Association between serum 25-hydroxyvitamin D and vitamin D dietary supplementation and risk of all-cause and cardiovascular mortality among adults with hypertension.

BACKGROUND: The relationship between vitamin D status and mortality among adults with hypertension remains unclear. METHODS: This prospective cohort study involved a sample of 19,500 adults with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. We utilized a weighted COX proportional hazard model to assess the association between vitamin D status and mortality. This statistical model calculates hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI). RESULTS: The study indicated that lower serum 25(OH)D concentration was associated with an increased risk of all-cause mortality among individuals with hypertension. Specially. Those with concentrations between 25.0 and 49.9 nmol/L (HR = 1.71, 95%CI = 1.22-2.40) and less than 25.0 nmol/L (HR = 1.97, 95%CI = 1.15-3.39) had higher hazard ratios for all-cause mortality. Individuals with hypertension who took vitamin D supplements had a lower risk of all-cause mortality, but not the risk of CVD mortality (HR 0.75, 95%CI 0.54-1.03), compared to those who did not supplement (HR = 0.76, 95%CI = 0.61-0.94). Subgroup analysis further revealed that vitamin D supplementation was associated with a reduced risk of all-cause mortality among individuals without diabetes (HR = 0.65, 95%CI = 0.52-0.81) and individuals without CVD (HR = 0.75, 95%CI = 0.58-0.97), and a decreased risk of CVD mortality among individuals without diabetes (HR = 0.63, 95%CI = 0.45-0.88) and without CVD (HR = 0.61, 95%CI = 0.40-0.92). Furthermore, higher-dose vitamin D supplementation was also associated with a greater reduction in all-cause mortality among hypertensive individuals, and there was the potential synergistic effect of combining normal-dose calcium and vitamin D supplementation, showing a superior effect on mortality compared to low-dose supplementation in adults with hypertension. CONCLUSIONS: This prospective cohort study demonstrated a significant association between lower serum 25 (OH)D concentration and increased all-cause mortality among adults with hypertension. Furthermore, the study found that vitamin D supplementation had a strong and significantly positive correlation with reduced all-cause and CVD mortality among hypertensive individuals without diabetes or CVD. This positive correlation suggests that vitamin D supplementation could potentially be an effective strategy to reduce the risk of mortality in this specific group of people.

VlMYB4 and VlCDF3 co-targeted the VlLOG11 promoter to regulate fruit setting in grape (Vitis vinifera L).

KEY MESSAGE: The VlLOG11 mediates the cytokinin signaling pathway to regulate grape fruit setting. Fruit set, as an accepted agronomic trait, is inextricably linked with fruit quality and yield. Previous studies have demonstrated that exogenous treatment with the synthetic cytokinin analog, forchlorfenuron (CPPU), significantly enhances fruit set. In this study, a significant reduction in endogenous cytokinins was found by measuring the content of cytokinins in young grape berries after CPPU treatment. LONELY GUYs (VlLOGs), a key cytokinin-activating enzyme working in the biosynthesis pathway of cytokinins, exhibited differential expression. Some differentially expressed VlLOGs genes were presented by RNA seq data and their functions and regulation patterns were further investigated. The results showed that VlLOG11 was differentially expressed in young grape berries after CPPU treatment. Overexpression of VlLOG11 in tomato increases the amount of fruit set, and upregulated the expression of genes associated with cytokinin signaling including SlHK4, SlHK5, SlHP3, SlHP4, SlPHP1, SlPHP2. VlMYB4 and VlCDF3 could regulate the expression of VlLOG11 by directly binding to its promoter in young grape berries during fruit set. These results strongly demonstrated that VlMYB4/VlCDF3-VlLOG11 regulatory module plays a key role in the process of fruit setting in grape. This provided a basis for the molecular mechanism of VlLOG11-mediated cytokinin biosynthesis in young grape fruit set.

PpGATA21 Enhances the Expression of PpGA2ox7 to Regulate the Mechanism of Cerasus humilis Rootstock-Mediated Dwarf in Peach Trees.

