Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model.

Atherosclerosis is the pathological cause of atherosclerotic cardiovascular disease (ASCVD), which rapidly progresses during the cellular senescence. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce major cardiovascular events in patients with ASCVD and have potential antisenescence effects. Here, we investigate the effects of the SGLT2 inhibitor dapagliflozin on cellular senescence in atherosclerotic mice. Compared with ApoE-/- control mice treated with normal saline, those in the ApoE-/- dapagliflozin group, receiving intragastric dapagliflozin (0.1 mg kg-1 d-1) for 14 weeks, exhibited the reduction in the total aortic plaque area (48.8%±6.6% vs. 74.6%±8.0%, P<0.05), the decrease in the lipid core area ((0.019±0.0037) mm2vs. (0.032±0.0062) mm2, P<0.05) and in the percentage of senescent cells within the plaques (16.4%±3.7% vs. 30.7%±2.0%, P<0.01), while the increase in the thickness of the fibrous cap ((21.6±2.1) µm vs. (14.6±1.5) µm, P<0.01). Transcriptome sequencing of the aortic arch in the mice revealed the involvement of the PPARα and the fatty acid metabolic signaling pathways in dapagliflozin's mechanism of ameliorating cellular aging and plaque progression. In vitro, dapagliflozin inhibited the expression of PPARα and its downstream signal FABP4, by which the accumulation of senescent cells in human aortic smooth muscle cells (HASMCs) was reduced under high-fat conditions. This effect was accompanied by a reduction in the intracellular lipid content and alleviation of oxidative stress. However, these beneficial effects of dapagliflozin could be reversed by the PPARα overexpression. Bioinformatics analysis and molecular docking simulations revealed that dapagliflozin might exert its effects by directly interacting with the RXRA protein, thereby influencing the expression of the PPARα signaling pathway. In conclusion, the cellular senescence of aortic smooth muscle cells is potentially altered by dapagliflozin through the suppression of the RXRA-PPARα-FABP4 signaling pathway, resulting in a deceleration of atherosclerotic progression.

Clinicopathologic features and surgery-related outcomes of duodenal adenocarcinoma: A multicenter retrospective study.

BACKGROUND: The incidence of duodenal adenocarcinoma is increasing, with limited studies on this disease published. This multicenter retrospective study aimed to analyze the clinicopathologic features of duodenal adenocarcinoma and identify prognostic factors for postoperative survival. METHODS: Demographic characteristics, clinicopathologic features, treatment outcomes, and survival of patients with duodenal adenocarcinoma undergoing surgical treatment at 16 Chinese medical centers from 2012 to 2023 were retrospectively analyzed. RESULTS: Among the 2,189 patients with duodenal adenocarcinoma included, 50.07% had extra-ampullary duodenal adenocarcinoma and 49.93% had peri-ampullary duodenal adenocarcinoma. The 1-, 3-, and 5-year overall survival rates for patients who underwent radical surgery were 91.78%, 69.30%, and 55.86%, respectively. The median overall survival was 73 months (range, 64-84), and the median progression-free survival was 64 months (range, 52-76). No differences in survival were observed between the laparotomy and minimally invasive surgery groups (log-rank P = .562); furthermore, no significant between-group differences in operation time, lymph node dissection, postoperative complications, or in-hospital mortality were observed (P > .05). The minimally invasive surgery group experienced less intraoperative blood loss (250 mL vs 100 mL, P < .001), fewer intraoperative blood transfusions (24.97% vs 18.84%, P = .002), and shorter hospital stays (28 days vs 23 days, P < .001). Multivariate Cox regression analysis revealed that advanced age, advanced stage, longer operation time, intraoperative blood transfusion, and postoperative hemorrhage were independent risk factors for poor prognosis. CONCLUSION: Radical surgery was associated with favorable overall survival among patients with duodenal adenocarcinoma, and no difference in survival was observed between patients with extra-ampullary duodenal adenocarcinoma and peri-ampullary duodenal adenocarcinoma. Minimally invasive surgery is a reliable alternative for duodenal adenocarcinoma treatment.

OSA modified porous starch acts as an efficient carrier for loading and sustainedly releasing naringin.

To select an efficient carrier for loading and sustainedly releasing naringin (NAR), complexes of porous starch (PS) and NAR (PS-NAR) as well as those of octenyl succinic anhydride (OSA) esterified PS and NAR (OSAPS-NAR) with different degree of substitution (DS) were prepared by an ultrasonic method with an ethanol solution. The micro-morphological features, structural and thermal properties of complexes and their constituents were characterized, and in vitro release rate and kinetic of NAR from complexes were investigated. The findings revealed that NAR was successfully loaded in PS/OSAPS in an amorphous form, and the NAR's loading efficiency improved as DS increased, reaching 86.85 % at DS 0.0427. NAR cumulative release rate from the complexes in simulated digestion fluids was much higher than that of free (unloaded) NAR, but decreased as DS increased. NAR's in vitro release from complexes mainly depended on the carrier rather than NAR itself, and OSAPS with higher DS had stronger protection and slower release effect on NAR. The results would provide a new means for starch-based carrier construction to develop an efficient delivery and sustainedly releasing system for NAR, thus broadening the application ranges both for modified starch and citrus flavonoids such as NAR.

Health care resource utilization and direct costs incurred over 24 months after initiating galcanezumab or standard-of-care preventive migraine treatments in the United States.

BACKGROUND: Health care resource utilization (HCRU) and direct costs incurred over 12 months following initiation of galcanezumab (GMB) or standard-of-care (SOC) preventive migraine treatments have been evaluated. However, a gap in knowledge exists in understanding longer-term HCRU and direct costs. OBJECTIVE: To compare all-cause and migraine-related HCRU and direct costs in patients with migraine initiating GMB or SOC preventive migraine treatments over a 24-month follow-up. METHODS: This retrospective study used Optum deidentified Market Clarity Data. The study included adults diagnosed with migraine, with at least 1 claim for GMB or SOC preventive migraine therapy (September 2018 to March 2020), with continuous enrollment for 12 months before and 24 months after (follow-up) the index date (date of first GMB or SOC claim). Propensity score (PS) matching (1:1) was used to balance cohorts. All-cause and migraine-related HCRU and direct costs for GMB vs SOC cohorts were reported as mean (SD) per patient per year (PPPY) over a 24-month follow-up and compared using a Z-test. Costs were inflated to 2022 US$. RESULTS: After PS matching, 2,307 patient pairs (mean age: 44.4 years; female sex: 87.3%) were identified. Compared with the SOC cohort, the GMB cohort had lower mean (SD) PPPY all-cause office visits (17.9 [17.7] vs 19.1 [18.7]; P = 0.023) and migraine-related office visits (2.6 [3.3] vs 3.0 [4.7]; P = 0.002) at follow-up. No significant differences were observed between cohorts in other all-cause and migraine-related events assessed including outpatient visits, emergency department (ED) visits, inpatient stays, and other medical visits. The mean (SD) costs PPPY were lower in the GMB cohort compared with the SOC cohort for all-cause office visits ($4,321 [7,518] vs $5,033 [7,211]; P < 0.001) at follow-up. However, the GMB cohort had higher mean (SD) PPPY all-cause total costs ($24,704 [30,705] vs $21,902 [28,213]; P = 0.001) and pharmacy costs ($9,507 [12,659] vs $5,623 [12,605]; P < 0.001) compared with the SOC cohort. Mean (SD) costs PPPY were lower in the GMB cohort for migraine-related office visits ($806 [1,690] vs $1,353 [2,805]; P < 0.001) compared with the SOC cohort. However, the GMB cohort had higher mean (SD) PPPY migraine-related total costs ($8,248 [11,486] vs $5,047 [9,749]; P < 0.001) and migraine-related pharmacy costs ($5,394 [3,986] vs $1,761 [4,133]; P < 0.001) compared with the SOC cohort. There were no significant differences between cohorts in all-cause and migraine-related costs for outpatient visits, ED visits, inpatient stays, and other medical visits. CONCLUSIONS: Although total costs were greater for GMB vs SOC following initiation, changes in a few categories of all-cause and migraine-related HCRU and direct costs were lower for GMB over a 24-month follow-up. Additional analysis evaluating indirect health care costs may offer insights into further cost savings incurred with preventive migraine treatment.

Synergistic impact of plasma albumin and cognitive function on all-cause mortality in Chinese older adults: a prospective cohort study.

