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Background and Aims Proctitis is the least extensive type of ulcerative colitis, for which rectal therapy is rarely studied and is underused. This study evaluated the efficacy, safety, and patient’s preference of a novel formulation of budesonide suppository 4 mg, compared with a commercially available budesonide rectal foam 2 mg, for the treatment of mild to moderate ulcerative proctitis. Methods This was a randomised, double-blind, double-dummy, active-controlled trial. Patients were randomly assigned in a 1:1 ratio to receive either budesonide 4 mg suppository or budesonide 2 mg foam once daily for 8 weeks. The co-primary endpoints were changes from baseline to Week 8 in clinical symptoms, for which clinical remission was defined as having a modified Ulcerative Colitis-Disease Activity Index [UC-DAI] subscore for stool frequency of 0 or 1 and a subscore for rectal bleeding of 0, and mucosal healing, defined as having a modified UC-DAI subscore for mucosal appearance of 0 or 1. Using a more stringent criterion, we additionally analysed deepened mucosal healing, which was defined as a mucosal appearance subscore of 0. Patient’s preference, physician’s global assessment, and quality of life were also assessed and analysed. Results Overall, 286 and 291 patients were included in the 4 mg suppository and 2 mg foam groups, respectively. Budesonide 4 mg suppository met the prespecified criterion for non-inferiority to the 2 mg foam in both co-primary endpoints of clinical remission and mucosal healing. Secondary endpoints consistently supported the non-inferiority of the suppository. Trends in favour of the suppository were observed in the subgroup of mesalazine non-responders. More patients reported a preference for the suppository over rectal foam. Conclusions In patients with ulcerative proctitis, budesonide 4 mg suppository was non-inferior to budesonide 2 mg foam in efficacy, and both were safe and well tolerated.

Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14We found that stromal-myeloid coculture reduces the frequency CD14Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.

Massive single-cell profiling efforts have accelerated our discovery of the cellular composition of the human body while at the same time raising the need to formalize this new knowledge. Here, we discuss current efforts to harmonize and integrate different sources of annotations of cell types and states into a reference cell ontology. We illustrate with examples how a unified ontology can consolidate and advance our understanding of cell types across scientific communities and biological domains.

The aim: To find out the impact of exercise on promotion of health and restoration of mental capacity of instructors of higher educational institutions with specific learning environment Materials and methods: The research was conducted in 2018-2021. Research methods: theoretical analysis of literature sources, documentary method, pedagogical observation. The theoretical analysis of literature sources and documentary method allowed to clarify the role, place and objectives of physical training in the professional activities of the instructors; the pedagogical observation was used in the analysis of the instructors’ professional activities. Conclusions: It was found that the instructors’ professional activities are influenced by many negative factors: low motor activity, length of working day and week, forced working position, stress, mental overload, stress, lack of time for physical training. These factors result in the appearance of excess weight, dysfunction of major body systems, reduced mental capacity, the emergence of various diseases and labour costs. All this has a negative impact on the learning process of cadets. The direction for improving the physical training of instructors is to increase the amount of general physical training, conducting training sessions with different orientations taking into account age, physical condition, teaching load of instructors, as well as class time. A high level of instructors’ general physical fitness will allow to effectively perform training tasks; strengthen their health; maintain a high level of mental capacity for a long time; extend professional longevity.

Schizophrenia is one of the most widespread and complex mental disorders. To characterize the impact of schizophrenia, we performed single-nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. In addition, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most marked in upper-layer GABAergic neurons, including down-regulation in energy metabolism and up-regulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Last, Visium spatial transcriptomics further corroborated upper-layer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults. When ccRCC is localized to the kidney, surgical resection or ablation of the tumor is often curative. However, in the metastatic setting, ccRCC remains a highly lethal disease. Here we use fresh patient samples that include treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. Single-cell transcriptomic analysis of tumor cells from the primary tumors reveals a distinct transcriptional signature that is predictive of metastatic potential and patient survival. Analysis of supporting stromal cells within the tumor environment demonstrates vascular remodeling within the endothelial cells. An in silico cell-to-cell interaction analysis highlights the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Our findings provide biological insights into the interplay between tumor cells and the ccRCC microenvironment.

Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.

