Changes in the mountain river discharge in the northern Tien Shan since the mid-20th Century: Results from the analysis of a homogeneous daily streamflow data set from seven catchments

This study is an assessment of the changes in seasonal and monthly flow in seven catchments draining the northern Tien Shan Mountains in Central Asia over a period from the 1950s to the present day. The purpose is to provide a first assessment of the flow response to climate change in regionally important catchments given their contribution to the water resource. All the catchments have a natural flow regime, and are therefore sensitive to climate change, but differ in area, elevation and glacial extent. Trends in flow were characterised using the Mann-Kendall test for standard meteorological seasons and individual months for mean flow, five flow quantiles and peak-over-threshold series for the period 1974–2013 at all sites and from the 1950s where data were available. The results were related to trends in seasonal temperature and precipitation from the regional high elevation meteorological stations and glacier mass balance, equilibrium line altitude (ELA) and accumulation area ratio (AAR) records from the Tuyuksu glacier. The results show no reduction in streamflow in any catchment or season in the northern Tien Shan since the 1950s. Positive trends in all flow indicators, including peak over- threshold frequency, were observed in catchments with higher glacierization of over 10% and extensive presence of rock glaciers and permafrost indicating increased melt over the period which is characterised by a long-term increase in temperature. These trends were most evident in autumn and winter. In catchments with low glacierization, variability in summer flow was controlled primarily by precipitation of the preceding cold season. Correlation with glacier mass balance was weak but changes in ELA and AAR indicate that production of liquid runoff at higher elevations contributes to increased streamflow partly compensating for the declining glacier area. The observed changes in streamflow do not suggest any immediate problems with water availability in the northern Tien Shan. On the contrary, increased autumn and winter flows point at a more prolonged recharge of reservoirs and aquifers though eventually this water source will be exhausted

Flow of a Second Grade Fluid through Constricted Tube using Integral Method

The steady flow of a second grade fluid through constricted tube for mild stenosis is modeled and analyzed theoretically. The governing equations are simplified by implying an order-of-magnitude analysis. Based on Karman Pohlhausen procedure polynomial solution for velocity profile is presented. Expressions for pressure gradient, shear stress, separation and reattachment points are also calculated. The effects of nondimensional parameters emerging in the model on the velocity profile, shear stress, pressure gradient are discussed and depicted graphically. The effect of non-Newtonian parameter on velocity profile, wall shear stress and pressure gradient is also analyzed. It is found that the Reynolds number strongly effect the wall shear stress, separation and reattachment points

β1-Adrenergic Receptor Contains Multiple IA\u3csup\u3ek\u3c/sup\u3e and IE\u3csup\u3ek\u3c/sup\u3e Binding Epitopes That Induce T Cell Responses with Varying Degrees of Autoimmune Myocarditis in A/J Mice

Myocarditis/dilated cardiomyopathy (DCM) patients can develop autoantibodies to various cardiac antigens and one major antigen is β1-adrenergic receptor (β1AR). Previous reports indicate that animals immunized with a β1AR fragment encompassing, 197–222 amino acids for a prolonged period can develop DCM by producing autoantibodies, but existence of T cell epitopes, if any, were unknown. Using A/J mice that are highly susceptible to lymphocytic myocarditis, we have identified β1AR 171–190, β1AR 181–200, and β1AR 211–230 as the major T cell epitopes that bind major histocompatibility complex class II/IAk or IEk alleles, and by creating IAk and IEk dextramers, we demonstrate that the CD4 T cell responses to be antigen-specific. Of note, all the three epitopes were found also to stimulate CD8 T cells suggesting that they can act as common epitopes for both CD4 and CD8 T cells. While, all epitopes induced only mild myocarditis, the disease- incidence was enhanced in animals immunized with all the three peptides together as a cocktail. Although, antigen-sensitized T cells produced mainly interleukin-17A, their transfer into naive animals yielded no disease. But, steering for T helper 1 response led the T cells reacting to one epitope, β1AR 181–200 to induce severe myocarditis in naive mice. Finally, we demonstrate that all three β1AR epitopes to be unique for T cells as none of them induced antibody responses. Conversely, animals immunized with a non-T cell activator, β1AR 201–220, an equivalent of β1AR 197–222, had antibodies comprising of all IgG isotypes and IgM except, IgA and IgE. Thus, identification of T cell and B cell epitopes of β1AR may be helpful to determine β1AR-reactive autoimmune responses in various experimental settings in A/J mice

Development of Paracetamol-Caffeine co-crystals to improve compressional, formulation and in-vivo performance

Paracetamol, a frequently used antipyretic and analgesic drug, has poor compression moldability owing to its low plasticity. In this study, new co-crystals of paracetamol (PCM) with caffeine (as a co-former) were prepared and delineated. Co-crystals exhibited improved compaction and mechanical behavior. A screening study was performed by utilizing a number of methods namely dry grinding, liquid assisted grinding (LAG), solvent evaporation (SE) and anti-solvent addition using various weight ratios of starting materials. LAG and SE were found successful in the screening study. Powders at 1:1 and 2:1 weight ratio of PCM/CAF by LAG and SE respectively resulted in the formation of co-crystals. Samples were characterized by PXRD, DSC and ATR-FTIR techniques. Compressional properties of PCM and developed co-crystals were analyzed by in-die heckle model. Mean yield pressure (Py), an inverse measure of plasticity, obtained from the heckle plots decreased significantly (p<0.05) for co-crystals than pure drug. Intrinsic dissolution profile of co-crystals showed up to 2.84 fold faster dissolution than PCM and physical mixtures in phosphate buffer pH 6.8 at 37 oC. In addition co-crystals formulated into tablets by direct compression method showed better mechanical properties like hardness and tensile strength. In vitro dissolution studies on tablets also showed enhanced dissolution profiles (~90- 97%) in comparison to the tablets of PCM prepared by direct compression (~55%) and wet granulation (~85%) methods. In a single dose sheep model study co-crystals showed up to two fold increase in AUC and Cmax. A significant (p < 0.05) decrease in clearance as compared to pure drug was also recorded. In conclusion new co-crystals of PCM were successfully prepared with improved tabletability in-vitro and in-vivo profile. Enhancement in AUC and Cmax of PCM by co-crystallisation might suggest the dose reduction and avoidance of side effects

Synthesis and in vitro antiproliferative activity of new 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea scaffold-based compounds

A new series of 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea derivatives were synthesized and subjected to in vitro antiproliferative screening against National Cancer Institute (NCI)-60 human cancer cell lines of nine different cancer types. Fourteen compounds 5a-n were synthesized with three different solvent exposure moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure. Substituents with different π and σ values were added on the terminal phenyl group. Compounds 5a-e with a 4-hydroxymethylpiperidine moiety showed broad-spectrum antiproliferative activity with higher mean percentage inhibition values over the 60-cell line panel at 10 µM concentration. Compound 5a elicited lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line. Two compounds, 5a and 5d showed promising mean growth inhibitions and thus were further tested at five-dose mode to determine median inhibitory concentration (IC50) values. The data revealed that urea compounds 5a and 5d are the most active derivatives, with significant efficacies and superior potencies than paclitaxel in 21 different cancer cell lines belonging particularly to renal cancer and melanoma cell lines. Moreover, 5a and 5d had superior potencies than gefitinib in 38 and 34 cancer cell lines, respectively, particularly colon cancer, breast cancer and melanoma cell lines

Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice

Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971–990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971–990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk. By creating IAk/and IEk/SERCA2a 971–990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971–990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971–990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971–990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971–990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions