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Context: Surgical site infections are frequently observed despite the availability of national guideline on surgical antimicrobial prophylaxis (SAP). These infections increase patient morbidity, mortality, and direct and indirect health-care costs. Open reduction internal fixation (ORIF) is a common orthopedic surgery for fracture. There is a paucity of Indian data on SAP in ORIF surgery. Aims: The present study was taken up aiming at the evaluation of appropriateness and pharmacoeconomics of SAP in ORIF based on the national guidelines. Subjects and Methods: One-year observational prospective cohort study was conducted among 412 participants, who underwent ORIF in the Department of Orthopedics in a Tertiary Care Hospital. Name, dose, route, timing, frequency, and duration of administration of prophylactic antimicrobials used were recorded. Statistical Analysis Used: Descriptive statistics were used wherever required. Results: The mean age of participants was 39.24 years, majority (60.92%) were male, and 49.52% had fracture of lower-limb bones. The appropriateness of preoperative SAP in terms of indication in ORIF, timing, and route of administration was 100%. Selection and dose of preoperative and postoperative antimicrobials were appropriate in only 13% of cases. Omission of intraoperative dose was appropriate in all participants. Duration of postoperative Antimicrobial agent administration was inappropriately long in all participants. None of the cases received completely appropriate regimen. Cost analysis showed the mean cost of SAP practiced in our hospital was eleven times higher than that with recommended SAP. Conclusions: Considering the inappropriateness of SAP practiced, monitoring of guideline implementation and awareness among health-care professionals are necessary to prevent SSI and to decrease economic burden on the patients.

Colorectal cancer (CRC) is the second-leading cause of cancer death in developed countries. While early detection (e.g., colonoscopy) generally yields excellent outcomes, metastatic and drug-resistant disease is uniformly fatal, and non-compliance for screening remains over 25%. Familial CRCs (10% of total cases) primarily include mutations in the gene APC. Somatic disease is linked to several environmental several risk factors, including mutations in WNT, KRAS, and TGFβ. To reflect the genesis/progression of CRC, a series of five discrete stages, from normal colon mucosa to fully invasive carcinoma, each regulated by specific “gatekeeper” genes, remains well-accepted after 20 years. However, many CRC tumors do not possess those particular mutations, suggesting alternative mechanisms. More recently, embryo-like “cancer stem cells” have been proposed to undergo self-renewal and drive tumorigenesis (and possibly, metastasis), as governed by specific “epigenomic” alterations. Here, we review recent literature describing possible mechanisms that underlie these phenotypes, including cancer “stemness,” believed by many to associate with the epithelial-to-mesenchymal transition (EMT). We further propose that the maintenance of undifferentiated phenotypes, by the activity of distinct transcription factors, facilitates chromatin remodeling and phenotypic plasticity. With that regard, we support recent assertions that EMT is not an “either/or” event, but rather a continuous spectrum of mesenchymal vs. epithelial phenotypes (in various degrees of aberrant differentiation/undifferentiation). Finally, we discuss possible methods of pharmacologically targeting such aberrant epigenomes, with regard to their possible relevance toward halting, or even reversing, colorectal cancer progression.

Genomes of most organisms on earth are written in a universal language of life, made up of four units – adenine (A), thymine (T), guanine (G), and cytosine (C), and understanding the way they are put together has been a great challenge to date. Multiple efforts have been made to annotate this wonderfully engineered string of DNA using different methods but they lack a universal character. In this article, we have investigated the structural and energetic profiles of both prokaryotes and eukaryotes by considering two essential genomic sites, viz., the transcription start sites (TSS) and exon–intron boundaries. We have characterized these sites by mapping the structural and energy features of DNA obtained from molecular dynamics simulations, which considers all possible trinucleotide and tetranucleotide steps. For DNA, these physicochemical properties show distinct signatures at the TSS and intron–exon boundaries. Our results firmly convey the idea that DNA uses the same dialect for prokaryotes and eukaryotes and that it is worth going beyond sequence-level analyses to physicochemical space to determine the functional destiny of DNA sequences. [ABSTRACT FROM AUTHOR]

