Automation Highlights from the LiteratureL ABORATORY A UTOMATION ANDH IGH-T HROUGHPUT C HEMISTRYRapid Multistep Synthesis of1,2,4-Oxadiazoles in a Single Continuous Microreactor SequenceA general method for the synthesis of bis-substituted1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single con-tinuous microreactor sequence is described by N.D.P.Cosford et al.The synthesis incorporates three sequential microreactors to produce1,2,4-oxa-diazoles in approximately30min in quantities (40e80mg)sufficient for full characterization and rapid library supply(.Chem.2009,73, 7219e23).Expanding the Chemical Space in Practice: Diversity-Oriented SynthesisDiversity-oriented synthesis(DOS)aims to broaden the frontier of accessible collections of complex and diverse small molecules.M.Peuch-maur and Y.-S.Wong dissect the DOS concept through three elements of diversity:building block, stereochemistry,and skeleton.Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported(Comb.Chem.High Throughput Screen. 2008,11,587e601).Selective Monolithiation of Dibromobiaryls Using Microflow SystemsSelective monolithiation of dibromobiaryls with one equivalent of n-butyllithium followed by the re-action with electrophiles is achieved by J.-I.Yoshida et ing a microflow system by virtue of fast mi-cromixing and precise temperature control.Sequen-tial introduction of two different electrophiles based on this method also is achieved using a microflow system composed of four micromixers and four mi-crotube reactors(Org.Lett.2008,10,3937e3940). Combinatorial Materials Research Applied to the Development of New Surface Coatings X: A High-Throughput Electrochemical Impedance Spectroscopy Method for Screening Organic Coatings for Corrosion InhibitionJ.He et al.report a high-throughput electrochem-ical impedance spectroscopy(HT-EIS)method for rapid and quantitative evaluation of corrosion pro-tective coatings.A12-element,spatially addressable electrochemical platform has been designed,fabri-cated,and validated.This platform is interfaced to a commercial electrochemical impedance spectros-copy(EIS)instrument through an automated elec-tronic switching unit.The HT-EIS system enables four parallel EIS measurements to be run simulta-neously,which significantly reduces characterization time compared to that of serial EIS measurements using a multiplexer.The performance of the HT-EIS system is validated using a series of model sys-tems,including a Randles equivalent circuit,anKerstin Thurow,Ph.D.Hilmar Weinmann,Ph.D.Correspondence:Hilmar Weinmann,Ph.D.,Bayer Schering PharmaAG,Global Drug Discovery,Medicinal Chemistry Berlin,D-13342Berlin,Germany;Phone:þ49.30.468.17892;Fax:þ49.30.468.18170;E-mail:Hilmar.Weinmann@bayerhealthcare.com;or Kerstin Thurow,Ph.D.,University of Rostock,Institute ofAutomation,R.Wagner,Street31,18119Rostock,Germany;Phone:þ49.381.498.7800;Fax:þ49.381.498.7802;E-mail:Kerstin.Thurow@uni-rostock.deJALA2009;14:1e5.1535-5535/$36.00Copyright c2009by The Association for Laboratory Automationdoi:10.1016/j.jala.2008.10.002Literature HighlightsJALA February20091electrochemical reaction(Ti/K4FeCN6,K3FeCN6),a highly uniform polymerfilm,and several polymer coatings.The re-sults of the validation studies show that the HT-EIS system enables a major reduction in characterization time and pro-vides high quality data comparable to data obtained with conventional,single-cell EIS measurement systems(b. Chem.2008,10,704e713).Resin Capsules:Permeable Containers for Parallel/ Combinatorial Solid-Phase Organic SynthesisA resin capsule is a permeable container for resin beads designed for combinatorial solid-phase organic synthesis. Resin capsules consist of a high-density polyethylene ring sealed with peek mesh on both sides.The cylindrical shape of resin capsules enables space-saving packing into plastic column-like reaction vessels commonly used for solid-phase organic synthesis.Resin capsules are evaluated by V. Krchnak et al.for use in combinatorial synthesis,and a set of model compounds with excellent purity is prepared(J. Comb.Chem.2008,10,714e720).H IGH-T HROUGHPUT A NALYTICSAmbient Molecular Imaging and Depth Profiling of Live Tissue by Laser Ablation Electrospray Ionization Mass SpectrometryIn conjunction with mass spectrometry,the demand for atmospheric pressure ionization methods that achieve effi-cient ion generation under native-like experimental condi-tions arises.A.Vertes and coworkers from W.M.Keck Institute for Proteomics Technology and Applications (George Washington University,Washington,DC)present the lateral mapping of metabolite distributions and their var-iations with depth on plant leaves with laser ablation electro-spray ionization mass spectrometry(LAESI-MS)(Anal. Chem.2008,80,4575e4582).In contrast to electrospray-assisted laser desorption/ioni-zation,which also relies on the postionization of neutrals in a laser plum by ESI,the laser energy used for LAESI causes a resonant process in water-rich targets.With the ESI source in axial spraying mode,the laser light (2940nm)hits the target18mm below and5e8mm down-stream from the tip of the emitter and results in a laser abla-tion area of350l m