Main migration routes of adventitious plants in Czechoslovakia

At the present time, three main migration routes of adventitious plants can be distinguished and defined in Czechoslovakia: (1) the Eastern Route, (2) the Elbe (Labe) Route, and (3) the Pannonian Route. Plant species approximately referring to individual routes are listed, too.     

Metabolic tinker: an online tool for guiding the design of synthetic metabolic pathways

One of the primary aims of synthetic biology is to (re)design metabolic pathways towards the production of desired chemicals. The fast pace of developments in molecular biology increasingly makes it possible to experimentally redesign existing pathways and implement de novo ones in microbes or using in vitro platforms. For such experimental studies, the bottleneck is shifting from implementation of pathways towards their initial design. Here, we present an online tool called ‘Metabolic Tinker’, which aims to guide the design of synthetic metabolic pathways between any two desired compounds. Given two user-defined ‘target’ and ‘source’ compounds, Metabolic Tinker searches for thermodynamically feasible paths in the entire known metabolic universe using a tailored heuristic search strategy. Compared with similar graph-based search tools, Metabolic Tinker returns a larger number of possible paths owing to its broad search base and fast heuristic, and provides for the first time thermodynamic feasibility information for the discovered paths. Metabolic Tinker is available as a web service at http://osslab.ex.ac.uk/tinker.aspx. The same website also provides the source code for Metabolic Tinker, allowing it to be developed further or run on personal machines for specific applications.     

Re-evaluating the Silk Road's Qinghai Route using dendrochronology

The opening of the Silk Road vigorously promoted economic and cultural exchanges between Central Asia, Europe, northern India and China. The easternmost section of the ancient trade route was established during the Qin-Han period (221 BC to 220 AD). Previous research has shown that there were three routes: the first is known as the “Hexi Route”, the second is known as the “Juyan Route” or “Prairie Route”, and the third is known as the “Qinghai Route”. The Qinghai Route has long been viewed as merely an auxiliary line of the Hexi Route which was used when the main Hexi Route was blocked by warfare. Others believe that the Qinghai Route was used during the 5th to 6th century when it was controlled by Tuyuhun Kingdom. Yet, by the 7th to 8th century, after the Tibetan occupation of the region, it was no longer a main trade route. Dendrochronology, the study of tree-rings, is a precise dating method that can be accurate to the year. In this study, wood remains excavated from tombs along the ancient Qinghai Route were studied by the means of dendrochronology in order to determine the date and better understand when Qinghai Route was used. In the tombs a lot of commercial goods such as silk products, pottery, lacquer carpentry were found. The date of the tombs determined by dendrochronology when viewed together with other archaeological data, showed that from the early Tang Dynasty to the High Tang Dynasty (early 7th century to late 8th century), the Qinghai Route was one of the routes of communication between the West and China. This disproves the hypothesis that this route was only used during the 5th to 6th century.     

MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization

We present MetaRoute, an efficient search algorithm based on atom mapping rules and path weighting schemes that returns relevant or textbook-like routes between a source and a product metabolite within seconds for genome-scale networks. Its speed allows the algorithm to be used interactively through a web interface to visualize relevant routes and local networks for one or multiple organisms based on data from KEGG. AVAILABILITY: http://www-bs.informatik.uni-tuebingen.de/Services/MetaRoute. SUPPLEMENTARY INFORMATION: Supplementary details are available at http://www-bs.informatik.uni-tuebingen.de/Services/MetaRoute.     

PSST-2.0

PSST-2.0 (Protein Data Bank [PDB] Sequence Search Tool) is an updated version of the earlier PSST (Protein Sequence Search Tool), and the philosophy behind the search engine has remained unchanged. PSST-2.0 is a Web-based, interactive search engine developed to retrieve required protein or nucleic acid sequence information and some of its related details, primarily from sequences derived from the structures deposited in the PDB (the database of 3-dimensional [3-D] protein and nucleic acid structures). Additionally, the search engine works for a selected subset of 25% or 90% non-homologous protein chains. For some of the selected options, the search engine produces a detailed output for the user-uploaded, 3-D atomic coordinates of the protein structure (PDB file format) from the client machine through the Web browser. The search engine works on a locally maintained PDB, which is updated every week from the parent server at the Research Collaboratory for Structural Bioinformatics, and hence the search results are up to date at any given time. AVAILABILITY: PSST-2.0 is freely accessible via http://pranag.physics.iisc.ernet.in/psst/ or http://144.16.71.10/psst/.     