Metal ions present in cellular microenvironment have been implicated as drivers of aggregation of amyloid forming proteins. Zinc (Zn2+) ions have been reported to directly interact with α-synuclein (AS), a causative agent of Parkinson’s disease and other neurodegenerative diseases, and promote its aggregation. AS is a small intrinsically disordered protein (IDP) i.e., understanding molecular factors that drive its misfolding and aggregation has been challenging since methods used routinely to study protein structure are not effective for IDPs. Here, we report the atomic details of Zn2+ binding to AS at physiological conditions using proton-less NMR techniques that can be applied to highly dynamic systems like IDPs. We also examined how human serum albumin (HSA), the most abundant protein in human blood, binds to AS and whether Zn2+ and/or ionic strength affect this. We conclude that Zn2+ enhances the anti-aggregation chaperoning role of HSA that relies on protecting the hydrophobic N-terminal and NAC regions of AS, rather than polar negatively charged C-terminus. This suggested a previously undocumented role of Zn2+ in HSA function and AS aggregation.

Selenium (SeNPs) and tellurium nanoparticles (TeNPs) were synthesized by green technology using the three new bacterial marine isolates (strains PL 2476, AF 2469 and G 2451). Isolates were classified as Pseudoalteromonas shioyasakiensis according to 16S rRNA sequence analysis, morphological characteristics, and biochemical reactions. The bioreduction processes of isolates were studied in comparison with the previously described Alteromonas macleodii (strain 2328). All strains exhibited significant tolerance to selenite and tellurite up to 1000 µg/mL. A comparative analysis of the bioreduction processes of the isolates demonstrated that the strains have a high rate of reduction processes. Characterization of biogenic red SeNPs and black TeNPs using scanning electron microscopy (SEM), EDX analysis, Dynamic Light Scattering, and micro-Raman Spectroscopy revealed that all the isolates form stable spherical selenium and tellurium nanoparticles whose size as well as elemental composition depend on the producer strain. Nanoparticles of the smallest size (up to 100 nm) were observed only for strain PL 2476. Biogenic SeNPs and TeNPs were also characterized and tested for their antimicrobial, antifouling and cytotoxic activities. Significant antimicrobial activity was shown for nanoparticles at relatively high concentrations (500 and 1000 µg/mL), with the antimicrobial activity of TeNPs being more significant than SeNPs. In contrast, against cell cultures (breast cancer cells (SkBr3) and human dermal fibroblasts (HDF) SeNPs showed greater toxicity than tellurium nanoparticles. Studies have demonstrated the high antifouling effectiveness of selenium and tellurium nanoparticles when introduced into self-polishing coatings. According to the results obtained, the use of SeNPs and TeNPs as antifouling additives can reduce the concentration of leachable biocides used in coatings, reducing the pressure on the environment.

The avidity index (AI) of IgG to the RBD of SARS-CoV-2 was determined for 71 patients with a mild (outpatient) course of COVID-19, including 39 primarily and 36 secondarily reinfected, and 92 patients with a severe (hospital) course of COVID-19, including 82 primarily and 10 secondarily infected. The AI was shown to correlate with the severity of repeated disease. In the group of outpatients with a mild course, the reinfected patients had significantly higher median AIs than those with primary infections (82.3% vs. 37.1%, p < 0.0001). At the same time, in patients with a severe course of COVID-19, reinfected patients still had low-avidity antibodies (median AI of 28.4% vs. 25% in the primarily infected, difference not significant, p > 0.05). This suggests that the presence of low-avidity IgG to RBD during reinfection is a negative prognostic factor, in which a patient’s risk of developing COVID-19 in a severe form is significantly increased. Thus, patients with IgG of low avidity (AI ≤ 40%) had an 89 ± 20.5% chance of a severe course of recurrent COVID-19, whereas the detection of high-avidity antibodies (AI ≥ 50%) gave a probability of 94 ± 7.9% for a mild course of recurrent disease (p < 0.05).