Background: Hypoalbuminemia and cognitive impairment (CI) each independently increase the mortality risk in older adults. However, these two geriatric syndromes can occur simultaneously. In community-dwelling older adults, is the combination of hypoalbuminemia and CI linked to a higher mortality risk than either condition alone? Objective: We aimed to investigate the association between plasma albumin, cognitive function, and their synergistic effect on mortality in Chinese community-dwelling older adults. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey (2012) included 1,858 participants aged ≥65. Baseline assessments comprised albumin levels and cognitive status. All-cause mortality was confirmed through 2014-2018 surveys. Cox proportional hazards models assessed associations, and restricted cubic splines explored albumin-mortality relationship. Results: During a median follow-up of 48.85 months, 921 deaths. Albumin≥35 g/L vs < 35g/L [HR: 1.33 (95%CI, 1.10, 1.62)] and CI vs normal cognition [HR: 1.69 (95%CI, 1.43, 1.99)] independently predicted mortality. A dose-response relationship with mortality was observed for albumin quartiles (p < 0.001). Each SD increase in MMSE or albumin correlated with 22% and 15% lower mortality risk, respectively. Combined hypoproteinemia and CI increased the mortality risk by 155%, with a notably higher risk in males, those aged <85 years, and individuals living in rural areas. Interaction effects of albumin and CI on mortality were observed (p < 0.001). In the single CI group, older adults had a 61% increased risk of mortality in the hypoproteinaemia group compared with the albumin-normal group. Restricted cubic spline revealed a reverse J-shaped association, particularly for participants without CI. For individuals with CI, albumin levels were inversely associated with mortality risk. Conclusion: Hypoproteinemia and CI, individually and combined, increased all-cause mortality risk in Chinese older adults, with stronger effects observed in males, younger older adults, and those living in rural areas. These findings emphasize the importance of targeted adjustments and early nutrition programs in health prevention and clinical care for older adults.

Exosomal miR-15a-5p from cardiomyocytes promotes myocardial fibrosis.

The emergence of myofibroblasts is a key step in myocardial fibrosis, but the trigger for the transformation of cardiac fibroblasts into myofibroblasts remains not entirely clear. Exosomes play a key role between cardiomyocytes and cardiac fibroblasts. Here, we not only investigated the relationship between exosomes derived from angiotensin (Ang)-II-treated cardiomyocytes and cardiac fibroblasts, the underlying mechanisms were also explored. Ang-II-treated C57 male mice and mouse cardiac fibroblasts were employed for in vivo and in vitro experiments, respectively. Transmission electron microscopy nanoparticle tracking analysis, and western blot of CD9, CD63, CD81 were performed to identify exosomes; QRT-PCR was performed to detect miR-15a-5p expression; luciferase reporter assay was employed to determine the interaction between miR-15a-5p and dyrk2; western blot was performed to examine the protein levels of fibrosis markers; Counting Kit-8 was performed to determine cell viability; HE and Masson staining were performed to assess the pathological changes of myocardial tissues. MiR-15a-5p expression was found up-regulated in serum of myocardial fibrosis patients, serum and myocardial tissues of Ang-II-treated mice, and Ang-II-treated cardiomyocytes. Mechanically, exosomes from Ang-II-treated cardiomyocytes shuttled miR-15a-5p to cardiac fibroblasts, where miR-15a-5p dephosphorylated NFAT by targeting dyrk2 to promote cell viability and elevated the protein levels of α-smooth muscle actin, collagen type 1 α1 and collagen type 3 α1, thus promoting myocardial fibrosis. This study identified a novel molecular target for anti-fibrotic therapeutic interventions.

Tuberostemonine may alleviates proliferation of lung fibroblasts caused by pulmonary fibrosis.

