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Effect of APOC3 Inhibition With Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study
BACKGROUND: Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS: We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS: Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56–70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197–331), and remnant cholesterol was 53 mg/dL (interquartile range, 38–76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2–213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, −3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS: Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05610280.
Positive emotion interventions as a non-pharmacological approach to boost colostrum secretion: a randomized controlled trial
Global and regional climate modes modulate armed conflict risk
Because of their impacts on droughts, famines, and floods, modes of climate variability can shape patterns of social instability. Yet the mechanisms linking climate variability to armed conflict remain contested, especially relative to the myriad sociopolitical and economic determinants of conflict. A key challenge is that most studies rely on coarse, state-level data and treat climatic teleconnections as invariant. As such, it is unknown whether there are distinct climate hazards that select for conflict risk; whether conflict scales with climate hazard exposure; and whether such associations exist for more regional forms of climate variability. Here we leverage empirical modeling using a high-resolution gridded dataset of armed conflicts and the natural experiment afforded by two major climate modes—the El Niño–Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD)—to clarify how systematic hydroclimatic anomalies influence conflict emergence. Our results reveal the following: First, conflict risk heightens during El Niño, but ENSO-associated risk does not scale linearly with teleconnection strength; and, evidence for threshold behavior varies with spatial aggregation. Second, El Niño-related increases in conflict risk arise through its dry teleconnections, with limited evidence for wet teleconnections. Finally, the more regionally confined IOD also influences conflict, with both positive and negative phases elevating risk in strongly teleconnected regions, namely the Horn of Africa and Southeast Asia. These results reveal that modes of climate variability can differentially shape conflict risk, offering insight into societies’ vulnerabilities to natural climate fluctuations and, by extension, anthropogenic climate change.
Incretin-Based Therapies and Cardiovascular Outcomes: Beyond Weight Loss
Development and characterization of nanocellulose sheets from rice husk through sequential pretreatment and hydrolysis
Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes
The lack of highly effective disease-modifying treatments for schizophrenia necessitates exploration of novel aspects of its pathophysiology, including attention to innate immune mechanisms outside the brain. C4 protein activation, associated with the complement cascade of innate immunity, associates with symptoms and predicts outcomes in schizophrenia. However, C4 protein activation does not coincide with expected changes to other proteins in the complement cascade, suggesting another source of C4 protein activation. Studying a combination of fresh whole blood from 10 anonymous donors and a large set of publicly available microarray data, we show that C4 protein is found and expressed primarily in neutrophils and monocytes. Then, we compared the correlation between C4 protein in neutrophils, classical monocytes, plasma, and the number of C4A gene copies. We determined the number of C4A genes using digital droplet PCR, C4 protein in neutrophils (15 patients/21 controls) and plasma (30 patients/38 controls) using Western blotting, and classical monocytes (30 patients/38 controls) using flow cytometry. We found a large positive correlation between the number of C4A gene copies and the amount of C4 protein only in neutrophils and only in the schizophrenia group (Spearman’s rho = 0.63, 95% BCa CI: 0.12 to 0.89, P = 0.012). Our results indicate a convergence of innate immunity mechanisms associated with schizophrenia. The involvement of innate immunity deserves further attention to determine whether it could be a target for therapy in schizophrenia.
Research on parameter adjustment strategies for combustion control in dual-fuel engines with high ammonia substitution rates
Deep-learning endomicroscope with large field-of-view and depth-of-field for real-time in vivo imaging of epithelial cancer hallmarks
In vivo microscopy (IVM) has shown great promise to improve early detection of epithelial precancer, but it suffers from fundamental trade-offs that limit the resolution, field-of-view (FOV) and depth-of-field (DOF). Here, we present PrecisionView, a compact, deep learning-enabled endomicroscope that breaks these constraints and achieves 20 mm 2 FOV and 500 µm DOF with 4 µm resolution, representing approximately 5× increase in FOV and 8× larger DOF compared to conventional IVM with similar resolution. PrecisionView integrates a deep learning-optimized phase mask and real-time reconstruction, enabling rapid in vivo assessment of two key hallmarks of cancer: epithelial cell nuclear morphology and subsurface microvasculature through fluorescence and reflectance imaging. By imaging the oral cavity of healthy volunteers and cervical specimens with precancerous lesions, PrecisionView generates large-scale (1 to 3 cm 2 ) coregistered maps of cellular and vascular structures, revealing distinct microscopic patterns associated with anatomic structures and precancerous lesions. Our results suggest the potential of this computational endomicroscope to address the unmet need for early cancer detection at the point of care.
Unlocking the stability and storage conditions of plant-derived nanovesicles through metabolomic and lipidomic profiling
Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid
Intrinsic apoptosis is a form of cell death which is activated, executed, and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structural model of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing interresidue distances and dynamic solvent accessibilities complemented by integrative modeling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBid’s C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis.
A novel diagnosis method based on multimodal-aware bi-objective competitive mechanism for Alzheimer’s disease
Hard and soft power in immigration enforcement
AI-enhanced virtual laboratories improve learning outcomes and student engagement in food microbiology education
Exploring entropy landscapes using hard particle Monte Carlo metadynamics
For more than two decades, metadynamics has been a powerful tool for improving the sampling of rare events and metastable states in molecular systems. It has been sparingly used, however, to study the crystallization of colloidal systems, especially those comprised of hard particles with anisotropic shapes. In this work, we propose a method, hard particle Monte Carlo metadynamics (HPMC-MetaD), that combines the HPMC-scheme with metadynamics, thereby extending the application of metadynamics to hard particle systems whose phase transitions are driven solely by entropy. As illustrative examples, we use HPMC-MetaD to study five shapes previously reported to be candidate glass formers because of their stubbornness to crystallization. With HPMC-MetaD, we observe crystallization for all five shapes and construct entropy landscapes. These results demonstrate the effectiveness of HPMC-MetaD as a tool for exploring self-assembly in hard particle systems, which will enable a more comprehensive understanding of the underlying mechanisms, ultimately allowing predictive control over the assembly pathways.
