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Association of Pulmonary Vascular Remodeling With Cardiac Structure and Function, Pulmonary Pressure, and Heart Failure in Late Life: The Atherosclerosis Risk in Communities (ARIC) Study
BACKGROUND: Aging is associated with increases in pulmonary pressure related to concomitant age-associated left ventricular remodeling, diastolic dysfunction, and declines in pulmonary function. Little is known regarding morphological changes in the pulmonary arterial vasculature underlying these associations. Our aim was to determine the associations between pulmonary vascular arterial remodeling, reflected in distal pruning and proximal dilation, and cardiac structure and function, pulmonary pressure, and functional outcomes. METHODS: Among 2275 participants in the community-based Atherosclerosis Risk in Communities study (ARIC) who underwent echocardiography and noncontrast cardiac computed tomography at study visit 7 (2018–2019), we quantified the fraction of total pulmonary vascular area comprised of arterial vessels with cross-sectional area <5 mm 2 (aBV5/aTBV) and arterial vessels with cross-sectional area >10 mm 2 (aBVg10/aTBV) using a validated image processing approach. We assessed the associations of aBV5/aTBV and aBVg10/aTBV with echocardiographic measures of cardiac structure and function and pulmonary artery systolic pressure using multivariable linear regression models adjusted for demographics and cardiovascular risk factors. We also evaluated associations of pulmonary vascular arterial remodeling metrics with circulating NT-proBNP (N-terminal pro–B-type natriuretic peptide), self-reported dyspnea, and incident heart failure. RESULTS: Mean age was 80±4 years, 61% were women, 22% reported Black race, and mean left ventricular ejection fraction was 64±7%. Mean aBV5/aTBV was 0.30±0.08, and aBVg10/aTBV was 0.45±0.09. Lower aBV5/aTBV, reflecting greater distal pruning, and higher aBVg10/aTBV, reflecting greater proximal dilation, were both associated with greater left ventricular remodeling, worse diastolic function, and worse systolic function. Lower aBV5/aTBV and higher aBVg10/aTBV demonstrated nonlinear associations with greater pulmonary artery systolic pressure. Both lower aBV5/aTBV and higher aBVg10/aTBV were associated with higher circulating NT-proBNP and greater odds of moderate to severe dyspnea. Higher aBVg10/aTBV, in particular, was associated with greater risk of incident heart failure over a 4-year follow-up with a hazard ratio of 1.25 (95% CI, 1.03–1.51) per one SD in aBVg10/TBV. CONCLUSIONS: Among older adults, pulmonary vascular arterial remodeling is associated with greater left ventricular remodeling, worse diastolic and systolic dysfunction, greater pulmonary artery systolic pressure, greater odds of significant dyspnea, and greater risk of heart failure development. Our findings clarify the morphologic changes in the pulmonary vasculature that link cardiac dysfunction to higher pulmonary pressure in late life and may appear before symptomatology.
Correction to: Forecasting the Burden of Cardiovascular Disease and Stroke in Women in the United States through 2050: A Scientific Statement from the American Heart Association
Loss of the Coronary Artery Disease Risk Gene <i>LMOD1</i> in Vascular Smooth Muscle Cells Triggers Rapid-Onset Coronary Atherosclerosis
BACKGROUND: Atherosclerosis is the primary underlying cause of coronary artery disease. LMOD1 is a coronary artery disease risk gene whose role in coronary artery pathophysiology is unknown. Whole-body loss of Lmod1 causes a lethal neonatal visceral myopathy in mice, necessitating unique approaches for the study of vascular smooth muscle cell (VSMC) phenotypes. METHODS: Control mice ( Lmod1 WT carrying a Cre recombinase allele) and VSMC-restricted Lmod1 knockout mice ( Lmod1 SMKO ) were subjected to various atherogenic regimens. Atherosclerosis and LMOD1 (leiomodin 1) expression in mouse and human coronary arteries were assessed by histopathology and confocal immunofluorescence microscopy. Coronary arteries from Lmod1 WT and Lmod1 SMKO mice were analyzed with assorted stains and antibodies, immunogold lineage tracing, and spatial metabolomics. Aortic smooth muscle cells from Lmod1 WT and Lmod1 SMKO mice were subjected to lipid loading with or without lentivirus carrying wild-type or actin nucleation–deficient Lmod1 ( Lmod1 ND . Mice harboring an intronic deletion of Lmod1 or Lmod1 ND were engineered using clustered regularly interspaced short palindromic repeats. RESULTS: A lethal neonatal visceral myopathy occurred in Lmod1 SMKO mice using Myh11-CreER T2 , prohibiting further investigation. In contrast, Lmod1 SMKO mice generated with Itga8-CreER T2 survived and were therefore used in all subsequent studies. Under atherogenic conditions, Lmod1 SMKO mice displayed little vascular disease in several organs but developed diffuse, occlusive coronary atherosclerosis with fibrous caps. No such