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Biomedical subjects

S Das

Publications and source records attributed to S Das.

At least 19 recordsLinked to original sources
PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife&#xae; combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗
PubMed2025

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries.

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (>&#x2009;91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population. METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure. RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p&#x2009;<&#x2009;0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Humans↗
PubMed2006

Direct observation of dijets in central Au+Au collisions at sqrt[sNN]=200 GeV.

The STAR Collaboration at the Relativistic Heavy Ion Collider reports measurements of azimuthal correlations of high transverse momentum (pT) charged hadrons in Au+Au collisions at higher pT than reported previously. As (pT) is increased, a narrow, back-to-back peak emerges above the decreasing background, providing a clear dijet signal for all collision centralities studied. Using these correlations, we perform a systematic study of dijet production and suppression in nuclear collisions, providing new constraints on the mechanisms underlying partonic energy loss in dense matter.

Journal Article↗
PubMed2006

Identified baryon and meson distributions at large transverse momenta from Au + Au collisions at square root sNN=200 GeV.

Transverse momentum spectra of pi+/-, p, and p up to 12 GeV/c at midrapidity in centrality selected Au + Au collisions at square root sNN=200 GeV are presented. In central Au + Au collisions, both pi +/- and p(p) show significant suppression with respect to binary scaling at pT approximately >4 GeV/c. Protons and antiprotons are less suppressed than pi+/-, in the range 1.5 approximately < pT approximately < 6 GeV/c. The pi-/pi+ and p/p ratios show at most a weak pT dependence and no significant centrality dependence. The p/pi ratios in central Au + Au collisions approach the values in p + p and d + Au collisions at pT approximately >5 GeV/c. The results at high pT indicate that the partonic sources of pi+/-, p, and p have similar energy loss when traversing the nuclear medium.

Journal Article↗
PubMed2006

Forward neutral pion production in p + p and d + Au collisions at square root sNN=200 GeV.

Measurements of the production of forward pi0 mesons from p + p and d + Au collisions at square root sNN=200 GeV are reported. The p + p yield generally agrees with next-to-leading order perturbative QCD calculations. The d + Au yield per binary collision is suppressed as eta increases, decreasing to approximately 30% of the p + p yield at eta =4.00, well below shadowing expectations. Exploratory measurements of azimuthal correlations of the forward pi0 with charged hadrons at eta approximately 0 show a recoil peak in p + p that is suppressed in d + Au at low pion energy. These observations are qualitatively consistent with a saturation picture of the low-x gluon structure of heavy nuclei.

Journal Article↗
PubMed2006

Strange baryon resonance production in sqrt s NN=200 GeV p+p and Au+Au collisions.

We report the measurements of Sigma(1385) and Lambda(1520) production in p+p and Au+Au collisions at sqrt[s{NN}]=200 GeV from the STAR Collaboration. The yields and the p(T) spectra are presented and discussed in terms of chemical and thermal freeze-out conditions and compared to model predictions. Thermal and microscopic models do not adequately describe the yields of all the resonances produced in central Au+Au collisions. Our results indicate that there may be a time span between chemical and thermal freeze-out during which elastic hadronic interactions occur.

Journal Article↗
PubMed2006

Reactive oxygen species level in follicular fluid--embryo quality marker in IVF?

BACKGROUND: The impact of oxidative stress in female reproduction is not clear. Contradictory reports on the effect of various oxidative stress markers on follicular fluid, oocytes and embryo quality and fertilization potential exist. The objectives of this study were to examine reactive oxygen species (ROS) levels in follicular fluid of women undergoing IVF and to relate these levels to embryo formation and quality. METHODS AND RESULTS: A total of 208 follicular fluid samples were obtained from 78 women undergoing controlled ovarian stimulation and analysed for ROS and lipid peroxidation (LPO). These samples were divided into groups I and II which represented follicular fluid containing grade III and grade II oocytes, respectively. These groups were further subdivided into groups IA, IB, IIA and IIB according to embryo quality. Subgroups IA and IIA consisted of follicular fluid samples corresponding to grade I/II embryo formation. Subgroups IB and IIB represented fertilization failure/pro-nucleolus (PN) arrest/grade III embryos. No significant correlation was observed in ROS levels on comparing groups I and II (P > 0.05). However, ROS levels were observed to be significantly different on comparing groups IA and IB (P < or = 0.01) and groups IIA and IIB (P < or = 0.05). LPO levels further supported our results. CONCLUSION: ROS levels in follicular fluid appear to play a significant role in embryo formation and quality.

Embryo Culture Techniques↗
PubMed2006

Moraxella keratitis: predisposing factors and clinical review of 95 cases.

