Fatigue Behavior and Fracture Surface Analysis of Corroded High-Strength Bridge Cable Wires.

Bridge cable wires suffer from alternating stress and environmental erosion, leading to premature failure prior to its design life. This paper investigates the fatigue and mechanical behaviors of corroded bridge cable wires with a zinc-aluminum (Zn-Al) alloy coating. Based on the salt spray corrosion test and microstructure analysis, the anti-corrosion resistance and corrosion appearance characteristics of the Zn-Al alloy coating and galvanized coating were investigated. The Zn-Al alloy coating was superior in resistance to corrosion fatigue for the improvement in toughness and the generation of anti-corrosion Zn-Al and Fe-Zn-Al phases. Equations of the accelerated corrosion depth of the steel wires had been regressed to roughly estimate the corrosion life of the Zn-Al alloy coating, which can reach 29.1 years with a thickness of 70 µm. The fatigue and mechanical properties of the bare wires after the salt spray test were further studied based on tensile tests and fatigue tests. The fatigue properties of the bridge cable wire would decrease with the corrosion degree due to the deterioration and embrittlement of materials, where ductility characterized by the elongation rate was the most affected. Fracture surfaces of the wires were captured and analyzed based on a method for recognizing graphical contours. Insufficient fatigue life may occur in the steel wires after corrosion and increase with the degree of corrosion. The pit depth logarithmically weakened the fatigue life of steel wires for the weakening of fatigue toughness and the bearing area. The flat fracture was more common with a single fatigue source, while multiple fatigue sources led to step-like fractures for the generation of multiple dispersed crack propagation regions. Corrosion fatigue was more sensitive to the existence of fatigue sources than the reduction. Multiple initiation sources significantly reduced the fatigue life due to the cracking facilitation of the joint effect of multiple pits. The electrochemical reactions of corrosion can lead to material embrittlement and a reducing effect on the fracture toughness of the steel wires.

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance.

Background: To identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs. Methods: Three datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the "most significant trait-related genes" (MSTRGs). Enrichment analysis and PPI network were performed to find common features and novel hub genes in ISTs. The shared genes of DEGs and genes between DEGs and MSTRGs across four ISTs were identified as key IR therapeutic target. The Attie Lab diabetes database and obese rats were used to verify candidate genes. A medical drug-gene interaction network was conducted by using the Comparative Toxicogenomics Database (CTD) to find potential targeted drugs. The candidate drug was validated in Hepa1-6 cells. Results: Lipid metabolic process, mitochondrion, and oxidoreductase activity as common features were enriched from ISTs under an obese context. Thirteen shared genes (Ubd, Lbp, Hp, Arntl, Cfd, Npas2, Thrsp., Tpx2, Pkp1, Sftpd, Mthfd2, Tnfaip2, and Vnn3) of DEGs across ISTs were obtained and confirmed. Among them, Ubd was the only shared gene between DEGs and MSTRGs across four ISTs. The expression of Ubd was significantly upregulated across four ISTs in obese rats, especially in the liver. The IR Hepa1-6 cell models treated with dexamethasone (Dex), palmitic acid (PA), and 2-deoxy-D-ribose (dRib) had elevated expression of Ubd. Knockdown of Ubd increased the level of p-Akt. A lowing Ubd expression drug, promethazine (PMZ) from CTD analysis rescued the decreased p-Akt level in IR Hepa1-6 cells. Conclusion: This study revealed Ubd, a novel and shared IR molecular signature across four ISTs, as an effective biomarker and provided new insight into the mechanisms of IR. PMZ was a candidate drug for IR which increased p-Akt level and thus improved IR by targeting Ubd and downregulation of Ubd expression. Both Ubd and PMZ merit further clinical translational investigation to improve IR.

Wnt5a/ß-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial-mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. METHODS: In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a ß-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFß1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. RESULTS: The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of ß-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active ß-catenin labeling. In vitro, Wnt5a/ROR1, active ß-catenin, and some other Wnt signaling molecules were upregulated in the TGFß1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active ß-catenin, as well as the EMT in TGFß1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. CONCLUSIONS: Our study reveals a reciprocal activation between Wnt5a and ß-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

Unveiling causal connections: Long-term particulate matter exposure and type 2 diabetes mellitus mortality in Southern China.

