Alport Syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties

Alport Syndrome is a genetic disease characterized by breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level structure–property relationships of this disease using a bottom-up computational materiomics approach implemented through large-scale molecular dynamics simulation. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of single-residue glycine substitution mutations of varying clinical severity are studied in short segments of type IV tropocollagen molecules. The segments with physiological amino acid sequences are equilibrated and then subjected to tensile loading. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration (with the kink located at the mutation site) and a significant alteration of the molecules’ stress–strain responses and stiffnesses. These results suggest that localized structural changes at amino acid level induce severe alterations of the molecular properties. Our study opens a new approach in pursuing a bottom-up multi-scale analysis of this disease.     

Side-by-side comparison of horizontal subsurface flow and free water surface flow constructed wetlands and artificial neural network (ANN) modelling approach

A horizontal subsurface flow (HSSF) and a free water surface flow (FWSF) constructed wetlands (4 m² of each) were set up on the campus of Harran University, Sanliurfa, Turkey. The main objective of the research was to compare the performance of two systems to decide the better one for future planning of wastewater treatment system on the campus. Both of the wetland systems were planted with Phragmites australis and Canna indica. During the observation period (10 months), environmental conditions such as pH, temperature and total chemical oxygen demand (COD), soluble COD, total biochemical oxygen demand (BOD), soluble BOD, total suspended solids (TSS), total phosphate (TP), total nitrogen (TN) removal efficiencies of the systems were determined. According to the results, average yearly removal efficiencies for the HSSF and the FWSF, respectively, were as follows: total COD (75.7% and 69.9%), soluble COD (85.4% and 84.3%), total BOD (79.6% and 87.6%), soluble BOD (87.7% and 95.3%), TN (33.2% and 39.4%), and TP (31.5% and 6.5%). Soluble COD and BOD removal efficiencies of both systems increased gradually since the start-up. After nine months of operation, above 90% removal of organic matters were observed. The treatment performances of the HSSF were better than that of the FWSF with regard to the removal of suspended solids and total COD at especially high temperatures. In FWSF systems, COD concentrations extremely exceeded the discharge limit values due to high concentrations of algae in spring months.The performance of the two systems was modelled using an artificial neural network-back-propagation algorithm. The ANN model was competent at providing reasonable match between the measured and the predicted concentrations of total COD (R = 0.90 for HSSF and R = 0.96 for FWSF), soluble COD (R = 0.90 for HSSF and R = 0.74 for FWSF) and total BOD (R = 0.94 for HSSF and R = 0.84 for FWSF) in the effluents of constructed wetlands.     

Performance of sulfidogenic anaerobic baffled reactor (ABR) treating acidic and zinc-containing wastewater

The applicability of anaerobic baffled reactor (ABR) was investigated for the treatment of acidic (pH 4.5–7.0) wastewater containing sulfate (1000–2000 mg/L) and Zn (65–200 mg/L) at 35 °C. The ABR consisted of four equal stages and lactate was supplemented (COD/SO₄²⁻ = 0.67) as carbon and energy source for sulfate reducing bacteria (SRB). The robustness of the system was studied by decreasing pH and increasing Zn, COD, and sulfate loadings. Sulfate-reduction efficiency quickly increased during the startup period and reached 80% within 45 days. Decreasing feed pH, increasing feed sulfate and Zn concentrations did not adversely affect system performance as sulfate reduction and COD removal efficiencies were within 62–90% and 80–95%, respectively. Although feed pH was steadily decreased from 7.0 to 4.5, effluent pH was always within 6.8–7.5. Over 99% Zn removal was attained throughout the study due to formation of Zn-sulfide precipitate.     

Computational analysis of the formation mechanisms of carbazoles

Journal of Molecular Modeling - The organoselenium compound ebselen has recently been investigated as a treatment for COVID-19; however, efforts to model ebselen in silico have been hampered by the...     

Agomelatine modulates calcium signaling through protein kinase C and phospholipase C-mediated mechanisms in rat sensory neurons

Agomelatine, a novel antidepressant exerting its effects through melatonergic and serotonergic systems, implicated to be effective against pain including neuropathic pain but without any knowledge of mechanism of action. To explore the possible role of agomelatine on nociceptive transmission at the peripheral level, the effects of agomelatine on intracellular calcium ([Ca²⁺]_i) signaling in peripheral neurons were investigated in cultured rat dorsal root ganglion (DRG) neurons. Using the fura-2-based calcium imaging technique, the effects of agomelatine on [Ca²⁺]_i and roles of the second messenger-mediated pathways were assessed. Agomelatine caused [Ca²⁺]_i signaling in a dose-dependent manner when tested at 10 and 100 μM concentration. Luzindole, a selective melatonin receptor antagonist, almost completely blocked the agomelatine-induced calcium signals. The agomelatine-induced calcium transients were also nearly abolished following pretreatment with the 100 ng/ml pertussis toxin, a Gi/o protein inhibitor. The stimulatory effects of agomelatine on [Ca²⁺]_i transients were significantly reduced by applications of phospholipase C (PLC) and protein kinase C (PKC) blockers, 10 μM U73122, and 10 μM chelerythrine chloride, respectively. The obtained results of agomelatine-induced [Ca²⁺]_i signals indicates that peripheral mechanisms are involved in analgesic effects of agomelatine. These mechanisms seems to involve G-protein-coupled receptor activation and PLC and PKC mediated mechanisms.     