Background Dexmedetomidine (DEX), is a highly selective alpha2 adrenoceptor (α2-AR) agonist, successfully used in various procedures including flexible bronchoscopy. Randomized controlled trials (RCTs) evaluating DEX sedation during bronchoscopy report equivocal results regarding respiratory and hemodynamic outcomes. Methods We conducted an RCT to evaluate the efficacy and safety of dexmedetomidine compared to propofol for sedation during bronchoscopy. The primary outcome was the number of desaturation events, secondary outcomes were transcutaneous Pco2 level, hemodynamic adverse events and physician and patient satisfaction. Results Overall, 63 patients were included, 30 and 33 in the DEX and propofol groups, respectively. The number of desaturation events was similar between groups, median (IQR) 1 (0–1) and 1 (0–2) in the DEX and control groups, respectively (P = 0.29). Median desaturation time was 1 (0–2) and 1 (0–3) minutes in the DEX and control groups, respectively (P = 0.48). Adverse events included hypotension, 33% vs 21.1% in intervention and control groups, respectively (P = 0.04), bradycardia, cough, and delayed recovery from sedation. Total adverse events were 22 and 7 in DEX and propofol groups, respectively (P = 0.009). Conclusion Dexmedetomidine sedation during bronchoscopy did not show differences in oxygen saturation and transcutaneous CO2 level in comparison to propofol. Moreover, DEX sedation required a significantly higher number of rescue boluses, due to inadequate sedation and was associated with a higher rate of adverse events. Trial registration NCT04211298, registration date: 26.12.2019.

Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate. Little is known about people's preferred responses to norm violations across countries. Here, in a study of 57 countries, the authors highlight cultural similarities and differences in people's perception of the appropriateness of norm violations., Swedish Foundation for Humanities and Social Sciences; Riksbankens Jubileumsfond; Czech Science Foundation; Czech Academy of Sciences; Institute of Psychology; Stockholm University

Tissue function depends on cellular organization. While the properties of individual cells are increasingly being deciphered using powerful single-cell sequencing technologies, understanding their spatial organization and temporal evolution remains a major challenge. Here, we present Image-seq, a technology that provides single-cell transcriptional data on cells that are isolated from specific spatial locations under image guidance, thus preserving the spatial information of the target cells. It is compatible with in situ and in vivo imaging and can document the temporal and dynamic history of the cells being analyzed. Cell samples are isolated from intact tissue and processed with state-of-the-art library preparation protocols. The technique therefore combines spatial information with highly sensitive RNA sequencing readouts from individual, intact cells. We have used both high-throughput, droplet-based sequencing as well as SMARTseq-v4 library preparation to demonstrate its application to bone marrow and leukemia biology. We discovered that DPP4 is a highly upregulated gene during early progression of acute myeloid leukemia and that it marks a more proliferative subpopulation that is confined to specific bone marrow microenvironments. Furthermore, the ability of Image-seq to isolate viable, intact cells should make it compatible with a range of downstream single-cell analysis tools including multi-omics protocols.

The aim: Using cluster analysis, to identify a high-risk group for NAFLD and develop a differential approach to examination, treatment and prevention of the disease based on IR indices, among NAFLD and non-NAFLD patients without type 2 diabetes mellitus (T2DM).Materials and methods: Clinical, anthropometric, laboratory methods, ultrasound, computational and statistical techniques were applied.Results: Cluster analysis was performed on the laboratory tests results: glucose, insulin, HOMA-IR index, HOMA2 Calculator (%B - beta-cell function, %S - insulin sensitivity, IR - insulin resistance). 5 groups of patients were formed, according to increasing HOMA-IR index and IR. Group II was found to be transient in IR formation, it included the majority of non-NAFLD patients (87%), and we consider it to be the risk group for NAFLD. Group V - with the highest IR scores, where 92% of patients had NAFLD and 73% had a high Fatty Liver Index - is considered to be a very high-risk group for developing T2DM.Conclusions: 1. According to the results of cluster analysis, 5 groups of patients with different IR levels were identified. 2. In the second group, where non-NAFLD patients predominate, insulin resistance begins to form. 3. Groups III and IV - patients with high HOMA-IR index - had significant ultrasound findings indicating hepatic steatosis. 4. Group V included patients with NAFLD, with high HOMA-IR index and the highest risk of developing T2DM.

