PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies.

BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

Vitamin D levels and five cardiovascular diseases: A Mendelian randomization study.

Cardiovascular disease is the leading cause of death worldwide, whilst vitamin D levels have been found to be associated with cardiovascular disease. To investigate the causal relationship between vitamin D levels and five cardiovascular diseases, a genome-wide association study (GWAS) was carried out using data on vitamin D levels (sample size = 79366), angina pectoris (18168 cases and 187840 controls), coronary heart disease (21012 cases and 197780 controls), lacunar stroke (6030 cases and 248929 controls), heart attack (10693 cases and 451187 controls), and hypertension (55917 cases and 162837 controls), with a Mendelian randomization (MR) analysis being subsequently performed. Six single nucleotide polymorphisms were used as instrumental variables (IVs). In addition, sensitivity analysis was performed to verify the reliability of the MR results here. The results showed a causal relationship between vitamin D levels and angina pectoris (OR = 0.51, 95 % CI: 0.28-0.93, P = 0.03), coronary heart disease (OR = 0.53, 95 % CI: 0.34-0.81, P = 0.004), and lacunar stroke (OR = 0.41, 95 % CI: 0.20-0.86, P = 0.02), but no causal relationship with heart attacks (OR = 1.00, 95 % CI: 0.99-1.01, P = 0.76) or hypertension (OR = 0.99, 95 % CI: 0.73-1.34, P = 0.94). Additionally, our IVs data showed no heterogeneity or pleiotropy, whilst the results of the MR analysis were reliable. This study contributes to the prevention and treatment of these five cardiovascular diseases.

Microplastics in drinking water: A review on methods, occurrence, sources, and potential risks assessment.

Microplastics in drinking water captured widespread attention following reports of widespread detection around the world. Concerns have been raised about the potential adverse effects of microplastics in drinking water on human health. Given the widespread interest in this research topic, there is an urgent need to compile existing data and assess current knowledge. This paper provides a systematic review of studies on microplastics in drinking water, their evidence, key findings, knowledge gaps, and research needs. The data collected show that microplastics are widespread in drinking water, with large variations in reported concentrations. Standardized methodologies of sampling and analysis are urgently needed. There were more fibrous and fragmented microplastics, with the majority being <10 µm in size and composed of polyester, polyethylene, polypropylene, and polystyrene. Little attention has been paid to the color of microplastics. More research is needed to understand the occurrence and transfer of microplastics throughout the water supply chain and the treatment efficiency of drinking water treatment plants (DWTPs). Methods capable of analyzing microplastics <10 µm and nanoplastics are urgently needed. Potential ecological assessment models for microplastics currently in use need to be improved to take into account the complexity and specificity of microplastics.

Multidimensional vision sensors for information processing.

The visual scene in the physical world integrates multidimensional information (spatial, temporal, polarization, spectrum and so on) and typically shows unstructured characteristics. Conventional image sensors cannot process this multidimensional vision data, creating a need for vision sensors that can efficiently extract features from substantial multidimensional vision data. Vision sensors are able to transform the unstructured visual scene into featured information without relying on sophisticated algorithms and complex hardware. The response characteristics of sensors can be abstracted into operators with specific functionalities, allowing for the efficient processing of perceptual information. In this Review, we delve into the hardware implementation of multidimensional vision sensors, exploring their working mechanisms and design principles. We exemplify multidimensional vision sensors built on emerging devices and silicon-based system integration. We further provide benchmarking metrics for multidimensional vision sensors and conclude with the principle of device-system co-design and co-optimization.

Optoelectronic Devices for In-Sensor Computing.

The demand for accurate perception of the physical world leads to a dramatic increase in sensory nodes. However, the transmission of massive and unstructured sensory data from sensors to computing units poses great challenges in terms of power-efficiency, transmission bandwidth, data storage, time latency, and security. To efficiently process massive sensory data, it is crucial to achieve data compression and structuring at the sensory terminals. In-sensor computing integrates perception, memory, and processing functions within sensors, enabling sensory terminals to perform data compression and data structuring. Here, vision sensors are adopted as an example and discuss the functions of electronic, optical, and optoelectronic hardware for visual processing. Particularly, hardware implementations of optoelectronic devices for in-sensor visual processing that can compress and structure multidimensional vision information are examined. The underlying resistive switching mechanisms of volatile/nonvolatile optoelectronic devices and their processing operations are explored. Finally, a perspective on the future development of optoelectronic devices for in-sensor computing is provided.

Characteristics of microplastics and their abundance impacts on microbial structure and function in agricultural soils of remote areas in west China.

As an emergent pollutant, microplastics (MPs) are becoming prevalent in the soil environment. However, the characteristics of MPs and the response of microbial communities to the abundance of MPs in agricultural soils in West China still need to be elucidated in detail. This study utilized the Agilent 8700 Laser Direct Infrared (LDIR) to analyze the characteristics of small-sized MPs (20-1000 µm) in soils from un-mulched and mulched agricultural fields in West China, and illustrated their correlation with microbial diversity. The results revealed a higher abundance of MPs in mulched soil ((4.12 ± 2.13) × 105 items kg-1) than that in un-mulched soil ((1.04 ± 0.26) × 105 items kg-1). The detected MPs were dominated by fragments, 20-50 µm and Polyamide (PA). High-throughput sequencing analysis indicated that alpha diversity (Chao1 and Shannon indices) in the plastisphere was lower compared to that in soil, and varied significantly with MPs abundance in soil. As the abundance of MPs increased, the proportion of soil about the degradation of organic matte and photoautotrophic taxa increased, which showed enrichment in the plastisphere. Functional predictions further indicated that MPs abundance affected potential soil functions, such as metabolic pathways associated with the C and N cycling. The plastisphere showed higher functional abundance associated with organic matter degradation, indicating higher potential health risks compared to soil environments. Based on the RDA analyses, it was determined that environmental physicochemical properties and MPs abundance had a greater impact on fungal communities than on bacterial communities. In general, the abundance of MPs affected the microbial diversity composition and potentially influenced the overall performance of soil ecosystems. This study offers empirical data on the abundance of MPs in long-term mulched agricultural fields and new insights for exploring the ecological risk issues associated with MPs.

Safety, tolerability, pharmacokinetics and pharmacodynamics of milvexian with aspirin and/or clopidogrel in healthy participants.

Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2-5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel.ClinicalTrials.gov Identifier: NCT03698513.

Hyperexpression of tumor necrosis factor receptor 2 inhibits differentiation of myeloid-derived suppressor cells by instigating apolarity during ageing.

During the ageing process, TNF-α can promote the expansion of myeloid-derived suppressor cells (MDSCs). However, it remains unclear which receptor(s) of TNF-α are involved in and how they modulate this process. Here, we report that TNFR2 hyperexpression induced by either TNF-α or IL-6, two proinflammatory factors of senescence-associated secretory phenotype (SASP), causes cellular apolarity and differentiation inhibition in aged MDSCs. Ex vivo overexpression of TNFR2 in young MDSCs inhibited their polarity and differentiation, whereas in vivo depletion of Tnfr2 in aged MDSCs promotes their differentiation. Consequently, the age-dependent increase of TNFR2 versus unaltered TNFR1 expression in aged MDSCs significantly shifts the balance of TNF-α signaling toward the TNFR2-JNK axis, which accounts for JNK-induced impairment of cell polarity and differentiation failure of aged MDSCs. Consistently, inhibiting JNK attenuates apolarity and partially restores the differentiation capacity of aged MDSCs, suggesting that upregulated TNFR2/JNK signaling is a key factor limiting MDSC differentiation during organismal ageing. Therefore, abnormal hyperexpression of TNFR2 represents a general mechanism by which extrinsic SASP signals disrupt intrinsic cell polarity behavior, thereby arresting mature differentiation of MDSCs with ageing, suggesting that TNFR2 could be a potential therapeutic target for intervention of ageing through rejuvenation of aged MDSCs.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. METHODS: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. RESULTS: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; ßTOPCAT=0.539; P<0.0001; ßPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; ßTOPCAT=0.571; P<0.0001; ßPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. CONCLUSIONS: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Urinary Proteomics and Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P=3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P=0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. CONCLUSIONS: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.