AIM: To analyse the clinical presentation, identify predisposing risk factors and evaluate the outcome of treatment of Moraxella keratitis. METHODS: A retrospective analysis was carried out of culture-proved cases of Moraxella keratitis from hospital records during a 10-year period (from December 1995 to November 2005) at the Corneal Unit of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. RESULTS: 95 episodes of Moraxella keratitis were identified in 92 patients. 3 (3.2%) patients had recurrent keratitis. The mean age of the patients was 70 (range 17-93) years. Multiple predisposing factors were identified in 23 (24%) eyes, including corneal graft (n = 15), previous herpes keratitis (n = 15) and eye lid diseases (n = 15). Adjunctive procedures were carried out in 42 eyes. These included botulinum toxin injection (n = 17), tarsorraphy (n = 12), penetrating keratoplasty (n = 8), enucleation (n = 3), tissue adhesive and bandage contact lens (n = 4), and conjunctival flap (n = 5). Polymicrobial infection was present in 17 eyes. Final visual acuity was counting finger or less in 25 (26%) eyes. CONCLUSIONS: Local ocular predisposing factors play a major role in Moraxella keratitis. This infection has a poor visual outcome attributable to both the nature of the infection and the predisposing factors.

Adolescent↗
PubMed2006

Earthquake rupture stalled by a subducting fracture zone.

We showed that the rupture produced by the great Peru earthquake (moment magnitude 8.4) on 23 June 2001 propagated for approximately 70 kilometers before encountering a 6000-square-kilometer area of fault that acted as a barrier. The rupture continued around this barrier, which remained unbroken for approximately 30 seconds and then began to break when the main rupture front was approximately 200 kilometers from the epicenter. The barrier had relatively low rupture speed, slip, and aftershock density as compared to its surroundings, and the time of the main energy release in the earthquake coincided with the barrier's rupture. We associate this barrier with a fracture zone feature on the subducting oceanic plate.

Journal Article↗
PubMed2006

Pregnancy outcomes, infant mortality, and arsenic in drinking water in West Bengal, India.

Between 2001 and 2003, the authors studied pregnancy outcomes and infant mortality among 202 married women in West Bengal, India. Reproductive histories were ascertained using structured interviews. Arsenic exposure during each pregnancy, including all water sources used, was assessed; this involved measurements from 409 wells. Odds ratios for spontaneous abortion, stillbirth, neonatal mortality, and infant mortality were estimated with logistic regression based on the method of generalized estimating equations. Exposure to high concentrations of arsenic (> or =200 microg/liter) during pregnancy was associated with a sixfold increased risk of stillbirth after adjustment for potential confounders (odds ratio (OR) = 6.07, 95% confidence interval (CI): 1.54, 24.0; p = 0.01). Arsenic-related skin lesions were found in 12 women who had a substantially increased risk of stillbirth (OR = 13.1, 95% CI: 3.17, 54.0; p = 0.002). The odds ratio for neonatal death was 2.81 (95% CI: 0.73, 10.8). No association was found between arsenic exposure and spontaneous abortion (OR = 1.01, 95% CI: 0.38, 2.70) or overall infant mortality (OR = 1.33, 95% CI: 0.43, 4.04). This study adds to the limited evidence that exposure to high concentrations of arsenic during pregnancy increases the risk of stillbirth. However, there was no indication of the increased rates of spontaneous abortion and overall infant mortality that have been reported in some studies.

Arsenic Poisoning↗
PubMed2006

Effects of protein kinase inhibitors on the in vitro growth of Babesia bovis.

Staurosporine, Ro-31-7549, and KN-93, which are inhibitors of serine/threonine protein kinase, protein kinase C, and calcium-modulin kinase, respectively, were tested for their effects on the in vitro growth of Babesia bovis. Staurosporine was the most effective inhibitor, completely clearing the parasitaemia as early as the first day of exposure at a concentration of 100 microM. Moreover, staurosporine caused a significant increase in the percentage of extracellular merozoites, most likely due to the inhibition of erythrocyte invasion by the parasite. Although 5 mM Ro-31-7549 and KN-93 had a suppressive action, this was not enough to destroy the parasite. Interestingly, concentrations of 0.5 to 5 mM KN-93 influenced the parasitic development within the infected erythrocytes. The present study suggests that B. bovis requires, to a certain extent, the phosphorylations mediated by parasite- or host erythrocyte-protein kinases, in particular, for the processes of successful invasion of erythrocytes and intraerythrocytic development.

Animals↗
PubMed2006

Effect of ascorbic acid on prevention of hypercholesterolemia induced atherosclerosis.

The notion that oxidation of lipids and propagation of free radicals may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. To circumvent the damage caused by oxygen free radicals, antioxidants are needed which provide the much needed neutralization of free radical by allowing the pairing of electrons. In this study we have investigated the effect of ascorbic acid, a water soluble antioxidant on the development of hypercholesterolemia induced atherosclerosis in rabbits. Rabbits were made hypercholesterolemic and atherosclerotic by feeding 100 mg cholesterol/day. Different doses of ascorbic acid were administered to these rabbits. Low dose of ascorbic acid (0.5 mg/100 g body weight/day) did not have any significant effect on the percent of total area covered by atherosclerotic plaque. However, ascorbic acid when fed at a higher dose (15 mg/100 g body weight/day) was highly effective in reducing the atherogenecity. With this dose the percent of total surface area covered by atherosclerotic plaque was significantly less (p < 0.001). This suggests that use of ascorbic acid may have great promise in the prevention of hypercholesterolemia induced atherosclerosis.