OBJECTIVES: Tuberostemonine has several biological activity, the aim of study examined the impact of tuberostemonine on the proliferation of TGF-ß1 induced cell model, and its ability to alleviate pulmonary fibrosis stimulated by bleomycin in mice. METHODS: In vitro, we assessed the effect of tuberostemonine (350, 550 and 750 µM) on the proliferation of cells stimulated by TGF-ß1 (10 µg/L), as well as on parameters such as α-SMA vitality, human fibronectin, collagen, and hydroxyproline levels in cells. In vivo, we analyzed inflammation, hydroxyproline, collagen activity and metabolomics in the lungs of mice. Additionally, a comprehensive investigation into the TGF-ß/smad signaling pathway was undertaken, targeting lung tissue as well as HFL cells. RESULTS: Within the confines of an in vitro setup, the tuberostemonine manifested a discerned IC50 of 1.9 mM. Furthermore, a significant reduction of over fifty percent was ascertained in the secretion levels of hydroxyproline, fibronectin, collagen type I, collagen type III and α-SMA. In vivo, tuberostemonine obviously improved the respiratory function percentage over 50% of animal model and decreased the hydroxyproline, lung inflammation and collagen deposition. A prominent decline in TGF-ß/smad pathway functioning was identified within both the internal and external cellular contexts. CONCLUSIONS: Tuberostemonine is considered as a modulator to alleviate fibrosis and may become a new renovation for pulmonary fibrosis.

Development and validation of a nomogram based on Lasso-Logistic regression for predicting splenomegaly secondary to acute pancreatitis.

PURPOSE: Investigate the clinical characteristics of splenomegaly secondary to acute pancreatitis (SSAP) and construct a nomogram prediction model based on Lasso-Logistic regression. METHODS: A retrospective case-control study was conducted to analyze the laboratory parameters and computed tomography (CT) imaging of acute pancreatitis (AP) patients recruited at Xuanwu Hospital from December 2014 to December 2021. Lasso regression was used to identify risk factors, and a novel nomogram was developed. The performance of the nomogram in discrimination, calibration, and clinical usefulness was evaluated through internal validation. RESULTS: The prevalence of SSAP was 9.2% (88/950), with the first detection occurring 65(30, 125) days after AP onset. Compared with the control group, the SSAP group exhibited a higher frequency of persistent respiratory failure, persistent renal failure, infected pancreatic necrosis, and severe AP, along with an increased need for surgery and longer hospital stay (P < 0.05 for all). There were 185 and 79 patients in the training and internal validation cohorts, respectively. Variables screened by Lasso regression, including platelet count, white blood cell (WBC) count, local complications, and modified CT severity index (mCTSI), were incorporated into the Logistic model. Multivariate analysis showed that WBC count ≦9.71 × 109/L, platelet count ≦140 × 109/L, mCTSI ≧8, and the presence of local complications were independently associated with the occurrence of SSAP. The area under the receiver operating characteristic curve was 0.790. The Hosmer-Lemeshow test showed that the model had good fitness (P = 0.954). Additionally, the nomogram performed well in the internal validation cohorts. CONCLUSIONS: SSAP is relatively common, and patients with this condition often have a worse clinical prognosis. Patients with low WBC and platelet counts, high mCTSI, and local complications in the early stages of the illness are at a higher risk for SSAP. A simple nomogram tool can be helpful for early prediction of SSAP.

Viral myocarditis: From molecular mechanisms to therapeutic prospects.

Myocarditis is characterized as local or diffuse inflammatory lesions in the myocardium, primarily caused by viruses and other infections. It is a common cause of sudden cardiac death and dilated cardiomyopathy. In recent years, the global prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the widespread vaccination have coincided with a notable increase in the number of reported cases of myocarditis. In light of the potential threat that myocarditis poses to global public health, numerous studies have sought to elucidate the pathogenesis of this condition. However, despite these efforts, effective treatment strategies remain elusive. To collate the current research advances in myocarditis, and thereby provide possible directions for further research, this review summarizes the mechanisms involved in viral invasion of the organism and primarily focuses on how viruses trigger excessive inflammatory responses and in result in different types of cell death. Furthermore, this article outlines existing therapeutic approaches and potential therapeutic targets for the acute phase of myocarditis. In particular, immunomodulatory treatments are emphasized and suggested as the most extensively studied and clinically promising therapeutic options.

Ensembled-SAMs for Enhanced Small Coronary Artery Segmentation in CCTA Images.

Accurate coronary artery segmentation is crucial for quantitative analysis of coronary arteries in noninvasive coronary computed tomography angiography (CCTA) images. However, current segmentation algorithms often have unsatisfactory recall due to the small size and complex morphology of coronary arteries, particularly in the distal segments. To address this issue, we introduce a new fully automated method named Ensembled-SAMs, which harnesses the strengths of the Segment Anything Model (SAM) and the no-new-U-Net (nnU-Net). First, noisy bounding box prompts are automatically generated by a vesselness algorithm that highlights the tubular structures in the CCTA images. These noisy prompts are then used to fine-tune the SAM and its two variants separately. The SAM variants introduce a classification head in their mask decoder to alleviate the false positives. In addition, an nnU-Net segmentation network is trained from scratch. Finally, the outputs of the SAMs and the nnU-Net are strategically aggregated to obtain the final segmentation result. Experiments on both a self-built dataset and the public Automated Segmentation of Coronary Arteries (ASOCA) challenge dataset demonstrate that the proposed Ensembled-SAMs outperforms the state-of-the-arts, achieving precise segmentation of coronary arteries, with particular enhancement in delineating small coronary artery segments.

Health Care Resource Use for Modern First-Line Treatments in Metastatic Renal Cell Carcinoma.

Importance: Immuno-oncology agents have changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). Such therapies improve survival but can impose considerable health care resource use (HCRU) and associated costs, necessitating their examination. Objective: To compare HCRU, costs, and clinical outcomes among patients receiving first-line pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N). Design, Setting, and Participants: This retrospective cohort study used data from an administrative claims database on patients with mRCC receiving first-line P+A or I+N that was initiated between January 2018 and May 2020. Data were analyzed from February 2021 to July 2022. Exposure: First-line P+A or I+N. Main Outcome and Measures: HCRU and costs during the first 90 days, full first-line treatment, and full follow-up periods were assessed. Using Kaplan-Meier analysis, time on treatment, overall survival, time to first emergency department (ED) visit, and time to first inpatient stay were compared. Results: Among 507 patients, there were 126 patients receiving P+A (91 male [72.2%]; mean [SD] age, 67.93 [9.66] y) and 381 patients receiving I+N (271 male [71.1%]; mean [SD] age, 66.52 [9.94] years). The median time on treatment was longer for the P+A compared with I+N group (12.4 months [95% CI, 8.40 months to not estimable] vs 4.1 months [95% CI, 3.07 to 5.30 months]; P < .001). The median time to first ED visit was longer for the P+A than I+N group (7.2 months [95% CI 3.9 to 11.1 months ] vs 3.3 months [95% CI, 2.6 to 3.9 months]; P = .005), as was time to first inpatient stay (9.0 months [95% CI 6.5 months to not estimable] vs 5.6 months [95% CI, 3.9 to 7.9 months]; P = .02). During the first 90 days, a lower proportion of the P+A than N+I group had ED visits (43 patients [34.1%] vs 182 patients [47.8%] and inpatient stays (24 patients [19.1%) vs144 patients [37.8%]; P < .001). During full follow-up, mean total adjusted costs were similar for P+A and I+N groups, but adjusted 12-month estimated total costs were higher for P+A than I+N groups ($325 574 vs $ 263 803; P = .03). Conclusions and Relevance: In this study, treatment with P+A was associated with longer time on treatment, time to first ED visit, and inpatient stay, while 12-month estimated costs were higher for the P+A group. This is among the first clinical studies to evaluate economic burden associated with modern treatments for mRCC.

Structural engineering evoked multifunctionality in molybdate nanosheets for industrial oxygen evolution and dual energy storage devices inspired by multi-method calculations.