disease was observed in Lmod1 WT mice. Time-course studies documented lipid insudation and VSMC migration into the intima of coronary arteries of Lmod1 SMKO mice as early as 8 days after the regimen. Immunogold lineage tracing revealed that 46% of coronary plaque cells were of VSMC origin. Spatial metabolomics uncovered multiple lipid species within coronary atheromata of Lmod1 SMKO mice. In vitro studies demonstrated elevated lipid accumulation in Lmod1 SMKO VSMCs, which was rescued by viral-mediated Lmod1 WT or Lmod1 ND expression. An intronic deletion of Lmod1 , comprising a conserved orthologous sequence where the single nucleotide variant associated with coronary artery disease exists, showed attenuated LMOD1 expression. Heterozygous Lmod1 SMKO mice, with a comparable reduction in LMOD1, displayed no coronary artery disease. Similarly, VSMC-restricted expression of Lmod1 ND resulted in negligible coronary atherosclerosis. CONCLUSIONS: Under atherogenic conditions, Lmod1 SMKO mice present with rapid-onset coronary atherosclerosis. LMOD1 safeguards coronary homeostasis, apparently in an actin nucleation–independent manner.
Response by DeRubertis et al to Letter Regarding Article, “Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty for Below-the-Knee Peripheral Artery Disease: 2-Year Results From the LIFE-BTK Trial”
Response by Fearon et al to Letter Regarding Article, “Cardiac Allograft Vasculopathy Inhibition With Alirocumab: The CAVIAR Trial”
Letter by Chen et al Regarding Article, “Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty for Below-the-Knee Peripheral Artery Disease: 2-Year Results From the LIFE-BTK Trial”
Correction for Newman et al., The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity
A generative model for bipartite gene-sharing networks
Gene-sharing networks provide a powerful framework to study the evolution of viruses and mobile genetic elements. These bipartite networks, which link genes to the genomes that contain them, exhibit characteristic degree distributions: a scale-free distribution for genes and an exponential-like decay for genomes. Here, we propose a mechanistic model that explains these patterns through fundamental evolutionary processes including horizontal gene transfer, capture of new genes, emergence of new genomes, and gene loss. Using a mean-field approximation, we derive analytical expressions for the asymptotic gene and genome degree distributions, recapitulating a power-law distribution for genes and an exponential distribution for genomes. Numerical simulations validate these predictions and yield parameter values that closely fit empirical data from dsDNA viruses, RNA viruses, and prokaryotic pangenomes. This simple model with only two parameters provides a generative framework for bipartite gene-sharing networks, offering qualitative and quantitative insights into the main evolutionary forces driving genome plasticity. Setting the gene loss rate to zero, the gene and genome degree distributions of the model closely fit the empirically observed distributions. Thus, evolution of viruses appears to be dominated by gene gain, in agreement with the results of independent reconstructions of viral evolution.
Spatiotemporal control of Atg2 association with the ER during autophagosome formation
Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2–Scs2 interaction functions as a spatiotemporal switch that controls Atg2–ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.
The Personal Data Protection Act, 2026 of Bangladesh, Privacy and Global Data Governance
Bangladesh has entered a transformative phase in its digital governance journey with the enactment of the Personal Data Protection Act, 2026, which evolved from the Personal Data Protection Ordinance, 2025, and its subsequent amendment in February 2026. Current research is a comprehensive analysis of Bangladesh's data protection framework, examining its legislative evolution, key statutory provisions, institutional architecture, and implementation challenges. Based on comparative analysis with the European Union's General Data Protection Regulation (GDPR), documented breach incidents involving Bangladesh's National Identity database and private-sector data-fiduciaries, and scholarly and civil-society critiques, the study explores significant structural concerns including regulatory independence, state surveillance risk, and the balance between individual rights and state prerogatives. While the Act is a historic shift by recognizing citizens' personal data as their own property, substantial gaps exist between legislative text and effective implementation, in the absence of a mandatory breach-notification duty to affected individuals and Prime Minister's Office as the enforcing Authority. Strengthening Bangladesh's data protection framework through enhanced institutional independence, and transparent safeguards on state exemptions will offer closer alignment with international human-rights standards.
Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals
Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8 + T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.
The 2026 Cybercrime Law of Oman and Digital Governance
On 1 June 2026, Royal Decree No. 61/2026, replaced the Sultanate of Oman's fifteen-year-old Cybercrime Law (Royal Decree No. 12/2011) with a substantially expanded statute governing digital conduct. The Decree 61/2026 modernizes Oman's technical cybercrime framework only incrementally, but expands liability for online expression, most visibly through Article 20's prohibition on "misleading information" and content deemed to undermine public order. Current research examines the new law's structure, its treatment of technical and content-based offenses, and its penalty architecture, situating the reform within Oman's obligations under international human rights instruments. The article situates the law within the broader regional pattern in which cybercrime statutes are deployed less against hacking than against dissent, and is a set of doctrinal and drafting recommendations aimed at narrowing the law's most indeterminate provisions.
A fungal effector inhibits plant MAPK signaling by acting as a decoy substrate of MKK5
Plant immune responses rely on mitogen-activated protein kinase (MAPK) cascade that integrates pattern-triggered immunity and effector-triggered immunity. How fungal pathogens suppress this central signaling hub remains poorly understood. Here, we identify a secreted effector from phytopathogenic fungus Verticillium dahliae , VdHCE1, that is required for full virulence and directly targets host MAPK signaling. VdHCE1 interacts with the MAPK kinase MKK5 and is phosphorylated at threonine 166 in planta. Biochemical analyses demonstrated that VdHCE1 competes with MPK3 and MPK6 as a substrate of MKK5, thereby attenuating downstream MAPK activation. Consistently, VdHCE1 suppresses elicitor- and NLR-triggered immune responses, while deletion of VdHCE1 compromises fungal virulence in Arabidopsis and cotton. Genetic disruption of MKK5 restores the virulence of VdHCE1-deficient strains, establishing MKK5 as the functional target of VdHCE1. These findings reveal a strategy by which a filamentous fungal pathogen suppresses plant immunity by acting as a decoy substrate within the MAPK cascade and provide a molecular framework for engineering resistance to vascular wilt disease.
ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis
Abstract Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development.
Effective mass of a migrating interface
Interfaces are ubiquitous in materials and play a central role in microstructural evolution and material properties. Although interface migration has been studied for more than a century and remains an active field, several foundational assumptions of interface kinetics remain largely untested. In particular, interfaces are commonly treated as massless objects governed by overdamped dynamics. In this study, we show that grain boundaries exhibit measurable inertial behavior under high-frequency oscillatory driving. We introduce a quantitative method to extract an effective interface mass from the phase lag between the applied force and the interface velocity and find that this mass scales with the atoms participating in boundary migration. Using this framework, we identify regimes in which inertial effects significantly modify interfacial kinetics, especially at frequencies relevant to thermal fluctuations. These results challenge the conventional overdamped description and establish effective interface mass as a key ingredient in a physically complete theory of interface migration.
A potassium-based single-atom catalyst enables acute lung injury immunotherapy in mice by inhibiting macrophage pyroptosis
Abstract Acute lung injury (ALI), which can have a mortality rate approaching 40%, lacks effective therapies. Macrophage pyroptosis represents a pro-inflammatory event and a potential therapeutic target. Here, we report a single-atom immunomodulator, a potassium-based single-atom catalyst (K-SAC) with K–N 4 sites, that suppresses macrophage pyroptosis for ALI therapy through antioxidant catalysis. Constructed from biocompatible potassium, the most abundant intracellular metal in humans, K-SAC displays potent superoxide dismutase- and catalase-like activities, with the underlying mechanisms revealed by density functional theory simulations. Following preferential macrophage uptake, K-SAC scavenges reactive oxygen species, downregulates gasdermin D and its N-terminal fragment, activates endosomal sorting complexes required for transport-mediated membrane repair, and promotes membrane phospholipid remodeling, thereby effectively inhibiting macrophage pyroptosis. Notably, this catalytic membrane repair mechanism offers a versatile strategy for restoring membrane integrity. Such catalytic inhibition of pyroptosis preserves pulmonary immune homeostasis and ameliorates lipopolysaccharide- or cecal ligation and puncture-induced ALI, establishing a catalytic immunotherapeutic approach using a physiologically abundant element for therapeutic applications.
