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The study of drugs of natural origin that increase endurance and/or accelerate recovery is an integral part of sports medicine and physiology. In this paper, decaffeinated green tea extract (GTE) and two ammonium salts—chloride (ACL) and carbonate (ACR)—were tested individually and in combination with GTE as stimulants of physical performance in a forced swimming rat experimental model. The determined parameters can be divided into seven blocks: functional (swimming duration); biochemistry of blood plasma; biochemistry of erythrocytes; hematology; immunology; gene expression of slow- and fast-twitch muscles (m. soleus, SOL, and m. extensor digitorum longus, EDL, respectively); and morphometric indicators of slow- and fast-twitch muscles. Regarding the negative control (intact animals), the maximum number of changes in all blocks of indicators was recorded in the GTE + ACR group, whose animals showed the maximum functional result and minimum lactate values on the last day of the experiment. Next, in terms of the number of changes, were the groups ACR, ACL, GTE + ACL, GTE and NaCl (positive control). In general, the number of identified adaptive changes was proportional to the functional state of the animals of the corresponding groups, in terms of the duration of the swimming load in the last four days of the experiment. However, not only the total number but also the qualitative composition of the identified changes is of interest. The results of a comparative analysis suggest that, in the model of forced swimming we developed, GTE promotes restoration of the body and moderate mobilization of the immune system, while small doses of ammonium salts, especially ammonium carbonate, contribute to an increase in physical performance, which is associated with satisfactory restoration of skeletal muscles and the entire body. The combined use of GTE with ammonium salts does not give a clearly positive effect. [ABSTRACT FROM AUTHOR]

Adaptation of humans to challenging environmental conditions, such as extreme temperature, malnutrition, or hypoxia, is an interesting phenomenon for both basic and applied research. Identification of the genetic factors contributing to human adaptation to these conditions enhances our understanding of the underlying molecular and physiological mechanisms. In our study, we analyzed the exomes of 22 high altitude mountaineers to uncover genetic variants contributing to hypoxic adaptation. To our surprise, we identified two putative loss‐of‐function variants, rs1385101139 in RTEL1 and rs1002726737 in COL6A1 in two extremely high altitude (personal record of more than 8500 m) professional climbers. Both variants can be interpreted as pathogenic according to medical geneticists' guidelines, and are linked to inherited conditions involving respiratory failure (late‐onset pulmonary fibrosis and severe Ullrich muscular dystrophy for rs1385101139 and rs1002726737, respectively). Our results suggest that a loss of gene function may act as an important factor of human adaptation, which is corroborated by previous reports in other human subjects. [ABSTRACT FROM AUTHOR]

Carvone belongs to the chemical family of terpenoids and is the main component of various plant oils. Carvone and its hydrogenated products are used in the flavouring and food industries. A quantitative thermodynamic analysis of the general network of carvone hydrogenation reactions was performed based on the thermochemical properties of the starting carvone and all possible intermediates and end products. The enthalpies of vaporisation, enthalpies of formation, entropies and heat capacities of the reactants were determined by complementary measurements and a combination of empirical, theoretical and quantum chemical methods. The energetics and entropy change in the hydrogenation and isomerisation reactions that take place during the conversion of carvone were derived, and the Gibbs energies of the reactions were estimated. It was shown that negative Gibbs energies are recorded for all reactions that may occur during the hydrogenation of carvone, although these differ significantly in magnitude. This means that all these reactions are thermodynamically feasible in a wide range from ambient temperature to elevated temperatures. Therefore, all these reactions definitely take place under kinetic and not thermodynamic control. Nevertheless, the numerical Gibbs energy values can help to establish the chemoselectivity of catalysts used to convert carvone to either carvacarol or to dihydro- and terahydrocarvone, either in carvotanacetone or carveol. [ABSTRACT FROM AUTHOR]

The identification of the genetic causes of inherited disorders from next-generation sequencing (NGS) data remains a complicated process, in particular due to challenges in interpretation of the vast amount of generated data and hundreds of candidate variants identified. Inconsistencies in variant classification, where genetic centers classify the same variant differently, can hinder accurate diagnoses for rare diseases. Publicly available databases that collect data on human genetic variations and their association with diseases provide ample opportunities to discover conflicts in variant interpretation worldwide. In this study, we explored patterns of variant classification discrepancies using data from ClinVar, a public archive of variant interpretations. We found that 5.7% of variants have conflicting interpretations (COIs) reported, and the vast majority of interpretation conflicts arise for variants of uncertain significance (VUS). As many as 78% of clinically relevant genes harbor variants with COIs, and genes with high COI rates tended to have more exons and longer transcripts, with a greater proportion of genes linked to several distinct conditions. The enrichment analysis of COI-enriched genes revealed that the products of these genes are involved in cardiac disorders, muscle development, and function. To improve diagnoses, we believe that specific variant interpretation rules could be developed for such genes. Additionally, our findings underscore the need for the publication of variant pathogenicity evidence and the importance of considering every variant as VUS unless proven otherwise. [ABSTRACT FROM AUTHOR]

Over the last two decades, numerous genome-wide association studies (GWAS) have been performed to unveil the genetic architecture of human complex traits. Despite multiple efforts aimed at the trans-biobank integration of GWAS results, no systematic analysis of the variant-level properties affecting the replication of known associations (or identifying novel ones) in genome-wide meta-analysis has yet been performed using biobank-scale data. To address this issue, we performed a systematic comparison of GWAS summary statistics for 679 complex traits in the UK Biobank (UKB) and FinnGen (FG) cohorts. We identified 37,148 index variants with genome-wide associations with at least one trait in either cohort or in the meta-analysis, only 3528 (9.5%) of which were shared between UKB and FG. Nearly twice as many variants (6577) were replicated in another dataset at the significance level adjusted for the number of variants selected for replication. However, as many as 9230 loci failed to be replicated. Moreover, as many as 5813 loci were observed as significant associations only in meta-analysis results, highlighting the importance of trans-biobank meta-analysis efforts. We showed that variants that failed to replicate in UKB or FG tend to correspond to rare, less pleiotropic variants with lower effect sizes and lower LD score values. Genome-wide associations specific to meta-analysis were also enriched in low-effect variants; however, such variants tended to be more common and have more consistent frequencies between populations. Taken together, our results show a relatively high rate of non-replication of genome-wide associations in the studied cohorts and highlight both widely appreciated and less acknowledged properties of the associations affecting their identification and replication. [ABSTRACT FROM AUTHOR]

A male factor, commonly associated with poor semen quality, is revealed in about 50% of infertile couples. CFTR gene (Cystic Fibrosis Transmembrane Conduction Regulator) variants are one of the common genetic causes of azoospermia-related male infertility. Notably, the spectrum and frequency of pathogenic CFTR variants vary between populations and geographical regions. In this work, we made an attempt to evaluate the allele frequency (AF) of 12 common CFTR variants in infertile Russian men and healthy individuals from different districts of Russia. Because of the limited number of population-based studies on Russian individuals, we characterized the population AFs based on data from the Registry of Russian cystic fibrosis (CF) patients. In addition to the CF patient registry, we estimated the local frequencies of the same set of variants based on the results of genotyping of CF patients in local biocollections (from St. Petersburg and Yugra regions). AFs of common CFTR variants calculated based on registry and biocollection data showed good concordance with directly measured population AFs. The estimated region-specific frequencies of CFTR variants allowed us to uncover statistically significant regional differences in the frequencies of the F508del (c.1521_1523del; p.Phe508del) and CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb; p.Ser18ArgfsX) variants. The data from population-based studies confirmed previous observations that F508del, CFTRdele2,3(21kb), and L138ins (c.413_415dup; p.Leu138dup)variants are the most abundant among infertile patients, and their frequencies are significantly lower in healthy individuals and should be taken into account during genetic monitoring of the reproductive health of Russian individuals. [ABSTRACT FROM AUTHOR]

–CoMo sulfide catalysts supported on aluminosilicate halloysite nanotubes (CoMoS/HNT) and on dealuminated halloysite nanotubes (CoMoS/HNT(deAl)) were synthesized by incipient wetness impregnation using pseudoboehmite as a binder. Both the supports and related catalysts were characterized by low-temperature nitrogen adsorption, energy dispersive X-ray fluorescence analysis, temperature-programmed reduction by hydrogen, FTIR spectroscopy of adsorbed pyridine, transmission electron microscopy, and X-ray photoelectron spectroscopy. The catalyst samples were further tested in hydrotreating of diesel feedstocks. Dealumination of halloysite was found to increase the area of Si-enriched surface segments, thus weakening interaction between the sulfide phase and the support and, hence, increasing the content of highly active sulfide particles. In the case of a mixed feedstock, CoMoS/HNT(deAl) + Al2O3 achieved a reaction rate constant of 0.605 ppm S–0.4/g(L–0.4 h) compared to 0.429 ppm S–0.4/g(L–0.4 h) for an alumina-supported sample. [ABSTRACT FROM AUTHOR]

Background: Potocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging. Case presentation: We report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region. Conclusions: Children with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) has revolutionized the field of rare disease diagnostics. Whole exome and whole genome sequencing are now routinely used for diagnostic purposes; however, the overall diagnosis rate remains lower than expected. In this work, we review current approaches used for calling and interpretation of germline genetic variants in the human genome, and discuss the most important challenges that persist in the bioinformatic analysis of NGS data in medical genetics. We describe and attempt to quantitatively assess the remaining problems, such as the quality of the reference genome sequence, reproducible coverage biases, or variant calling accuracy in complex regions of the genome. We also discuss the prospects of switching to the complete human genome assembly or the human pan-genome and important caveats associated with such a switch. We touch on arguably the hardest problem of NGS data analysis for medical genomics, namely, the annotation of genetic variants and their subsequent interpretation. We highlight the most challenging aspects of annotation and prioritization of both coding and non-coding variants. Finally, we demonstrate the persistent prevalence of pathogenic variants in the coding genome, and outline research directions that may enhance the efficiency of NGS-based disease diagnostics. [ABSTRACT FROM AUTHOR]

Ganglioside-monosialic acid (GM1) gangliosidosis (ICD-10: E75.1; OMIM: 230500, 230600, 230650) is a rare autosomal recessive hereditary disease, lysosomal storage disorder caused by mutations in the GLB1 gene that lead to the absence or insufficiency of β-galactosidase. In this study, we report a case of a Russian family with a history of GM1 gangliosidosis. The family had a child who, from the age of 6 months, experienced a gradual loss of developmental skills, marked by muscle flaccidity, psychomotor retardation, hepatosplenomegaly, and the onset of tonic seizures by the age of 8 months. Funduscopic examination revealed a «cherry red spot» in the macula, which is crucial for the diagnosis of lipid storage disorders. To find the pathogenic variants responsible for these clinical symptoms, the next-generation sequencing approach was used. The analysis revealed two variants in the heterozygous state: a frameshift variant c.699delG (rs1452318343, ClinVar ID 928700) in exon 6 and a missense variant c.809A>C (rs371546950, ClinVar ID 198727) in exon 8 of the GLB1 gene. The spouses were advised to plan the pregnancy with assisted reproductive technology (ART), followed by preimplantation genetic testing for monogenic disorder (PGT-M) on the embryos. Trophectoderm biopsy was performed on 8 out of 10 resulting embryos at the blastocyst stage. To perform PGT-M, we developed a novel testing system, allowing for direct analysis of disease-causing mutations, as well as haplotype analysis based on the study of polymorphic markers--short tandem repeats (STR), located upstream and downstream of the GLB1 gene. The results showed that four embryos were heterozygous carriers of pathogenic variants in the GLB1 gene (#1, 2, 5, 8). Two embryos had a compound heterozygous genotype (#3, 4), while the embryos #7 and 9 did not carry disease-causing alleles of the GLB1 gene. The embryo #7 without pathogenic variants was transferred after consideration of its morphology and growth rate. Prenatal diagnosis in the first trimester showed the absence of the variants analyzed in the GLB1 gene in the fetus. The pregnancy resulted in the delivery of a female infant who did not inherit the disease-causing variants in the GLB1 gene. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy is a neuromuscular disorder caused by mutations in both copies of the survival motor neuron gene 1 (SMN1), which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with many more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still has not been identified. This study aimed to describe a fast and reliable method using the number of gems in cell nuclei as a potential tool for assessment of splicing correction of oligonucleotide efficacy in SMA cells. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gem number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from a healthy individual. We discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. The SMA fibroblasts treated with antisense oligonucleotide showed beneficial effects in correcting the abnormal splicing of SMN2 exon 7. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcript sharing. Based on our findings, we propose using the quantity of gems as a reliable biomarker for SMA drug development. [ABSTRACT FROM AUTHOR]

