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.

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.

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.

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.

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.

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.

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.

PTBP1 plays an important role in the development of gastric cancer.

BACKGROUND: Polypyrimidine tract binding protein 1 (PTBP1) has been found to play an important role in the occurrence and development of various tumors. At present, the role of PTBP1 in gastric cancer (GC) is still unknown and worthy of further investigation. METHODS: We used bioinformatics to analyze the expression of PTBP1 in patients with GC. Cell proliferation related experiments were used to detect cell proliferation after PTBP1 knockdown. Skeleton staining, scanning electron microscopy and transmission electron microscopy were used to observe the changes of actin skeleton. Proliferation and actin skeleton remodeling signaling pathways were detected by Western Blots. The relationship between PTBP1 and proliferation of gastric cancer cells was further detected by subcutaneous tumor transplantation. Finally, tissue microarray data from clinical samples were used to further explore the expression of PTBP1 in patients with gastric cancer and its correlation with prognosis. RESULTS: Through bioinformatics studies, we found that PTBP1 was highly expressed in GC patients and correlated with poor prognosis. Cell proliferation and cycle analysis showed that PTBP1 down-regulation could significantly inhibit cell proliferation. The results of cell proliferation detection related experiments showed that PTBP1 down-regulation could inhibit the division and proliferation of GC cells. Furthermore, changes in the morphology of the actin skeleton of cells showed that PTBP1 down-regulation inhibited actin skeletal remodeling in GC cells. Western Blots showed that PTBP1 could regulate proliferation and actin skeleton remodeling signaling pathways. In addition, we constructed PTBP1 Cas9-KO mouse model and performed xenograft assays to further confirm that down-regulation of PTBP1 could inhibit the proliferation of GC cells. Finally, tissue microarray was used to further verify the close correlation between PTBP1 and poor prognosis in patients with GC. CONCLUSIONS: Our study demonstrates for the first time that PTBP1 may affect the proliferation of GC cells by regulating actin skeleton remodeling. In addition, PTBP1 is closely related to actin skeleton remodeling and proliferation signaling pathways. We suppose that PTBP1 might be a potential target for the treatment of GC.

PD-L1 upregulation promotes drug-induced pulmonary fibrosis by inhibiting vimentin degradation.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.

Novel plant-derived exosome-like nanovesicles from Catharanthus roseus: preparation, characterization, and immunostimulatory effect via TNF-α/NF-κB/PU.1 axis.

BACKGROUND: Plant-derived exosomes-like nanovesicles (PDENs) have been found to be advantageous in disease treatment and drug delivery, but research on their biogenesis, compositional analysis, and key marker proteins is still in its infancy, which limits the standardized production of PDENs. Efficient preparation of PDENs continues to be a major challenge. RESULTS: Novel PDENs-based chemotherapeutic immune modulators, Catharanthus roseus (L.) Don leaves-derived exosome-like nanovesicles (CLDENs) were isolated from apoplastic fluid. CLDENs were membrane structured vesicles with a particle size of 75.51 ± 10.19 nm and a surface charge of -21.8 mV. CLDENs exhibited excellent stability, tolerating multiple enzymatic digestions, resisting extreme pH environments, and remaining stable in the gastrointestinal simulating fluid. Biodistribution experiments showed that CLDENs could be internalized by immune cells, and targeted at immune organs after intraperitoneal injection. The lipidomic analysis revealed CLDENs' special lipid composition, which contained 36.5% ether-phospholipids. Differential proteomics supported the origin of CLDENs in multivesicular bodies, and six marker proteins of CLDENs were identified for the first time. 60 ~ 240 µg/ml of CLDENs promoted the polarization and phagocytosis of macrophages as well as lymphocyte proliferation in vitro. Administration of 20 mg/kg and 60 mg/kg of CLDENs alleviated white blood cell reduction and bone marrow cell cycle arrest in immunosuppressive mice induced by cyclophosphamide. CLDENs strongly stimulated the secretion of TNF-α, activated NF-κB signal pathway and increased the expression of the hematopoietic function-related transcription factor PU.1 both in vitro and in vivo. To ensure a steady supply of CLDENs, plant cell culture systems of C. roseus were established to provide CLDENs-like nanovesicles which had similar physical properties and biological activities. Gram-level nanovesicles were successfully obtained from the culture medium, and the yield was three times as high as the original. CONCLUSIONS: Our research supports the use of CLDENs as a nano-biomaterial with excellent stability and biocompatibility, and for post-chemotherapy immune adjuvant therapy applications.

Clinical observational study on the efficacy of induction chemotherapy sequential concurrent radiotherapy combined with targeted therapy in patients with locally advanced EGFR-positive nasopharyngeal carcinoma: prediction model construction and efficacy testing.

