How long-term PM exposure may affect all-site cancer mortality: Evidence from a large cohort in southern China.

BACKGROUND: Evidence of a potential causal link between long-term exposure to particulate matter (PM) and all-site cancer mortality from large population cohorts remained limited and suffered from residual confounding issues with traditional statistical methods. AIMS: We aimed to examine the potential causal relationship between long-term PM exposure and all-site cancer mortality in South China using causal inference methods. METHODS: We used a cohort in southern China that recruited 580,757 participants from 2009 through 2015 and tracked until 2020. Annual averages of PM1, PM2.5, and PM10 concentrations were generated with validated spatiotemporal models. We employed a causal inference approach, the Marginal Structural Cox model, based on observational data to evaluate the association between long-term exposure to PM and all-site cancer mortality. RESULTS: With an increase of 1 µg/m³ in PM1, PM2.5, and PM10, the hazard ratios (HRs) and 95% confidence interval (CI) for all-site cancer were 1.033 (95% CI: 1.025-1.041), 1.032 (95% CI: 1.027-1.038), and 1.020 (95% CI: 1.016-1.025), respectively. The HRs (95% CI) for digestive system and respiratory system cancer mortality associated with each 1 µg/m³ increase in PM1 were 1.022 (1.009-1.035) and 1.053 (1.038-1.068), respectively. In addition, inactive participants, who never smoked, or who lived in areas of low surrounding greenness were more susceptible to the effects of PM exposure, the HRs (95% CI) for all-site cancer mortality were 1.042 (1.031-1.053), 1.041 (1.032-1.050), and 1.0473 (1.025-1.070) for every 1 µg/m³ increase in PM1, respectively. The effect of PM1 tended to be more pronounced in the low-exposure group than in the general population, and multiple sensitivity analyses confirmed the robustness of the results. CONCLUSION: This study provided evidence that long-term exposure to PM may elevate the risk of all-site cancer mortality, emphasizing the potential health benefits of improving air quality for cancer prevention.

Potential causal links of long-term exposure to PM2.5 and its chemical components with the risk of nasopharyngeal carcinoma recurrence: A 10-year cohort study in South China.

There is a lack of evidence from cohort studies on the causal association of long-term exposure to ambient fine particulate matter (PM2.5) and its chemical components with the risk of nasopharyngeal carcinoma (NPC) recurrence. Based on a 10-year prospective cohort of 1184 newly diagnosed NPC patients, we comprehensively evaluated the potential causal links of ambient PM2.5 and its chemical components including black carbon (BC), organic matter (OM), sulfate (SO4 2-), nitrate (NO3 -), and ammonium (NH4 +) with the recurrence risk of NPC using a marginal structural Cox model adjusted with inverse probability weighting. We observed 291 NPC patients experiencing recurrence during the 10-year follow-up and estimated a 33% increased risk of NPC recurrence (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.02-1.74) following each interquartile range (IQR) increase in PM2.5 exposure. Each IQR increment in BC, NH4 +, OM, NO3 -, and SO4 2- was associated with HRs of 1.36 (95%CI: 1.13-1.65), 1.35 (95%CI: 1.07-1.70), 1.33 (95%CI: 1.11-1.59), 1.32 (95%CI: 1.06-1.64), 1.31 (95%CI: 1.08-1.57). The elderly, patients with no family history of cancer, no smoking history, no drinking history, and those with severe conditions may exhibit a greater likelihood of NPC recurrence following exposure to PM2.5 and its chemical components. Additionally, the effect estimates of the five components are greater among patients who were exposed to high concentration than in the full cohort of patients. Our study provides solid evidence for a potential relationship between long-term exposure to PM2.5 and its components and the risk of NPC recurrence.

Pharmacokinetics, Safety, and Immunogenicity of Intravenous and Subcutaneous Single-Dose QX002N Injection in Healthy Subjects: A Randomized, Open, Parallel, Single-Center, Phase I Study.

INTRODUCTION: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. METHODS: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. CONCLUSIONS: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. TRIAL REGISTRATION: www.chinadrugtirals.org.cn , CTR20220430.

