipid peroxidation in central nervous system of rats (Feng et al.,2005;Balu et al.,2006).Aged rats given GSE showed improved memory performance,reduced reactive oxygen species production,decreased protein carbonyl level,increased thiol level and reduced hyp-oxic ischaemic brain injury in their central nervous systems.Recent studies show that resveratrol could exert neuroprotection against ischaemia,seizure and neurodegenerative diseases (Markus &Morris,2008).In the study conducted by Zhang et al.(2010),rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resve-ratrol-mediated neuroprotection.The results clearly show that resveratrol protected dopamine neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration-and time-dependent manners through the inhibition of microglial activation and thesubsequent reduction in proinﬂammatory factor release.Mechanistically,resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase.Antioxidant activities of GP polyphenols in foodsAntioxidant activity is the most notable bioactivity of phenolic compounds from GP.The antioxidative characteristics have been widely studied,including scavenging of free radicals,inhibition of lipid oxida-tion,reduction in hydroperoxide formation and so on (Xia et al.,2010).Polyphenols are proven to be strong antioxidants against lipid oxidation in food system.Grape seed phenolics (GSE)were reported to inhibit lipid oxidation and warmed-over ﬂavour development in meat products such as raw and cooked beef products (Ahn et al.,2002,2007;Mielnik et al.,2006;Brannan &Mah,2007).GSE has reduced rancid ﬂavour development and associated primary and secondary lipid oxidation products in various meat products like raw and cooked beef,pork patties,turkey,ﬁsh oil,frozen ﬁsh and ground chicken breast and thigh meat (Ahn et al.,2002;Banon et al.,2007;Brannan &Mah,2007;Brannan,2009;Carpenter et al.,2007;Lau &King,2003;Miel-nik et al.,2006;Pazos et al.,2005)without altering the pH,water activity,binding strength or yield of the meat.The minimum concentration level of GSE required to produce an antioxidant eﬀect was 400l g g À1in cooked pork and 0.1%(w/w)in ground chicken (Lau &King,2003).However,GSE did alter the colour of both raw and precooked chicken breast patties (Brannan,2009).The degree of discoloration caused by adding GSE may depend on the variety of grape,type of meat and dosage.GSE may be more suitable for red meat than white meat.The GSE that contains less anthocyanins may be bet-ter choice as antioxidant in meat products.Antimicrobial activities of polyphenols from GPIn addition to antioxidant activities and therapeutic functions,many plant phenolic extracts have been shown to have antimicrobial activity against speciﬁc strains of bacteria such as Streptococcus Mutans ,Staphylococcus aureus,Escherichia coli and Candida albicans (O’Keefe &Wang 2006;Daglia et al.,2007),S.aureus,E.coli and C.albicans (C.albicans )(Papad-opoulou et al.,2005).Ahn and others (Ahn et al.,2007)reported that 1.0%GSE in cooked ground beef reduced the growth of E.coli O157:H7,L.monocytoge-nes,S.Typhimurim and A.Hydrophila by 1.5,2,1and 3LogCFU,respectively,during a 9-day storage.By using scanning and transmission electron microscopy,these authors also found grape seed polyphenols functioned as bactericidal,which caused disruption of©2012The AuthorsInternational Journal of Food Science and Technology ©2012Institute of Food Science and TechnologyInternational Journal of Food Science and Technology 2012Functional components of grape pomace J.Yu and M.Ahmedna226。

First-Order Phase Transition in Potts Models with finite-range interactions

arXiv:math-ph/0609051v1 18 Sep 2006
First-Order Phase Transition in Potts Models with ﬁnite-range interactions
T. Gobron and I. Merola
Abstract. We consider the Q-state Potts model on Zd , Q ≥ 3, d ≥ 2, with Kac ferromagnetic interactions and scaling parameter γ . We prove the existence of a ﬁrst order phase transition for large but ﬁnite potential ranges. More precisely we prove that for γ small enough there is a value of the temperature at which coexist Q + 1 Gibbs states. The proof is obtained by a perturbation around mean-ﬁeld using Pirogov-Sinai theory. The result is valid in particular for d = 2, Q = 3, in contrast with the case of nearest-neighbor interactions for which available results indicate a second order phase transition. Putting both results together provides an example of a system which undergoes a transition from second to ﬁrst order phase transition by changing only the ﬁnite range of the interaction.

NOVEL THERAPEUTIC EXTRACTS AND MOLECULES FOR DEGEN

专利名称：NOVEL THERAPEUTIC EXTRACTS AND MOLECULES FOR DEGENERATIVECONDITIONS发明人：PATELL, VILLOO, MORAWALA申请号：IB2004002531申请日：20040723公开号：WO2005016224A3公开日：20060316专利内容由知识产权出版社提供摘要：In this invention we have characterized plant extracts derived from common plants used in Indian traditional medicine using a) chemical fingerprinting by HPLC and b) etiology based in-vitro cell assays in order to reduce the extracts to minimum constituent to use for therapeutic purpose against degenerative conditions like cardiovascular diseases, Diabetes mellitus, Hypertension, All types of Cancers, Obesity & weight problems, Arthritis & pain, Alzheimer's disease, Multiple sclerosis & Autoimmune diseases, Asthma & Allergies, Osteoporosis & bone health, Parkinson's disease, Stress, Disorders & diseases of the eye. The current status of the extracts is that all of them have been chemically fingerprinted and have gone through assays to screen anti-diabetic activity. Thus currently we are applying for the specific leads that have shown very specific anti d iabetic activity. However we are also working in parallel, to test these extracts in other assays, for generating information of there applicability in the prevention or treatment of degenerative conditions as mentioned above. As and when we will have data to support disease specific application of individual extracts we will amend our claims accordingly. The present invention relates to a composition for curing or treatingdegenerative disorders, a process for the preparation of the same, and usage of the same and, more particularly, to the composition having as a major component a single extract or multiple extracts containing therapeutically relevant bioactive, obtained from a certain kind of plant/plants and being capable of lowering or reducing a level of glucose in the blood of a patient suffering from diabetes mellitus by alleviating or ameliorating various symptoms caused by or associated with the diabetes mellitus as well as preventing the glucose level in the blood of the diabetic patient with high certainty from arising again. The invention also relates to the in-vitro screening of plant extracts for anti-diabetic activities in multiple cell based and biochemical systems. Studies have shown eleven potential leads, which are very valuable as they could lead to bioactives having therapeutic activity in the treatment of like cardiovascular diseases, Diabetes mellitus, Hypertension, All types of Cancers, Obesity & weight problems, arthritis and pain, Alzheimer's disease, multiple sclerosis and autoimmune diseases, asthma and allergies, osteoporosis and bone health, Parkinson's disease, stress, disorders and diseases of the eye.申请人：AVESTHA GENGRAINE TECHNOLOGIES PVT LTD,PATELL, VILLOO, MORAWALA 更多信息请下载全文后查看。