Search strategies of ants in landmark-rich habitats

Search is an important tool in an ant’s navigational toolbox to relocate food sources and find the inconspicuous nest entrance. In habitats where landmark information is sparse, homing ants travel their entire home vector before searching systematically with ever increasing loops. Search strategies have not been previously investigated in ants that inhabit landmark-rich habitats where they typically establish stereotypical routes. Here we examine the search strategy in one such ant, Melophorus bagoti, by confining their foraging in one-dimensional channels to determine if their search pattern changes with experience, location of distant cues and altered distance on the homebound journey. Irrespective of conditions, we found ants exhibit a progressive search that drifted towards the fictive nest and beyond. Segments moving away from the start of the homeward journey were longer than segments heading back towards the start. The right tail distribution of segment lengths was well fitted by a power function, but slopes less than −3 on a log-log plot indicate that the process cannot be characterized as Lévy searches that have optimal slopes near –2. A double exponential function fits the distribution of segment lengths better, supporting another theoretically optimal search pattern, the composite Brownian walk.     

Large‐scale identification of genetic design strategies using local search

In the past decade, computational methods have been shown to be well suited to unraveling the complex web of metabolic reactions in biological systems. Methods based on flux–balance analysis (FBA) and bi‐level optimization have been used to great effect in aiding metabolic engineering. These methods predict the result of genetic manipulations and allow for the best set of manipulations to be found computationally. Bi‐level FBA is, however, limited in applicability because the required computational time and resources scale poorly as the size of the metabolic system and the number of genetic manipulations increase. To overcome these limitations, we have developed Genetic Design through Local Search (GDLS), a scalable, heuristic, algorithmic method that employs an approach based on local search with multiple search paths, which results in effective, low‐complexity search of the space of genetic manipulations. Thus, GDLS is able to find genetic designs with greater in silico production of desired metabolites than can feasibly be found using a globally optimal search and performs favorably in comparison with heuristic searches based on evolutionary algorithms and simulated annealing.     

Metabolic design: how to engineer a living cell to desired metabolite concentrations and fluxes

A biotechnological aim of genetic engineering is to increase the intracellular concentration or secretion of valuable compounds, while making the other concentrations and fluxes optimal for viability and productivity. Efforts to accomplish this based on over-expression of the enzyme, catalyzing the so-called "rate-limiting step," have not been successful. Here we develop a method to determine the enzyme concentrations that are required to achieve such an aim. This method is called Metabolic Design Analysis and is based on the perturbation method and the modular ("top-down") approach-formalisms that were first developed for the analysis of biochemical regulation such as, Metabolic Control Analysis. Contrary to earlier methods, the desired alterations of cellular metabolism need not be small or confined to a single metabolite or flux. The limits to the alterations of fluxes and metabolite concentrations are identified. To employ Metabolic Design Analysis, only limited kinetic information concerning the pathway enzymes is needed.     

Routes of migrating soaring birds

Soaring migrants travelling through Israel use three principal routes which are used in the opposite directions during the spring and autumn: (1) the Western Route lies mainly along the western edge of the central mountain range, (2) the Eastern Route lies mainly along the Jordan Valley, crossing the mountain range during part of the day, continuing southward along the Dead Sea towards the Sinai, and joining the Western Route in autumn and (3) the Southern-Elat Mountains Route. The geomorphological structure of Israel, with a central mountain range dividing the country roughly into three landscape units, plays a central role in route selection. In the autumn, the Western Route migration axis is deflected at the beginning of the day from east to west for 10–25 km, depending on weather conditions and the flock's roosting locations. Between 10.00 h and 11.00 h, the daily breeze blowing from the Mediterranean Sea influences the migration axis, which is slowly deflected back to the east. A parallel deflection of the migration axis occurs in the Eastern Route in the autumn. The route moves southwest over the eastern slopes of the central mountain range during the morning hours and over the slope, which absorbs direct radiation from the sun, creating good soaring conditions. Towards late afternoon, when the breeze from the sea starts, the axis is deflected to the east, to the Jordan Valley. In the Elat Mountains, the wind flow plays a similar role, but because the topography of the southern Arava Valley causes a change in wind direction, the axis moves during the day in a north-south direction. In addition to the axis movement on a daily scale, a seasonal deflection of the migration axis from east to west also exists. During autumn migration, early migrants (e.g. White Storks Ciconia ciconia) tend to travel on an eastern route, while late migrants (e.g. White Pelican Pelecanus onocrotalus) travel along the Mediterranean coast. This fluctuation was probably because of sub-optimal soaring conditions along the coastal plain during August. In September, temperature differences between the sea and land decrease and the influence of the marine inversion gradually declines, until its influence disappears completely in October. A comparison of the numbers of soaring birds seen over Israel in the autumn and spring shows significant seasonal differences in the use of the various routes. For example, only one species, the Steppe Eagle Aquila nipalensis, flies over the Elat Mountains in the autumn, compared to more than 30 species in the spring. In the autumn, White Storks pass over only along the Jordan Valley axis, whereas in the spring, about half the migrating storks also pass over the western edge of the central mountain range. Honey Buzzards Pernis apivorus fly along the Western Route in large numbers in the autumn, while concentrating almost totally over the Elat Mountains in the spring. These differences are related to the global migration routes between the breeding and the wintering grounds in relation to the Red Sea, which birds avoid crossing, thus causing them to follow different routes in autumn, and spring.     

Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein–protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the ‘Drug-like’, larger ‘Flexible’, and ‘Macrocycle’ compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles.     

MedEvi: retrieving textual evidence of relations between biomedical concepts from Medline

Search engines running on MEDLINE abstracts have been widely used by biologists to find publications that are related to their research. The existing search engines such as PubMed, however, have limitations when applied for the task of seeking textual evidence of relations between given concepts. The limitations are mainly due to the problem that the search engines do not effectively deal with multi-term queries which may imply semantic relations between the terms. To address this problem, we present MedEvi, a novel search engine that imposes positional restriction on occurrences matching multi-term queries, based on the observation that terms with semantic relations which are explicitly stated in text are not found too far from each other. MedEvi further identifies additional keywords of biological and statistical significance from local context of matching occurrences in order to help users reformulate their queries for better results. AVAILABILITY: http://www.ebi.ac.uk/tc-test/textmining/medevi/     

Route design,the foundation of successful chemical development

Route Design is the first step in the strategic development process for manufacture of a new active pharmaceutical ingredient (API). Numerous benefits can be realised for the project and the broader performance of the company. We present an appreciation of some of the potential challenges and describe the principles and practices that have shaped the Route Design culture within AstraZeneca. This is exemplified with case histories and we describe some of the activities that have supported our scientists and the simple messages used to educate the broader organisation.     

Synthesis of 6I-amino-6I-deoxy-2I-VII,3I-VII-tetradeca-O-methyl-cyclomaltoheptaose

The preparation of 6(I)-amino-6(I)-deoxy-2(I-VII),3(I-VII)-tetradeca-O-methyl-cyclomaltoheptaose is reported. Two different routes (A and B), both starting from beta-cyclodextrin (betaCD), have been examined. Route A involved: (i) synthesis of heptakis(6-O-tert-butyldimethylsilyl)-betaCD from betaCD; (ii) permethylation of the secondary hydroxyl groups with methyl iodide and sodium hydride; (iii) desilylation of the primary hydroxyls with ammonium fluoride; (iv) monotosylation at O-6 position of per-(2,3-O-methyl)-betaCD; (5) nucleophilic replacement of the tosyl group with azide anion; (v) reduction of the azido group by catalytic transfer hydrogenation using hydrazine hydrate in the presence of Pd/C in methanol/water. Route B started from the known 6(I)-monoazido-6(I)-monodeoxy-beta-CD (two steps from beta-CD) and entailed: (i) protection of the remaining primary hydroxyls using tert-butyldimethylsilylchloride (TBDMSCl); (ii) exhaustive methylation of the secondary hydroxyls with methyl iodide and sodium hydride; (iii) removal of the TBDMS protecting groups with ammonium fluoride; (iv) reduction of the azido group as above. Route A was found to be less convenient than Route B due to the inherent difficulty of controlling the monotosylation of per-(2,3-O-methyl)-betaCD.     

Protein design for pathway engineering

Design and construction of biochemical pathways has increased the complexity of biosynthetically-produced compounds when compared to single enzyme biocatalysis. However, the coordination of multiple enzymes can introduce a complicated set of obstacles to overcome in order to achieve a high titer and yield of the desired compound. Metabolic engineering has made great strides in developing tools to optimize the flux through a target pathway, but the inherent characteristics of a particular enzyme within the pathway can still limit the productivity. Thus, judicious protein design is critical for metabolic and pathway engineering. This review will describe various strategies and examples of applying protein design to pathway engineering to optimize the flux through the pathway. The proteins can be engineered for altered substrate specificity/selectivity, increased catalytic activity, reduced mass transfer limitations through specific protein localization, and reduced substrate/product inhibition. Protein engineering can also be expanded to design biosensors to enable high through-put screening and to customize cell signaling networks. These strategies have successfully engineered pathways for significantly increased productivity of the desired product or in the production of novel compounds.     