Background: Currently approved oral antivirals for chronic HBV infection target the reverse transcriptase (RT) domain of the HBV polymerase. Emergence of drug resistance has been reported in a small proportion of chronic HBV patients on prolonged treatment with antivirals. We recently reported ZINC20451377, a small molecule targeting hepatitis B surface antigen (HBsAg) that effectively inhibits both WT HBV and tenofovir-resistant HBV. Due to the partial overlap between the RT domain and HBsAg, drug-resistant mutants are associated with corresponding mutations in HBsAg.Objectives: To evaluate the efficacy of ZINC20451377 against nine clinically relevant drug-resistant HBV mutants that lead to simultaneous mutations in the overlapping HBsAg gene.Methods: Huh7 cells were transfected with 1.2× HBV replicons corresponding to WT HBV or drug-resistant HBV mutants and treated with different concentrations of ZINC20451377. We assessed the IC50 values of ZINC20451377 for HBsAg levels in the culture supernatants using ELISAs. HBV secretion was measured by immunocapture of secreted virions followed by real-time PCR quantitation of virion-associated DNA.Results: ZINC20451377 led to a dose-dependent inhibition of secreted HBsAg encoded by WT HBV and all nine drug-resistant mutants tested and the IC50 values were in the low micromolar range. ZINC20451377 inhibited HBV secretion from drug-resistant mutants except for mutants harbouring the rtL180M + rtM204V (MV) mutation.Conclusions: The small molecule ZINC20451377 inhibits HBsAg and virion secretion in some of the clinically relevant drug-resistant HBV mutants. ZINC20451377 has a modest overall effect, and it was not effective against the MV mutants (lamivudine- and entecavir-resistant mutants). [ABSTRACT FROM AUTHOR]

Abstract Background Computational methods utilizing the structural and functional information help to understand specific molecular recognition events between the target biomolecule and candidate hits and make it possible to design improved lead molecules for the target. Results Sanjeevini represents a massive on-going scientific endeavor to provide to the user, a freely accessible state of the art software suite for protein and DNA targeted lead molecule discovery. It builds in several features, including automated detection of active sites, scanning against a million compound library for identifying hit molecules, all atom based docking and scoring and various other utilities to design molecules with desired affinity and specificity against biomolecular targets. Each of the modules is thoroughly validated on a large dataset of protein/DNA drug targets. Conclusions The article presents Sanjeevini, a freely accessible user friendly web-server, to aid in drug discovery. It is implemented on a tera flop cluster and made accessible via a web-interface at http://www.scfbio-iitd.res.in/sanjeevini/sanjeevini.jsp. A brief description of various modules, their scientific basis, validation, and how to use the server to develop in silico suggestions of lead molecules is provided.

Abstract Background Protein-protein interactions are important for several cellular processes. Understanding the mechanism of protein-protein recognition and predicting the binding sites in protein-protein complexes are long standing goals in molecular and computational biology. Methods We have developed an energy based approach for identifying the binding site residues in protein–protein complexes. The binding site residues have been analyzed with sequence and structure based parameters such as binding propensity, neighboring residues in the vicinity of binding sites, conservation score and conformational switching. Results We observed that the binding propensities of amino acid residues are specific for protein-protein complexes. Further, typical dipeptides and tripeptides showed high preference for binding, which is unique to protein-protein complexes. Most of the binding site residues are highly conserved among homologous sequences. Our analysis showed that 7% of residues changed their conformations upon protein-protein complex formation and it is 9.2% and 6.6% in the binding and non-binding sites, respectively. Specifically, the residues Glu, Lys, Leu and Ser changed their conformation from coil to helix/strand and from helix to coil/strand. Leu, Ser, Thr and Val prefer to change their conformation from strand to coil/helix. Conclusions The results obtained in this study will be helpful for understanding and predicting the binding sites in protein-protein complexes.