The spatio-temporal dynamics of plasma in a symmetrical dual-frequency 81 MHz/1.76 MHz capacitive discharge under the influence of a low-frequency 1.76 MHz field has been studied. Using phase-resolved optical emission spectroscopy, the dynamics of argon and xenon emission intensity in the plasma was obtained. Measurements of the electron energy probability function (EEPF) at the center of the discharge were performed using a Langmuir probe, and electron density measurements were made using a hairpin probe. The main result is the dynamics of the intensity ratios of selected argon and xenon lines under different conditions: at pressures of 40, 200, and 400 mTorr, low-frequency voltage amplitudes of 100, 200, and 400 V, and input power at 81 MHz of 3 and 15 W. The dynamics of high-energy electrons was investigated based on a two-temperature approximation of the electron energy probability function. [ABSTRACT FROM AUTHOR]

One of the steps in scaling the technology for the synthesis of zeolite-containing catalysts from the laboratory to commercial level is support forming. In this study, halloysite nanotubes and aluminum oxide were used as binders for preparing a support based on MFI (ZSM-5) zeolite. The Pt catalysts (Pt/ZSM-5/Al2O3 and Pt/ZSM-5/Hall) were tested in isomerization of the aromatic C8 fraction. The forming of supports influenced not only mechanical but also physicochemical properties of the catalysts. On introducing binders into the catalytic system, the fraction of mesopores in the total pore volume of the supports increased, the acidity of the samples decreased, and the ratio of the amounts of the weak and strong acid sites changed. The use of aluminum oxide and halloysite as binders leads to different pathways of the transformation of the aromatic feedstock. The main side reactions observed in the presence of Pt/ZSM-5/Al2O3 and Pt/ZSM-5/Hall catalysts are hydrocracking of alkylaromatic hydrocarbons and their transalkylation/disproportionation, respectively. The best results were obtained at 380°C and feed space velocity of 6 h–1 with Pt/ZSM-5/Hall: p-/о-xylene ratio 1.05, loss of xylenes 4.31%, and ethylbenzene conversion 34%. [ABSTRACT FROM AUTHOR]

Preeclampsia is a disorder that can occur during pregnancy and is one of the leading causes of death among pregnant women. This disorder occurs after the 20th week of pregnancy and is characterized by arterial hypertension, proteinuria, fetoplacental, and multiple organ dysfunctions. Despite the long history of studying preeclampsia, its etiology and pathogenesis remain poorly understood, and therapy is symptomatic. One of the factors of the disorder is believed to be misfolded proteins that are prone to form amyloid aggregates. The CRD tests, utilizing the binding of the amyloid-specific dye Congo red to urine components, demonstrate high efficiency in diagnosing preeclampsia. However, these tests have also been found to be positive in other disorders with proteinuria, presumably associated with concomitant amyloidosis. To assess the limitations of the CRD tests, we examined urine congophilia and protein components mediating Congo red positivity in patients with proteinuria, including preeclampsia, amyloid and non-amyloid nephropathies. We stained the urine samples and calculated congophilia levels. We also assessed the contribution of large protein aggregates to congophilia values using ultracentrifugation and determined the molecular weights of congophilic urinary proteins using centrifugal concentrators. All proteinuric groups demonstrate positive results in the CRD tests and congophilia levels were more than two times higher compared with the control non-proteinuric groups (p <0.01). There was a strong correlation between urine protein excretion and congophilia in amyloid nephropathy (rs = 0.76), non-amyloid nephropathies (rs = 0.90), and preeclampsia (rs = 0.90). Removal of large aggregates from urine did not affect the congophilia levels. Separation of urine protein fractions revealed congophilic components in the range of 30–100 kDa, including monomeric serum albumin. Our results indicate limitations of CRD tests in preeclampsia diagnostics in women with renal disorders and underscore the need for further research on the mechanisms of Congo red binding with urine components. [ABSTRACT FROM AUTHOR]

The combustion process of porous spherical titanium particles with diameters in the range of 100-400 μm was studied in free fall in air (as single particles), and in composite propellant (as metallic fuel). The particles burning times in air at atmospheric pressure were determined by video recording. Twelve composite propellant containing 60% AP of sieve fraction 180-250 μm, 20% energetic binder, and 20% titanium powder of various size and type (with porous particles and with rolled in ball mill pseudospherical particles) were studied. The propellant burning rate and the agglomeration parameters were determined at pressures of 0.35 MPa in nitrogen and at 0.1 MPa in air. It was established that the smallest agglomerates are formed when titanium powders of the smallest dimensions are used. [ABSTRACT FROM AUTHOR]

Simple Summary: Genome-wide association studies (GWAS) are a powerful tool for the identification of genes affecting human traits. Still, the interpretation of GWAS results is complicated, and new tools are actively being developed. Due to the scarcity of available datasets, simulation of GWAS data with known genetic effects is important as it enables accurate evaluation of such tools. In this study, we developed a flexible tool, bioGWAS, that provides a set of important functionalities for simulating GWAS results. We demonstrate that bioGWAS can efficiently generate GWAS results with predefined causal genes and biological processes and is capable of recapitulating the results of published GWAS studies. We thus believe that bioGWAS is an excellent method for testing bioinformatics software for GWAS results processing, as well as for the generation of datasets for educational purposes. Genome-wide association studies (GWAS) have proven to be a powerful tool for the identification of genetic susceptibility loci affecting human complex traits. In addition to pinpointing individual genes involved in a particular trait, GWAS results can be used to discover relevant biological processes for these traits. The development of new tools for extracting such information from GWAS results requires large-scale datasets with known biological ground truth. Simulation of GWAS results is a powerful method that may provide such datasets and facilitate the development of new methods. In this work, we developed bioGWAS, a simple and flexible pipeline for the simulation of genotypes, phenotypes, and GWAS summary statistics. Unlike existing methods, bioGWAS can be used to generate GWAS results for simulated quantitative and binary traits with a predefined set of causal genetic variants and/or molecular pathways. We demonstrate that the proposed method can recapitulate complete GWAS datasets using a set of reported genome-wide associations. We also used our method to benchmark several tools for gene set enrichment analysis for GWAS data. Taken together, our results suggest that bioGWAS provides an important set of functionalities that would aid the development of new methods for downstream processing of GWAS results. [ABSTRACT FROM AUTHOR]

