Intra-articular delivery of an AAV-anti-TNF-α vector alleviates the progress of arthritis in a RA mouse model.

Rheumatoid Arthritis is a chronic, inflammatory autoimmune disease marked by joint destruction and functional impairment. Tumor Necrosis Factor (TNF) plays a critical role in RA pathogenesis. While TNF-targeting drugs are clinically effective, their need for frequent and long-term administration often results in poor patient adherence and suboptimal outcomes. This study developed a gene therapy approach using engineered adeno-associated virus (AAV) vectors to deliver an anti-TNF agent directly into the joint cavity of RA animal models. Animals receiving this therapy demonstrated sustained improvement in clinical scores, inflammatory markers, and joint tissue health. Immunofluorescence staining revealed that AAV vectors could transduce various cell types, including T cells, type A synoviocytes, and dendritic cells. Experimental results indicated that a single administration of this gene therapy provided long-term efficacy. The finding suggest that AAV-mediated anti-TNF gene therapy is highly effective in RA animal models, offering prolonged relief from clinical symptoms and reducing inflammatory damage. This innovative approach presents a promising potential for gene therapy with significant clinical prospects.

Autoimmune hypothyroidism GWAS reveals independent autoimmune and thyroid-specific contributions and an inverse relation with cancer risk.

The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p < 5x10 - 8 ), more than half of which have not previously been documented in thyroid disease. In 48 of these, a protein-coding variant is the lead SNP or is highly correlated (r 2 > 0.95) with the lead SNP at the locus, including low-frequency coding variants at LAG3 , ZAP70 , TG, TNFSF11, IRF3, S1PR4, HABP2, ZNF429 as well as established variants at ADCY7, IFIH1 and TYK2 . The variants at LAG3 (P67T), ZAP70 (T155M), and TG (Q655X) are highly enriched in Finland and functional experiments in T-cells demonstrate that the ZAP70 :T155M allele reduces T-cell activation. By employing a large-scale scan of non-thyroid autoimmunity and a published meta-analysis of TSH levels, we use a Bayesian classifier to dissect the associated loci into distinct groupings and from this estimate, a significant proportion are involved in systemic (i.e., general to multiple autoimmune conditions) autoimmunity (34%) and another subset in thyroid-specific dysfunction (17%). By comparing these association results further to other common disease endpoints, we identify a noteworthy overlap with skin cancer, with 10% of AIHT loci showing a consistent but opposite pattern of association where alleles that increase the risk of hypothyroidism have protective effects for skin cancer. The association results, including genes encoding checkpoint inhibitors and other genes affecting protein levels of PD1, bolster the causal role of natural variation in autoimmunity influencing cancer outcomes.

Novel carbazole-oxadiazole derivatives as anti-α-glucosidase and anti-α-amylase agents: Design, synthesis, molecular docking, and biological evaluation.

To find novel inhibitors of α-glucosidase and α-amylase, a series of new carbazole-oxadiazole derivatives (6a-6n) were prepared, and screened for their anti-α-glucosidase and anti-α-amylase effects. Most of the tested derivatives showed different degrees of α-glucosidase and α-amylase inhibitory activity (IC50: 21.39 ± 0.69-92.05 ± 1.54 µM, 45.53 ± 1.50-126.14 ± 6.33 µM, respectively) compared to the standard acarbose (IC50: 427.00 ± 9.56 µM, 24.68 ± 1.10 µM, respectively). Thereinto, 6c (IC50 = 21.39 ± 0.69 µM) displayed the most effective anti-α-glucosidase activity and 6e presented the best anti-α-amylase activity with an IC50 value of 45.53 ± 1.50 µM. Lineweaver-Burk plot analysis suggested that 6c and 6e behaved as mixed α-glucosidase inhibitor and mixed α-amylase inhibitor, respectively. The results of circular dichroism, atomic force microscope, and molecular docking simulation exposed interaction mechanisms between two preferred compounds (6c and 6e) and their corresponding enzymes. Combined with the possible properties of reducing the elevation in postprandial blood glucose, oral activity, positive bioavailability, and low cytotoxicity of 6c and 6e, it could be concluded that the target derivatives may be able to act as lead molecules for the development of new hypoglycemic agents.

Rational designing NiVO3@CoNi-MOF heterostructures on activated carbon cloth for high-performance asymmetric supercapacitors and oxygen evolution reaction.

Binder-free self-supported carbon cloth electrode provides novel strategies for the preparation of MOFs, effectively improving the conductivity and promoting charge transfer. Combining MOFs with vanadate to form a unique heterogeneous structure provides a large specific surface area and more active sites, further enhancing the kinetics of MOFs. Herein, a self-supported carbon cloth electrode is prepared by in-situ growth of CoNi-MOFs on activated carbon cloth (AC) and coating with NiVO3. The heterostructure increases the specific surface area and exposes more active sites to promote the adsorption and diffusion of ions, thus enhancing the kinetic activity and optimizing charge storage behavior. As expected, the NiVO3@CoNi-MOF/AC exhibits a specific capacitance of up to 19.20 F/cm2 at 1 mA/cm2. The asymmetric supercapacitors (ASCs) assembled by NiVO3@CoNi-MOF/AC and annealed activated carbon cloth achieve an energy density of 1.27 mWh/cm2 at a power density of 4 mW/cm2 and have a capacitance retention of 96.43 % after 10,000 cycles. In addition, the NiVO3@CoNi-MOF/AC as electrocatalyst has an overpotential of 370 mV at 10 mA/cm2 and a Tafel slope of 208 mV dec-1, demonstrating remarkable electrocatalytic oxygen evolution reaction performance. These unique heterostructures endow the electrode with more electrochemical selectivity and provide new key insights for designing multifunctional materials.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Time-varying impacts of green credit on carbon productivity in China: New evidence from a non-parametric panel data model.

In the context of global climate change threatening human survival, and in a post-pandemic era that advocates for a global green and low-carbon economic recovery, conducting an in-depth analysis to assess whether green finance can effectively support low-carbon economic development from a dynamic perspective is crucial. Unlike existing research, which focuses solely on the average effects of green credit (GC) on carbon productivity (CP), we introduce a non-parametric panel data model to investigate GC's impact on CP across 30 provinces in China from 2003 to 2021, verifying a significant time-varying effect. Specifically, during the first phase (2003-2008), GC negatively impacted CP. In the second phase (2009-2014), this negative influence gradually diminished and transformed into a positive effect. In the third phase (2015-2021), GC continued to positively influence CP, although this effect became insignificant during the pandemic. Further subgroup analysis reveals that in the regions with low environmental regulations, GC did not significantly boost CP throughout the sample period. In contrast, in the regions with high environmental regulations, GC's positive effect persisted in the mid to late stages of the sample period. Additionally, compared to the regions with low levels of marketization, the impact of GC on CP was more pronounced in highly marketized regions. This indicates that the promoting effect of GC on CP depends on strong support from environmental regulations and well-functioning market mechanisms. By adopting a non-parametric approach, this study reveals variations in the impact of GC on CP across different stages and under the influence of the pandemic shock, offering new insights into the relationship between GC and China's CP.

Malignant Extrarenal Rhabdoid tumor derived from the greater omentum: A case report and literature review.

BACKGROUND: Malignant extrarenal rhabdoid tumor (MERT) is a rare and highly metastatic tumor, which is more than 75% of patients dying within 6 months of initial diagnosis, and it often leads to misdiagnosis and delayed treatment. CASE: This paper reports a 16-year-old girl who presented with the chief complaint of acute abdominal pain. She underwent laparoscopic exploration and excisional biopsy, then pathological examination and immunohistochemistry revealed "extrarenal malignant rhabdomyoma." One month after operation, she died of intra-abdominal hemorrhage and multiple organ dysfunction. CONCLUSION: MERT were often misdiagnosed and had a poor prognosis. The surgery and chemotherapy are usually beneficial to prolong the survival time of patients with MERT.

An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species.

Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

Impact factors and obstetric outcomes of preeclampsia in twin pregnancies by prepregnancy body mass index: a six-year retrospective cohort study.

