Search for a way to improve the serum albumin binding function and the functional state of the liver when hypertension combined with non-alcoholic fatty liver disease

Recently, there has been a significant increase in interest in research on hypertension (HT), primarily due to its high prevalence. The interest in studying this problem is also exacerbated by the often insufficient effectiveness of existing treatments. The effect of concomitant pathologies on HT, in particular non-alcoholic fatty liver disease (NAFLD), remains poorly understood. The aim of the study – to evaluate the changes in the serum albumin binding function (SABF) and its relationship with the biochemical parameters of the blood when HT and HT combined with NAFLD and to suggest ways of medical correction of the detected disorders. Material and methods. 76 individuals with stage 2 HT with degree 2–3 arterial hypertension were examined. They were divided into two groups. Group 1 included 28 patients with HT without concomitant diseases who received basic hypertension therapy, and group 2 included patients with concomitant NAFLD. The latter in turn was divided into two subgroups: 2a – 27 patients who in addition to basic HT therapy received additional Antral hepatoprotector 200 mg three times a day for 2 months, and 2b – 21 patients who received only basic HT therapy. All of them underwent a standard clinical examination, as well as SABF, protein fractions, and liver function indicators. The comparison group consisted of 25 healthy individuals, comparable in age and sex. Results and Discussion. Patients in group 1 showed moderate changes in the functional state of the liver, but they did not exceed the norm, patients in group 2 – a significant decrease in SABF, as well as protein metabolism (decrease in total protein, albumin, albumin-globulin ratio and increase globulins) and liver function (increased activity of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase, thymol levels, alkaline phosphatase and total bilirubin). After treatment, the majority of patients in subgroup 2 had a statistically significant increase in SABF and a quantitative improvement in protein fractions and functional state of the liver. In subgroup 2-b, where hepatoprotective treatment was not performed, significant changes in most indicators did not occur. The results may be related to the positive effect of the drug on the liver, which leads to improved functional status of hepatocytes and their protein-synthesizing ability. In subgroup 2 b, where hepatoprotective treatment was not performed, significant changes in most indicators did not occur. The results may be related to the positive effect of the drug on the liver leading to improved functional status of hepatocytes and their protein-synthesizing ability. Conclusions. Changes of the functional state of the liver are observed when HT without concomitant pathology. HT with NAFLD is accompanied by a significant decrease in SABF, changes in protein metabolism and the functional state of the liver. Prescribing Antral to such patients helps to increase SABF, normalize protein metabolism and improve the functional state of the liver.

Quantification of nuclear transport inhibition by SARS-CoV-2 ORF6 using a broadly applicable live-cell dose-response pipeline

SARS coronavirus ORF6 inhibits the classical nuclear import pathway to antagonize host antiviral responses. Several models were proposed to explain its inhibitory function, but quantitative measurement is needed for model evaluation and refinement. We report a broadly applicable live-cell method for calibrated dose-response characterization of the nuclear transport alteration by a protein of interest. Using this method, we found that SARS-CoV-2 ORF6 is ~5 times more potent than SARS-CoV-1 ORF6 in inhibiting bidirectional nuclear transport, due to differences in the NUP98-binding C-terminal region that is required for the inhibition. The N-terminal region was also required, but its membrane binding function was dispensable, since loss of the inhibitory function due to N-terminal truncation was rescued by forced oligomerization using a soluble construct. Based on these data, we propose that the hydrophobic N-terminal region drives oligomerization of ORF6 to multivalently cross-link the FG domains of NUP98 at the nuclear pore complex.

Assessment of the impact of the main technological characteristics of wells on the power consumption of pumps

The issue of assessing the impact of the main technological characteristics of wells on the power consumption of pumps is one of the important issues. Based on the analysis of the data obtained in the article, the electric energy consumption of the well pump device the rotational speed of the pump (co); the density of the solution (liquid) (p); the pressure generated by the pump (H); the performance of the pump aggregate (q); depth of the well (H); hydrodynamic resistance (dp); Also, on the basis of the STATISTICA program, the calculation work is carried out, the binding function of the pumps is determined to what extent the factor affects the electricity consumption, and is described in the Pareto diagram.