Evidence of the potential causal links between long-term exposure to particulate matters (PM, i.e., PM1, PM2.5, and PM1-2.5) and T2DM mortality based on large cohorts is limited. In contrast, the existing evidence usually suffers from inherent bias with the traditional association assessment. A prospective cohort of 580,757 participants in the southern region of China were recruited during 2009 and 2015 and followed up through December 2020. PM exposure at each residential address was estimated by linking to the well-established high-resolution simulation dataset. Hazard ratios (HRs) were calculated using time-varying marginal structural Cox models, an established causal inference approach, after adjusting for potential confounders. During follow-up, a total of 717 subjects died from T2DM. For every 1 µg/m3 increase in PM2.5, the adjusted HRs and 95% confidence interval (CI) for T2DM mortality was 1.036 (1.019-1.053). Similarly, for every 1 µg/m3 increase in PM1 and PM1-2.5, the adjusted HRs and 95% CIs were 1.032 (1.003-1.062) and 1.085 (1.054-1.116), respectively. Additionally, we observed a generally more pronounced impact among individuals with lower levels of education or lower residential greenness which as measured by the Normalized Difference Vegetation Index (NDVI). We identified substantial interactions between NDVI and PM1 (P-interaction = 0.003), NDVI and PM2.5 (P-interaction = 0.019), as well as education levels and PM1 (P-interaction = 0.049). The study emphasizes the need to consider environmental and socio-economic factors in strategies to reduce T2DM mortality. We found that PM1, PM2.5, and PM1-2.5 heighten the peril of T2DM mortality, with education and green space exposure roles in modifying it.

Mapping prodromal symptoms in patients with bipolar disorder: A network perspective.

Bipolar disorder (BD) is a major mental disorder that significantly impairs behavior and social functioning. This study assessed the network structure of prodromal symptoms in patients with BD prior to their index mood episode. Semi-structured interviews were conducted with the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R) to examine patients' prodromal symptoms. Network analysis was conducted to elucidate inter-relations between prodromal symptoms. A total of 120 eligible patients participated in this study. Network analysis indicated that the observed model was stable. The edge Mania3-Depression9 ('Racing thoughts' - 'Thinking about suicide', edge weight = 14.919) showed the strongest positive connection in the model, followed by the edge Mania1-depression1 ('Extremely energetic/active' - 'Depressed mood', edge weight = 14.643). The only negative correlation in the model was for Mania7-depression2 ('Overly self-confident' - 'Tiredness or lack of energy', edge weight = -1.068). Nodes Mania3 ('Racing thoughts'), Depression9 ('Thinking about suicide'), Mania1 ('Extremely energetic/active'), and Depression1 ('Depressed mood') were the most central symptoms. Both depressive and manic or hypomanic symptoms appeared in the prodromal phase. Symptoms reflecting 'Racing thoughts', 'Thinking about suicide', 'Extremely energetic/active', and 'Depressed mood' should be thoroughly assessed and targeted as crucial prodromal symptoms in interventions to reduce the risk of BD episodes.

LncRNA S100PBP promotes proliferation and steroid hormone synthesis of granulosa cells by sponging MiR-2285bc-BMPR2 in bovine.

In bovine follicular development, the proliferation of bovine granulosa cells (GCs) affect follicular selection, atresia, and cystic follicle formation. With the proliferation of GCs and secretion of steroid hormones, follicles develop further and increase in diameter. However, when cystic follicles appear on the ovaries, GCs stop proliferating, resulting in the reduction of GCs layer. In our previous study, the whole transcriptome sequencing revealed that Bone morphogenetic protein receptor 2 (BMPR2) was differentially expressed (DE) between cystic and normal follicular GCs. We speculated that lncRNA may act as ceRNA targeting miRNAs and then regulating the expression of BMPR2 and the function of GCs, thereby affecting follicular development and cyst formation. In this study, the results elucidated that lncRNA S100PBP (NONBTAT011846.2) directly bound miR-2285bc, which targeted in the BMPR2 3'-UTR. miR-2285bc suppresses GCs proliferation by downregulating BMPR2 expression. Furthermore, lncRNA S100PBP was silenced by small interfering RNA (siRNA), and lncRNA S100PBP regulated BMPR2 expression by sponging miR-2285bc investigated through cross-verification. When siRNA of lncRNA S100PBP was transfected into GCs, the results revealed similar molecular changes as those transfected with miR-2285bc mimics. Silencing lncRNA S100PBP or overexpressing miR-2285bc altered the expressions of some follicular development-related genes, which could be related to follicular cyst occurrence. In conclusion, our findings support that lncRNA S100PBP regulates the expression of BMPR2 through sponge miR-2285bc, promotes the proliferation of GCs, inhibits their apoptosis, and increases the synthesis and secretion of follicular steroid hormones, thus promoting the development of bovine follicles and potentially inhibiting the formation of follicular cysts.

Artificial Neural Synapses Based on Microfluidic Memristors Prepared by Capillary Tubes and Ionic Liquid.