Circuit, system and method for monitoring an optic

专利名称：Circuit, system and method for monitoringan optical fibre network发明人：Vandewege, Jan,De Mulder, Bert,Wei(William), Chen,Xing Zhi, Qiu申请号：EP06121540.6申请日：20060929公开号：EP1772979A2公开日：20070411专利内容由知识产权出版社提供专利附图：摘要：The present invention is related to a front-end circuit for an opticalcommunication system comprising a laser module (10) arranged for transmitting burstsof data signals over an optical network and a driving circuit (12) for providing the bursts of data signals to the laser module (10). The front-end circuit further comprises receiver means (14) in connection with said laser module (10) and arranged for receiving from the optical network optical echo signals. The laser module (10) comprises a laser diode (16) arranged for transmitting the bursts of data signals. The driving circuit (12) is arranged for setting a disabling signal for stopping the laser diode (16) from transmitting bursts of the data signals. Fibre-related information can be extracted from the echo signals, such as distance-resolved optical fibre reflections and fibre attenuation.申请人：INTERUNIVERSITAIR MICROELEKTRONICA CENTRUM ( IMEC),UNIVERSITEIT GENT地址：Kapeldreef 75 3001 Leuven BE,St. Pietersnieuwstraat 25 9000 Gent BE国籍：BE,BE代理机构：pronovem更多信息请下载全文后查看。

Device and Method for Determining the Degree of Di

专利名称：Device and Method for Determining theDegree of Disinfection of a Liquid发明人：Martin Wesian申请号：US13581328申请日：20110217公开号：US20120318997A1公开日：20121220专利内容由知识产权出版社提供专利附图：摘要：The invention relates to a device and also a method for determining the degree of disinfection, and for determining the time point when a defined degree of disinfection is reached by a liquid, in particular drinking water, that is situated in a container which islight-permeable at least in a UV range. The device comprises in this case a UV measuring appliance for measuring the intensity of the UV radiation in the region of the container, a data analysis unit to which the values of the UV intensity which are measured by the UV measuring device are fed, and wherein the data analysis unit converts the UV intensity values measured at the start of a measurement at defined time points to form a characteristic, and wherein the data analysis unit compares the characteristics determined at defined time points with a predetermined characteristic, which predetermined characteristic corresponds to a defined degree of disinfection of the liquid, and wherein the device comprises at least one signal output appliance which, in the event that the determined characteristics reaches or exceeds the value of the predetermined characteristic, provides the signal output.申请人：Martin Wesian地址：Vienna AT国籍：AT更多信息请下载全文后查看。

低速夹层上瑞雷波频散曲线快速稳定反演算法

低速夹层上瑞雷波频散曲线快速稳定反演算法宋先海l肖柏勋l赵凌l张学强2邓世坤2朱培民2（l.长江工程地球物理勘测研究院武汉市4300l0 2.中国地质大学应用地球物理系武汉市430074）提要该文提出了TDWLSA 反演算法，有效地解决了对初始模型的选取。

等厚薄层的应用，提高了横波速度的反演精度，引入权重矩阵提高数据分辨率，采用自适应修改阻尼因子提高迭代效果并协调分辨率与解的关系。

实测资料试算结果表明，用该算法对低速软弱夹层瞬态瑞雷波频散曲线进行反演，不但具有稳定性好、精度高、分辨能力强的特点，而且能自动分层和反演地层参数。

关键词TDWLSA低速软弱夹层瞬态瑞雷波频散曲线横波速度Fast and Reliable Method for lnversion of Rayleigh WaveDispersion Curves for Lower Velocity LayersSong Xianhai lXiao Boxun l Zhao Ling l Zhang Xuegiang 2Deng Shikun 2Zhu Peimin 2（l.Institute of Changjiang Engineering Geophysicai Prospecting 2.Department of Appiied Geophysics ，China University of Geosciences ）Abstract Thinned Damped Weighted Least Sguare Aigorithm is used to invert transient Rayieigh wavedispersion curves for iower veiocity iayers.The new efficient aigorithm can overcome such serious short-comings as the strict dependence on initiai modei ，improve shear wave accuracy and resoiution using thi-nned iayers and weighted matrix and enhance iterative effect and adjust the reiationship between resoiution and soiution by seif -adaptation iterative damped factor.Inversion resuits of fieid data indicate thatTDWLSA is characterized by good stabiiity ，high accuracy and strong resoiution ，and aiso automaticaiiy invert shear wave veiocity and thickness.Keywords Thinned Damped Weighted Least Sguare Aigorithm ；iower veiocity iayers ；transient Rayieigh wave ；dispersion curves ；shear wave veiocity基金项目：“九·五”国家重点科技攻关项目（No.96-22l -0l -02-05）；长江水利委员会综合勘测局科技发展基金资助项目（No.KY2000-4）作者简介：宋先海，男，l973年生，硕士，高级工程师，主要从事瑞雷波正反演研究及软件开发工作。

离子色谱法同时分析洗涤剂中9种螯合剂

第42 卷第 6 期2023 年6 月Vol.42 No.6699~706分析测试学报FENXI CESHI XUEBAO（Journal of Instrumental Analysis）离子色谱法同时分析洗涤剂中9种螯合剂李晓芳1，2，周伟1，2，杨立威2，王梦瑶2，张蕾1，2，蔡国强1，2*（1．浙江省绿色清洁技术及洗涤用品重点实验室，浙江丽水323000；2．纳爱斯浙江科技有限公司，浙江杭州310056）摘要：建立了一种离子色谱测定洗涤剂样品中9种螯合剂含量的分析方法。

洗涤剂样品经去离子水稀释，IC－RP固相萃取小柱净化后，选择高容量的Dionex IonPac TM AS11－HC型阴离子色谱柱进行分离，以自动淋洗液发生器电解产生的高纯KOH溶液为流动相进行梯度淋洗，流速1.0 mL/min，采用高压离子色谱仪电导检测器进行测定，外标法定量。

结果显示，葡萄糖酸钠、甲基甘氨酸二乙酸三钠、次氮基三乙酸、羟基乙叉二膦酸、柠檬酸钠、焦磷酸钠、谷氨酸二乙酸四钠和三聚磷酸钠在1 ~ 200 mg/L范围内、乙二胺四乙酸二钠（EDTA－2Na）在50 ~ 500 mg/L范围内线性良好，相关系数（r） > 0.999。

EDTA－2Na的检出限（S/N = 3）为12.5 mg/L，定量下限（S/N = 10）为40 mg/L；其余8种螯合剂的检出限为0.02 ~ 0.07 mg/L，定量下限为0.06 ~0.25 mg/L。

9种螯合剂在低、中、高3个加标水平下的平均回收率为92.7 %~106 %，相对标准偏差（RSD）为1.0 % ~ 7.9 %，均满足检测要求。

该方法无需衍生化处理，前处理简单，测定快速，结果准确，灵敏度高，适用于洗涤剂样品中9种螯合剂的定量分析，为洗涤用品的质量评价提供了强有力的方法支持。

关键词：离子色谱法；螯合剂；洗涤剂；同时分析中图分类号：O657.75；F767.8文献标识码：A 文章编号：1004-4957（2023）06-0699-08Simultaneous Determination of Nine Chelators in Detergents byIon ChromatographyLI Xiao-fang1，2，ZHOU Wei1，2，YANG Li-wei2，WANG Meng-yao2，ZHANG Lei1，2，CAI Guo-qiang1，2*（1．Key Laboratory of Green Cleaning Technology & Detergent of Zhejiang Province，Lishui 323000，China；2．NICE Zhejiang Technology Co. Ltd.，Hangzhou 310056，China）Abstract：A novel method based on ion chromatography was established for the determination of nine chelators in detergent samples．The samples were firstly diluted with deionized water，then purified with IC－RP solid phase extraction columns to eliminate the damage of surfactants in the detergent samples to the chromatographic column，followed by separation on a Dionex IonPac TM AS11－HC an⁃ion analysis column with high capacity，using a gradient elution with a high purity of potassium hy⁃droxide（KOH） aqueous solution as the eluent at a flow rate of 1.0 mL/min，which was produced by an automatic generator，and finally detected by Thermo Fisher Intergrion high pressure ion chromato⁃graph with conductivity detector，and quantified using an external standard method．Sodium gluco⁃nate（GNa），trisodium methylglycine diacetate（MGDA），nitrous triacetic acid（NTA），hydroxyl ethylidene diphosphonic acid（HEDP），sodium citrate（CANa），sodium pyrophosphate（TSPP），tetrasodium glutamate diacetate（GLDA） and sodium tripolyphosphate（STPP） showed good linear re⁃lationships within the range of 1－200 mg/L．Disodium ethylenediamine tetraacetate（EDTA－2Na）showed a good linear relationship in the range of 50－500 mg/L．The correlation coefficients（r） were greater than 0.999．The limit of detection（S/N = 3） and limit of quantitation（S/N = 10） for EDTA－2Na were 12.5 mg/L and 40 mg/L，respectively．The limits of detection and the limits of quantita⁃tion for the other eight chelators were in the range of 0.02－0.07 mg/L and 0.06－0.25 mg/L，re⁃spectively．The average spiked recoveries at high，medium and low three levels ranged from 92.7% to 106%，with the relative standard deviations（RSDs） of 1.0 %－7.9%，of which all met the detec⁃tion requirements．Furthermore，twenty-seven detergent samples bought from the market were se⁃doi：10.19969/j.fxcsxb.23010301收稿日期：2023－01－03；修回日期：2023－02－27基金项目：浙江省“领雁”研发攻关计划项目（2022C01174）∗通讯作者：蔡国强，博士，高级工程师，研究方向：功能助剂的分析，E-mail：caigq84@700分析测试学报第 42 卷lected for testing．The results showed that NTA and STPP were not detected in all samples，butEDTA－2Na was found in one dishwasher tablet and one baby bottle cleanser，respectively，andTSPP was detected in three dishwasher powders．GLDA was used as the chelator for most samples oflaundry detergents and dishwashing detergents，with the contents of 0.10%－0.25%．The contentsof chelators in dishwasher detergents were higher than those in dishwashing detergents and laundry de⁃tergents．Chelator played an important role as the main builder in dishwasher detergents．It couldnot only soften water by complexing calcium，magnesium and heavy metal ions and inhibit the growthof inorganic salt crystals to prevent scale formation，but also disperse the stains in solution and syner⁃gize the cleaning effect of surfactants on the stains on tablewares．The total contents of chelatorsranged from 3.15% to 25.58% in twelve dishwasher detergents，which were determined in this exper⁃iment．Overall，this method was suitable for the determination of nine chelators in detergents for itsderivatization-free procedure，simplicity，rapidness，accuracy and sensitivity．Moreover，it couldprovide a method support for the quality evaluation of detergents.Key words：ion chromatography；chelators；detergents；simultaneous determination螯合剂是日常洗涤用品中的重要助洗剂，可以络合产品中微量的Ca2+、Mg2+、Fe3+等金属离子并形成具有高溶解性的牢固环状结构，阻止金属离子与配方中的其它阴离子形成不溶性沉淀［1－2］，减缓洗涤剂变质或变色，在维持体系稳定中具有关键作用［3］。

