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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.
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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.
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Aspirina , Clopidogrel , Interações Medicamentosas , Voluntários Saudáveis , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/farmacocinética , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Aspirina/farmacocinética , Aspirina/administração & dosagem , Masculino , Feminino , Adulto , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Pessoa de Meia-Idade , Estudos Cross-Over , Adulto JovemRESUMO
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.
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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.
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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.
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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.
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Proteína 2 Semelhante a Angiopoietina , Biomarcadores , Insuficiência Cardíaca , Proteômica , Volume Sistólico , Humanos , Insuficiência Cardíaca/urina , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Masculino , Feminino , Proteômica/métodos , Idoso , Biomarcadores/urina , Biomarcadores/sangue , Pessoa de Meia-Idade , Prognóstico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Função Ventricular Esquerda , Fatores de Risco , Medição de Risco , Proteinúria/urina , Proteinúria/diagnósticoRESUMO
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.
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Água Potável , Monitoramento Ambiental , Microplásticos , Poluentes Químicos da Água , Microplásticos/análise , Água Potável/química , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Medição de Risco , Abastecimento de Água , Purificação da Água/métodosRESUMO
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.
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Insuficiência Cardíaca , Proteômica , Humanos , Proteínas Sanguíneas , Volume Sistólico , Função Ventricular Esquerda , Análise da Randomização MendelianaRESUMO
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.
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Doença da Artéria Coronariana , Trombose , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Ticagrelor/uso terapêutico , Fibrinolíticos/uso terapêutico , Doença da Artéria Coronariana/metabolismo , Aspirina , Agregação Plaquetária , Plaquetas/metabolismoRESUMO
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.
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Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Humanos , Volume Sistólico/fisiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Proteômica , Prognóstico , Fragmentos de Peptídeos , Inflamação , Fibrose , BiomarcadoresRESUMO
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.
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The influences of TRIM28 on the gastric tumorigenesis together with potential molecular mechanisms remain to be studied. We aimed at exploring the important effects of TRIM28 on gastric cancer (GC) and uncovering underling molecular mechanisms. Through immunohistochemistry analysis of 20 pairs of GC and the peritumoral tissues, the expression level of TRIM28 was determined. A variety of assays were applied to explore the important roles of TRIM28 in GC. Western blotting and qRT-PCR analyses were used to analyze the association between TRIM28 and the Wnt/ß-catenin signaling pathway. TRIM28 was highly expressed in GC tissues than peritumoral tissues. And high expression level of TRIM28 in GC was associated with good prognostic effects. In vitro functional assays suggested TRIM28 knockdown enhanced the proliferation and clone formation of GC cell. Moreover, TRIM28 knockdown enhanced the expression level of stemness markers, strengthened sphere-forming and drug-resistance properties of GC cells, suggesting important effect on GC cell stemness. Besides, our analysis showed that the Wnt/ß-catenin signaling was involved in the effect of TRIM28 on GC cell stemness property, and blocking Wnt/ß-catenin signaling pathway obviously rescued the promotion influence of TRIM28 knockdown. Overall, TRIM28 has an important influence on regulating the stem-like property of GC cell via Wnt/ß-catenin signaling, suggesting TRIM28 a promising drug target and a potential predictor of prognosis.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Via de Sinalização Wnt/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Proteína 28 com Motivo Tripartido/metabolismoRESUMO
Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR. Higher UPCR was associated with older age, a greater proportion of female gender, smaller prevalence of previous myocardial infarction, and greater prevalence of diabetes, insulin use, smoking, and statin use, in addition to a lower estimated glomerular filtration rate, hematocrit, and diastolic blood pressure. Growth differentiation factor 15 (GDF-15; ß = 0.15, p <0.0001), followed by N-terminal proatrial natriuretic peptide (NT-proANP; ß = 0.774, p <0.0001), adiponectin (ß = 0.0005, p <0.0001), fibroblast growth factor 23 (FGF-23, ß = 0.177; p <0.0001), and soluble tumor necrosis factor receptors I (ß = 0.002, p <0.0001) and II (ß = 0.093, p <0.0001) revealed the strongest associations with UPCR. Network analysis showed that UPCR is linked to various proteins primarily through FGF-23, which, along with GDF-15, indicated node characteristics with strong connectivity, whereas UPCR did not. In a model that included FGF-23 and UPCR, the former was predictive of the risk of death or heart-failure hospital admission (standardized hazard ratio 1.83, 95% confidence interval 1.49 to 2.26, p <0.0001) and/or all-cause death (standardized hazard ratio 1.59, 95% confidence interval 1.22 to 2.07, p = 0.0005), whereas UPCR was not prognostic. Proteinuria in HFpEF exhibits distinct proteomic correlates, primarily through its association with FGF-23, a well-known prognostic marker in HFpEF. However, in contrast to FGF-23, UPCR does not hold independent prognostic value.
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Insuficiência Cardíaca , Humanos , Feminino , Fator 15 de Diferenciação de Crescimento , Creatinina , Volume Sistólico/fisiologia , Proteômica , Biomarcadores , Prognóstico , ProteinúriaRESUMO
OBJECTIVES: Long, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB). METHODS: We conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen. RESULTS: A total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants. CONCLUSION: The primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs.
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BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 µM and 25 µM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.
Why was the study done? Antiplatelet therapies have shortcomings that limit their clinical utility, and there is an unmet need for a new, safe, and effective antiplatelet agent with reduced bleeding risk.PAR4 antagonists are a promising novel class of antiplatelet drugs due to late-stage inhibition of thrombus growth with minimal effects on platelet-driven hemostasis.BMS-986141 is a novel, potent, orally bioavailable, small-molecule antagonist specific for PAR4.What is new? BMS-986141 is safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range.BMS-986141 has robust antithrombotic activity and low bleeding risk.What is the impact? BMS-986141 has the potential to improve the benefitrisk of antiplatelet therapy in patients with atherothrombosis.
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Inibidores da Agregação Plaquetária , Agregação Plaquetária , Humanos , Administração Oral , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Hemorragia/induzido quimicamenteRESUMO
Bioinspired by native nervous tracts, a spinal cord-mimicking model system that was composed of multiple nanofibrous yarns (NYs) ensheathed in a nanofibrous tube was constructed by an innovative electrospinning-based fabrication and integration strategy. The infilling NYs exhibited uniaxially aligned nanofibrous architecture that had a great resemblance to spatially-arranged native nervous tracts, while the outer nanofibrous tubes functioned as an artificial dura matter to provide a stable intraluminal microenvironment. The three-dimensional (3D) NYs were demonstrated to induce alignment, facilitate migration, promote neuronal differentiation, and even phenotypic maturation of seeded neural stem and progenitor cells (NSPCs), while inhibiting gliogenesis. Single-cell transcriptome analysis showed that the NSPC-loaded 3D NY model shared many similarities with native spinal cords, with a great increase in excitatory/inhibitory (EI) neuron ratio. Curcumin, as a model drug, was encapsulated into nanofibers of NYs to exert an antioxidant effect and enhanced axon regeneration. Overall, this study provides a new paradigm for the development of a next-generation in vitro neuronal model system via anatomically accurate nervous tract simulation and constructs a blueprint for the research on NSPC diversification in the biomimetic microenvironment.
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Nanofibras , Alicerces Teciduais , Axônios , Regeneração Nervosa , Neurônios , Diferenciação CelularRESUMO
Motion processing has proven to be a computational challenge and demands considerable computational resources. Contrast this with the fact that flying insects can agilely perceive real-world motion with their tiny vision system. Here we show that phototransistor arrays can directly perceive different types of motion at sensory terminals, emulating the non-spiking graded neurons of insect vision systems. The charge dynamics of the shallow trapping centres in MoS2 phototransistors mimic the characteristics of graded neurons, showing an information transmission rate of 1,200 bit s-1 and effectively encoding temporal light information. We used a 20 × 20 photosensor array to detect trajectories in the visual field, allowing the efficient perception of the direction and vision saliency of moving objects and achieving 99.2% recognition accuracy with a four-layer neural network. By modulating the charge dynamics of the shallow trapping centres of MoS2, the sensor array can recognize motion with a temporal resolution ranging from 101 to 106 ms.