Pregnancy loss is the most frequent complication of a pregnancy which is devastating for affected families and poses a significant challenge for the health care system. Genetic factors are known to play an important role in the etiology of pregnancy loss; however, despite advances in diagnostics, the causes remain unexplained in more than 30% of cases. In this review, we aggregated the results of the decade-long studies into the genetic risk factors of pregnancy loss (including miscarriage, termination for fetal abnormality, and recurrent pregnancy loss) in euploid pregnancies, focusing on the spectrum of point mutations associated with these conditions. We reviewed the evolution of molecular genetics methods used for the genetic research into causes of pregnancy loss, and collected information about 270 individual genetic variants in 196 unique genes reported as genetic cause of pregnancy loss. Among these, variants in 18 genes have been reported by multiple studies, and two or more variants were reported as causing pregnancy loss for 57 genes. Further analysis of the properties of all known pregnancy loss genes showed that they correspond to broadly expressed, highly evolutionary conserved genes involved in crucial cell differentiation and developmental processes and related signaling pathways. Given the features of known genes, we made an effort to construct a list of candidate genes, variants in which may be expected to contribute to pregnancy loss. We believe that our results may be useful for prediction of pregnancy loss risk in couples, as well as for further investigation and revealing genetic etiology of pregnancy loss. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2D) is a chronic metabolic disease characterized by insulin resistance and β-cell dysfunction and leading to many micro- and macrovascular complications. In this study we analyzed the circulating miRNA expression profiles in plasma samples from 44 patients with T2D and 22 healthy individuals using next generation sequencing and detected 229 differentially expressed miRNAs. An increased level of miR-5588-5p, miR-125b-2-3p, miR-1284, and a reduced level of miR-496 in T2D patients was verified. We also compared the expression landscapes in the same group of patients depending on body mass index and identified differential expression of miR-144-3p and miR-99a-5p in obese individuals. Identification and functional analysis of putative target genes was performed for miR-5588-5p, miR-125b-2-3p, miR-1284, and miR-496, showing chromatin modifying enzymes and apoptotic genes being among the significantly enriched pathways. [ABSTRACT FROM AUTHOR]

A tetrahedral structure model has been proposed to estimate the size of metal agglomerates during combustion of a composite solid propellant. According to this model, oxidizer particles are located at the vertices of a regular tetrahedron and the internal volume of the pyramid is occupied by a mixture of a fuel-binder and metal—the so-called "pocket." Experimental data are compared with the results of calculations using the tetrahedral model, the Cohen model, and the empirical correlations proposed by Hermsen, Salita, Beckstead, Grigoriev, and Duterque. The comparison was made for a composite propellant containing ammonium perchlorate, a binder, and aluminum. It is shown that in some cases the tetrahedral model better predicts the diameter of agglomerates than the other models. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) and acute graft-versus-host disease (GVHD) are associated with persistent intestinal dysfunction preceded by gut bacterial dysbiosis. There are limited data on intestinal bacteriophages in these conditions. The aim of the present work was to detect associations between dominant intestinal bacteria by means of 16S rRNA gene sequencing, and some clinically significant viruses detected with a customized primer panel for NGS-based study. The clinical group included patients with Crohn's disease (IBD, n = 9), or GVHD (n = 6) subjected to fecal microbiota transplantation (FMT) from healthy donors. The stool specimens were taken initially, and 5 times post-FMT until day 120. Using NGS approach, we have found a higher abundance of Proteobacterota phylum in GVHD, especially, at later terms post-FMT. Moreover, we found an early increase of Klebsiella and E. coli/Shigella abundance in GVHD, along with decreased relative content of Faecalibacterium. Upon evaluation of intestinal phageome, the relative amount of Caudoviricetes class was higher in GVHD. A significant correlation was found between Proteobacteria and Caudoviricetes, thus suggesting their association during the post-FMT period. Moreover, the relative amounts of five Caudoviricetes phage species showed distinct correlations with Klebsiella and Enterococcus ratios at different terms of FMT. In conclusion, parallel use of 16S rRNA gene sequencing and targeted NGS viral panel is a feasible and useful option for tracing specific viral strains in fecal microbiota. The developed array of viral primers may be extended to detect other phages infecting the clinically relevant bacteria. [ABSTRACT FROM AUTHOR]

Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease caused by mutations in the SMN1 gene. Existing therapies demonstrate positive results on SMA patients but still might be ameliorated in efficacy and price. In the presented study we designed antisense oligonucleotides (AONs), targeting intronic splicing silencer sites, some were modified with 2′-O-methyl, others with LNA. The AONs have been extensively tested in different concentrations, both individually and combined, in order to effectively target the ISS-N1 and A+100G splicing silencer regions in intron 7 of the SMN2 gene. By treating SMA-cultured fibroblasts with certain AONs, we discovered a remarkable increase in the levels of full-length SMN transcripts and the number of nuclear gems. This increase was observed to be dose-dependent and reached levels comparable to those found in healthy cells. When added to cells together, most of the tested molecules showed a remarkable synergistic effect in correcting splicing. Through our research, we have discovered that the impact of oligonucleotides is greatly influenced by their length, sequence, and pattern of modification. [ABSTRACT FROM AUTHOR]

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene–disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene–disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity. [ABSTRACT FROM AUTHOR]

