A Glutathione Peroxidase, Intracellular Peptidases and the TOR Complexes Regulate Peptide Transporter PEPT-1 in C. elegans

The intestinal peptide transporter PEPT-1 in Caenorhabditis elegans is a rheogenic H+-dependent carrier responsible for the absorption of di- and tripeptides. Transporter-deficient pept-1(lg601) worms are characterized by impairments in growth, development and reproduction and develop a severe obesity like phenotype. The transport function of PEPT-1 as well as the influx of free fatty acids was shown to be dependent on the membrane potential and on the intracellular pH homeostasis, both of which are regulated by the sodium-proton exchanger NHX-2. Since many membrane proteins commonly function as complexes, there could be proteins that possibly modulate PEPT-1 expression and function. A systematic RNAi screening of 162 genes that are exclusively expressed in the intestine combined with a functional transport assay revealed four genes with homologues existing in mammals as predicted PEPT-1 modulators. While silencing of a glutathione peroxidase surprisingly caused an increase in PEPT-1 transport function, silencing of the ER to Golgi cargo transport protein and of two cytosolic peptidases reduced PEPT-1 transport activity and this even corresponded with lower PEPT-1 protein levels. These modifications of PEPT-1 function by gene silencing of homologous genes were also found to be conserved in the human epithelial cell line Caco-2/TC7 cells. Peptidase inhibition, amino acid supplementation and RNAi silencing of targets of rapamycin (TOR) components in C. elegans supports evidence that intracellular peptide hydrolysis and amino acid concentration are a part of a sensing system that controls PEPT-1 expression and function and that involves the TOR complexes TORC1 and TORC2

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Presence of antibiotic resistant bacteria along the pharmaceuticals production line

The antimicrobial susceptibility of forty-five bacterial isolates obtained from different pharmaceutical raw materials of several companies in Cairo, Egypt during June to august, 2008 was determined using agar diffusion method. Only fourteen out of forty-five antibiotic resistant bacterial isolates were selected according to their sensitivity to equal or more than two antibiotics used. Isolates were subjected to antimicrobial susceptibility testing. The percent of resistance to seven antibiotics were Colis. (16.7%), Azithr. (78.6%), Oxytet. (0.0%), Amox. (21.4%), Kan. (42.8%), Cipro. (0.0%), and Spictin. (100.0%). Active potency of the raw materials was determined by incubating the drugs with and without microbes using HPLC and UV spectrophotometer. Among 14 selected isolates two were found to contain plasmids that are probably related to their drug resistance

Software bug prediction using weighted majority voting techniques

Mining software repositories is a growing research field where rich data available in the different development software repositories, are analyzed and cross-linked to uncover useful information. Bug prediction is one of the potential benefits that can be gained through mining software repositories. Predicting potential defects early as they are introduced to the version control system would definitely help in saving time and effort during testing or maintenance phases. In this paper, defect prediction models that uses ensemble classification techniques have been proposed. The proposed models have been applied using different sets of software metrics as attributes of the classification techniques and tested on datasets of different sizes. The results show that change metrics outperform static code metrics and the combined model of change and static code metrics. Ensembles tend to be more accurate than their base classifiers. Defect prediction models using change metrics and ensemble classifiers have revealed the best performance, especially when the datasets used have imbalanced class distribution. Keywords: Modeling and prediction, Product metrics, Process metrics, Classifier design and evaluatio

SKIN TARGETING OF AN OPTIMIZED CAFFEINE NANOSTRUCTURED LIPID CARRIER WITH IMPROVED EFFICIENCY AGAINST CHEMOTHERAPY INDUCED ALOPECIA

Objective: The current investigation was designed to develop and optimize caffeine-loaded nanostructured lipid carriers (NLCs) for topical alopecia treatment. Methods: Screening of drug solubility in various excipients was executed. The 23 full factorial design was employed for NLCs optimization. Lipid type, surfactant type, and drug concentration were the independent variables. Entrapment efficiency (EE), particle size, polydispersity index (PDI) and % drug release were the chosen responses. Physiochemical evaluation, in vitro release, ex-vivo permeation, and stability study were achieved. Results: The solubility of caffeine in stearic acid and glyceryl monostearate (GMS) was 47.11±3.048 and 32.67±2.955 mg/g, respectively. Oleic acid: garlic oil mixture at a ratio of 1:1 v/v was the oily phase. Tween 80 and Cremophor EL, Transcutol HP, carbonate buffer (pH 10.8 and ionic strength 200 mmol) were chosen as a surfactant, co-surfactant, and aqueous phase, respectively. The optimized formula showed particle size, %EE, PDI, zeta potential of 358 nm±1.45, 72.55 %±0.12, 0.912±0.030,-24.8 mv±0.70, respectively. The % release was 92.9±4.9 % after 2 h. Confocal laser scanning microscopy showed an improved permeation of caffeine-loaded NLCs to the whole skin layers. Conclusion: The histological examination proved the efficiency of caffeine NLCs optimized formula in promoting hair growth compared to the market formula