in diameter and a depth of50l m. Details of the produced ablation craters are investigated by scanning electron microscopy and correlated with the re-corded MS data.As an example,the distribution of metabo-lites in the green and yellow sectors of a Zebra plant leaf is analyzed.At this,over40metabolites are detected and36 could be assigned.The results are in good conformance with other techniques.Summarized,their results demonstrate that LAESI-MS opens a new way for ambient molecular three-dimensional imaging of metabolites in biological tissues and live organisms.Online Coupling of Gas Chromatography to Nuclear Magnetic Resonance Spectroscopy:Method for the Analysis of Volatile StereoisomersAlthough HPLC-NMR has evolved into a versatile tool in the analysis of complex samples,the coupling of GC and NMR is still in an early stage of development,despite the fact thatfirst experiments were conducted in the1970s.In their article,K.Albert and colleagues(Institute of Organic Chemistry,Chemisches Zentralinstitut,University of Tu bin-gen)describe a new system of coupled GC e NMR for the analysis of volatile cis/trans stereoisomers of alkenes for continuous-and stopped-flow gas-phase experiments(Anal. Chem.2007,80,5481e5486)In addition to a short review about earlier GC e NMR developments,the authors describe their new technical assembly in detail.In contrast to former experiments,the larger inner diameter of the transfer capil-laries as well as of the inlet of the detection cell dramatically reduces the necessary injection amount,hitherto a major drawback.Furthermore,the recent NMR spectrometer with higherfield strength facilitates very short dwell times and crucially enhances the signal-to-noise ratio.With the chosen assembly,it is possible to separate the cis and trans isomers of2-pentene and2-hexene in the gas phase and perform con-tinuous-flow NMR detection to obtain a definite2D contour plot.It is also shown that when stopped-flow experiments use reference spectra from an available spectra database,distinc-tion between two cis/trans stereoisomers can be achieved. The presented results demonstrate the high potential of the coupling of capillary GC and microprobe1H-NMR detec-tion,but some technical challenges still must be overcome.B IOAUTOMATION AND S CREENINGNew Connections across Pathways and Cellular Processes:Industrialized Mutant Screening Reveals Novel Associations between Diverse Phenotypes in ArabidopsisIt is widely known that high-throughput approaches are not limited to thefields of drug discovery and white biotech-nology.These techniques enter into many other areas,among them,different parts of plant biology.High-throughput anal-yses led to the sequencing of thefirst genome of a higher eu-karyotic organism,the mouse-ear cress Arabidopsis thaliana, and were also essential for setting up large repositories of clones,microarray data and mutants from different model and crop plants.Today,these partially publicly available re-sources are indispensable for progress in anyfield of plant re-search,but the future of high-throughput approaches is not limited to particularfields.These plant biology techniques can be helpful in any area of research.Lu et al.present an interesting example for this develop-ment.The authors analyze13different Arabidopsis mutants biochemically and phenotypically.The biochemical analyses are performed with different LC,GC,and MS methods to determine the contents of free amino acids,fatty acids,2JALA February2009 Literature Highlightsstarch,and chlorophyll in different organs.One result of the data is that several new phenotypes are discovered in partic-ular mutants.In a further approach,statistical and bioinfor-matic calculations are performed with the data sets,which reveal novel connections and associations between different metabolic and catabolic pathways.In one conclusion by Lu et al.,parallel analyses of plant germplasm,like mutants or ecotypes,harbors an enormous potential for plant biology, especially for plant breeding.The exploitation of this poten-tial depends on the application of high-throughput methods, especially of automated ones.Currently,such methods need to be improved or invented in thefield of plant research to address future needs for crop plants(Plant Physiol.2008, 146,1482e1500).Live-Cell High-Content Screening in Drug DevelopmentCell-based assays are state of the art in drug discovery and development.They provide toxicological data during an early phase of drug discovery and can thus help to reduce costs.The power of high-content screening technology using living cells is summarized by M.Bickle(Eur.Pharm.Rev. 2008,4,54e60).Live-cell imaging means a further level of complexity to high-content screening(HCS),and relates to new technological challenges.Examples of live-cell HCS ap-plications,such as toxicity assays in HepG2cells,the moni-toring of subcellular localization changes,or the determination of pharmacokinetic data are presented.They show,that live-cell HCS will become more and more popular in drug development in future.One aspect of the article addresses the challenges and re-quirements for software solutions,for