Migratory connectivity of American woodcock derived using satellite telemetry

American woodcock (Scolopax minor; woodcock) migratory connectivity (i.e., association between breeding and wintering areas) is largely unknown, even though current woodcock management is predicated on such associations. Woodcock are currently managed in the Eastern and Central management regions in the United States with the boundary between management regions analogous to the boundary between the Atlantic and Mississippi flyways, based largely on analysis of band returns from hunters. Factors during migration influence survival and fitness, and existing data derived from banding and very high frequency telemetry provide only coarse-scale information to assess factors influencing woodcock migratory movement patterns and behavior. To assess whether current management-region boundaries correspond with woodcock migratory connectivity in the Central Management Region and to describe migration patterns with higher resolution than has been previously possible, we deployed satellite transmitters on 73 woodcock (25 adult and 28 juvenile females, and 8 adult and 12 juvenile males) and recorded 87 autumn or spring migration paths from 2014 to 2016. Marked woodcock used 2 primary migrations routes: a Western Route and a Central Route. The Western Route ran north-south, connecting the breeding and wintering grounds within the Central Management Region. The hourglass-shaped Central Route connected an area on the wintering grounds reaching from Texas to Florida, to sites throughout northeastern North America in both the Eastern Management Region and Central Management Region and woodcock following this route migrated through the area between the Appalachian Mountains and the Mississippi Alluvial Valley in western Tennessee during autumn and spring. Two of 17 woodcock captured associated with breeding areas in Michigan, Wisconsin, or Minnesota migrated to wintering sites in the Eastern Management Region and 12 marked woodcock captured on wintering areas in Texas and Louisiana migrated to breeding sites in the Eastern Management Region. Woodcock that used the Western Route exhibited high concentrations of stopovers during spring in the Arkansas Ozark Mountains and northern Missouri, and along the Mississippi River on the border between Wisconsin and Minnesota, and autumn concentrations of stopovers in southwestern Iowa, central Missouri, the Arkansas portion of the Ozark Mountains, and around the junction of Texas, Louisiana, Oklahoma, and Arkansas. Woodcock that used the Central Route exhibited high concentrations of stopovers during spring in northern Mississippi through western Tennessee, western Kentucky, and the Missouri Bootheel, and autumn concentrations of stopovers in northern Illinois, southwestern Ohio, and the portions of Kentucky and Tennessee west of the Appalachian Mountains. We suggest that current management of woodcock based on 2 management regions may not be consistent with the apparent lack of strong migratory connectivity we observed. Our results also suggest where management of migration habitat might be most beneficial to woodcock. © 2019 The Wildlife Society.     

Model-based probe set optimization for high-performance microarrays

A major challenge in microarray design is the selection of highly specific oligonucleotide probes for all targeted genes of interest, while maintaining thermodynamic uniformity at the hybridization temperature. We introduce a novel microarray design framework (Thermodynamic Model-based Oligo Design Optimizer, TherMODO) that for the first time incorporates a number of advanced modelling features: (i) A model of position-dependent labelling effects that is quantitatively derived from experiment. (ii) Multi-state thermodynamic hybridization models of probe binding behaviour, including potential cross-hybridization reactions. (iii) A fast calibrated sequence-similarity-based heuristic for cross-hybridization prediction supporting large-scale designs. (iv) A novel compound score formulation for the integrated assessment of multiple probe design objectives. In contrast to a greedy search for probes meeting parameter thresholds, this approach permits an optimization at the probe set level and facilitates the selection of highly specific probe candidates while maintaining probe set uniformity. (v) Lastly, a flexible target grouping structure allows easy adaptation of the pipeline to a variety of microarray application scenarios. The algorithm and features are discussed and demonstrated on actual design runs. Source code is available on request.     

msatcommander: detection of microsatellite repeat arrays and automated, locus-specific primer design

msatcommander is a platform-independent program designed to search for microsatellite arrays, design primers, and tag primers using an automated routine. msatcommander accepts as input DNA sequence data in single-sequence or concatenated, fasta-formatted files. Search data and locus-specific primers are written to comma-separated value files for subsequent use in spreadsheet or database programs. Binary versions of the graphical interface for msatcommander are available for Apple OS X and Windows XP. Users of other operating systems may run the graphical interface version using the available source code, provided their environment supports at least Python 2.4, Biopython 1.43, and wxPython 2.8. msatcommander is available from http://code.google.com/p/msatcommander/.     

OMSSAGUI: An open-source user interface component to configure and run the OMSSA search engine

We here present a user-friendly and extremely lightweight tool that can serve as a stand-alone front-end for the Open MS Search Algorithm (OMSSA) search engine, or that can directly be used as part of an informatics processing pipeline for MS driven proteomics. The OMSSA graphical user interface (OMSSAGUI) tool is written in Java, and is supported on Windows, Linux, and OSX platforms. It is an open source under the Apache 2 license and can be downloaded from http://code.google.com/p/mass-spec-gui/.