Eight-year total, cognitive-affective, and somatic depressive symptoms trajectories and risks of cardiac events.

In this study, we analyzed pooled data from two prospective population-based cohorts-the Health Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA)-to explore the association between trajectories of depressive symptoms and the risk of cardiac events. Depressive symptoms were assessed using the 8-item CES-D scale and categorized into somatic and cognitive-affective subtypes. Trajectories were tracked for four surveys from baseline. Heart disease was identified based on self-reported physician-diagnosed conditions. Hazard ratios and 95% confidence intervals were calculated with Cox proportional risk models that adjusted for potential confounders. In total, 17,787 subjects (59.7% female, median age 63 years) were enrolled at baseline. During a 10-year follow-up, 2409 cases of heart disease were identified. Participants with fluctuating (HR = 1.13, 95% CI: 1.06-1.20), increasing (HR = 1.43, 95% CI: 1.25-1.64), and consistently high (HR = 1.64, 95% CI: 1.45-1.84) depressive symptom trajectories exhibited an increased risk of heart disease compared to those with consistently low depressive symptoms, while a decreasing (HR = 1.07, 95% CI: 0.96-1.19) depressive symptom trajectory did not significantly affect the risk of heart disease. Moreover, the association between heart disease and somatic depressive symptoms was found to be stronger than with cognitive-affective symptoms. These findings suggest a significant link between depressive symptom trajectories and heart disease, with particular emphasis on stronger associations with somatic symptoms. It is recommended that the identification and management of depressive symptoms be incorporated into heart disease prevention strategies.

A nomogram for individualized prediction of new-onset postoperative atrial fibrillation in acute type A aortic dissection patients: a retrospective study.

Objective: The objective of this study is to explore the risk factors associated with new-onset postoperative atrial fibrillation (POAF) following Sun's surgery(total arch replacement using a tetrafurcate graft with stented elephant trunk implantation) for acute type A aortic dissection(AAAD) and to develop a predictive model for assessing the likelihood of new-onset POAF in patients undergoing Sun's surgery for AAAD. Methods: We reviewed the clinical parameters of patients diagnosed with AAAD who underwent Sun's surgery at Qilu Hospital between December 1, 2017 and December 31, 2022. The data was analyzed through univariable and multivariable logistic regression analysis. Variance inflation factor was used to investigate for variable collinearity. A nomogram for predicting new-onset POAF was developed and verified by bootstrap resampling. In addition, the calibration of our model was evaluated by the calibration curve and Hosmer-Lemeshow test. Furthermore, the clinical utility of our model was evaluated using the net benefit curve. Results: This study focused on a cohort of 242 patients with AAAD, among whom 42 experienced new-onset POAF, indicating an incidence rate of 17.36%. Age, left atrial diameter (LA), right atrial diameter (RA), preoperative red blood cells (RBC), and previous acute coronary syndrome (preACS) emerged as independent influences on new-onset POAF following Sun's surgery, as identified by univariable and multivariable logistic regression analysis. Collinearity analysis with demonstrated no collinearity among the variables. A user-friendly prediction nomogram for new onset POAF following Sun's surgery was formulated. The model demonstrated commendable diagnostic accuracy with an area under the curve (AUC) of 0.7852. Validation of the model through bootstrapping (1,000 repetitions) yielded an AUC of 0.8080 (95% CI: 0.8056-0.8104). affirming its robustness. Additionally, the model exhibited favorable fit, calibration, and positive net benefits in decision curve analysis. Conclusions: Drawing upon these findings, we have developed a predictive model for the occurrence of new-onset POAF. These results suggest the potential efficacy of this prediction model for identifying patients at risk of developing POAF. The visualization of this model empowers healthcare professionals to conveniently and promptly assess the risk of AF in patients, thereby facilitating the timely intervention implementation.

Oriented Synthesis of Glycine from CO2, N2, and H2O via a Cascade Process.