example,kinetic HCS offer tracking of objects capabilities.There are very few commercially available software products,and one is described briefly(Eur.Pharm.Rev.2008,4,54e60). Chemogenomics:A Discipline at the Crossroad of High-Throughput Technologies,Biomarker Research, Combinatorial Chemistry,Genomics, Cheminformatics,Bioinformatics,and Artificial IntelligenceE.Marechal gives an overview on chemogenomics and re-lated technologies.Chemogenomics is the study of the inter-action of functional biological systems with exogenous small molecules,or in a broader sense,the study of the intersection of biological and chemical spaces.Chemogenomics requires expertises in biology,chemistry,and computational sciences. Chemogenomics is a descendent of conventional pharmaceu-tical approaches,because it involves the screening of chemi-cal libraries for their effects on biological targets,and benefits from the advances in the corresponding enabling technolo-gies and the introduction of new biological markers(Comb. Chem.High Throughput Screen.2008,11,583e586).Cell-Based Assays in Practice:Cell Markers from Autofluorescent Proteins of the GFP Family The recently discovered anthozoanfluorescent proteins (FPs)and the classic Aequorea victoria Green Fluorescent Protein(avGFP)as well as their derivatives have become ver-satile tools as live-cell markers influorescence microscopy.R. Heilker et al.review the use of these FPs in drug discovery assays.Assay examples are given for the application of FPs in multiplexed imaging,as photosensitizers,asfluorescent timers,as pulse-chase labels,and for robotically integrated compound testing.The development of fast microscopic im-aging devices enables the application of automatedfluores-cence microscopy combined with image analysis to pharmaceutical high-throughput drug discovery assays,gen-erally referred to as high-content screening(Comb.Chem. High Throughput Screen.2008,11,602e609).Design of Phenotypic Screens for Bioactive Chemicals and Identification of their Targets by Genetic and Proteomic ApproachesCell-based screening using phenotypic assays is a useful means of identifying bioactive chemicals for use as tools to elu-cidate complex cellular processes.M.Roberge et al.describe how cell-based screening assays can be designed to maximize the likelihood of discovering selective compounds through the choice of positive readouts,low chemical concentrations, and long incubation periods.Identifying the cellular targets of active chemicals can be especially demanding.Strategies for unbiased target identification by sampling potential targets at the genome-wide and proteome-wide levels also are discussed (Comb.Chem.High Throughput Screen.2008,11,610e616). Chemogenomics and Cancer Chemotherapy:Cell-Based Assays to Screen for Small Molecules that Impair Microtubule DynamicsMicrotubules are still a promising target for new thera-peutic agents.Thus,there is ongoing interest in compounds that are able to modify microtubule assembly.Because of its dynamic characteristics,the microtubule cytoskeleton is a suitable target for small molecules that rapidly diffuse in the cell cytoplasm.Moreover,compounds targeting the mi-crotubule cytoskeleton prove to be valuable tools for basic research in cell fanechere reviews the potential and impact of chemogenomics and cell-based assays in the discovery of new therapeutic compounds and of new regula-tors of the microtubule cytoskeleton(Comb.Chem.High Throughput Screen.2008,11,617e623). Chemogenomics and Parasitology:Small Molecules and Cell-Based Assays to Study Infectious Processes Infectious diseases caused by protozoan parasites remain chronic problems for humanity.Current advances in high-throughput screening(HTS)technologies and availability of diverse small molecule libraries offer the promise of accel-erated discovery of new drug targets and new drugs that willJALA February20093Literature Highlightsreduce disease burdens imposed on humanity by parasitic protozoa.M.-J.Gubbels et al.provide a status report on HTS technologies in hand and cell-based assays under devel-opment for biological investigations and drug discovery directed toward the three best characterized parasitic proto-zoa:Trypanosoma brucei,Plasmodium falciparum,and Toxo-plasma gondii.Small molecules that interfere with specific aspects of protozoan biology,identified in such screens,will be valuable tools for dissecting parasite cell biology and de-veloping antiprotozoan drugs(Comb.Chem.High Through-put Screen.2008,11,624e646).Plant Pathogen Recognition as a Natural,Original, and Simple Model for Chemogenomics:A Brief Overview of Cell-Based Assays to Screen for Peptides Acting as Plant Defense ActivatorsAs plants lack a circulatory system and adaptive immune system,they have evolved their own defense systems distinct from animals in which each plant cell is capable of defending itself from pathogens.Plants induce a number of defense re-sponses,which are triggered by a variety of molecules derived from pathogenic microorganisms,referred to as microbe-associated molecular patterns(MAMPs).MAMPs include peptides,proteins,lipopolysaccharide,b-glucan,chitin,and ergosterol.The interaction between plants and chemicals in the context of plant defense represents a natural and simple model for chemogenomics at the intersection of chemical and biological diversities.To protect crop plants from dis-eases,it has been shown to effectively stimulate plant immu-nity by chemical compounds,the so-called plant defense binatorial chemistry techniques can be ap-plied to the search for novel plant defense activators,but it is essential to establish an efficient and reliable screening sys-tem for library screening.M.Miyashita et al.describe the cell-based lawn format assay for identification of peptides acting as plant defense activators from combinatorial peptide libraries.The requirements and limitations in constructing the screening system using combinatorial libraries in the studies of plant sciences are also discussed(Comb.Chem. High Throughput Screen.2008,11,647e652).Building a Biological Space Based on Protein Sequence Similarities and Biological Ontologies Assignment of function to protein sequence is a task of growing importance in the life sciences as new high-through-put sequencing DNA technologies generate ever-increasing quantities of genomic data.Clustering similar sequences is a useful technique forfinding conserved sequences.The CluSTr database is a publicly available database that ar-ranges proteins in a hierarchy structured by similarity.The protein classification tool InterProScan builds on this ap-proach by applying a range of methods to detect proteins that contain signatures indicative of the presence of particu-lar conserved domains.P.Kersey et al.review the use of on-tologies to describe a protein function that provides aflexible and abstract language to classify proteins(Comb.Chem. High Throughput Screen.2008,11,653e660).Building a Chemical Space Based on Fragment DescriptorsI.Baskin and A.Varnek review the application of frag-ment descriptors at different stages of virtual screening dfil-tering,similarity search,and direct activity assessment d using QSAR/QSPR models.They demonstrate that the power of fragment descriptors stems from their universality, very high computational efficiency,simplicity of interpreta-tion,and versatility(Comb.Chem.High Throughput Screen. 2008,11,661e668).A Ligand-Based Approach to Mining the Chemogenomic Space of DrugsThe practical implementation and validation of a ligand-based approach to mining the chemogenomic space of drugs is presented by J.Mestres et al.and applied to the in silico target profiling of767drugs against684targets of therapeu-tic relevance.The results reveal that drugs targeting aminer-gic G protein-coupled receptors(GPCRs)show the most promiscuous pharmacological profiles.The detection of cross-pharmacologies between aminergic GPCRs and the opioid,sigma,NMDA,and5-HT3receptors aggravate the potential promiscuity of those drugs,which predominantly include analgesics,antidepressants,and antipsychotics (Comb.Chem.High Throughput Screen.2008,11,669e676). Machine Learning for In Silico Virtual Screening and Chemical Genomics:New StrategiesSupport vector machines and kernel methods belong to the same class of machine learning algorithms that has recently be-come prominent in both computational biology and chemis-try,although bothfields have largely ignored each other. These methods are based on a sound mathematical and com-putationally efficient framework that implicitly embeds the data of interest,respectively,proteins and small molecules, in high-dimensional feature spaces where various classification or regression tasks can be performed with linear algorithms. J.-P.Vert and L.Jacob present the main ideas underlying these approaches,survey how both the biological and the chemical spaces have been separately constructed using the same math-ematical framework and tricks,and suggest different avenues to unify both spaces for the purpose of in silico chemogenomics (Comb.Chem.High Throughput Screen.2008,11,677e685). LIMS AND P ROCESS C ONTROL S YSTEMSInformation Automation in R&D Laboratories:Past and FutureCh.Sodano,author and founder of eOrganizedWorld,con-siders IT trends of e-records in an article that traces the history of Laboratory Information Management Systems(LIMS)and Electronic Laboratory Journals(ELNs).The way thefirst4JALA February2009 Literature Highlightscommercial LIMS appeared in the1980s to the future are dis-cussed in terms of general requirements,interfacing,the need of standardization,and IT infrastructure for collaboration networks.The overviews help to interpret new developments. The retention time for experiments captured in paper-based laboratory notebook or by microfilm is compared with elec-tronic records(life time of storage media,etc).One of the prob-lems identified is the availability of system software to interpret analytical data after a lot of years,but one of the central points of long life data access is the question of data or information structures.Therefore,the need and importance of general ISO standards for all types of LIMS-and ELN-related data structures are underlined.The general known convergence between LIMS and ELN is confirmed by the author.If