The aim of the study is to investigate the changes in the maternal healthcare system during the pandemic and their associations with maternal mental health in Russia. A sample of Russian women who gave birth during the first year of the COVID-19 pandemic (n = 1645) and matched controls, i.e., women who gave birth before the COVID-19 pandemic (n = 611), completed an anonymous Internet survey about recent childbirth. They were assessed for childbirth-related posttraumatic stress disorder (PTSD) and postpartum depression (PPD). Clinically relevant symptoms of PPD and PTSD were high before the pandemic and showed no significant change during the pandemic (p = 0.48 and p = 0.64, respectively). We found a notable increase in the frequency of obstetric violence (p = 0.015) during the pandemic, which, in turn, has a strong correlation with birth-related PTSD and PPD. The problem of ethical communication with patients among maternal healthcare professionals is acute in Russia, and it has been exacerbated by the pandemic. Family and doula support during labor can be a potential protective factor against obstetric violence.

The aim: The aim of the study is a statistical analysis of the mucosa of the stomach affected by Helicobacter pylori in young people studying at the university.Materials and methods: The work contains the results of the study of chronic gastritis of type B in university volunteer students. The study was attended by students of 1-4courses, aged 17 to 25 years, a total of 50 people. Among them were 28 men and 22 women.Results: Various forms of chronic gastritis were found in the mucosa of the topographic-anatomical sections of the stomach, 90% of which were associated with Helicobacterpylori (HP). In all departments there is a different amount of common forms of chronic gastritis. In the pyloric section only atrophic gastritis was detected - 31.0 ± 8.5. Atrophic gastritis was also dominant on the lesser curvature - 32.3 ± 7.8, but its forms were significantly (p0.5) less pronounced than in the pyloric section. In the area of the body, the above variants of chronic gastritis were found in 34.3 ± 8.7 cases, and the majority were flat erosive gastritis 51.0 ± 9.3. There is a tendency to reduce the degree of bacterial contamination of the gastric mucosa from its pyloric section and the lesser curvature to the walls of the body. With a decrease in the degree of bacterial contamination of the gastric mucosa, the degree of leukocyte infiltration also decreases. Between the degree of contamination of the mucous membrane of Helicobacter pylori and the degree of leukocyte infiltration of the mucous membrane, the Pearson correlation coefficient is rxy - 0,935, the correlation is very strong, the coefficient of determination is D=rxy^2 - 0,874, the statistically significant dependence on the probability is 0.99.Conclusions: Atrophic or hyperplastic gastritis associated with HP is found in the gastric mucosa, respectively, 90% of cases. The degree of bacterial contamination correlates with the degree of leukocyte infiltration of the gastric mucosa. Atrophic or hyperplastic gastritis Helicobacter pylori-associated is a common disease of people in young and working age.

Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations., An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome., Childhood neuroblastoma can be separated into high and low risk groups, with prognosis depending on age at diagnosis. Here, the authors show that low and high risk neuroblastoma tumours are composed of different cell types with different malignancy potential.

Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions., HuBMAP supports technology development, data acquisition, and spatial analyses to generate comprehensive molecular and cellular three-dimensional tissue maps.

Single-cell RNA-seq is being increasingly applied in complex study designs, commonly spanning multiple individuals, conditions, or tissues. Analysis of such heterogeneous collections requires a way of identifying recurrent cell subpopulations. We developed Conos, an approach that relies on multiple plausible inter-sample mappings to construct a global graph connecting all measured cells. The graph enables identification of recurrent cell clusters and propagation of information between datasets in multi-sample or atlas-scale collections.

Background There are approximately 1.5 million internally displaced persons (IDPs) in Ukraine as a result of the conflict in eastern Ukraine. Exposure to violence, forced displacement and increased mental disorders are potential risk-factors for alcohol use disorder (AUD). The aim of this study was to estimate the prevalence of and risk factors for AUD among Ukrainian IDPs and investigate the relationship between AUD, mental health service utilization and coping behaviours. Methods A nation-wide cross-sectional survey of 2203 IDPs was conducted. Data were collected on AUD [using alcohol use disorder identification test (AUDIT)], mental health disorders, utilization of health services and coping behaviours. Multivariable logistic regression was used to identify risk factors for AUD, and to estimate the odds ratios for the association between alcohol use and utilization of health services and coping behaviours. Results Of 2203 IDPs surveyed, 8.4% of men and 0.7% of women screened positive for AUD (AUDIT >7). Among current drinkers, AUD was present in 14.9% of men and 1.8% of women. Age, cumulative trauma exposure and anxiety were significantly associated with AUD in multivariable analysis. Alcohol users were 43% less likely to access health services for mental health compared with non-users. AUD was associated with more negative coping behaviours. Conclusions AUD is present within the male Ukrainian IDP population. Alcohol use was significantly associated with lower utilization of mental health services and more negative coping behaviours. AUD screening and low-intensity treatment services should be expanded for IDPs in Ukraine, particularly if integrated into mental health and psychosocial support programmes.