Air contains carbon, hydrogen, oxygen, and nitrogen elements that are essential for the constitution of amino acids. Converting the air into amino acids, powered with renewable electricity, provides a green and sustainable alternative to petrochemical-based methods that produce waste and pollution. Here, taking glycine as an example, we demonstrated the complete production chain for electrorefining amino acids directly from CO2, N2, and H2O. Such a prospective scheme was composed of three modules, linked by a spontaneous C-N bond formation process. The high-purity bridging intermediates, separated from the stepwise synthesis, boosted both the carbon selectivity from CO2 to glycine of 91.7% and nitrogen selectivity from N2 to glycine of 98.7%. Under the optimum condition, we obtained glycine with a partial current density of 160.8 mA cm-2. The high-purity solid glycine product was acquired with a separation efficiency of 98.4%. This work unveils a green and sustainable method for the abiotic creation of amino acids from the air components.

Ruthenium Single-Atom Modulated Protonated Iridium Oxide for Acidic Water Oxidation in Proton Exchange Membrane Electrolysers.

Proton exchange membrane water electrolysers promise to usher in a new era of clean energy, but they remain a formidable obstacle in designing active and durable electrocatalysts for the acidic oxygen evolution reaction (OER). In this study, a protonated iridium oxide embedded with single-atom dispersed ruthenium atoms (H3.8Ir1- xRuxO4) that demonstrates exceptional activity and stability in acidic water oxidation is introduced. The single Ru dopants favorably induce localized oxygen vacancies in the Ir─O lattice, synergistically strengthening the adsorption of OOH* intermediates and enhancing the intrinsic OER activity. In addition, the preferential oxidation of Ru and the electronegativity of the oxygen vacancies significantly stabilize the Ir─O active sites, improving the OER stability. Consequently, the H3.8Ir1─ xRuxO4 catalyst shows an overpotential of 255 mV at 10 mA cm-2 and displays exceptional catalytic endurance in acidic electrolytes, surpassing 1100 h, representing a remarkable one-order-of-magnitude increase in stability compared to that of pristine H3.8IrO4. A proton exchange membrane electrolyser utilizing the H3.8Ir1- xRuxO4 catalyst as an anode exhibits stable performance for more than 1280 h under a high current density of 2 A cm-2.

Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database.

Esketamine nasal spray (ESK-NS) is a new drug for treatment-resistant depression, and we aimed to detect and characterize the adverse events (AEs) of ESK-NS using the Food and Drug Administration (FDA) adverse event reporting system (FAERS) database between 2019 Q1 and 2023 Q4. Reporting odds ratio (ROR), proportional reporting ratio (PRR), and multi-item gamma Poisson shrinker (MGPS) were performed to detect risk signals from the FAERS data to identify potential ESK-NS-AEs associations. A total of 14,606 reports on AEs with ESK-NS as the primary suspected drug were analyzed. A total of 518 preferred terms signals and 25 system organ classes mainly concentrated in psychiatric disorders (33.20%), nervous system disorders (16.67%), general disorders and administration site conditions (14.21%), and others were obtained. Notably, dissociation (n = 1,093, ROR 2,257.80, PRR 899.64, EBGM 876.86) exhibited highest occurrence rates and signal intensity. Moreover, uncommon but significantly strong AEs signals, such as hand-eye coordination impaired, feeling guilty, and feelings of worthlessness, were observed. Additionally, dissociative disorder (n = 57, ROR 510.92, PRR 506.70, EBGM 386.60) and sedation (n = 688, ROR 172.68, PRR 155.53, and EBGM 142.05) both presented strong AE signals, and the former is not recorded in the Summary of Product Characteristics (SmPC). In clinical applications, close attention should be paid to the psychiatric disorders and nervous system disorders, especially dissociation. Meanwhile, clinical professionals should be alert for the occurrence of AEs signals not mentioned in the SmPC and take preventive measures to ensure the safety of clinical use.

Turning copper into an efficient and stable CO evolution catalyst beyond noble metals.