Structural engineering, including electronic and geometric modulations, is a good approach to improve the activity of electrocatalysts. Herein, we employed FeOOH and the second metal center Ni to modulate the electronic structure of CoMoO4 and used a low temperature solvothermal route and a chemical etching method to prepare the special hollow hierarchical structure. Based on the prediction of multi-method calculations by density functional theory (DFT) and ab initial molecular dynamics (AIMD), a series of materials were fabricated. Among them, the optimal hollow FeOOH/(Ni1Co1)MoO4 by coating (NiCo)MoO4 nanosheets on FeOOH nanotubes showed excellent performances toward high current density oxygen evolution reaction (OER) in alkaline and simulated seawater solutions, hybrid supercapacitor (HSC), and aqueous battery due to the well-controlled electronic and geometric structures. The optimal FeOOH/(Ni1Co1)MoO4 required overpotentials of 225 and 546 mV to deliver 10 and 1000 mA cm-2 current densities toward alkaline OER, and maintained a good stability for 100 h at 200 mA cm-2 with negligible attenuation. The FeOOH/(Ni1Co1)MoO4//Pt/C electrolyzer exhibited a low cell voltage of 1.52 and 1.79 V to drive 10 and 200 mA cm-2 and retained a long-term durability nearly 100 h at 1.79 V. As the electrode of energy storage devices, it possessed a specific capacity of 342 mA h g-1 at 1 A g-1. HSC and SC-type battery devices were fabricated. The assembled HSC kept a capacitance retention of 94 % after 10,000 cycles. This work provided a way to fabricate effective and stable multifunctional materials for energy storage and conversion with the aid of multi-method calculations.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 × 10 - 31 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 × 10 - 24 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 × 10 - 5 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 × 10 - 13 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 × 10 - 5 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

Plasticity in single-crystalline Mg3Bi2 thermoelectric material.

Most of the state-of-the-art thermoelectric materials are inorganic semiconductors. Owing to the directional covalent bonding, they usually show limited plasticity at room temperature1,2, for example, with a tensile strain of less than five per cent. Here we discover that single-crystalline Mg3Bi2 shows a room-temperature tensile strain of up to 100 per cent when the tension is applied along the (0001) plane (that is, the ab plane). Such a value is at least one order of magnitude higher than that of traditional thermoelectric materials and outperforms many metals that crystallize in a similar structure. Experimentally, slip bands and dislocations are identified in the deformed Mg3Bi2, indicating the gliding of dislocations as the microscopic mechanism of plastic deformation. Analysis of chemical bonding reveals multiple planes with low slipping barrier energy, suggesting the existence of several slip systems in Mg3Bi2. In addition, continuous dynamic bonding during the slipping process prevents the cleavage of the atomic plane, thus sustaining a large plastic deformation. Importantly, the tellurium-doped single-crystalline Mg3Bi2 shows a power factor of about 55 microwatts per centimetre per kelvin squared and a figure of merit of about 0.65 at room temperature along the ab plane, which outperforms the existing ductile thermoelectric materials3,4.

Efficacy of the tetravalent protein COVID-19 vaccine, SCTV01E: a phase 3 double-blind, randomized, placebo-controlled trial.

Evolution of SARS-CoV-2 variants emphasizes the need for multivalent vaccines capable of simultaneously targeting multiple strains. SCTV01E is a tetravalent COVID-19 vaccine derived from the spike protein of SARS-CoV-2 variants Alpha, Beta, Delta, and Omicron BA.1. In this double-blinded placebo-controlled pivotal efficacy trial (NCT05308576), the primary endpoint was vaccine efficacy (VE) against COVID-19 seven days post-vaccination in individuals without recent infection. Other endpoints included evaluating safety, immunogenicity, and the VE against all SARS-CoV-2 infections in individuals meeting the study criteria. Between December 26, 2022, and January 15, 2023, 9,223 individuals were randomized at a 1:1 ratio to receive SCTV01E or a placebo. SCTV01E showed a VE of 69.4% (95% CI: 50.6, 81.0) 7 days post-vaccination, with 75 cases in the placebo group and 23 in the SCTV01E group for the primary endpoint. VEs were 79.7% (95% CI: 51.0, 91.6) and 82.4% (95% CI: 57.9, 92.6), respectively, for preventing symptomatic infection and all SARS-CoV-2 infections 14 days post-vaccination. SCTV01E elicited a 25.0-fold higher neutralizing antibody response against Omicron BA.5 28 days post-vaccination compared to placebo. Reactogenicity was generally mild and transient, with no reported vaccine-related SAE, adverse events of special interest (AESI), or deaths. The trial aligned with the shift from dominant variants BA.5 and BF.7 to XBB, suggesting SCTV01E as a potential vaccine alternative effective against present and future variants.