Contemplative practices serve as complementary mental health strategies in nationally representative samples from Australia and New Zealand
Abstract Contemplative practices (including meditation and yoga) are increasingly popular worldwide, especially as alternatives and/or complements to mental health treatment. However, nationally representative samples that allow for accurate estimates of prevalence and relation to mental health are scarce. We conducted a nationally representative, cross-sectional survey in Australia and New Zealand ( N = 2640). Sampling was stratified by age, gender, ancestry/ethnicity, region and income. Two pre-registered questions were analysed to explore participants’ engagement in contemplative practices and associations to psychological distress and mental healthcare use. We used posthoc regression analyses to further clarify relationships between variables. Overall, 70% of participants engaged in contemplative practices over the past year, most commonly meditation (31%), relaxation (25%), breathing techniques (24%), and yoga (21%). Improving health and wellbeing were the primary motivations for practice. All contemplative practice users reported significantly higher psychological distress and mental healthcare use than non-practitioners ( p ’s<0.05). Adjusting for sociodemographic differences removed associations with distress among yoga and relaxation practitioners (β relaxation = 0.02, β yoga = − 0.03, n.s. ). For meditators, the association disappeared when we accounted for mental healthcare use (β meditation = 0.01, n.s. ). Breathing practice was associated with increased distress in all models (β breathing = 0.04–0.11, p’s< 0.05). Notably, meditators and relaxation practitioners with unmet healthcare needs reported less distress than non-practitioners with unmet needs ( d meditation =0.38, d relaxation =0.35). Contemplative practices are widespread among Australians and New Zealanders and may play a complementary and/or alternative role in managing mental health. Further research is needed to study their complex associations with mental health, and which types of contemplative practices are beneficial and safe for whom.
Evaluation of three ELISA assays for detection of Mycobacterium avium subsp. paratuberculosis antibodies in serum of sika deer (Cervus nippon)
Abstract ELISA-based assay testing offers a practical, high-throughput approach for early detection of Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne’s disease (JD), particularly for identifying subclinically infected animals within a herd. As no ELISA has been developed specifically for sika deer, the aim of this study was to compare the diagnostic performance of two commercial ELISA assays (ID.VET and IDEXX) designed for cattle, sheep and goats, and the Paralisa™ assay developed for red deer. Serum and faecal samples ( n = 105) were collected from 36 clinically affected sika deer at postmortem, 40 apparently healthy sika deer from the same infected herd at slaughter, and 29 sika deer from a JD-free herd at postmortem. Individual liquid faecal culture confirmed infection and MAP shedding status, with 73 animals (69.5%) testing culture positive. Sensitivities were 48% (Paralisa™), 43% (ID.VET) and 4% (IDEXX), while all assays showed 100% specificity. Paralisa™ and ID.VET assays demonstrated almost perfect agreement (κ = 0.86), whereas the IDEXX assay showed poor agreement with both assays. ID.VET assay also showed excellent inter-laboratory repeatability (ICC = 0.93). Overall, Paralisa™ and ID.VET assays provided superior sensitivity for MAP antibody detection in sika deer and may aid JD monitoring in infected herds.
Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes
Defective proteostasis is a hallmark of aging cells and tissues. Among the different components of the proteostasis network, in this study, we focus on a selective form of autophagy known as chaperone-mediated autophagy (CMA), and we set out to understand its physiological role in the retina. Using mice deficient for CMA [knockout for lysosome-associated membrane protein type 2A ( Lamp2A )], we have found that CMA blockade leads to impaired visual function, altered retinal proteostasis, and photoreceptor cell death. Conversely, mice that overexpress human LAMP2A show higher resistance to chemically induced photoreceptor degeneration and slower visual function decline. We found a similar protective effect against retinal degeneration upon pharmacological activation of CMA. To start elucidating the mechanisms behind CMA’s protective role in the retina, we used comparative proteomics and found elevated levels of enzymes related with glucose metabolism in CMA-deficient retinas that phenocopy those observed in old mice retinas. Overall, our results highlight a cytoprotective role for CMA in retina, in part through proteostatic regulation of enzymes involved in glucose metabolism, and support the feasibility of pharmacologically upregulating CMA against retinal degeneration.
The effect of vaping and smoking on colonic anastomosis healing in an experimental animal model
Abstract Anastomotic leakage is a serious complication after colorectal surgery. Smoking is known to impair anastomotic healing. The use of electronic cigarettes is increasing worldwide, and information about their effects on wound healing remains limited. The aim of this study is to investigate and compare the effects of electronic cigarettes and conventional cigarettes on rats. Thirty male Wistar Albino rats were divided into control, smoking, and vaping groups. Exposures were given twice daily for 30 days, and cotinine levels confirmed nicotine intake. On day 30 all animals underwent colonic anastomosis and were sacrificed seven days later. Bursting pressure, histopathology, and hydroxyproline levels were assessed. Cotinine levels were similar in the smoking and vaping groups. Bursting pressure showed no significant differences. Hydroxyproline content and histological scores, however, were significantly reduced in both exposure groups compared with controls, indicating impaired healing. In conclusion, vaping and smoking did not reduce mechanical strength but both impaired collagen synthesis and tissue repair. These results suggest that electronic cigarettes may not be a safer alternative to smoking in the surgical setting.