Genetic analysis of SLC47A1, SLC22A1, SLC22A2, ATM gene polymorphisms among diabetics in an Indian population

Background: Metformin is a first-line therapy for type 2 diabetes mellitus. However, the glycaemic response to metformin is likely to be affected by polymorphisms of transporter genes. Therefore, the study was done with the  aim to assess demographic distribution of transporter genotypes involved in disposition and action of metformin.Methods: This cross-sectional, observational, single centre, clinical study was conducted in 80 diabetic patients recruited from medicine OPD. Descriptive analysis was done for distribution of the four transporter genotypes viz. SLC47A1 (rs2289669), ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342). Genotyping was determined by DNA extraction, agarose gel electrophoresis, estimation of DNA concentration, polymerase chain reaction, DNA sequencing, sequencing analysis.Results: Transporter genotype analysis showed that for SLC47A1 (rs2289669) transporter, 31.25% and 26.25% were homozygous for AA and GG allele respectively, while 42.5% were heterozygous (AG). For ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342) transporter, 45% and 10%, 1.25% and 80%, 58.75% and 7.50% were homozygous for AA and CC allele respectively; while 45%, 18.75%, 33.75% were heterozygous (AC) respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 (rs622342) and ATM (rs11212617) gene polymorphism were observed when compared with other major populations.Conclusions: In the genotypic distribution of four transporter genotype study showed that there was an ethnic variation in allelic distribution of allele A and C of ATM (rs11212617) and SLC22A1 (rs622342) while AA genotype of SLC22A2 (rs316019) was rare genotype and allele ‘A’ was major allele found in our study. The study data observed would justify further pharmacogenetic studies to evaluate the role of gene polymorphism in the therapeutic efficacy of metformin.

Composition and Habitability of Europa’s Ocean Over Time

Introduction: Europa is proposed to host a global liquid water ocean that is in contact with a silicate interior [1]. Understanding the composition of this ocean and the underlying rock is crucial for evaluating the habitability of Europa. However, the presence of an ice shell impedes direct observation or analysis of the ocean and rock, leaving their compositions largely unknown. Previous modelling work has shown that, if Europa accreted entirely from CI or CM chondritic material, sufficient volatiles could be released during prograde metamorphism to account for the current size of the hydrosphere [2]. However, thermal models predict that temperatures in Europa’s interior would gradually increase over billions of years [e.g. 3], where the progressive release of volatiles would change the ocean composition over time. In this study, possible ocean compositions were explored using computer modelling to simulate the thermal evolution of Europa’s interior over its ~4.5 Gyr lifetime and assess the volatiles released from the starting material as it is heated. Methods: The composition of Murchison (a CM chondrite) was chosen to represent the silicate material that accreted to form Europa because the CMs: formed close to early Jupiter (unlike the CIs [4]), contain sufficient water (largely held within hydrated silicates [5]), and can produce fluid compositions consistent with salts observed on Europa’s surface [2, 6]. A 1-dimensional thermal evolution code was used to model the temperatures achieved within Europa’s interior [3]. Temperature-depth profiles were then extracted at two points in time to reflect the formation of the proto-ocean (i.e. ~1600 Myr since the calcium-aluminium-rich inclusions (CAIs)) and the current-day ocean (~4568 Myr since the CAIs). Rcrust [7] and Perple_X [8] were used to predict the electrolytic fluid speciation from the starting material when heated to the temperatures predicted by the first temperature-depth profile (Stage 1; 4 – ~1600 Myr) and then the second (Stage 2; ~1600 – ~4568 Myr). Pyrrhotite was extracted from the starting material past the Fe-FeS eutectic temperature (which was also calculated using Rcrust and Perple_X) to approximate core formation. The volatiles forming the proto-ocean (i.e. those released in Stage 1) were then equilibrated using CHIM-XPT [9], where supersaturated gases were exsolved and minerals precipitated. The further volatiles (i.e. those released in Stage 2) were then added to the proto-ocean in CHIM-XPT, forming the current-day ocean. Results and Discussion: Released volatiles for the proto-ocean are predicted to form a ~77.9 km deep layer around Europa. With the addition of the further volatiles, the current-day ocean would be ~84.8 km deep. The extraction of pyrrhotite, which occurs after proto-ocean formation, would form a metallic core of ~271.5 km radius by the current day. The current-day ocean depth and core radius predicted here agree with those inferred for current-day Europa based on observations [3]. The model predicts that both the proto- and current-day oceans would be rich in Na+, Cl-, and CO32-, which may explain the recent observation of NaCl and CO2 in geologically-disrupted regions of Europa’s surface [10, 11]. Large concentrations of NH3 and NH4+ are predicted for both the proto- and current-day oceans, despite the lack of any clear detection of nitrogen species on the surface. However, this abundance may be explained by the absence of thermodynamic data for solid nitrogen-bearing phases in the model resulting in an overestimation of nitrogen release during metamorphism (mainly as NH3). A key difference between the proto- and current-day oceans is their HS- concentration, where the current-day ocean has only ~0.2% that of the proto-ocean. This is due to the addition of the iron-rich Stage 2 volatiles to the proto-ocean causing the precipitation of pyrite (removing HS- from solution). Conclusion: We find that Europa’s ocean composition would have varied over time as a result of continued prograde metamorphism, with particular changes in HS- concentration. The significant decrease in HS- content could affect the potential for energy generation by sulfide-oxidising microbes in the current-day ocean and, thus, would have implications for Europa’s continuous habitability. References: [1] Běhounková M. et al. (2021) Geophys. Res. Lett., 48. [2] Melwani Daswani M. et al. (2021) Geophys. Res. Lett., 48. [3] Trinh K. T. et al. (2023) Sci. Adv., 9, eadf3955. [4] Desch S. J. et al. (2018), ApJS. 238, 11. [5] Howard K. T. et al. (2011) Geochim. Cosmochim. Acta., 75, 2735–2751. [6] Fanale F. P. et al. (2001) J. Geophys. Res., 106, 14595–14600. [7] Mayne M. J. et al. (2016), J. Metamorph. Geol., 34, 663–682. [8] Connolly J. A. D. (2005) Earth Planet. Sci. Lett., 236, 524–541. [9] Reed M. H. et al. (2010) J. Chem. Inf. Model., 53, 1689–1699. [10] Trumbo S. K. et al. (2019) Sci. Adv., 5, eaaw7123. [11] Villanueva G. L. et al. (2023) Science., 381, 1305–1308. Part of this work was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under contract to the National Aeronautics and Space Administration

