Low-dose radiation-induced SUMOylation of NICD1 negatively regulates osteogenic differentiation in BMSCs.

Various biological effects of ionizing radiation, especially continuous exposure to low-dose radiation (LDR), have attracted considerable attention. Impaired bone structure caused by LDR has been reported, but little is known about the mechanism involved in the disruption of bone metabolism. In this study, given that LDR was found to (at a cumulative dose of 0.10 Gy) disturb the serum Mg2+ level and Notch1 signal in the mouse femur tissues, the effects of LDR on osteogenesis and the underlying molecular mechanisms were investigated based on an in vitro culture system for bone marrow stromal cells (BMSCs). Our data showed that cumulative LDR suppressed the osteogenic potential in BMSCs as a result of upregulation of Notch1 signaling. Further analyses indicated that the upregulation of NICD1 (Notch1 intracellular domain), the key intracellular domain for Notch1 signaling, under LDR was a consequence of enhanced protein stabilization caused by SUMOylation (small ubiquitin-like modification). Specifically, the downregulation of SENP1 (sentrin/SUMO-specific protease 1) expression induced by LDR enhanced the SUMOylation of NICD1, causing the accumulation of Notch1 signaling, which eventually inhibited the osteogenic potential of BMSCs. In conclusion, this work expounded on the mechanisms underlying the impacts of LDR on bone metabolism and shed light on the research on bone regeneration under radiation.

The Impact of Proton Pump Inhibitors on the Efficacy of Immune Checkpoint Inhibitor Combinations in Patients with HBV-Associated Advanced Hepatocellular Carcinoma.

Purpose: There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs. Methods: We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients' survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated. Results: A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient's OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024). Conclusion: PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.

Clinical characteristics and outcome of double-seropositive patients with anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies.

OBJECTIVE: To explore the clinical characteristics of double-seropositive patients (DPPs) with anti-glomerular basement membrane (Anti-GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We collected patients with both ANCA and anti-GBM positive glomerulonephritis who were hospitalized in the Department of Nephrology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to August 2022. Retrospective analysis of the baseline clinical characteristics of patients and follow-up to explore relevant factors affecting renal and patient survival. RESULTS: A total of 386 patients, including 69 ANCA negative anti-GBM glomerulonephritis patients, 296 anti-GBM negative ANCA associated vasculitis (AAV) patients, and 21 DPPs were enrolled in this study. Among the 21 DPPs aged 68.0 years (59.5, 74.0), there were 11 males and 10 females. The median serum creatinine at diagnosis was 629.0 (343.85, 788.75) µmol/L, and the median eGFR (CKD-EPI) was 7.58 (4.74, 13.77) mL/min. Fifteen cases (71.4 %) underwent initial RRT. After a follow-up of 40.0 (11.0, 73.0) months, 13 out of 21 DPPs (61.9 %) received maintenance RRT, while 49 out of 69 (71.0 %) ANCA negative anti-GBM-GN patients and 124 out of 296 (41.9 %) anti-GBM negative AAV patients received maintenance RRT (P < 0.001). Kaplan-Meier survival analysis showed that DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients (P = 0.001). Among the 21 patients with DPPs, renal survival was significantly better in patients with better initial renal function, including those who did not receive initial RRT (P = 0.003), with lower serum creatinine levels (Cr < 629.0 µmol/L, P = 0.004) and higher eGFR levels (eGFR ≥ 7.60 ml/min, P = 0.005) than those with poor initial renal function. At the end of follow-up, 14 out of 21 DPPs (66.7 %) survived. Survival analysis showed no significant difference among patients in DPPs group, ANCA negative anti-GBM-GN group, and anti-GBM negative AAV group. CONCLUSIONS: DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients. In DPPs, the poor renal function at diagnosis might be a risk factor associated with poor renal survival.

Real­world evidence of advanced non­small cell lung carcinoma treated with an immune checkpoint inhibitor plus chemotherapy.