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Percepção de Movimento , Neurônios , Neurônios/química , Elétrons , Redes Neurais de Computação , Animais , Visão Ocular , Drosophila melanogasterRESUMO
Milvexian (BMS-986177/JNJ-70033093) is a potent, oral small molecule that inhibits the active form of factor XI with high affinity and selectivity. This study assessed the single-dose pharmacokinetic and pharmacodynamic properties of milvexian co-administered with rifampin, an organic anion transport protein (OATP) inhibitor and potent cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) inducer. In this open-label, nonrandomized, single-sequence study, healthy participants (N = 16) received single doses of milvexian on Day 1 (100 mg), milvexian and rifampin (600 mg) on Day 4, rifampin on Days 5-11, milvexian and rifampin on Day 12, and rifampin on Days 13-14. Pharmacokinetic data were summarized using descriptive statistics. Administration of milvexian, alone or in combination with rifampin, was generally safe and well tolerated. Single-dose co-administration of rifampin and milvexian demonstrated no meaningful changes in milvexian exposure versus milvexian alone (Cmax, 110%; AUC[0-T], 102%; AUC[INF], 101%). After multiple doses of rifampin and milvexian, peak and total milvexian exposure substantially decreased versus milvexian alone (Cmax, 22%; AUC[0-T], 15%; AUC[INF], 15%). Results were consistent with preclinical data, indicating that milvexian is a substrate for CYP3A4/5 and P-gp but not OATP. The implications of these results on the need for dose adjustment of milvexian will be further elucidated following the completion of phase 2 and 3 trials.Trial registration The study was registered with ClinicalTrials.gov (NCT02959060; submitted 7/11/2016, first posted 8/11/2016).
Assuntos
Fator XIa , Rifampina , Humanos , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Fator XIa/metabolismo , Voluntários Saudáveis , Rifampina/farmacologiaRESUMO
BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.
Assuntos
Produtos Biológicos , Insuficiência Cardíaca , Insulinas , Apelina/farmacologia , Apelina/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Caspases/farmacologia , Caspases/uso terapêutico , Humanos , Insulinas/uso terapêutico , Receptores X do Fígado , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Proteínas de Transferência de Fosfolipídeos/farmacologia , Proteínas de Transferência de Fosfolipídeos/uso terapêutico , Proteoma , Proteômica , Espironolactona/efeitos adversos , Volume Sistólico/fisiologia , Resultado do TratamentoRESUMO
High operating cost caused by electric energy consumption is a common problem challenging many municipal wastewater treatment plants (WWTPs). Due to the characteristics of intermittent inflow and aeration, WWTPs using sequencing batch reactor technology and its variants can be managed to relieve operating cost through taking advantage of time-of-use electricity pricing. However, little attention has been paid to the scheduling of treatment processes in the context of WWTPs. In this paper, a novel mixed-integer linear programming model is established for scheduling the batch operation of a WWTP under time-of-use electricity pricing, which considers constraints arising from task allocation, processing sequence, and processing duration. The modeling method is developed from the event-based continuous-time approach. The start time and end time of each treatment task are optimized to shift electricity consumption from peak hours to off-peak hours to the greatest extent, thus minimizing electricity cost. A case study demonstrates that the proposed model can quickly generate precise operational plans for the investigated WWTP. By implementing the optimum schedules, the WWTP can save on its electricity bill without changing the treatment capacity or the treatment process. The widening of peak and off-peak electricity pricing gap is favorable for the proposed model to display a more significant effect in reducing electricity cost.