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Efficacy and Safety of Very Low Achieved LDL Cholesterol in Patients With Previous Ischemic Stroke
BACKGROUND: Patients with previous ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events. The benefits of achieving very low levels of low-density lipoprotein cholesterol (LDL-C) in such patients is unclear. METHODS: We analyzed patients with previous ischemic stroke enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), a randomized placebo-controlled trial studying evolocumab in patients with stable atherosclerotic cardiovascular disease (median follow-up, 2.2 years), and through the open-label extension (FOURIER-OLE) period (additional median follow-up, 5 years), to examine the relationship between achieved LDL-C and the long-term incidence of the primary end point (cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization) and stroke-related end points. RESULTS: The analysis included 5291 patients with previous ischemic stroke (>4 weeks). Of these, 666 (12.6%), 1410 (26.6%), 586 (11.1%), 508 (9.6%), and 2121 (40.1%) patients achieved LDL-C values of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. The incidence of the primary end point, all stroke, and ischemic stroke each decreased in a monotonic fashion with lower achieved LDL-C levels on a continuous scale ( P trend <0.001, 0.002, and 0.002, respectively). Compared with patients with LDL-C ≥70 mg/dL, those who achieved levels <40 mg/dL had incidence rate ratios of 0.69 (95% CI, 0.57–0.84), 0.73 (95% CI, 0.53–0.99), and 0.75 (95% CI, 0.54–1.05) for the outcomes of the primary end point, all stroke, and ischemic stroke, respectively. Hemorrhagic strokes were infrequent and unrelated to achieved LDL-C ( P trend =0.85). CONCLUSIONS: In patients with previous ischemic stroke, it appeared that the lower the LDL-C, down to levels <40 mg/dL, the lower the risk of major adverse cardiovascular events, including recurrent stroke, without a clear increase in risk of hemorrhagic stroke. These findings support the concept that more intensive LDL-C lowering in patients with previous ischemic stroke may be warranted. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633/NCT01764633.
Domestication drives repeated evolution of sexual–asexual life cycle trade-offs in yeast
For thousands of years, humans have domesticated animals and cultivated crops by managing reproduction and selecting for desirable traits. In contrast, microbial domestication has often occurred unintentionally, and the variation of life cycle as well as its impact on genome evolution remain poorly understood. Here, we systematically examined life cycle variation across a diverse panel of 771 diploid Saccharomyces cerevisiae isolates from both wild and domesticated lineages. We identified widespread alterations in sexual reproduction, including impairments of sporulation, spore viability, and mating-type switching. These changes led to the emergence of two distinct life cycle strategies, favoring either asexual or sexual reproduction, which were notably enriched in domesticated clades. Haplotype analyses of the HO mating-type switching gene revealed multiple, independent loss-of-function mutations, indicating convergent evolution of heterothallism. While a preference for sexual life cycle often correlated with increased genomic heterozygosity in domesticated and human-associated clades, this relationship was not uniform across all lineages. We propose that the co-occurrence of altered sexual and asexual cycle preferences results in a trade-off that balances outcrossing and the subsequent maintenance of heterozygosity in domesticated populations. Finally, we provide a CRISPR-based molecular toolbox and a stable haploid strain collection spanning global genetic diversity, enabling further genetic research and industrial applications.
Letter by Zhao Regarding Article, “Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial”
Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle
Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibro-adipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in the muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration.
Multivalve Involvement in Aortic Stenosis: Insights From a Narrative Review
Many patients with severe aortic stenosis present with concomitant multivalvular heart disease. The management of this condition remains challenging and requires a multidisciplinary approach that integrates clinical, hemodynamic, and multimodality imaging data to define the most effective and durable treatment strategy. Although randomized evidence to guide treatment decisions in this setting is limited, percutaneous interventions to address additional valvular lesions are being increasingly adopted. This review provides an overview of the pathophysiology of valvular diseases commonly associated with severe aortic stenosis, highlighting their prognostic implications after surgical or transcatheter treatment and their impact on risk stratification and therapeutic management.