Neuromorphic simulation, i.e., the use of electronic devices to simulate the neural networks of the human brain, has attracted a lot of interest in the fields of data processing and memory. This work provides a new method for preparing a 1,3-dimethylimidazolium nitrate ([MMIm][NO3]:H2O) microfluidic memristor that is ultralow cost and technically uncomplicated. Such a fluidic device uses capillaries as memory tubes, which are structurally similar to interconnected neurons by simple solution treatment. When voltage is applied, the transmission of anions and cations in the tube corresponds to the release of neurotransmitters from the presynaptic membrane to the postsynaptic membrane. The change of synaptic weights (plasticity) also can be simulated by the gradual change of conductance of the fluid memristor. The learning process of microfluidic memristors is very obvious, and the habituation and recovery behaviors they exhibit are extremely similar to biological activities, representing its good use for simulating neural synapses.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

The impact of long-term PM1 exposure on all-cause mortality and its interaction with BMI: A nationwide prospective cohort study in China.

BACKGROUND: China has a serious air pollution problem and a high prevalence of obesity. The interaction between the two and its impact on all-cause mortality is a public health issue of great concern. OBJECTIVES: This study aimed to investigate the association between long-term exposure to particulate matter with aerodynamic diameter ≤ 1 µm (PM1) and all-cause mortality, as well as the interaction effect of body mass index (BMI) in the association. METHODS: A total of 33,087 participants from 162 counties in 25 provinces in China were included, with annual average PM1 exposure being estimated based on the county address. The PM1-mortality relation was evaluated using the time-varying Cox proportional hazards models, with the dose-response relationship being fitted using the penalized splines. Besides, the potential interaction effect of BMI in the PM1-mortality relation was evaluated. RESULTS: The incidence of all-cause deaths was 76.99 per 10,000 person-years over a median of 8.2 years of follow-up. After controlling for potential confounders, the PM1-mortality relation was approximately J-shaped. The full-adjustment analysis observed the hazard ratio (HR) of all-cause mortality was 1.114 [95 % confidence interval (CI): 1.017-1.220] corresponding to a 10 µg/m3 rise in PM1 concentration. Further stratified analyses suggested the adverse effects of PM1 might be more pronounced among the underweight. DISCUSSION: Higher PM1 concentrations were associated with an increase in all-cause mortality. The BMI might further alter the relation, and the underweight population was the sensitive subgroup of the population that needed to be protected.

RNA-seq analysis of small intestine transcriptional changes induced by starvation stress in piglets.

Piglets may experience a variety of stress injuries, but the molecular regulatory mechanisms underlying these injuries are not well understood. In this study, we analysed the ileum of Large White (LW) and Mashen (MS) piglets at different times of starvation using chemical staining and transcriptome analysis. The intestinal barrier of piglets was damaged after starvation stress, but the intestinal antistress ability of MS piglets was stronger than LW piglets. A total of 8021 differentially expressed genes (DEGs) were identified in two breeds. Interestingly, the immune capacity (CHUK, TLR3) of MS piglets increased significantly after short-term starvation stress, while energy metabolism (NAGS, PLA2G12B, AGCG8) was predominant in LW piglets. After long-term starvation stress, the level of energy metabolism (PLIN5, PLA2G12B) was significantly increased in MS piglets. The expression of immune (HLA-DQB1, IGHG4, COL3A1, CD28, LAT) and disease (HSPA1B, MINPPI, ADH1C, GAL3ST1) related genes were significantly increased in two breeds of piglets. These results suggest that short-term stress mainly enhances immunity and energy metabolism in piglets, while long-term starvation produces greater stress on piglets, making it difficult for them to compensate for the damage to their bodies through self-regulation. This information can help improve the stress resistance of piglets through molecular breeding.

Multi-heteroatom-doped porous carbon with high surface adsorption energy of potassium derived from biomass waste for high-performance supercapacitors.

Sustainable and renewable biomass-derived porous carbon (BPC) have garnered considerable attention owing to their low cost, high specific surface area, and outstanding electrochemical performance. However, the subpar energy density severely restricts the applications of BPC in high-energy-density devices. Herein, a high-surface-area porous carbon with multiple heteroatoms doping was derived from rapeseed meals by hydrothermal carbonization and high-temperature activation. The rapeseed meal-derived activated carbon (RMAC) exhibits a remarkable surface area of 3291 m2 g-1 and is doped with nitrogen (1.05 at.%), oxygen (7.4 at.%), phosphorus (0.31 at.%), and sulfur, resulting in an impressive specific capacitance of 416 F g-1 at 1 A g-1. Furthermore, even after 10,000 cycles, the optimized RMAC-800 electrode maintains 92 % of its initial capacitance, attesting to its exceptional performance. Through comprehensive density functional theory (DFT) calculations, the elements O, N, P, and S can significantly enhance the electron negativity and density, improving the adsorption and diffusion of K+ to attain a high capacitance. To assess the RMAC-800's practical performance, an asymmetric supercapacitor with 1 M [BMIM]BF4/AN electrolyte was produced that delivered a high energy density of 195.94 Wh kg-1 at a power density of 1125 W kg-1. Thus, we propose an eco-friendly strategy for producing BPC materials with outstanding electrochemical performance for supercapacitors.