Human serum albumin (HSA) acts as a carrier for testosterone, other sex hormones, fatty acids, and drugs. However, the dynamics of testosterone's binding to HSA and the structure of its binding sites remain incompletely understood. Here, we characterize the dynamics of testosterone's binding to HSA and the stoichiometry and structural location of the binding sites using 2-dimensional nuclear magnetic resonance (2D NMR), fluorescence spectroscopy, 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt partitioning, and equilibrium dialysis, complemented by molecular modeling. 2D NMR studies showed that testosterone competitively displaced 18-[13C]-oleic acid from at least 3 known fatty acid binding sites on HSA that also bind many drugs. Binding isotherms of testosterone's binding to HSA generated using fluorescence spectroscopy and equilibrium dialysis were nonlinear and the apparent dissociation constant varied with different concentrations of testosterone and HSA. The binding isotherms neither conformed to a linear binding model with 1:1 stoichiometry nor to 2 independent binding sites; the binding isotherms were most consistent with 2 or more allosterically coupled binding sites. Molecular dynamics studies revealed that testosterone's binding to fatty acid binding site 3 on HSA was associated with conformational changes at site 6, indicating that residues in in these 2 distinct binding sites are allosterically coupled. There are multiple, allosterically coupled binding sites for testosterone on HSA. Testosterone shares these binding sites on HSA with free fatty acids, which could displace testosterone from HSA under various physiological states or disease conditions, affecting its bioavailability. [ABSTRACT FROM AUTHOR]

Motivation Despite conservation in general architecture of promoters and protein–DNA interaction interface of RNA polymerases among various prokaryotes, identification of promoter regions in the whole genome sequences remains a daunting challenge. The available tools for promoter prediction do not seem to address the problem satisfactorily, apparently because the biochemical nature of promoter signals is yet to be understood fully. Using 28 structural and 3 energetic parameters, we found that prokaryotic promoter regions have a unique structural and energy state, quite distinct from that of coding regions and the information for this signature state is in-built in their sequences. We developed a novel promoter prediction tool from these 31 parameters using various statistical techniques. Results Here, we introduce SEProm, a novel tool that is developed by studying and utilizing the in-built structural and energy information of DNA sequences, which is applicable to all prokaryotes including archaea. Compared to five most recent, diverged and current best available tools, SEProm performs much better, predicting promoters with an ' F -value' of 82.04 and 'Precision' of 81.08. The next best ' F -value' was obtained with PromPredict (72.14) followed by BProm (68.37). On the basis of 'Precision' value, the next best 'Precision' was observed for Pepper (75.39) followed by PromPredict (72.01). SEProm maintained the lead even when comparison was done on two test organisms (not involved in training for SEProm). Availability and implementation The software is freely available with easy to follow instructions (www.scfbio-iitd.res.in/software/TSS%5fPredict.jsp). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Despite Plasmodium vivax being the main offender in the majority of malarial infections, very little information is available about its adaptation and development in humans. Its capability for activating relapsing infections through its dormant liver stage and resistance to antimalarial drugs makes it as one of the major challenges in eradicating malaria. Noting the immediate necessity for the availability of a comprehensive and reliable structural and functional repository for P. vivax proteome, here we developed a web resource for the new reference genome, PvP01, furnishing information on sequence, structure, functions, active sites and metabolic pathways compiled and predicted using some of the state-of-the-art methods in respective fields. The PvP01 web resource comprises organized data on the soluble proteome consisting of 3664 proteins in blood and liver stages of malarial cycle. The current public resources represent only 163 proteins of soluble proteome of PvP01, with complete information about their molecular function, biological process and cellular components. Also, only 46 proteins of P. vivax have experimentally determined structures. In this milieu of extreme scarcity of structural and functional information, PvP01 web resource offers meticulously validated structures of 3664 soluble proteins. The sequence and structure-based functional characterization led to a quantum leap from 163 proteins available presently to whole soluble proteome offered through PvP01 web resource. We believe PvP01 web resource will serve the researchers in identifying novel protein drug targets and in accelerating the development of structure-based new drug candidates to combat malaria. Database Availability: http://www.scfbio-iitd.res.in/PvP01 [ABSTRACT FROM AUTHOR]