Association of gastrointestinal symptoms with mortality in patients with severe fever with thrombocytopenia syndrome.

Background: The clinical significance of gastrointestinal (GI) symptoms in patients with severe fever and thrombocytopenia syndrome (SFTS) is poorly characterized. This study aimed to determine the prevalence and effect of GI symptoms on the prognosis of patients with SFTS. Methods: This was a retrospective multi-center cohort study that included hospitalized patients with SFTS from three institutions between October 2010 and August 2022. The risk factors for mortality and intensive care unit (ICU) admission were identified by Cox and logistic regression analyses, respectively. Kaplan-Meier curves were used to analyze the cumulative mortality risk. Results: Among 304 patients, the median age was 62.0 years and 51.0 % of the patients were male. A total of 202 patients (66.4 %) had at least one GI symptom on admission. Diarrhea (69.8 %) and nausea (57.4 %) were the most common symptoms. Patients with GI symptoms had lower male proportion (46.0 % vs. 60.8 %, P = 0.015), higher aspartate aminotransferase (177.5 U/L vs. 118.0 U/L, P = 0.010) and lactic dehydrogenase (771.0 U/L vs. 666.5 U/L, P = 0.017) levels than that of patients without GI symptoms. However, there was no significant difference in mortality rates (23.8 % vs. 21.6 %, P = 0.668) and ICU admission (14.4 % vs. 12.7 %, P = 0.701) between SFTS patients with and without GI symptoms. Multivariate analysis suggested that GI symptoms at admission were not associated with mortality and ICU admission. Conclusions: GI symptoms are common in patients with SFTS. However, the presence of GI symptoms was not an independent risk factor for poor prognosis.

Correlative analysis of transcriptome and 16S rDNA in Procambarus clarkii reveals key signaling pathways are involved in Chlorantraniliprole stress response by phosphoinositide 3-kinase (PI3K).

Chlorantraniliprole (CAP), a diamide insecticide, is extensively used in agricultural production. With the increasing adoption of the rice-crayfish integrated farming model, pesticide application has become more frequent. However, the potential risk of CAP to crayfish (Procambarus clarkii) remains unclear. In this study, crayfish were exposed to 30, 60, 90 mg/L CAP for 96 h. As CAP exposure time and concentration increased, crayfish survival rates and total hemocyte counts (THC) decreased. Biochemical indicators revealed that CAP exposure induced oxidative stress and immunosuppression in crayfish, leading to metabolic disorders and reduced ATP content. Additionally, pathological analysis and 16S rDNA sequencing demonstrated that CAP exposure compromised the intestinal barrier of crayfish, altered the intestinal microbial community structure, and caused apoptosis. Differential gene expression analysis showed that CAP exposure significantly suppressed the expression of genes related to immune and energy metabolism pathways, resulting in immune dysfunction and insufficient energy supply, while activating the PI3K/AKT/mTOR signaling pathway. PI3K knockdown reduced antioxidant and digestive activities, increased the expression of proinflammatory and apoptosis genes, and exacerbated CAP-induced intestinal toxicity. This study is the first to explore the characterization and function of PI3K in crustaceans, providing new insights for further research on crustacean antioxidants and defense mechanisms.

Association between the proportion of HDL-Cholesterol subclasses and the severity of coronary artery stenosis in patients with Acute Myocardial Infarction.

BACKGROUND: Past research has shown an inverse correlation between high-density lipoprotein (HDL) and coronary heart disease (CHD), while recent studies have shown that extremely high or low HDL levels increase the risk of cardiovascular death. OBJECTIVE: To explore the relationships between HDL subtypes and the degree of coronary artery stenosis in patients with acute myocardial infarction (AMI). METHODS: This was a single-center cross-sectional study. Ultimately, we included 1,200 adult participants with AMI hospitalized from 2017 to 2023. Patients were classified into mild and moderate-severe groups according to their Gensini score. Restricted cubic spline and multivariate logistic regression models were used to explore the associations between HDL subclasses and the severity of coronary stenosis. RESULTS: The adjusted odds ratios (ORs), 95 % confidence intervals (CIs), and p values for HDL subclasses in the multivariate logistic model (adjusted for age, gender, hypertension status, diabetes status, stroke status, and kidney disease status) were as follows: HDL-2b: 0.97 (0.95-1.00, p= 0.018) and HDL-3: 0.98 (0.97-0.99, p= 0.008). Subgroup analysis revealed that HDL-3 exhibited a statistically significant impact on the severity of coronary stenosis among individuals aged <75 years of age and among men, and the influence of HDL-2b on the severity of coronary stenosis was statistically significant only in individuals aged ≥75 years. CONCLUSION: The relationship between reduced levels of HDL-2b and HDL-3 and the risk of coronary stenosis exhibited a linear pattern and was significantly modified by age. Subgroup analysis identified specific populations that warrant attention regarding HDL-2b and HDL-3.

Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial.

Importance: Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited. Objective: To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset. Design, Setting, and Participants: The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement. Interventions: Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures: The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality. Results: Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]). Conclusions and Relevance: In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04915729.

A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles.

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

The Value of Adjunctive Left Atrial Posterior Wall Isolation on Clinical Outcomes in Atrial Fibrillation Patients: A Systematic Review and Meta-Analysis.

Background: Although pulmonary vein isolation (PVI) remains the mainstream way of atrial fibrillation (AF) ablation. The left atrial posterior wall (LAPW) may contributes to the development of AF as an arrhythmogenic substrate. The efficacy of additional left atrial posterior wall isolation (LAPWI) beyond PVI is in AF patients remains undefined. This study explored the influence of posterior wall isolation (PWI) on clinical outcomes in AF patients. Methods: PubMed, EMBASE, and Cochrane Library databases were searched for studies comparing the outcomes of AF with and without PWI. The efficacy outcomes were recurrence of all atrial arrhythmia (AA), atrial fibrillation (AF), and atrial flutter (AFL)/atrial tachycardia (AT). The safety outcomes were mainly focused on procedural adverse events. Results: A total of 16 studies (7 randomized controlled trials (RCTs), 3 prospective studies and 6 retrospective analyses) with 3340 AF patients were enrolled (1550 patients in PVI with PWI group and 1790 in PVI alone group). 12 studies included persistent atrial fibrillation patients, 3 studies with paroxysmal AF patients and 1 study with paroxysmal AF and persistent AF concurrently. Mean follow-up period was 16.56 months. In AF patients, adjunctive PWI obviously reduced the recurrence of all atrial arrhythmias (risk ratio (RR) 0.78 [95% CI 0.64-0.95], I 2 = 79%, p = 0.01) and the recurrence of AF (RR 0.68 [95% CI 0.53-0.88], I 2 = 75%, p = 0.004); Meanwhile, additional PWI left no impact substantially on lower recurrence of AFL/AT (RR 1.23 [95% CI 0.94-1.60], I 2 = 49%, p = 0.12). The results seemed to be no significant differences in occurrence rate of procedural complications between the PVI only and PWI+PVI (RR 1.19 [95% CI 0.80-1.79], I 2 = 0%, p = 0.39). In subgroup analyses, the benefit of adjunctive PWI compared with PVI only was more distinct in persistent AF group and cryoballoon ablation group. Notably, adjunctive PWI with radiofrequency ablation may induce a slight increase of recurrent AFL/AT compared with PVI only (RR 1.56 [95% CI 1.02-2.39], I 2 = 30%, p = 0.04). Conclusions: Compared with PVI alone, additional PWI to PVI appeared to be associated with decreased recurrence of AF and atrial arrhythmias without an increased occurrence of procedural complications, especially in persistent AF patients. Cryoballoon ablation seemed more suitable for PWI compared with radiofrequency ablation. More RCTs are needed to verify the conclusion.

Precranial artery calcification burden: a potential indicator of the clinical outcome of reperfusion in patients with acute large artery occlusion.

OBJECTIVE: With mechanical thrombectomy (MT), we investigated the prognostic importance of aortic arch calcification (AoAC) and carotid sinus calcification (CaSC) for symptomatic intracerebral hemorrhage (sICH) and poor outcome in acute large artery occlusion (LAO). METHODS: In this retrospective observational study, we calculated pre-cranial artery calcification burden (PACB) scores (burden score of AoAC and CaSC) using the AoAC grading scale score plus Woodcock visual score. The outcome measure was sICH per the European Cooperative Acute Stroke Study III definition. A 3-month modified Rankin scale score 3-6 was designated as poor outcome. RESULTS: Compared with patients who had PACB <3, those with PACB ≥3 showed substantially higher risks of sICH (odds ratio [OR] = 2.567, 95% confidence interval [CI] = 1.187-5.550) and poor outcome (OR = 4.777, 95% CI = 1.659-13.756). According to receiver operating characteristic (ROC) curves, adding PACB to the regression model enhanced the predictive value for poor outcome (area under the ROC curve [AUC]: 0.718 vs. 0.519, Z = 2.340) and in patients receiving MT (AUC: 0.714 vs. 0.584, Z = 2.021), independently. CONCLUSIONS: Factors related to PACB were consistent with common risk factors of systemic atherosclerosis. Low PACB scores indicated better prognosis. In patients with LAO following MT, PACB was useful in predicting sICH and poor clinical outcome.

