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CALHM5 deficiency alleviates aortic aneurysm by regulating smooth muscle calcium homeostasis

Ion channels are the second most common clinical drug target besides G protein–coupled receptors. Aneurysmal diseases pose a significant threat to human life. Novel drug targets for its treatment remain to be explored. We investigated the role of an ion channel, calcium homeostasis modulators 5 (CALHM5), on the development of aortic aneurysms. We characterized CALHM5 as a plasma membrane ion channel abundant in smooth muscle cells of both humans and mice, playing a pivotal role in regulating calcium homeostasis. Notably, CALHM5 deficiency suppressed the transcription of the L-type calcium channel (LTCC) pore-forming subunit by downregulating cAMP-response element binding proteins. This in turn diminished blood vessel contractility and decreased blood flow. Intriguingly, CALHM5 expression is downregulated in smooth muscle tissues of aortic aneurysm patients. Furthermore, CALHM5 deficiency was observed to ameliorate the development of abdominal aortic aneurysms in mice, partly by stimulating smooth muscle cell proliferation. CALHM5 emerges as an ion channel prominently expressed in arterial smooth muscles, serving as a physiological regulator of smooth muscle contraction and presenting itself as a promising therapeutic target for aortic aneurysms.

Letter by Xu and Sun Regarding Article, “Subclinical Primary Aldosteronism and Major Adverse Cardiovascular Events: A Longitudinal Population-Based Cohort Study”

Germline-targeted baboon apolipoprotein L-1 protects mice against African trypanosomes

Some primates are immune to infection by most African trypanosome parasites due to apolipoprotein L-1 (APOL1), a primate-specific ion channel-forming protein. Our long-term objective has been to reduce African trypanosomiasis in livestock by genetic bioengineering of cattle with primate APOL1 . To select which primate APOL1 , we analyzed Papio ssp. APOL1 proteins and found that Papio hamadryas APOL1 was a strong candidate for transgenic animal production based on its trypanosome-killing capacity, ion channel properties, and stability. We generated seven transgenic murine lines based on the P. hamadryas APOL1 sequence and used these mice to investigate the level of APOL1 expression required for trypanosome immunity in vivo. We challenged the murine lines with three human and four livestock trypanosome isolates. P. hamadryas APOL1 provided protection against all of the human and three of the livestock trypanosome isolates, though not against Trypanosoma vivax despite the logical hypothesis that APOL1 plays a role in primate immunity to that parasite. Occasionally, lower APOL1 expression in heterozygote mice selected for the emergence of APOL1 resistant parasites in several trypanosome spp. Alarmingly, these resistant parasites were also resistant to high levels of APOL1 in homozygous mice, indicating an increase in virulence. A more-highly expressed chimeric APOL1 transgene encoding Homo sapiens APOL1 with the P. hamadryas APOL1 C-terminus was more effectively protective in heterozygote mice; however, we could not produce homozygous mice, suggesting endogenous toxicity to the mice. Together, these data bear relevance to our long-term objective to generate transgenic APOL1 cattle, the feasibility of which is discussed.

Forecasting the Burden of Cardiovascular Disease and Stroke in Women in the United States Through 2050: A Scientific Statement From the American Heart Association

BACKGROUND: Forecasts for the future prevalence of cardiovascular disease and stroke are crucial to guide efforts to improve health outcomes across the life course for women. METHODS: Using historical trends from the 2015 to 2020 National Health and Nutrition Examination Survey, 2015 to 2019 Medical Expenditure Panel Survey, and census estimates for population growth, we estimated trends in prevalence through 2050 for cardiovascular risk factors based on suboptimal levels of Life’s Essential 8 and clinical cardiovascular disease and stroke, overall and by age and race and ethnicity. RESULTS: Among adult women overall, the prevalence of hypertension is estimated to increase from 48.6% in 2020 to 59.1% in 2050. Diabetes (14.9% to 25.3%) and obesity (43.9% to 61.2%) will increase, whereas hypercholesterolemia will decline (42.1% to 22.3%). Prevalences of suboptimal diet, inadequate physical activity, and smoking will decline over time, and inadequate sleep will increase. Prevalences of coronary disease (6.85% to 8.21%), heart failure (2.45% to 3.60%), stroke (4.14% to 6.74%), atrial fibrillation (1.58% to 2.31%), and total cardiovascular disease and stroke (10.7% to 14.4%) will rise. Similar trends are projected in girls 2 to 19 years of age, with an increase from 19.6% to 32.0% projected in obesity. Most adverse trends are projected to be more pronounced among women and girls identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic. CONCLUSIONS: The prevalence of cardiovascular risk factors and disease in women and girls will increase over the next 30 years. Focused clinical and public health interventions are needed across the life course to address these adverse trends.

Giant photorefractive and photoexpansion effects in a van der Waals semiconductor

Nanophotonics relies on precise nanoscale structuring, yet conventional fabrication techniques remain complex and costly. Layered van der Waals (vdW) materials, with their intrinsic anisotropy and high refractive indices, offer a promising route toward simplified nanostructuring and tunable optical functionality. However, no vdW material has previously been shown to exhibit a strong photorefractive effect—a key requirement for light-based modulation. Here, we report a giant photorefractive response (Δ n up to 0.3) in crystalline arsenic trisulfide (As 2 S 3 ), observed at low optical intensities. In addition to refractive-index modulation, light exposure enables controlled thickness tuning of As 2 S 3 . The material exhibits a giant photoexpansion of up to 7%, depending on the illumination intensity, which may originate from light-induced generation of point defects, consistent with molecular-dynamics modeling. Building on this photoexpansion effect, we introduce a maskless nanopatterning technique based on continuous-wave laser writing, achieving ~500 nm pitch (~50,000 dpi) without the need for ultrafast lasers. The combination of high photosensitivity, anisotropy, ease of exfoliation and transfer, and optical transparency positions vdW As 2 S 3 as a practical platform for integrated photonics, adaptive optics, reconfigurable photonic elements, and dense optical encoding.

Response by Gao et al to Letter Regarding Article, “G Protein–Coupled Receptor Kinase 3 Exacerbates Diabetic Heart Injuries Through Direct Phosphorylation of Cannabinoid Receptor 2 in Humans and Mice”

Correspondence of large-scale functional brain network decline across aging mice and humans

Human aging is marked by progressive reorganization of large-scale functional brain networks; these brain network changes have been linked to cognitive decline and disease vulnerability. Conversely, while mice have served as powerful models for understanding the molecular and cellular changes that occur over the lifespan, an absence of precise characterization of age-related changes in large-scale functional brain network organization has limited cross-species translational insights. Here, using densely sampled resting-state functional MRI data acquired cross-sectionally and longitudinally in awake mice over a broad range of adulthood (n = 82; 3 to 20 mo), we describe organizational features and age-related alterations of the mouse’s functional connectome. Mouse resting-state functional connectivity recapitulates known functional circuits, demonstrating the organizational validity of these signals. Graph theoretic analysis applied to functional connectivity reveals that mice exhibit modular architectures of functional brain network organization and that increasing age is associated with decreasing system segregation, indicative of network dedifferentiation analogous to observations in humans. Notably, mouse resting-state brain networks are more segregated than those of humans [determined using data from the Human Connectome Project and its developmental- and aging-counterparts (n = 1,179; 18 to 90 y)], attributable to mice exhibiting a diminished contribution of long-range functional relationships that integrate distributed systems. Mice also exhibit slower rates of age-related decline in brain network organization relative to humans, highlighting important species differences in functional brain network organization and trajectories of brain network aging. These findings establish a model of large-scale functional brain network aging in mice and provide a translational bridge across species and spatial scales of analysis.

Group 1 Pulmonary Hypertension With Elevated Pulmonary Artery Wedge Pressure: Characterizing A Complex Phenotype

Competing Risks in Cardiovascular Research: A Practical Perspective

Specialization of independently acquired flagellar FliC proteins in plant-associated <i>Sphingomonas</i> balances swimming and immunogenicity

Plants monitor their environment for microbial invaders using pattern-recognition receptors that detect microbe-associated molecular patterns (MAMPs). Flagellin, the main component of bacterial flagellum, contains the flg22 epitope recognized by the plant immune receptor FLS2. Immune recognition can create an evolutionary conflict, requiring bacteria to balance flagellar function and immune evasion. Here, we show that plant-associated Sphingomonas resolve this constraint by partitioning two flagellar functions, motility and colonization, across two divergent and independently acquired flagellin genes. Comparative genomics revealed widespread coexistence of FliC proteins expressing either an immunogenic variant (FliC-H) or a nonimmunogenic variant (FliC-L). The nonimmunogenic FliC-L is necessary and sufficient for full directional swimming, whereas FliC-H is dispensable for swimming, but sufficient for full attachment and colonization. Flagellin expression patterns mirror these functions. Thus, FLS2 recognizes the flagellar variant required for colonization rather than motility, potentially restricting colonizing bacteria from entering internal leaf and root tissues.

Correction to: Alcohol Use and Cardiovascular Disease: A Scientific Statement From the American Heart Association

Life-like behavior emerging in active and flexible microstructures

Many organisms leverage an interplay between shape and activity to generate motion and adapt to their environment. Embedding such mechanical feedback into synthetic micrometer-sized robots could eliminate the need for sensors, software, and actuators. Current active micrometer-scale systems, however, do not possess a flexible body with which they can autonomously sense and react to their environment. Here, we experimentally realize active and flexible structures by concatenating anisotropic micrometer-sized units using 3D microprinting and activating them using AC fields. We demonstrate that this minimal design integrates mechanical feedback between activity and shape, resulting in a rich array of modes of motion—including railway and undulatory locomotion, rotation, and beating. It furthermore gives rise to emergent sense-response abilities, which enable autonomous reorientation, navigation, and collision avoidance. Our approach offers a versatile platform for designing biomimetic model systems and autonomously operating microrobots with embodied intelligence.

Malnutrition and Cachexia in Inpatients With Acute Cardiac Conditions: A Scientific Statement From the American Heart Association

Malnutrition can affect patients with various acute cardiovascular disease conditions, including acute coronary syndromes, arrhythmias, or valvular disease; however, most of the literature has focused on patients with heart failure. Malnutrition prevalence estimates range from 20% to 60% for hospitalized patients. Use of Global Leadership Initiative on Malnutrition criteria for malnutrition diagnosis for patients with cardiovascular disease has confirmed prognostic value, correlating with poorer physical function and higher mortality. Nutritional support plays a key role for inpatients, particularly in the cardiac intensive care unit, and includes initiation of feeding within 48 hours of hospitalization, preferably through enteral nutrition. Enteral nutrition is more cost-effective compared with parenteral nutrition and can decrease mortality and shorten lengths of stay. Parenteral nutrition is reserved for patients with severe gastrointestinal dysfunction or to supplement nutrition when enteral nutrition is contraindicated, for example, during high pressor doses that preclude adequate intestinal perfusion or when achieving &lt;70% of nutritional targets after the first week. The optimal protein intake for patients with cardiogenic shock is an area of ongoing research, with higher protein approaches not appearing beneficial in recent critical care trials.

Chromatin accessibility regulates age-dependent nuclear mechanotransduction

The integration of environmental cues into cellular programs is crucial for cell function. Yet, how this integration is modulated due to cellular aging remains unclear. We propose that the 3D chromatin organization filters these signals and investigated how age-related chromatin changes in human dermal fibroblasts affect responses to mechanical tension and TGF-β. Young fibroblasts exhibited synergistic gene expression enhancement in response to combined stimuli, a response that was markedly blunted or divergent in aged cells. These distinct outcomes correlated with significant age-related differences in chromatin accessibility. We identified the AP-1 complex and other transcription factors with age-specific activity as pivotal in remodeling chromatin and orchestrating these divergent mechanochemical responses during cellular aging. We validated that disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery. Our findings establish chromatin as a key integrator of mechanochemical signals and characterize the age-related alterations to this integration that modify the cellular responsiveness of aged cells, highlighting AP-1 and its network as potential therapeutic targets against age-related decline.

Pulmonary Arterial Hypertension Risk With BCR-ABL Tyrosine Kinase Inhibitors: Refining Risk With Nationwide Data

Ultrasensitive measurement of brain penetration mechanics and blood vessel rupture with microscale probes

Microscale electrodes, on the order of 10 to 100 µm, are rapidly becoming critical tools for neuroscience and brain–machine interfaces for their high channel counts and spatial resolution, yet the mechanical details of how probes at this scale insert into brain tissue are largely unknown. Here, we performed quantitative measurements of the force and compression mechanics together with real-time microscopy for in vivo insertion of a systematic series of microelectrode probes as a function of diameter (7.5 to 100 µm and rectangular Neuropixels) and tip geometry (flat, angled, and electrochemically sharpened). These results elucidated the role of tip geometry, surface forces, and mechanical scaling with diameter. Surprisingly, the insertion force postpia penetration was constant with distance and did not depend on tip shape. Real-time microscopy revealed that at small enough lengthscales (&lt;25 µm), blood vessel rupture and bleeding during implantation could be entirely avoided. This appears to occur via vessel displacement, avoiding capture on the probe surface which led to elongation and tearing for larger probes. We propose a three-zone model to account for the probe size dependence of bleeding, and provide mechanistic guidance for probe design.

Letter by Wu et al Regarding Article, “G Protein–Coupled Receptor Kinase 3 Exacerbates Diabetic Heart Injuries Through Direct Phosphorylation of Cannabinoid Receptor 2 in Humans and Mice”

Fibro-adipogenic progenitor cells from murine SMA muscles are intrinsically adipogenic

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. Although classically viewed as a neurogenic disease, SMA patients exhibit poor skeletal muscle regeneration and increased fatty-fibrotic infiltration. Fibro-adipogenic progenitors (FAPs) are mesenchymal precursor cells that contribute to muscle remodeling and underlie fat and fibrosis formation. Because FAPs transiently express Smn1 during regeneration, FAPs were examined in muscles from adult C/C SMA and control mice to determine if reduced Smn activity altered their properties. We performed a nonbiased screen of FAPs following BaCl 2 -induced injury using an in situ cell surface proteomic strategy that probed the cellular membrane and environment of FAPs in early regeneration. Proteomic profiling revealed early adipogenic priming in SMA tissues, with increased levels of perilipin-4 and adipocyte lipid-binding proteins. Significantly more adipocytes accumulated in C/C SMA muscles after glycerol injection versus controls. Further, SMA FAPs produced more fat than control FAPs when transplanted into glycerol injured muscles lacking FAPs. RNA sequencing of FAPs isolated after BaCl 2 or glycerol injury identified transcriptional enrichment of lipid biosynthesis and dysregulated lipid metabolism in SMA FAPs. Primary FAPs isolated from C/C SMA muscles mirrored heightened adipocyte formation, which was normalized by increasing Smn activity with Risdiplam. Conversely, adipogenesis of primary FAPs from control muscles was enhanced when subjected to siRNA Smn1 knockdown. Together, these findings demonstrate that reduced Smn activity potentiates intrinsic adipogenic bias in FAPs that may contribute to pathological fat deposition in SMA muscle.

Transient <i>Sprr1a</i> Expression Defines a Population of Border Zone Cardiomyocytes That Survive Ischemic Injury

Probing charge-transfer processes in Pt/TiO ₂ photocatalysts by amperometric/potentiometric photo-SECM

Electrocatalysts in combination with photoelectrodes can provide higher activity and/or lower overpotential for a broad range of photoelectrochemical processes. Although cocatalyst nanoparticles (NPs) on semiconductor surfaces have been extensively studied, spatially resolved kinetic measurements of charge-transfer processes in such systems remain challenging. Here, we introduce a unique approach based on a single setup employing contact amperometric/potentiometric photo-scanning electrochemical microscopy for quantitative, high-resolution measurements of photoelectrochemical processes in nanostructured photocatalysts. Amperometric SECM experiments are coupled with nanoscale local potential measurements made using the same nanotip, which is brought within the tunneling distance from the sample surface. Pt NPs electrodeposited on the surface of Nb-doped TiO 2 rutile (110) single crystals are used as a model experimental system to demonstrate the capabilities of the developed technique for probing local rates of photogenerated hole/electron transfers, such as overall water splitting (OWS) with coevolved H 2 and O 2 , as well as the oxidation/reduction of a reversible redox mediator (e.g., ferro/ferricyanide). This methodology resolves spatial variations in photocatalytic reactivity of nanoscale cocatalysts supported on semiconductors with a spatial resolution on the order of 10 nm. In the Pt/Nb:TiO2 system, this method identifies distinct cathodic and anodic sites separated by ~150 nm, with local surface potentials of approximately −0.53 V and +0.58 V vs. Ag/AgCl, respectively. Complementary structural/compositional and spectroscopic analyses reveal the coexistence of metallic Pt and oxidized Pt species under OWS conditions, establishing asymmetric surface energetics consistent with a ~1.5 eV difference in local band-edge position and thereby driving directional carrier separation within Nb:TiO 2 .