Virtual Screening of Drugs against HIV-1 Protease

The life-threatening infections and pandemic spread of Human Immunodeficiency virus-1 (HIV-1), the etiologic agent of AIDS, has promoted an unending scientific effort to understand and control the disease. The resultant understanding of HIV-1 life cycle has defined many different targets for potential drug intervention. HIV protease enzyme responsible for cleaving large polyprotein precursors into biologically active protein products is an important target for the treatment of AIDS. However drug resistance is a persistent problem and new protease inhibitors are needed. Tipranavir, one of the protease inhibitors most recently approved for clinical use has been shown to be potent against viruses harbouring multidrug resistance mutations such as V82A and L90M, but even this drug is shown to lose potency due to certain mutations or mutation patterns. Thus 10 derivatives of the drug Tipranavir, chemically diverse from the initial hit were generated and screened to determine their ability to interact with protease. Further analysis revealed one unique compound with high binding ability from the initial hit and its possibility for new class of protease inhibitors is discussed in this report

The Bombay duck

Bombay duck fishery showed declining trend in the earlier half of the seventies, picked up considerably in the latter half and reached the maximum in 1978 and 1979. However, it is seen that in 1979 the average sizes of the fishes landed at the centres of observation in Maharashtra and Gujarat, the two important states contributing to the major part of the Bombay duck fishery of the country, differed considerably. This would perhaps indicate that the fishery of these two states is supported by two independent stocks. Detailed studies for delimitation of stocks, both statistical and serological are necessary to establish the identity of stock

A STUDY ON ANTIMICROBIAL SENSITIVITY AND COST ANALYSIS OF ANTIBIOTICS IN PEDIATRIC UNIT AT A TERTIARY CARE HOSPITAL.

 Objectives: (1) To determine the antimicrobial susceptibility pattern in pediatrics, (2) to identify the pattern of empirical antibiotic usage, (3) to determine the cost analysis of generic antibiotic usage pattern, (4) to assess the different dosage forms of antibiotics.Methods: A retrospective observational study was carried out. The study population included the medical records of children aged day 1–15 years with bacterial infection who got admitted in the pediatric department of the hospital. The average cost for each generic dosage form of antibiotic was calculated.Result: Among the 176 cases taken for the study, sepsis (35.8%) was found to be the most common disease. Bacterial infection showed gender predominance in males (62.5%) and occurrence of sepsis was highly found in age groups of 0–1 years (55.68%). Among the 14 causative organisms, methicillin-resistant coagulase negative staphylococci (61.93%) was predominant in Gram-positive and Escherichia coli (38.06%) for Gram-negative. Highly prescribed drug for empirical therapy was considered to be amikacin (39.20%). Widely prescribed antibiotics were amikacin (21%), ceftriaxone (15.1%), ampicillin (12.34%) and meropenem (9.57%), among which meropenem was found to be of high cost.Conclusion: It should be taken care that the drug should be given not only based on the sensitivity pattern but can also consider the economic affordability of the patient, with reference to existing brands from the formulary. This would help in reducing the burden of health-care cost for the patients

Wastewater re-use for peri-urban agriculture: a viable option for adaptive water management?

Urbanization is known to spur land modification in the form of conversion of common land to human settlements. This factor, combined with climate variability, can alter the duration, frequency and intensity of storm drain overflows in urban areas and lead to public health risks. In peri-urban regions where these risks are especially high it has been argued that, when domestic wastewater is managed, better prospects for freshwater water savings through swaps between urban water supply and irrigated agriculture may be possible. As a consequence of re-use of domestic wastewater, expenditure on inorganic inputs by farmers may decline and source sustainability of water supply could be enhanced. Given the fact that, at present, approximately 20 million ha of land worldwide is being cultivated by re-using domestic wastewater, this paper draws on evidence from India to explore: (1) the economic costs-benefits of wastewater reuse in the context of hypothesized links to climate variability; (2) the role of local farming practices, market conditions and crop variety in influencing wastewater reuse in agriculture; and (3) the role of inter-governmental financing in influencing the selection of technical adaptation options for collection, treatment and disposal of wastewater.ASC – Publicaties niet-programma gebonde

Studies on Composite Extrudable Propellant with varied Burning Rate Pressure Index 'n'

