Phylogenetic studies reveal existence of multiple lineages of a single genotype of DENV-1 (genotype III) in India during 1956–2007

<p>Abstract</p> <p>Background</p> <p>Dengue virus type 1 (DENV-1) have been mostly circulating silently with dominant serotypes DENV-2 and DENV-3 in India. However recent times have marked an increase in DENV-1 circulation in yearly outbreaks. Many studies have not been carried out on this virus type, leaving a lacunae pertaining to the circulating genotypes, since its earliest report in India. In the present study, we sequenced CprM gene junction of 13 DENV-1 isolated from Delhi and Gwalior (North India) between 2001–2007 and one 1956 Vellore isolate as reference. For comparison, we retrieved 11 other Indian and 70 global reference sequences from NCBI database, making sure that Indian and global isolates from all decades are available for comparative analysis.</p> <p>Results</p> <p>The region was found to be AT rich with no insertion or deletion. Majority of the nucleotide substitutions were silent, except 3 non-conservative amino acid changes (I → T, A → T and L → S at amino acid positions 59,114 and 155 respectively) in the Indian DENV-1 sequences, sequenced in this study. Except two 1997–98 Delhi isolates, which group in genotype I; all other Indian isolates group in genotype III. All Indian genotype III DENV-1 exhibited diversity among them, giving rise to at least 4 distinct lineages (India 1–4) showing proximity to isolates from diverse geographic locations.</p> <p>Conclusion</p> <p>The extensive phylogenetic analysis revealed consistent existence of multiple lineages of DENV-1 genotype III during the last 5 decades in India.</p

The role of potential vorticity anomalies in the Somali Jet on Indian summer monsoon intraseasonal variability

The climate of the Indian subcontinent is dominated by rainfall arising from the Indian summer monsoon (ISM) during the summer season (June to September). Intraseasonal variability during the monsoon is characterized by periods of heavy rainfall interspersed by drier periods, known as active and break events respectively. Understanding and predicting such events is of vital importance for forecasting human impacts such as water resources. The Somali Jet is a key regional feature of this circulation. In the present study, we find that the spatial structure of Somali Jet potential vorticity (PV) anomalies varies considerably during active and break periods. Analysis of these anomalies shows a mechanism whereby sea surface temperature (SST) anomalies propagate north/northwestwards through the Arabian Sea, caused by a positive feedback loop joining anomalies in SST, convection, modification of PV by diabatic heating and mixing in the atmospheric boundary layer, wind stress curl, and upwelling processes. The feedback mechanism is consistent with observed coupled ocean-atmosphere system variability timescales of approximately 20 days. This research suggests that better understanding and prediction of monsoon subseasonal variability in the South Asian monsoon may be gained by analysis of the day-to-day dynamical evolution of PV in the Somali Jet

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date

Crystal, Solution and In silico Structural Studies of Dihydrodipicolinate Synthase from the Common Grapevine

Dihydrodipicolinate synthase (DHDPS) catalyzes the rate limiting step in lysine biosynthesis in bacteria and plants. The structure of DHDPS has been determined from several bacterial species and shown in most cases to form a homotetramer or dimer of dimers. However, only one plant DHDPS structure has been determined to date from the wild tobacco species, Nicotiana sylvestris (Blickling et al. (1997) J. Mol. Biol. 274, 608–621). Whilst N. sylvestris DHDPS also forms a homotetramer, the plant enzyme adopts a ‘back-to-back’ dimer of dimers compared to the ‘head-to-head’ architecture observed for bacterial DHDPS tetramers. This raises the question of whether the alternative quaternary architecture observed for N. sylvestris DHDPS is common to all plant DHDPS enzymes. Here, we describe the structure of DHDPS from the grapevine plant, Vitis vinifera, and show using analytical ultracentrifugation, small-angle X-ray scattering and X-ray crystallography that V. vinifera DHDPS forms a ‘back-to-back’ homotetramer, consistent with N. sylvestris DHDPS. This study is the first to demonstrate using both crystal and solution state measurements that DHDPS from the grapevine plant adopts an alternative tetrameric architecture to the bacterial form, which is important for optimizing protein dynamics as suggested by molecular dynamics simulations reported in this study

Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase Inhibitors

Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(epsilon)-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(epsilon)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors

Consequences of the Expanding Global Distribution of Aedes albopictus for Dengue Virus Transmission

The dramatic global expansion of Aedes albopictus in the last three decades has increased public health concern because it is a potential vector of numerous arthropod-borne viruses (arboviruses), including the most prevalent arboviral pathogen of humans, dengue virus (DENV). Ae. aegypti is considered the primary DENV vector and has repeatedly been incriminated as a driving force in dengue's worldwide emergence. What remains unresolved is the extent to which Ae. albopictus contributes to DENV transmission and whether an improved understanding of its vector status would enhance dengue surveillance and prevention. To assess the relative public health importance of Ae. albopictus for dengue, we carried out two complementary analyses. We reviewed its role in past dengue epidemics and compared its DENV vector competence with that of Ae. aegypti. Observations from “natural experiments” indicate that, despite seemingly favorable conditions, places where Ae. albopictus predominates over Ae. aegypti have never experienced a typical explosive dengue epidemic with severe cases of the disease. Results from a meta-analysis of experimental laboratory studies reveal that although Ae. albopictus is overall more susceptible to DENV midgut infection, rates of virus dissemination from the midgut to other tissues are significantly lower in Ae. albopictus than in Ae. aegypti. For both indices of vector competence, a few generations of mosquito colonization appear to result in a relative increase of Ae. albopictus susceptibility, which may have been a confounding factor in the literature. Our results lead to the conclusion that Ae. albopictus plays a relatively minor role compared to Ae. aegypti in DENV transmission, at least in part due to differences in host preferences and reduced vector competence. Recent examples of rapid arboviral adaptation to alternative mosquito vectors, however, call for cautious extrapolation of our conclusion. Vector status is a dynamic process that in the future could change in epidemiologically important ways

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Towards understanding the traits contributing to performance of pearl millet open-pollinated varieties in phosphorus-limited environments of West Africa

Aims Pearl millet [Pennisetum glaucum (L.) R. Br.] open-pollinated varieties, which are the predominant cultivars, have never been systematically evaluated for adaptation to low-soil phosphorus (P), a major constraint on pearl millet production in West Africa (WA). Methods We evaluated grain yield (GY), flowering time (FLO), harvest index (HI), and residual grain yields (RGY) of 102 open-pollinated varieties from WA under low-P (−P) and high-P (+P) field conditions in six environments of WA. In addition, PE-related traits of the varieties were evaluated at early growth stage in a pot experiment. Results Significant genetic variation was observed for GY, FLO, HI and PE-related traits. P-efficient varieties had higher yield under −P conditions. Varietal performance under −P varied across environments depending on FLO, relative flowering delay under −P (FD) and RGY measured in the field. Low-P-susceptible varieties had higher FLO, lower HI than low-P-tolerant varieties. Response to direct selection under −P field conditions was 20.1 g m−2, whereas indirect selection response under +P was 16.3 g m−2. Conclusions Selection under −P field conditions while taking into account seasonal variations for FLO, FD and PE is expected to be important for improving GY specifically targeting −P environments in WA