The Multiple System HD 27638

a r X i v :a s t r o -p h /0512254v 1 9 D e c 2005The Multiple System HD 27638Guillermo TorresHarvard-Smithsonian Center for Astrophysics,60Garden St.,Cambridge,MA 02138gtorres@ABSTRACTWe report spectroscopic observations of HD 27638B,the secondary in a visual binary in which the physically associated primary (separation ∼19′′)is a B9V star.The secondary shows strong Li λ6708absorption suggesting youth,and has attracted attention in the past as a candidate post-T Tauri star although this has subsequently been ruled out.It was previously known to be a double-lined spectroscopic binary (F8+G6)with a period of 17.6days,and to show velocity residuals indicating a more distant massive third companion with a period of at least 8years.Based on our radial velocity measurements covering more than two cycles of the outer orbit,along with other measurements,we derive an accurate triple orbital solution giving an outer period of 9.447±0.017yr.The third object is more massive than either of the other two components of HD 27638B,but is not apparent in the spectra.We derive absolute visual magnitudes and eﬀective temperatures for the three visible stars in HD 27638.Isochrone ﬁtting based on those properties gives an age of 200±50Myr for the system.We infer also an inclination angle of ∼53.◦3for the inner orbit of HD 27638B.We detect a near-infrared excess in HD 27638B which we attribute to the third star being a close binary composed of late-type stars.This explains its large mass and lack of a visible signature.Modeling of this excess allows us to infer not only the masses of the components of the unseen companion,but also the inclination angle of the outer orbit (∼73◦).The HD 27638system is thus at least quintuple.Subject headings:binaries:spectroscopic —binaries:visual —stars:individual (HD 27638)—stars:late-type —techniques:radial velocities —techniques:spectroscopic1.IntroductionHD 27638(also known as χTau,59Tau,HIP 20430,HR 1369,α=4h 22m 34.s 94,δ=+25◦37′45.′′5,J2000,V =5.395,SpT =B9V )is the brighter component in a visual binary sys-tem (ADS 3161,STF 528)with an angular sep-aration of about 19′′.The relative position of the companion,HD 27638B (V =8.423,SpT =G2V ),was ﬁrst recorded by William Herschel in 1782(see Lewis 1906)and has not changed much since,indicating the physical association between the stars.An investigation by Murphy (1969)in-cluded this and many other physical pairs com-posed of a B-type and a late-type component to establish the absolute magnitudes of the primaries by reference to the better known magnitudes of the secondaries.Since the B stars must be rela-tively young,the HD 27638system was included also in a study by Lindroos (1986)that concluded that many of the secondaries in such pairs are post-T Tauri stars,and show other indicators of youth such as Ca II H and K emission,H αemis-sion,strong Li λ6708absorption,strong X-rays,infrared excess,or a location in the H-R diagram above the Zero Age Main Sequence (ZAMS).The age of HD 27638A was estimated to be 123Myr by comparison with stellar evolution models.HD 27638B was reported to be a double-lined spectroscopic binary by Mart´ın,Magazz`u &Re-bolo (1992),and independently by Pallavicini,Pasquini &Randich (1992).Both teams detected signiﬁcant Li λ6708absorption.The spectroscopic orbit of the binary with a period of 17.6days and an eccentricity of 0.3was ﬁrst derived byTokovinin(1999),who pointed out also that the residuals clearly indicated the presence of a third, rather massive star in the system with a period of a few years.The elements of the double-lined orbit were published by Tokovinin&Gorynya(2001), along with a preliminary solution for the outer or-bit for which∼70%of the estimated8-year cycle was covered.Thisﬁt allowed those authors to con-ﬁrm that the mass of the third star is larger than either of the objects in the inner pair,despite there being no sign of it in their spectra.We report here our own spectroscopic obser-vations of HD27638B giving full coverage of the outer orbit over more than two cycles.We model the properties of the system andﬁnd compelling evidence that the third star is itself a close binary, making the HD27638system at least quintuple.2.Spectroscopic observations and reduc-tionsSpectroscopic observations of HD27638B were conducted at the CfA between September1988 and December2004(with a6-year gap from March1990to November1996)mostly with an echelle spectrograph on the1.5-m Wyeth reﬂector at the Oak Ridge Observatory(Harvard,Mas-sachusetts).A single order was recorded with an intensiﬁed Reticon diode array giving a spectral coverage of about45˚A at a central wavelength of 5187˚A.The resolving power isλ/∆λ≈35,000. Occasional observations were made also with nearly identical instruments on the1.5-m Tilling-hast reﬂector at the F.L.Whipple Observatory (Mt.Hopkins,Arizona)and the Multiple Mirror Telescope(also on Mt.Hopkins,Arizona),prior to its conversion to a monolithic mirror.A total of72 spectra were collected,including one archival ob-servation taken at the Tillinghast reﬂector much earlier for a diﬀerent program(October1983). The signal-to-noise(S/N)ratios of these observa-tions range from10to40per resolution element of8.5km s−1.The double-lined nature of the system is evident already in ourﬁrst(archival)spectrum from1983. Radial velocities were derived from all our obser-vations using TODCOR(Zucker&Mazeh1994), a two-dimensional cross-correlation algorithm well suited to our relatively low S/N spectra.TOD-COR uses two templates,one for each component of the binary(hereafter stars Ba and Bb),and sig-niﬁcantly reduces systematics due to line blend-ing that are often unavoidable in standard one-dimensional cross-correlation techniques(see,e.g., Latham et al.1996).The templates were selected from a large library of synthetic spectra based on model atmospheres by R.L.Kurucz(available at ),computed for us by Jon Morse(see also Nordstr¨o m et al.1994; Latham et al.2002).These calculated spectra are available for a wide range of eﬀective temperatures (T eﬀ),projected rotational velocities(v sin i),sur-face gravities(log g)and metallicities.Experi-ence has shown that radial velocities are largely insensitive to the surface gravity and metallicity adopted for the templates.Consequently,the op-timum template for each star was determined from grids of cross-correlations over broad ranges in temperature and rotational velocity(see Torres, Neuh¨a user&Guenther2002),seeking to maximize the average correlation weighted by the strength of each exposure.Solar metallicity was assumed to begin with,along with surface gravities of log g=4.5for both stars,appropriate for dwarfs. We obtained bestﬁt values for the temperatures of6180K and5620K for the primary and sec-ondary,respectively,with estimated uncertainties of150K.These correspond to spectral types of F8 and G6(Gray1992).The rotational broadening of the stars was found to be very small(formally v sin i=1±3km s−1for both stars),consistent with the estimates by Tokovinin&Gorynya(2001) of2.9±0.6km