OBJECTIVES: Among many risk factors for preeclampsia (PE), prepregnancy body mass index (BMI) is one of few controllable factors. However, there is a lack of stratified analysis based on the prepregnancy BMI. This study aimed to determine the influencing factors for PE and assess the impact of PE on obstetric outcomes in twin pregnancies by prepregnancy BMI. METHODS: This was a retrospective cohort study between January 1, 2017, and December 31, 2022, in Southwest China. Impact factors and associations between PE and obstetric outcomes were analyzed separately for twin pregnancies with prepregnancy BMI < 24kg/m2 (non-overweight group) and BMI ≥ 24kg/m2 (overweight group). RESULTS: In total, 3602 twin pregnancies were included, of which, 672 women were allocated into the overweight group and 11.8% of them reported with PE; 2930 women were allocated into the non-overweight group, with a PE incidence of 5.6%. PE had a negative effect on birthweight and increased the incidence of neonatal intensive care unit admission in both the overweight and non-overweight groups (43.0% vs. 28.0%, p = .008; 45.7% vs. 29.1%, p < .001). Among overweight women, PE increased the proportion of postpartum hemorrhage (15.2% vs. 4.4%, p < .001). After adjustments, multivariate regression analysis showed that excessive gestational weight gain (aOR = 1.103, 95% CI: 1.056-1.152; aOR = 1.094, 95% CI: 1.064-1.126) and hypoproteinemia (aOR = 2.828, 95% CI: 1.501-5.330; aOR = 6.932, 95% CI: 4.819-9.971) were the shared risk factors for PE in both overweight and non-overweight groups. In overweight group, in vitro fertilization was the other risk factor (aOR = 2.713, 95% CI: 1.183-6.878), whereas dichorionic fertilization (aOR = 0.435, 95% CI: 0.193-0.976) and aspirin use during pregnancy (aOR = 0.456, 95% CI: 0.246-0.844) were protective factors. Additionally, anemia during pregnancy (aOR = 1.542, 95% CI: 1.090-2.180) and growth discordance in twins (aOR = 2.451, 95% CI: 1.215-4.205) were connected with an increased risk of PE only in non-overweight twin pregnancies. CONCLUSIONS: Both discrepancy and similarity of impact factors on developing PE were found between overweight and non-overweight twin pregnancies in this study. However, the dosage and initiation time of aspirin, as well as twin chorionicity on the occurrence of PE in two subgroups, are still debated.

Effects of ant nests on soil CH4 emissions from Syzygium oblatum communities of a secondary tropical forest.

Exploring the effects of ant nests on soil CH4 emissions in the secondary tropical forests is of great scientific significance to understand the contribution of soil faunal activities to greenhouse gas emissions. With static chamber-gas chromatography method, we measured the dry-wet seasonal dynamics of CH4 emissions from ant nests and control soils in the secondary forest of Syzygium oblatum communities in Xishuangbanna. We also examined the linkages of ant-mediated changes in functional microbial diversity and soil physicochemical properties with CH4 emissions. The results showed that: 1) Ant nests significantly accelerated soil CH4 emissions, with average CH4 emissions in the ant nests being 2.6-fold of that in the control soils. 2) The CH4 emissions had significant dry-wet seasonal variations, which was a carbon sink in the dry seasons (from -0.29±0.03 to -0.53±0.02 µg·m-2·h-1) and a carbon source in the wet seasons (from 0.098±0.02 to 0.041±0.009 µg·m-2·h-1). The CH4 emissions were significantly higher in ant nests than in control soils. The CH4 emissions from the ant nests had smaller dry-wet seasonal variation (from -0.38±0.01 to 0.12±0.02 µg·m-2·h-1) than those in the control soils (from -0.65±0.04 to 0.058±0.006 µg·m-2·h-1). 3) Ant nests significantly increased the values (6.2%-37.8%) of soil methanogen diversity (i.e., Ace and Shannon indices), temperature and humidity, carbon pools (i.e., total, easily oxidizable, and microbial carbon), and nitrogen pools (i.e., total, hydrolyzed, ammonium, and microbial biomass nitrogen), but decreased the diversity (i.e., Ace and Chao1 indices) of methane-oxidizing bacteria by 21.9%-23.8%. 4) Results of the structural equation modeling showed that CH4 emissions were promoted by soil methanogen diversity, temperature and humidity, and C and N pools, but inhibited by soil methane-oxidizing bacterial diversity. The explained extents of soil temperature, humidity, carbon pool, nitrogen pool, methanogen diversity, and methane-oxidizing bacterial diversity for the CH4 emission changes were 6.9%, 21.6%, 18.4%, 15.2%, 14.0%, and 10.8%, respectively. Therefore, ant nests regulated soil CH4 emission dynamics through altering soil functional bacterial diversities, micro-habitat, and carbon and nitrogen pools in the secondary tropical forests.

Mechanism of microplastics effects on the purification of heavy metals in piggery effluents by microalgae.

Microalgae is an effective bioremediation technique employed for treating piggery effluent. However, there is insufficient study on how the presence of microplastics (MPs) in wastewater affects the ability of microalgae to remove heavy metals from piggery effluent. This study aims to investigate the influence of two prevalent heavy metals found in piggery wastewater, Cu2+ (2 mg/L) and Zn2+ (2 mg/L), on their removal by microalgae (Desmodesmus sp. CHX1) in the presence of four types of MPs: polyethylene (PE), polyvinyl chloride (PVC), polypropylene (PP), and polyethylene terephthalate (PET). The results revealed that smaller particle size MPs promoted chlorophyll accumulation, while larger particles inhibits it. Additionally, higher concentrations of MPs promoted chlorophyll accumulation, while lower concentrations inhibited it. As for heavy metals, the presence of microplastics reduced the removal efficiency of Cu2+ and Zn2+ by Desmodesmus sp. CHX1. The highest inhibition of Cu2+ was 30%, 10%, 19%, and 16% of the control (CK), and the inhibition of Zn2+ was 7%, 4%, 4%, and 13%, respectively, under the treatments of PE, PVC, PP and PET MPs. Furthermore, Desmodesmus sp. CHX1 can secrete more extracellular polymeric substances (EPS) and form heterogeneous aggregates with MPs to counteract their pressure. These findings elucidate the impact of MPs on microalgae in bioremediation settings and offer useful insights into the complex relationships between microalgae, MPs, and heavy metals in the environment.

Profiling the selected hotspots for ear traits in two maize-teosinte populations.

KEY MESSAGE: Eight selected hotspots related to ear traits were identified from two maize-teosinte populations. Throughout the history of maize cultivation, ear-related traits have been selected. However, little is known about the specific genes involved in shaping these traits from their origins in the wild progenitor, teosinte, to the characteristics observed in modern maize. In this study, five ear traits (kernel row number [KRN], ear length [EL], kernel number per row [KNR], cob diameter [CD], and ear diameter [ED]) were investigated, and eight quantitative trait loci (QTL) hotspots were identified in two maize-teosinte populations. Notably, our findings revealed a significant enrichment of genes showing a selection signature and expressed in the ear in qbdCD1.1, qbdCD5.1, qbpCD2.1, qbdED1.1, qbpEL1.1, qbpEL5.1, qbdKNR1.1, and qbdKNR10.1, suggesting that these eight QTL are selected hotspots involved in shaping the maize ear. By combining the results of the QTL analysis with data from previous genome-wide association study (GWAS) involving two natural panels, we identified eight candidate selected genes related to KRN, KNR, CD, and ED. Among these, considering their expression pattern and sequence variation, Zm00001d025111, encoding a WD40/YVTN protein, was proposed as a positive regulator of KNR. This study presents a framework for understanding the genomic distribution of selected loci crucial in determining ear-related traits.

Copper/Chiral Phosphoric-Acid-Catalyzed Intramolecular Reductive Isocyanide-Alkene (1 + 2) Cycloaddition: Enantioselective Construction of 2-Azabicyclo[3.1.0]hexanes.

Enantioenriched 2-azabicyclo[3.1.0]hexanes are accessed from readily available allyl substituted α-isocyanoesters by intramolecular (1 + 2) cycloaddition with the olefinic moiety and isocyano carbon as the respective C2 and C1 units. Cyclopropanation is initiated by 1,1-hydrocupration of isocyanide followed by formimidoylcopper to copper α-aminocarbenoid equilibration and subsequent (1 + 2) cycloaddition. The unprecedented copper/chiral phosphoric acid (CPA) catalytic system can be operated in the presence of water under air, delivering a variety of 2-azabicyclo[3.1.0]hexanes containing an angular all-carbon quaternary stereocenter in good to excellent yields and enantioselectivity.

Multi-agent Continuous Control with Generative Flow Networks.

Generative Flow Networks (GFlowNets) aim to generate diverse trajectories from a distribution in which the final states of the trajectories are proportional to the reward, serving as a powerful alternative to reinforcement learning for exploratory control tasks. However, the individual-flow matching constraint in GFlowNets limits their applications for multi-agent systems, especially continuous joint-control problems. In this paper, we propose a novel Multi-Agent generative Continuous Flow Networks (MACFN) method to enable multiple agents to perform cooperative exploration for various compositional continuous objects. Technically, MACFN trains decentralized individual-flow-based policies in a centralized global-flow-based matching fashion. During centralized training, MACFN introduces a continuous flow decomposition network to deduce the flow contributions of each agent in the presence of only global rewards. Then agents can deliver actions solely based on their assigned local flow in a decentralized way, forming a joint policy distribution proportional to the rewards. To guarantee the expressiveness of continuous flow decomposition, we theoretically derive a consistency condition on the decomposition network. Experimental results demonstrate that the proposed method yields results superior to the state-of-the-art counterparts and better exploration capability. Our code is available at https://github.com/isluoshuang/MACFN.

A DFT study on regulating the active center of v-Ti2XT2 MXene through surface modification for efficient nitrogen fixation.

The electrochemical conversion of nitrogen to ammonia provides an encouraging method to substitute the traditional Haber-Bosch process, owing to its high efficiency and mild reaction conditions. The search for high-performance catalysts and comprehension of catalytic mechanisms remains significant challenges. Herein, we conduct a systematic theoretical calculation of the NRR performance and mechanism of 24 Ti2XT2 (X = B, C, N; T = F, Cl, Br, I, O, S, Se, Te) MXenes with a T-vacancy to explore the influence of surface functional terminations and non-metallic center elements. Our findings demonstrate that surface functionalization significantly reduces the limiting potential by altering the rate-determining step. This change ranges from -1.24 V (Ti2NF2) to -0.21 V (Ti2BSe2), signifying the remarkable efficacy of modification of the surrounding environment of the exposed transition metal active center in promoting electrocatalytic performance. Detailed investigation of the charge density difference and orbital interaction reveals that the different NRR performance originates from the surface termination and non-metallic atoms regulate the electronic properties of the active Ti atoms. We also introduce the free energy change of *NNH2 (ΔG*NNH2) as a descriptor to predict the performance of NRR, which exhibits satisfactory linear relationship with free energy change of different intermediates and displays favourable volcano plot with limiting potential. Moreover, we highlight the pivotal role of work function in tuning the energy barrier of the rate-determining step, which can be regulated through the surface modification of MXenes. Our study not only offers a comprehensive understanding of the crucial impact of surface modification on the catalytic activities of defective MXenes, but also provides a rational perspective for designing efficient NRR catalysts.

Evening versus morning dosing regimen drug therapy for hypertension.

BACKGROUND: Variation in blood pressure levels display circadian rhythms. Complete 24-hour blood pressure control is the primary goal of antihypertensive treatment and reducing adverse cardiovascular outcomes is the ultimate aim. This is an update of the review first published in 2011. OBJECTIVES: To evaluate the effectiveness of administration-time-related effects of once-daily evening versus conventional morning dosing antihypertensive drug therapy regimens on all-cause mortality, cardiovascular mortality and morbidity, total adverse events, withdrawals from treatment due to adverse effects, and reduction of systolic and diastolic blood pressure in people with primary hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register via Cochrane Register of Studies (17 June 2022), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2022); MEDLINE, MEDLINE In-Process and MEDLINE Epub Ahead of Print (1 June 2022); Embase (1 June 2022); ClinicalTrials.gov (2 June 2022); Chinese Biomedical Literature Database (CBLD) (1978 to 2009); Chinese VIP (2009 to 7 August 2022); Chinese WANFANG DATA (2009 to 4 August 2022); China Academic Journal Network Publishing Database (CAJD) (2009 to 6 August 2022); Epistemonikos (3 September 2022) and the reference lists of relevant articles. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the administration-time-related effects of evening with morning dosing monotherapy regimens in people with primary hypertension. We excluded people with known secondary hypertension, shift workers or people with white coat hypertension. DATA COLLECTION AND ANALYSIS: Two to four review authors independently extracted data and assessed trial quality. We resolved disagreements by discussion or with another review author. We performed data synthesis and analyses using Review Manager Web for all-cause mortality, cardiovascular mortality and morbidity, serious adverse events, overall adverse events, withdrawals due to adverse events, change in 24-hour blood pressure and change in morning blood pressure. We assessed the certainty of the evidence using GRADE. We conducted random-effects meta-analysis, fixed-effect meta-analysis, subgroup analysis and sensitivity analysis. MAIN RESULTS: We included 27 RCTs in this updated review, of which two RCTs were excluded from the meta-analyses for lack of data and number of groups not reported. The quantitative analysis included 25 RCTs with 3016 participants with primary hypertension. RCTs used angiotensin-converting enzyme inhibitors (six trials), calcium channel blockers (nine trials), angiotensin II receptor blockers (seven trials), diuretics (two trials), α-blockers (one trial), and ß-blockers (one trial). Fifteen trials were parallel designed, and 10 trials were cross-over designed. Most participants were white, and only two RCTs were conducted in Asia (China) and one in Africa (South Africa). All trials excluded people with risk factors of myocardial infarction and strokes. Most trials had high risk or unclear risk of bias in at least two of several key criteria, which was most prominent in allocation concealment (selection bias) and selective reporting (reporting bias). Meta-analysis showed significant heterogeneity across trials. No RCTs reported on cardiovascular mortality and cardiovascular morbidity. There may be little to no differences in all-cause mortality (after 26 weeks of active treatment: RR 0.49, 95% CI 0.04 to 5.42; RD 0, 95% CI -0.01 to 0.01; very low-certainty evidence), serious adverse events (after 8 to 26 weeks of active treatment: RR 1.17, 95% CI 0.53 to 2.57; RD 0, 95% CI -0.02 to 0.03; very low-certainty evidence), overall adverse events (after 6 to 26 weeks of active treatment: RR 0.89, 95% CI 0.67 to 1.20; I² = 37%; RD -0.02, 95% CI -0.07 to 0.02; I² = 38%; very low-certainty evidence) and withdrawals due to adverse events (after 6 to 26 weeks active treatment: RR 0.76, 95% CI 0.47 to 1.23; I² = 0%; RD -0.01, 95% CI -0.03 to 0; I² = 0%; very low-certainty evidence), but the evidence was very uncertain. AUTHORS' CONCLUSIONS: Due to the very limited data and the defects of the trials' designs, this systematic review did not find adequate evidence to determine which time dosing drug therapy regimen has more beneficial effects on cardiovascular outcomes or adverse events. We have very little confidence in the evidence showing that evening dosing of antihypertensive drugs is no more or less effective than morning administration to lower 24-hour blood pressure. The conclusions should not be assumed to apply to people receiving multiple antihypertensive drug regimens.

Genome-wide analysis of ATP-binding cassette (ABC) transporter in Penaeus vannamei and identification of two ABC genes involved in immune defense against Vibrio parahaemolyticus by affecting NF-κB signaling pathway.

