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The Long Life Family Study (LLFS) enrolled 4953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS, and gene expression-trait association by Correlated Meta-Analysis (CMA). Across all traits, CMA identified 64 significant genes after Bonferroni correction (p ≤ 2.8 × 10-7), 29 of which replicated in the Framingham Heart Study (FHS) cohort. Notably, 20 of the 29 replicated genes do not have a previously known trait-associated variant in the GWAS Catalog within 50 kb. Thirteen modules in Protein-Protein Interaction (PPI) networks are significantly enriched in genes with low meta-analysis p-values for at least one trait, three of which are replicated in the FHS cohort. The functional annotation of genes in these modules showed a significant over-representation of trait-related biological processes including sterol transport, protein-lipid complex remodeling, and immune response regulation. Among major findings, our results suggest a role of triglyceride-associated and mast-cell functional genes FCER1A, MS4A2, GATA2, HDC, and HRH4 in atherosclerosis risks. Our findings also suggest that lower expression of ATG2A, a gene we found to be associated with BMI, may be both a cause and consequence of obesity. Finally, our results suggest that ENPP3 may play an intermediary role in triglyceride-induced inflammation. Our pipeline is freely available and implemented in the Nextflow workflow language, making it easily runnable on any compute platform ( https://nf-co.re/omicsgenetraitassociation ).

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Currently, severe combined abdominal trauma ranks third among all causes of mortality In Russia, second only to cardiovascular and oncologic diseases. In the period from 2019 to 2020 in our country, a slight decrease in traumatism is noted due to a decrease in the number of traffic accidents as the main cause of combined and multiple trauma. The number of abdominal injuries from the total number of injuries In Russian regions ranges from 1.5 to 36.5% and is accompanied by a high level of disability (25-80% in combined trauma and 5-8% in isolated trauma). Despite modern medical advances, lethality in combined trauma of abdominal organs varies from 10.7 to 69.7%, with closed abdominal trauma accounting for up to 6% of fatal outcomes. OBJECTIVE: Improving treatment outcomes in patients with closed abdominal trauma through comprehensive diagnosis of SCN and optimization of enteral therapy in patients with closed abdominal trauma. MATERIAL AND METHODS: The study included 40 patients (29 (72.5%) men and 11 (27.5%) women), who underwent examination and treatment at the State Budgetary Institution "Research Institute of SP. Im. N.V. Sklifosovsky Research Institute of St. Petersburg State Medical Center with the diagnosis: Closed abdominal trauma. The age of the patients varied from 25 to 81 years (Mean age was 49.6±13.1). To evaluate the effectiveness of intensive therapy, the patients were divided into 2 groups: the comparison group (n=26) included patients who were treated with complex conservative therapy. Patients of the main group (n=14) conservative therapy was supplemented with the use of ER to restore the functional activity of the intestine under the control of ultrasound and assessment of the degree of intra-abdominal hypertension, as well as with Intestamine to stimulate the intestinal trauma. RESULTS: In the course of the study it was found that, as a result of complex enteral therapy in the patients of the main group, starting from the 7th day of stay in the ORIT, positive dynamics was observed, consisting in a statistically significant decrease in the levels of lactate, ALT, AST, LDH, and CRP. By the 14th day there was also a statistically significant decrease in leukocyte and PCT levels. The lethality in the main group amounted to 7.2%, n=1. At the same time, in patients of the comparison group only by the 7th day there was a decrease in concentration of CRP (p=0.065), by the 10th day - ALT (<0.001) and by the 14th day there was a decrease in leukocytes level (p=0.038). Lethality in this group amounted to 23.1%, n=6. CONCLUSION: Timely initiation of pathogenetic enteral therapy contributes to faster normalization of clinical and laboratory parameters, protection of intestinal barrier function, prevention of complications associated with bacterial translocation and bacterial overgrowth syndrome, increase in immunoresistance of the organism.

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Acute coronary events (ACEs) associated with a SARS-CoV-2 infection can significantly differ from classic ACEs. New biomarkers, such as ceramides, may help in the diagnosis and treatment of this disease. This study included 73 ACE patients for whom the SARS-CoV-2 infection was verified. Two subgroups were formed: the favorable outcome subgroup and the fatal outcome subgroup. Plasma samples were collected from all patients at the time of admission for a metabolomic analysis. The analysis of metabolites revealed that the ceramide levels were significantly lower in the fatal outcome subgroup than in the survivor subgroup. Therefore, determining ceramide levels in patients with ACEs in conjunction with COVID-19 may help assess the prognosis of these patients and manage their risks.