Pathogenic role of MIF receptor (CD74) expressing T cells in inflammatory arthritis
High expression alleles of the innate cytokine, macrophage migration inhibitory factor (MIF), are associated with the development or the severity of autoimmune inflammatory diseases, including rheumatoid arthritis. Numerous studies support MIF’s role in activating inflammatory pathways and MIF inhibition reduces joint pathology in different experimental models of arthritis. We examined the impact of gene deletion of MIF or its cognate receptor CD74 in the T cell–dependent model of collagen-induced arthritis (CIA) and observed the complete absence of arthritis development, suggesting an unforeseen role for MIF/CD74 signaling in the development of arthritogenic T cells. While MIF has been shown in model systems to contribute to T cell activation by augmenting innate responses, fewer than 1% of T lineage cells express CD74 in naive spleens and lymph nodes, and its functional consequences in pathogenic T cell subpopulations have not been studied. We found CD74+ T cells to expand during CIA and to increase in number within joint synovium, where they express an effector memory phenotype and recapitulate CIA development upon transfer into naive mice. We further found evidence for the presence of CD74+ T cells in the circulation and joint synovium of patients with rheumatoid arthritis. MIF-dependent, CD74+ T cells may contribute to the chronicity of rheumatoid synovitis and to disease relapse in previously inflamed joints.
François Abboud: Pioneer, Mentor, and Friend to Many
Enhanced episodic specificity and socioemotional content in older adults’ everyday autobiographical thoughts
Cognitive aging research has long observed that older adults’ autobiographical memories and future thoughts, as assessed in laboratory contexts, lack spatiotemporal detail compared to young adults. Does this pattern also hold in everyday contexts? Across two studies, we examined characteristics of autobiographical thinking in real-world settings using ecological momentary assessment (EMA). Study 1 included an adult lifespan sample (N = 3,847). Study 2 (preregistered) included 217 young and older adults whose autobiographical memories were also assessed with a traditional lab-based interview. Contrary to lab-based findings commonly reported in the literature, older adults across both studies reported more episodic specificity in their everyday autobiographical thoughts than younger adults, as well as shifts toward positive and social focus rather than on the self. Linguistic analyses validated self-report data, revealing greater concreteness and perceptual detail with increasing age. Together, these findings highlight discrepancies between measurement approaches in autobiographical thinking in older age, emphasizing the significance of motivational and contextual factors in its study.
Response by Sittichokkananon et al to Letter Regarding Article, “Genetic and Lifestyle Risks for Coronary Artery Disease and Long-Term Risk of Incident Dementia Subtypes”
Implementing the Kunming-Montreal Biodiversity Targets
The Kunming-Montreal Biodiversity Targets present the most ambitious and serious conservation agenda ever developed—the overarching goal of preserving 30% of the planet by 2030. An organizational framework is now in place to deliver stable, predictive, and adaptive actions to monitor and measure the Earth’s biodiversity, assess ecological and evolutionary changes, identify key drivers of those changes, and, at the core, apply effective scientific, financial, and governmental treatments to halt biodiversity decline for a sustainable future. Is this implementable? We summarize the essence of the Targets to raise key questions about their execution. We show that the reports of large conservation organizations connect to these Targets only infrequently. Yet, there is abundant evidence to measure the successes and failures of the conservation enterprise. Generally, global financial commitments are substantial and increasing. We specify improvements and continual reassessments toward protected areas, developing countries, and indigenous communities. To achieve success, we recommend actionable plans to improve implementation leading up to and following the next CBD-COP meetings.
Letter by Yang and Lu Regarding Article, “Genetic and Lifestyle Risks for Coronary Artery Disease and Long-Term Risk of Incident Dementia Subtypes”
Early life-stage thermal resilience is determined by climate-linked regulatory variation
The ecological context of developmental physiology remains largely unexplored. We previously showed that thermal selection primarily targets early embryos in Drosophila melanogaster . Here, we used advanced introgression and pooled whole-genome resequencing to map the genomic basis of enhanced embryonic heat tolerance in a neotropical line of D. melanogaster . We identified two loci on chromosomes 2R and X that were consistently targeted by 16 generations of thermal selection across six replicate introgressions. Global population comparisons revealed that two SNPs in these genomic regions exhibit clinal and seasonal patterns linked to environmental variability in average precipitation and temperature variance across space and time. The two SNPs lie in putative regulatory regions of the genes SP70 and sog , where allelic variation in gene expression correlates with heat tolerance. Using the Drosophila Genetic Reference Panel, we confirmed that tropical alleles at these loci increase embryonic heat tolerance and interact epistatically, demonstrating the genotype-to-phenotype link in an independent set of diverse genetic backgrounds. Overall, our study extends previous work in developmental genetics by showcasing developmental regulatory variants that appear to be under natural selection.
Circulating Extracellular Vesicles in the Pathogenesis of Heart Failure in Patients With Chronic Kidney Disease
BACKGROUND: Cardiovascular disease causes >50% of deaths in patients with advanced chronic kidney disease (CKD). Clinical studies suggest that kidney-derived factors contribute to cardiovascular disease development in CKD, independently of comorbidities. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has been identified. In this cross-sectional study, we investigate how, in patients with CKD, circulating extracellular vesicles (EVs) facilitate pathological kidney-heart communication, thereby causing cardiotoxicity, impairing cardiac function, and contributing to heart failure progression. METHODS: We investigated the function of EVs from patients with CKD and adenine diet–induced CKD mice on cardiomyocyte and cardiac contractility. microRNA (miRNA) cargo of EVs was identified by small RNA sequencing and quantitative reverse transcription polymerase chain reaction, and their cardiotoxicity was tested by using miRNA mimics. Tissue and cellular origin of CKD-EV-miRNAs were determined from their corresponding primary miRNA expressions in mice. RESULTS: EVs from plasma of patients with CKD, but not from healthy controls, were cardiotoxic; they significantly induced apoptosis both in vitro and in vivo and impaired contractility of adult rat primary cardiomyocytes in vitro. Likewise, EVs from both plasma and kidneys of CKD mice were cardiotoxic. Pharmacologically depleting circulating EVs in CKD mice significantly recovered cardiac function and ameliorated heart failure, improvements that suggest CKD-EVs play a causal role in heart failure pathogenesis. Both human and mouse CKD-EVs were enriched in distinct miRNAs compared with control EVs. CKD-EV-miRNA mimics were cardiotoxic, impairing contractility and downregulating contractile gene expression in human induced pluripotent stem cell–derived cardiomyocytes. It is interesting that levels of endogenous primary miRNAs corresponding to circulating CKD-EV-miRNAs were significantly higher in CKD kidney tissues, specifically in CD45 -ve CD31 -ve renal cells, but not in CKD hearts, CKD livers, or CKD-peripheral blood mononuclear cells, a result that indicates CKD-EV-miRNAs originate renally. It is remarkable that CKD-EV-miRNA levels correlated with established markers of cardiac injury, thus uncovering the presence of subclinical heart disease and demonstrating heterogeneity in reno-cardiac disease. CONCLUSIONS: Collectively, our human subject and mouse studies show that circulating CKD-EVs, carrying distinct renal-derived miRNAs, mediate the molecular crosstalk that contributes to the pathogenesis of heart failure in CKD. Consequently, CKD-EVs hold promise as diagnostic and prognostic biomarkers for early disease detection and as targets for novel therapeutic interventions in chronic reno-cardiac disease.
The anticipation of imminent events is time-scale invariant
Humans predict the timing of imminent events to generate fast and precise actions, decisions, and other behaviors. Such temporal anticipation is critical over wide timescales, and especially salient over the range from hundreds of milliseconds to a few seconds. Despite advances in our understanding of basic timing behavior and its underlying neural mechanisms, it remains an open question whether anticipation is stable across these short time scales. Recent work shows that the brain models the probability density function (PDF) of events across time, suggesting a canonical mechanism for temporal anticipation. Here, we investigate whether this computation holds when the event distribution covers different time spans. We show that, irrespective of the time span, anticipation, measured as reaction time, scales with the event distribution. This demonstrates that the key computation—the estimation of event probability density—is invariant across temporal scales. We further show that the precision of anticipation is also scale invariant which contradicts Weber’s law. The results are established in vision and audition, suggesting that the core computations in temporal anticipation are independent of sensory modality. Perceptual systems exploit probability estimation over time independently of temporal scale to anticipate imminent events.
Transcatheter Closure of Patent Foramen Ovale With a Novel Biodegradable Device: A Prospective, Multicenter, Randomized Controlled Clinical Trial
BACKGROUND: Novel biodegradable patent foramen ovale (PFO) closure devices offer a promising therapeutic option. The efficacy and safety of the novel biodegradable devices compared with nitinol devices have not yet been investigated in a randomized clinical trial. METHODS: This multicenter, randomized, noninferiority trial examined whether the novel biodegradable PFO closure device achieves comparable closure success rates as traditional nitinol devices while demonstrating disappearance of the protruding parts of the device on echocardiography. A total of 190 patients with PFO were enrolled and randomly assigned to receive either the biodegradable device (n=96) or the nitinol device (n=94). The primary efficacy end point was PFO closure success rate at 6 months postprocedure as demonstrated by contrast echocardiography. We continued to evaluate device-related complications, device disappearance on echocardiography, and closure success rates over a 24-month follow-up period. RESULTS: Successful PFO closure was achieved in 87 patients (90.63%) in the biodegradable device group and 86 patients (91.49%) in the nitinol device control group. The lower limit of the 95% CI of absolute difference was −8.98%, greater than the predefined noninferiority margin of −10%, confirming that the biodegradable device was not inferior to the nitinol device in terms of closure success. One patient in the trial group required surgical device removal because of intraprocedural deformation. No deaths, embolism, thrombus on the device, or erosion were observed in either group throughout the entire study period. Transthoracic echocardiography revealed that the hyperechoic area corresponding to the biodegradable device began decreasing within the first year after implantation and disappeared on echocardiography by 24 months after implantation. CONCLUSIONS: The novel biodegradable PFO closure device, which disappears on echocardiography within 24 months after implantation, demonstrates noninferiority to the traditional nitinol device in both efficacy and safety.
T-bet-expressing Tr1 cells driven by dietary signals dominate the small intestinal immune landscape
Intestinal immunity defends against enteric pathogens, mediates symbiotic relationships with the resident microbiota, and provides tolerance to food antigens, safeguarding critical nutrient absorption and barrier functions of this mucosal tissue. Despite the abundance of tissue resident activated T cells, their contributions to these various roles remain poorly understood. Here, we identify a dominant population of IL-10 producing, T-bet-expressing Tr1 T cells, residing in the small intestinal lamina propria at homeostasis. Remarkably, these intestinal Tr1 cells emerge at the time of weaning and accumulate independently of the microbiota displaying similar abundance, function, and TCR repertoire under germ-free conditions. Instead, the small intestinal T-bet + Tr1 program is driven and shaped by dietary antigens, and accumulates in a cDC1-IL-27-dependent manner. Upon activation, these cells robustly express IL-10 and multiple inhibitory receptors, establishing a distinct suppressive profile. Altogether, this work uncovers a previously unappreciated dominant player in homeostatic small intestinal immunity with the potential to play critical suppressive roles in this tissue, raising important implications for the understanding of immune regulation in the intestine.
Correction to: Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction
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Adult neural stem cells mediate hippocampal synapse elimination for circuit homeostasis through MERTK
Although radial-like neural stem cells (rNSCs) give rise to functional neurons throughout life in discrete regions of the adult brain, their functions are not limited to neurogenesis. Recent studies indicate that the processes of rNSCs approach and/or wrap synapses. However, the function of these processes at synapses remains unknown. In this study, we report a role for rNSCs in actively engulfing synapses in the adult hippocampus. Mice in which rNSCs lack the phagocytic receptor MERTK exhibit reduced elimination of excitatory synapses, defective synaptic plasticity, and impaired formation of hippocampal learning and memory, but normal neurogenesis. Furthermore, we show that MERTK-dependent phagocytosis of excitatory synapses by rNSCs contributes to voluntary exercise-induced cognitive enhancements. Together, our data suggest that rNSCs eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MERTK, thereby maintaining circuit connectivity and cognitive function independently of neurogenesis.