Association between life's essential 8 and metabolic dysfunction-associated steatotic liver disease among US adults.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease(MASLD) is the most common cause of chronic liver disease. Clinical evidences have demonstrated the link between MASLD and the increased risk of cardiovascular disease (CVD) development. We aimed to investigate the relationship between Life's Essential 8 (LE8), an enhanced approach to assessing cardiovascular health(CVH), and MASLD. METHODS: Data were extracted from the National Health and Nutrition Examination Survey (NHANES) in 2017-2020 cycles. MASLD was assessed by the latest diagnostic criteria. LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health factor and health behavior scores. Multivariable logistic and restricted cubic spline models were used to assess the associations. RESULTS: 5646 participants were included based on the inclusion and exclusion criteria, 2616 (46.33%) participants were diagnosed with MASLD. After adjusting for confounding variables, higher LE8 scores were associated with a lower risk of MASLD (OR = 0.19, 95%CI 0.17-0.21; P < 0.001), similar associations were also observed between health behavior and health factor scores with MASLD. Subgroup analyses illustrated that the negative association between LE8 score and MASLD was stronger among younger, non - Hispanic White, and never married participants. CONCLUSIONS: In this nationally representative sample of U.S. adults, LE8 scores, health behavior scores, and health factor scores were negatively associated with the prevalence of MASLD in non-linear fashions. Subjects maintaining ideal health factors and health behaviors are less likely to develop MASLD. Public health policies are needed to advocate healthy behaviors and factors.

Dectin-1 induces TRPV1 sensitization and contributes to visceral hypersensitivity of irritable bowel syndrome in male mice.

BACKGROUND: Visceral hypersensitivity is considered the core pathophysiological mechanism that causes abdominal pain in patients with irritable bowel syndrome (IBS). Fungal dysbiosis has been proved to contribute to visceral hypersensitivity in IBS patients. However, the underlying mechanisms for Dectin-1, a major fungal recognition receptor, in visceral hypersensitivity are poorly understood. This study aimed to explore the role of Dectin-1 in visceral hypersensitivity and elucidate the impact of Dectin-1 activity on the function of transient receptor potential vanilloid type 1 (TRPV1). METHODS: Visceral hypersensitivity model was established by the intracolonic administration of 0.1 mL TNBS (130 µg/mL in 30% ethanol) in the male mice. Fluconazole and nystatin were used as fungicides. Laminarin, a Dectin-1 antagonist and gene knockout (Clec7a-/-) mice were used to interrupt the function of Dectin-1. Colorectal distension-electromyogram recording was performed to assess visceral sensitivity. Immunostaining experiment was performed to determine the localization of Dectin-1 in dorsal root ganglion (DRG) neurons. Calcium imaging study was performed to assay TRPV1-mediated calcium influx in acutely dissociated DRG neurons. RESULTS: Pretreatment with fungicides, administration of laminarin or genetic deletion of Clec7a alleviated TNBS-induced visceral hypersensitivity in male mice. The expression of Dectin-1 was upregulated in the DRG and colon of TNBS-treated mice. Colocalization of Dectin-1 and TRPV1 was observed in DRG neurons. Importantly, pretreatment with curdlan, a Dectin-1 agonist, increased TRPV1-mediated calcium influx. CONCLUSIONS: Dectin-1 contributes to visceral hypersensitivity in IBS or in inflammatory bowel disease in remission and activation of Dectin-1 induces TRPV1 sensitization. SIGNIFICANCE STATEMENT: This work provides direct evidence for the functional regulation of TRPV1 channel by Dectin-1 activity, proposing a new mechanism underlying TRPV1 sensitization. Control of intestinal fungi might be beneficial for the treatment of refractory abdominal pain in patients with IBS or IBD in remission.

Enhanced Thermoelectric Performance in Flexible Sulfur-Alloyed Ag2Se Thin Films.

Flexible thermoelectric generators can directly convert thermal energy harvested from the human body into electricity. The Ag2Se flexible film, a promising material for wearable thermoelectric generators, normally demonstrates an inferior electrical transport property due to its weakened in-plane mobility. In this study, the in-plane electrical transport properties of flexible Ag2Se films were optimized by alloying with additional sulfur. This optimization is achieved by leveraging the differences in elemental electronegativity and the preferred orientation of the Ag2Se films. The sulfur-alloyed Ag2Se thin film, with a nominal ratio of 3 atom %, can reach a maximum mobility of 1150 cm-2 V-1 s-1 at 300 K. So, the optimized room-temperature power factor increases to 1935 µW m-1 K-2. Furthermore, the Ag2Se film alloyed with 3 atom % sulfur exhibits excellent flexibility even after 1000 bending cycles with a radius of 5 mm, characterized by a relative resistance increment of less than 3%. In addition, the corresponding π-type flexible thermoelectric generator possesses a maximum power density of 51 W m-2 at a temperature difference of 50 K.