Animals↗
PubMed2006

In treatment-naïve and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100.

AIMS/HYPOTHESIS: We hypothesised that loss of peripheral fat in HIV patients would result in decreased plasma adipocytokines, in particular adiponectin, and that this decrease would be associated with changes in VLDL, IDL and LDL apolipoprotein B kinetics. METHODS: Plasma adiponectin, leptin and other cytokines were measured in uninfected control subjects (n=12) and three HIV-positive groups comprising treatment-naïve patients (n=15) and patients on triple antiretroviral therapy containing protease inhibitors (PI, n=15) or non-nucleoside reverse transcriptase inhibitors (NNRTI, n=25). VLDL, IDL and LDL apolipoprotein B kinetics were measured with an infusion of [1-(13)C] leucine. Regional body fat was measured with a dual energy X-ray absorptiometry scan. Insulin resistance was calculated using homeostasis model assessment (HOMA). RESULTS: Adiponectin (median [interquartile range]) was reduced in the treatment-naive (5.4 microg/ml [4.7-8.5]), PI (5.0 microg/ml [3.3-6.4]) and NNRTI (5.0 microg/ml [3.1-6.7]) groups compared with controls (9.7 microg/ml [6.9-13.3]) (p<0.05). In all subjects adiponectin correlated positively with HDL-cholesterol levels, the VLDL, IDL and LDL apolipoprotein B fractional clearance rates, and with the limb fat:lean body mass ratio (all p<0.01). Adiponectin correlated negatively with plasma triglyceride levels and HOMA (p<0.001). In a linear regression model that included HOMA, adiponectin was an independent predictor of VLDL and HDL-cholesterol levels and the IDL fractional clearance rate. TNF was higher in treatment-naive and PI subjects, and soluble TNF receptor superfamily, members 1A and 1B (previously known as TNF receptors 1 and 2) was higher in PI patients than in control subjects (p<0.05). CONCLUSIONS/INTERPRETATION: Adiponectin levels are significantly reduced in treated and untreated HIV patients and are predictive of VLDL and IDL apolipoprotein B fractional clearance rates. Adiponectin may have a direct effect on lipoprotein metabolism, which may be independent of insulin.

Adiponectin↗
PubMed2006

Does repeated electro-ejaculation improve sperm quality in spinal cord injured men?

STUDY DESIGN: Retrospective analysis. OBJECTIVES: To assess the effect of repeated electro-ejaculation on the sperm quality in spinal cord injured men. SETTING: Regional Spinal Injuries Unit, Southport, UK and Hewitt Center for Reproductive Medicine, Liverpool, UK. METHOD: Retrospective, observational study of men with spinal cord injuries undergoing repeated electro-ejaculation as a part of fertility treatment. RESULT: There was no improvement in the volume, sperm concentration, motility or the total motile count in the successive antegrade and retrograde samples following repeated electro-ejaculations. CONCLUSION: Electro-ejaculation is an invasive procedure and its use should be restricted to obtaining semen sample for carrying out assisted conception procedures only.

Adult↗
PubMed2006

The introduction of the stilbene synthase gene enhances the natural antiradical activity of Lycopersicon esculentum mill.

Tomato (Lycopersicon esculentum) is a vegetable rich in antioxidants, such as lycopene, lutein, and zeaxanthin. Their presence is responsible for the characteristic ability of this product to inhibit the formation of reactive oxygen species, including singlet oxygen. The grapes and wines derived from grapes also contain powerful antioxidants. The antioxidant effect is derived from the polyphenols such as resveratrol and proanthocyanidin. Resveratrol is phytoalexin that is synthesized via the activation of the gene, stilbene synthase (STS). We decided to determine if the introduction of this gene into Lycopersicon esculentum Mill could modify its antioxidant activity. Using Electronic Paramagnetic Resonance (EPR) spectroscopy, which permits the detection of antiradical activity, especially *OH (hydroxyl radical), we showed that the antioxidant activity of the products, into which the gene STS had been introduced, was almost double than that of natural products and that their activity was especially pronounced due to ripening. Moreover, resveratrol concentrations in modified tomatoes were much higher than that found in the individual fruit. In the isolated hearts subjected to ischemia/reperfusion, the rats fed with modified tomato exhibited better cardiac performance, reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes, and reduced oxidative stress compared to unmodified tomato or resveratrol alone indicating superior cardioprotective abilities of modified tomatoes.

Acyltransferases↗