A posttranslational modification of fimbriae drives pathogenicity in <i> <i>Klebsiella pneumoniae</i> </i>
Antimicrobial resistance is a severe public health burden. Especially concerning are multidrug resistant (MDR) infections, which restrict treatment options and significantly increase mortality risk. A major cause of MDR infections worldwide is carbapenem-resistant Klebsiella pneumoniae (CR Kp ). The predominant CR Kp sequence type worldwide is ST258. However, the factors underlying ST258’s epidemic success are not well defined. Genomic analyses of clinical isolates of CR Kp have found that the two-component regulatory system CrrAB is a genomic feature of ST258, suggesting that it may contribute to its global dominance. Despite this, the molecular details underpinning CrrAB’s contribution to ST258 Kp biology and pathogenicity are poorly understood. We used RNA-sequencing to identify the regulon of CrrA and found that CrrAB induces the expression of a gene, encoding Crr-regulated fimbriae modifying protein (CfmP), that is essential for pathogenesis driven by this two-component system. We performed mass spectrometry analyses of fimbriae purified from Kp expressing or lacking cfmP and found that CfmP induces a novel oxidation to a histidine residue in the major pilin subunit of fimbriae, FimA. We demonstrate that this oxidation significantly increases host cell adhesion and high bacterial loads within the host. CrrAB also drives high antibiotic resistance in CR Kp . Thus, our results place CrrAB at the intersection of pathogenicity and antibiotic resistance supporting its function as an important regulatory system driving the global dominance of ST258.
Multi-omics integration unravels four molecular subgroups of corticotroph pituitary neuroendocrine tumours with distinct clinicopathological features
Abstract Corticotroph pituitary neuroendocrine tumours (PitNETs)/adenomas are heterogeneous sellar neoplasms. Currently established histopathological classification approaches are often considered limited in fully capturing the clinical and biological complexity of these tumours. Thus far, a molecular-based classification has not been established in corticotroph PitNETs. We compile molecular data of 270 corticotroph PitNETs (111 internal, 159 external), encompassing epigenome, transcriptome, and proteome profiles. Comprehensive integrative analyses are performed to identify, validate and characterise definitive molecular subgroups. Corticotroph PitNETs separate into four robust and clinicopathologically distinct molecular subgroups, which are broadly distinguishable by microscopy using SSTR1, GATA3 and SSTR5 immunohistochemistry. An integrated stratification model incorporating these molecular subgroups demonstrates significant prognostic utility. Our findings support the establishment of a refined molecular-based corticotroph PitNET classification, the full clinical value of which will require validation in prospective studies. To facilitate future research, we provide an easy-to-use epigenomic classifier for corticotroph PitNETs.
Sediment accumulation rate predicts the temporal resolution of marine fossil assemblages
Time averaging (TA), the mixing of noncontemporaneous organisms in fossil assemblages, governs the resolution of paleontological data and determines which biological and environmental processes are recorded in the geological record. To assess variation in TA and its dependence on external drivers, we used amino acid and radiocarbon methods to individually date 7,593 specimens across 384 samples from late Quaternary marine assemblages of calcifying organisms. Bivalve mollusks dominated the data, but 65 samples represented other taxa. Estimates of TA, measured by dispersion of specimen ages within samples, ranged from decades to millennia and scaled proportionally ( r 2 = 0.77) with sediment accumulation time (SAT), an inverse of sediment accumulation rate (SAR) that accounts for the stratigraphic span of samples. In agreement with numerical modeling, the observed TA estimates were an order-of-magnitude higher than SAT and modulated by SAT-dependent effects of vertical mixing and skeletal disintegration. When SAT is short, effective disintegration rates are too slow to suppress the amplifying role of mixing but increase in importance when SAT is long. The strong dependency of TA on SAT points to the overriding role of SAR in controlling the temporal resolution of fossil assemblages, notwithstanding other interacting drivers known to influence TA. These results demonstrate a long-suspected paleontological rule: The temporal resolution of fossil assemblages scales predictably with SAR. This straightforward relationship provides a quantitative guideline for determining the temporal adequacy of sedimentary records as archives of Earth system processes.