Massive localized lymphedema (MLL) is a rare disease caused by the obstruction of lymphatic vessels with specific clinical morphological and radiological characteristics. People with morbid obesity are mainly affected by MLL. Lymphedema is easily confused with soft tissue sarcoma and requires differential diagnosis, both the possibility of an MLL and also carcinoma manifestations in the soft tissues. The possible causes of massive lymphedema include trauma, surgery, and hypothyroidism. This report is the first case of MLL treated surgically in the Russian Federation. Detailed computed tomography (CT) characteristics and an electron microscope picture of MLL are discussed. A 50-year-old woman (body mass index of 43 kg/m 2) with MLL arising from the anterior abdominal wall was admitted to the hospital for surgical treatment. Its mass was 22.16 kg. A morphological study of the resected mass confirmed the diagnosis of MLL. We review etiology, clinical presentation, diagnosis, and treatment of MLL. We also performed an electron-microscopic study that revealed interstitial Cajal-like cells telocytes not previously described in MLL cases. We did not find similar findings in the literature. It is possible that the conduction of an ultrastructural examination of MLL tissue samples will further contribute to the understanding of MLL pathogenesis. [ABSTRACT FROM AUTHOR]

A method is developed to produce large titanium monolithic burning particles with a diameter of 250–550 μm. The combustion of titanium particles in free fall in air is investigated. The characteristic times of the beginning of fragmentation, end of fragmentation, and end of burning as well as the laws of motion of particles (in particular, coordinate and velocity at the starting moment of fragmentation) are determined using video recording. The size of particles at which the fragmentation mode changes from "star" to "fir branch" is estimated. [ABSTRACT FROM AUTHOR]

Upgrading the properties of diesel fractions is considered one of the crucial processes in the petrochemical industry; and for this purpose in laboratory-scale researching it is studied on the base of the hydroisomerization of n-hexadecane as a main model reaction. Recently, zeolite-based bifunctional catalysts have proven their efficiency due to their remarkable acidity, shape-selectivity and relative resistance to deactivation. In this review, different topological-type zeolite-based catalysts, the mechanism of their catalytic effect in n-C16 isomerization, and the principles of shape-selectivity are reviewed. A comparison of their structural-operational characteristics is made. The impact of some feedstock impurities on the catalyst's performance and deactivation due to carbonaceous deposits as well as various modern eco-friendly cost-effective synthesis techniques are also discussed. [ABSTRACT FROM AUTHOR]

The present study investigates a series of gallium-based catalysts supported on natural and composite aluminosilicate mesoporous supports in the CO2-assisted oxidative dehydrogenation of propane. The catalyst supports were prepared by mixing a functional material with a boehmite binder, the functional materials being derived from natural halloysite nanotubes (HNTs). Three different supports were used: pristine HNTs; HNTs with MCM-41 synthesized around halloysite; and HNTs with MCM-41 synthesized inside the halloysite lumen. The CO2-assisted oxidative propane dehydrogenation was tested in the range of 550–700°C at a CO2/C3H8 molar ratio of 2.0. All the catalysts showed comparable propane conversion (from 10–13% to 70–80%) and propylene selectivity (from 80–84 to 30–32%). The highest propylene space-time yield (6.5 mol kgcat–1 h–1) was observed for the Ga/HNT catalyst at 650°C. [ABSTRACT FROM AUTHOR]

This review discusses recent advances in catalytic hydrodeoxygenation of lignocellulosic biomass. Lignocellulosic biomass is the most promising plant-based raw material for the production of liquid engine fuels or individual petrochemical monomers. Among the several existing techniques for biomass processing, pyrolysis offers superior efficiency. Given that the bio-oil produced by biomass pyrolysis has unsatisfactory performance characteristics caused by the presence of oxygenates, this bio-oil cannot be used directly as a fuel. Hydrodeoxygenation using selective catalysts is able to reduce the oxygen content in bio-oil and to improve its performance characteristics. To this end, bifunctional catalysts that contain active metal sites on an acid support hold promise. Noble metals (e.g., Pt, Pd, and Ru) and/or transition metals (e.g., Ni, Co, and Mo), as well as sulfides and phosphides of transition metals, can be used as an active catalytic phase. Metal oxides (e.g., ZrO2, CeO2, Al2O3, and TiO2), carbon, zeolites (e.g., ZSM-5, Y, Beta, and SAPO-11), and mesoporous silica-based materials (e.g., SBA-15 and MCM-41) have been most often used as supports in hydrodeoxygenation catalysts. However, the implementation and upscaling of the hydrodeoxygenation of biomass pyrolytic bio-oil is limited because of the rapid deactivation of the catalyst in the presence of water, due to sintering and leaching the active phase with acidic components of bio-oil. Therefore, the development of catalysts that would provide high activity and stability under bio-oil hydrodeoxygenation conditions has become one of the most pressing issues for the petrochemical industry. [ABSTRACT FROM AUTHOR]

On 24 February 2022, Russia launched a full-scale invasion of Ukraine, which is now in its second year. The invasion disrupted higher education institutions across the country and forced both staff and students to adapt to the new reality. This article focuses on the experiences of university students to understand how their educational process was impacted by the invasion. The research data comprise written testimonies from 81 students at the Taras Shevchenko National University of Kyiv. Thematic analysis of the data resulted in three themes: organisation of studies by the university; self-organisation of studies; and personal experiences. The article concludes that the invasion shifted the educational process online; however, students are often prevented from accessing the virtual classrooms due to constant air raids, power outages and connectivity issues with the internet, thus leading students towards more self-studying. [ABSTRACT FROM AUTHOR]

An overview of the tribe Lomechusini (Coleoptera: Staphylinidae) from Ukraine is presented. It summarises all published data and new information on the group. Totally, six genera with 18 species are presented. The genera are: Lomechusa with three species (L. emarginata, L. paradoxa and L. pubicollis), Lomechusoides with one species (L. strumosus strumosus), Drusilla with one species (D. canaliculata), Myrmoecia with one species (M. plicata), Pella with nine species (P. cognata, P. funesta, P. hampei, P. humeralis, P. laticollis, P. limbata, P. lugens, P. ruficollis and P. similis) and Zyras with three species (Z. collaris, Z. fulgidus and Z. haworthi). The information on the distribution of the species recorded from the territory of Ukraine is clarified and supplemented. [ABSTRACT FROM AUTHOR]

