Deleterious genetic changes in AGTPBP1 result in teratozoospermia with sperm head and flagella defects.

Approximately 10%-15% of couples worldwide are infertile, and male factors account for approximately half of these cases. Teratozoospermia is a major cause of male infertility. Although various mutations have been identified in teratozoospermia, these can vary among ethnic groups. In this study, we performed whole-exome sequencing to identify genetic changes potentially causative of teratozoospermia. Out of seven genes identified, one, ATP/GTP Binding Protein 1 (AGTPBP1), was characterized, and three missense changes were identified in two patients (Affected A: p.Glu423Asp and p.Pro631Leu; Affected B: p.Arg811His). In those two cases, severe sperm head and tail defects were observed. Moreover, AGTPBP1 localization showed a fragmented pattern compared to control participants, with specific localization in the neck and annulus regions. Using murine models, we found that AGTPBP1 is localized in the manchette structure, which is essential for sperm structure formation. Additionally, in Agtpbp1-null mice, we observed sperm head and tail defects similar to those in sperm from AGTPBP1-mutated cases, along with abnormal polyglutamylation tubulin and decreasing △-2 tubulin levels. In this study, we established a link between genetic changes in AGTPBP1 and human teratozoospermia for the first time and identified the role of AGTPBP1 in deglutamination, which is crucial for sperm formation.

A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner.

MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

Tethering factors as organizers of intracellular vesicular traffic.

Intracellular trafficking entails the budding, transport, tethering, and fusion of transport vesicles and other membrane carriers. Here we review recent progress toward a mechanistic understanding of vesicle tethering. The known tethering factors are large complexes important for one or more intracellular trafficking pathways and are capable of interacting directly with many of the other principal components of the cellular trafficking machinery. Our review emphasizes recent developments in the in vitro reconstitution of vesicle tethering and the structural characterization of multisubunit tethering factors. The combination of these and other approaches has led to exciting progress toward understanding how these essential nanomachines work.

Efficacy of Lemon Mouthwash in Improving Dry Mouth Symptoms and Salivary Flow in Hemodialysis Patients.

OBJECTIVES: Gargling mouthwash is a safe and convenient oral care intervention; it rinses the mouth and increases salivary flow rate. The effectiveness of lemon mouthwash in relieving xerostomia and increasing the salivary flow rate among hemodialysis patients has not been studied. Our study sought to analyze the effectiveness of varying concentrations of lemon in mouthwash solutions on xerostomia and salivary flow rate. METHODS: A multi-concentration test was used to assess lemon mouthwash at 20%, 15%, 10%, 5%, and 2.5% concentrations to determine the optimal concentration for relieving dry mouth and increasing salivary flow rate. Generalized estimating equations were used to analyze the differences between various concentrations of lemon mouthwash and baseline values. RESULTS: In total, 44 patients were recruited. The 10% lemon concentration mouthwash was the most effective for increasing salivary flow rate, but the 5% and 2.5% were better accepted by the participants. Our findings can help establish intervention guidelines to relieve xerostomia among hemodialysis patients. CONCLUSION: Our findings can help establish intervention guidelines to relieve xerostomia among hemodialysis patients.

Dog sperm cryopreservation using cryovials and different dilution steps.

BACKGROUND: The conventional sperm freezing method for dog sperm is with straws and includes two-step dilution and a long equilibration time. OBJECTIVE: To develop a more efficient freezing method using cryovials. MATERIALS AND METHODS: Three freezing protocols using cryovials (0.5 mL) were conducted with dog spermatozoa at 1 x 108 sperm/mL: Group 1 spermatozoa were cooled in cryovials and extender 1 (E1) and extender 2 (E1 +1 M glycerol) at 4 degree C for 50 min and then frozen over LN2 for 20 min; Group 2 sperm was cooled and frozen in cryovials with a mixture of E1 and E2 (1:1) in a deep freezer (-80 degree C) for 30 min; Group 3 sperm in cryovials and E1 were cooled at 4 degree C for 20 min, cooled for an additional 20 min after addition of E2 (E1:E2, 1:1), and then frozen using LN2/ vapour for 20 min. The control (Group 4) consisted of spermatozoa in straws being frozen using the conventional freezing method using two-step dilution. All groups were plunged and stored in LN2 after freezing and their functional performance and gene expression determined. RESULTS: Progressive motility and acrosome integrity were highest (P < 0.05) in Groups 2, 3 and 4 (only acrosome integrity). Viability in Group 3 was significantly better that in the other Groups, and the reactive oxygen species (ROS) level and phosphatidylserine (PS) translocation index were significantly lower in Group 2 than the other Groups. The expression of sperm mitochondria-associated cysteine-rich protein (SMCP) and anti-apoptotic B-cell lymphoma 2 (BCL2) genes was highest (P < 0.05) in Group 2 and the expression of pro-apoptotic Bcl2-associated X protein (BAX) was lowest (P < 0.05) in Group 4. CONCLUSION: The sperm frozen using cryovials, one step dilution and the deep freezer (Group 2) proved to be a simple and suitable cryopreservation method for dog sperm. https://doi.org/10.54680/fr24110110312.

[The Generative Artificial Intelligence Revolution in Nursing: A New Chapter in Enhancing Care Quality and Education].

Artificial intelligence (AI) represents a recent major breakthrough in technology development and, in recent years, generative AI has emerged as another trendsetter. The application of generative AI technologies in the healthcare sector has not only opened new possibilities for improving the efficiency of medical diagnoses but also provided healthcare professionals with more-accurate patient monitoring capabilities and optimized care processes. Combining generative AI with nursing expertise holds out the potential of creating a more valuable model of nursing care. The impact of generative AI on the nursing profession poses both challenges and opportunities. By applying appropriate strategies, it is possible to create more advanced and humane nursing values that enhance overall nursing efficiencies and align the nursing field with modern technological advancements. In this article, the development of AI and generative AI is reviewed, and the potential for their application to nursing care is discussed, with the goal of stimulating innovative thinking and new strategies for interdisciplinary collaboration between technology and nursing.

Polymorphic Loci of Xenobiotic Biotransformation Genes in Accumulated Mercury Pollution Liquidators and in Workers with Chronic Mercury Vapors Exposure.

The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.

Antiplatelet and Antithrombotic Properties of Compound L-36, a 6H-1,3,4-Thiadiazine Derivative.

Compound L-36, a new derivative of 6H-1,3,4-thiadiazine, was studied in in vitro and in vivo experiments. This compound exhibits high antiplatelet and antithrombogenic activity. In in vitro experiments, compound L-36 by its antiplatelet activity (by IC50) was superior to acetylsalicylic acid by 9.4 times. In in vivo experiments, compound L-36 by its ED50 value was close to the comparison drug. On the model of pulmonary artery thrombosis, compound L-36 ensured better survival of experimental animals than acetylsalicylic acid. Morphological studies showed that compound L-36 effectively attenuated the thrombosis processes in the pulmonary tissue induced by intravenous injection of a thrombogenic mixture (epinephrine and collagen).

Associations of ECG Signs of Ischemic and Non-Specific Signs of Metabolic Changes in the Myocardium With Unfavorable Cardiovascular Prognosis in a 7-Year Prospective Follow-Up of Young People Under 45 Years.

AIM: To study ischemic and/or nonspecific ECG signs of metabolic changes in the myocardium and to determine their relationship with unfavorable cardiovascular prognosis in a 7-year prospective observation of young people under 45 years of age. MATERIAL AND METHODS: A cross-sectional population survey of a random sample aged 25-44 years (n=1363) was conducted in Novosibirsk. The survey program used the standardized epidemiological Rose questionnaire. Biochemical tests were used to measure blood concentrations of total cholesterol (C), triglycerides (TG), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), and fasting blood plasma glucose. Systolic and diastolic BP (SBP, DBP), the presence of arterial hypertension (AH), body mass index (BMI), waist circumference (WC), and smoking status were assessed. ECG was recorded at rest in 12 standard leads followed by interpretation according to the Minnesota Code. The presence of ischemic and/or nonspecific ECG signs of metabolic changes in the myocardium was determined. Subjects with ECG signs of ischemic changes in the myocardium were selected for long-term follow-up and additional examination by cardiologists. Then the whole cohort was monitored for 7 years, and cardiovascular events were recorded, including using data from the WHO Myocardial Infarction Registry in Novosibirsk. For statistical analysis of the results, cardiovascular events were combined into a composite endpoint. RESULTS: During 7 years, 40 people (27 men and 13 women) had an unfavorable cardiovascular prognosis. Multivariate regression analysis showed that a 7-year unfavorable cardiovascular prognosis in people younger than 45 years was associated with signs of ischemic myocardial alterations identified on the background ECG (OR 5.319, 95% CI: 1.543-18.342, p=0.008) and nonspecific ECG signs of metabolic changes in the myocardium (OR 2.978, 95% CI: 1.216-7.216, p=0.017) regardless of age, gender, the presence of arterial hypertension (AH) and type 2 diabetes mellitus (DM2). CONCLUSION: In young people under 45 years of age, not only ECG signs of ischemic changes in the myocardium, but also nonspecific ECG signs of metabolic changes in the myocardium are associated with an unfavorable cardiovascular prognosis, directly and independently on age and gender, in a long-term, 7-year period.

Biomolecules of Adipose Tissue in Atherosclerotic Plaques of Men With Coronary Atherosclerosis.

AIM: To study metabolic molecules (adiponectin, adipsin, resistin, glucagon-like peptide-1 (GLP-1), glucagon, secretin) of adipose tissue in atherosclerotic plaques (AP) and their associations with AP instability in men with coronary atherosclerosis. MATERIAL AND METHODS: Metabolic molecules (adipocytokines and metabolic hormones) of adipose tissue can act as enzymes, hormones or growth factors in modulating insulin resistance and lipid and glucose metabolism and indirectly influence the course of the atherosclerotic process. This study included 48 men from whom 139 coronary artery (CA) samples were collected during coronary artery bypass grafting, after obtaining the informed consent. According to the histological conclusion, 84 (60.4%) CA plaques were stable, 44 (31.7%) were unstable, and 11 histological samples had a conditionally unchanged CA intima (7.9%). The concentrations of adiponectin, adipsin, resistin, GLP-1, glucagon, and secretin were measured in AP homogenates by multiplex analysis using the Human Metabolic Hormone V3 panel (MILLIPLEX, Germany). During the study, demographic and anthropometric characteristics, medical history, and presence of chronic diseases were recorded. RESULTS: The glucagon concentration in the conditionally unchanged intima was 16.7% lower and in the fragments of unstable atherosclerotic plaques 41.2% lower than in fragments of stable APs. However, the glucagon concentration in stable APs was 28% higher than in unstable APs. The secretin concentration in the conditionally unchanged intima was also lower than in stable APs by 41.2%, while in stable APs, the secretin concentration was 20% higher than in unstable APs. The adiponectin concentrations were directly correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations (r=0.286; p=0.002), while the secretin concentrations were inversely correlated with serum HDL-C concentrations (r= -0.199; p=0.038). The probability of having an unstable AP (in relation to conditionally unchanged intima) increases by 35.8% with an increase in the AP glucagon concentration by 1 pg/mg protein. The probability of having a stable AP (in relation to unchanged intima) increases by 29.4% with an increase in the AP glucagon concentration by 1 pg/mg protein and by 10.1% with an increase in the AP secretin concentration by 1 pg/mg protein. CONCLUSION: The AP adiponectin concentration directly correlates and the AP secretin concentration inversely correlates with the serum concentration of HDL-C. The presence of both stable and unstable APs is directly associated with the AP glucagon concentration in men with coronary atherosclerosis. The AP secretin concentration is directly associated with plaque stability in men with coronary atherosclerosis. Further thorough study of the identified markers in atherosclerotic lesions will allow using them as potential targets for therapy.

[Repeated liver resections for recurrent intrahepatic cholangiocarcinoma]. / Povtornye rezektsii pecheni pri retsidive vnutripechenochnoi kholangiokartsinomy.

OBJECTIVE: To evaluate the safety and advisability of repeated liver resection (RLR) for recurrent intrahepatic cholangiocarcinoma (ICC). MATERIAL AND METHODS: The results of RLR for ICC recurrence (n=10) were retrospectively analyzed between 1999 and 2023. The control group consisted of patients undergoing primary liver resection for ICC (n=195). RESULTS: Surgery time (p=0.001) and blood loss (p=0.038) were lower in the RLR group. There were no blood transfusions (0 vs. 31.8%, p=0.034) and 90-day mortality (0 vs. 3.2%, p=1.0) in the same group. The risk of complications (30.0% vs.45.6%, p=0.517) and adverse events grade ≥ III (20.0% vs. 17.9%, p=1.0) was similar in both groups. Multifocal intrahepatic nodes were more common in the RLR group (60% vs. 37.9%, p=0.193), while there were no negative factors such as lymph nodes involvement (0 vs. 34.4%, p=0.032) and invasion of surrounding structures (0 vs. 38.5%, p=0.015). Dimensions of the largest node were smaller in repeated resection (2 vs. 8 cm, p<0.0001). Incidence of R0 resections (80.0% vs. 82.1%, p=1.0) was comparable. Long-term results were similar: five-year overall survival 17.2% and 34.7% (p=0.912), three-year disease-free survival 20.0% and 26.5% (p=0.421). CONCLUSION: Similar results of repeated and primary liver resections confirm advisability of RLR for intrahepatic recurrence of ICC.

[Results of the first All-Russian consensus conference on bariatric surgery]. / Rezul'taty pervoi vserossiiskoi konsensus-konferentsii po bariatricheskoi khirurgii.

Until now, there has not been organized consensus for standardization in bariatric surgery In Russia. We present the results of the first Bariatric Surgery Consensus Conference conducted in Barnaul (March, 2023). A list of questions was proposed within 6 blocks: 1) general issues of bariatric surgery, 2) sleeve gastrectomy, 3) one-anastomosis gastric bypass («mini-gastric bypass¼), 4) Roux-en-Y Gastric Bypass, 5) Single Anastomosis Duodenal Switch and other options for biliopancreatic bypass, 6) rare procedures. Consensus (>70% agreement) was reached for 51 out of 96 statements. Stratification by the level of expertise was carried out, and responses of the expert group were compared with responses of all participants.

[Surgical treatment and prognostic factors in perihilar tumors]. / Khirurgicheskoe lechenie i faktory prognoza pri perikhilyarnoi opukholi.

OBJECTIVE: To study the results of surgical treatment in patients with perihilar tumors. MATERIAL AND METHODS: We analyzed 98 patients with perihilar tumors who underwent surgery. RESULTS: We prefer percutaneous transhepatic biliary drainage (n=58) for jaundice. Retrograde interventions were performed in 18 cases (20.5%), complications grade III-IV were more common (p=0.037) in the last group. Postoperative mortality was 12%. Complications developed in 81 patients (82.7%), grade ≥3 - in 39 (39.8%) cases. Portal vein resection (n=26) increased the incidence of complications grade ≥III (p=0.035) and portal vein thrombosis (p=0.0001). Chemotherapy after surgery was performed in 47 patients (48.0%), photodynamic therapy - in 7 (7.1%) patients. A 5-year overall survival was 28.1%, the median survival - 29 months. R2 resection and/or M1 stage (n=12) significantly worsened the prognosis and overall survival (16.5 vs. 31 months, p=0.0055). Lymph node (LN) lesion, microscopic status (R0 vs. R1) of resection margin, technique of decompression and isolated resection of extrahepatic bile ducts did not affect the prognosis, and we combined appropriate patients (n=72) for analysis. SI resection and excision of ≥6 lymph nodes were independent positive factors for disease-free survival (p=0.042 and p=0.007, respectively). Blood transfusion and high preoperative neutrophil-lymphocyte index (NLI ≥2.15) worsened overall (p=0.009 and p=0.002, respectively) and disease-free survival (p=0.002 and 0.007, respectively). The absence of adjuvant therapy worsened disease-free survival alone (p=0.024). CONCLUSION: SI liver resection, adequate lymph node dissection and adjuvant therapy should be used for perihilar tumors. Isolated resection of extrahepatic bile ducts is permissible in some cases. Blood transfusion and NLI ≥2.15 are independent negative prognostic factors.

[220th anniversary of the Department of Forensic Medicine of Sechenov University]. / 220 let kafedre sudebnoi meditsiny Sechenovskogo Universiteta.

The article presents a review of scientific and educational activities of the Department of Forensic Medicine of Sechenov University in different historical periods of establishment and development. The information about founders of the domestic forensic medicine, who held the position of the head of the department in the period from 1804 to 2024, their contribution to the development of forensic medical science and the main scientific research directions is given. The modern stage of the department's existence under the leadership of Yu.I. Pigolkin is marked by new successes and scientific achievements based on continuity and preservation of the department's traditions for 220 years.

