3-Aryl-1-phenyl-1H-pyrazole derivatives as new multitarget directed ligands for the treatment of Alzheimer's disease, with acetylcholinesterase and monoamine oxidase inhibitory properties

A series of 3-aryl-1-phenyl-1H-pyrazole derivatives was synthesized in good yield and assayed in vitro as inhibitors of the mice acetylcholinesterase (AChE) and two goat liver monoamine oxidase (MAO) isoforms, MAO-A and MAO-B. Most of the compounds demonstrated a good AChE and selective MAO-B inhibitory activities in the nanomolar or low micromolar range. N-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) benzenamine (3e, pIC50 = 4.2) and N-((4-fluorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) methanamine (3f, pIC50 = 3.47) were the most potent AChE and highly selective MAO-B inhibitors respectively. Structure activity relationships showed that chloro derivatives were more effective AChE inhibitors as compared to fluoro derivatives while reverse trend was observed in MAO-B inhibitory activity. With the aid of modeling studies, potential binding orientations as well as interactions of the compounds in the AChE and MAO-B active sites were examined

Optimization of laccase production from Aspergillus flavus by design of experiment technique: Partial purification and characterization

AbstractThe present study describes isolation of laccase producing fungal strain and optimization of the process parameters by design of experiment (DOE) technique to achieve the maximum production of extracellular laccases by Aspergillus flavus obtained from natural habitat. Bromophenol blue dye and ABTS (2,2′-azinobis 3-ethyl-benzothiazoline-6-sulfonate) were used as substrates for the screening of laccase activity. Design expert 8.0.7.1 software was used to optimize culture conditions such as carbon source, nitrogen source, temperature and pH. Subsequently, optimization for inoculums size was also carried out. The optimization studies revealed that the laccase yield was highest when operated at the following conditions: carbon source – cellulose (8%), nitrogen source – peptone (2%), temperature – 35°C, pH – 7 and inoculum of size 1.5cm

Assessment of Disease Activity and Complications in Patients of Pulmonary Tuberculosis by High Resolution Computed Tomography

Background: Tuberculosis (TB) is a global health problem and the second most common infectious cause of death. High-resolution computed tomography (HRCT) is far more superior to chest radiography as well as conventional CT for analyzing the pulmonary parenchyma. This study aimed to evaluate the role of HRCT in pulmonary tuberculosis (PTB) with respect to disease activity and complication after anti-tubercular therapy (ATT). Methods: This prospective observational study was conducted in the Department of Radiodiagnosis, Teerthanker Mahaveer Medical College & Research Centre (TMMC&RC) for a period of 1.5 years. A total of 50 cases of newly diagnosed TB were included in the study and a standard six-month ATT was given to the patients. Pulmonary involvement was evaluated by HRCT (128 slice multi-detector PHILIPS INGENUITY CT scanner), twice for each patient (first scan after diagnosis and second after treatment completion). The acquired HRCT images were reconstructed on a highresolution lung algorithm and parenchymal, bronchial, and extra parenchymal findings were recorded systematically. Results: Out of the 50 patients, 5 died within two months of the initiation of treatment and four were lost to follow-up. Thus, post treatment follow-up sample size was reduced to 41 patients. Ill-defined nodules (96%), tree-in-bud pattern (74%), consolidation (86%), cavitary lesions (98%), and ground glass opacities (58%) were the main imaging features of active cases of TB on HRCT. Resolution to thin-walled cavitary lesions (36.5%), bronchiectasis (41.5%), and fibrotic (parenchymal) bands (66%) were common complications or sequelae which were observed after completion of treatment. Conclusion: HRCT thorax is a sensitive modality for evaluation of parenchymal and airway manifestations in cases of PTB and can aid in differentiation of active disease from healed disease. It allows early identification of post-treatment complications and sequelae in patients of PTB

Heat Transfer and Friction Factor Correlations Development for Double Pass Solar Air Heater Artificially Roughened With Perforated Multi-V Ribs