Lopes–Maciel–Rodan syndrome (LOMARS) is an extremely rare disorder, with only a few cases reported worldwide. LOMARS is caused by a compound heterozygous mutation in the HTT gene. Little is known about LOMARS pathogenesis and clinical manifestations. Whole exome sequencing (WES) was performed to achieve a definitive molecular diagnosis of the disorder. All NGS-identified variants underwent the Sanger confirmation. In addition, a literature review on genetic variations in the HTT gene was conducted. The paper reports a case of LOMARS in a pediatric patient in Russia. A preterm girl of non-consanguineous parents demonstrated severe psychomotor developmental delays in her first 12 months. By the age of 6 years, she failed to develop speech but was able to understand everyday phrases and perform simple commands. Autism-like behaviors, stereotypies, and bruxism were noted during the examination. WES revealed two undescribed variants of unknown clinical significance in the HTT gene, presumably associated with the patient's phenotype (c.2350C>T and c.8440C>A). Medical re-examination of parents revealed that the patient inherited these variants from her father and mother. Lopes–Maciel–Rodan syndrome was diagnosed based on overlapping clinical findings and the follow-up genetic examination of parents. Our finding expands the number of reported LOMARS cases and provides new insights into the genetic basis of the disease. [ABSTRACT FROM AUTHOR]

The Fischer–Tropsch process is considered one of the most promising eco-friendly routes for obtaining synthetic motor fuels. Fischer–Tropsch synthesis is a heterogeneous catalytic process in which a synthesis gas (CO/H2) transforms into a mixture of aliphatic hydrocarbons, mainly linear alkanes. Recently, an important direction has been to increase the selectivity of the process for the diesel fraction. Diesel fuel synthesized via the Fischer–Tropsch method has a number of advantages over conventional fuel, including the high cetane number, the low content of aromatic, and the practically absent sulfur and nitrogen impurities. One of the possible ways to obtain a high yield of diesel fuel via the Fischer–Tropsch process is the development of selective catalysts. In this review, the latest achievements in the field of production of diesel via Fischer–Tropsch synthesis using catalysts are reviewed for the first time. Catalytic systems based on Al2O3 and mesoporous silicates, such as MCM-41, SBA-15, and micro- and mesoporous zeolites, are observed. Together with catalytic systems, the main factors that influence diesel fuel selectivity such as temperature, pressure, CO:H2 ratio, active metal particle size, and carrier pore size are highlighted. The motivation behind this work is due to the increasing need for alternative processes in diesel fuel production with a low sulfur content and better exploitation characteristics. [ABSTRACT FROM AUTHOR]

Mixed sulfided CoMo catalysts supported on γ-Al2O3 and halloysite nanotubes (HNTs) were synthesized by incipient wetness impregnation with salt solutions of Keggin-type phosphorus- and vanadium-containing heteropolyacids. The synthesized materials were characterized by low-temperature nitrogen adsorption, energy dispersive X-ray fluorescence analysis, temperature-programmed reduction (both for the oxide and sulfide catalysts), and Raman spectroscopy, and were tested in hydrogenation of naphthalene and hydrodesulfurization of dibenzothiophene. The HNT-supported catalyst exhibited a greater activity in these reactions. [ABSTRACT FROM AUTHOR]

Gram-scale Ru-containing catalysts templated on structured mesoporous silica of MCM-41 type reinforced with natural aluminosilicate halloysite nanotubes (HNT), as well as their analogues based on pristine halloysite, were synthesized by wetness impregnation under microwave irradiation. The structural properties and elemental composition of the catalysts were studied by TEM, XRD, TPR-H2, and XRF. Textural characteristics were determined by low-temperature nitrogen adsorption/desorption. The catalytic properties in hydrogenation of aromatic-rich model feed and gasoline fraction were studied in batch reactors in the temperature range of 60–150 °C, under hydrogen pressure of 3 MPa, and a substrate/Ru molar ratio of 2000 for 3 h. Comparing the results of the catalytic tests, we can conclude that each material has its own advantage for the treatment of aromatic-rich feed under specific operating conditions. The Ru/HNT and Ru/MCM-41/HNT catalysts performed best in the 60–100 °C and 60–80 °C temperature regions, respectively, for the removal of aromatics, e.g. benzene, to meet ecological restrictions while retaining the octane numbers. [ABSTRACT FROM AUTHOR]

Bacterial microbiota in stool may vary over a wide range, depending on age, nutrition, etc. The purpose of our work was to discriminate phyla and genera of intestinal bacteria and their biodiversity within a healthy population (North-Western Russia) compared to the patients with type 1 diabetes mellitus (T1DM). The study group included 183 healthy persons 2 to 53 years old (a mean of 26.5 ± 1.0 years old), and 41 T1DM patients (mean age 18.2 ± 1.8 years old). The disease onset was at 11 ± 1.5 years, with a T1DM experience of 7 ± 1.5 years. Total DNA was isolated from the stool samples, and sequencing libraries were prepared by amplifying the V3–V4 region of the 16S rRNA gene sequenced by Illumina MiSeq. Bioinformatic processing of NGS databases was adapted for microbiota evalutaion. Despite the broad scatter, the biological diversity for bacterial microbiota expressed as the Shannon index was significantly increased from younger to older ages in the comparison group, higher in adult healthy persons, with a trend for decrease in the Actinomycetota phylum which includes Bifidobacterium longum species. Similar but non-significant age trends were noted in the T1DM group. Concordant with the Bacillota prevalence in stool samples of diabetic patients, some anaerobic bacteria (Faecalibacteria, Lachnospira and Ruminococcae, Roseburia) were enriched in the T1DM microbiome against controls. Hence, correction of microbiota for Ruminococcus and Lachnospiraceae requires future search for new probiotics. Lower abundance of Actinomycetota and Bifidobacter in T1DM suggests potential usage of Bifidobacter-based probiotics in this cohort. [ABSTRACT FROM AUTHOR]