Safety and immunogenicity of primary vaccination with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants aged 18 years or more: Two randomized, observer-blinded, placebo-controlled and dose-escalation phase 1 clinical trials.

Vaccination plays a key role in preventing morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the safety and immunogenicity of a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine SYS6006. In the two randomized, observer-blinded, placebo-controlled phase 1 trials, 40 adult participants aged 18-59 years and 40 elderly participants aged 60 years or more were randomized to receive two doses of SYS6006 or placebo (saline). Adverse events (AEs) were collected through 30 days post the second vaccination. Immunogenicity was assessed by live-virus neutralizing antibody (Nab), spike protein (S1) binding antibody (S1-IgG), and cellular immunity. The result showed that 7/15, 9/15 and 4/10 adult participants, and 9/15, 8/15 and 4/10 elderly participants reported at least one AE in the 20-µg, 30-µg and placebo groups, respectively. Most AEs were grade 1. Injection-site pain was the most common AE. Two adults and one elder reported fever. No vaccination-related serious AE was reported. SYS6006 elicited wild-type Nab response with a peak geometric mean titer of 232.1 and 130.6 (adults), and 48.7 and 66.7 (elders), in the 20-µg and 30-µg groups, respectively. SYS6006 induced moderate-to-robust Nab response against Delta, and slight Nab response against Omicron BA.2 and BA.5. Robust IgG response against wild type and BA.2 was observed. Cellular immune response was induced. In conclusion, two-dose primary vaccination with SYS6006 demonstrated good safety and immunogenicity during a follow-up period of 51 days in immunologically naive population aged 18 years or more. (Trial registry: Chictr.org.cn ChiCTR2200059103 and ChiCTR2200059104).

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Development and validation of a network calculator model for safety and efficacy after pancreaticoduodenectomy in the elderly patients with pancreatic head cancer.

BACKGROUND: Benefiting from increased life expectancy and improved perioperative management, more elderly patients with pancreatic head cancer (PHC) underwent pancreaticoduodenectomy (PD). However, individualized predictive models for the safety and efficacy of PD is still lacking. this study aimed to developed three safety- and efficacy-related risk calculators for elderly (> = 65 years) PHC patients. METHODS: This study was designed with two research cohorts, namely, the training cohort and the validation cohort, and comprises four general steps: (1) Risk factors were analyzed for the incidence of postoperative complications, cancer-specific survival (CSS), and overall survival (OS) in the training cohort (N = 271) using logistic and Cox-regression analysis. (2) Nomograms were then plotted based on the above results. (3) The accuracy of the developed nomogram models was then verified with the validation cohort (N = 134) data using consistency index (C-index) and calibration curves. (4) We then evaluated the efficacy of these nomograms using decision curve analysis (DCA) in both the training and validation cohorts, and ultimately constructed three online calculators based on these nomograms. RESULTS: We identified ASA, diabetes, smoking, and lymph node invasion as predisposing risk factors for postoperative complications, and the predictive factors that affected both OS and CSS were ASA, diabetes, BMI, CA19-9 level, and tumor diameter. By integrating the above risk factors, we constructed three nomograms on postoperative complication, CSS, and OS. The C-index for complication, CSS, and OS were 0.824, 0.784, and 0.801 in the training cohort and 0.746, 0.718, and 0.708 in the validation cohort. Moreover, the validation curves and DCA demonstrated good calibration and robust compliance in both training and validation cohorts. We then developed three web calculators (https://caiming.shinyapps.io/CMCD/, https://caiming.shinyapps.io/CMCSS/, and https://caiming.shinyapps.io/CMOS/) to facilitate the use of the nomograms. CONCLUSIONS: The calculators demonstrated promising performance as an tool for predicting the safety and efficacy of PD in elderly PHC patients.

Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response.

BACKGROUND: T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC). METHODS: A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells. RESULTS: Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice. CONCLUSIONS: Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.

Long-term particulate matter exposure and the risk of neurological hospitalization: Evidence from causal inference of a large longitudinal cohort in South China.

