CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns.

AIMS/HYPOTHESIS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD). METHODS: Untargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease (n=35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied. RESULTS: Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median (interquartile range 25-75%) of 49.0 (44.0-57.0) mmol/mol (7.9%, [7.10-9.20%]) to 42.2 (39.7-47.7) mmol/mol (6.8%, [6.40-7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9-159.0) mg/mmol to 47.0 (26.0-93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. CONCLUSIONS/INTERPRETATION: In conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.

Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance.

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.

TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress of hepatocytes plays a causative role in non-alcoholic fatty liver disease (NAFLD). Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. Whether ER stress regulates HNF4α expression remains unknown. The aim of this study was to delineate the machinery of HNF4α protein degradation and explore a therapeutic strategy based on protecting HNF4α stability during NAFLD progression. METHODS: Correlation of HNF4α and tribbles homologue 3 (TRIB3), an ER stress sensor, was evaluated in human and mouse NAFLD tissues. RNA-sequencing, mass spectrometry analysis, co-immunoprecipitation, in vivo and in vitro ubiquitination assays were used to elucidate the mechanisms of TRIB3-mediated HNF4α degradation. Molecular docking and co-immunoprecipitation analyses were performed to identify a cell-penetrating peptide that ablates the TRIB3-HNF4α interaction. RESULTS: TRIB3 directly interacts with HNF4α and mediates ER stress-induced HNF4α degradation. TRIB3 recruits tripartite motif containing 8 (TRIM8) to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470. Abrogating the degradation of HNF4α attenuated the effect of TRIB3 on a diet-induced NAFLD model. Moreover, the TRIB3 gain-of-function variant p.Q84R is associated with NAFLD progression in patients, and induces lower HNF4α levels and more severe hepatic steatosis in mice. Importantly, disrupting the TRIB3-HNF4α interaction using a cell-penetrating peptide restores HNF4α levels and ameliorates NAFLD progression in mice. CONCLUSIONS: Our findings unravel the machinery of HNF4α protein degradation and indicate that targeting TRIB3-TRIM8 E3 complex-mediated HNF4α polyubiquitination may be an ideal strategy for NAFLD therapy. IMPACT AND IMPLICATIONS: Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. However, the mechanism of HNF4α protein degradation remains unknown. Herein, we reveal that TRIB3-TRIM8 E3 ligase complex is responsible for HNF4α degradation during NAFLD. Inhibiting the TRIB3-HNF4α interaction effectively stabilized HNF4α protein levels and transcription factor activity in the liver and ameliorated TRIB3-mediated NAFLD progression. Our findings demonstrate that disturbing the TRIM8-TRIB3-HNF4α interaction may provide a novel approach to treat NAFLD and even other liver diseases by stabilizing the HNF4α protein.

Nocturnal burst emissions of germacrene D from the open disk florets of pyrethrum flowers induce moths to oviposit on a nonhost and improve pollination success.

Recent studies show that nocturnal pollinators may be more important to ecosystem function and food production than is currently appreciated. Here, we describe an agricultural field study of pyrethrum (Tanacetum cinerariifolium) flower pollination. Pyrethrum is genetically self-incompatible and thus is reliant on pollinators for seed set. Our pollinator exclusion experiment showed that nocturnal insects, particularly moths, significantly contribute to seed set and quality. We discovered that the most abundant floral volatile, the sesquiterpene (-)-germacrene D (GD), is key in attracting the noctuid moths Peridroma saucia and Helicoverpa armigera. Germacrene D synthase (GDS) gene expression regulates the specific GD production and accumulation in flowers, which, in contrast to related species, lose the habit of closing at night. We did observe that female moths also oviposited on pyrethrum leaves and flower peduncles, but found that only a small fraction of those eggs hatched. Larvae were severely stunted in development, most likely due to the presence of pyrethrin defense compounds. This example of exploitative mutualism, which blocks the reproductive success of the moth pollinator and depends on nocturnal interactions, is placed into an ecological context to explain why it may have developed.

Molecular Dynamics Simulation of the Interaction within the Carboxymethyl Cellulose-Modified Montmorillonite Lamellae at Aggressive CuCl2 Concentrations.

To elucidate the degradation mechanism of the CMC-modified MMT composite at aggressive Cu2+ concentrations, large scale molecular dynamics simulation was conducted for CuCl2 concentrations ranging from 0 to 800 mM. Both CMC and MMT followed the Langmuir isotherm for Cu2+ adsorption, and the adsorption capacity of CMC (8.75 mmol/g) was much higher than that of MMT (0.83 mmol/g). Despite the CMC mass ratio being only 4.1%, it adsorbed up to 34.3% of the total adsorbed Cu2+. The Cu2+ attraction ability hierarchy of oxygen-containing functional groups in the CMC is as follows: carboxylic oxygens > alcoholic oxygens > carbinolic oxygens > bridging oxygens > glucose oxygens. Carboxyls were the most effective in chelating and complexing with Cu2+, and they could be intentionally added in artificially synthesized polymer-MMT composites for Cu2+ containment. Formation of the Cu2+ cation bridge between CMC and MMT at aggressive CuCl2 concentrations contributed to the transition of CMC density distribution from unimodality to bimodality and enhanced resistance of polymer elution. As the CuCl2 concentration increased, the stoichiometric ratio between the chelated Cu2+ and carboxylic oxygens increased from 1:2 to 1:1, suggesting the evolution of the Cu2+ chelation mechanism.

Exploring the role of mitochondrial-associated and peripheral neuropathy genes in the pathogenesis of diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and serious complication of diabetes mellitus, impacting the nerves in the limbs and leading to symptoms like pain, numbness, and diminished function. While the exact molecular and immune mechanisms underlying DPN remain incompletely understood, recent findings indicate that mitochondrial dysfunction may play a role in the advancement of this diabetic condition. METHODS: Two RNA transcriptome datasets (codes: GSE185011 and GSE95849), comprising samples from diabetic peripheral neuropathy (DPN) patients and healthy controls (HC), were retrieved from the Gene Expression Omnibus (GEO) database hosted by the National Center for Biotechnology Information (NCBI). Subsequently, differential expression analysis and gene set enrichment analysis were performed. Protein-protein interaction (PPI) networks were constructed to pinpoint key hub genes associated with DPN, with a specific emphasis on genes related to mitochondria and peripheral neuropathy disease (PND) that displayed differential expression. Additionally, the study estimated the levels of immune cell infiltration in both the HC and DPN samples. To validate the findings, quantitative polymerase chain reaction (qPCR) was employed to confirm the differential expression of selected genes in the DPN samples. RESULTS: This research identifies four hub genes associated mitochondria or PN. Furthermore, the analysis revealed increased immune cell infiltration in DPN tissues, particularly notable for macrophages and T cells. Additionally, our investigation identified potential drug candidates capable of regulating the expression of the four hub genes. These findings were corroborated by qPCR results, reinforcing the credibility of our bioinformatics analysis. CONCLUSIONS: This study provides a comprehensive overview of the molecular and immunological characteristics of DPN, based on both bioinformatics and experimental methods.

Gas-to-Particle Partitioning of Products from Ozonolysis of Δ3-Carene and the Effect of Temperature and Relative Humidity.

Formation of oxidized products from Δ3-carene (C10H16) ozonolysis and their gas-to-particle partitioning at three temperatures (0, 10, and 20 °C) under dry conditions (<2% RH) and also at 10 °C under humid (78% RH) conditions were studied using a time-of-flight chemical ionization mass spectrometer (ToF-CIMS) combined with a filter inlet for gases and aerosols (FIGAERO). The Δ3-carene ozonolysis products detected by the FIGAERO-ToF-CIMS were dominated by semivolatile organic compounds (SVOCs). The main effect of increasing temperature or RH on the product distribution was an increase in fragmentation of monomer compounds (from C10 to C7 compounds), potentially via alkoxy scission losing a C3 group. The equilibrium partitioning coefficient estimated according to equilibrium partitioning theory shows that the measured SVOC products distribute more into the SOA phase as the temperature decreases from 20 to 10 and 0 °C and for most products as the RH increases from <2 to 78%. The temperature dependency of the saturation vapor pressure (above an assumed liquid state), derived from the partitioning method, also allows for a direct way to obtain enthalpy of vaporization for the detected species without accessibility of authentic standards of the pure substances. This method can provide physical properties, beneficial for, e.g., atmospheric modeling, of complex multifunctional oxidation products.

Investigating the role of TGF-ß and BDNF in cancer-related depression: a primary cross-sectional study.

BACKGROUND: Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-ß (TGF-ß), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-ß and BDNF in cancer-related depression. METHODS: This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-ß and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The study revealed elevated plasma TGF-ß levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-ß and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-ß and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-ß and BDNF between cancer and non-cancer groups (P = 0.041). CONCLUSIONS: These findings underscore the active involvement of TGF-ß and BDNF crosstalk in the context of cancer-related depression.

Identification of symptom clusters and sentinel symptoms during the first cycle of chemotherapy in patients with lung cancer.

PURPOSE: To identify symptom clusters (SCs) in patients with lung cancer who are undergoing initial chemotherapy and to identify the sentinel symptoms of each SC. METHODS: A convenience sampling method was used to recruit patients with lung cancer who were undergoing their initial chemotherapy treatment. Patient information was collected using the General Demographic Questionnaire, MD Anderson Symptom Inventory (including the lung cancer module) and a schedule documenting the initial occurrence of symptoms. The Walktrap algorithm was employed to identify SCs, while sentinel symptoms within each SC were identified using the Apriori algorithm in conjunction with the initial occurrence time of symptoms. RESULTS: A total of 169 patients with lung cancer participated in this study, and four SCs were identified: the psychological SC (difficulty remembering, sadness, dry mouth, numbness or tingling, and distress), somatic SC (pain, fatigue, sleep disturbance, and drowsiness), respiratory SC (coughing, expectoration, chest tightness, and shortness of breath), and digestive SC (nausea, poor appetite, constipation, vomiting, and weight loss). Sadness, fatigue, and coughing were identified as sentinel symptoms of the psychological, somatic, and respiratory SCs, respectively. However, no sentinel symptom was identified for the digestive SC. CONCLUSION: Patients with lung cancer who are undergoing chemotherapy encounter a spectrum of symptoms, often presenting as SCs. The sentinel symptom of each SC emerges earlier than the other symptoms and is characterized by its sensitivity, significance, and driving force. It serves as a vital indicator of the SC and assumes a sentry role. Targeting sentinel symptoms might be a promising strategy for determining the optimal timing of interventions and for mitigating or decelerating the progression of the other symptoms within the SC.

Symptom clusters and impact on quality of life in lung cancer patients undergoing chemotherapy.

PURPOSE: To identify symptom clusters (SCs) in lung cancer patients undergoing chemotherapy and explore their impact on health-related quality of life (HRQoL). METHODS: Patients were invited to complete the Chinese version of the M.D. Anderson Symptom Inventory with the Lung Cancer Module and the Quality of Life Questionnaire-core 30. Network analysis was employed to identify SCs. The associations between SCs and each function of HRQoL were examined using the Pearson correlation matrix. Multiple linear regression was applied to analyze the influencing factors of each function of HRQoL. RESULTS: A total of 623 lung cancer patients who were receiving chemotherapy were recruited. The global health status of lung cancer patients was 59.71 ± 21.09, and 89.73% of patients developed symptoms. Three SCs (Somato-psychological SC, Respiratory SC, and Gastrointestinal SC) were identified, and Somato-psychological SC and Gastrointestinal SC were identified as influencing factors for HRQoL in lung cancer patients. CONCLUSION: Most lung cancer patients who undergo chemotherapy experience a range of symptoms, which can be categorized into three SCs. The Somato-psychological SC and Gastrointestinal SC negatively impacted patients' HRQoL. Health care providers should prioritize monitoring these SCs to identify high-risk patients early and implement targeted preventive and intervention measures for each SC, aiming to alleviate symptom burden and enhance HRQoL.

Trajectories of depression and predictors in lung cancer patients undergoing chemotherapy: growth mixture model.

BACKGROUND: Depression is prevalent among lung cancer patients undergoing chemotherapy, and the symptom cluster of fatigue-pain-insomnia may influence their depression. Identifying characteristics of patients with different depression trajectories can aid in developing more targeted interventions. This study aimed to identify the trajectories of depression and the fatigue-pain-insomnia symptom cluster, and to explore the predictive factors associated with the categories of depression trajectories. METHODS: In this longitudinal study, 187 lung cancer patients who were undergoing chemotherapy were recruited and assessed at the first (T1), second(T2), and fourth(T3) months using the Patient Health Questionnaire-9 (PHQ-9), the Brief Pain Inventory (BPI), the Brief Fatigue Inventory (BFI), and the Athens Insomnia Scale (AIS). Growth Mixture Model (GMM) and Latent Class Analysis (LCA) were used to identify the different trajectories of the fatigue-pain-insomnia symptom cluster and depression. Binary logistic regression was utilized to analyze the predictive factors of different depressive trajectories. RESULTS: GMM identified two depressive trajectories: a high decreasing depression trajectory (40.64%) and a low increasing depression trajectory (59.36%). LCA showed that 48.66% of patients were likely members of the high symptom cluster trajectory. Binary logistic regression analysis indicated that having a history of alcohol consumption, a higher symptom cluster burden, unemployed, and a lower monthly income predicted a high decreasing depression trajectory. CONCLUSIONS: Depression and fatigue-pain-insomnia symptom cluster in lung cancer chemotherapy patients exhibited two distinct trajectories. When managing depression in these patients, it is recommended to strengthen symptom management and pay particular attention to individuals with a history of alcohol consumption, unemployed, and a lower monthly income.

ZO-1 and IL-1RAP Phosphorylation: Potential Role in Mediated Brain-Gut Axis Dysregulation in Irritable Bowel Syndrome-like Stressed Mice.

Background and Objectives: Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder often exacerbated by stress, influencing the brain-gut axis (BGA). BGA dysregulation, disrupted intestinal barrier function, altered visceral sensitivity and immune imbalance defects underlying IBS pathogenesis have been emphasized in recent investigations. Phosphoproteomics reveals unique phosphorylation details resulting from environmental stress. Here, we employ phosphoproteomics to explore the molecular mechanisms underlying IBS-like symptoms, mainly focusing on the role of ZO-1 and IL-1RAP phosphorylation. Materials and Methods: Morris water maze (MWM) was used to evaluate memory function for single prolonged stress (SPS). To assess visceral hypersensitivity of IBS-like symptoms, use the Abdominal withdrawal reflex (AWR). Colonic bead expulsion and defecation were used to determine fecal characteristics of the IBS-like symptoms. Then, we applied a phosphoproteomic approach to BGA research to discover the molecular mechanisms underlying the process of visceral hypersensitivity in IBS-like mice following SPS. ZO-1, p-S179-ZO1, IL-1RAP, p-S566-IL-1RAP and GFAP levels in BGA were measured by western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay to validate phosphorylation quantification. Fluorescein isothiocyanate-dextran 4000 and electron-microscopy were performed to observe the structure and function of the intestinal epithelial barrier. Results: The SPS group showed changes in learning and memory ability. SPS exposure affects visceral hypersensitivity, increased fecal water content, and significant diarrheal symptoms. Phosphoproteomic analysis displayed that p-S179-ZO1 and p-S566-IL-1RAP were significantly differentially expressed following SPS. In addition, p-S179-ZO1 was reduced in mice's DRG, colon, small intestine, spinal and hippocampus and intestinal epithelial permeability was increased. GFAP, IL-1ß and p-S566-IL-1RAP were also increased at the same levels in the BGA. And IL-1ß showed no significant difference was observed in serum. Our findings reveal substantial alterations in ZO-1 and IL-1RAP phosphorylation, correlating with increased epithelial permeability and immune imbalance. Conclusions: Overall, decreased p-S179-ZO1 and increased p-S566-IL-1RAP on the BGA result in changes to tight junction structure, compromising the structure and function of the intestinal epithelial barrier and exacerbating immune imbalance in IBS-like stressed mice.

Role and mechanism of specialized pro-resolving mediators in obesity-associated insulin resistance.

With the changing times, obesity has become a characteristic epidemic in the context of the current era. Insulin resistance (IR) is most commonly caused by obesity, and IR is a common basis of the pathogenesis of many diseases such as cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes, which seriously threaten human life, as well as health. A major pathogenetic mechanism of obesity-associated IR has been found to be chronic low-grade inflammation in adipose tissue. Specialized pro-resolving mediators (SPMs) are novel lipid mediators that both function as "stop signals" for inflammatory reaction and promote inflammation to subside. In this article, we summarize the pathogenesis of obesity-associated IR and its treatments and outline the classification and biosynthesis of SPMs and their mechanisms and roles in the treatment of obesity-associated IR in order to explore the potential of SPMs for treating metabolic diseases linked with obesity-associated IR.

YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions.

BACKGROUND: The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient mitophagy and RTEC senescence. Yeast mitochondrial escape 1-like 1 (YME1L), an inner mitochondrial membrane metalloprotease, maintains mitochondrial integrity. Its functions in DKD remain unclear. Here, we investigated whether YME1L can prevent the progression of DKD by regulating mitophagy and cellular senescence. METHODS: We analyzed YME1L expression in renal tubules of DKD patients and mice, explored transcriptomic changes associated with YME1L overexpression in RTECs, and assessed its impact on RTEC senescence and renal dysfunction using an HFD/STZ-induced DKD mouse model. Tubule-specific overexpression of YME1L was achieved through the use of recombinant adeno-associated virus 2/9 (rAAV 2/9). We conducted both in vivo and in vitro experiments to evaluate the effects of YME1L overexpression on mitophagy and mitochondrial function. Furthermore, we performed LC-MS/MS analysis to identify potential protein interactions involving YME1L and elucidate the underlying mechanisms. RESULTS: Our findings revealed a significant decrease in YME1L expression in the renal tubules of DKD patients and mice. However, tubule-specific overexpression of YME1L significantly alleviated RTEC senescence and renal dysfunction in the HFD/STZ-induced DKD mouse model. Moreover, YME1L overexpression exhibited positive effects on enhancing mitophagy and improving mitochondrial function both in vivo and in vitro. Mechanistically, our LC-MS/MS analysis uncovered a crucial mitophagy receptor, BCL2-like 13 (BCL2L13), as an interacting partner of YME1L. Furthermore, YME1L was found to promote the phosphorylation of BCL2L13, highlighting its role in regulating mitophagy. CONCLUSIONS: This study provides compelling evidence that YME1L plays a critical role in protecting RTECs from cellular senescence and impeding the progression of DKD. Overexpression of YME1L demonstrated significant therapeutic potential by ameliorating both RTEC senescence and renal dysfunction in the DKD mice. Moreover, our findings indicate that YME1L enhances mitophagy and improves mitochondrial function, potentially through its interaction with BCL2L13 and subsequent phosphorylation. These novel insights into the protective mechanisms of YME1L offer a promising strategy for developing therapies targeting DKD.

Current Status of ChatGPT Use in Medical Education: Potentials, Challenges, and Strategies.

ChatGPT, a generative pretrained transformer, has garnered global attention and sparked discussions since its introduction on November 30, 2022. However, it has generated controversy within the realms of medical education and scientific research. This paper examines the potential applications, limitations, and strategies for using ChatGPT. ChatGPT offers personalized learning support to medical students through its robust natural language generation capabilities, enabling it to furnish answers. Moreover, it has demonstrated significant use in simulating clinical scenarios, facilitating teaching and learning processes, and revitalizing medical education. Nonetheless, numerous challenges accompany these advancements. In the context of education, it is of paramount importance to prevent excessive reliance on ChatGPT and combat academic plagiarism. Likewise, in the field of medicine, it is vital to guarantee the timeliness, accuracy, and reliability of content generated by ChatGPT. Concurrently, ethical challenges and concerns regarding information security arise. In light of these challenges, this paper proposes targeted strategies for addressing them. First, the risk of overreliance on ChatGPT and academic plagiarism must be mitigated through ideological education, fostering comprehensive competencies, and implementing diverse evaluation criteria. The integration of contemporary pedagogical methodologies in conjunction with the use of ChatGPT serves to enhance the overall quality of medical education. To enhance the professionalism and reliability of the generated content, it is recommended to implement measures to optimize ChatGPT's training data professionally and enhance the transparency of the generation process. This ensures that the generated content is aligned with the most recent standards of medical practice. Moreover, the enhancement of value alignment and the establishment of pertinent legislation or codes of practice address ethical concerns, including those pertaining to algorithmic discrimination, the allocation of medical responsibility, privacy, and security. In conclusion, while ChatGPT presents significant potential in medical education, it also encounters various challenges. Through comprehensive research and the implementation of suitable strategies, it is anticipated that ChatGPT's positive impact on medical education will be harnessed, laying the groundwork for advancing the discipline and fostering the development of high-caliber medical professionals.

Developing a psychological care competences framework for nurses in China: a mixed methods study.

BACKGROUND: With social transformation, rapid economic development and deepening awareness of psychological health in China, people's demand for psychological health services is becoming increasingly urgent. A key challenge for Chinese medical organizations is to train enough qualified psychological care nurses. A greater understanding of psychological care competences (PCC) can help in clinical nurse selection, training, and assessment. OBJECTIVE: To develop a PCC framework for Chinese nurses and obtain a consensus on the framework among experts. METHODS: A descriptive mixed methods study was designed consisting of a literature review and semi-structured interviews followed by three Delphi rounds. The experts (n = 16) involved were nurses, nursing managers and educators from nine Chinese provinces with a specific interest in psychological care. Descriptive statistics assisted in data analysis. RESULTS: Using the Iceberg Model as a theoretical foundation, five main dimensions and associated subdomains were integrated from 39 chosen articles. The semi-structured interviews with 24 nursing managers and nurses confirmed all of the themes from the literature review while generating new themes, both of which were incorporated into the initial PCC framework. After three Delphi rounds, the experts reached consensus on the PCC framework, including five domains (knowledge, skills, professional ethics, personal traits, internal motivations) and 22 subdomains with connotations. The response rate (RR) values for the three rounds of consultation were 80.00%, 87.50% and 92.86%, the composite reliability (Cr) values were 0.89-0.90, and the Kendall coordination coefficients were 0.155-0.200 (P < 0.05). CONCLUSIONS: On the basis of the Iceberg Model, literature review and qualitative research methods along with Delphi technique were used to develop a scientific and systematic PCC framework. The research methods were feasible and the results were reliable, thereby providing a basis for adopting this framework into nursing education. A formal assessment tool should be developed to test the PCC of nurses in clinical practice.

Population genomics highlights structural variations in local adaptation to saline coastal environments in woolly grape.