Dwarfing rootstocks enhance planting density, lower tree height, and reduce both labor in peach production. Cerasus humilis is distinguished by its dwarf stature, rapid growth, and robust fruiting capabilities, presenting substantial potential for further development. In this study, Ruipan 4 was used as the scion and grafted onto Amygdalus persica and Cerasus humilis, respectively. The results indicate that compared to grafting combination R/M (Ruipan 4/Amygdalus persica), grafting combination R/O (Ruipan 4/Cerasus humilis) plants show a significant reduction in height and a significant increase in flower buds. RNA-seq indicates that genes related to gibberellin (GA) and auxin metabolism are involved in the dwarfing process of scions mediated by C. humilis. The expression levels of the GA metabolism-related gene PpGA2ox7 significantly increased in R/O and are strongly correlated with plant height, branch length, and internode length. Furthermore, GA levels were significantly reduced in R/O. The transcription factor PpGATA21 was identified through yeast one-hybrid screening of the PpGA2ox7 promoter. Yeast one-hybrid (Y1H) and dual-luciferase reporter (DLR) demonstrate that PpGATA21 can bind to the promoter of PpGA2ox7 and activate its expression. Overall, PpGATA21 activates the expression of the GA-related gene PpGA2ox7, resulting in reduced GA levels and consequent dwarfing of plants mediated by C. humilis. This study provides new insights into the mechanisms of C. humilis and offers a scientific foundation for the dwarfing and high-density cultivation of peach trees.

Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data.

BACKGROUND: Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists. METHODS: All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS. RESULTS: LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965-0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications. CONCLUSIONS: LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis. METHODS: The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR. RESULTS: This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64-0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12-0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12-0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34-0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05-3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02-16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10-23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12-3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51-8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77-0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82-0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44-0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76-0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58-0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172-3.61, p = 0.01). CONCLUSIONS: The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF. TRIAL REGISTRATION: CRD42022336311.

Application Value of Systemic Inflammatory Indexes in the Clinical Evaluation of Patients with Heart Failure with Preserved Ejection Fraction (HFpEF).

Background: In areas where medical resources are scarce, an economical and convenient way to assess patients' condition so that treatment plans can be adjusted in a timely manner makes sense. The clinical value of systemic inflammatory indexes (SII) such as neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), albumin-to-gamma-glutamyl-transferase ratio (AGR), white-blood-cell-count-to-mean-platelet-volume ratio (WMR), high-density-lipoprotein-cholesterol-to-C-reactive-protein ratio (HCR), etc. were explored in heart failure (HF) with preserved ejection fraction (HFpEF) because of their easy availability and clinical value in the diagnosis, therapy and prognosis of cardiovascular diseases. Methods: 189 inpatients (including 48 patients with New York Heart Association (NYHA) I in the control group, and 141 patients with NYHA II-IV in the study group) from The First Affiliated Hospital of Jinan University, during the period July 2018 to March 2022, were included by retrieving electronic medical records. Logistic regression analysis, Spearman's correlation coefficient, operating characteristic curve, etc. were used to analyze the data. Results: In patients with HFpEF, LMR (OR = 0.463, 95% CI 0.348−0.617, p = 0.000), NLR and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independent predictors for the presence of HF, and LMR (OR = 2.630, 95% CI 2.016−3.435, p = 0.000), NLR, FAG, MHR, AGR and NT-proBNP were independent predictors for increased NYHA functional classification. There were good correlations (r > 0.4) between LMR (r = −0.667, p = 0.000), NLR, WMR, HCR, NT-proBNP (r = −0.681, p = 0.000) and NYHA functional classification, and LMR (AUC = 0.803, 95% CI 0.729−0.849, p = 0.0001), NLR and NT-proBNP (AUC = 0.805, 95% CI 0.738−0.861, p = 0.0001) had good diagnostic values (AUC > 0.7) for HF in patients with HFpEF. In addition, there were certain correlations between LMR, NT-proBNP and echocardiography indicators of cardiac structural. Conclusions: SII have a potential application value in the clinical evaluation of patients with HFpEF in the follow-up, especially in areas with limited medical resources, as they are more convenient and cost effective. Among different SII, LMR is probably the most promising metric. However, large-scale clinical trials are needed in the future to confirm these findings.

Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents.

To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 µM, 14.37 µM, 7.39 µM, 7.10 µM, and 16.85 µM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.

Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition.

Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.

Efficient Expression of Human Lysozyme Through the Increased Gene Dosage and Co-expression of Transcription Factor Hac1p in Pichia pastoris.

In this work, the high-level expression of the human lysozyme (HLY) was achieved by both optimization of the gene copy number and co-expression of the transcription factor Hac1p for the unfolded protein response (UPR) in the host strain Pichia pastoris KM71H. A series of recombinant constructs with various numbers of HLY expression cassettes was generated for the production of recombinant strains integrated with different copies of the HLY gene. The copy number of the HLY gene was determined by real-time quantitative polymerase chain reaction, and the recombinant strains of P. pastoris carrying one, two, three, four, or six copies of the HLY gene were obtained. Maximum extracellular protein and lysozyme enzyme activity reached 436.99 ± 26.08 µg/mL and 61,900 ± 2036.47 U/mL, respectively, in the recombinant strain HLYH4-3 with the four copies of the HLY gene after shaking flask fermentation. Moreover, the co-expression of the transcription factor Hac1p in the recombinant strains further enhanced the HLY yields. Extracellular protein and lysozyme enzyme activity, respectively, reached 517.82 ± 4.19 µg/mL and 78,600 ± 1134.95 U/mL by using the Hac1p co-expression strain HLYH4-3/Hac1p. These values are the highest recorded level of human lysozyme expressed by P. pastoris in shaking flask fermentation so far.

Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine and quinazoline derivatives as potent antitumor agents.

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC50 values of 1.78 µM, 1.02 µM, 1.98 µM, 0.41 µM and 0.22 µM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC50 value of 0.20 µM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno[3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno[3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity.

Hsa-miR-342-3p and hsa-miR-360 may be the key molecules that promote periodontitis in type 2 diabetes mellitus.

Background: Periodontitis (PD) has been acknowledged as a complication associated with type 2 diabetes mellitus (T2DM). However, the precise mechanism through which T2DM fosters the development of PD remains elusive. Our objective is to elucidate the connection between these two conditions by conducting bioinformatics analysis. Methods: In this study, we analyzed miRNA datasets pertaining to T2DM and PD sourced from GEO. Through differential expression analysis, we identified common differentially expressed miRNAs (DE-miRNAs) and subsequently analyzed the functional enrichment of these common DE-miRNAs. We further leveraged the PD transcriptome database to select DE-miRNA-targeted mRNAs and examined their association with immune infiltration. Finally, machine learning was used to further screen hub DE-miRNA-targeted mRNAs and validate our data in external datasets. Results: Two common DE-miRNAs, namely hsa-miR-342-3p and hsa-miR-360, were identified from the miRNA datasets of PD and T2DM. Functional enrichment analysis indicated that these two common DE-miRNAs predominantly participate in Ras, PI3K-Akt, p53, and MAPK signaling pathways. Integration of the PD transcriptome dataset revealed a total of 21 DE-miRNA-targeted mRNAs in PD, with strong correlations observed with plasma cells and dendritic cells. Finally, three hub DE-miRNA-targeted mRNAs (hsa-miR-342-3p-/hsa-miR-360-RASAL2, hsa-miR-360-ENTPD1/PLXDC2) were identified. ENTPD1 exhibited a robust positive correlation with plasma cells and a negative correlation with resting dendritic cells. Conclusions: Therefore, hsa-miR-342-3p-/hsa-miR-360-RASAL2, as well as hsa-miR-360-ENTPD1/PLXDC2, may serve as diagnostic and therapeutic targets for T2DM-associated PD.

Drug deconjugation-assisted peptide mapping by LC-MS/MS to identify conjugation sites and quantify site occupancy for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a heterogeneous mixture of conjugated species with varied drug loadings. Depending on conjugation sites, linkers and drugs can exhibit different stability as influenced by the solvent-accessibility and local charge, resulting in different ADC efficacy, pharmacokinetics, and toxicity. Conjugation site analysis is critical for ADC structural characterization to assure product quality and consistency. It enables early conjugation studies at site-specific levels, confirms the absence of unexpected products to support conjugation process development, and aids in ensuring lot-to-lot consistency for comparability studies. Peptide mapping using liquid chromatography-tandem mass spectrometry is the industry standard method for analyzing conjugation sites. However, some concerns remain for this approach as the large and hydrophobic drug moieties often result in poor MS/MS fragmentation quality and impede the identification of conjugation sites. Additionally, the ionization discrepancy between conjugated and unconjugated peptides can lead to a relatively large bias for site occupancy calculation. In this work, we present a simple drug deconjugation-assisted peptide mapping method to identify and quantify the drug conjugation for ADCs with protease-cleavable linkers. Papain-based drug deconjugation was used to remove the highly hydrophobic drug moiety, which significantly improved the quantitation accuracy of conjugation level and the fragmentation quality. Sample preparation conditions were optimized to avoid introducing artificial modifications, allowing the tracking of initial sample status and subsequent changes of quality attributes during process development and stability assessment. This method was applied to analyze thermally-stressed ADC samples to monitor changes of site-specific conjugation levels, DAR, succinimide hydrolysis of the linker, and various PTMs. We believe this is an effective and straightforward tool for conjugation site analysis while simultaneously monitoring multiple quality attributes for ADCs with protease-cleavable linkers.

First Principles Study of the Structure-Performance Relation of Pristine Wn+1Cn and Oxygen-Functionalized Wn+1CnO2 MXenes as Cathode Catalysts for Li-O2 Batteries.

Li-O2 batteries are considered a highly promising energy storage solution. However, their practical implementation is hindered by the sluggish kinetics of the oxygen reduction (ORR) and oxygen evolution (OER) reactions at cathodes during discharging and charging, respectively. In this work, we investigated the catalytic performance of Wn+1Cn and Wn+1CnO2 MXenes (n = 1, 2, and 3) as cathodes for Li-O2 batteries using first principles calculations. Both Wn+1Cn and Wn+1CnO2 MXenes show high conductivity, and their conductivity is further enhanced with increasing atomic layers, as reflected by the elevated density of states at the Fermi level. The oxygen functionalization can change the electronic properties of WC MXenes from the electrophilic W surface of Wn+1Cn to the nucleophilic O surface of Wn+1CnO2, which is beneficial for the activation of the Li-O bond, and thus promotes the Li+ deintercalation during the charge-discharge process. On both Wn+1Cn and Wn+1CnO2, the rate-determining step (RDS) of ORR is the formation of the (Li2O)2* product, while the RDS of OER is the LiO2* decomposition. The overpotentials of ORR and OER are positively linearly correlated with the adsorption energy of the RDS LixO2* intermediates. By lowering the energy band center, the oxygen functionalization and increasing atomic layers can effectively reduce the adsorption strength of the LixO2* intermediates, thereby reducing the ORR and OER overpotentials. The W4C3O2 MXene shows immense potential as a cathode catalyst for Li-O2 batteries due to its outstanding conductivity and super-low ORR, OER, and total overpotentials (0.25, 0.38, and 0.63 V).

Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair.

Histone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.

Efficacy of atosiban for repeated embryo implantation failure: A systematic review and meta-analysis.