Thermo-hydraulic performance of a Double Pass Parallel Flow Solar Air Heater (DPPFSAH) roughened with perforated multi-V ribs has been studied experimentally in a prior study and the effect of variation in open area ratio and change in relative roughness width has been analysed and reported. The current work builds upon the aforementioned earlier study by discussing in detail the methodology and various steps involved in the development of a correlation for variable parameters with Nusselt number and friction factor for DPPFSAH. The outcomes show that perforations in the multi-V ribs lead to a considerable rise in the Nusselt number, a 9.66 times increase in the thermo-hydraulic performance parameter and nearly a four times increase in friction factor compared to multi-V ribs with smoothed walls. Empirical correlations for the Nusselt number and friction factor were obtained for the double pass parallel flow solar air heater with perforated multi-V ribs established with ±14% and ±7%

Multi-level, Forming Free, Bulk Switching Trilayer RRAM for Neuromorphic Computing at the Edge

Resistive memory-based reconfigurable systems constructed by CMOS-RRAM integration hold great promise for low energy and high throughput neuromorphic computing. However, most RRAM technologies relying on filamentary switching suffer from variations and noise leading to computational accuracy loss, increased energy consumption, and overhead by expensive program and verify schemes. Low ON-state resistance of filamentary RRAM devices further increases the energy consumption due to high-current read and write operations, and limits the array size and parallel multiply & accumulate operations. High-forming voltages needed for filamentary RRAM are not compatible with advanced CMOS technology nodes. To address all these challenges, we developed a forming-free and bulk switching RRAM technology based on a trilayer metal-oxide stack. We systematically engineered a trilayer metal-oxide RRAM stack and investigated the switching characteristics of RRAM devices with varying thicknesses and oxygen vacancy distributions across the trilayer to achieve reliable bulk switching without any filament formation. We demonstrated bulk switching operation at megaohm regime with high current nonlinearity and programmed up to 100 levels without compliance current. We developed a neuromorphic compute-in-memory platform based on trilayer bulk RRAM crossbars by combining energy-efficient switched-capacitor voltage sensing circuits with differential encoding of weights to experimentally demonstrate high-accuracy matrix-vector multiplication. We showcased the computational capability of bulk RRAM crossbars by implementing a spiking neural network model for an autonomous navigation/racing task. Our work addresses challenges posed by existing RRAM technologies and paves the way for neuromorphic computing at the edge under strict size, weight, and power constraints

The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

The TNF-related cytokine TWEAK promotes skeletal muscle atrophy that is associated with classical disuse syndromes

Multiple Analytical Approaches Reveal Distinct Gene-Environment Interactions in Smokers and Non Smokers in Lung Cancer

Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11–2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25–0.65,p<0.001 and OR = 0.51;95%CI = 0.33–0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33–10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15–7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer

Integrating transcriptomic and proteomic data for accurate assembly and annotation of genomes

© 2017 Wong et al.; Published by Cold Spring Harbor Laboratory Press. Complementing genome sequence with deep transcriptome and proteome data could enable more accurate assembly and annotation of newly sequenced genomes. Here, we provide a proof-of-concept of an integrated approach for analysis of the genome and proteome of Anopheles stephensi, which is one of the most important vectors of the malaria parasite. To achieve broad coverage of genes, we carried out transcriptome sequencing and deep proteome profiling of multiple anatomically distinct sites. Based on transcriptomic data alone, we identified and corrected 535 events of incomplete genome assembly involving 1196 scaffolds and 868 protein-coding gene models. This proteogenomic approach enabled us to add 365 genes that were missed during genome annotation and identify 917 gene correction events through discovery of 151 novel exons, 297 protein extensions, 231 exon extensions, 192 novel protein start sites, 19 novel translational frames, 28 events of joining of exons, and 76 events of joining of adjacent genes as a single gene. Incorporation of proteomic evidence allowed us to change the designation of more than 87 predicted noncoding RNAs to conventional mRNAs coded by protein-coding genes. Importantly, extension of the newly corrected genome assemblies and gene models to 15 other newly assembled Anopheline genomes led to the discovery of a large number of apparent discrepancies in assembly and annotation of these genomes. Our data provide a framework for how future genome sequencing efforts should incorporate transcriptomic and proteomic analysis in combination with simultaneous manual curation to achieve near complete assembly and accurate annotation of genomes

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection