The TATA-box binding protein-associated factor TAF12b facilitates the degradation of type-B response regulators to negatively regulate cytokinin signaling.

Cytokinins (CKs) are one of important classes of plant hormones essential for plant growth and development. The TATA-box binding protein-associated factor 12b (TAF12b) is involved in cytokinin (CK) signaling, but its molecular and biochemical mechanisms remain unclear. In this study, TAF12b of Nicotiana benthamiana (NbTAF12b) was found to mediate CK response by directly interacting with type-B response regulators (B-RRs), which are positive regulators of CK signaling, and inhibiting their transcriptional activities. The co-factor specifically facilitated the proteasomal degradation of non-phosphorylated B-RRs by recruiting the KMD family of F-box proteins. Such interactions between TAF12b and B-RRs also occur in other plant species. Genetic transformation experiments further showed that overexpression of NbTAF12b attenuates the CK-hypersensitive phenotype conferred by NbRR1 overexpression. Taken together, these results suggest a conserved mechanism that TAF12b negatively regulates CK responses through promoting 26S proteasome-mediated degradation of B-RRs degradation in multiple plant species, which provides novel insights into the regulatory network of CK signaling in plants.

The involvement of tumor necrosis factor receptor-associated factor 6 in regulating immune response by NF-κB at pre-molt stage of Chinese mitten crab (Eriocheir sinensis).

Molting is a crucial biological process of crustaceans. Crustaceans go through three separate stages throughout their molting process, including pre-molt, post-molt and inter-molt. However, the exact mechanism of immunological modulation during molting remains unclear. Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been extensively documented to participate in immune defense. In the present study, a TRAF6 gene with two TRAF-type zinc finger domains was identified from Eriocheir sinensis (designed as EsTRAF6), and its role in regulating immune response during molting process was explored. The mRNA expression level of EsTRAF6 at pre-molt stage was higher than that at post-molt stage and inter-molt stage. After Aeromonas hydrophila stimulation, the expression levels of EsTRAF6, EsRelish and anti-lipopolysaccharide factors (ALFs) genes exhibited a considerable increase at three molting stages. Subsequently, the expression patterns of EsTRAF6 and EsRelish in response to the treatment with 20-hydroxyecdysone (20E) were examined. The mRNA expression of EsTRAF6 and EsRelish were significantly increased at 12 h after 20E injection. Additionally, the protein expression level of TRAF6 was also up-regulated in 20E group compared to control group. Furthermore, the role of EsTRAF6 in regulating the anti- ALFs expression at pre-molt stage post A. hydrophila stimulation was investigated. Following the inhibition of the EsTRAF6 transcript using RNAi or the injection of inhibitor (TMBPS), there was a notable decrease of the EsALF1, EsALF2 and EsALF3 transcripts. Moreover, a significant reduction in the phosphorylation level of NF-κB at pre-molt stage was observed after A. hydrophila stimulation in TRAF6-inhibited crabs. Collectively, our results suggest that EsTRAF6 could be induced by 20E and promoted the EsALFs expression by activating NF-κB at pre-molt stage, which provides a novel insight into the research of immune regulatory mechanism during the process of molting of crustaceans.

Epidemiological features of suicidal ideation among the elderly in China based meta-analysis.

BACKGROUND: Studies on the prevalence of suicidal ideation (SI) and its associated factors among the elderly in China show considerable variability. This meta-analysis aims to clarify the epidemiological features of SI in this population. METHODS: We systematically searched English and Chinese databases for relevant literature up to September 15, 2022. The extracted data facilitated the calculation of prevalence and odds ratios (ORs) for factors associated with SI among China's elderly. RESULTS: We analyzed 31 cross-sectional studies, comprising a total of 79,861 participants from over 20 provinces and municipalities. The pooled prevalence of SI was found to be 11.47% [95% confidence interval (CI): 7.82-15.71%]. Significant variations in prevalence were influenced by residence, physical health (including chronic diseases and daily living capabilities), mental health (depressive symptoms and life satisfaction), economic status, and time-specific assessment tools. Notably, the prevalence from 2011-2020 (15.59%, 95% CI: 9.08-23.44%) was almost double that of 2001-2010 (7.85%, 95% CI: 5.08-11.16%). The SI prevalence in the eastern region (8.06%, 95% CI 5.59-10.94%) was significantly lower than in the central and western regions (16.97%, 95% CI 12.04-22.53%). Fourteen factors exhibited a significant pooled OR greater than 1 (p < 0.05), and two factors had ORs less than 1 (p < 0.05), indicating notable association with SI among the elderly. CONCLUSION: SI among China's elderly showed relatively high prevalence and considerable heterogeneity across different characteristics and associated factors. This underscores the need for targeted intervention strategies and standardized temporal assessments of SI to effectively address suicide risk in this population.

Nrf2 Signaling Pathway: Focus on Oxidative Stress in Spinal Cord Injury.

Spinal cord injury (SCI) is a serious, disabling injury to the central nervous system that can lead to motor, sensory, and autonomic dysfunction below the injury plane. SCI can be divided into primary injury and secondary injury according to its pathophysiological process. Primary injury is irreversible in most cases, while secondary injury is a dynamic regulatory process. Secondary injury involves a series of pathological events, such as ischemia, oxidative stress, inflammatory events, apoptotic pathways, and motor dysfunction. Among them, oxidative stress is an important pathological event of secondary injury. Oxidative stress causes a series of destructive events such as lipid peroxidation, DNA damage, inflammation, and cell death, which further worsens the microenvironment of the injured site and leads to neurological dysfunction. The nuclear factor erythrocyte 2-associated factor 2 (Nrf2) is considered to be a key pathway of antioxidative stress and is closely related to the pathological process of SCI. Activation of this pathway can effectively inhibit the oxidative stress process and promote the recovery of nerve function after SCI. Therefore, the Nrf2 pathway may be a potential therapeutic target for SCI. This review deeply analyzed the generation of oxidative stress in SCI, the role and mechanism of Nrf2 as the main regulator of antioxidant stress in SCI, and the influence of cross-talk between Nrf2 and related pathways that may be involved in the pathological regulation of SCI on oxidative stress, and summarized the drugs and other treatment methods based on Nrf2 pathway regulation. The objective of this paper is to provide evidence for the role of Nrf2 activation in SCI and to highlight the important role of Nrf2 in alleviating SCI by elucidating the mechanism, so as to provide a theoretical basis for targeting Nrf2 pathway as a therapy for SCI.

Resilience and mental health among perinatal women: a systematic review.

Objective: This review aimed to assess the current evidence on the relationship between resilience and mental health employed in response to the impacts of mental health. Method: This review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). The protocol of this review was registered on the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023470966). Three authors searched peer-reviewed articles using several electronic databases, including Scopus, PubMed/MEDLINE, Psych Info, EMBASE, and Web of Science, from September to October 2023 and included all the studies from any time until November 1, 2023. The review included all eligible quantitative observational and qualitative studies, irrespective of geographical boundaries. Result: Depression, anxiety, and post-traumatic stress disorders were found to be the most common, but not the only, mental health disorders during the perinatal period, and higher maternal resilience during perinatal periods was found to reduce mental health disorders. It was also found that pregnant women were more resilient to mental health disorders than postpartum women. Tolerance of uncertainty and a positive cognitive appraisal, women's self-behavior and family functioning, and protective psychosocial resources such as dispositional optimism, parental sense of mastery, self-esteem, gratitude, and forgiveness were found to be the most common mechanisms of resilience among perinatal women. Older age, having an adolescent partner, family income, and distress were found to affect resilience. Conclusion: Noting that women's resilience is an important tool to prevent perinatal mental health disorders, maternal healthcare providers need to counsel perinatal women on resilience-boosting mechanisms, such as applying self-behavior and having social support or close family relationships. It is recommended to counsel or provide psychosocial interventions for the woman's companion or partner to give strong support for the woman in each of the perinatal periods. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=470966, identifier CRD42023470966.

Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors.

In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.

Assessment of impaired glomerular filtration rate and associated factors in South West Ethiopia: a cross-sectional study.

INTRODUCTION: Currently, kidney disease is an increasing major health problem worldwide. It is expected to be the 5th ranked cause of death by 2040. If it is early detected, further complication caused by kidney disease will be minimized. An assessment of impaired glomerular filtration rate (eGFR) has potential aids in early identification and treatment of kidney disease. However, in hospital practice instead of using eGFR, direct measurement of serum creatinine level is used for assessing renal function. Hence, this study is aimed to assess the magnitude and associated factors of impaired glomerular filtration rate among admitted patients in Wolkite University Specialized Teaching Hospital (WKUSTH). OBJECTIVE: To assess the magnitude and associated factors of impaired glomerular filtration rate in WKUSTH, Ethiopia 2023. METHOD: Institutional based cross-sectional study with secondary data was conducted. 338 participants were selected by a convenient sampling technique. Epidata 3.1 version for data entry and SPSS version 20 for data analysis was used. Bivariate analysis was used to screen candidate variables for multivariate analysis. In the multivariate analysis a P-value < 0.05 were considered statistically significant. RESULTS: The study enrolled 338 patients admitted to WUSTH. Seventy (20.7%) (95% CI: 16.6-25.4%) of them had impaired eGFR according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and Modification of Diet in Renal Disease (MDRD-4). older age (AOR 3.38, 95% CI; 1.31, 8.71), hypertension (AOR 17.8, 95% CI; 7.75, 41.22), anemia (AOR 2.51, 95% CI; 1.11, 5.83) DM (AOR 11.2, 95% CI; 4.11, 30.73), and high BMI (AOR 7.56, 95% CI; 3.16, 18.08), were independently associated with impaired eGFR. CONCLUSIONS: The magnitude of impaired eGFR was prevalent among adult patients admitted to WKUSTH medical ward with different medical conditions. Old age, Hypertension, Diabetes, high body mass index, and Anemia were significantly associated with impaired eGFR both in CKD-EPI and MDRD-4 equation. Estimation of GFR for all hospitalized adults with known CKD risk factors might help in early detection of CKD and prevent complications.

Inhibition of TRAF6 alleviates secondary brain injury by reducing neuronal pyroptosis after intracerebral hemorrhage.

Secondary brain injury (SBI) is one of the main causes of high mortality and disability rates following intracerebral hemorrhage (ICH). TRAF6 plays a crucial role in the process of pyroptosis, and modulating its expression may present a novel therapeutic strategy for mitigating brain injury. This study aims to explore the mechanisms of TRAF6 in pyroptosis after ICH. C57BL/6J mice were used to establish the ICH model. Brain was collected at different time points for q-PCR and western blot to detect the level of TRAF6. After the C25-140 (the TRAF6 inhibitor) was administrated, the mice were divided into four groups. Then, the neurological deficit, brain water content, and blood-brain barrier (BBB) ​​damage were detected. Immunofluorescence and western blot were used to detect the level of pyroptosis proteins, and enzyme-linked immunosorbent assay (ELISA) and q-PCR were used to detect the levels of IL-18 and IL-1ß. TRAF6 expression was upregulated after ICH and was mainly expressed in neurons. Inhibition of TRAF6 expression with C25-140 alleviated neurological deficits and reduced brain edema after ICH. In addition, inhibition of TRAF6 also reduced the expression of pyroptosis inflammasomes such as GSDMD, NLRP3, and ASC, as well as neurological damage caused by IL-18 and IL-1ß after ICH. TRAF6 regulates neuronal pyroptosis in SBI after ICH. Inhibition of TRAF6 may be a potential target for alleviating inflammatory damage after ICH.

Uncovering the Interaction between TRAF1 and MAVS in the RIG-I Pathway to Enhance the Upregulation of IRF1/ISG15 during Classical Swine Fever Virus Infection.

Classical swine fever (CSF) is caused by the classical swine fever virus (CSFV), which poses a threat to swine production. The activation of host innate immunity through linker proteins such as tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) is crucial for the induction of the NF-κB pathway. Recent research has revealed the involvement of mitochondrial antiviral-signaling protein (MAVS) in the interaction with TRAF2, 3, 5, and 6 to activate both the NF-κB and IRF3 pathways. This study revealed that CSFV infection led to the upregulation of TRAF1 mRNA and protein levels; moreover, TRAF1 overexpression inhibited CSFV replication, while TRAF1 knockdown promoted replication, highlighting its importance in the host response to CSFV infection. Additionally, the expression of RIG-I, MAVS, TRAF1, IRF1, and ISG15 were detected in PK-15 cells infected with CSFV, revealing that TRAF1 plays a role in regulating IRF1 and ISG15 within the RIG-I pathway. Furthermore, Co-IP, GST pull-down, and IFA analyses demonstrated that TRAF1 interacted with MAVS and co-localized in the cytoplasm during CSFV infection. Ultimately, TRAF1 acted as a novel member of the TRAF family, bound to MAVS as a linker molecule, and functioned as a mediator downstream of MAVS in the RIG-I/MAVS pathway against CSFV replication.

Aerobic training attenuates cardiac remodeling in mice post-myocardial infarction by inhibiting the p300/CBP-associated factor.

Aerobic training (AT), an effective form of cardiac rehabilitation, has been shown to be beneficial for cardiac repair and remodeling after myocardial infarction (MI). The p300/CBP-associated factor (PCAF) is one of the most important lysine acetyltransferases and is involved in various biological processes. However, the role of PCAF in AT and AT-mediated cardiac remodeling post-MI has not been determined. Here, we found that the PCAF protein level was significantly increased after MI, while AT blocked the increase in PCAF. AT markedly improved cardiac remodeling in mice after MI by reducing endoplasmic reticulum stress (ERS). In vivo, similar to AT, pharmacological inhibition of PCAF by Embelin improved cardiac recovery and attenuated ERS in MI mice. Furthermore, we observed that both IGF-1, a simulated exercise environment, and Embelin protected from H2O2-induced cardiomyocyte injury, while PCAF overexpression by viruses or the sirtuin inhibitor nicotinamide eliminated the protective effect of IGF-1 in H9C2 cells. Thus, our data indicate that maintaining low PCAF levels plays an essential role in AT-mediated cardiac protection, and PCAF inhibition represents a promising therapeutic target for attenuating cardiac remodeling after MI.

Effects of novel lactoferrin peptides on LPS-induced alveolar bone destruction in a rat model.

To develop novel bovine lactoferrin (bLF) peptides targeting bLF-tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) binding sites, we identified two peptides that could target bLF-TRAF6 binding sites using structural analysis. Moreover, another peptide that could bind to the TRAF6 dimerization area was selected from the bLF sequence. The effects of each peptide on cytokine expression in lipopolysaccharide (LPS)-stimulated osteoblasts (ST2) and on osteoclastogenesis were examined using an LPS-treated co-culture of primary bone marrow cells (BMCs) with ST2 cells and a single culture of osteoclast precursor cells (RAW-D) treated with soluble receptor activator of NF-κB ligand. Finally, the effectiveness of these peptides against LPS-induced alveolar bone destruction was assessed. Two of the three peptides significantly suppressed LPS-induced TNF-α and interleukin-1ß expression in ST2 cells. Additionally, these peptides inhibited and reversed LPS-induced receptor activator of NF-κB ligand (RANKL) upregulation and osteoprotegerin (OPG) downregulation, respectively. Furthermore, both peptides significantly reduced LPS-induced osteoclastogenesis in the BMC-ST2 co-culture and RANKL-induced osteoclastogenesis in RAW-D cells. In vivo, topical application of these peptides significantly reduced the osteoclast number by downregulating RANKL and upregulating OPG in the periodontal ligament. It is indicated that the novel bLF peptides can be used to treat periodontitis-associated bone destruction.

Prevalence and factors associated with antenatal depressive symptoms across trimesters: a study of 110,584 pregnant women covered by a mobile app-based screening programme in Shenzhen, China.

BACKGROUND: Antenatal depression is a significant public health issue affecting pregnant women both globally and in China. Using data from a mobile app-based screening programme, this study explored the prevalence and factors associated with antenatal depressive symptoms across different trimesters in Shenzhen. METHODS: A retrospective cross-sectional study was conducted on pregnant women who gave birth in any hospital in Shenzhen between July 2021 and May 2022 and underwent depression screening using an official maternal and infant health mobile app at least once during pregnancy. Depressive symptoms were evaluated using the 9-item Patient Health Questionnaire (PHQ-9), with cut-off scores of 5 and 10 for mild and high level of symptoms, respectively. The prevalence for each trimester was determined by calculating the proportion of women scoring 5 or higher. A variety of sociodemographic, obstetric, psychological, and lifestyle factors were assessed for their association with depressive symptoms. Chi-square test and multivariate logistic regression were performed to identify significant predictors. RESULTS: A total of 110,584 pregnant women were included in the study, with an overall prevalence of depressive symptoms of 18.0% and a prevalence of high-level symptoms of 4.2%. Depressive symptoms were most prevalent in the first trimester (10.9%) and decreased in the second (6.2%) and third trimesters (6.3%). Only a small proportion (0.4%) of women showed persistent depressive symptoms across all trimesters. Anxiety symptoms in early pregnancy emerged as the most significant predictor of depressive symptoms. Other factors linked to an increased risk throughout pregnancy include lower marital satisfaction, living with parents-in-law, experience of negative life events, as well as drinking before and during pregnancy. Factors associated with a reduced risk throughout pregnancy include multiparity and daily physical activity. CONCLUSIONS: This large-scale study provides valuable insights into the prevalence and factors associated with antenatal depressive symptoms in Shenzhen. The findings underscore the need for targeted interventions for high-risk groups and the integration of mental health care into routine antenatal services. Continuous, dynamic monitoring of depressive symptoms for pregnant women and ensuring at-risk women receive comprehensive follow-up and appropriate psychological or psychiatric care are crucial for effectively addressing antenatal depression and improving maternal and infant health outcomes.

Frailty Trajectories and Its Associated Factors in Japanese Older Adults.

BACKGROUND: Associated factors for frailty development according to age group remain unclear. OBJECTIVES: To identify frailty score trajectories among community-dwelling older Japanese individuals and examine their associated factors. DESIGN: 13-year longitudinal study. SETTING: Kusatsu Town in Gunma Prefecture, Japan. PARTICIPANTS: 1706 older adults aged ≥ 65 years who completed an annual frailty assessment at least once between 2007 and 2019. MEASUREMENTS: Frailty status was determined using an index based on the Fried frailty phenotype criteria. Potential associated factors for frailty trajectory included physical, biological, lifestyle-related, and psychological factors, as well as comorbidities. RESULTS: We identified five trajectory patterns in the frailty score from age of 65 to 90 years -individuals who were robust (Group 1, 10.5%) as well as individuals with late-onset frailty (Group 2, 16.1%), middle-onset frailty (Group 3, 25.6% and Group 4, 35.2%), and early-onset frailty (Group 5, 12.7%). Compared with the other groups, the early-onset group showed a higher prevalence of cerebrovascular diseases, bone and joint diseases, poor nutrition, sarcopenia, hospitalization, low cognitive function, and smoking at the end of follow-up. Associated factors in the middle-onset group largely overlapped with those of the early-onset group. The late-onset frailty group tended to have a higher association with heart disease and bone and joint diseases compared with the robust group. CONCLUSION: Our findings from a 13-year longitudinal study identified five frailty trajectory patterns and seven associated factors for frailty trajectory. Proposed effective population-based frailty prevention strategies in each age group may contribute to effective strategies to extend healthy life expectancy in aging, aged, and super-aged communities.

Cultural competence and associated factors among nurses working in public hospitals of South Wollo zone, Northeast Ethiopia: a multi-center cross-sectional study.

BACKGROUND: Enhancing cultural competence stands as a cornerstone in the realm of clinical nursing. Consequently, nurses engaging with culturally diverse communities encounter significant challenges. In Ethiopia, nurses providing care often prioritize physical well-being, the therapeutic journey, and medical interventions, while overlooking the critical cultural dimensions of patient care. Therefore, this study aims to assess the level of cultural competence and its determining factors among nurses employed in public hospitals located in the South Wollo Zone of northeastern Ethiopia. METHODS: A multicenter, institution-based cross-sectional study was conducted, involving 629 nurses employed in public hospitals across northeastern Ethiopia. Participants were selected using a simple random sampling method. Data were gathered using a structured, self-administered English version of the Nurse Cultural Competence Scale Questionnaire (NCCSQ), and subsequently entered into Epi-data 4.6 for analysis. Statistical analysis was performed using SPSS version 26, employing multiple linear regression analysis to identify determining factors. RESULT: The participants' overall mean score for cultural competence was 3.198 [95% CI: 3.161, 3.234]. Specifically, factors such as being a female nurse (ß = 0.089, CI: 0.019-0.159), having a diploma level of education (ß = -0.084, CI: -0.101 to -0.007), having 11-20 years of work experience (ß = 0.412, CI: 0.090-0.815), a 1:15 nurse-to-patient ratio (ß = 0.081, CI: 0.010-0.162), experience with caring for culturally and ethnically diverse patients (ß = 0.362, CI: 0.248-0.476), comprehensive hospital level (ß = 0.699, CI: 0.496-0.903), and attending cultural training (ß = 0.002, CI: 0.234-0.931) were predictors of the mean score for cultural competence. CONCLUSION: In this study, the level of cultural competence was found to be at a moderate level and need more effort. Factors such as gender, years of work experience, nurse-to-patient ratio, experience in caring for culturally and ethnically diverse patients, hospital level, educational attainment, attendance of cultural training, and the presence of a feedback system for cultural competence were identified as predictors of cultural competence level. Sharing experiences from higher-level hospitals to lower-level ones and strengthening cultural competence training sessions for nurses can significantly enhance cultural competence within clinical settings.