Background: Repeated embryo implantation failure (RIF) posed a significant challenge in assisted reproduction. Evidence of its therapeutic effectiveness including atosiban used around embryo transfer to improve pregnancy outcomes in RIF patients undergoing in vitro fertilization-embryo transfer (IVF-ET) remained inconsistent. This study aimed to explore the efficacy of atosiban on pregnancy outcomes of patients with RIF who received IVF-ET. Methods: The research was designed using the PICOS format. A systematic search of four English databases, PubMed, EMBASE, Web of Science, Cochrane Library, and one Chinse database, China National Knowledge Infrastructure (CNKI) was conducted. The time range was from inception to December 10, 2022. Then trials comparing the efficacy of atosiban and control group on pregnancy outcomes in RIF patients who receive IVF-ET were included. Subgroup analysis and sensitivity analysis were performed to reduce the influence of heterogeneity between included studies. Risk ratio (RR) and 95% confidence interval (CI) were calculated. The main outcome measure was clinical pregnancy rate (CPR). For the analyses, StataMP 17.0 (Stata Corporation, USA) was used. Results: Two prospective randomized controlled trials (RCTs), one prospective cohort study and four retrospective cohort studies were included. Our results showed that atosiban was associated with higher clinical pregnancy rate (RR=1.54, 95% CI: 1.365-1.735, P < 0.001, I2 = 0.0%). The results of subgroup analysis based on study types (prospective randomized controlled clinical trial, retrospective cohort study and prospective cohort study) showed that in all types of studies, CPR of atosiban group was significantly higher than controlled group. The results of subgroup analysis based upon the diagnostic criteria of number of previous embryo transfer failures showed that the intervention of atosiban improved the CPR whether in participants with 2 previous ET failures or in participants with 3 previous ET failures. Nevertheless, the incidence of ectopic pregnancy, multiple pregnancy, and miscarriages were not significantly different between the case and control groups. Conclusion: For women who are undergoing IVF-ET and have experienced repeated embryo implantation failure, atosiban may be an important factor in enhancing pregnancy outcomes. To confirm this conclusion, more thorough, prospective randomized controlled studies of sizable sample sizes with well design are required.

Graph Polish: A Novel Graph Generation Paradigm for Molecular Optimization.

Molecular optimization, which transforms a given input molecule X into another Y with desired properties, is essential in molecular drug discovery. The traditional approaches either suffer from sample-inefficient learning or ignore information that can be captured with the supervised learning of optimized molecule pairs. In this study, we present a novel molecular optimization paradigm, Graph Polish. In this paradigm, with the guidance of the source and target molecule pairs of the desired properties, a heuristic optimization solution can be derived: given an input molecule, we first predict which atom can be viewed as the optimization center, and then the nearby regions are optimized around this center. We then propose an effective and efficient learning framework, Teacher and Student polish, to capture the dependencies in the optimization steps. A teacher component automatically identifies and annotates the optimization centers and the preservation, removal, and addition of some parts of the molecules; a student component learns these knowledges and applies them to a new molecule. The proposed paradigm can offer an intuitive interpretation for the molecular optimization result. Experiments with multiple optimization tasks are conducted on several benchmark datasets. The proposed approach achieves a significant advantage over the six state-of-the-art baseline methods. Also, extensive studies are conducted to validate the effectiveness, explainability, and time savings of the novel optimization paradigm.

Rapid and Online Detection of Foodborne Bacteria via a Novel Ultraviolet Photoionization Time-of-Flight Mass Spectrometry.

Foodborne bacteria are widespread contaminated sources of food; hence, the real-time monitoring of pathogenic bacteria in food production is important for the food industry. In this study, a novel rapid detection method based on microbial volatile organic compounds (MVOCs) emitted from foodborne bacteria was established by using ultraviolet photoionization time-of-flight mass spectrometry (UVP-TOF-MS). The results showed obvious differences of MVOCs among the five species of bacteria, and the characteristic MVOCs for each bacterium were selected by a feature selection algorithm. Online monitoring of MVOCs during bacterial growth displayed distinct metabolomic patterns of the five species. MVOCs were most abundant and varied among species during the logarithmic phase. Finally, MVOC production by bacteria in different food matrixes was explored. The machine learning models for bacteria cultured in different matrixes showed a good classification performance for the five species with an accuracy of over 0.95. This work based on MVOC analysis by online UVP-TOF-MS achieved effective rapid detection of bacteria and showed its great application potential in the food industry for bacterial monitoring.

The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials.

AIM: We aimed to assess the association between the use of Glucagon-like peptide-1 receptor agonists and the risk of 12 respiratory diseases in patients with type 2 diabetes, obesity, or overweight. METHOD: The PubMed (MEDLINE), EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from the establishment of the database to December 24, 2022. Dichotomous outcomes were analyzed using RR and 95% CI calculated from fixed-effects models. RESULTS: Twenty-eight RCTs were ultimately included for analysis, involving a total of 77,485 participants. Compared to controls, patients with GLP-1RAs have a 14% lower risk of respiratory disease (RR 0.86, 95% CI 0.81-0.93 p < 0.0001), with Semaglutid (RR 0.82, 95% CI 0.68-0.97, p = 0.02), Liraglutide (RR 0.86. 95% CI 0.75-0.98, p = 0.03), Dulaglutide (RR 0.82, 95% CI 0.70-0.96, p = 0.02), Albiglutide (RR 0.93,95% CI 0.79-1.10, p = 0.40), Exenatide (RR 0.93, 95% CI 0.74-1.18, p = 0.55), Lixisenatide (RR 0.83, 95% CI 0.62-1.12, p = 0.22), and Efpeglenatide (RR 0.76, 95% CI 0.46-1.24, p = 0.27). Semaglutide, Liraglutide and Dulaglutide reduce the risk of respiratory diseases by 18%, 14% and 18%, respectively.Trial duration, control type, and indication were not associated with the impact of GLP-1 receptor agonists on overall respiratory disease. Among secondary outcomes, the risk of Pulmonary edema (RR 0.66, 95% CI 0.44-0.98, p = 0.04), and Bronchitis (RR 0.86, 95% CI 0.74-1.00, p = 0.04) was reduced. CONCLUSION: In conclusion, GLP-1RAs were linked to a lower risk of overall respiratory diseases, especially Pulmonary edema and Bronchitis. In the future, physicians should pay attention to the relationship between GLP-1 RA and the risk of respiratory diseases and evaluate the efficacy of GLP-1RAs in the primary and secondary prevention of respiratory diseases. Trial registration CRD42023396138.

Feruloyl oligosaccharides, isolated from bacterial fermented wheat bran, exhibit antioxidant effects in IPEC-J2 cells and zebrafish model.

Feruloyl oligosaccharides (FOs) were produced by solid-state fermentation of wheat bran using Bacillus subtilis, Bacillus licheniformis, and Saccharomyces cerevisiae, and its antioxidant activity was investigated using IPEC-J2 cells and zebrafish embryo model. Preliminary structure analysis revealed that FOs has an average molecular weight of 11.81 kDa and consists of mannose, ribose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, xylose, arabinose, and fucose. The obtained FOs possess superior reducing power and DPPH and hydroxyl free radical scavenging activities. In IPEC-J2 cells, antioxidant enzymes activities and GSH level were significantly increased, while MDA level was reduced by FOs. Further studies showed that FOs achieved the aforementioned effects by activating Nrf2 signaling pathway. In zebrafish embryo, FOs effectively suppressed ROS production, lipid peroxidation, and cell death by increasing SOD and GSH-Px activities. Our findings suggested that FOs from solid-state fermented wheat bran with mixed bacteria can be used as an antioxidant food additive or drugs.

Gcn5- and Bre1-mediated Set2 degradation promotes chronological aging of Saccharomyces cerevisiae.

Loss of transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3) contributes to shorter lifespans in eukaryotes. However, the molecular mechanism of the decline of H3K36me3 during aging remains poorly understood. Here, we report that the degradation of the methyltransferase Set2 is the cause of decreased H3K36me3 levels during chronological aging in budding yeast. We show that Set2 protein degradation during cellular senescence and chronological aging is mainly mediated by the ubiquitin-conjugating E2 enzyme Ubc3 and the E3 ligase Bre1. Lack of Bre1 or abolishment of the ubiquitination stabilizes Set2 protein, sustains H3K36me3 levels at the aging-related gene loci, and upregulates their gene expression, thus leading to extended chronological lifespan. We further illustrate that Gcn5-mediated Set2 acetylation is a prerequisite for Bre1-catalyzed Set2 polyubiquitination and proteolysis during aging. We propose that two sequential post-translational modifications regulate Set2 homeostasis, suggesting a potential strategy to target the Gcn5-Bre1-Set2 axis for intervention of longevity.