Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

A Comparative Survey of the Frequency and Distribution of Polymorphism in the Genome of Xenopus tropicalis

Naturally occurring DNA sequence variation within a species underlies evolutionary adaptation and can give rise to phenotypic changes that provide novel insight into biological questions. This variation exists in laboratory populations just as in wild populations and, in addition to being a source of useful alleles for genetic studies, can impact efforts to identify induced mutations in sequence-based genetic screens. The Western clawed frog Xenopus tropicalis (X. tropicalis) has been adopted as a model system for studying the genetic control of embryonic development and a variety of other areas of research. Its diploid genome has been extensively sequenced and efforts are underway to isolate mutants by phenotype- and genotype-based approaches. Here, we describe a study of genetic polymorphism in laboratory strains of X. tropicalis. Polymorphism was detected in the coding and non-coding regions of developmental genes distributed widely across the genome. Laboratory strains exhibit unexpectedly high frequencies of genetic polymorphism, with alleles carrying a variety of synonymous and non-synonymous codon substitutions and nucleotide insertions/deletions. Inter-strain comparisons of polymorphism uncover a high proportion of shared alleles between Nigerian and Ivory Coast strains, in spite of their distinct geographical origins. These observations will likely influence the design of future sequence-based mutation screens, particularly those using DNA mismatch-based detection methods which can be disrupted by the presence of naturally occurring sequence variants. The existence of a significant reservoir of alleles also suggests that existing laboratory stocks may be a useful source of novel alleles for mapping and functional studies

3-(2,4-Dichloro­phen­yl)-5-methyl-1,2,4-oxadiazole

In the title compound, C9H6Cl2N2O, the dihedral angle between the oxadiazole and benzene rings is 1.7 (2)°. In the crystal, the mol­ecules are linked into chains along the b axis by short inter­molecular Cl⋯O contacts [3.019 (3) Å]

Developmental expression patterns ofTbx1,Tbx2,Tbx5, andTbx20 inXenopus tropicalis

T-box genes have diverse functions during embryogenesis and are implicated in several human congenital disorders. Here, we report the identification, sequence analysis, and developmental expression patterns of four members of the T-box gene family in the diploid frog Xenopus tropicalis. These four genes—Tbx1, Tbx2, Tbx5, and Tbx20—have been shown to influence cardiac development in a variety of organisms, in addition to their individual roles in regulating other aspects of embryonic development. Our results highlight the high degree of evolutionary conservation between orthologs of these genes in X. tropicalis and other vertebrates, both at the molecular level and in their developmental expression patterns, and also identify novel features of their expression. Thus, X. tropicalis represents a potentially valuable vertebrate model in which to further investigate the functions of these genes through genetic approaches

Standardizing Navigation Data: A Status Update

This paper presents the work of the Navigation Working Group of the Consultative Committee for Space Data Systems (CCSDS) on development of standards addressing the transfer of orbit, attitude and tracking data for space objects. Much progress has been made since the initial presentation of the standards in 2004, including the progression of the orbit data standard to an accepted standard, and the near completion of the attitude and tracking data standards. The orbit, attitude and tracking standards attempt to address predominant parameterizations for their respective data, and create a message format that enables communication of the data across space agencies and other entities. The messages detailed in each standard are built upon a keyword = value paradigm, where a fixed list of keywords is provided in the standard where users specify information about their data, and also use keywords to encapsulate their data. The paper presents a primer on the CCSDS standardization process to put in context the state of the message standards, and the parameterizations supported in each standard, then shows examples of these standards for orbit, attitude and tracking data. Finalization of the standards is expected by the end of calendar year 2007

Monokine-induced gene expression of a human endothelial cell-derived neutrophil chemotactic factor

Monokines have been increasingly recognized as communication signals that interact with both immune and non-immune cells during inflammation. Specifically, interleukin-1alpha (IL-lalpha), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) possess potent effector activities on various cell types. We present novel data demonstrating that human endothelial cells are a major source of a neutrophil chemotactic factor (NCF) synthesized upon stimulation with either IL-1alpha, IL-1beta, or TNF-alpha; but not with interleukin-6 (IL-6). Northern blot analysis demonstrated that 20 ng/ml of either IL-1 or TNF-alpha could induce endothelial cells to express significant levels of NCF mRNA, while IL-6 was not active in this system. These data demonstrate that monokines play an important role in mediating acute inflammation via induction of an endothelial cell-derived NCF.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27070/1/0000060.pd

3-(2,4-Dichloro­phen­yl)-5-phenyl-1,2,4-oxadiazole

In the title compound, C14H8Cl2N2O, the dihedral angles between the plane of the oxadiazole ring and those of the benzene rings are 2.3 (1) and 9.5 (1)°. In the crystal, mol­ecules are linked into chains along the c axis by C—H⋯Cl inter­actions. These chains are stacked along the a axis

5-(2,4-Dichloro­phen­yl)-3-(4-nitro­phen­yl)-1,2,4-oxadiazole

In the title compound, C14H7Cl2N3O3, the dichloro­phenyl and nitro­phenyl rings form dihedral angles of 5.4 (2) and 4.0 (2)°, respectively, with the oxadiazole ring. The nitro group is twisted out of the attached benzene ring by a dihedral angle of 10.4 (3)°. In the crystal, mol­ecules are linked into a chain along the a axis by C—H⋯N hydrogen bonds

Educational effectiveness of gynaecological teaching associates: a multi-centre randomised controlled trial

This trial was funded by The Medical College St Bartholo-mew’s Hospital Trust (reference number: 8368137)

Xenopus: An emerging model for studying congenital heart disease

Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well-studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes