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Microplastics Exposure Linked to Cardiovascular Disease Risk, Chronic Health Conditions
Response by Silbernagel et al to Letters Regarding Article, “Associations of Circulating ANGPTL3, C-Terminal Domain–Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality”
Cellular Reprogramming by PHF7 Enhances Cardiac Function Following Myocardial Infarction
BACKGROUND: Direct reprogramming of fibroblasts to cardiomyocytes is a potentially curative strategy for ischemic heart disease. However, current reprogramming strategies require excessive factors due to epigenetic barriers of adult mouse and human fibroblasts. Recently, we identified the epigenetic factor PHF7 from a screen of gene-regulatory factors as the most potent activator of adult fibroblast-to-cardiomyocyte reprogramming in vitro. METHODS: Through in vitro assays coupled with genome-wide studies, we interrogated the ability of PHF7 to induce reprogramming events with minimal reprogramming factors. Using in vivo murine models of myocardial infarction and intramyocardial reprogramming factor delivery coupled with genetic fibroblast lineage tracing, we delivered retroviral PHF7 cocktails to the murine heart and interrogated reprogramming events as well as the acute and chronic functional impact of these cocktails. Deployment of 10X multiomics in vivo generated a combinatorial single-nucleus transcriptomic and epigenomic atlas of PHF7 reprogramming in the infarcted heart. RESULTS: Genome-wide in vitro transcriptomic analyses revealed that addition of PHF7 to Tbx5 or Mef2c and Tbx5 in fibroblasts induced global reprogramming through upregulation of unique cardiac transcriptomes. Further, PHF7 itself upregulated cardiac master regulators when overexpressed in dermal fibroblasts. Delivery of PHF7 cocktails to the infarcted murine heart induced in vivo reprogramming events and improved cardiac function and remodeling in both acute and chronic heart failure. When delivered as a single factor to the infarcted heart, PHF7 improved survival, function, and fibrosis up to 16 weeks after injury. Genetic lineage tracing analyses revealed that PHF7 induced bona fide fibroblast-to-cardiomyocyte reprogramming events in vivo. Comprehensive multiomics of PHF7 cocktails in the infarcted heart exposed the impact of PHF7 on chromatin structure, generating population-level shifts in nonmyocyte and cardiomyocyte cellular identity. CONCLUSIONS: Here, we report the ability of a single epigenetic factor, PHF7, to induce reprogramming and improve cardiac function in the mouse heart following myocardial infarction. Together, these data support the premise that a single factor, when deployed into the infarcted mouse heart, can induce reprogramming events and recover function in the ischemic heart.
Implementation of Evidence-Based Behavioral Interventions for Cardiovascular Disease Prevention in Community Settings: A Scientific Statement From the American Heart Association
Extending cardiovascular disease prevention beyond health care settings is needed to improve population health and to advance health equity. Furthermore, evidence-based practices in community settings leverage assets and strengths (eg, community trust, reach) of organizations and practitioners. Using the Roadmap for Leveraging Implementation Science to Achieve Cardiovascular Health Equity, we conducted a narrative review to determine the scope of studies describing implementation strategies of cardiovascular health evidence-based practices in community settings and to identify bright spots and gaps in what is known about implementing cardiovascular health evidence-based practices in community settings. Evidence for the effect of interventions delivered in community settings to improve cardiovascular health behaviors is emerging in various community settings. Evidence-based practices were identified, selected, and culturally adapted through community engagement, particularly in faith-based and social service/other settings (eg, salons/barbershops). We found several interventions and adaptations aimed at improving outcomes in groups that have historically been excluded by the health care system. The Designing for Dissemination and Sustainability approach supports consideration of contextual factors (eg, alignment of evidence-based practice with the mission, workflow, time, and priorities of the setting) in selecting and adapting evidence-based practices. Development of implementation strategies must engage those who will be asked to implement the intervention and the organization in which it will be implemented. Key research opportunities include high-quality studies that explicitly compare well-specified implementation strategies in various community settings. Taken together, there are bright spots and opportunities for enhanced impact through implementation of evidence-based practices for cardiovascular disease prevention in community settings.
Letter by Shi et al Regarding Article “Associations of Circulating ANGPTL3, C-Terminal Domain–Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality”
A Proposal to Elevate the Status of Troponin and B-Type Natriuretic Peptides as Atherosclerotic Cardiovascular Disease Risk Enhancers
MYCN Regulates Cardiomyocyte Proliferation, Metabolism, and Regeneration in the Mammalian Heart
Evaluation of Lipoprotein(a) as a Prognostic Marker of Extracoronary Atherosclerotic Vascular Disease Progression
BACKGROUND: Despite current treatment strategies for atherosclerotic vascular disease focusing on lifestyle modification and lowering cholesterol, a significant residual risk of major atherosclerotic complication remains, prompting investigation into lipoprotein(a) (Lp(a)) as a potential predictive biomarker. The objective of this study was to determine the usefulness of Lp(a) in identifying patients at high risk of incident extracoronary atherosclerotic vascular disease and complications. METHODS: Data from 460 544 participants in the UK Biobank with prospectively measured Lp(a) concentrations were included in this analysis. Cox proportional hazards regressions modeled the associations of Lp(a) concentrations with incident peripheral artery disease (PAD) and incident carotid artery stenosis and progression to the first major adverse limb event and the first stroke, respectively. RESULTS: Of the study participants, the median [interquartile range] age at study enrollment was 58 [51–64] years, 54.2% were male, 94.4% were European, 5.5% had diabetes, and 10.5% were smokers. Over a median follow-up time of 13.6 [12.9–14.4] years, 6347 (1.4%) and 1972 (0.43%) developed the first incidence of PAD and carotid stenosis, respectively. Among participants with prevalent PAD and carotid stenosis at enrollment, 196 (2.7%) and 67 (1.9%) progressed to the first incidence of major adverse limb event and stroke, respectively. Median Lp(a) concentrations were significantly different in those without atherosclerotic vascular disease at 19.5 nmol/L [7.6–73.5] compared with incident PAD at 25.3 nmol/L [8.3–107.3], progression to major adverse limb event at 33.3 nmol/L [8.7–158.2], incident carotid stenosis at 29.5 nmol/L [8.5–116.3], and carotid stenosis progression to stroke at 37.8 nmol/L [11.1–158.3]. The risk estimate per 75 nmol/L Lp(a) for incident PAD (hazard ratio [HR], 1.18 [95% CI, 1.15–1.20]; P <0.0001) was similar to that for incident carotid stenosis (HR, 1.17 [95% CI, 1.13–1.20]; P <0.0001). Among participants with PAD, those with high Lp(a) concentrations had 1.57 times the risk of developing major adverse limb event than participants with normal Lp(a) concentrations (95% CI, 1.14–2.16; P =0.006). Among participants with carotid stenosis, participants had 1.40 times the risk of developing an ischemic stroke with high Lp(a) concentrations, although this was not significant (95% CI, 0.81–2.40; P =0.228). CONCLUSIONS: High concentrations of Lp(a) are associated with both incident extracoronary atherosclerotic vascular disease and progression to major complications.
PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations
BACKGROUND: Hereditary hemorrhagic telangiectasia is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function variations in activin receptor-like kinase 1 ( ALK1 ) cause type 2 hereditary hemorrhagic telangiectasia, and Alk1 knockout mice develop AVMs, along with overactivation of vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. The full spectrum of signaling alterations resulting from ALK1 variations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed. METHODS: Single-cell RNA sequencing of endothelial-specific Alk1 knockout mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human type 2 hereditary hemorrhagic telangiectasia lesions. Genetic and pharmacological PIEZO1 inhibition was tested in Alk1 knockout mice, along with downstream PIEZO1 signaling. RESULTS: A cluster of Alk1 mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle, and vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. Piezo1 deletion and pharmacological inhibition in Alk1 -deficient mice mitigated AVM formation, whereas Piezo1 overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated vascular endothelial growth factor receptor 2/AKT, ERK5-p62-KLF4, endothelial nitric oxide synthase, hypoxia, proliferation, and inflammation in ALK1-deficient endothelium. CONCLUSIONS: PIEZO1 expression and signaling are elevated in type 2 hereditary hemorrhagic telangiectasia. PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.
Intimate Partner Violence as a Risk Factor for CVD Deserves Its “Me Too” Movement
Gonadotropin-releasing hormone regulates transcription of the inhibin B co-receptor, TGFBR3L, via early growth response one
Imaging‐Based High‐Content Screening with Clickable Probes Identifies XPB Inhibitors
Abstract High‐content screening (HCS) has become a powerful tool in drug discovery; however, its reliance on indirect readouts and surrogate markers limits HCS's ability to directly assess drug‐protein interactions at endogenous levels, particularly in subcellular contexts. Here, we report an approach to address these limitations by combining confocal imaging‐based HCS and bio‐orthogonal labeling with clickable probes. As a proof‐of‐concept, we synthesized a probe Triptolide‐alkyne (TL‐alk) that rapidly and specifically labels xeroderma pigmentosum type B (XPB), a critical protein in nucleotide excision repair (NER). Probe‐labeled XPB was conjugated to TAMRA to visualize the occupation of active sites, and EGFP and DAPI signals indicated XPB expression in the nucleus. Such a colorimetric HCS assay enabled the direct and precise measurement of drug occupancy rates in nuclear XPB of live cells. With this platform, pelitinib was identified as a novel ligand to bind XPB out of 1874 compounds containing. Food and Drug Administration (FDA)‐approved drugs. Pelitinib formed a covalent bond with cysteine residue 342 of XPB, suppressed XPB's ATPase activity, impaired NER, and synergistically enhanced chemotherapy. This study not only overcomes limitations of HCS, but also demonstrates the transformative potential of bio‐orthogonal labeling, such as in integration with HCS technologies, offering a novel framework for drug discovery targeting challenging protein systems.
Deuterated Multi‐Resonance Thermally Activated Delayed Fluorescence Emitters for Pure‐Green Organic Light‐Emitting Diodes with CIE Coordinates of (0.16, 0.75) and Long Lifetimes
Abstract Multi‐resonance thermally activated delayed fluorescence (MR‐TADF) emitters, especially high‐order B/N MR‐TADF emitters, offer new opportunities in obtaining wide‐color‐gamut, high color purity, and highly efficient organic light‐emitting diodes (OLEDs). Extending the device durability is still very challengeable for these emitters. Deuteration of emitters to slow down their degradation and lengthen device lifespan is a promising strategy. However, how to access deuterated high‐order MR‐TADF emitters remains to be explored. Herein, a synthetic protocol of high‐order B/N products is proposed using deuterated starting materials and sequential borylation. Combining with fine‐tuning electronic effect through adjusting position of tert ‐butyl ( t Bu) substituents, we successfully obtained deuterated triboron MR‐TADF material ω’‐DABNA‐D that delivers precisely tuned pure‐green emission with close‐to‐unity quantum yield and rapid reverse intersystem crossing (RISC). The resulting binary OLED approaches the BT.2020 standard with CIE coordinates of (0.16, 0.75) and demonstrates impressive external quantum efficiency (EQE) of 34.6% at maximum and 30.7% at 1000 cd m −2 . Additionally, an Ir(ppy) 3 ‐sensitized device shows excellent operational stability, with an extrapolated lifetime (LT 80 ) of 6078 h at an initial luminance of 1000 cd m −2 . This study hence offers a promising methodology toward high‐performance OLED with long device lifetime.
Lead-free perovskite KCsSnI1.7Cl1.3 material exhibiting superior photocatalytic antimicrobial activity
Abstract The development of environmentally friendly and highly efficient materials is critical for next-generation antibacterial and optoelectronic applications. In this study, we present the successful synthesis of a novel lead-free perovskite, KCsSnI1.7Cl1.3, via a rapid and scalable chemical bath deposition method at 150 °C for just 5 min. The resulting film features well-defined orthorhombic, pyramid-like crystals with uniform grain sizes (800–1000 nm) and a compact, pinhole-free morphology. Remarkably, the material exhibits strong optical absorption up to 800 nm, positioning it as a promising candidate for hot electron generation and light-driven applications. KCsSnI1.7Cl1.3 also demonstrated outstanding antibacterial performance, showing broad-spectrum activity against multiple bacterial strains. The highest inhibition was recorded against Staphylococcus aureus, with inhibition zones increasing from 17 mm in the dark to 35 mm under UV illumination—highlighting its efficient photocatalytic response. The antibacterial effect followed the order: S. aureus > B. subtilis > E. coli > Salmonella sp., and was significantly enhanced with increasing concentrations (100–400 ppm). No inhibition was observed in control wells, confirming the selective activity of the material. With its lead-free composition, strong light-harvesting ability, and exceptional antibacterial properties, KCsSnI1.7Cl1.3 emerges as a highly promising material for future applications in antibacterial coatings, water purification systems, and advanced optoelectronic devices. Its green synthesis, scalability, and multifunctionality offer a sustainable pathway toward real-world deployment in environmental and biomedical fields.
Identification and characterization of nanobodies specific for the human ubiquitin–like ISG15 protein
Janus‐Type Photophysics of Rotational Isomers in a Diphenylanthracene Dimer
Abstract Organic molecular dimers serve as valuable model systems for manipulating and exploring interchromophore interactions. However, the structural flexibility introduced by linker or chromophore rotation gives rise to conformational isomers with distinct atomic arrangements, complicating the interpretation of photophysical processes. In this study, we investigate 9,9′,10,10′‐tetraphenyl‐2,2′‐bianthracene ( TPBA ) to elucidate the distinct electronic characteristics of its two primary rotational isomers: syn ‐ and anti ‐TPBA . To address the “Janus‐type” photophysical behavior of these isomers, we employed a comprehensive suite of static and time‐resolved spectroscopic techniques, including excitation‐wavelength‐dependent time‐resolved photoluminescence, transient absorption, and time‐resolved electron paramagnetic resonance, complemented by theoretical calculations. syn ‐ and anti ‐TPBA exhibit markedly different emissive properties and charge‐transfer characteristics, reflecting their unique exciton coupling behaviors. Additionally, they showcase distinct triplet formation rates and exhibit environment‐dependent triplet formation mechanisms. This in‐depth study of the Janus‐like electronic properties of TPBA underscores the critical role of conformational isomerism in organic molecular dimers. Neglecting these structural variations can obscure the true photophysical landscape and lead to misinterpretations of mechanistic processes, highlighting the necessity of considering conformational heterogeneity in molecular design and photophysical studies.
Profiling plasma protease activity with charge-changing peptides enables detection and classification of gastrointestinal cancers
Abstract Early detection of gastrointestinal (GI) cancers—including colorectal cancer (CRC), gastric cancer (GC), and esophagogastric junction cancer (EGJC)—is essential for improving patient outcomes. However, current diagnostic methods such as endoscopy and colonoscopy are invasive, costly, and not widely accessible. Proteases are elevated in many cancers and are detectable in peripheral blood, making them promising candidates for noninvasive diagnostic strategies. We employed a six-probe charge-changing peptide (CCP) panel to profile cancer-associated protease activity in human plasma. Each CCP undergoes a charge shift upon cleavage by a specific protease, enabling detection via gel electrophoresis. Plasma samples from GI cancer patients (CRC, GC, EGJC; N = 68) and healthy controls (HC; N = 31) were analyzed. Protease activity profiles were analyzed using statistical tests, principal component analysis, and binary logistic regression (LR) models trained on the most informative probes. Model performance was evaluated through repeated cross-validation. Distinct protease activity profiles were observed among CRC, upper GI cancers (UGIC; GC + EGJC), and HC groups. Probe designed to be cleaved by cathepsin B showed the strongest discrimination between cancer and control samples, while probes designed to be cleaved by ubiquitin-specific peptidase 15 and plasmin were identified as the most informative subtype-specific markers for UGIC and CRC, respectively. LR models built on these single probes demonstrated excellent diagnostic performance, with AUCs exceeding 0.95, and both sensitivity and specificity greater than 90%. Our findings highlight CCP-based protease profiling as a minimally invasive, accurate, and scalable method for GI cancer detection and classification. This platform holds strong potential for clinical application in cancer screening, pending further validation in larger, independent cohorts.
Gut microbiota–derived metabolite trimethylamine N-oxide alters the host epigenome through inhibition of S-adenosylhomocysteine hydrolase
Cooperative Activation of CO and Pyridine by an Aluminum(I) Complex Ligated with a Silylene–Borane Ligand
Abstract Cooperative main‐group systems based on alumylenes are highly attractive due to their potential for activating and transforming inert chemical bonds and small molecules. However, their development has been hindered by the scarcity of suitable supporting ligands. Herein, we report the synthesis of an amphiphilic carboranyl silylene–borane ligand ( 1 ) and demonstrate its effectiveness in stabilizing an aluminum(I) complex 2 . Complex 2 has been unambiguously characterized by spectroscopic analysis, X‐ray diffraction analysis, and DFT calculations, which reveals a unique structure featuring both silicon(II)→aluminum(I) and aluminum(I)→boron(III) donor–acceptor bonds. The synergistic interplay between the silylene–borane ligand and the aluminum(I) center in 2 drives its unusual reactivity toward CO and pyridine activation, facilitating cleavage of the C≡O bond and dearomatization of pyridine.