With limited evidence on the neurological impact of particulate matter (PM) exposure in China, particularly for PM1 which is smaller but more toxic, we conducted a large Chinese cohort study using causal inference approaches to comprehensively clarify such impact. A total of 36,271 participants in southern China were recruited in 2015 and followed up through 2020. We obtained the neurological hospitalizations records by linking the cohort data to the electronic reports from 418 medical institutions across the study area. By using high-resolution PM concentrations from satellite-based spatiotemporal models and the cohort data, we performed marginal structural Cox models under causal assumptions to assess the potential causal links between time-varying PM exposure and neurological hospitalizations. Our findings indicated that increasing PM1, PM2.5, and PM10 concentrations by 1 µg/m³ were associated with higher overall neurological hospitalization risks, with hazard ratios (HRs) of 1.10 (95% confidence interval (CI) 1.04-1.16), 1.09 (95% CI 1.04-1.14), and 1.03 (95% CI 1.00-1.06), respectively. PM1 appeared to have a stronger effect on neurological hospitalization, with a 1% and 7% higher impact compared to PM2.5 and PM10, respectively. Additionally, each 1-µg/m3 increase in the annual PM1 concentration was associated with an elevated risk of hospitalizations for ischemic stroke (HR: 1.15; 95% CI, 1.06-1.26), which tended to be larger than the estimates for PM2.5 (HR: 1.13, 95% CI, 1.04-1.23) and PM10 (HR: 1.05, 95% CI, 1.00-1.09). Furthermore, never-married or female individuals tended be at a greater risk compared with their counterparts. Our study provides important insights into the health impact of particles, particularly smaller particles, on neurological hospitalization risk and highlights the need for clean-air policies that specifically target these particles.

Polynuclear Rare-Earth Cluster-Directed Self-Assembly of Highly Porous Zeolite-like Metal-Organic Frameworks with Methane Storage Property.

Due to their intrinsic structural features, the design and synthesis of a new type of zeolite-like metal-organic frameworks (ZMOFs) is highly desirable but challenging. Herein, solvothermal reactions between an angular dicarboxylate linker and rare-earth (RE) ions afforded two RE-MOFs, namely, Tb-ZMOF-2 and Tb-ZMOF-3, respectively. Structural analyses reveal that Tb-ZMOF-2 encompasses a novel [446482] cage, while Tb-ZMOF-3 contains nonanuclear (i.e., D6R) and hexanuclear (i.e., D4R) RE clusters simultaneously, subsequently resulting in two new zeolitic topologies. Thanks to its high surface area and pore volume, Tb-ZMOF-2 demonstrates considerably high gravimetric and volumetric methane storage working capacities.

Two birds with one stone: facile fabrication of an iron-cobalt bimetallic sulfide nanosheet-assembled nanosphere for efficient energy storage and hydrogen evolution.

Transition metal sulfides are widely regarded as the most promising electrode materials for supercapacitors. Herein, we utilized a straightforward electrodeposition method to prepare an iron-cobalt bimetallic sulfide nanosheet-assembled nanosphere on nickel foam (FeCo2S4/NF). The synergistic effect between bimetals and the unique three-dimensional structure significantly improved its capacitive performance. As a result, it demonstrated a remarkable specific capacitance, brilliant long-term stability and acceptable rate capability. Moreover, FeCo2S4/NF and active carbon (AC) were used to assemble an asymmetric supercapacitor (ASC), and FeCo2S4//AC displays a maximum energy density of 29.4 W h kg-1 at 800 W kg-1. Moreover, when adopted as an electrocatalyst for the hydrogen evolution reaction (HER), FeCo2S4/NF exhibited excellent catalytic properties (η10 = 165 mV). Our research provides a valuable insight into the multidisciplinary integration of high-performance energy materials.

Association between MTHFR c.677C>T variant and erectile dysfunction among males attending fertility clinic.

ABSTRACT: Genetic risk factors have been shown to contribute to the development of sexual dysfunction. However, the role of methylenetetrahydrofolate reductase (MTHFR) gene variants in the risk of erectile dysfunction (ED) remains unclear. In this study, we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5. The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction (PCR). No significant difference in the genotypic frequency of the MTHFR C677T polymorphism (CC, CT, and TT) was observed between men from the ED and non-ED groups. In addition, on binary logistic regression analysis, both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism. Interestingly, a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED (P = 0.02). The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis, even after adjusting for potential confounders (odds ratio [OR] = 2.46, 95% confidence interval [CI]: 1.15-5.50, P = 0.02). These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED. Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routine clinical diagnosis.