s−1and0km s−1for the primary and secondary,respectively.We repeated the pro-cedure for metallicities between[m/H]=−1.5and [m/H]=+0.5,in steps of0.5dex,and found the best match to be for solar composition.This is consistent with the results presented in§3.Following Zucker&Mazeh(1994),we deter-mined also the light ratio between the secondary and the primary of HD27638B at the mean wave-length of our spectroscopic observations(5187˚A), which is close to the V band:ℓBb/ℓBa=0.37±0.01.This corresponds to a magnitude diﬀerence ∆m=1.08±0.03,and agrees well with the inde-pendent estimate by Tokovinin&Gorynya(2001) of∆m=1.1.Table1lists the radial velocities for both components,referred to the heliocentric frame.Typical uncertainties are given below.The stability of the zero-point of our velocity systemwas monitored by means of exposures of the dusk and dawn sky,and small systematic run-to-run corrections were applied in the manner described by Latham(1992).The accuracy of the CfA ve-locity system,which is within about0.14km s−1 of the reference frame deﬁned by minor planets in the solar system,is documented in the previous citation and also by Stefanik,Latham&Torres (1999)and Latham et al.(2002).2.1.Orbital solutionThe original motivation for our early observa-tions(prior to March1990)was to investigate sys-tematic errors in the determination of radial veloc-ities for early-type versus late-type stars by using physical pairs such as HD27638AB(tham 2005,m.).Although it was soon realized that no meaningful velocities could be obtained for the early-type star with our instrumentation,the double-lined nature of the secondary was certainly noticed and was the reason for collecting nearly 30spectra up to that date.However,no orbit was published at the time.After the implementa-tion of the TODCOR algorithm at the CfA there was renewed interest in the object as a potentially young system,and observations were resumed in late1996.It then became obvious that the cen-ter of mass of the17.6-day binary was changing in response to an additional component,and the system was monitored more regularly to complete the outer orbit.Only later did we learn of the in-dependent eﬀorts by Tokovinin&Gorynya(2001) revealing the same trend.An orbital solution based on all CfA spectra is presented in the second column of Table2.Be-cause the outer period is much longer than the inner period,we have assumed toﬁrst order that the hierarchical triple system may be separated into an inner orbit and an outer orbit,the latter being treated as a“binary”composed of the third star(Bc)and the center of mass of the inner pair (Ba–Bb).Both orbits were solved simultaneously (12adjustable parameters)using standard itera-tive non-linear least-squares methods.In partic-ular,we applied the Levenberg-Marquardt tech-nique,which is described in detail by Press et al. (1992).The iterations converged quickly to the ﬁnal solution,and experiments in which we var-ied the initial values of the elements within reason yielded the same results.Although the light travel time eﬀect is small,we have included the appropri-ate corrections for the inner pair.These depend on the orbital elements,so they were iterated dur-ing the solution.The outer orbit has a period of 9.4years,and our data cover2.2cycles.The rms residual of the observations,indicative of the pre-cision of the radial velocities,is0.59km s−1for Ba and1.03km s−1for Bb.As mentioned earlier,the observations reported originally by Tokovinin&Gorynya(2001)do not quite cover a full cycle of the outer orbit.Those measurements were made with a CORAVEL-type radial-velocity spectrometer(“Radial Veloc-ity Meter”,hereafter RVM;Tokovinin1987)on the0.7-m telescope at Moscow University and the1-m telescope at the Simeis Observatory in Crimea,and have a precision similar to ours.The observations with this instrument were contin-ued after publication,and the authors were kind enough to provide us with an updated list of their RVM velocities for Ba and Bb.These observations are presented with their permission in Table3,and now cover nearly one full cycle of the outer orbit. An independent orbital solution from these data is given in the third column of Table2.There is ex-cellent agreement with the CfA solution for all of the orbital elements.Therefore we have combined the measurements,allowing for a possible velocity oﬀset between the two data sets by incorporating an additional adjustable parameter(∆RV).The relative weighting of the observations was deter-mined by iterations separately for the primary and secondary components in each data set,based on the scatter of the measurements.For the RVM velocities it was found that the original internal errors(Table3)required the application of scaling factors of2.3and1.7to achieve reducedχ2values near unity for stars Ba and Bb,respectively.The combined CfA+RVM solution is listed in theﬁnal column of Table2.Residuals for the individual CfA and RVM observations from thisﬁt are given in Table1and Table3.The light travel correc-tions applied to the dates of the inner pair appear in the last column(the Julian dates shown are the original values,without corrections).Phases in the inner and outer orbits are also given.The radial velocities in the inner orbit are pre-sented graphically in Figure1,where the motion of the center of mass in the wide orbit has been subtracted from the individual primary and sec-ondary velocities.Similarly,the velocities in the outer orbit are shown in Figure2both as a func-tion of phase and time,with the motion in the in-ner orbit removed.The period of the wide orbit, P Bab−c=9.447±0.017yr,is formally determined with a relative precision better than0.2%.It is of interest to note that the lines of ap-sides of the inner and outer orbits appear to be nearly perfectly aligned,according to our solu-tion in Table2:the diﬀerence between the lon-gitudes of periastronωBa andωBab is0.◦8±1.◦5. This is unlikely to be accidental,and is presum-ably a result of dynamical interactions in the triple system.The outer period happens to be very close to an integer multiple of the inner period (P Bab−c/P Bab=196.03),although the formal un-certainty in this ratio(0.32)is large enough that it is not particularly signiﬁcant.An improvement in P Bab−c by an order of magnitude would be needed for a more deﬁnitive conclusion.Of greater inter-est,as reported by Tokovinin&Gorynya(2001),is the fact that the mass function(or,equivalently, the minimum mass of the unseen companion of HD27638B)is unusually large.For any reason-able values of the masses of Ba and Bb(see below) the inferred mass of Bc is larger than either Ba or Bb,yet no light from the third star is obvious in our spectra.Tokovinin&Gorynya(2001)made an attempt to detect Bc spectroscopically by obtaining strong exposures at the phases of maximum velocity sep-aration between Ba and Bb.No sign of the third star was seen,and they estimated it must be at least5times fainter than Bb.We made a similar attempt using our CfA spectra,by reprocessing all of them with an extension of the two-dimensional cross-correlation algorithm TODCOR to three di-mensions(Zucker,Torres&Mazeh1995).Again we failed to detect star Bc.As suggested by Tokovinin&Gorynya(2001),one possibility is that Bc is obscured by circumstellar dust.This would require at least2to3magnitudes of ex-tinction in the visible to account for our inability to see it.Alternatively,Bc could itself be a pair of late-type stars,or perhaps a massive white dwarf. We examine these possibilities further below.3.Properties of the HD27638systemAs mentioned in§1,measurements of the rela-tive position of HD27638A and HD27638B over the past200years(some70observations to date) show that this is a physical pair1,with only a very slight indication of change suggesting perhaps or-bital motion.Radial velocities for the brighter star have been measured occasionally but show signiﬁcant scatter,possibly due to the large ro-tational broadening that makes those measure-ments diﬃcult(v sin i measures have ranged be-tween225km s−1and340km s−1;Abt,Levato& Grosso2002;Uesugi&Fukuda1982).A repre-sentative average of the radial velocity measures of HD27638A has been given by Barbier-Brossat &Figon(2000)as+15.3±3.4km s−1.This is consistent with the center-of-mass velocity of HD 27638B(γ=+14.694±0.081km s−1;Table2), supporting the physical association.No trigono-metric parallax determination is available for HD 27638B,but HD27638A does have an entry in the Hipparcos Catalog(ESA1997)and the measured parallax isπHIP=12.19±1.00milli-arc seconds (mas)corresponding to a distance of about82pc.The brightness of both HD27638A and HD 27638B has been measured separately in a vari-ety of photometric systems.The primary is listed in the Hipparcos Catalog as an‘unsolved variable’, with a variability amplitude of0.036±0.010mag in the H p passband.No other mention of variability could be found in the literature.The secondary was reported as marginally variable by Lindroos (1986)with a maximum change of∆V=0.07mag based on4measurements.However,no variabil-ity appears to have been detected by Hu´e lamo et al.(2004)or Mart´ın,Magazz`u&Rebolo(1992) from more intensive measurements in several pass-bands.For our purposes we assume that neither the primary nor the secondary of the visual pair are signiﬁcantly variable in brightness.Adopting the Hipparcos distance of HD27638A for the system,along with Johnson V-band pho-tometry as compiled by Mermilliod,Mermilliod& Hauck(1997)2and our light ratioℓBb/ℓBa in§2,wecomputed absolute visual magnitudes for the three visible stars:M A V=0.82±0.18,M Ba V=4.20±0.18, and M Bb V=5.27±0.18.The errors here are dom-inated by the uncertainty in the parallax.Tem-peratures for stars Ba and Bb were given in§2(T Ba eﬀ=6180±150K and T Bbeﬀ=5620±150K).For HD27638A we have used absolute photome-try in the Johnson,Str¨o mgren,and Geneva sys-tems(Mermilliod,Mermilliod&Hauck1997)toderive the eﬀective temperature based on a largenumber of color/temperature calibrations(Popper1980;Moon&Dworetsky1985;Gray1992;Napi-wotzki,Sch¨o nberner&Wenske1993;Balona1994;Smalley&Dworetsky1995;K¨u nzli et al.1997;Cox2000).The various estimates are in good agree-ment,and yield an average of T A eﬀ=10300±300K,where the uncertainty is a conservative estimate toaccount for possible systematics.Gerbaldi,Farag-giana&Balin(2001)obtained results consistentwith ours.Reddening estimates based on Genevaand Str¨o mgren photometry give negligible valuesusing calibrations by Crawford(1978)and K¨u nzliet al.(1997),in agreement with Lindroos(1986)and Gerbaldi,Faraggiana&Balin(2001).We then used the absolute visual magnitudesand temperatures of the three visible stars to com-pare their location in the H-R diagram with stellarevolution models from the Yonsei-Yale series(Yi etal.2001;Demarque et al.2004).We performed agrid search and tested a large number of isochronesover a range of metal abundances and ages.Foreach metallicity/age combination we varied themasses of the stars,seeking the best match to theobservables.With the additional constraint on themass ratio for HD27638B(q≡M Bb/M Ba),orequivalently the minimum masses of the compo-nents(M sin3i Bab;see Table2),we reduced theproblem to one ofﬁnding the best values of M Aand the inclination of the inner orbit(i Bab)foreach age/metallicity combination.The result ofthis grid search is illustrated in Figure3,where thedots represent models that agree with the observa-tions within the errors.The bestﬁt isochrone hasa metallicity of Z=0.021and an age of200Myr,with uncertainties estimated to be roughly0.005in Z(or0.1dex in[Fe/H])and50Myr for theage.The agreement with the measured magni-3This is their estimate for HD27638A.The ages they derivedfor HD27638B are much younger(12–19Myr)because theyassumed it was a post-T Tauri star and used models for thepre-main sequence phase.strongly suggestive of a near-infrared excess for HD27638B,which in all likelihood is related to the unseen companion.4.The nature of the tertiary of HD27638BThe presence of an infrared excess may ap-pear to support the idea advanced by Tokovinin &Gorynya(2001)that star Bc is perhaps sur-rounded by a dust disk that is obscuring the star and preventing its direct detection.However, given the age of the system(∼200Myr),the possi-bility that it harbors a circumstellar disk substan-tial enough to produce2–3magnitudes of optical extinction(see§2.1)is highly unlikely,since such disks in T Tauri stars are known to dissipate after ∼10Myr(e.g.,Mamajek et al.2004,and refer-ences therein).The age and infrared excess also rule out the possibility that star Bc is a massive white dwarf.We are left with the hypothesis that it is instead a binary composed of late-type dwarfs, and we explore this here by attempting to model the infrared excess using theoretical isochrones.Even though the Yonsei-Yale isochrones used above reach masses as low as0.4M⊙,they are not speciﬁcally intended for the lower main-sequence and are thus not expected to reproduce the ra-diative properties of real M dwarfs as closely as needed for our purposes.Other series of mod-els are available that are designed for low-mass stars and incorporate a more realistic equation of state,more complete tables of molecular opacities, and non-grey boundary conditions,all of which have been shown to be critical for this regime (see,e.g.,Chabrier&Baraﬀe1997).In partic-ular,the Baraﬀe et al.(1998)models have been found to match the observed colors of late-type objects fairly well.However,they are not pub-licly available for the full range of stellar masses we require,and the range of metallicities available is also limited.Due to the latter restriction,we adopt in the following the solar composition for HD27638,which is well within the uncertainties of our determination in the previous section.At this metallicity,the best match to the magnitudes and temperatures of the three visible stars using the Yonsei-Yale models is240Myr,which is also within the errors and which we adopt hereafter. This solar-metallicity/240-Myr isochrone is shown with a solid line in Figure4,and is nearly indis-tinguishable from the Z=0.021/200-Myr model (dashed line)near the observations.A further complication for our modeling of the infrared excess has to do with the mixing length parameter,αML.The value adopted by Baraﬀe et al.