Using renewable electricity to convert CO2 into CO offers a sustainable route to produce a versatile intermediate to synthesize various chemicals and fuels. For economic CO2-to-CO conversion at scale, however, there exists a trade-off between selectivity and activity, necessitating the delicate design of efficient catalysts to hit the sweet spot. We demonstrate here that copper co-alloyed with isolated antimony and palladium atoms can efficiently activate and convert CO2 molecules into CO. This trimetallic single-atom alloy catalyst (Cu92Sb5Pd3) achieves an outstanding CO selectivity of 100% (±1.5%) at -402 mA cm-2 and a high activity up to -1 A cm-2 in a neutral electrolyte, surpassing numerous state-of-the-art noble metal catalysts. Moreover, it exhibits long-term stability over 528 h at -100 mA cm-2 with an FECO above 95%. Operando spectroscopy and theoretical simulation provide explicit evidence for the charge redistribution between Sb/Pd additions and Cu base, demonstrating that Sb and Pd single atoms synergistically shift the electronic structure of Cu for CO production and suppress hydrogen evolution. Additionally, the collaborative interactions enhance the overall stability of the catalyst. These results showcase that Sb/Pd-doped Cu can steadily carry out efficient CO2 electrolysis under mild conditions, challenging the monopoly of noble metals in large-scale CO2-to-CO conversion.

Integrated Methylome and Transcriptome Analysis between Wizened and Normal Flower Buds in Pyrus pyrifolia Cultivar 'Sucui 1'.

Here, cytosine methylation in the whole genome of pear flower buds was mapped at a single-base resolution. There was 19.4% methylation across all sequenced C sites in the Pyrus pyrifolia cultivar 'Sucui 1' flower bud genome. Meantime, the CG, CHG, and CHH sequence contexts (where H = A, T or C) exhibited 47.4%, 33.3%, and 11.9% methylation, respectively. Methylation in different gene regions was revealed through combining methylome and transcriptome analysis, which presented various transcription trends. Genes with methylated promoters exhibited lower expression levels than genes with non-methylated promoters, while body-methylated genes displayed an obvious negative correlation with their transcription levels. The methylation profiles of auxin- and cytokinin-related genes were estimated. And some of them proved to be hypomethylated, with increased transcription levels, in wizened buds. More specifically, the expression of the genes PRXP73, CYP749A22, and CYP82A3 was upregulated as a result of methylation changes in their promoters. Finally, auxin and cytokinin concentrations were higher in wizened flower buds than in normal buds. The exogenous application of paclobutrazol (PP333) in the field influenced the DNA methylation status of some genes and changed their expression level, reducing the proportion of wizened flower buds in a concentration-dependent manner. Overall, our results demonstrated the relationship between DNA methylation and gene expression in wizened flower buds of P. pyrifolia cultivar 'Sucui 1', which was associated with changes in auxin and cytokinin concentrations.

Can proximal gastrectomy with double-tract reconstruction replace total gastrectomy? a meta-analysis of randomized controlled trials and propensity score-matched studies.

BACKGROUND: According to the 5th edition of the Japanese Guidelines for the Treatment of Gastric Cancer, proximal gastrectomy is recommended for patients with early upper gastric cancer who can retain the distal half of the residual stomach after R0 resection. However, a large number of recent clinical studies suggest that surgical indications for proximal gastrectomy in the guidelines may be too narrow. Therefore, this meta-analysis included patients with early and advanced gastric cancer and compared short- and long-term postoperative outcomes between the two groups. At the same time, we only had high-quality clinical studies such as propensity score-matched studies and randomized controlled trials, which made our research more authentic and credible. METHODS: Data were retrieved from PubMed, EMBASE, Medline, and Cochrane Library up to June 2023, and included treatment outcomes after proximal gastrectomy with double-tract reconstruction and total gastrectomy with Roux-en-Y reconstruction. The primary results were Early-phase complications(Anastomotic leakage, Anastomotic bleeding, Abdominal abscess, Abdominal infection, Pulmonary infection, Incision infection, Intestinal obstruction, Dumping syndrome, Pancreatic fistula), Late-phase complications(Intestinal obstruction, Anastomosis stricture, Dumping syndrome, Reoperation, Internal hernia, Incidence of endoscopic gastroesophageal reflux), Serious complications (≥ Grade III C-D score), Quality of life[Gastroesophageal reflux symptom evaluation (Visick score)(≥ III), Los Angeles classification(C or D)], Nutritional status(Hemoglobin, Receipt of vitamin B12 supplementation), Oncologic Outcomes(The 5-year overall survival rates). Secondary outcomes were surgical outcomes (Operative time, Estimated blood loss, Postoperative hospital stay, Number of harvested lymph nodes, Gas-passing, Postoperative mortality).The Cochrane risk-of-bias tool and Newcastle‒Ottawa scale were used to assess the quality of the included studies. RESULTS: After screening, 11 studies were finally included, including 1154 patients. Results from the combined literature showed that total gastrectomy had a significant advantage over proximal gastrectomy with double-tract reconstruction in mean operating time (MD = 4.92, 95% CI: 0.22∼9.61 P = 0.04). However, meta-analysis results showed that Hemoglobin (MD = 7.12, 95% CI:2.40∼11.84, P = 0.003) and Receipt of vitamin B12 supplementation (OR = 0.12, 95% CI:0.05∼0.26, P < 0.00001) in the proximal gastrectomy with double-tract reconstruction group were better than those in the total gastrectomy with Roux-en-Y reconstruction group. There is no significant difference between the proximal gastrectomy with double-tract reconstruction and the total gastrectomy with Roux-en-Y reconstruction group in Early-phase complications(OR = 1.14,95% CI:0.79∼1.64, P = 0.50), Late-phase complications(OR = 1.37,95% CI:0.78∼2.39, P = 0.27), Gastroesophageal reflux symptom evaluation (Visick score)(≥ III)(OR = 0.94,95% CI:0.14∼1.07 P = 0.07), Los Angeles classification(C or D)(OR = 0.33,95% CI:0.01∼8.21, P = 0.50), the 5-year overall survival rates (HR = 1.01, 95% CI: 0.83 ~ 1.23, P = 0.89). CONCLUSION: Proximal gastrectomy with double-tract anastomosis is a safe and feasible treatment for upper gastric carcinoma. However, the operating time was slightly longer in the proximal gastrectomy with double-tract group compared to the total gastrectomy with Roux-en-Y group. The two groups were comparable to the total gastrectomy with Roux-en-Y group in terms of serious complications (≥ Grade III C-D score), early-phase complications, late-phase complications, and quality of life. Although the scope of proximal gastrectomy is smaller than that of total gastrectomy, it does not affect the 5-year survival rate, indicating good tumor outcomes for patients. Compared to total gastrectomy with Roux-en-Y group, proximal gastrectomy with double-tract reconstruction had higher hemoglobin levels, lower probability of vitamin B12 supplementation, and better long-term efficacy. In conclusion, proximal gastrectomy with double-tract reconstruction is considered one of the more rational surgical approaches for upper gastric cancer.

A systematic investigation of peracetic acid oxidation and polymeric coagulants re-flocculation to enhance activated sludge dewatering: Multi-porous skeleton structures.

In this research, the effects of peracetic acid (PAA), polymeric flocculants, and their combined conditioning on improving the dewatering performance were comprehensively evaluated. The results showed that sludge cake moisture content, capillary suction time (CST), and specific resistance to filtration (SRF) were 70.6%, 48.1 s, and 3.42 × 1012 m/kg after adding 0.10 g/gMLSS PAA for 50 min, representing reductions of 12.60%, 40.32%, and 33.98%, respectively. Additionally, conditioning of sludge with polyferric sulfate (PFS), polyaluminum chloride (PAC), and cationic polyacrylamide (CPAM) enhanced sludge properties in the following order: CPAM > PAC > PFS. After the PAA oxidation and re-flocculation process, the optimal dosages of PFS, PAC, and CPAM were reduced to 1.5 g/L, 0.9 g/L, and 0.04 g/L, respectively. The sludge dewatering performance significantly improved, with sludge cake moisture content measuring 65.8%, 66.3%, and 61.7%, respectively. Moreover, the spatial multi-porous skeleton structures were formed via re-flocculation to improve the sludge dewatering. Furthermore, economic evaluation validated that the pre-oxidation and re-flocculation process could be considered an economically viable option. These research findings could serve as a valuable reference for practical engineering applications.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Association of four metalloids in the serum and urine of individuals with major depressive disorders: a case-control study.

Background: Major depressive disorder (MDD) pathogenesis may involve metalloids in a significant way. The aim of our study was to identify potential links between MDD and metalloid elements [boron (B), germanium (Ge), arsenic (As), antimony (Sb)]. Methods: A total of 72 MDD cases and 75 healthy controls (HCs) were recruited from Zhumadian Second People's Hospital in Henan Province, China. The levels of four metallic elements (B, Ge, As, and Sb) in the serum and urine were measured using inductively coupled plasma mass spectrometry (ICP-MS). Results: In comparison to the HCs, the B, As, and Sb levels were considerably lower in the MDD group (p < 0.05) in the serum; the MDD group had significantly higher (p < 0.05) and significantly lower (p < 0.001) B and Sb levels in the urine. After adjusting for potential confounders, serum B (OR = 0.120; 95% CI, 0.048, 0.300; p < 0.001) and Sb (OR = 0.133; 95% CI, 0.055, 0.322; p < 0.001) showed a negative correlation with MDD. Urine B had a negative correlation (OR = 0.393; 95% CI, 0.193, 0.801; p = 0.01) with MDD, while urine Sb had a positive correlation (OR = 3.335; 95% CI, 1.654, 6.726; p = 0.001) with MDD. Conclusion: Our current research offers insightful hints for future investigation into the function of metalloids in connection to MDD processes.

The Downregulation of ITGAX Exacerbates Amyloid-ß Plaque Deposition in Alzheimer's Disease by Increasing Polarization of M1 Microglia.

Background: Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Objective: Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. Methods: We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Results: Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-ß (Aß) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aß plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. Conclusions: This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

A two-site Kitaev chain in a two-dimensional electron gas.

Artificial Kitaev chains can be used to engineer Majorana bound states (MBSs) in superconductor-semiconductor hybrids1-4. In this work, we realize a two-site Kitaev chain in a two-dimensional electron gas by coupling two quantum dots through a region proximitized by a superconductor. We demonstrate systematic control over inter-dot couplings through in-plane rotations of the magnetic field and via electrostatic gating of the proximitized region. This allows us to tune the system to sweet spots in parameter space, where robust correlated zero-bias conductance peaks are observed in tunnelling spectroscopy. To study the extent of hybridization between localized MBSs, we probe the evolution of the energy spectrum with magnetic field and estimate the Majorana polarization, an important metric for Majorana-based qubits5,6. The implementation of a Kitaev chain on a scalable and flexible two-dimensional platform provides a realistic path towards more advanced experiments that require manipulation and readout of multiple MBSs.

Electrocatalytic Reforming of Polylactic Acid Plastic Hydrolysate over Dynamically Formed γ-NiOOH.

Upcycling plastic waste into valuable commodity chemicals with clean energy is an appealing strategy for mitigating environmental issues. Polylactic acid (PLA), a biodegradable plastic that is produced annually in millions of tons, can be chemically recycled to valuable products instead of being degraded to carbon dioxide. Here, we demonstrate an electrochemical reforming of PLA hydrolysate to acetate and acetonate using nickel phosphide nanosheets on nickel foam (Ni2P/NF) as the catalyst. The Ni2P/NF catalyst was synthesized by electrochemical deposition and phosphide treatment and showed excellent catalytic activity and ∼100% Faraday efficiency for electroreforming PLA to acetate and acetonate in an H-cell. Moreover, a stable performance of more than 90% Faraday efficiency for value-added organics was achieved for a duration of 100 h in a flow cell at a current density of 100 mA cm-2 and a potential below 1.5 V vs. RHE. In situ characterization revealed that the catalyst underwent electrochemical reforming during the reaction to produce γ-phase NiOOH with high electrochemical activity. This work introduces a new and green solution for the treatment of waste PLA, presenting a low-cost and highly efficient strategy for electrically reforming plastics.

Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment.

NIK plays a crucial role in the noncanonical NF-κB signaling pathway associated with diverse inflammatory and autoimmune diseases. Our study presents compound 54, a novel NIK inhibitor, designed through a structure-based scaffold-hopping approach from the previously identified B022. Compound 54 demonstrates remarkable selectivity and potency against NIK both in vitro and in vivo, effectively suppressing pro-inflammatory cytokines and nitric oxide production. In mouse models, compound 54 protected against LPS-induced systemic sepsis, reducing AST, ALT, and AKP liver injury markers. Additionally, it also attenuates sepsis-induced lung and kidney damage. Mechanistically, compound 54 blocks the noncanonical NF-κB signaling pathway by targeting NIK, preventing p100 to p52 processing. This work reveals a novel class of NIK inhibitors with significant potential for sepsis therapy.

Retracted: Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Tian-Wei Zhang, Li Xing, Jun-Long Tang, Jing-Xiao Lu, Chun-Xiao Liu. Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress. Med Sci Monit, 2015; 21: 3570-3576. DOI: 10.12659/MSM.894476.

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

Comprehensive Evolutionary Analysis of the SMXL Gene Family in Rosaceae: Further Insights into Its Origin, Expansion, Diversification, and Role in Regulating Pear Branching.

SMXL genes constitute a conserved gene family that is ubiquitous in angiosperms and involved in regulating various plant processes, including branching, leaf elongation, and anthocyanin biosynthesis, but little is known about their molecular functions in pear branching. Here, we performed genome-wide identification and investigation of the SMXL genes in 16 angiosperms and analyzed their phylogenetics, structural features, conserved motifs, and expression patterns. In total, 121 SMXLs genes were identified and were classified into four groups. The number of non-redundant SMXL genes in each species varied from 3 (Amborella trichopoda Baill.) to 18 (Glycine max Merr.) and revealed clear gene expansion events over evolutionary history. All the SMXL genes showed conserved structures, containing no more than two introns. Three-dimensional protein structure prediction revealed distinct structures between but similar structures within groups. A quantitative real-time PCR analysis revealed different expressions of 10 SMXL genes from pear branching induced by fruit-thinning treatment. Overall, our study provides a comprehensive investigation of SMXL genes in the Rosaceae family, especially pear. The results offer a reference for understanding the evolutionary history of SMXL genes and provide excellent candidates for studying fruit tree branching regulation, and in facilitating pear pruning and planting strategies.

Nodakenin Ameliorates Ovariectomy-Induced Bone Loss by Regulating Gut Microbiota.

Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). Nodakenin has been shown to ameliorate osteoporosis; however, its anti-osteoporotic mechanism is unknown. This study aimed to further reveal the mechanism of the anti-osteoporotic action of nodakenin from the perspective of the microbiome and metabolome. An osteoporosis model was induced in mice through ovariectomy (OVX), with bone mass and microstructure assessed using µCT. Subsequently, ELISA and histologic examination were used to detect biochemical indicators of bone conversion and intestinal morphology. Using metabolomics and 16S rRNA sequencing, it was possible to determine the composition and abundance of the gut microbiota in feces. The results revealed that nodakenin treatment improved the bone microstructure and serum levels of bone turnover markers, and increased the intestinal mucosal integrity. 16S rRNA sequencing analysis revealed that nodakenin treatment decreased the relative abundance of Firmicutes and Patescibacteria, as well as the F/B ratio, and elevated the relative abundance of Bacteroidetes in OVX mice. In addition, nodakenin enhanced the relative abundance of Muribaculaceae and Allobaculum, among others, at the genus level. Moreover, metabolomics analysis revealed that nodakenin treatment significantly altered the changes in 113 metabolites, including calcitriol. A correlation analysis revealed substantial associations between various gut microbiota taxa and both the osteoporosis phenotype and metabolites. In summary, nodakenin treatment alleviated OVX-induced osteoporosis by modulating the gut microbiota and intestinal barrier.

Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study.

AIM: This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. METHODS: A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. RESULTS: In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer-related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer-related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50-1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50-818.50]). LIMITATIONS: EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. CONCLUSIONS: A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer-related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.