Mesenchymal stem cells (MSCs) are broadly applied in regenerative therapy to replace cells that are lost or impaired during disease. The low survival rate of MSCs after transplantation is one of the major limitations heavily influencing the success of the therapy. Unfavorable microenvironments with inflammation and oxidative stress in the damaged regions contribute to MSCs loss. Most of the strategies developed to overcome this obstacle are aimed to prevent stress-induced apoptosis, with little attention paid to senescence—another common stress reaction of MSCs. Here, we proposed the strategy to prevent oxidative stress-induced senescence of human endometrial stem cells (hMESCs) based on deferoxamine (DFO) application. DFO prevented DNA damage and stress-induced senescence of hMESCs, as evidenced by reduced levels of reactive oxygen species, lipofuscin, cyclin D1, decreased SA-β-Gal activity, and improved mitochondrial function. Additionally, DFO caused accumulation of HIF-1α, which may contribute to the survival of H2O2-treated cells. Importantly, cells that escaped senescence due to DFO preconditioning preserved all the properties of the initial hMESCs. Therefore, once protecting cells from oxidative damage, DFO did not alter further hMESCs functioning. The data obtained may become the important prerequisite for development of a new strategy in regenerative therapy based on MSCs preconditioning using DFO.

Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions., The contribution of distinct types of dorsal root ganglion neurons to chronic pain is unclear. Here, the authors molecularly profile non-human primate sensory neurons and show that genome-wide associations converge on two neuronal types with different genetic susceptibilities for chronic pain.

Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.

Introduction: Small intestinal bacterial overgrowth may cause the hyperlipidemia appearance by enterohepatic circulation disturbance which evolves on the background of the early bile acids deconjugation with further endotoxin production and oxidative stress in the liver with hyperproduction of cholesterol and atherogenic lipoproteins. The aim: the determination of prevalence and features of SIBO in a series of patients with hyperlipidemia and in control subjects.Materials and methods: Nineteen patients with hyperlipidemia and ten control subjects were studied. Small intestinal bacterial overgrowth was assessed by a lactulose breath test. Such biochemical markers as CRP, ALT, AST, GGTP, apolipoprotein B, bilirubin, cholesterol and lipid profile were determined. Except the routine interpretation of lactulose breath test, which contains the SIBO detection, small intestinal transit time and hydrogen level evaluation with next comparison between groups of patients was realized.Results: Small intestinal bacterial overgrowth was present in 78.9% of patients with hyperlipidemia and 40% in control subjects. The maximal dose of H2 was particularly higher in patients with hyperlipidemia in comparison with control group (94,7±13,69 vs. 36,13±5,4). There was a strong correlation between AST level and SIBO existence in both groups (r=1). Positive connection between LDL, TG, VLDL and the dose of exhaled hydrogen on 120 minute (r=0.6, r= 0.62, r=0.7 respectively) and strong negative correlation between HDL and 120 minute dose (r=-0.74) in main group was marked.Conclusions: Patients with hyperlipidemia have a higher prevalence of small intestinal bacterial overgrowth and there is a relationship between H2 rate and LDL, TG, VLDL.