Immunotherapy is an effective treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Although clinical trials on immunotherapy have provided promising results, real-world research in clinical practice is needed to assess the effectiveness and safety of immunotherapy. The present study aimed to characterize real-world outcomes in patients with advanced NSCLC treated with immune checkpoint inhibitor (ICI)-based regimens. The medical records of patients with advanced NSCLC, who were treated with programmed cell death protein-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitors, were reviewed for data collection. The primary objectives were to evaluate progression-free survival (PFS) and overall survival (OS). Therefore, multiple Cox regression models were used to investigate the predictive factors for survival outcomes. Furthermore, survival curves for PFS and OS were created using Kaplan-Meier estimates and compared using the log-rank test. The present study included a total of 133 patients with advanced NSCLC who received therapy with ICIs between January 1, 2019 and December 31, 2022. The final follow-up date was August 24, 2023. The median PFS and OS times were 9.8 and 27.2 months, respectively. Univariate Cox regression analysis demonstrated that sex, clinical stage, PD-L1 status, previous systemic therapy, and brain and liver metastases were associated with PFS, while Eastern Cooperative Oncology Group (ECOG) status, clinical stage, PD-L1 status and brain metastasis were associated with OS. Furthermore, multivariate Cox regression analysis demonstrated that a PD-L1 tumor proportion score (TPS) of ≥50% was an indicator of favorable PFS and OS. An ECOG performance status score of ≥1 was also associated with poor OS but not with PFS. Furthermore, brain metastasis was an indicator for poor PFS and OS, while liver metastasis was only associated with a poor PFS. Finally, the results of the present study demonstrated that PD-L1 status was an independent predictor for PFS and OS in patients with advanced NSCLC, especially adenocarcinoma, who were treated with ICIs plus chemotherapy. The results also suggested that patients with a PD-L1 TPS of ≥50% could benefit when the aforementioned regimens were administrated as a first-line or later-line therapy.

The type of COVID-19 vaccination does not affect reproductive function and pregnancy outcomes in infertile couples.

Introduction: Studies on the effect of vaccine type and two other vaccines other than inactivated vaccines approved in China on in vitro fertilization (IVF) pregnancy outcomes are rare. To complement and confirm the existing findings, this research aimed to investigate whether there are adverse effects of different vaccine types in females and males on reproductive function and clinical pregnancy. Methods: This retrospective study enrolled 6,455 fresh embryo transfer cycles at the First Affiliated Hospital of Zhengzhou University between May 1, 2021, and October 31, 2022. The primary outcome is the clinical pregnancy rate (CPR). At the same time, the secondary results are the number of oocytes retrieved, two pronuclei (2PN) rate, blastocyst formation rate, high-quality blastocyst rate, and semen parameters (volume, density, sperm count, forward motility rate, total motility rate, immobility rate, and DNA fragment index (DFI) rate). Results: In the comparison of ovarian stimulation indicators, no statistically significant differences (P > 0.05) were found in Gn days, endometrial thickness, 2PN rate, metaphase 2 (MII) rate, high-quality embryo rate, and blastocyst formation rate. No significant differences (P>0.05) were found in age, body mass index (BMI), education level, and semen parameters (volume, density, sperm count, forward motility rate, total motility rate, immobility rate, and DFI rate) in these four groups. The multivariate regression model showed that neither the types of vaccines nor the vaccination status of both infertile couples significantly affected clinical pregnancy. Discussion: The type of vaccine does not appear to have an unfavorable effect on ovarian stimulation, embryo development, semen parameters, and clinical pregnancy.

Protein aggregation in plant mitochondria lacking Lon1 inhibits translation and induces unfolded protein responses.

Loss of Lon1 led to stunted plant growth and accumulation of nuclear-encoded mitochondrial proteins including Lon1 substrates. However, an in-depth label-free proteomics quantification of mitochondrial proteins in lon1 revealed that the majority of mitochondrial-encoded proteins decreased in abundance. Additionally, we found that lon1 mutants contained protein aggregates in the mitochondrial that were enriched in metabolic enzymes, ribosomal subunits and PPR-containing proteins of the translation apparatus. These mutants exhibited reduced general mitochondrial translation as well as deficiencies in RNA splicing and editing. These findings support the role of Lon1 in maintaining a functional translational apparatus for mitochondrial-encoded gene translation. Transcriptome analysis of lon1 revealed a mitochondrial unfolded protein response reminiscent of the mitochondrial retrograde signalling dependent on the transcription factor ANAC017. Notably, lon1 mutants exhibited transiently elevated ethylene production, and the shortened hypocotyl observed in lon1 mutants during skotomorphogenesis was partially alleviated by ethylene inhibitors. Furthermore, the short root phenotype was partially ameliorated by introducing a mutation in the ethylene receptor ETR1. Interestingly, the upregulation of only a select few target genes was linked to ETR1-mediated ethylene signalling. Together this provides multiple steps in the link between loss of Lon1 and signalling responses to restore mitochondrial protein homoeostasis in plants.

Detection of minimal hepatic encephalopathy in patients with cirrhosis based on the Stroop-CN model (NCRCID-CHESS 2106): a prospective multicenter study.

Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.

Cannabidiol mitigates radiation-induced intestine ferroptosis via facilitating the heterodimerization of RUNX3 with CBFß thereby promoting transactivation of GPX4.

Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor ß (CBFß) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.

Manipulated C5aR1 over/down-expression associates with IL-6 expression during bacterial inflammation in half-smooth tongue sole (Cynoglossus semilaevis).

The complement component 5a/complement component 5 receptor 1 (C5a/C5aR1) pathway plays a crucial role in the onset and development of inflammation, but relevant studies in fish are lacking. In this study, we successfully characterized the relationship between half-smooth tongue sole (Cynoglossus semilaevis) C5aR1 (CsC5aR1) and bacterial inflammation. First, we showed that the overexpression of CsC5aR1 significantly increased bacterial pathological damage in the liver and intestine, whereas inhibition attenuated the damage. The in vitro experiments suggested that CsC5aR1 was able to positively regulate the phagocytic activity and respiratory burst of tongue sole macrophages. In terms of both transcriptional and translational levels, overexpression/inhibition of CsC5aR1 was followed by a highly consistent up-regulation/decrease of its downstream canonical inflammatory factor interleukin-6 (CsIL-6). Furthermore, we stimulated macrophages by lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and found a broad-spectrum response to bacterial infections by the C5a/C5aR1 complement pathway together with the downstream inflammatory factor CsIL-6. Subsequently, we directly elucidated that CsIL-6 is an indicator of C5a/C5aR1-mediated inflammation at different infection concentrations, different infectious bacteria (Vibrio anguillarum and Mycobacterium marinum), and different detection levels. These results might provide a new inflammation bio-marker for early warning of bacteria-induced hyperinflammation leading to fish mortality and a promising target for the treatment of bacterial inflammation in teleost.

Mediterranean diet in the targeted prevention and personalized treatment of chronic diseases: evidence, potential mechanisms, and prospects.

The prevalence of chronic diseases is currently a major public health issue worldwide and is exploding with the population growth and aging. Dietary patterns are well known to play a important role in our overall health and well-being, and therefore, poor diet and malnutrition are among the most critical risk factors for chronic disease. Thus, dietary recommendation and nutritional supplementation have significant clinical implications for the targeted treatment of some of these diseases. Multiple dietary patterns have been proposed to prevent chronic disease incidence, like Dietary Approaches to Stop Hypertension (DASH) and Diabetes Risk Reduction Diet (DRRD). Among them, the MedDiet, which is one of the most well-known and studied dietary patterns in the world, has been related to a wide extent of health benefits. Substantial evidence has supported an important reverse association between higher compliance to MedDiet and the risk of chronic disease. Innovative strategies within the healthcare framework of predictive, preventive, and personalized medicine (PPPM/3PM) view personalized dietary customization as a predictive medical approach, cost-effective preventive measures, and the optimal dietary treatment tailored to the characteristics of patients with chronic diseases in primary and secondary care. Through a comprehensive collection and review of available evidence, this review summarizes health benefits of MedDiet in the context of PPPM/3PM for chronic diseases, including cardiovascular disease, hypertension, type 2 diabetes, obesity, metabolic syndrome, osteoporosis, and cancer, thereby a working hypothesis that MedDiet can personalize the prevention and treatment of chronic diseases was derived.

Curcumin inhibits PAT-induced renal ferroptosis via the p62/Keap1/Nrf2 signalling pathway.

Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo, supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.

LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy.

Various low-density lipoprotein receptors (LPRs) have been identified as entry factors for alphaviruses, and structures of the corresponding virion-receptor complexes have been determined. Here, we analyze the similarities and differences in the receptor binding modes of multiple alphaviruses to understand their ability to infect a wide range of hosts. We further discuss the challenges associated with the development of broad-spectrum treatment strategies against a diverse range of alphaviruses.

Quality control, safety assessment and preparation approaches of low molecular weight heparin.

Low Molecular Weight Heparins (LMWHs) are well-established for use in the prevention and treatment of thrombotic diseases, and as a substitute for unfractionated heparin (UFH) due to their predictable pharmacokinetics and subcutaneous bioavailability. LMWHs are produced by various depolymerization methods from UFH, resulting in heterogeneous compounds with similar biochemical and pharmacological properties. However, the delicate supply chain of UFH and potential contamination from animal sources require new manufacturing approaches for LMWHs. Various LMWH preparation methods are emerging, such as chemical synthesis, enzymatic or chemical depolymerization and chemoenzymatic synthesis. To establish the sameness of active ingredients in both innovator and generic LMWH products, the Food and Drug Administration has implemented a stringent scientific method of equivalence based on physicochemical properties, heparin source material and depolymerization techniques, disaccharide composition and oligosaccharide mapping, biological and biochemical properties, and in vivo pharmacodynamic profiles. In this review, we discuss currently available LMWHs, potential manufacturing methods, and recent progress for manufacturing quality control of these LMWHs.

Predictive nomogram model for severe coronary artery calcification in end-stage kidney disease patients.

INTRODUCTION: The Agatston coronary artery calcification score (CACS) is an assessment index for coronary artery calcification (CAC). This study aims to explore the characteristics of CAC in end-stage kidney disease (ESKD) patients and establish a predictive model to assess the risk of severe CAC in patients. METHODS: CACS of ESKD patients was assessed using an electrocardiogram-gated coronary computed tomography (CT) scan with the Agatston scoring method. A predictive nomogram model was established based on stepwise regression. An independent validation cohort comprised of patients with ESKD from multicentres. RESULTS: 369 ESKD patients were enrolled in the training set, and 127 patients were included in the validation set. In the training set, the patients were divided into three subgroups: no calcification (CACS = 0, n = 98), mild calcification (0 < CACS ≤ 400, n = 141) and severe calcification (CACS > 400, n = 130). Among the four coronary branches, the left anterior descending branch (LAD) accounted for the highest proportion of calcification. Stepwise regression analysis showed that age, dialysis vintage, ß-receptor blocker, calcium-phosphorus product (Ca × P), and alkaline phosphatase (ALP) level were independent risk factors for severe CAC. A nomogram that predicts the risk of severe CAC in ESKD patients has been internally and externally validated, demonstrating high sensitivity and specificity. CONCLUSION: CAC is both prevalent and severe in ESKD patients. In the four branches of the coronary arteries, LAD calcification is the most common. Our validated nomogram model, based on clinical risk factors, can help predict the risk of severe coronary calcification in ESKD patients who cannot undergo coronary CT analysis.

Association of advanced lung cancer inflammation index with all-cause and cardiovascular mortality in US patients with rheumatoid arthritis.

Introduction: As a systemic autoimmune disorder, the prognosis of rheumatoid arthritis (RA) is intricately linked to inflammation. This study aimed to investigate the association between the advanced lung cancer inflammation index (ALI), a comprehensive indicator of inflammation combined with nutritional status, and all-cause and cardiovascular mortality among patients diagnosed with RA. Methods: The 2,305 RA patients from NHANES (2001-2018) included in the analysis were categorized into three groups according to ALI tertiles. Weighted Kaplan-Meier and multivariate COX regression analyses evaluated the relationship between ALI and mortality. The time-dependent characteristic curve (ROC) was used to assess the prediction accuracy of ALI. Results: During a median follow-up of 7.92 years, 591 participants died from all causes, including 197 from cardiovascular diseases. Increased ALI was associated with a decreased probability of death. The full COX model revealed lower all-cause mortality hazard risks in the T2 (HR: 0.67, 95%CI: 0.54-0.83) and T3 (HR: 0.47 95%CI: 0.33-0.67, p for tend <0.001) groups compared to T1, and the risk of cardiovascular mortality was also lower in the groups of T2 (HR: 0.47, 95%CI: 0.31-0.70) and T3 (HR: 0.34, 95%CI: 0.19-0.62, p for trend <0.001). Furthermore, the ROC analysis underscored the strong predictive capability of ALI (AUC for 1-year all-cause and cardiovascular mortality were 0.73 and 0.79, respectively). Conclusion: This cohort study demonstrated the higher accuracy of ALI in predicting mortality in RA patients, highlighting the important clinical value of ALI in risk assessment and prognosis evaluation.

Sodium arsenite induces hepatic stellate cells activation by m6A modification of TGF-ß1 during liver fibrosis.

The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-ß/Smad signaling, which could be reversed by TGF-ß1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-ß1 and enhanced the TGF-ß1 mRNA stability. Notably, NaAsO2-induced TGF-ß/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-ß1, which may open up new therapeutic options for LF brought on by environmental hazards.

The survival, gene expression, and DNA methylation of Paralichthys olivaceus impacted by the decay of green tide and bacterial infection in both laboratory and field simulation experiments.

The recurring appearance of Ulva prolifera green tides has become a pressing environmental issue, especially for marine transportation, tourism, and aquaculture in the stage of decomposition. An abundance of decaying U. prolifera leads to water acidification, hypoxia and pathogenic microorganism proliferation, threatening marine germplasm resources, particularly benthic organisms with weak escape ability. Epigenetic modification is considered to be one of the molecular mechanisms involved in the plastic adaptive response to environmental changes. However, few studies concerning the specific impact of decaying green tide on benthic animals at the epigenetic level. In this study, decomposing algal effluents of U. prolifera, sediments containing uncorrupted U. prolifera, pathogenic microorganism were considered as impact factors, to reveal the effect of decaying U. prolifera on marine economic benthic species, Paralichthys olivaceus, using both field and laboratory simulation experiments. Field simulation experiment showed higher mortality rates and serious histopathological damage than the laboratory simulation experiment. And both the decaying U. prolifera and the sediment containing U. prolifera were harmful to P. olivaceus. Genome-wide DNA methylation and transcription correlation analyses showed that the response of P. olivaceus to green tide stress and bacterial infection was mainly mediated by immune signaling pathways such as PI3K-Akt signaling pathway. DNA methylation regulates the expression of immune-related genes involved in the PI3K-Akt signaling pathway, which enables P. olivaceus to adapt to the adverse environmental stresses by resisting apoptosis. In summary, this research analyzed the potential role of P. olivaceus in decaying U. prolifera, which is of great significance for understanding the impact of decaying green tide on marine commercial fish and also provides some theoretical guidance for the proliferation and release of fish seedlings.