This paper discusses the development of composite propellantextrusion technique and the study of burning rate pressure indices nwith respect to compositional variations. The n is found to vary from0.35 to plateau and plateau to mesa by suitable compositionalmodifications. Compositional influence on burning rate with specificreference to plateau and mesaburning additives is described. Detailsof the process parameters like fluidity of the slurry, extrusion pressure,extrusion rate and die-swell are presented. This propellant is based onISRO-CTPB binder using ISRO-AP as oxidizer. Ammonium perchlorate (AP) particle size variation and inclusion of additives likePVC, lead stearate, ammonium sulphate, lithium fluoride etc. are foundto influence the burning rate pressure index n

HPLC-LIF for early detection of oral cancer

At present, the diagnosis of many cancers relies on the subjective interpretation of morphological changes in biopsy samples. This usually provides only late diagnosis. Early detection, which can provide more successful therapy, is expected to be possible by identification of tumour markers in physiological samples. Immunoassay used at present for this purpose has several drawbacks. It is applicable only for known markers, can usually detect only one marker at a time, and may also fail to detect a marker when there exist conditions, which may mask or prevent the interaction between antigen and the antibody. We have developed a high performance liquid chromatography- laser induced fluorescence (HPLC-LIF) technique to detect and record simultaneously spectra and chromatograms of physiological samples, which will enable the detection of multiple 'markers' in a single physiological sample in a short time. Samples of saliva and serum from normal and oral cancer subjects have been studied with the set up. The present studies show that body fluids like saliva and serum of normal, premalignant and malignant subjects have substantially different protein profiles. By simultaneous recording of the chromatographic peaks and corresponding fluorescence spectra, it is possible to carry out unambiguous discrimination between normal, premalignant and malignant cases even when markers are present in femto/subfemtomole quantities, which should assist in early diagnosis of neoplasia

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Prevalence and determinants of substance use among indigenous tribes in South India: Findings from a tribal household survey

Background: Indigenous populations have higher substance use than non-indigenous populations. Current evidence on indigenous substance use is largely derived from national household surveys, while there are no specifically designed, culturally specific methodological studies available to determine the prevalence of substance abuse among the indigenous tribes. The present study examined the prevalence and predictors of alcohol use, smoking, and betel quid chewing among indigenous tribes in South India. Method: We conducted a cross-sectional population-based random survey of 2186 tribal households in the Wayanad District, Kerala. A self-prepared, pilot-tested structured interview schedule was used to collect information on sociodemographic variables and substance use. Multivariate logistic regression models were used to examine the sociodemographic predictors of substance use. Results: The overall prevalence of current alcohol use, current smoking and daily betel quid use was 17.2%, 18.8% and 47.6% respectively. Consistently, male gender (alcohol use OR = 13.55; smoking OR = 3.42; betel quid use OR = 1.65), increasing age (OR = 1.32; OR = 1.01; OR = 1.03), Paniya tribe status (OR = 2.24; OR = 1.39; OR = 5.38) and employment status being working (OR = 2.07; OR = 1.77; OR = 1.26) increased the risk of alcohol use, smoking and betel quid chewing. Furthermore, having ‘no formal education’ was associated with smoking (OR = 1.35), and betel quid chewing (OR = 3.27). Conclusion: Substance use was high among the indigenous tribes. The male gender, increasing age, Paniya tribe and working status significantly influenced alcohol use, smoking and betel quid chewing. The results underscore the need for indigenous specific de-addiction policies and programmes, alongside a consideration of the critical sociodemographic predictors

Structural behaviour of fully coupled spar–mooring system under extreme wave loading

Floating spar platform has been proven to be an economical and efficient type of offshore oil and gas exploration structure in deep and ultra-deep seas. Associated nonlinearities, coupled action, damping effect and extreme sea environments may modify its structural responses. In this study, fully coupled spar–mooring system is modelled integrating mooring lines with the cylindrical spar hull. Rigid beam element simulates large cylindrical spar hull and catenary mooring lines are configured by hybrid beam elements. Nonlinear finite element analysis is performed under extreme wave loading at severe deep sea. Morison's equation has been used to calculate the wave forces. Spar responses and mooring line tensions have been evaluated. Though the maximum mooring line tensions are larger at severe sea-state, it becomes regular after one hour of wave loading. The response time histories in surge, heave, pitch and the maximum mooring tension gradually decreases even after attaining steady state. It is because of damping due to heavier and longer mooring lines in coupled spar–mooring system under deep water conditions. The relatively lesser values of response time histories in surge, heave, pitch and the maximum mooring tension under extreme wave loading shows the suitability of a spar platform for deep water harsh and uncertain environmental conditions