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Here the hypothesis that linearized esculentin 2EM (E2EM-lin) from Glandirana emeljanovi possesses pH dependent activity is investigated. The peptide showed weak activity against Gram-negative bacteria (MLCs ≥ 75.0 μM) but potent efficacy towards Gram-positive bacteria (MLCs ≤ 6.25 μM). E2EM-lin adopted an α-helical structure in the presence of bacterial membranes that increased as pH was increased from 6 to 8 (↑ 15.5–26.9%), whilst similar increases in pH enhanced the ability of the peptide to penetrate (↑ 2.3–5.1 mN m−1) and lyse (↑ 15.1–32.5%) these membranes. Theoretical analysis predicted that this membranolytic mechanism involved a tilted segment, that increased along the α-helical long axis of E2EM-lin (1–23) in the N → C direction, with − µH > increasing overall from circa − 0.8 to − 0.3. In combination, these data showed that E2EM-lin killed bacteria via novel mechanisms that were enhanced by alkaline conditions and involved the formation of tilted and membranolytic, α-helical structure. The preference of E2EM-lin for Gram-positive bacteria over Gram-negative organisms was primarily driven by the superior ability of phosphatidylglycerol to induce α-helical structure in the peptide as compared to phosphatidylethanolamine. These data were used to generate a novel pore-forming model for the membranolytic activity of E2EM-lin, which would appear to be the first, major reported instance of pH dependent AMPs with alkaline optima using tilted structure to drive a pore-forming process. It is proposed that E2EM-lin has the potential for development to serve purposes ranging from therapeutic usage, such as chronic wound disinfection, to food preservation by killing food spoilage organisms.

Aims: Split-hand/split-foot malformation (SHFM) is a developmental and congenital limb malformation characterized by variable degrees of medial clefting or absence of one or more digits in hands and/or feet. The aim of this study was to identify the underlying cause of three consanguineous Pakistani families showing various types of SHFM-related features. Materials and Methods: Standard molecular methods, including whole-genome sequencing (WGS), whole-exome sequencing (WES), microsatellite markers-based genotyping, and Sanger sequencing were performed to search for the likely causative variants. Results: In family A, WES revealed a novel homozygous missense variant [c.338G>A, p.(Gly113Asp)] in the WNT10B gene. In family B, microsatellite-based genotyping followed by Sanger sequencing revealed a novel homozygous 13 base pairs deletion [c.884-896delTCCAGCCCCGTCT, p.(Phe295Cysfs*87)] in the same gene. In family C, WGS divulged a previously reported heterozygous missense variant [c.956G>A, p.(Arg319His)] in the TP63 gene. Conclusions: Mapping and sequencing genes and variants for severe skeletal disorders, such as SHRM, will facilitate establishing specific genotype-phenotype correlations and providing genetic counseling for the families suffering from such conditions.

Proteins are key player in the prognosis and therapeutics of carcinomas through the interactions of downstream signalling cascades. Current work insight the structural and mutational analysis of DACH1 in association with carcinogenesis. The homology modelling was employed to predict mutant and wild protein models and their reliability and accuracy was verified through multiple online approaches. Furthermore, MD simulation technique was employed to check the mutation effects on the stability of DACH1 through root mean square deviation and fluctuation graphs. Our results proposed that DACH1 mutation (C188Y) may cause lethal effects and can disturb the DACH1 structure. The observed mutational results showed that C188Y may cause some lethal effect in human body. Based on aforementioned computational assessments, it has concluded that DACH1 could be used as good therapeutic target in the prognosis and therapeutic of carcinoma insurgence.Communicated by Ramaswamy H. Sarma.

Worsening renal function in patients with heart failure with preserved ejection fraction is associated with poor outcomes. Pulmonary arterial capacitance is a novel right heart catheterization derived hemodynamic metric representing pulmonary arterial tree distensibility and right ventricle afterload. Given the strong association between heart failure, pulmonary hypertension, and kidney function, the goal of this study is to investigate the correlation between Pulmonary arterial capacitance and long-term renal function in patients with heart failure with preserved ejection fraction. In this retrospective single center study, data from 951 patients with the diagnosis of heart failure, who underwent right heart catheterization were analyzed. Eight hundred and one patients with reduced ejection fraction, end-stage kidney disease on hemodialysis, acute myocardial infarction, and severe structural valvular disorders, were excluded. Pulmonary arterial capacitance was calculated as the stroke volume divided by pulmonary artery pulse pressure (mL/mmHg). Hemodynamic and clinical variables including baseline renal function were obtained at the time of the right heart catheterization, and renal function was also obtained at 3-5 years after right heart catheterization. The final cohort consisted of 150 subjects with a mean age 68 ( ± 14.2) years, 93 (62%) were female. The mean value for Pulmonary arterial capacitance was 2.82 ( ± 2.22) mL/mm Hg and the mean Glomerular Filtration Rate was 60.32 mL/min/l.73 m² ( ± 28.36). After multivariate linear regression analysis (including baseline Estimated Glomerular Filtration Rate as one of the variates), only age and Pulmonary arterial capacitance greater than 2.22 mL/mm Hg were predictors of long term Glomerular Filtration Rate. Pulmonary arterial capacitance as a novel right heart catheterization index could be a predictor of long-term renal function in patients with heart failure with preserved ejection fraction.