Pseudoexon activation by deep intronic variation in GNE myopathy with thrombocytopenia.

INTRODUCTION/AIMS: GNE myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. Although over 300 GNE variants have been reported, some patients remain undiagnosed with monoallelic pathogenic variants. This study aims to analyze the entire GNE genomic region to identify novel pathogenic variants. METHODS: Patients with clinically compatible GNE myopathy and monoallelic pathogenic variants in the GNE gene were enrolled. The other GNE pathogenic variant was verified using comprehensive methods including exon 2 quantitative polymerase chain reaction and nanopore long-read single-molecule sequencing (LRS). RESULTS: A deep intronic GNE variant, c.862+870C>T, was identified in nine patients from eight unrelated families. This variant generates a cryptic splice site, resulting in the activation of a novel pseudoexon between exons 5 and 6. It results in the insertion of an extra 146 nucleotides into the messengerRNA (mRNA), which is predicted to result in a truncated humanGNE1(hGNE1) protein. Peanut agglutinin（PNA） lectin staining of muscle tissues showed reduced sialylation of mucin O-glycans on sarcolemmal glycoproteins. Notably, a third of patients with the c.862+870C>T variant exhibited thrombocytopenia. A common core haplotype harboring the deep intronic GNE variant was found in all these patients. DISCUSSION: The transcript with pseudoexon activation potentially affects sialic acid biosynthesis via nonsense-mediated mRNA decay, or resulting in a truncated hGNE1 protein, which interferes with normal enzyme function. LRS is expected to be more frequently incorporated in genetic analysis given its efficacy in detecting hard-to-find pathogenic variants.

Topology Optimization Method of Stamping Structures Based on the Directional Density Field.

The stamping process produces thin-walled structures that, in general, have uniform wall thickness and no enclosed cavity. However, it is difficult to satisfy the above geometric requirements with the current density-based topology optimization method, since configuring the related geometric constraints is challenging. In order to solve this problem, a topology optimization method for stamping structures based on a directional density field is proposed. Specifically, the directional density field is developed to enable the adding and removing of materials only along the stamping direction, so as to avoid internal voids and concave features. The geometric control for uniform wall thickness is realized by tuning the truncation threshold of the Heaviside projection that processes the directional density field into the 0-1 binary field. At the same time, a calibrated filter radius of the truncation thresholds will facilitate the drawing angle control of the stamping ribs. The effectiveness of the established method has been verified by a number of numerical case studies. Results show that the proposed method can perform topology optimization for stamping structures with tunable uniform thickness and drawing angle control of the ribs. No internal voids or undercuts appear in the results. The results also disclose that a constant truncation threshold increment does not guarantee uniform wall thickness, and varying the threshold increments through surface offset and polynomial fitting is necessary.

ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support.

ADMETlab 3.0 is the second updated version of the web server that provides a comprehensive and efficient platform for evaluating ADMET-related parameters as well as physicochemical properties and medicinal chemistry characteristics involved in the drug discovery process. This new release addresses the limitations of the previous version and offers broader coverage, improved performance, API functionality, and decision support. For supporting data and endpoints, this version includes 119 features, an increase of 31 compared to the previous version. The updated number of entries is 1.5 times larger than the previous version with over 400 000 entries. ADMETlab 3.0 incorporates a multi-task DMPNN architecture coupled with molecular descriptors, a method that not only guaranteed calculation speed for each endpoint simultaneously, but also achieved a superior performance in terms of accuracy and robustness. In addition, an API has been introduced to meet the growing demand for programmatic access to large amounts of data in ADMETlab 3.0. Moreover, this version includes uncertainty estimates in the prediction results, aiding in the confident selection of candidate compounds for further studies and experiments. ADMETlab 3.0 is publicly for access without the need for registration at: https://admetlab3.scbdd.com.