Generation and Characterization of a Novel Knockin Mouse Model Expressing PSEN1 D385A: Implications for Investigating Herbal Drug Effects in γ-Secretase Activity.

Background: Presenilin (PSEN, PS) is essential for γ-secretase function, and mutations can disrupt amyloid-ß (Aß) production in familial Alzheimer's disease. Targeting γ-secretase is complex due to its broad involvement in physiological processes. Objective: Our aim was to create a novel knockin (KI) mouse model expressing PSEN1 D385A mutation and investigate the efficacy of a Geniposide and Ginsenoside Rg1 combination (NeuroProtect modified formula, NP-2) in restoring γ-secretase activity. Methods: Using gene manipulation, we established the PS1 D385A KI mouse model and confirmed the mutation, mRNA, and protein levels using Southern blotting, northern blotting, and western blotting, respectively. In vitro γ-secretase assay was conducted to measure γ-secretase activity, while histological analyses examined neurogenesis effects. NP-2 administration evaluated its impact on γ-secretase activity. Results: The PS1 D385A KI homozygotes displayed severe cerebral hemorrhage, postnatal lethality, developmental disorders, reduced proliferation of neural progenitor cells, and disrupted γ-secretase function. The mutation abolished PS1 protein self-shearing, leading to compromised γ-secretase activity. NP-2 intervention effectively restored γ-secretase activity in the heterozygous mice. Conclusions: PS1 D385A mutant disrupted PS1 protein self-cleaving, impairing γ-secretase activity in KI mice. NP-2 restored γ-secretase function, offering potential for novel AD treatment strategies despite the challenges posed by γ-secretase's complex role in physiological processes.

Ischemic cardio-cerebrovascular disease and all-cause mortality in Chinese elderly patients: a propensity-score matching study.

BACKGROUND: Ischemic cardio-cerebrovascular disease is the leading cause of mortality worldwide. However, studies focusing on elderly and very elderly patients are scarce. Hence, our study aimed to characterize and investigate the long-term prognostic implications of ischemic cardio-cerebrovascular diseases in elderly Chinese patients. METHODS: This retrospective cohort study included 1026 patients aged ≥ 65 years who were categorized into the mono ischemic cardio-cerebrovascular disease (MICCD) (either coronary artery disease or ischemic stroke/transient ischemic attack) (n = 912) and the comorbidity of ischemic cardio-cerebrovascular disease (CICCD) (diagnosed with both coronary artery disease and ischemic stroke/transient ischemic attack at admission) (n = 114). The primary outcome was all-cause death. The mortality risk was evaluated using the Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score-based approaches. RESULTS: Of the 2494 consecutive elderly patients admitted to the hospital, 1026 (median age 83 years [interquartile range]: 76.5-86.4; 94.4% men) met the inclusion criteria. Patients with CICCD consisted mostly of very elderly (79.2% vs. 66.1%, P < 0.001) individuals with a higher burden of comorbidities. Over a median follow-up of 10.4 years, 398 (38.8%) all-cause deaths were identified. Compared with the MICCD group, the CICCD group exhibited a higher adjusted hazard ratio (HR) (95% confidential interval, CI) of 1.71 (1.32-2.39) for long-term mortality after adjusting for potential confounders. The sensitivity analysis results remained robust. After inverse probability of treatment weighting (IPTW) modeling, the CICCD group displayed an even worse mortality risk (IPTW-adjusted HR: 2.07; 95% CI 1.47-2.90). In addition, anemia (adjusted HR: 1.48; 95% CI 1.16-1.89) and malnutrition (adjusted HR: 1.43; 95% CI 1.15-1.78) are also independent risk factors for all-cause mortality among elderly and very elderly patients. CONCLUSIONS: Our results thus suggest that elderly patients with ischemic cardio-cerebrovascular disease and anemia or malnutrition may have higher mortality, which may be predicted upon admission. These findings, however, warrant further investigation.