Iron- and Cu–Zn-containing carbon dioxide hydrogenation catalysts based on natural aluminosilicate nanotubes and zeolite H-ZSM-5 are synthesized. Their textural and acidic properties are studied via low-temperature nitrogen adsorption–desorption, temperature-programmed desorption of ammonia, temperature-programmed reduction of hydrogen, and elemental analysis. The effect the temperatures of the reaction have on the conversion of CO2 and distribution of its product is studied. Catalysts based on aluminosilicate halloysite nanotubes exhibit methanol and С2–С4 hydrocarbon selectivities of 88 and 16%, respectively. [ABSTRACT FROM AUTHOR]

The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. The reflective sympathetic constriction of the resistive vessels is realized via ADRA1A. It has been shown that ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with changes in tonus in vessel walls. Moreover, the Cys347 allele has been shown to regulate systolic blood pressure. The aim of this work was to evaluate whether the ADRA1A polymorphism affected the pulmonary vascular reactions in men and women in response to the diving reflex. Men (n = 52) and women (n = 50) untrained in diving aged 18 to 25 were recruited into the study. The vascular reactions and blood flow were examined by integrated rheography and rheography of the pulmonary artery. Peripheral blood circulation was registered by plethysmography. The ADRA1A gene polymorphism (p.Arg347Cys; rs1048101) was determined by PCR-RFLP. In both men and women, reflective pulmonary vasodilation did occur in response to the diving reflex, but in women this vasodilation was more pronounced and was accompanied by a higher filling of the lungs with blood.. Additionally, ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with sex. Interestingly, women with the Arg347 allele demonstrated the highest vasodilation of the lung vessels. Therefore, our data may help to indicate women with the most prominent adaptive reactions to the diving reflex. Our data also indicate that women and men with the Cys allele of the ADRA1A gene polymorphism have the highest risk of developing lung hypertension in response to the diving reflex. The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. [ABSTRACT FROM AUTHOR]

Gliomas, one of the most severe malignant tumors of the central nervous system, have a high mortality rate and an increased risk of recurrence. Therefore, early glioma diagnosis and the control of treatment have great significance. The blood plasma samples of glioma patients, patients with skull craniectomy defects, and healthy donors were studied using terahertz time-domain spectroscopy (THz-TDS). An analysis of experimental THz data was performed by machine learning (ML). The ML pipeline included (i) THz spectra smoothing using the Savitzky–Golay filter, (ii) dimension reduction with principal component analysis and t-distribution stochastic neighborhood embedding methods; (iii) data separability analyzed using Support Vector Machine (SVM), Random Forest (RF), and Extreme Gradient Boosting (XGBoost). The ML models' performance was evaluated by a k-fold cross validation technique using ROC-AUC, sensitivity, and specificity metrics. It was shown that tree-based ensemble methods work more accurately than SVM. RF and XGBoost provided a better differentiation of the group of patients with glioma from healthy donors and patients with skull craniectomy defects. THz-TDS combined with ML was shown to make it possible to separate the blood plasma of patients before and after tumor removal surgery (AUC = 0.92). Thus, the applicability of THz-TDS and ML for the diagnosis of glioma and treatment monitoring has been shown. [ABSTRACT FROM AUTHOR]

The oxidative dehydrogenation of alkanes is a prospective method for olefins production. CO2-assisted propane dehydrogenation over metal oxide catalysts provides an opportunity to increase propylene production with collateral CO2 utilization. We prepared the chromia catalysts on various mesoporous aluminosilicate supports, such as halloysite nanotubes, nanostructured core/shell composites of MCM-41/halloysite (halloysite nanotubes for the core; silica of MCM-41-type for the shell), and MCM-41@halloysite (silica of MCM-41-type for the core; halloysite nanotubes for the shell). The catalysts have been characterized by X-ray fluorescence analysis, low-temperature nitrogen adsorption, X-ray diffraction, temperature-programmed reduction, temperature-programmed desorption of ammonia, transmission electron microscopy with energy-dispersive X-ray spectroscopy, and thermogravimetric analysis. The catalysts' performance in carbon-dioxide-assisted propane dehydrogenation has been estimated in a fixed-bed reactor at atmospheric pressure. The most stable catalyst is Cr/halloysite, having the lowest activity and the largest pore diameter. The catalyst, Cr/MCM-41/HNT, shows the best catalytic performance: having the highest conversion (19–88%), selectivity (83–30%), and space–time yield (4.3–7.1 mol C3H6/kg catalyst/h) at the temperature range of 550–700 °C. The highest space–time yield could be related to the uniform distribution of the chromia particles over the large surface area and narrow pore size distribution of 2–4 nm provided by the MCM-41-type silica and transport channels of 12–15 nm from the halloysite nanotubes. [ABSTRACT FROM AUTHOR]

This paper describes the method and results of an experimental study of unsteady burning rate of high-energy materials containing metal powder additives under depressurization at a rate of 140–160 MPa/s. The method based on stating and solving the inverse problem of internal ballistics is used to determine the unsteady burning rate. The studies are carried out for high-energy materials, including energy additives in the form of metal powders (ASD-4, ASD-6, and Alex aluminum powders), aluminum diboride, and dodecaboride. It is shown by analyzing the this study that the unsteady burning rate of high-energy materials under sharp depressurization is oscillatory and depends on the energy additive type. [ABSTRACT FROM AUTHOR]