Association between Peripheral Arterial Lactate Levels and Malignant Brain Edema Following Endovascular Treatment for Ischemic Stroke.

AIMS: To investigate the factors of postoperative malignant brain edema (MBE) in patients with acute ischemic stroke (AIS) treated with endovascular treatment (EVT). BACKGROUND: MBE is a severe complication following EVT for AIS, and it is essential to identify risk factors early. Peripheral arterial lactate (PAL) levels may serve as a potential predictive marker for MBE. OBJECTIVE: To determine whether immediate postoperative PAL levels and the highest PAL level within 24 hours of EVT are independently associated with MBE development in AIS patients. METHODS: We retrospectively analyzed patients with AIS who underwent EVT from October 2019 to October 2022. Arterial blood was collected every 8 h after EVT to measure PAL, and record the immediate postoperative PAL and the highest PAL level within 24 h. Brain edema was evaluated using brain computed tomography scans within 7 days of EVT. RESULTS: The study included 227 patients with a median age of 71 years, of whom 59.5% were male and MBE developed in 25.6% of patients (58/227). Multivariate logistic regression analysis showed that the immediate postoperative PAL (odds ratio, 1.809 [95% confidence interval (CI), 1.215-2.693]; p = 0.004) and the highest PAL level within 24 h of EVT (odds ratio, 2.259 [95% CI, 1.407-3.629]; p = 0.001) were independently associated with MBE. The area under the curve for predicting MBE based on the highest PAL level within 24 hours of EVT was 0.780 (95% CI, 0.711-0.849). CONCLUSION: Early increase in PAL levels is an independent predictor of MBE after EVT in AIS patients.

An updated meta-analysis of optimal medical therapy with or without invasive therapy in patients with stable coronary artery disease.

BACKGROUND: The efficacy of optimal medical therapy (OMT) with or without revascularization therapy in patients with stable coronary artery disease (SCAD) remains controversial. We performed a meta-analysis of randomized controlled trials (RCTs) that compared OMT with or without revascularization therapy for SCAD patients. METHODS: Studies were searched in PubMed, EMBASE, and the Cochrane Central Register of Clinical Trials from January 1, 2005, to December 30, 2023. The main efficacy outcome was a composite of all-cause death, myocadiac infarction, revascularization, and cerebrovascular accident. Results were pooled using random effects model and fixed effects model and are presented as odd ratios (ORs) with 95% confidence intervals (CI). RESULTS: Ten studies involving 12,790 participants were included. The arm of OMT with revascularization compared with OMT alone was associated with decreased risks for MACCE (OR 0.55 [95% CI 0.38-0.80], I²=93%, P = 0.002), CV death (OR 0.84 [95% CI 0.73-0.97], I²=36%, P = 0.02), revascularization (OR 0.32 [95% CI 0.20-0.50], I²=92%, P < 0.001), and MI (OR 0.85 [95% CI 0.76-0.96], I²=45%, P = 0.007). While there was no significant difference between OMT with revascularization and OMT alone in the odds of all-cause death (OR 0.94 [95% CI 0.84-1.05], I²=0%, P = 0.30). CONCLUSIONS: The current updated meta-analysis of 10 RCTs shows that in patients with SCAD, OMT with revascularization would reduce the risk for MACCE, cardiovascular death, and MI. However, the invasive strategy does not decrease the risks for all-cause mortality when comparing with OMT alone.