Changes in Liver Tissue Trace Element Concentrations During Hepatitis B Viral Infection Treatment

Biological Trace Element Research - Approximately 350–400 million people in the world have Hbs Ag (hepatitis B virus surface antigen) positivity. In the international guidelines, the...     

Predictors of the paroxysmal atrial fibrillation recurrence following cryoballoon-based pulmonary vein isolation: Assessment of left atrial volume,left atrial volume index,galectin-3 level and neutrophil-to-lymphocyte ratio

Background

Cryoballoon-based pulmonary vein isolation (PVI) is a treatment option for atrial fibrillation (AF). Left atrial volume (LAV) and left atrial volume index (LAVi) are important parameters for long term success of PVI. Galectin-3 (Gal-3) and neutrophil to lymphocyte ratio (N/L ratio) are biomarkers to demonstrate the cardiac fibrosis and remodelling.

Boron ameliorates arsenic‐induced DNA damage,proinflammatory cytokine gene expressions,oxidant/antioxidant status,and biochemical parameters in rats

Arsenic, an element found in nature, causes hazardous effects on living organisms. Meanwhile, natural compounds exhibit protective effects against hazardous substances. This study evaluated the effects of boron against arsenic‐induced genotoxicity and altered biochemical parameters in rats. Thirty‐five male Wistar albino rats were equally divided into five groups, and the experimental period lasted 30 days. One group was used as the control, and another group was treated with 100 mg/L arsenic in drinking water. The other groups were orally treated with 5, 10, and 20 mg/kg boron plus arsenic (100 mg/L via drinking water). Arsenic caused changes in biochemical parameters, total oxidant/antioxidant status, and DNA damage in mononuclear leukocytes. Moreover, it increased IFN‐γ, IL‐1β, TNF‐α, and NFκB mRNA expression levels in rat tissue. However, boron treatment improved arsenic‐induced alterations in biochemical parameters and increases in DNA damage and proinflammatory cytokine gene expressions.     

Offspring sex is not related to maternal allocation of yolk steroids in the lizard Bassiana duperreyi (Scincidae)

The eggs of birds and reptiles contain detectable levels of several steroid hormones, and experimental application of such steroids can reverse genetically determined sex of the offspring. However, any causal influence of maternally derived yolk steroids on sex determination in birds and reptiles remains controversial. We measured yolk hormones (dihydrotestosterone, testosterone, and 17 beta-estradiol) in newly laid eggs of the montane scincid lizard Bassiana duperreyi. This species is well suited to such an analysis because (1) offspring sex is influenced by incubation temperatures and egg size as well as by sex chromosomes, suggesting that yolk hormones might somehow be involved in the complex pathways of sex determination, and (2) experimental application of either estradiol or fadrozole to such eggs strongly influences offspring sex. We obtained yolk by biopsy, before incubating the eggs at a temperature that produces a 50:50 sex ratio. Yolk steroid levels varied over a threefold range between eggs from different clutches, but there were no significant differences in yolk steroids, or in relative composition of steroids, between eggs destined to become male versus female. Further, yolk steroid concentrations were not significantly related to egg size. Thus, yolk steroid hormones do not appear to play a critical role in sex determination for B. duperreyi.     

Collagen’s primary structure determines collagen:HSP47 complex stoichiometry

Collagens play important roles in development and homeostasis in most higher organisms. In order to function, collagens require the specific chaperone HSP47 for proper folding and secretion. HSP47 is known to bind to the collagen triple helix, but the exact positions and numbers of binding sites are not clear. Here, we employed a collagen II peptide library to characterize high-affinity binding sites for HSP47. We show that many previously predicted binding sites have very low affinities due to the presence of a negatively charged amino acid in the binding motif. In contrast, large hydrophobic amino acids such as phenylalanine at certain positions in the collagen sequence increase binding strength. For further characterization, we determined two crystal structures of HSP47 bound to peptides containing phenylalanine or leucine. These structures deviate significantly from previously published ones in which different collagen sequences were used. They reveal local conformational rearrangements of HSP47 at the binding site to accommodate the large hydrophobic side chain from the middle strand of the collagen triple helix and, most surprisingly, possess an altered binding stoichiometry in the form of a 1:1 complex. This altered stoichiometry is explained by steric collisions with the second HSP47 molecule present in all structures determined thus far caused by the newly introduced large hydrophobic residue placed on the trailing strand. This exemplifies the importance of considering all three sites of homotrimeric collagen as independent interaction surfaces and may provide insight into the formation of higher oligomeric complexes at promiscuous collagen-binding sites.