records must be kept in electronic formats for more than10years, a strategy of planning for continuous migration becomes imperative(Eur.Pharm.Rev.2008,4,61e64).Extensible Open Source Content Management Systems and Frameworks:a Solution for Many Needs of a Bioinformatics GroupAuthors from the Center for Computational Biology and Bioinformatics at Indiana University School of Medicine,fo-cus on the availability of information via Internet or stan-dard Web browsers.Basics and reviews about well-known Web site management tools are discussed and compared with the needs of user groups that conduct research-specific activ-ities.The use of content management systems(CMSs)is de-scribed as an interesting alternative to other IT solutions for exchanging scientific content.The article provides a good overview to existing types of CMS application and stand-alone tools;and popular open source CMS programming languages and application software are listed with their homepage addresses.The authors divide several types of CMS use in biomedicine,including collaborative Web sites, conference Web sites,content databases in laboratory intra-nets,and write about the use and development of CMS appli-cation plug-ins.The article ends with CMS customization experiences and examples of solutions and recommendations. Comparability of Data in Process and Laboratory As in process automation,equipment and data standard-ization is required for laboratory automation.LIMSs collect and organize information,but are mostly proprietary solu-tions that do not communicate with an organization’s pro-duction area.Profibus is the world’s most popularfieldbus,and it offers a fully integrated solution for discrete and process applica-tions.The basic functions,controls,and communication ser-vices are defined in standardized device profiles.The Profibus user organization was thefirst of the majorfieldbus organi-zations,specified a device profile that is especially dedicated to the requirements of laboratory equipment.U.Jecht and C.Diedrich provide an overview of the de-vice in‘‘LabDevices’’(CIT plus.2008,11(5),13e16).For the specific functions of labor devices,three new function blocks(Human Interface,Ramp,and Lab Control Unit) have been developed for the‘‘LabDevices’’profile.The new profile‘‘LabDevices’’is a door opener for the seamless integration of labs into Profibus systems,and by means of object linking and embedding for process control into other automation worlds.Application of‘‘LabDevices’’allows the use of uniform Profibus technology in production and lab automation,and provides significant savings poten-tial even if they are not in the samefieldbus system.Data Sharing in Distributed Databases and Peer-to-Peer DatabasesContent-sharing systems on the Web have renewed inter-est in the design and development of decentralized database management systems.The need for large-scale data sharing between autonomous and possibly heterogeneous decentral-ized systems on the Web give rise to the concept of peer-to-peer(P2P)database systems.A recently published paper provides insight into this new P2P data management technol-ogy,and compares more established decentralized models, commonly referred to as distributed,federated,and multida-tabases.The goal was to clarify some of the essential differ-ences and similarities from a data management point of view.A database system(DBS)is a software that manages one or more databases.A distributed database system is a soft-ware that manages one or more logically related databases, spanning a network.Both a federated database system and a multidatabase system are collections of preexisting DBSs in which operations can be applied to multiple heterogeneous component DBSs in a coordinated manner.The authors dis-tinguish between db-centric and P2P-centric features.The various DBS are characterized by three dimensions:distribu-tion,autonomy,and heterogeneity.The most important features of P2P paradigm are scal-ability in terms of the number of nodes and distribution; direct access to the data at the source,which guarantees freshness in contrast to centralized repositories;robustness and resilience against attacks and churn by exploiting self or-ganization principles;and simplified deployment,because re-sources from the edge of the Internet can be used and no special infrastructure is required to join the network.A P2P database system is conceived as a collection of autono-mous local repositories that interact in a P2P style with es-tablished correspondences or exchange query and update requests.The local repositories are autonomous peers with equal rights,and are linked to only a small number of neigh-bors.The main data integration and interoperability idea in peer data management is to avoid a global schema by provid-ing mappings between pairs of information sources.Map-pings between all pairs are not necessary.An export schema contains only the elements of the local schema that a peer wants to share with the outside world.Open and challenging issues in P2P data management are anonymity,security,and access control problems(SIGMOD Rec.2008,37(1),5e11).JALA February20095Literature Highlights。