Introduction: The sharp deterioration in the physical development of the younger generation is worrying. The morbidity of youth has increased by 29.9% compared with the last century. More than 33% of boys and girls, among first-year students with chronic diseases. The aim: Assessing the state of the students' body by examining the results of a survey among the second- and third-year students of the university using a specially designed questionnaire.Materials and methods: The material on the assessment of the state of health and the characteristics of the organism has been processed by studying the results of a survey of young men and women aged 20-23, obtained on the basis of using the developed questionnaire.Results: Physical development has been studied in accordance with the state of health of the students, as well as a thorough study of a number of criteria: diseases of the musculoskeletal system were 37.1%, 49.7% and 43.45 among boys aged 20, 22 and 23 and respectively 33.3 %, 38.6% and 47.7% among girls in their 20s, 22s and 23s. The morbidity of eye was 18.0%, 3.8% and 9.9% among boys aged 20, 22 and 23 years and 17.7%, 17.1% and 7.7% among girls aged 20, 22 and 23 years.Conclusions: In the structure of morbidities are diseases of the musculoskeletal system, diseases of the nervous system and the organ of vision. Correlation of the characteristics of the level of students' health and their physical development have indicators on the level of educational adaptation and the number of diseases.

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

Amplification of chromosomal region 8p11–12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1–3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11–12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11–12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11–12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11–12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition. The histone H3K36 methyltransferase NSD3, which is associated with the common 8p11–12 chromosomal amplification, is an oncogenic driver in lung squamous cell carcinoma.

The urgency of the problem of coxyellosis in children is determined by the endemic nature of this pathology for a number of regions of Russia. The purpose of the study: to evaluate the results of diagnosis of coxyellosis in children using the methods of complement binding reaction (RSC), enzyme immunoassay (ELISA), and polymerase chain reaction (PCR). Retrospective analysis of the survey on Coxiella in 3 groups of children aged 7 to 17 years: group 1 (n=30) method RSK; group 2 (n=34) - by ELISA; group 3 (n=35) - PCR, were hospitalized in GBUZ «Regional clinical infectious hospital named. A. M. Nicholi» Astrakhan in the period from January 2010 to January 2020. The most informative methods of diagnosis of coxyellosis in children during the first 7 days from the onset of the disease is the PCR reaction (specificity-94%, sensitivity-91%), after the 7th day of the disease ELISA (specificity -91%, sensitivity - 94%).The sensitivity of the RSC method is 70%, the specificity is 87%.

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.

Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation., Unlike human teeth, mouse incisors grow throughout life, based on stem and progenitor cell activity. Here the authors generate single cell RNA-seq comparative maps of continuously-growing mouse incisor, non-growing mouse molar and human teeth, combined with lineage tracing to reveal dental cell complexity.

The aim of the study was to evaluate the role of poikilocytosis in the acne vulgaris comorbidity with demodicosis and functional gallbladder disorder.Materials and methods: The study included 140 people with a diagnosis of moderate acne: group 1 - patients with AV, group 2 - patients with AV + Demodicosis, group3- AV + Demodicosis + functional gallbladder disorder (FGD). Biochemical analysis of lipid profile and liver enzymes, bilirubin was performed with semi-automatic analyzer HUMALYZER 3000. Scanning electron microscopy was performed using scanning electron microscope PEI-106I "SELMI". Ultrasound investigation was carried out by the SonoScape S6Pro US-diagnostic system with 3 - 5 MHz Ultrasound Probe Transducer С354.Results: The most significant changes in blood erythrocytes morphology were observed in patients with comorbidity of acne, demodicosis and FGD with highest increasing of deformed erythrocytes up to 21%, mainly due to echinocytes І, ІІ order. Correlation analysis has revealed a strong direct association r = +0.75 (p0.05) between the poikilocytosis and comorbidity of acne vulgaris with demodicosis and FGD.Conclusions: A strong direct association between acne vulgaris comorbid pathology and the increased number of deformation shapes of erythrocytes confirms the impact of FGD on morphological characteristics of erythrocytes and developing of poikilocytosis.

Summary Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.

Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate.

Summary The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.

Posterior reversible encephalopathy (PRES) is a clinical syndrome characterized by headaches, seizures, cortical blindness, and altered mental status up to coma and by a radiological syndrome defined by edematous alteration on Magnetic Resonance Imaging (MRI)-Scans of the white matter. In the following, we present the case of a 73 years old post-operative patient with PRES in the context of hypertension and endocarditis with E. coli. The initial presentation included a series of seizures, sopor, and cortical blindness. In MRI-Scans a marked cerebral edema could be identified. After successful treatment of underlying conditions, the patient has made a good recovery. However, homonymous hemianopsia towards right due to laminar necrosis in the left occipital lobe remained as a residuum.