Prenatal diagnosis of auriculocondylar syndrome with a novel missense variant of GNAI3: a case report

Background Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant. Case presentation A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities. Conclusion Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.

Integrin activation is an essential component of SARS-CoV-2 infection

SARS-CoV-2 infection depends on binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn2+, which induces integrin extension, enhances cell entry of SARS-CoV-2R18. We also show that one class of integrin antagonist, which binds to the αI MIDAS site and stabilizes the inactive, closed conformation, selectively inhibits the engagement of SARS-CoV-2R18 with basal state integrins, but is ineffective against Mn2+-activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2R18 binding regardless of integrin activation status. Integrins transmit signals bidirectionally: 'inside-out' signaling primes the ligand-binding function of integrins via a talin-dependent mechanism, and 'outside-in' signaling occurs downstream of integrin binding to macromolecular ligands. Outside-in signaling is mediated by Gα13. Using cell-permeable peptide inhibitors of talin and Gα13 binding to the cytoplasmic tail of an integrin's β subunit, we demonstrate that talin-mediated signaling is essential for productive infection.

AbmR is a mycobacterial dual-function transcription factor and ribonucleoprotein with distinct DNA and RNA-binding determinants

ABSTRACTThe bacterium Mycobacterium tuberculosis (Mtb) must adapt to myriad host-associated stressors. A recently identified transcription factor, AbmR (ATP-binding mcr11-regulator), regulates expression of an essential stress-responsive small RNA (Mcr11) and inhibits the growth of Mtb. Previously, AbmR was found to make 39S complexes of unknown function. Here we report that AbmR 39S complexes are comprised of AbmR and co-purifying RNAs and that RNA-binding inhibits AbmR’s DNA-binding function. While AbmR binds DNA and regulates gene expression in a sequence specific manner, RNA-binding is not sequence specific. Amino acid R146 is important for DNA-binding but completely dispensable for RNA-binding and 39S complex formation, establishing that the RNA- and DNA-binding functions of AbmR are distinct. RNA bound by AbmR was protected from RNase digestion, supporting an RNA modulatory function for the 39S complex. We also found that abmR is required for optimal survival during treatment with the ATP-depleting antibiotic bedaquiline, which is associated with extended RNA stability. These data establish a paradigm wherein a transcription factor assembles into large complexes to transition between mutually exclusive DNA-binding gene regulatory and RNA-binding RNA modulatory functions. Our findings indicate that AbmR is a dual-function protein that may have novel RNA regulatory roles in stress adapted Mtb.

Recurrent de novo single point mutation on the gene encoding Na+/K+ pump results in epilepsy

The etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo mutation of ATP1A2 (c.2426 T>G, p.Leu809Arg), which encodes the α2 subunit of Na+/K+-ATPase, from a family with idiopathic epilepsy. This mutation caused seizures in the study patients. We generated the point mutation mouse model Atp1a2L809R, which recapitulated the epilepsy observed in the study patients. In Atp1a2L809R/WT mice, convulsions were observed and cognitive and memory function was impaired. This mutation affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Our work revealed that ATP1A2L809R mutations cause a predisposition to epilepsy. Moreover, we first provide a point mutation mouse model for epilepsy research and drug screening.

Conformational changes of loops highlight a potential binding site in Rhodococcus equi VapB

Virulence-associated proteins (Vaps) contribute to the virulence of the pathogen Rhodococcus equi, but their mode of action has remained elusive. All Vaps share a conserved core of about 105 amino acids that folds into a compact eight-stranded antiparallel β-barrel with a unique topology. At the top of the barrel, four loops connect the eight β-strands. Previous Vap structures did not show concave surfaces that might serve as a ligand-binding site. Here, the structure of VapB in a new crystal form was determined at 1.71 Å resolution. The asymmetric unit contains two molecules. In one of them, the loop regions at the top of the barrel adopt a different conformation from other Vap structures. An outward movement of the loops results in the formation of a hydrophobic cavity that might act as a ligand-binding site. This lends further support to the hypothesis that the structural similarity between Vaps and avidins suggests a potential binding function for Vaps.