OBJECTIVE: To establish a nomogram for prediction of prognosis in EGFR-positive advanced nasopharyngeal carcinoma (NPC) patients who were treated with induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT). The clinical data of 124 NPC patients who received IC sequential CCRT combined with targeted therapy at the Department of Oncology of the Affiliated Hospital of North Sichuan Medical College between June 2017 and September 2022 were retrospectively reviewed. Logistic regression analysis was used to identify the prognostic factors for building the nomogram. RESULTS: Multifactorial regression analysis showed that the use of targeted drugs and T stage were independent factors of prognosis (p < 0.05) and the equation Y = 0.476 + 2.733X1 + - 0.758 × 2 (Y = efficacy, X1 = targeted drug therapy, X2 = T stage) was obtained. Then, a prognostic nomogram prediction model was constructed. The prediction model was validated internally for 1000 times using the Bootstrap resampling method with an accuracy of 79.29%. The calibration curve suggests that the predicted values fit well with the true values. The clinical decision curve (DCA) shows that the model has good clinical predictive value. CONCLUSION: The use of targeted therapy significantly improved the prognosis of patients with EGFR-positive advanced NPC. For advanced NPC patients with T1 and T2 stages, IC sequenced with CCRT is more effective, and the addition of targeted therapy can further improve patients' prognosis. For advanced NPC patients with T3 and T4 stages, IC sequenced with CCRT is ineffective, and the addition of targeted therapy can significantly improve patient prognosis.

Effects of low temperature and highlight stress on lipid accumulation and cell structure of Tropidoneis maxima.

Tropidoneis maxima is a marine diatom with a rapid growth rate that produces high levels of lipids. To explore whether the lipid content could be further enhanced, cultures were first incubated under optimal conditions and then stressed under low temperature (10°C), a high light intensity level (80 µmol/m2 ·s), and the two factors together (interaction treatment). The results indicated that high light intensity and the temperature-light interaction exhibited greater impacts on lipid synthesis of T. maxima than low temperature. The two stress treatments increased lipid content by 17.16% and 16.6% compared to the control. In particular, higher biomass concentration was obtained with high light intensity (1.082 g L-1 ) and low temperature (1.026 g L-1 ). Moreover, high light intensity (9.06%) and interaction (10.3%) treatments yielded lower starch content compared to low temperature (14.27%) at the end of the stress culture. After 3 days of stress culture, the high light intensity treatment resulted in a 97.01% increase in cell wall thickness and an 18.46% decrease in cell diameter. The results suggest that high light intensity stress on T. maxima would open a new approach to cost-effective biolipid production.

Monitoring the remediation of groundwater polluted by MSW landfill leachates by activated carbon and zeolite with spectral induced polarization technique.

The municipal solid waste (MSW) landfill in Hangzhou, China utilized zeolite and activated carbon (AC) as permeable reactive barrier (PRB) fill materials to remediate groundwater contaminated with MSW leachates containing ammonium, chemical oxygen demand (COD), and heavy metals. The spectral induced polarization (SIP) technique was chosen for monitoring the PRB because of its sensitivity to pore fluid chemistry and mineral-fluid interface composition. During the experiment, authentic groundwater collected from the landfill site was used to permeate two columns filled with zeolite and AC, and the SIP responses were measured at the inlet and outlet over a frequency range of 0.01-1000 Hz. The results showed that zeolite had a higher adsorption capacity for COD (7.08 mg/g) and ammonium (9.15 mg/g) compared to AC (COD: 2.75 mg/g, ammonium: 1.68 mg/g). Cation exchange was found to be the mechanism of ammonium adsorption for both zeolite and AC, while FTIR results indicated that π-complexation, π-π interaction, and electrostatic attraction were the main mechanisms of COD adsorption. The Cole-Cole model was used to fit the SIP responses and determine the relaxation time (τ) and normalized chargeability (mn). The calculated characteristic diameters of zeolite and AC based on the Schwarz equation and relaxation time (τ) matched the pore sizes observed from SEM and MIP, providing valuable information on contaminant distribution. The mn of zeolite was positively linear with adsorbed ammonium (R2 = 0.9074) and COD (R2 = 0.8877), while the mn of AC was negatively linear with adsorbed ammonium (R2 = 0.8192) and COD (R2 = 0.7916), suggesting that mn could serve as a surrogate for contaminant saturation. The laboratory-based real-time non-invasive SIP results showed good performance in monitoring saturation and provide a strong foundation for future field PRB monitoring.

Biopsy-Proven Giant Cell Arteritis Associated Vision Loss in Chinese Subjects: A Case Series and Review of the Literature.

Only a few case reports of biopsy-proven GCA (BpGCA)-associated vision loss in Chinese subjects have been published. We describe three elderly Chinese subjects with BpGCA who presented with vision loss. We also searched the literature in order to review BpGCA-associated blindness in Chinese subjects. Case 1 presented as simultaneous right ophthalmic artery occlusion and left anterior ischaemic optic neuropathy (AION). Case 2 presented as sequential bilateral AION. Case 3 presented as bilateral posterior ischaemic optic neuropathy and ocular ischaemic syndrome (OIS). The diagnosis was confirmed by temporal artery biopsy in all three. Magnetic resonance imaging (MRI) in Cases 1 and 2 demonstrated retrobulbar optic nerve ischaemia. Enhancement of the optic nerve sheath and inflammatory changes of the ophthalmic artery on enhanced orbital MRI was also noted in Cases 2 and 3. All of the subjects were treated with steroids, either intravenously or orally. In the literature review, 11 cases (17 eyes) of BpGCA-associated vision loss in Chinese subjects were found including AION, central retinal artery occlusion, combined AION and cilioretinal artery occlusion, and orbital apex syndrome. In the 14 cases (including ours), the median age at diagnosis was 77 years, and 9 (61.5%) were males. The most common extraocular manifestations were temporal artery abnormalities, headache, jaw claudication, and scalp tenderness. Thirteen (56.5%) eyes had visual acuity of no light perception at the initial visit and failed to respond to the treatment. Although rare, in elderly Chinese subjects with ocular ischaemic diseases, the diagnosis of GCA must be considered.