DOCKING STUDIES IN TARGET PROTEINS INVOLVED IN ANTIBACTERIAL ACTION MECHANISMS: ALKALOIDS ISOLATED FROM SCUTELLARIA GENUS

Objective: In the present work, docking study was performed for 22 selected alkaloids isolated from the genus Scutellaria to evaluate their affinity to bacterial proteins that are known targets for many antibiotics with a different mechanism of action: Inhibitors of cell wall synthesis, inhibitors of nucleic acids synthesis and antimetabolites.Methods: Molecular docking study was carried out using AutoDock 4.2 version and the visualization result using Chimera 1.10 and DiscoveryStudio 4.5.Result: Among the 22 alkaloids studied, with the DNA gyrase protein 1KZN and a dihydropteroate synthase enzyme 3TYE, the compound scutebarbatine E showed a docking score of −8.5 and −8.7 Kcal/mol, respectively, involving with hydrophilic and hydrophobic interactions. With respect to MurD ligase involved in cell wall synthesis 1UAG and 2X5O, the compound 6,7,nicotinyl scutebarbatine G fared well with a docking score of −10.1 and −10.2 Kcal/mol, respectively. Scutebarbatine G performed well with respect to 3UDI with binding scores of −9.3 K cal/mol.Conclusion: Overall, it seems that for the selected alkaloids from the genus Scutellaria, the main mechanism of the action is the inhibition of cell wallsynthesis.Keywords: Scutebarbatine, Alkaloids, Molecular docking, Antimicrobial studies

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies

Interaction of Curves Proposed for Design and Analysis of Hollow Reinforced Concrete Columns

This Study is aimed to present a simplified approach enable to construction of a new design charts for hollow section reinforced concrete columns subjected to an axial compressive load and uniaxial bending. These design charts can be used directly in the analysis and design of hollow section columns. These charts can be used in design to determine the required amount of steel reinforcing in addition to the required column dimensions, while in the analysis by using these charts; the column load capacity can be estimated. Two design examples are given to explain the use of the new design charts. It has been shown by these examples that the new proposed charts are very simple to use in structural design applications

Multi-walled carbon nanotubes grow under low pressure hydrogen, air, and argon ambient by arc discharge plasma

Multi-walled carbon nanotubes (MWCNTs) were grown on cathode deposit by arc discharge plasma under H2, Ar, and air ambient environment. The influence of ambient gas pressure on the structure and physical properties of carbon nanotube were compared. Herein, we highlight the influence of ambient environment and pressure to grow high quality carbon nanotubes. Field emission scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and X-ray diffraction were used for structural characterization and yield determination. The result revealed that background gas and pressure were crucial factor for growing highly crystalline and highly graphitic with ID/IG ratio 0.237 obtained for MWCNTs’ synthesized in H2 environment with extreme low defects

Presentation and outcome of Middle East respiratory syndrome in Saudi intensive care unit patients.

BACKGROUND: Middle East respiratory syndrome coronavirus infection is associated with high mortality rates but limited clinical data have been reported. We describe the clinical features and outcomes of patients admitted to an intensive care unit (ICU) with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. METHODS: Retrospective analysis of data from all adult (>18 years old) patients admitted to our 20-bed mixed ICU with Middle East respiratory syndrome coronavirus infection between October 1, 2012 and May 31, 2014. Diagnosis was confirmed in all patients using real-time reverse transcription polymerase chain reaction on respiratory samples. RESULTS: During the observation period, 31 patients were admitted with MERS-CoV infection (mean age 59 ± 20 years, 22 [71 %] males). Cough and tachypnea were reported in all patients; 22 (77.4 %) patients had bilateral pulmonary infiltrates. Invasive mechanical ventilation was applied in 27 (87.1 %) and vasopressor therapy in 25 (80.6 %) patients during the intensive care unit stay. Twenty-three (74.2 %) patients died in the ICU. Nonsurvivors were older, had greater APACHE II and SOFA scores on admission, and were more likely to have received invasive mechanical ventilation and vasopressor therapy. After adjustment for the severity of illness and the degree of organ dysfunction, the need for vasopressors was an independent risk factor for death in the ICU (odds ratio = 18.33, 95 % confidence interval: 1.11-302.1, P = 0.04). CONCLUSIONS: MERS-CoV infection requiring admission to the ICU is associated with high morbidity and mortality. The need for vasopressor therapy is the main risk factor for death in these patients