Response of phosphorus fractions transformation and microbial community to carbon-to-phosphorus ratios during sludge composting.

Phosphorus (P) is one of the essential nutrient elements for plant growth and development. Sludge compost products can be used as an important source of soil P to solve the shortage of soil P. The difference in the initial carbon-to-phosphorus ratio (C/P) will lead to difference in the bacterial community, which would affect the biological pathway of P conversion in composting. However, few studies have been reported on adjusting the initial C/P of composting to explore P conversion. Therefore, this study investigated the response of P component transformations, bacterial community and P availability to C/P during sludge composting by adjusting initial C/P. The results showed that increasing C/P promoted the mineralization of organic P and significantly increased the content of the labile P. High C/P also increased the relative content of available P, especially when the C/P was at 45 and 60, it reached 60.51% and 60.47%. High C/P caused differences in the community structure, and improved the binding ability of microbial network modules and the competitiveness of microbial communities. Additionally, high C/P strengthened the effect of microbial communities on the transformation of P components. Finally, the study showed that C/P was the main contributor to P content variation (64.7%) and indirectly affected P component conversion by affecting the microbial community. Therefore, adjusting the C/P is crucial to improve the P utilization rate of composting products.

The fibrosis-4 index is a prognostic factor for cholangiocarcinoma patients who received immunotherapy.

Background: Research of immunotherapy for cholangiocarcinoma has yielded some results, but more clinical data are needed to prove its efficacy and safety. Moreover, there is a need to identify accessible indexes for selecting patients who may benefit from such treatments. Methods: The medical records of 66 cholangiocarcinoma patients who underwent immunotherapy were retrospectively collected. The effectiveness of immunotherapy was assessed by tumor response, progression-free survival (PFS), and overall survival (OS), while safety was evaluated by adverse events during treatment. Univariate and multivariate Cox regression analyses were performed to identify prognostic risk factors for PFS and OS, and Kaplan-Meier curves of potential prognostic factors were drawn. Results: Overall, in this study, immunotherapy achieved an objective response rate of 24.2% and a disease control rate of 89.4% for the included patients. The median PFS was 445 days, and the median OS was 772.5 days. Of the 66 patients, 65 experienced adverse events during treatment, but none had severe consequences. Multivariate Cox analysis indicated that tumor number is a prognostic risk factor for disease progression following immunotherapy in cholangiocarcinoma patients, while tumor differentiation and the fibrosis-4 (FIB-4) index are independent risk factors for OS. Conclusion: In general, immunotherapy for cholangiocarcinoma is safe, with adverse events remaining within manageable limits, and it can effectively control disease progression in most patients. The FIB-4 index may reflect the potential benefit of immunotherapy for patients with cholangiocarcinoma.

Prevalence of monoclonal gammopathy of undetermined significance in Shenzhen, China.

BACKGROUND: Data on the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in China are very limited. Our aim was to determine the prevalence and clinical characteristics of MGUS in a large Chinese population. METHODS: This study included 49,220 healthy people who received serum immunofixation electrophoresis (sIFE) and serum protein electrophoresis (SPE) tests. Serum free light chain ratio, immunoglobulin quantification, and other clinically correlates of MGUS were performed for all patients with M-protein. RESULTS: A total of 576 MGUS patients were identified by sIFE, with a median age of 58 years and an overall prevalence of 1.17% (95% CI, 1.08-1.27). Among those aged 50 years and older, the prevalence of MGUS was 2.26% (95% CI, 2.04-2.50). The prevalence of MGUS was significantly higher in males than in females (P < 0.05). The median concentration of M-protein was 3.1 g/L, ranging from 0.5 g/L to 25.1 g/L. The M-protein type was IgG in 55.4% of MGUS patients, followed by IgA (31.1%), IgM (9.5%), IgD (0.5%), biclonal (2.3%), and light chain (1.2%). Abnormalities in SPE, FLC ratios, and immunoglobulin levels were observed in 78.3%, 31.1%, and 38.4% of MGUS patients, respectively. CONCLUSIONS: The prevalence of MGUS is substantially lower in southern China than in whites and blacks.

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.

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.

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.

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.

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.

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.

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.

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.