Data sharing in DHT based P2P systems

International audienceThe evolution of peer-to-peer (P2P) systems triggered the building of large scale distributed applications. The main application domain is data sharing across a very large number of highly autonomous participants. Building such data sharing systems is particularly challenging because of the "extreme" characteristics of P2P infrastructures: massive distribution, high churn rate, no global control, potentially untrusted participants... This article focuses on declarative querying support, query optimization and data privacy on a major class of P2P systems, that based on Distributed Hash Table (P2P DHT). The usual approaches and the algorithms used by classic distributed systems and databases forproviding data privacy and querying services are not well suited to P2P DHT systems. A considerable amount of work was required to adapt them for the new challenges such systems present. This paper describes the most important solutions found. It also identies important future research trends in data management in P2P DHT systems

Studies on the antidiarrhoeal activity of Aegle marmelos unripe fruit: Validating its traditional usage

<p>Abstract</p> <p>Background</p> <p><it>Aegle marmelos </it>(L.) Correa has been widely used in indigenous systems of Indian medicine due to its various medicinal properties. However, despite its traditional usage as an anti-diarrhoeal there is limited information regarding its mode of action in infectious forms of diarrhoea. Hence, we evaluated the hot aqueous extract (decoction) of dried unripe fruit pulp of <it>A. marmelos </it>for its antimicrobial activity and effect on various aspects of pathogenicity of infectious diarrhoea.</p> <p>Methods</p> <p>The decoction was assessed for its antibacterial, antigiardial and antirotaviral activities. The effect of the decoction on adherence of enteropathogenic <it>Escherichia coli </it>and invasion of enteroinvasive <it>E. coli </it>and <it>Shigella flexneri </it>to HEp-2 cells were assessed as a measure of its effect on colonization. The effect of the decoction on production of <it>E. coli </it>heat labile toxin (LT) and cholera toxin (CT) and their binding to ganglioside monosialic acid receptor (GM1) were assessed by GM1-enzyme linked immuno sorbent assay whereas its effect on production and action of <it>E. coli </it>heat stable toxin (ST) was assessed by suckling mouse assay.</p> <p>Results</p> <p>The decoction showed cidal activity against <it>Giardia </it>and rotavirus whereas viability of none of the six bacterial strains tested was affected. It significantly reduced bacterial adherence to and invasion of HEp-2 cells. The extract also affected production of CT and binding of both LT and CT to GM1. However, it had no effect on ST.</p> <p>Conclusion</p> <p>The decoction of the unripe fruit pulp of <it>A. marmelos</it>, despite having limited antimicrobial activity, affected the bacterial colonization to gut epithelium and production and action of certain enterotoxins. These observations suggest the varied possible modes of action of <it>A. marmelos </it>in infectious forms of diarrhoea thereby validating its mention in the ancient Indian texts and continued use by local communities for the treatment of diarrhoeal diseases.</p

The rise of britain's super-indies: Policy-making in the age of the global media market

This article analyses Britain’s remarkable performance in the European television industry. In the space of a few years the UK has risen to become the world’s leading exporter of TV formats and the world’s second exporter, behind the Unites States, of finished TV programmes. The first section compares and contrasts British TV exports data with that of France, before examining the emergence of London as Europe’s media hub. The second part argues that this significant progress is essentially due to deft policy making. In 2003, the British government operated a strategic shift in favour of content producers and created a new intellectual property regime. This regime has enabled producers to keep hold of their rights and become asset-owning businesses, eventually giving rise to a new breed of production companies: the super-indies. This paper shows how these super-indies have acquired the scale to compete in an international TV market and drive today’s British TV exports. Contrasting again Britain’s performance in the European TV trade with France, this article also analyses historical influences and claims it is Britain’s imperial past that helps her performance in the European TV marketplace. In addition to the globalization of the English language and the cultural affinities this nurtures, the trading heritage of the British Empire has facilitated Britain’s political elite’s understanding of the role that trade and the market can play in the creative industries, and enabled them to frame a broadcasting policy that is adapted to the global age

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland

Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (&lt;135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration &gt;10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was &gt;3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care

A distributed algorithm for robust data sharing and updates in P2P database networks

In this paper we thoroughly analyze a distributed procedure for the problem of local database update in a network of database peers, useful for data exchange scenarios. The algorithm supports dynamic networks: even if nodes and coordination rules appear or disappear during the computation, the proposed algorithm will eventually terminate with a sound and complete result