Red Blood Cell Distribution Width Predicts Mortality in Hospitalized Patients with Severe Fever with Thrombocytopenia Syndrome.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease with high mortality rate. This study aimed to investigate the association of red blood cell distribution width (RDW) and mortality risk in hospitalized SFTS patients. Methods: Clinical data of SFTS patients was retrospectively collected from three hospitals between October 2010 and August 2022. Cox proportional hazards model was used to identity the risk factors for fatal outcome. The predictive value of RDW for fatal outcome was evaluated by the receiver operating characteristic (ROC) analysis and Kaplan-Meier methods. Results: Of 292 patients, the median age was 61.5 years. Non-survivors showed higher RDW value than survivors (13.6% vs.13.0%, P < 0.001). The mortality rate was 44.8% in patients with elevated RDW compared to 18.4% of patients with normal RDW, with a relative risk (RR) of 2.439. Elevated RDW was an independent risk factor of mortality (hazards ratio: 1.167, P = 0.019). Patients with elevated RDW had a higher cumulative mortality than patients with normal RDW. The area under the ROC curve (AUC) of RDW for the prediction of mortality was 0.690 (P < 0.001). Conclusion: Elevated RDW was associated with higher mortality risk for patients hospitalized for SFTS. RDW may be helpful for risk stratification in SFTS patients.

Sulfoxide-containing polymers conjugated prodrug micelles with enhanced anticancer activity and reduced intestinal toxicity.

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery.

Genome-wide identification and expression analysis of the SPL transcription factor family and its response to abiotic stress in Pisum sativum L.

Squamous promoter binding protein-like (SPL) genes encode plant-specific transcription factors (TFs) that play essential roles in modulating plant growth, development, and stress response. Pea (Pisum sativum L.) is a coarse grain crop of great importance in food production, biodiversity conservation and molecular genetic research, providing genetic information and nutritional resources for improving agricultural production and promoting human health. However, only limited researches on the structure and functions of SPL genes exist in pea (PsSPLs). In this study, we identified 22 PsSPLs and conducted a genome-wide analysis of their physical characteristics, chromosome distribution, gene structure, phylogenetic evolution and gene expression patterns. As a result, the PsSPLs were unevenly distributed on the seven chromosomes of pea and harbored the SBP domain, which is composed of approximately 76 amino acid residues. The phylogenetic analysis revealed that the PsSPLs clustered into eight subfamilies and showed high homology with SPL genes in soybean. Further analysis showed the presence of segmental duplications in the PsSPLs. The expression patterns of 22 PsSPLs at different tissues, developmental stages and under various stimulus conditions were evaluated by qRT-PCR method. It was found that the expression patterns of PsSPLs from the same subfamily were similar in different tissues, the transcripts of most PsSPLs reached the maximum peak value at 14 days after anthesis in the pod. Abiotic stresses can cause significantly up-regulated PsSPL19 expression with spatiotemporal specificity, in addition, four plant hormones can cause the up-regulated expression of most PsSPLs including PsSPL19 in a time-dependent manner. Therefore, PsSPL19 could be a key candidate gene for signal transduction during pea growth and development, pod formation, abiotic stress and plant hormone response. Our findings should provide insights for the elucidating of development regulation mechanism and breeding for resistance to abiotic stress pea.

Potential Moderators of the Effects of Blood Flow Restriction Training on Muscle Strength and Hypertrophy: A Meta-analysis Based on a Comparison with High-Load Resistance Training.

BACKGROUND: While it has been examined whether there are similar magnitudes of muscle strength and hypertrophy adaptations between low-load resistance training combined with blood-flow restriction training (BFR-RT) and high-load resistance training (HL-RT), some important potential moderators (e.g., age, sex, upper and lower limbs, frequency and duration etc.) have yet to be analyzed further. Furthermore, training status, specificity of muscle strength tests (dynamic versus isometric or isokinetic) and specificity of muscle mass assessments (locations of muscle hypertrophy assessments) seem to exhibit different effects on the results of the analysis. The role of these influencing factors, therefore, remains to be elucidated. OBJECTIVES: The aim of this meta-analysis was to compare the effects of BFR- versus HL-RT on muscle adaptations, when considering the influence of population characteristics (training status, sex and age), protocol characteristics (upper or lower limbs, duration and frequency) and test specificity. METHODS: Studies were identified through database searches based on the following inclusion criteria: (1) pre- and post-training assessment of muscular strength; (2) pre- and post-training assessment of muscular hypertrophy; (3) comparison of BFR-RT vs. HL-RT; (4) score ≥ 4 on PEDro scale; (5) means and standard deviations (or standard errors) are reported or allow estimation from graphs. In cases where the fifth criterion was not met, the data were requested directly from the authors. RESULTS: The main finding of the present study was that training status was an important influencing factor in the effects of BFR-RT. The trained individuals may gain greater muscle strength and hypertrophy with BFR-RT as compared to HL-RT. However, the results showed that the untrained individuals experienced similar muscle mass gains and superior muscle strength gains in with HL-RT compared to BFR-RT. CONCLUSION: Compared to HL-RT, training status is an important factor influencing the effects of the BFR-RT, in which trained can obtain greater muscle strength and hypertrophy gains in BFR-RT, while untrained individuals can obtain greater strength gains and similar hypertrophy in HL-RT.

Atmosphere teleconnections from abatement of China aerosol emissions exacerbate Northeast Pacific warm blob events.

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

miR-199a-5p modulates choroidal neovascularization by regulating Wnt7b/Wnt/ß-catenin signaling pathway.

Choroidal neovascularization (CNV) can be seen in many fundus diseases, and lead to fundus exudation, bleeding, or vision loss. miRNAs are vital regulator in CNV. miR-199a-5p has been proved to be involved in regulating vascular formation of endothelial cells, but its role in CNV remains unclear. This study aims to study the role of miR-199a-5p in CNV. Laser irradiation was used to induce CNV model. The lesion area of CNV was calculated by high-resolution angiography with fluorescein isothiocyanate-dextran. Wnt family member 7b (Wnt7b), ß-catenin, and Wnt pathway proteins was measured by western blot. Immunofluorescence was performed to test Wnt7b, ß-catenin, CD31, and p-p65. miR-199a-5p and Wnt7b mRNA were tested by reverse transcription real-time polymerase chain reaction. Cell count kit-8, wound healing, Transwell, tube formation, and flow cytometry were used to detect the function of miR-199a-5p and Wnt7b on human retinal microvascular endothelial cells (HRMEC). TargetScan database and dual-luciferase reporter assay verified the interaction between miR-199a-5p and Wnt7b. The results revealed that Wnt7b increased in CNV rats. Knocking down Wnt7b repressed cell proliferation, migration, invasion, and angiogenesis, and accelerated cell apoptosis of HRMEC. Dual-luciferase reporter assay verified that miR-199a-5p targeted Wnt7b. Overexpression of miR-199a-5p inhibited the angiogenesis of HRMEC and promoted cell apoptosis by inhibiting Wbt7b. In vivo experiment found that Wnt7b rescued the promotion of miR-199a-5p inhibition on CNV lesion of rats. In addition, Wnt7b positively regulated Wnt/ß-catenin signaling pathway and promoted the angiogenesis of HRMEC. In conclusion, overexpression of miR-199a-5p inhibited the angiogenesis of HRMEC by regulating Wnt7b/Wnt/ß-catenin signaling pathway, which may serve as a promising therapy target of CNV.

Association of liver function and prognosis in patients with severe fever with thrombocytopenia syndrome.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an epidemic emerging infectious disease with high mortality rate. We investigated the association between liver injury and clinical outcomes in patients with SFTS. METHODS: A total of 291 hospitalized SFTS patients were retrospectively included. Cox proportional hazards model was adopted to identify risk factors of fatal outcome and Kaplan-Meier curves were used to estimate cumulative risks. RESULTS: 60.1% of patients had liver injury at admission, and the median alanine transaminase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) levels were 76.4 U/L, 152.3 U/L, 69.8 U/L and 9.9 µmol/L, respectively. Compared to survivors, non-survivors had higher levels of AST (253.0 U/L vs. 131.1 U/L, P < 0.001) and ALP (86.2 U/L vs. 67.9 U/L, P = 0.006), higher proportion of elevated ALP (20.0% vs. 4.4%, P < 0.001) and liver injury (78.5% vs. 54.9%, P = 0.001) at admission. The presence of liver injury (HR 2.049, P = 0.033) at admission was an independent risk factor of fatal outcome. CONCLUSIONS: Liver injury was a common complication and was strongly associated with poor prognosis in SFTS patients. Liver function indicators should be closely monitored for SFTS patients.

A dynamic nomogram for predict individual risk of malignant brain edema after endovascular thrombectomy in acute ischemic stroke.