(1998)for solar-type stars isαML=1.9,which is the bestﬁt to the properties of the Sun.This value is presumably also appropriate for stars Ba and Bb in HD27638,which are close to a solar mass.However,these models only reach as low as 0.6M⊙for thisαML,and may limit our predic-tions for Bc if the components are even smaller. For lower-mass stars Baraﬀe et al.(1998)adopt a diﬀerent mixing length ofαML=1.0(with the rest of the physics in the models being the same), which has been found to give satisfactory results in modeling the colors of these objects even down to the brown dwarf regime,but does not repro-duce the properties of solar-type stars.There-fore,we proceeded as follows:Weﬁrst used an isochrone with the higher value ofαML to deter-mine the masses of stars Ba and Bb that provide the best match to their eﬀective temperatures and absolute visual magnitudes.These masses and the corresponding infrared colors(which are similar to our previous results using the Yonsei-Yale models) were then heldﬁxed,and a Baraﬀe et al.(1998) isochrone with the same age and metallicity but withαML=1.0was used to explore which com-bination of masses for the individual components of Bc gives the best match to the observed val-ues of V−J,V−H,and V−K when adding also the light of Ba and Bb.The observed col-ors were converted to the CIT system of Elias et al.(1983)for consistency with the passbands of these isochrones,following Carpenter(2001).The masses of the Bc components are not completely arbitrary:their sum is constrained by the mass function in the outer orbit(see Table2),but de-pends also on the inclination angle of that orbit (i Bab−c).Therefore,we performed a grid search varying i Bab−c and q Bc(the mass ratio between the secondary and the primary of Bc)over wide ranges,seeking to reproduce the colors.The best match was found for i Bab−c=73◦±6◦and equal-mass stars(q Bc=1.0).The corresponding masses for the Bc components are0.70M⊙each.These parameters reproduce the combined near-infrared colors of HD27638B very well,as seen in the lowerpart of Table4.In Figure5we show a contour plotof theχ2surface corresponding to the twoﬁttedvariables.The inferred visual brightness of eachstar in Bc is M V=7.87,which is about3.7magfainter than star Ba,and explains why neither wenor Tokovinin&Gorynya(2001)were able to de-tect them spectroscopically.The location of Bc inthe H-R diagram is shown in Figure4.5.Discussion and concluding remarksOur modeling of the infrared excess of HD27638B shows that the unseen and over-massivethird star is well explained as an equal-mass bi-nary composed of late-type stars of M≈0.70M⊙(spectral type approximately K4).As indicatedabove,the alignment of the major axes of the in-ner(Ba–Bb)and outer(Bab–Bc)orbits in thisqquadruple system as evidenced by the nearlyidentical longitudes of periastron is a sign thatdynamical interactions are at play.Our esti-mates of the inclination angles of the two or-bits(i Bab and i Bab−c)provide some informa-tion on the relative inclination angleφ,whichis of considerable dynamical importance.Thatangle is given by cosφ=cos i Bab cos i Bab−c+sin i Bab sin i Bab−c cos(ΩBab−ΩBab−c)(e.g.,Fekel1981).The position angles of the nodes(ΩBab andΩBab−c)are unknown,so we can only set limitsto cos(ΩBab−ΩBab−c)between−1and+1,whichleads to i Bab−c−i Bab≤φ≤i Bab−c+i Bab.A lowerlimit toφcan thus be placed atφmin=20◦±6◦,which appears to exclude coplanarity.With our estimates of i Bab and i Bab−c the to-tal mass of HD27638B is3.6M⊙.The angularsemimajor axis of the wide orbit in this system istherefore a=83.6mas,corresponding to6.86AU.Given the eccentricity and orientation of the orbit,the angular separation can be as large as90mas attimes.The combined brightness of the stars in Bcis expected to be approximately3.3mag fainterthan Ba+Bb in V,which should make it feasibleto resolve Bc,e.g.,by the speckle interferometrytechnique in the visible on a4-m class telescope.The brightness diﬀerence in the K band is evenmore favorable(∆K≈1.5mag)4.in Zelenchuk,Russia.The companion was not resolved:theresolution limit was90mas,and the predicted separationaccording to our orbit was about60mas.From the evidence presented here at leastﬁve components are known in the HD27638system. The B-type star itself has been examined for du-plicity by the lunar occultation technique(Meyer et al.1995)but was found to be unresolved.We note,however,that the Hipparcos Catalog lists the star as a‘suspected non-single’(ESA1997) based on the quality of the astrometric solution, although no convincing non-single star solution was found.The radial velocity measurements of HD27638A are too few in number and too poor in quality to be of much help in this regard.Thus, it is still possible that additional components are present,making this a very interesting multiple system.Thanks are due to J.Caruso,R.J.Davis,D.W. Latham,R.D.Mathieu,R.P.Stefanik,and J.Za-jac for obtaining most the CfA spectroscopic ob-servations used in this work,and to R.J.Davis for additionally maintaining the CfA echelle database. The author is also grateful to A.A.Tokovinin and N.A.Gorynya for providing their RVM observa-tions of HD27638B.We thank the anonymous referee for a prompt reading of the manuscript and helpful comments.Partial support for this work from NSF grant AST-0406183and NASA’s MASSIF SIM Key Project(BLF57-04)is acknowl-edged.This research has made use of the SIMBAD database,operated at CDS,Strasbourg,France, of NASA’s Astrophysics Data System Abstract Service,of the Washington Double Star Catalog maintained at the U.S.Naval Observatory,and of data products from the Two Micron All Sky Survey,which is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technol-ogy,funded by NASA and the NSF.REFERENCESAbt,H.,Levato,H.,&Grosso,M.2002,ApJ,573, 359Balona,L.A.1994,MNRAS,268,119Baraﬀe,I.,Chabrier,G.,Allard,F.,&Hauschildt, P.H.1998,A&A,337,403Barbier-Brossat,M.,&Figon,P.2000,A&AS, 142,217Bessell,M.S.,&Brett,J.M.1988,PASP,100, 1134Carpenter,J.M.2001,AJ,121,2851Chabrier,G.,&Baraﬀe,I.1997,A&A,327,1039Cox,A.N.2000,Allen’s Astrophysical Quantities, 4th Ed.(Berlin:Springer),388Crawford,D.L.1978,AJ,83,48Demarque,P.,Woo,J.-H.,Kim,Y.-C.,&Yi,S.K.2004,ApJS,155,667do Nascimento,J.D.Jr.,Canto Martins,B.L., Melo, C.H. F.,Porto de Mello,G.,&De Medeiros,J.R.2003,A&A,405,723Duncan,D.K.1981,ApJ,248,651Elias,J.H.,Frogel,J.A.,Hyland,A.R.,&Jones, T.J.1983,AJ,88,1027ESA1997,The Hipparcos and Tycho Catalogues, ESA SP-1200Fekel,F.C.Jr.1981,ApJ,246,879Gahm,G.F.,Ahlin,P.,&Lindroos,K.P.1983, A&AS,51,143Gerbaldi,M.,Faraggiana,R.,&Balin,N.2001, A&A,379,162Gray,D.F.1992,The Observation and Analysis of Stellar Photospheres,2nd Ed.(Cambridge: Cambridge Univ.Press),430Høg,E.,Fabricius,C.,Makarov,V.V.,Urban,S., Corbin,T.,Wycoﬀ,G.,Bastian,U.,Schwek-endiek,P.,&Wicenec,A.2000,A&A,355,L27 Hu´e lamo,N.,Fern´a ndez,M.,Neuh¨a user,R.,& Wolk,S.J.2004,A&A,428,953。