Developing drought-smart, ready-to-grow future crops

Breeding crop plants with increased yield potential and improved tolerance to stressful environments is critical for global food security. Drought stress (DS) adversely affects agricultural productivity worldwide and is expected to rise in the coming years. Therefore, it is vital to understand the physiological, biochemical, molecular, and ecological mechanisms associated with DS. This review examines recent advances in plant responses to DS to expand our understanding of DS-associated mechanisms. Suboptimal water sources adversely affect crop growth and yields through physical impairments, physiological disturbances, biochemical modifications, and molecular adjustments. To control the devastating effect of DS in crop plants, it is important to understand its consequences, mechanisms, and the agronomic and genetic basis of DS for sustainable production. In addition to plant responses, we highlight several mitigation options such as omics approaches, transgenics breeding, genome editing, and biochemical to mechanical methods (foliar treatments, seed priming, and conventional agronomic practices). Further, we have also presented the scope of conventional and speed breeding platforms in helping to develop the drought-smart future crops. In short, we recommend incorporating several approaches, such as multi-omics, genome editing, speed breeding, and traditional mechanical strategies, to develop drought-smart cultivars to achieve the ‘zero hunger’ goal

Health-related quality of life variations by sociodemographic factors and chronic conditions in three metropolitan cities of South Asia: The CARRS study

Objectives: Health-related quality of life (HRQOL) is a key indicator of health. However, HRQOL data from representative populations in South Asia are lacking. This study aims to describe HRQOL overall, by age, gender and socioeconomic status, and examine the associations between selected chronic conditions and HRQOL in adults from three urban cities in South Asia.Methods: We used data from 16 287 adults aged ≥20 years from the baseline survey of the Centre for Cardiometabolic Risk Reduction in South Asia cohort (2010-2011). HRQOL was measured using the European Quality of Life Five Dimension-Visual Analogue Scale (EQ5D-VAS), which measures health status on a scale of 0 (worst health status) to 100 (best possible health status).Results: 16 284 participants completed the EQ5D-VAS. Mean age was 42.4 (±13.3) years and 52.4% were women. 14% of the respondents reported problems in mobility and pain/discomfort domains. Mean VAS score was 74 (95% CI 73.7 to 74.2). Significantly lower health status was found in elderly (64.1), women (71.6), unemployed (68.4), less educated (71.2) and low-income group (73.4). Individualswith chronic conditions reported worse health status than those without (67.4 vs 76.2): prevalence ratio, 1.8 (95% CI 1.61 to 2.04).Conclusions: Our data demonstrate significantly lower HRQOL in key demographic groups and those with chronic conditions, which is consistent with previous studies. These data provide insights on inequalities in population health status, and potentially reveal unmet needs in the community to guide health policies

Theoretical Investigation of Inclusion Complex between Omeprazole Enantiomers and Carboxymethyl-β-Cyclodextrin

Host-guest inclusion complexes between R/S-Omeprazole (R/S-OME) enantiomers with Carboxymethyl-β-Cyclodextrin (CM-β-CD) is proposed to predicts the separation of its enantiomers that considering the interaction energy and inclusion geometry. The inclusion complex structures were built into two orientations i.e. 1:1 and 2:1 as the ratio of host to guest. All structures were optimized by two methods i.e. molecular mechanic docking and quantum semi empiric PM3. Based on the value of binding energy obtained from the computational modelling, it was found that inclusion complex of S-Omeprazole with Carboxymethyl-β-Cyclodextrin (SOME/CM-β-CD) is more stable than the inclusion complex of R-Omeprazole with Carboxymethyl-β-Cyclodextrin (R-OME/CM-β-CD). Moreover, R/S-Omeprazole can form stable inclusion complexes with Carboxymethyl-β-Cyclodextrin by the ratio of host: guest equal to 2:1. Other thermodynamic parameter values, i.e. Enthalpy (ΔH), Entropy (ΔS), and Gibbs free energy (ΔG) show that the inclusion complex of S-OME/CM-β-CD is more exothermic, more spontaneous, and preferably formed when compared to inclusion complex of R-OME/CM-β-CD. In addition, the formation of the R/S-OME inclusion complex with Carboxymethyl-β-Cyclodextrin (CM-β-CD) is an enthalpy driven process based on these values