Aggressive versus Low Dose Inhibition of the Renin-Angiotensin System for the Treatment of Microalbuminuria in Type 2 Diabetic Patients: A Pilot Study

Objective. This study compares low dose versus aggressive inhibition of the renin angiotensin system (RAS) to treat microalbuminuria (MA). Methods. Patients with MA after a run-in period to control BP to <130/80 mm Hg with 10 mg benazepril plus other drugs and HbA1c levels to <8.0% were randomized to either continue 10 mg benazepril (N = 12) or to take maximal doses of benazepril plus losartan in monthly stepwise increases to achieve normoalbuminuria (N = 11). Because MA is associated with CVD and inflammation, carotid intima medial thickness (CIMT) and endothelial function by peripheral arterial tonometry (PAT) as surrogate indices of atherosclerosis and highly sensitive C-reactive protein (hs-CRP) to assess inflammation were measured every six months. Results. BP, HbA1c levels, albumin : creatinine ratios, CIMT, PAT, and hs-CRP did not differ over a mean of 12 months between the two groups. Conclusions. Aggressive inhibition of the RAS is unnecessary to treat MA

Prevalence of and factors associated with anxiety and depression among women in a lower middle class semi-urban community of Karachi, Pakistan

Objective: To study the prevalence of, and factors associated with anxiety and depression among women.Design: A cross sectional survey.SETTING: A lower middle class semi-urban community of Karachi, Pakistan.PARTICIPANTS: A total of 1218 women between the ages of 18-50 years.METHODOLOGY: Systematically every third household was identified from which a woman was randomly selected. The Aga Khan University Anxiety and Depression Scale and a socio-demographic questionnaire were administered verbally by trained interviewers for assessing the prevalence of, and associated factors for anxiety and depression.Results: A prevalence of 30% was found. Increasing age, lack of education and verbal abuse were the associated factors found to have an independent relationship.CONCLUSION: Providing education and reducing domestic abuse could lead to decrease in the prevalence of anxiety and depression in women

Density Estimation on Small Data Sets

How might a smooth probability distribution be estimated with accurately quantified uncertainty from a limited amount of sampled data? Here we describe a field-theoretic approach that addresses this problem remarkably well in one dimension, providing an exact nonparametric Bayesian posterior without relying on tunable parameters or large-data approximations. Strong non-Gaussian constraints, which require a nonperturbative treatment, are found to play a major role in reducing distribution uncertainty. A software implementation of this method is provided. © 2018 authors. Published by the American Physical Society

Evaluation of some biological activities of Abelia triflora R Br (Caprifoliaceae) constituents

Purpose: To investigate the antioxidant, anti-inflammatory, antidiabetic,  cardiovascular and cytotoxic activities of the leaf extract and major compounds isolated from Abelia triflora R. Br. (Caprifoliaceae)Methods: The chloroform soluble fraction of A. triflora leaves was subjected to several column chromatographic separations to isolate its constituents.  Anti-inflammatory and antioxidant activities were determined in terms of the ability to inhibit NF-kB, iNOS activity and lipoxygenase enzyme, and to decrease oxidative stress in HepG2 cells. Antidiabetic and cardiovascular activities were determined by screening for peroxisome proliferator-activated receptor alpha (PPARα) and PPARɣ agonistic activities. In vitro cytotoxic activity was determined against a set of four human cancer cell lines (SK-MEL, KB, BT-549, SK-OV-3) and two  non-cancerous kidney cell lines (LLC-PK1 and VERO). Cell viability was measured by neutral red assay.Results: Three triterpene acids were isolated from the chloroform fraction namely; ursolic acid (4), 2, 3-dihydroxy ursolic acid (5) and 2, 3, 21-trihydroxy ursolic acid (6). The results showed that ursolic acid exhibited potent inhibition of lipoxygenase enzyme and iNOS (inducible nitric oxide synthase) activity with IC50 (half-maximal inhibitory concentration) value of 13.0 μg/mL, compared to parthenolide positive standard (IC50, 0.3μg/mL); furthermore, it inhibited NF-kB (nuclear factor-kappa B) with IC50 of 25.0 μg/mL, compared to parthenolide (positive standard, (IC50, 0.5 μg/mL). Also, ursolic acid possessed the highest cytotoxic effect against the three cell lines, SK-MEL (IC50, 14.5 μg/mL), BT-549 (IC50, 16.0 μg/mL) and SK-OV-3 (IC50, 12.5 μg/mL). Only 2,3-dihydroxy ursolic acid activated PPARɣ (1.5-fold at 25 μM), compared to rosiglitazone (positive standard, 3.7 fold at 10 μM)Conclusion: Among the investigated compounds, ursolic acid exhibited the highest anti-inflammatory and cytotoxic activities, while 2,3-dihydroxy ursolic acid demonstrated antidiabetic activity via activation of PPARɣ.Keywords: Abelia triflora, Anti-inflammatory, Antidiabetic, Cardiovascular activity, Antioxidant, Cytotoxi

MAVE-NN: learning genotype-phenotype maps from multiplex assays of variant effect

Multiplex assays of variant effect (MAVEs) are a family of methods that includes deep mutational scanning experiments on proteins and massively parallel reporter assays on gene regulatory sequences. Despite their increasing popularity, a general strategy for inferring quantitative models of genotype-phenotype maps from MAVE data is lacking. Here we introduce MAVE-NN, a neural-network-based Python package that implements a broadly applicable information-theoretic framework for learning genotype-phenotype maps-including biophysically interpretable models-from MAVE datasets. We demonstrate MAVE-NN in multiple biological contexts, and highlight the ability of our approach to deconvolve mutational effects from otherwise confounding experimental nonlinearities and noise

Evolution of DNA replication origin specification and gene silencing mechanisms.

DNA replication in eukaryotic cells initiates from replication origins that bind the Origin Recognition Complex (ORC). Origin establishment requires well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. A 3.9 Å structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed that a loop within Orc2 inserts into a DNA minor groove and an α-helix within Orc4 inserts into a DNA major groove. Using a massively parallel origin selection assay coupled with a custom mutual-information-based modeling approach, and a separate analysis of whole-genome replication profiling, here we show that the Orc4 α-helix contributes to the DNA sequence-specificity of origins in S. cerevisiae and Orc4 α-helix mutations change genome-wide origin firing patterns. The DNA sequence specificity of replication origins, mediated by the Orc4 α-helix, has co-evolved with the gain of ORC-Sir4-mediated gene silencing and the loss of RNA interference

Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study

This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc

The prospective non-conventional alternate and renewable energy sources in Pakistan - A focus on biomass energy for power generation, transportation, and industrial fuel

Pakistan is experiencing an undersupply of electricity, causing load shedding several hours per day due to the adherence to conventional energy resources having quantitative and environmental limitations. Fossil fuels generate more than half of the country's total electricity, but they will ultimately run out due to their limited supply. Their combustion emits greenhouse gases, posing environmental threats. Since the world is tending toward efficient and sustainable alternative methods for harvesting energy from nature, Pakistan has also been investigating an elevated deployment of renewable energy projects. This paper presents a critical analysis of the present energy sector of Pakistan along with global scenarios. Pakistan relies on mainly thermal, hydro, and nuclear energy for power generation. National solar, wind, geothermal, and biomass resources have not been extensively explored and implemented. This paper provides an insight into the potential of these resources in Pakistan to generate electricity for the national grid on a large scale. It focuses on biomass energy, which can be harnessed from bagasse, poultry waste, and municipal waste for power production, and biomass-based fuel for industries and transportation. It concludes that biomass is the most sustainable, available, implementable, and environment-friendly resource that can be utilized to lessen the energy demand and supply gap in Pakistan.University of Malay

Structural and mechanistic basis of σ-dependent transcriptional pausing

In σ-dependent transcriptional pausing, the transcription initiation factor σ, translocating with RNA polymerase (RNAP), makes sequence-specific protein-DNA interactions with a promoter-like sequence element in the transcribed region, inducing pausing. It has been proposed that, in σ-dependent pausing, the RNAP active center can access off-pathway “backtracked” states that are substrates for the transcript-cleavage factors of the Gre family, and on-pathway “scrunched” states that mediate pause escape. Here, using site-specific protein-DNA photocrosslinking to define positions of the RNAP trailing and leading edges and of σ relative to DNA at the λPR’ promoter, we show directly that σ-dependent pausing in the absence of GreB in vitro predominantly involves a state backtracked by 2-4 bp, and that σ-dependent pausing in the presence of GreB in vitro and in vivo predominantly involves a state scrunched by 2-3 bp. Analogous experiments with a library of 47 (∼16,000) transcribed-region sequences show that the state scrunched by 2-3 bp--and only that state--is associated with the consensus sequence, T-3N-2Y-1G+1, (where -1 corresponds to the position of the RNA 3’ end), which is identical to the consensus for pausing in initial transcription, and which is related to the consensus for pausing in transcription elongation. Experiments with heteroduplex templates show that sequence information at position T-3 resides in the DNA nontemplate strand. A cryo-EM structure of a complex engaged in σ-dependent pausing reveals positions of DNA scrunching on the DNA nontemplate and template strands and suggests that position T-3 of the consensus sequence exerts its effects by facilitating scrunching

α-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate

BACKGROUND: A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H2O2 that promoted cell death. METHODS: The redox-silent vitamin E analogue a-tocopheryl succinate (a-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells. RESULTS: Prostate cancer cells were sensitive to a-TOS and VK3 treatment, but resistant to AA upto 3.2mM. When combined, a synergistic effect was found for VK3\u2013AA, whereas a-TOS\u2013VK3 and a-TOS\u2013AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA\u2013VK3 combination combined with a sub-toxic dose of a-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal\u2013mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected. CONCLUSION: These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity