NCACO-score: An effective main-chain dependent scoring function for structure modeling

<p>Abstract</p> <p>Background</p> <p>Development of effective scoring functions is a critical component to the success of protein structure modeling. Previously, many efforts have been dedicated to the development of scoring functions. Despite these efforts, development of an effective scoring function that can achieve both good accuracy and fast speed still presents a grand challenge.</p> <p>Results</p> <p>Based on a coarse-grained representation of a protein structure by using only four main-chain atoms: N, Cα, C and O, we develop a knowledge-based scoring function, called NCACO-score, that integrates different structural information to rapidly model protein structure from sequence. In testing on the Decoys'R'Us sets, we found that NCACO-score can effectively recognize native conformers from their decoys. Furthermore, we demonstrate that NCACO-score can effectively guide fragment assembly for protein structure prediction, which has achieved a good performance in building the structure models for hard targets from CASP8 in terms of both accuracy and speed.</p> <p>Conclusions</p> <p>Although NCACO-score is developed based on a coarse-grained model, it is able to discriminate native conformers from decoy conformers with high accuracy. NCACO is a very effective scoring function for structure modeling.</p

Effects of biochar and arbuscular mycorrhizal fungi on winter wheat growth and soil N2O emissions in different phosphorus environments

IntroductionPromoting crop growth and regulating denitrification process are two main ways to reduce soil N2O emissions in agricultural systems. However, how biochar and arbuscular mycorrhizal fungi (AMF) can regulate crop growth and denitrification in soils with different phosphorus (P) supplies to influence N2O emission remains largely unknown.MethodHere, an eight-week greenhouse and one-year field experiments biochar and/or AMF (only in greenhouse experiment) additions under low and high P environments were conducted to characterize the effects on wheat (Triticum aestivum L.) growth and N2O emission.ResultsWith low P supply, AMF addition decreased leaf Mn concentration (indicates carboxylate-releasing P-acquisition strategies), whereas biochar addition increased leaf Mn concentration, suggesting biochar and AMF addition regulated root morphological and physiological traits to capture P. Compared with low P supply, the high P significantly promoted wheat growth (by 16-34%), nutrient content (by 33-218%) and yield (by 33-41%), but suppressed soil N2O emissions (by 32-95%). Biochar and/or AMF addition exhibited either no or negative effects on wheat biomass and nutrient content in greenhouse, and biochar addition promoted wheat yield only under high P environment in field. However, biochar and/or AMF addition decreased soil N2O emissions by 24-93% and 32% in greenhouse and field experiments, respectively. This decrease was associated mainly with the diminished abundance of N2O-producing denitrifiers (nirK and nirS types, by 17-59%, respectively) and the increased abundance of N2O-consuming denitrifiers (nosZ type, by 35-65%), and also with the increased wheat nutrient content, yield and leaf Mn concentration.DiscussionThese findings suggest that strengthening the plant-soil-microbe interactions can mitigate soil N2O emissions via manipulating plant nutrient acquisition and soil denitrification

Rapid Estimation of Binding Activity of Influenza Virus Hemagglutinin to Human and Avian Receptors

A critical step for avian influenza viruses to infect human hosts and cause epidemics or pandemics is acquisition of the ability of the viral hemagglutinin (HA) to bind to human receptors. However, current global influenza surveillance does not monitor HA binding specificity due to a lack of rapid and reliable assays. Here we report a computational method that uses an effective scoring function to quantify HA-receptor binding activities with high accuracy and speed. Application of this method reveals receptor specificity changes and its temporal relationship with antigenicity changes during the evolution of human H3N2 viruses. The method predicts that two amino acid differences at 222 and 225 between HAs of A/Fujian/411/02 and A/Panama/2007/99 viruses account for their differences in binding to both avian and human receptors; this prediction was verified experimentally. The new computational method could provide an urgently needed tool for rapid and large-scale analysis of HA receptor specificities for global influenza surveillance.National Key Project (2008ZX10004-013)National Institutes of Health (U.S.) (grant AI07443)Singapore-MIT Alliance for Research and TechnologyMassachusetts Institute of Technology. International Science and Technology Initiatives Global Seed FundNational Basic Research Program (973 Program) (2009CB918503)National Basic Research Program (973 Program) (2006CB911002

Synuclein gamma predicts poor clinical outcome in colon cancer with normal levels of carcinoembryonic antigen

<p>Abstract</p> <p>Background</p> <p>Synuclein gamma (SNCG), initially identified as a breast cancer specific gene, is aberrantly expressed in many different malignant tumors but rarely expressed in matched nonneoplastic adjacent tissues. In this study, we investigated the prognostic potential of SNCG in colon cancer particularly in the patients with normal carcinoembryonic antigen (CEA) levels.</p> <p>Methods</p> <p>SNCG levels were assessed immunohistochemically in cancer tissues from 229 colon adenocarcinoma patients with a mean follow-up of 44 months. Correlations between SNCG levels and clinicopathologic features, preoperative serum CEA level, and clinical outcome were analyzed statistically using SPSS.</p> <p>Results</p> <p>SNCG levels in colon adenocarcinoma were closely associated with intravascular embolus and tumor recurrence but independent of preoperative serum CEA levels. SNCG expression was an independent prognostic factor of a shorter disease-free survival (DFS) and overall survival (OS) (<it>P </it>< 0.0001). Multivariate analysis revealed that both tissue SNCG and serum CEA were independent prognostic factors of DFS (<it>P </it>= 0.001, <0.0001, respectively) for 170 patients with colon adenocarcinomas. Importantly, SNCG remained a prognostic determinant of DFS and OS (<it>P </it>= 0.001, 0.002) for 97 patients with normal preoperative serum CEA level.</p> <p>Conclusions</p> <p>Our results suggest for the first time that SNCG is a new independent predicator for poor prognosis in patients with colon adenocarcinoma, including those with normal CEA levels. Combination of CEA with SNCG improves prognostic evaluation for patients with colon adenocarcinoma.</p

Crystal structures from the Plasmodium peroxiredoxins: new insights into oligomerization and product binding

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>is the protozoan parasite primarily responsible for more than one million malarial deaths, annually, and is developing resistance to current therapies. Throughout its lifespan, the parasite is subjected to oxidative attack, so <it>Plasmodium </it>antioxidant defences are essential for its survival and are targets for disease control.</p> <p>Results</p> <p>To further understand the molecular aspects of the <it>Plasmodium </it>redox system, we solved 4 structures of <it>Plasmodium </it>peroxiredoxins (Prx). Our study has confirmed <it>Pv</it>Trx-Px1 to be a hydrogen peroxide (H₂O₂)-sensitive peroxiredoxin. We have identified and characterized the novel toroid octameric oligomer of <it>Py</it>Trx-Px1, which may be attributed to the interplay of several factors including: (1) the orientation of the conserved surface/buried arginine of the NNLA(I/L)GRS-loop; and (2) the <it>C</it>-terminal tail positioning (also associated with the aforementioned conserved loop) which facilitates the intermolecular hydrogen bond between dimers (in an A-C fashion). In addition, a notable feature of the disulfide bonds in some of the Prx crystal structures is discussed. Finally, insight into the latter stages of the peroxiredoxin reaction coordinate is gained. Our structure of <it>Py</it>Prx6 is not only in the sulfinic acid (RSO₂H) form, but it is also with glycerol bound in a way (not previously observed) indicative of product binding.</p> <p>Conclusions</p> <p>The structural characterization of <it>Plasmodium </it>peroxiredoxins provided herein provides insight into their oligomerization and product binding which may facilitate the targeting of these antioxidant defences. Although the structural basis for the octameric oligomerization is further understood, the results yield more questions about the biological implications of the peroxiredoxin oligomerization, as multiple toroid configurations are now known. The crystal structure depicting the product bound active site gives insight into the overoxidation of the active site and allows further characterization of the leaving group chemistry.</p

Immune-checkpoint protein VISTA in allergic, autoimmune disease and transplant rejection

Negative checkpoint regulators (NCRs) reduce the T cell immune response against self-antigens and limit autoimmune disease development. V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint in the B7 family, has recently been identified as one of the NCRs. VISTA maintains T cell quiescence and peripheral tolerance. VISTA targeting has shown promising results in treating immune-related diseases, including cancer and autoimmune disease. In this review, we summarize and discuss the immunomodulatory role of VISTA, its therapeutic potential in allergic, autoimmune disease, and transplant rejection, as well as the current therapeutic antibodies, to present a new method for regulating immune responses and achieving durable tolerance for the treatment of autoimmune disease and transplantation

Methylation levels at IGF2 and GNAS DMRs in infants born to preeclamptic pregnancies

BACKGROUND: Offspring of pregnancy complicated with preeclampsia are at high risk for hypertension, stroke and possibly obesity. The mechanisms behind the association of intrauterine exposure to preeclampsia and high risk of health problems in the later life remain largely unknown. The aims of the current investigation were to determine the changes in DNA methylation at IGF2 and GNAS DMR in offspring of preeclamptic pregnancy and to explore the possible mechanisms underlying the association between maternal preeclampsia and high risk for health problems in the later life of their offspring. RESULTS: Umbilical cord blood was taken from infants born to women of preeclampsia (n=56), gestational hypertension (n=23) and normal pregnancy (n=81). DNA methylation levels of IGF2 and GNAS DMR were determined by Massarray quantitative methylation analysis. Methylation levels at IGF2 DMR were significantly lower in preeclampsia than normal pregnancy. The average methylation level at IGF2 DMR was significantly correlated with preeclampsia even after birth weight, maternal age, gestational age at delivery and fetal gender were adjusted. The difference in methylation level was not significantly different between mild and severe preeclampsia. The methylation level at GNAS DMR was not significantly correlated with birth weight, maternal age, gestational age at delivery, fetal gender, preeclampsia or gestational hypertension. CONCLUSIONS: We concluded preeclampsia induced a decrease in methylation level at IGF 2 DMR, and this might be among the mechanisms behind the association between intrauterine exposure to preeclampsia and high risk for metabolic diseases in the later life of the infants

Riboneogenesis in Yeast

SummaryGlucose is catabolized in yeast via two fundamental routes, glycolysis and the oxidative pentose phosphate pathway, which produces NADPH and the essential nucleotide component ribose-5-phosphate. Here, we describe riboneogenesis, a thermodynamically driven pathway that converts glycolytic intermediates into ribose-5-phosphate without production of NADPH. Riboneogenesis begins with synthesis, by the combined action of transketolase and aldolase, of the seven-carbon bisphosphorylated sugar sedoheptulose-1,7-bisphosphate. In the pathway's committed step, sedoheptulose bisphosphate is hydrolyzed to sedoheptulose-7-phosphate by the enzyme sedoheptulose-1,7-bisphosphatase (SHB17), whose activity we identified based on metabolomic analysis of the corresponding knockout strain. The crystal structure of Shb17 in complex with sedoheptulose-1,7-bisphosphate reveals that the substrate binds in the closed furan form in the active site. Sedoheptulose-7-phosphate is ultimately converted by known enzymes of the nonoxidative pentose phosphate pathway to ribose-5-phosphate. Flux through SHB17 increases when ribose demand is high relative to demand for NADPH, including during ribosome biogenesis in metabolically synchronized yeast cells