[Vibrational spectroscopy use for forensic purposes combined with machine learning]. / Ispol'zovanie kolebatel'noi spektroskopii v sochetanii s mashinnym obucheniem dlya zadach sudebnoi meditsiny.

Vibrational spectroscopy combined with machine learning has a great potential for forensic research. Portable Raman spectrometers are already being used by law-enforcement agencies to identify drugs. Several new technologies based on vibrational spectroscopy, that can be used in forensic science to analyze documents, gunshot traces, cloths, soil, hair, nails and lacquer, are being developed nowadays. The article considers the use of vibrational spectroscopy in forensic practice for conducting serological studies with an emphasis on the development of a universal method of identifying the main secretions of the body. The method allows to determine the time elapsed since the trace was made, as well as the phenotypic profile of host, including sex, race and age.

[Forensic assessment of neck organs alterations in hanging depending on the noose position]. / Sudebno-meditsinskaya otsenka izmenenii v organokomplekse shei pri poveshenii v zavisimosti ot polozheniya petli.

OBJECTIVE: To reveal statistical patterns in the localization of alterations in organs and tissues of the neck in hanging depending on the noose location. MATERIAL AND METHODS: In this study 222 forensic examination reports of corpses of those who died from hanging, conducted in the Bureau of Forensic Medical Expertise of Moscow Oblast for 2019, were investigated. Standard methods of mathematical statistics, including Mann-Whitney U Test and the Fisher's Exact Test, were used for calculations. Sex and age characteristics of hanging cases were given. RESULTS: Retrospective statistical analysis has shown that the pattern of injuries revealed in organs and tissues of the neck both depends (in cases of Amussat's sign) and does not depend (in cases of hemorrhages in the legs of sternocleidomastoid muscle, fractures of the hyoid bone and thyroid cartilage, Martin's sign) on the noose position. CONCLUSION: The obtained results can be used to develop measures aimed at improving the quality of forensic examination of hanging cases.

[Innovations in forensic medicine: accuracy, evidence and effectiveness of expertises in emergencies in case of mass fatality]. / Innovatsii v sudebnoi meditsine: dostovernost', dokazatel'nost' i effektivnost' provodimykh ekspertiz v usloviyakh chrezvychainoi situatsii pri massovoi gibeli lyudei.

The article presents the main innovative methods used in forensic expert practice at the current stage, reveals the principle and algorithms of the developed software complex for registration and identification of the deceased. The proposed program automatically generates four documents, which reduces the time required for forensic expertise in the conditions of mass admission of deceased. The article's authors substantiate prospects of further application of computer technologies in forensic practice to improve organizational and methodological activities in emergencies with a large number of deceased.

[Modern opportunities of using computer programs and mobile devices in the frame of personality identification]. / Sovremennye vozmozhnosti ispol'zovaniya komp'yuternykh programm i mobil'nykh ustroistv v ramkakh identifikatsii lichnosti.

A technology of mobile devices on the basis of Android and iOS sharing, in which previously trained neural networks on the mobile device with the use of the Skull-face program place the reference points in automatic mode with subsequent analysis of the images and obtaining the result in less than 1 min, has been developed. Data processing and acquisition of results immediately at the scene of an accident can provide invaluable assistance in the mass admission of unidentified corpses in cases of emergency; will allow to rapidly, excluding the influence of subjective factor, solve expert tasks, improve the accuracy, effectiveness and performance of forensic personality identification.

[Forensic characteristic of damages caused by offensive grenades detonation]. / Sudebno-meditsinskaya kharakteristika povrezhdenii, prichinennykh pri vzryve nastupatel'nykh granat.

OBJECTIVE: To determine the specific morphological features of damages on the cloth and biological simulator of the human body in the detonation of RGD-5 and RGN fragmentation hand offensive grenades. MATERIAL AND METHODS: The study was carried out on the 12 targets from a biological simulator of the human body wrapped in cotton cloth by detonation of examined grenades at a distance of 50 cm and 1 m from the target. RESULTS: The character and features of damages of cloth and human body biological simulator, features of soot deposition made it possible to determine specific signs for each of examined offensive grenades types. CONCLUSIONS: The complex of obtained data allows to determine with high accuracy the detonation distance and the type of explosive device.