Treatment non-adherence among methadone maintenance patients and associated factors: a multicenter, cross-sectional study in Vietnam.

OBJECTIVE: This multicenter, cross-sectional study was conducted to investigate the prevalence of treatment non-adherence and its associated factors among methadone maintenance patients in Vietnam. METHODS: This secondary data analysis was conducted using the data from a previous study. Six hundred patients were interviewed face-to-face to collect data on their demographic characteristics and social support. Information about the treatment characteristics and patients' non-adherence was gathered from medical records and books monitoring their treatment process. Treatment non-adherence was defined as missing at least one methadone dose in the last three months. RESULTS: The overall prevalence of non-adherence was 45.7%. The average social support score of patients who completely adhered to treatment was significantly higher than that of those who did not (p < 0.001). In the multivariate logistic regression model, for each one-unit increase in social support (one score), treatment time (a year), and patient's monthly income (one million Vietnam dongs), the odds of non-adherence decreased by 28% (aOR = 0.72, 95%CI 0.59-0.88, p = 0.002), 15% (aOR = 0.85, 95%CI 0.80-0.91, p < 0.001) and 9% (aOR = 0.91, 95%CI 0.85-0.97, p = 0.004), respectively. Patients living in Son La (a mountainous province) were 1.72 times (95%CI 1.09-2.71) more likely to be non-adherent as compared to those in other areas (p = 0.020). As per univariate analyses, other associated factors could be age, education level, family monthly income, occupation, and opioid relapse (p < 0.001). CONCLUSIONS: A high non-adherence rate was found among Vietnamese methadone maintenance patients. Interventions involving social support, occupation, income, and education are needed to improve their treatment adherence.

[Dermatoses of elderly inpatients in Casablanca: epidemiology and factors associated with length of stay]. / Dermatoses du sujet âgé en hospitalisation à Casablanca : épidémiologie et facteurs associés à la durée de séjour.

Geriatric in-patient dermatoses are diverse. Few data in Morocco describe the epidemiological profile and factors associated with average length of stay (LOS). Our aim was to identify these dermatoses and determine the factors associated with LOS.

4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20.

CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.

Identifying factors associated with locomotive syndrome using machine learning methods: The third survey of the research on osteoarthritis/osteoporosis against disability study.

AIM: To identify factors associated with locomotive syndrome (LS) using medical questionnaire data and machine learning. METHODS: A total of 1575 participants underwent the LS risk tests from the third survey of the research on osteoarthritis/osteoporosis against disability study (ROAD) study. LS was defined as stage 1 or higher based on clinical decision limits of the Japanese Orthopaedic Association. A total of 1335 items of medical questionnaire data came from this study. The number of medical questionnaire items was reduced from 1335 to 331 in data cleaning. From the 331 items, identify factors associated with LS use by light gradient boosting machine-based recursive feature elimination with cross-validation. The performance of each set was evaluated using an average of seven performance metrics, including 95% confidence intervals, using a bootstrapping method. The smallest set of items is determined with the highest average of receiver operating characteristic area under the curve (ROC-AUC) under 20 items as association factors of LS. Additionally, the performance of the selected items was compared with the LS risk tests and Loco-check. RESULTS: The nine items have the best average ROC-AUC under 20 items. The nine items show an average ROC-AUC of 0.858 (95% confidence interval 0.816-0.898). Age and back pain during walking were strongly associated with the prevalence of LS. The ROC-AUC of nine items is higher than that of existing questionnaire-based LS assessments, including the 25-question Geriatric Locomotor Scale and Loco-check. CONCLUSIONS: The identified nine items could aid early LS detection, enhancing understanding and prevention. Geriatr Gerontol Int 2024; 24: 806-813.

Epigenetics.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.

The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia-parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.