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Objective: To investigate the molecular mechanisms of chronic rhinosinusitis (CRS), to identify key cell subgroups and genes, to construct effective diagnostic models, and to screen for potential therapeutic drugs. Methods: Key cell subgroups in CRS were identified through single-cell transcriptomic sequencing data. Essential genes associated with CRS were selected and diagnostic models were constructed by hdWGCNA (high dimensional weighted gene co-expression network analysis) and various machine learning algorithms. Causal inference analysis was performed using Mendelian randomization and colocalization analysis. Potential therapeutic drugs were identified using molecular docking technology, and the results of bioinformatics analysis were validated by immunofluorescence staining. Graphpad Prism, R, Python, and Adobe Illustrator software were used for data and image processing. Results: An increased proportion of basal and suprabasal cells was observed in CRS, especially in eosinophilic CRS with nasal polyps (ECRSwNP), with P=0.001. hdWGCNA revealed that the "yellow module" was closely related to basal and suprabasal cells in CRS. Univariate logistic regression and LASSO algorithm selected 13 key genes (CTSC, LAMB3, CYP2S1, TRPV4, ARHGAP21, PTHLH, CDH26, MRPS6, TENM4, FAM110C, NCKAP5, SAMD3, and PTCHD4). Based on these 13 genes, an effective CRS diagnostic model was developed using various machine learning algorithms (AUC=0.958). Mendelian randomization analysis indicated a causal relationship between CTSC and CRS (inverse variance weighted: OR=1.06, P=0.006), and colocalization analysis confirmed shared genetic variants between CTSC and CRS (PPH4/PPH3>2). Molecular docking results showed that acetaminophen binded well with CTSC (binding energy:-5.638 kcal/mol). Immunofluorescence staining experiments indicated an increase in CTSC+cells in CRS. Conclusion: This study integrates various bioinformatics methods to identify key cell types and genes in CRS, constructs an effective diagnostic model, underscores the critical role of the CTSC gene in CRS pathogenesis, and provides new targets for the treatment of CRS.

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BACKGROUND: Detection of cancer and identification of tumor origin at an early stage improve the survival and prognosis of patients. Herein, we proposed a plasma cfDNA-based approach called TOTEM to detect and trace the cancer signal origin (CSO) through methylation markers. METHODS: We performed enzymatic conversion-based targeted methylation sequencing on plasma cfDNA samples collected from a clinical cohort of 500 healthy controls and 733 cancer patients with seven types of cancer (breast, colorectum, esophagus, stomach, liver, lung, and pancreas) and randomly divided these samples into a training cohort and a testing cohort. An independent validation cohort of 143 healthy controls, 79 liver cancer patients and 100 stomach cancer patients were recruited to validate the generalizability of our approach. RESULTS: A total of 57 multi-cancer diagnostic markers and 873 CSO markers were selected for model development. The binary diagnostic model achieved an area under the curve (AUC) of 0.907, 0.908 and 0.868 in the training, testing and independent validation cohorts, respectively. With a training specificity of 98%, the specificities in the testing and independent validation cohorts were 100% and 98.6%, respectively. Overall sensitivity across all cancer stages was 65.5%, 67.3% and 55.9% in the training, testing and independent validation cohorts, respectively. Early-stage (I and II) sensitivity was 50.3% and 45.7% in the training and testing cohorts, respectively. For cancer patients correctly identified by the binary classifier, the top 1 and top 2 CSO accuracies were 77.7% and 86.5% in the testing cohort (n = 148) and 76.0% and 84.0% in the independent validation cohort (n = 100). Notably, performance was maintained with only 21 diagnostic and 214 CSO markers, achieving a training AUC of 0.865, a testing AUC of 0.866, and an integrated top 2 accuracy of 83.1% in the testing cohort. CONCLUSIONS: TOTEM demonstrates promising potential for accurate multi-cancer detection and localization by profiling plasma methylation markers. The real-world clinical performance of our approach needs to be investigated in a much larger prospective cohort.