20世纪60年代美国政府应对青年反战思潮的方式及其启示

型!!生巡堡燮兰婴婴幽第14卷，第3期北京青年政治学院学报V01．14 N o ．3 坠：型堕域外青年20世纪60年代美国政府应对青年反战思潮的方式及其启示张永红(清华大学人文学院马克思主义研究中心，北京 1删)摘要：20世纪60年代，美国政府对青年反战思潮的不同应对方式产生了不同的结果：谎言和暴行使青年反战思潮激化，而法治传统所蕴涵的宽容精神则使青年和社会的矛盾趋于缓和。

它启示我们，宽容是实现社会和谐稳定的介质。

关键词：美国青年青年思潮青年工作中图分类号：D4 文献标识码：A 文章编号：1008—4002(2005)03—0021—06 Abs 旬隐ct ：Ttle dif[brent way s me Anlel‘c 锄goVemment too k to 恹-a t t|le y 伽tll a n ti w a r m 仉Ight in 1960s produced ‰ce d 证feI 即t 甜&ts ，tlla t con 酬in is ，l ie s aIld Violent act s radicalized the 锄tiwar mought ，wⅫe tlle spirit oftlle t 瑚I d i t i o n of kv aIld o 耐er eased up co n n i ct s be ㈣youtll and 吐le soc ie 哆．It幽Iow s tl lat to l eI an ce is tl le m ed i uI Il t l l m u g h w|lich tlle kmIlonious stabili 哆of tlle society c 锄be acllieVed ． K 哟哪or ds ：Ame ric an youtll Y 叫吐l t}lought Y 叫Ⅱ1 woIk 20世纪60年代①的美国青年反战思潮是随着越南战争(1961一1975年)的爆发和逐步升级发生和发展的，它是由青年掀起的美国历史上规模最大的反战思潮。

微生物次级代谢产物合成基因簇预测分析

18
Analysis tools of antiSMASH
NCBI BLAST+ HMMer 3, Muscle 3 Glimmer 3 FastTree
TreeGraph 2 Indigo-depict PySVG JQuery SVG
19
Pipeline for genomic analysis of secondary metabolites
PKS PKS PKS (neg.)
PKS PKS PKS
PKS_KS PKS_AT fabH
ene_KS mod_KS t2clf
SMART SMART This study
Yadav et al. (2009) Yadav et al. (2009) This study
Terpene Terpene ……….
gene prediction by Glimmer3 (prokaryotic data) or GlimmerHMM
(eukaryotic data) Transform the predicted results to EMBL format
21
Detection of gene clusters
nonribosomal peptides 非核糖体肽(NRP) bacteriocins 细菌素 aminocoumarins 基香豆素
butyrolactones 丁内酯
terpenes 萜烯 beta-lactams β-内酰胺 siderophores 铁载体
indoles 吲哚类
lantibiotics 羊毛硫抗生素
22
NRPS/PKS domain architecture analysis