Structural and evolutionary relationships among protein tyrosine phosphatase domains

With the current access to the whole genomes of various organisms and the completion of the first draft of the human genome, there is a strong need for a structure-function classification of protein families as an initial step in moving from DNA databases to a comprehensive understanding of human biology. As a result of the explosion in nucleic acid sequence information and the concurrent development of methods for high-throughput functional characterization of gene products, the genomic revolution also promises to provide a new paradigm for drug discovery, enabling the identification of molecular drug targets in a significant number of human diseases. This molecular view of diseases has contributed to the importance of combining primary sequence data with three-dimensional structure and has increased the awareness of computational homology modeling and its potential to elucidate protein function. In particular, when important proteins or novel therapeutic targets are identified—like the family of protein tyrosine phosphatases (PTPs) (reviewed in reference 53)—a structure-function classification of such protein families becomes an invaluable framework for further advances in biomedical science. Here, we present a comparative analysis of the structural relationships among vertebrate PTP domains and provide a comprehensive resource for sequence analysis of phosphotyrosine-specific PTPs

Risk factors of visceral leishmaniasis in East Africa: a case-control study in Pokot territory of Kenya and Uganda

BACKGROUND: In East Africa, visceral leishmaniasis (VL) is endemic in parts of Sudan, Ethiopia, Somalia, Kenya and Uganda. It is caused by Leishmania donovani and transmitted by the sandfly vector Phlebotomus martini. In the Pokot focus, reaching from western Kenya into eastern Uganda, formulation of a prevention strategy has been hindered by the lack of knowledge on VL risk factors as well as by lack of support from health sector donors. The present study was conducted to establish the necessary evidence-base and to stimulate interest in supporting the control of this neglected tropical disease in Uganda and Kenya. METHODS: A case-control study was carried out from June to December 2006. Cases were recruited at Amudat hospital, Nakapiripirit district, Uganda, after clinical and parasitological confirmation of symptomatic VL infection. Controls were individuals that tested negative using a rK39 antigen-based dipstick, which were recruited at random from the same communities as the cases. Data were analysed using conditional logistic regression. RESULTS: Ninety-three cases and 226 controls were recruited into the study. Multivariate analysis identified low socio-economic status and treating livestock with insecticide as risk factors for VL. Sleeping near animals, owning a mosquito net and knowing about VL symptoms were associated with a reduced risk of VL. CONCLUSIONS: VL affects the poorest of the poor of the Pokot tribe. Distribution of insecticide-treated mosquito nets combined with dissemination of culturally appropriate behaviour-change education is likely to be an effective prevention strategy

Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis

Background: Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood. Methodology/Principal Findings: The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, ,40% of the ,2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three ,90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors. Conclusions/Significance: The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance

Generalized Weierstrass Relations and Frobenius reciprocity

This article investigates local properties of the further generalized Weierstrass relations for a spin manifold $S$ immersed in a higher dimensional spin manifold $M$ from viewpoint of study of submanifold quantum mechanics. We show that kernel of a certain Dirac operator defined over $S$, which we call submanifold Dirac operator, gives the data of the immersion. In the derivation, the simple Frobenius reciprocity of Clifford algebras $S$ and $M$ plays important roles.Comment: 17pages. to be published in Mathematical Physics, Analysis and Geometr

Ginnerup Revisited. New Excavations at a Key Neolithic Site on Djursland, Denmark

New excavations of an enclosure-related site at Ginnerup on Djursland, Denmark, in 2020 resulted in the identification of several features containing depositions of marine shells. One of these, A4, is a natural depression with a fill comprised of four consecutively deposited layers, forming an undisturbed stratigraphy, dated by several 14C dates to between c. 3150 and 2950 BC. The oldest layer contained finds from phase MN A Ib of the Funnel Beaker culture, while the remaining three layers yielded finds from the latest Funnel Beaker culture on Djursland (MN A II/III, Ferslev style) with an upwardly increasing content of Pitted Ware culture elements, thereby allowing the emergence of this culture in Denmark to be followed for the first time. Preservation conditions for organic material were excellent due to a content of marine shells, mainly from oysters and mussels, in all layers. In this preliminary account, a survey of the material culture in the four layers is presented, together with 14C dates, zoological investigations of mammal and fish bones, isotope analyses (d13C, d15N and d34S) and aDNA analyses of mammal bones and examinations of plant macro-remains. The abundant bones of wild horses also hold a huge potential for zoological and genetic studies, the results of which can qualify the ongoing debate about the rewilding of horses in present-day Europe

Cell-penetrating peptides as transporters for morpholino oligomers: effects of amino acid composition on intracellular delivery and cytotoxicity

Arginine-rich cell-penetrating peptides (CPPs) are promising transporters for intracellular delivery of antisense morpholino oligomers (PMO). Here, we determined the effect of L-arginine, D-arginine and non-α amino acids on cellular uptake, splice-correction activity, cellular toxicity and serum binding for 24 CPP−PMOs. Insertion of 6-aminohexanoic acid (X) or β-alanine (B) residues into oligoarginine R8 decreased the cellular uptake but increased the splice-correction activity of the resulting compound, with a greater increase for the sequences containing more X residues. Cellular toxicity was not observed for any of the conjugates up to 10 μM. Up to 60 μM, only the conjugates with ⩾ 5 Xs exhibited time- and concentration-dependent toxicity. Substitution of L-arginine with D-arginine did not increase uptake or splice-correction activity. High concentration of serum significantly decreased the uptake and splice-correction activity of oligoarginine conjugates, but had much less effect on the conjugates containing X or B. In summary, incorporation of X/B into oligoarginine enhanced the antisense activity and serum-binding profile of CPP−PMO. Toxicity of X/B-containing conjugates was affected by the number of Xs, treatment time and concentration. More active, stable and less toxic CPPs can be designed by optimizing the position and number of R, D-R, X and B residues