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PURPOSE: Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS: Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS: ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION: This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

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More than a quarter of the world's population is infected with Mycobacterium tuberculosis. However, only about 10% of those infected develop active TB. This indicates a key role for innate immunity in limiting M. tuberculosis replication. Most often, bacteria can regulate the expression of host-specific molecules and weaken host immunity. OBJECTIVE: To use a biological model, in order to determine significant molecular immunohistochemical markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of the M. tuberculosis Beijing genotype in lung tissue. MATERIAL AND METHODS: Lung samples of the C57BL/6 male mice were obtained during experimental infection with M. tuberculosis strains: the reference laboratory strain H37Rv, multidrug-resistant clinical strains 396 (highly lethal and hypervirulent «Buryat¼ genotype Beijing 14717-15) and 6691 (low-lethal and low-virulent "Omsk" genotype Beijing 1071-32) on days 14, 21, 60 and 120. They were studied by histological and immunohistochemical methods. The relative areas of expression of IL-6, IL-12A, iNOS, and TNF-α in the lung tissue of model animals were established. RESULTS: A study of strain 396 showed that both disease progression and damage to lung tissue are associated with a highly reactive immune response and increased synthesis of iNOS and strain characteristics that block the production of TNF-α. On the contrary, for strain 6691 a low reactivity of the immune response was revealed, with statistically significantly lower values of the relative area of expression of NOS and TNF-α during all observation periods (days 14-120). All animals that survived to day 120 showed a similar morphological picture with differences in cytokine levels, indicating a nonlinear relationship between proinflammatory factors and the damage substratum. CONCLUSION: The progression of the disease and damage of lung tissue were associated with a highly reactive immune response and increased synthesis of iNOS, strain properties that block the TNF-α production. Thus, iNOS and TNF-α can act as molecular markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of M. tuberculosis in lung tissue.

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Malignant effusion complicates more than 15% of all cancers in delayed stages of progression. The most common causes of metastatic pleuritis are lung cancer, breast cancer, ovarian cancer, lymphoproliferative diseases or dissemination of gastrointestinal tumors. Malignant effusion is associated with negative prognosis for overall survival regardless of etiology of tumor, significantly complicates the course of the underlying disease, impairs life quality and complicates treatment. Despite various methods for pleural cavity obliteration in recurrent metastatic pleuritis, there is still no a uniform approach to choosing the optimal treatment strategy. We analyzed the main methods of conservative and surgical treatment of recurrent metastatic pleuritic regarding efficacy, risk of recurrence and reproducibility.

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We studied the effect of separate and combined influence of chronic forced physical activity reduction and high-fat and high-carbohydrate diet containing cholesterol on some indicators of carbohydrate, lipid, and cholesterol metabolism in growing male Wistar rats. Used combination of factors simulating a sedentary lifestyle and unhealthy diet did not have a synergistic effect on the selected biomarkers. On the contrary, the effect was antagonistic: body weight and appetite decreased and insulin resistance increased. The obtained results indicate certain prospects of hypercholesterolemia model using in preclinical studies of specialized food products to optimize the diet of individuals with disorders of carbohydrate and lipid metabolism.

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The article "LncRNA UCA1 affects osteoblast proliferation and differentiation by regulating BMP-2 expression", by R.-F. Zhang, J.-W. Liu, S.-P. Yu, D. Sun, X.-H. Wang, J.-S. Fu, Z. Xie, published in Eur Rev Med Pharmacol Sci 2019; 23 (16): 6774-6782-DOI: 10.26355/eurrev_201908_18715-PMID: 31486475 has been retracted by the authors for the following reasons: - The data presented in the manuscript require further validation, which may affect the results. After careful consideration, we have decided to withdraw it to ensure its reliability and reproducibility. All authors concur with this decision. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/18715.

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1. The development of chicken skeletal muscle is directly relevant to poultry husbandry production. Numerous studies have suggested that circular RNA play pivotal roles in muscle development. However, the functions and mechanisms of most circRNA in chicken myogenesis remain largely unknown.2. This study identified a novel circSESN1 based on existing sequencing data and examined its authenticity and subcellular localisation by enzyme digestion and RNA fluorescence in situ hybridisation. Additionally, there was a positive correlation between the expression levels of circSESN1 and the developmental stage of chicken muscle.3. Mechanistically, knockdown or overexpression of circSESN1 was performed in primary myoblasts to validate its function. The interactions between circSESN1, miR-16-5p, and the target gene sestrin 1 (SESN1) were investigated using bioinformatics analysis and a dual fluorescein reporter system. Real-time qPCR, a cell proliferation assay, and immunofluorescence staining techniques were used to investigate the promotion effect of circSESN1 on myoblast proliferation and differentiation by miR-16-5p/SESN1 pathway.4. The results demonstrated that the newly identified chicken circSESN1 directly sponges gga-miR-16-5p to regulate SESN1 gene expression, promoting myoblast proliferation and differentiation.