The ATP-binding cassette (ABC) transporters have crucial roles in various biological processes such as growth, development and immune defense in eukaryotes. However, the roles of ABC transporters in the immune system of crustaceans remain elusive. In this study, 38 ABC genes were systematically identified and characterized in Penaeus vannamei. Bioinformation analysis revealed that PvABC genes were categorized into ABC A-H eight subfamilies with 17 full-transporters, 11 half transporters and 10 soluble proteins, and multiple immunity-related cis-elements were found in gene promoter regions. Expression analysis showed that most PvABC genes were widely and highly expressed in immune-related tissues and responded to the stimulation of Vibrio parahaemolyticus. To investigate whether PvABC genes mediated innate immunity, PvABCC5, PvABCF1 and PvABCB4 were selected for dsRNA interference experiment. Knockdown of PvABCF1 and PvABCC5 not PvABCB4 increased the cumulative mortality of P. vannamei and bacterial loads in hepatopancreas after infection with V. parahaemolyticus. Further analysis showed that the PvABCF1 and PvABCC5 knockdown decreased expression levels of NF-κB pathway genes and antimicrobial peptides (AMPs). Collectively, these findings indicated that PvABCF1 and PvABCC5 might restrict V. parahaemolyticus challenge by positively regulating NF-κB pathway and then promoting the expression of AMPs, which would contribute to overall understand the function of ABC genes in innate immunity of invertebrates.

Learning to Aggregate Multi-Scale Context for Instance Segmentation in Remote Sensing Images.

The task of instance segmentation in remote sensing images, aiming at performing per-pixel labeling of objects at the instance level, is of great importance for various civil applications. Despite previous successes, most existing instance segmentation methods designed for natural images encounter sharp performance degradations when they are directly applied to top-view remote sensing images. Through careful analysis, we observe that the challenges mainly come from the lack of discriminative object features due to severe scale variations, low contrasts, and clustered distributions. In order to address these problems, a novel context aggregation network (CATNet) is proposed to improve the feature extraction process. The proposed model exploits three lightweight plug-and-play modules, namely, dense feature pyramid network (DenseFPN), spatial context pyramid (SCP), and hierarchical region of interest extractor (HRoIE), to aggregate global visual context at feature, spatial, and instance domains, respectively. DenseFPN is a multi-scale feature propagation module that establishes more flexible information flows by adopting interlevel residual connections, cross-level dense connections, and feature reweighting strategy. Leveraging the attention mechanism, SCP further augments the features by aggregating global spatial context into local regions. For each instance, HRoIE adaptively generates RoI features for different downstream tasks. Extensive evaluations of the proposed scheme on iSAID, DIOR, NWPU VHR-10, and HRSID datasets demonstrate that the proposed approach outperforms state-of-the-arts under similar computational costs. Source code and pretrained models are available at https://github.com/yeliudev/CATNet.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Water Electric Field Induced Modulation of the Wetting of Hexagonal Boron Nitride: Insights from Multiscale Modeling of Many-Body Polarization.

Understanding the behavior of water contacting two-dimensional materials, such as hexagonal boron nitride (hBN), is important in practical applications, including seawater desalination and energy harvesting. Water, being a polar solvent, can strongly polarize the hBN surface via the electric fields that it generates. However, there is a lack of molecular-level understanding about the role of polarization effects at the hBN/water interface, including its effect on the wetting properties of water. In this study, we develop a theoretical framework that introduces an all-atomistic polarizable force field to accurately model the interactions of water molecules with hBN surfaces. The force field is then utilized to self-consistently describe the water-induced polarization of hBN using the classical Drude oscillator model, including predicting the hBN-water binding energies which are found to be in excellent agreement with diffusion Monte Carlo (DMC) predictions. By carrying out molecular dynamics (MD) simulations, we demonstrate that the polarizable force field yields a water contact angle on multilayered hBN which is in close agreement with the recent experimentally reported values. Conversely, an implicit modeling of the hBN-water polarization energy utilizing a Lennard-Jones (LJ) potential, a commonly utilized approximation in previous MD simulation studies, leads to a considerably lower water contact angle. This difference in the predicted contact angles is attributed to the significant energy-entropy compensation resulting from the incorporation of polarization effects at the hBN-water interface. Our work highlights the importance of self-consistently modeling the hBN-water polarization energy and offers insights into the wetting-related interfacial phenomena of water on polarizable materials.