We investigated Polygonum hydropiper L. (P. hydropiper) for phenolic contents, antioxidant, anticholinesterase activities, in an attempt to rationalize its use in neurological disorders.

Serotonin reuptake inhibitors were recently reported to possess antimicrobial potentials, potentiate activity of several antibiotics, reverse multidrug resistant phenotypes of bacteria and make them susceptible to previously resistant drugs. We investigated antimicrobial potentials of sertraline (SR) against ATCC strains, clinical isolates of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa alone and in-combination with seven antibiotics. Antifungal activity was investigated against four fungal strains including Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Fusarium solani. Intrinsic antibacterial action and Minimum Inhibitory Concentrations (MICs) were determined using well assay, nutrient broth and agar dilution techniques. Disk diffusion and nutrient broth methods were used to study bacterial susceptibility to SR. Minimum Fungicidal Concentrations (MFCs) of SR were determined using Sabouraud dextrose Agar (SDA). Sertraline possesses strong intrinsic antibacterial, antifungal activities and has augmented the antibacterial activities of antibiotics. For S. aureus ATCC 6538, E. coli ATCC 8739 and P. aeruginosa ATCC 9027, the MICs of SR were 20, 40 and 60 μg ml−1, respectively, whereas 55.5% clinical isolates of S. aureus and 50% of E. coli strains were inhibited at 20 and 60 μg ml−1 of SR, respectively. Among the tested fungi, 60% of A. niger and A. fumigatus were inhibited at 40 and 80 μg ml−1, respectively. MFCs were 60 and 80 μg ml−1 for A. flavus and F. solani, respectively. Antibacterial activities of all antibiotics were significantly increased (p < 0.001) with the addition of SR 100 μg ml−1 against all tested bacteria. Combination study revealed that SR had significantly increased the activity of antibiotics, and some previously resistant strains were made susceptible. Thus antidepressants are potential sources of resistance modifying agents when used in combination.

Background: Vulvovaginal candidiasis (VVC) is considered as a pervasive gynecological problem among women worldwide. Owing to this fact, in the current study, we aimed at assessing the prevalence rate of Candida spp. causing VVC in symptomatic pregnant women and their antifungal susceptibility pattern. Methods: This study was carried out in the tertiary care hospitals of Peshawar during the period of July 1, 2016 to December 31, 2016. The study group included 450 pregnant women in the age group of 17–44 years with symptoms of excessive vaginal discharge, pain and pruritis. In all, 108 pregnant women were culture positive for Candida. Antimicrobial susceptibility testing (AST) was conducted on specimens against various azoles and polyene F group of antifungals. Results: Out of 108 Candida spp. isolated from vaginal swabs, there were 45 (41.7%) Candida albicans, 18 (16.7%) Candida tropicalis, 18 (16.7%) Candida krusei, 16 (14.8%) Candida glabrata and 11 (10.2%) Candida dubliniensis. According to age distribution, 27 years was the mean age. Pregnancy trimester distribution among patients was as follows: 21 (19.4%) patients were in their first trimester, 65 (60.2%) patients were in their second trimester and 22 (20.4%) patients were in the third trimester. Susceptibility of fluconazole was determined as follows: 33.3% of the Candida isolates were sensitive, 4.6% were susceptible dose dependent (SDD) and 62% were resistant. Susceptibility of Candida spp. with respect to nystatin in patients with VVC was as follows: 25% were sensitive, 16.7% were SDD and 58.3% were resistant. Susceptibility of clotrimazole was analyzed, and it was sensitive in 21.3% of patients, SDD in 19.4% of patients and resistant in 59.3% of patients. Voriconazole susceptibility was recorded to be sensitive in 85.2% of patients, SDD in 4.6% of patients and resistant in 10.2% of patients suffering from VVC. Susceptibility results for itraconazole in patients with VVC were as follows: 42.6% of patients were sensitive, 16.7% of patients were SDD, and 40.7% of patients were resistant. Conclusion: In this study, frequency of VVC was noted to be high in the second trimester of pregnancy, with the highest frequency of C. albicans isolated, followed by C. tropicalis and C. krusei. Antifungal susceptibility testing revealed that fluconazole was exceedingly resistant against Candida species (62%), followed by clotrimazole (59.3%) and nystatin (58.3%). On the contrary, voriconazole had the highest antimicrobial activity against Candida species (85.2%).

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.