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ConspectusFacilitated by the unique triple-helical protein structure, fibrous collagens, the principal proteins in animals, demonstrate a dual function of serving as building blocks for tissue scaffolds and as a bioactive material capable of swift renewal in response to environmental changes. While studies of triple-helical collagen mimetic peptides (CMPs) have been instrumental in understanding the molecular forces responsible for the folding and assembly of triple helices, as well as identifying bioactive regions of fibrous collagen molecules, single-strand CMPs that can specifically target and hybridize to denatured collagens (i.e., collagen hybridizing peptides, CHPs) have proven useful in identifying the remodeling activity of collagen-rich tissues related to development, homeostasis, and pathology. Efforts to improve the utility of CHPs have resulted in the development of new skeletal structures, such as dimeric and cyclic CHPs, as well as the incorporation of artificial amino acids, including fluorinated proline and N-substituted glycines (peptoid residues). In particular, dimeric CHPs were used to capture collagen fragments from biological fluid for biomarker study, and the introduction of peptoid-based collagen mimetics has sparked renewed interest in peptidomimetic research because peptoids enable a stable triple-helical structure and the presentation of an extensive array of side chain structures offering a versatile platform for the development of new collagen mimetics.This Account will cover the evolution of our research from CMPs as biomaterials to ongoing efforts in developing triple-helical peptides with practical theranostic potential in targeting denatured and damaged collagens. Our early efforts in functionalizing natural collagen scaffolds via noncovalent modifications led to the discovery of an entirely new use of CMPs. This discovery resulted in the development of CHPs that are now used by many different laboratories for the investigation of pathologies associated with changes in the structures of extracellular matrices including fibrosis, cancer, and mechanical damage to collagen-rich, load-bearing tissues. Here, we delve into the essential design features of CHPs contributing to their collagen binding properties and practical usage and explore the necessity for further mechanistic understanding of not only the binding processes (e.g., binding domain and stoichiometry of the hybridized complex) but also the biology of collagen degradation, from proteolytic digestion of fibrils to cellular processing of collagen fragments. We also discuss the strengths and weaknesses of peptoid-based triple-helical peptides as applied to collagen hybridization touching on thermodynamic and kinetic aspects of triple-helical folding. Finally, we highlight current limitations and future directions in the use of peptoid building blocks to develop bioactive collagen mimetics as new functional biomaterials.

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We compared alpha diversity indices of the intestinal microbiota in adolescents with obesity and normal body weight, taking into account their ethnicity. Intestinal biocenosis was studied by metasequencing of amplicon libraries of V3-V4 fragments of the 16S rRNA gene. The alpha diversity of the microbiota was assessed using classical and alternative indices. Statistically significant differences in intestinal microbiota were observed between Russians with obesity and Buryats with normal body weight, as well as between Russians with obesity and Buryats with obesity when assessing the Shannon-Weaver, Chao1 indices, Faith phylogenetic diversity index, ACE, Fisher, Gini coefficient, Margalef, and Menkhinik indices. It was shown that alpha diversity indices can be used to assess significance of differences and variability of the intestinal microbiota in multifactorial diseases such as obesity in adolescents; however, the scope of application of the criteria should be considered.

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The expression of marker proteins of acute kidney injury after administration of high doses of lithium carbonate was assessed to evaluate the possibility of lithium use in neutron capture therapy. In mice with implanted skin melanoma B16, the expression of Kim1 (kidney injury molecule 1) and NGAL (neutrophil gelatinase-associated lipocalin) proteins in the kidneys was evaluated immunohistochemically 15, 30, 90, 180 min, and 7 days after peroral administration of lithium carbonate at single doses of 300 and 400 mg/kg. An increase in the expression of the studied proteins was found in 30 and 90 min after administration of 400 mg/kg lithium carbonate, however, 7 days after the drug administration, the expression returned to the level observed in the control group. It can be suggested that single administration of lithium carbonate in the studied doses effective for lithium neutron capture therapy will not significantly affect the renal function.