We report on the case of prenatal detection of trisomy 2 in placental biopsy and further algorithm of genetic counseling and testing. A 29-year-old woman with first-trimester biochemical markers refused chorionic villus sampling and preferred targeted non-invasive prenatal testing (NIPT), which showed low risk for aneuploidies 13, 18, 21, and X. A series of ultrasound examinations revealed increased chorion thickness at 13/14 weeks of gestation and fetal growth retardation, a hyperechoic bowel, challenging visualization of the kidneys, dolichocephaly, ventriculomegaly, increase in placental thickness, and pronounced oligohydramnios at 16/17 weeks of gestation. The patient was referred to our center for an invasive prenatal diagnosis. The patient's blood and placenta were sampled for whole-genome sequencing-based NIPT and array comparative genomic hybridization (aCGH), respectively. Both investigations revealed trisomy 2. Further prenatal genetic testing in order to confirm trisomy 2 in amniocytes and/or fetal blood was highly questionable because oligohydramnios and fetal growth retardation made amniocentesis and cordocentesis technically unfeasible. The patient opted to terminate the pregnancy. Pathological examination of the fetus revealed internal hydrocephalus, atrophy of brain structure, and craniofacial dysmorphism. Conventional cytogenetic analysis and fluorescence in situ hybridization revealed chromosome 2 mosaicism with a prevalence of trisomic clone in the placenta (83.2% vs. 16.8%) and a low frequency of trisomy 2, which did not exceed 0.6% in fetal tissues, advocating for low-level true fetal mosaicism. To conclude, in pregnancies at risk of fetal chromosomal abnormalities that refuse invasive prenatal diagnosis, whole-genome sequencing-based NIPT, but not targeted NIPT, should be considered. In prenatal cases of trisomy 2, true mosaicism should be distinguished from placental-confined mosaicism using cytogenetic analysis of amniotic fluid cells or fetal blood cells. However, if material sampling is impossible due to oligohydramnios and/or fetal growth retardation, further decisions should be based on a series of high-resolution fetal ultrasound examinations. Genetic counseling for the risk of uniparental disomy in a fetus is also required. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) is a method that focuses on the analysis of gene expression profile in individual cells. This method has been successfully applied to answer the challenging questions of the pathogenesis of multifactorial diseases and open up new possibilities in the prognosis and prevention of reproductive diseases. In this article, we have reviewed the application of scRNA-seq to the analysis of the various cell types and their gene expression changes in normal pregnancy and pregnancy complications. The main principle, advantages, and limitations of single-cell technologies and data analysis methods are described. We discuss the possibilities of using the scRNA-seq method for solving the fundamental and applied tasks related to various pregnancy-associated disorders. Finally, we provide an overview of the scRNA-seq findings for the common pregnancy-associated conditions, such as hyperglycemia in pregnancy, recurrent pregnancy loss, preterm labor, polycystic ovary syndrome, and pre-eclampsia. [ABSTRACT FROM AUTHOR]

Introduction: Floating Harbor syndrome (FHS) is an extremely rare disorder, with slightly more than a hundred cases reported worldwide. FHS is caused by heterozygous mutations in the SRCAP gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment. Methods: Whole-exome sequencing (WES) was performed for the definitive molecular diagnosis of the disease. Identified variants were validated using Sanger sequencing. In addition, systematic literature and public data on genetic variation in SRCAP and the effects of growth hormone (GH) treatment was conducted. Results: We herein report the first case of FHS in the Russian Federation. The male proband presented with most of the typical phenotypic features of FHS, including short stature, skeletal and facial features, delayed growth and bone age, high pitched voice, and intellectual impairment. The proband also had partial growth hormone deficiency. We report the history of treatment of the proband with GH, which resulted in modest improvement in growth prior to puberty. WES revealed a pathogenic c.7466C>G (p.Ser2489*) mutation in the last exon of the FHS-linked SRCAP gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in SRCAP and confirmed the lack of pathogenicity for variants outside of exons 33 and 34. Finally, we suggested a new model of FHS pathogenesis which provides possible basis for the dominant negative nature of FHS-causing mutations and explains limited effects of GH treatment in FHS. Conclusion: Our findings expand the number of reported FHS cases and provide new insights into disease genetics and the efficiency of GH therapy for FHS patients. [ABSTRACT FROM AUTHOR]

Although high altitude training has been increasingly popular among endurance athletes, the molecular and cellular bases of this adaptation remain poorly understood. We aimed to define the underlying physiological changes and screen for potential biomarkers of adaptation using transcriptional profiling of whole blood. Seven elite female speed skaters were profiled on the 18th day of high-altitude adaptation. Whole blood RNA-seq before and after an intense 1 h skating bout was used to measure gene expression changes associated with exercise. In order to identify the genes specifically regulated at high altitudes, we have leveraged the data from eight previously published microarray datasets studying blood expression changes after exercise at sea level. Using cell type-specific signatures, we were able to deconvolute changes of cell type abundance from individual gene expression changes. Among these were PHOSPHO1, with a known role in erythropoiesis, and MARC1 with a role in endogenic NO metabolism. We find that platelet and erythrocyte counts uniquely respond to altitude exercise, while changes in neutrophils represent a more generic marker of intense exercise. Publicly available data from both single cell atlases and exercise-related blood profiling dramatically increases the value of whole blood RNA-seq for the dynamic evaluation of physiological changes in an athlete's body. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has drawn the attention of many researchers to the interaction between pathogen and host genomes. Over the last two years, numerous studies have been conducted to identify the genetic risk factors that predict COVID-19 severity and outcome. However, such an analysis might be complicated in cohorts of limited size and/or in case of limited breadth of genome coverage. In this work, we tried to circumvent these challenges by searching for candidate genes and genetic variants associated with a variety of quantitative and binary traits in a cohort of 840 COVID-19 patients from Russia. While we found no gene- or pathway-level associations with the disease severity and outcome, we discovered eleven independent candidate loci associated with quantitative traits in COVID-19 patients. Out of these, the most significant associations correspond to rs1651553 in MYH14p = 1.4 × 10−7), rs11243705 in SETX (p = 8.2 × 10−6), and rs16885 in ATXN1 (p = 1.3 × 10−5). One of the identified variants, rs33985936 in SCN11A, was successfully replicated in an independent study, and three of the variants were found to be associated with blood-related quantitative traits according to the UK Biobank data (rs33985936 in SCN11A, rs16885 in ATXN1, and rs4747194 in CDH23). Moreover, we show that a risk score based on these variants can predict the severity and outcome of hospitalization in our cohort of patients. Given these findings, we believe that our work may serve as proof-of-concept study demonstrating the utility of quantitative traits and extensive phenotyping for identification of genetic risk factors of severe COVID-19. [ABSTRACT FROM AUTHOR]