The aim of this study was to develop a dynamic nomogram combining clinical and imaging data to predict malignant brain edema (MBE) after endovascular thrombectomy (EVT) in patients with large vessel occlusion stroke (LVOS). We analyzed the data of LVOS patients receiving EVT at our center from October 2018 to February 2023, and divided a 7:3 ratio into the training cohort and internal validation cohort, and we also prospectively collected patients from another stroke center for external validation. MBE was defined as a midline shift or pineal gland shift > 5 mm, as determined by computed tomography (CT) scans obtained within 7 days after EVT. A nomogram was constructed using logistic regression analysis, and its receiver operating characteristic curve (ROC) and calibration were assessed in three cohorts. A total of 432 patients were enrolled in this study, with 247 in the training cohort, 100 in the internal validation cohort, and 85 in the external validation cohort. MBE occurred in 24% (59) in the training cohort, 16% (16) in the internal validation cohort and 14% (12) in the external validation cohort. After adjusting for various confounding factors, we constructed a nomogram including the clot burden score (CBS), baseline neutrophil count, core infarct volume on CTP before EVT, collateral index, and the number of retrieval attempts. The AUCs of the training cohorts were 0.891 (95% CI 0.840-0.942), the Hosmer-Lemeshow test showed good calibration of the nomogram (P = 0.879). And our nomogram performed well in both internal and external validation data. Our nomogram demonstrates promising potential in identifying patients at elevated risk of MBE following EVT for LVOS.

The Janus face of HIF-1α in ischemic stroke and the possible associated pathways.

Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.

Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer.

Background & Aims: The programmed death-ligand 1 (PD-L1) is a major co-inhibitory checkpoint factor that controls T-cell activities in tumours. PD-L1 is expressed on immune cells and tumour cells. Whether tumour cell-expressed PD-L1 affects tumour cells in an immune cell-independent fashion remains largely elusive. In this study, we investigated the significance of tumour cell-expressed PD-L1 with a focus on downstream signals and changes in lipid metabolism. Methods: Immune-independent functions of PD-L1 in tumour growth were investigated in vitro and in immuno-deficient mice in vivo. The global influence of PD-L1 in targeted/untargeted lipidomic metabolites was studied by comprehensive mass spectrometry-based metabolomic analysis in liver cancer. Effects on lipid metabolism were confirmed by triglyceride and cholesterol assays as well as by Oil Red O staining in liver, pancreatic, breast, and oesophageal squamous cancer. Underlying mechanisms were investigated by real-time quantitative PCR, Western blot analysis, co-immunoprecipitation, pull-down assays, immunofluorescence staining, and RNA sequencing. Results: PD-L1 enhanced the accumulation of triglycerides, cholesterol, and lipid droplets in tumours. PD-L1 influenced targeted/untargeted lipidomic metabolites in hepatoma, including lipid metabolism, glucose metabolism, amino acid metabolism, nucleotide metabolism, and energy metabolism, suggesting that PD-L1 globally modulates the metabolic reprogramming of tumours. Mechanistically, PD-L1 activated epidermal growth factor receptor (EGFR) and/or integrin ß4 (ITGB4) by forming a complex of PD-L1/EGFR/ITGB4 in the cell membrane, prior to activating PI3K/mTOR/SREBP1c signalling, leading to reprogramming of lipid metabolism in tumours. Functionally, PD-L1-mediated lipid metabolism reprogramming supported the tumour growth in vitro and in vivo through EGFR and/or ITGB4 in an immune cell-independent manner. Conclusions: Our findings on lipogenesis and EGFR activation by tumour cell-expressed PD-L1 suggest that, in addition to its immunostimulatory effects, anti-PD-L1 may restrict lipid metabolism and EGFR/ITGB4 signalling in liver cancer therapy. Impact and implications: In this study, we present evidence that PD-L1 drives the reprogramming of lipid metabolism in tumours. PD-L1 forms a complex with epidermal growth factor receptor (EGFR) and ITGB4, activating the PI3K/Akt/mTOR/SREBP1c signalling pathway and thereby contributing to lipid metabolism in cancer progression. Our findings offer novel insights into the mechanisms by which PD-L1 initiates the reprogramming of lipid metabolism in tumours. From a clinical perspective, the anti-PD-L1 antibody may alleviate resistance to the anti-EGFR antibody cetuximab and inhibit the reprogramming of lipid metabolism in tumours.