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1. The liver of chickens is a dominant lipid biosynthetic tissue and plays a vital role in fat deposition, particularly in the abdomen. To determine the molecular mechanisms involved in its lipid metabolism, the livers of chickens with high (H) or low (L) abdominal fat content were sampled and sequencing on long non-coding RNA (lncRNA), messenger RNA (mRNA) and small RNA (microRNA) was performed.2. In total, 351 expressed protein-coding genes for long non-coding RNA (DEL; 201 upregulated and 150 downregulated), 400 differentially expressed genes (DEG; 223 upregulated and 177 downregulated) and 10 differentially expressed miRNA (DEM; four upregulated and six downregulated) were identified between the two groups. Multiple potential signalling pathways related to lipogenesis and lipid metabolism were identified via pathway enrichment analysis. In addition, 173 lncRNA - miRNA - mRNA interaction regulatory networks were identified, including 30 lncRNA, 27 mRNA and seven miRNA.3. These networks may help regulate lipid metabolism and fat deposition. Five promising candidate genes and two lncRNA may play important roles in the regulation of adipogenesis and lipid metabolism in chickens.

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PURPOSE: This study compares the changes in the parameters of the anterior chamber of the eye using anterior segment optical coherence tomography (AS-OCT) in patients with a natural and artificial lens after treatment of neovascular age-related macular degeneration (nAMD) by multiple intravitreal injections (IVI) of anti-VEGF drugs. MATERIAL AND METHODS: The patients were divided into 2 groups: group 1 (control) included 30 patients (30 eyes) with a natural lens, group 2 - 30 patients (30 eyes) with an intraocular lens (IOL). AS-OCT was performed using the Revo NX tomograph (Optopol, Poland) to analyze anterior chamber depth (ACD) and the parameters of anterior chamber angle (ACA). Intraocular pressure (IOP) was measured with a contact tonometer ICare Pro. RESULTS: In patients with an IOL, the IOP level 1 minute after intravitreal injection (IVI) of an anti-VEGF drug was statistically lower than in the control group, on average by 17.8% during the first IVI and by 28.7% after 1 year of observation (p<0.001). ACD before treatment was statistically significantly higher in patients with IOL compared to patients of group 1 by an average of 39.3% (p<0.001). ACA from the nasal and temporal sides in the meridian 0°-180° before the start of treatment was statistically significantly wider in phakic patients than in the control group, by an average of 15.9±9.3° (p<0.001) and 16.9±8.2° (p<0.001), respectively. According to AS-OCT, there was no shift of the iris-lens diaphragm in patients with an IOL after multiple IVI of an anti-VEGF drug, in contrast to the control group. CONCLUSIONS: AS-OCT was used to determine for the first time the changes in the parameters of the anterior chamber of the eye in patients with a natural and artificial lens after multiple injections of an anti-VEGF drug in the treatment of nAMD.

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Circulating tumor DNA (ctDNA) is cell-free DNA released by tumors or circulating tumor cells, containing abundant tumor-specific information that can serve as biomarkers for cancer early screening, monitoring, prognosis, and prediction of treatment response. This is particularly attractive in the field of gastric cancer, where high-quality screening, monitoring, and prediction methods are currently lacking. Gastric cancer exhibits significant tumor heterogeneity, with large differences in genetic and epigenetic characteristics among different subgroups. Methylated ctDNA has high sensitivity and specificity, which can help clarify tumor genotyping and facilitate the formulation of precise diagnostic and therapeutic strategies. Furthermore, numerous studies have confirmed the unique advantages of methylated DNA in predicting treatment response, adjuvant therapy, and drug resistance assessment, which may be used in the future to enhance the efficacy of chemotherapy regimens and improve patient chemotherapeutic response, and even treat multidrug resistance. However, there are several challenges associated with methylated ctDNA, such as low sensitivity and specificity at single-target sites, limited association between some gastric cancer subtypes and ctDNA, off-target risks, and the lack of large-scale and high-quality clinical research evidence. This review mainly summarizes current research on the methylation status of ctDNA in gastric cancer and connects these findings to early screening, recurrence monitoring, and potential treatment opportunities for gastric cancer. With advances in technology and the deepening of interdisciplinary research, ctDNA detection will reveal more disease information and become an essential foundation for gastric cancer research and precision medicine treatment.

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