Structural variations (SVs) are a feature of plant genomes that has been largely unexplored despite their significant impact on plant phenotypic traits and local adaptation to abiotic and biotic stress. In this study, we employed woolly grape (Vitis retordii), a species native to the tropical and subtropical regions of East Asia with both coastal and inland habitats, as a valuable model for examining the impact of SVs on local adaptation. We assembled a haplotype-resolved chromosomal reference genome for woolly grape, and conducted population genetic analyses based on whole-genome sequencing (WGS) data from coastal and inland populations. The demographic analyses revealed recent bottlenecks in all populations and asymmetric gene flow from the inland to the coastal population. In total, 1,035 genes associated with plant adaptive regulation for salt stress, radiation, and environmental adaptation were detected underlying local selection by SVs and SNPs in the coastal population, of which 37.29% and 65.26% were detected by SVs and SNPs, respectively. Candidate genes such as FSD2, RGA1, and AAP8 associated with salt tolerance were found to be highly differentiated and selected during the process of local adaptation to coastal habitats in SV regions. Our study highlights the importance of SVs in local adaptation; candidate genes related to salt stress and climatic adaptation to tropical and subtropical environments are important genomic resources for future breeding programs of grapevine and its rootstocks.

A scoping review of the links between early childhood caries and clean water and sanitation: the Sustainable Development Goal 6.

INTRODUCTION: The United Nation's Sustainable Development Goal (SDG) 6 calls for universal access to clean water, sanitation and hygiene (WASH), which are crucial elements of health and well-being and fundamental for a life in dignity. Early childhood caries (ECC) is a preventable disease affecting health and quality of life of millions of young children worldwide. This scoping review aims to explore the connection between ECC and access to clean water and sanitation. METHODS: This scoping review, registered on the Open Science Framework and following PRISMA-ScR guidelines, conducted a thorough search in databases (PubMed, Web of Science, Embase, Google Scholar, SciELO) and websites (via Google) in November 2023. The search, without date limitations, targeted studies in English and Spanish linking ECC to SDG6. Exclusions were made for studies solely focusing on ECC without a direct connection to clean water and sanitation. Descriptive statistics summarized the retrieved papers. RESULTS: The initial search yielded 303 articles. After removing duplicates, 264 articles remained for title and abstract screening after which 244 were excluded and one report was added through citation searching. The 21 remaining articles underwent full text review. There were no studies on a direct association between access to clean water and sanitation and the prevalence of ECC. There were nine studies that showed indirect associations between ECC and access to clean water and sanitation through the links of: water and sanitation access as a marker for poverty (n = 1), water consumption as a feeding practice (n = 4), and the effectiveness of water fluoridation (n = 4). These were used to develop a conceptual model. CONCLUSIONS: While it is conceivable that a direct link exists between ECC and access to clean water and sanitation, the available body of research only offers evidence of indirect associations. The exploration of potential pathways connecting water access to ECC warrants further investigation in future research.

PTBP1 drives c-Myc-dependent gastric cancer progression and stemness.

BACKGROUND: Gastric cancer (GC) tumorigenesis and treatment failure are caused by cancer stem cells. Polypyrimidine tract binding protein 1 (PTBP1) was shown to be involved in the development of embryonic stem cells and is now being considered as a therapeutic target for tumour progression and stem-cell characteristics. METHODS: PTBP1 expression in GC samples was detected using tissue microarrays. Proliferation, colony formation, spheroid formation and stem-cell analysis were used to examine PTBP1's role in tumorigenesis and stem-cell maintenance. In AGS and HGC-27 cells with or without PTBP1 deficiency, ubiquitin-related protein expression and co-precipitation assays were performed. RESULTS: We identified that PTBP1 was aberrantly highly expressed and represented a novel prognostic factor in GC patients. PTBP1 maintained the tumorigenic activity and stem-cell characteristics of GC in vitro and in vivo. PTBP1 directly interacts with c-Myc and stabilises its protein levels by preventing its proteasomal degradation. This is mediated by upregulating the ubiquitin-specific proteases USP28 and limiting FBW7-mediated ubiquitination of c-Myc. Moreover, the depletion of PTBP1-caused tumour regression was significantly compromised by exogenous c-Myc expression. CONCLUSIONS: By preserving the stability of c-Myc through the ubiquitin-proteasome pathway, the oncogene PTBP1 supports stem-cell-like phenotypes of GC and is involved in GC progression.