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Establishing early physical activity (PA) habits is vital for long-term health, with parents considered as key influencers on children's PA. Yet, most previous parent-offspring dyads examining PA associations were cross-sectional, rarely used device-based measures, and often overlooked movement composition. The aim of this study was to determine whether mother's and father's waking movement composition is cross-sectionally or longitudinally associated with those of their children. The SOPHYA cohort recruited families from a nation-wide population-based random sample stratified by child's sex, birth year, and language. All youth aged 6-16 years and their parents officially residing in Switzerland, were eligible. Baseline and follow-up assessment occurred in 2013-2015 and 2019-2020, respectively. Questionnaire information and accelerometer measurements were collected remotely. The main predictor was parental movement composition at baseline. The associations between parental and child movement compositions were examined using Dirichlet regression models, adjusting for child's age and sex, parental education, and language region. The endpoints were children's movement composition at baseline (cross-sectional) and follow-up (longitudinal), respectively. Baseline assessment provided accelerometer and self-reported covariate data for the same measurement week in 686 mother-child and 373 father-child pairs. Follow-up assessment provided accelerometer data for 263 children with maternal and 149 with paternal baseline data. Cross-sectionally, replacing parental sedentary behaviour (SB) with moderate-to-vigorous activity (MVPA) (mothers: 0.10, p < 0.001; fathers: 0.09, p = 0.002) or replacing SB with light physical activity (LPA) (mothers: 0.13; < 0.001; fathers: 0.09; p < 0.005) was associated with similar, but smaller shifts in children. Longitudinally, replacing parental SB with LPA was associated with similar, but smaller shifts in children five years later (mothers: coefficient: 0.12, p = 0.021; fathers: coefficient: 0.10, p = 0.108). The cross-sectional change in children's LPA/SB ratio predicted from a parent's 20% decrease in SB and corresponding 20% increase in LPA was about 18-fold smaller than the observed maternal shift and about 29-fold smaller than the paternal shift from which it was predicted. Dirichlet regression results suggest that parental movement composition may predict children's movement composition, highlighting parental movement patterns, particularly SB, as potentially effective targets for short- and long-term interventions to increase PA in both parents and children. Show less

Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes, as bioactive extracellular vesicles, have underexplored potential in regulating brain neuroinflammatory responses. This study aimed to characterize desert milk exosomes (D-Exo) and investigate their neuroprotective and anti-neuroinflammatory effects in LPS-induced HNF mice model and an LPS-stimulated BV2 microglia. Exosomes were isolated from desert and non-desert milk (ND-Exo) for proteomic analysis. After pretreating BV2 cells with exosomes and stimulating with LPS, their inflammatory responses and polarization were assessed by RT-PCR. Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. D-Exo exhibited superior stability and a unique proteomic profile enriched with proteins linked to neuroinflammation and blood-brain barrier (BBB) integrity, notably within the AMPK signaling pathway. In vitro, D-Exo shifted LPS-stimulated microglia from the M1 to the M2 phenotype. In vivo, it alleviated HNF and cognitive decline, reduced Aβ D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive decline by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential. Show less

The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, using a CRISPR/Cas9-mediated Show less

Health apps designed to monitor, motivate, and educate people towards their health goals are getting more users and features each time. These apps offer valuable support for self-managing health behaviors and achieving long-term objectives. However, there is limited understanding of user preferences regarding essential app features. The aim of the study is to get insights about potential users' preferences, in order to tailor better apps for lifestyle management. We conducted a three-part web survey with 389 respondents from four countries as part of the DigiCare4You European Union (EU) project. In the first part, we collected the socioeconomic characteristics and health status of each respondent. In the following stage, we asked five questions on a Likert scale to ascertain the individual level of usage and general attitude towards technology. Finally, we performed a discrete choice experiment (DCE) using an unlabeled design and estimated the odds ratio for each feature using conditional logit analysis. We also ran alternative estimations stratifying by non-communicable disease (NCD) patients and non-NCD patients, and explored latent profile analysis (LPA) to understand whether the general attitude towards technology impacts the preference pattern between users. The DCE revealed that respondents showed a clear preference for monitoring physical health over emotional status. They favored receiving lifestyle achievement notifications weekly rather than daily, and daily rather than more frequently. Similarly, respondents preferred uploading body weight measurements on a weekly or monthly basis rather than daily. Users expressed a preference for collaborating with their doctors to set exercise and diet goals, rather than either deciding independently or delegating entirely to their doctors. End-users also show a pattern of preferring notifications for goals instead of challenging other users. Preferences regarding the subjects of health content between workout routines, food recipes, and new scientific evidence were not significant; also, no statistical significance was found for the decision between follow-up visits with their doctor in person or remotely. LPA returned two groups regarding their general attitude towards technology: a lower, an intermediate, and a higher usage in their private life based on their responses to the questionnaire. Stratified DCEs have shown heterogeneity of users' preferences according to their specific attitude towards technology. Our study indicates that potential mobile health (mHealth) app users managing chronic conditions prefer platforms that enable shared responsibility with their doctors in defining health goals while having an intermediate level of interaction frequency with the app. These findings are key to tailoring mHealth apps that can optimize motivation triggers, support healthier lifestyles, and empower patients with chronic conditions. Show less

G protein-coupled receptors (GPCRs) rapidly transmit extracellular signals by activating effector proteins, thereby producing well-characterized second messenger molecules. Free, unanchored polyubiquitin chains have been proposed as secondary messengers in immune and inflammatory pathways that regulate cellular responses to invading pathogens and the inflammatory cytokine Interleukin-1 beta (IL-1β). It remains unknown whether these molecules play a role in GPCR signaling. The present study used primary, immortalized, and transformed cellular models, together with loss-of-function approaches, to demonstrate the presence and functions of unanchored polyubiquitin chains in inflammatory signaling pathways that activate the activator protein 1 (AP-1) and nuclear factor-kappa B (NF-κB) transcription factors. In response to inflammatory GPCR agonists Angiotensin II (Ang II), lysophosphatidic acid (LPA), and thrombin (Thr), the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early signaling events that lead to T-loop phosphorylation of Transforming Growth Factor β-activated kinase 1 (TAK1), IκB kinase beta (IKKβ), c-Jun N-terminal kinases (JNK1/2), and p38 mitogen-activated protein kinases (p38). In parallel, we document the rapid, transient TRAF6-dependent production of unanchored lysine (K)63-linked polyubiquitin chains that accumulate in TAK1 and IKKβ immunocomplexes. Pull-down assays specifically designed to capture unanchored polyubiquitin chains in cellular extracts from stimulated cells further support their transient nature. Lastly, stable expression of a zinc finger ubiquitin-binding protein (ZnF-UBP) domain, which specifically binds unanchored polyubiquitin chains in immortalized keratinocytes exposed to LPA and Thr, shows that this production occurs in the proximity to the plasma membrane and diminishes the T-loop phosphorylation of TAK1, IKKβ, JNK1/2, and p38, thereby affecting the induction of early transcriptional events. Our results support a novel paradigm in GPCR signal transduction, identifying unanchored K63-linked polyubiquitin chains as second messenger molecules. The online version contains supplementary material available at 10.1186/s12964-025-02646-6. Show less

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and adeno-associated virus (AAV) vectors, to introduce premature stop codons into LPA. This strategy produced robust and durable lowering of circulating apolipoprotein(a) (apo(a)) in LPA-transgenic mice. Using SMRT-seq with single-molecule unique molecular identifiers, we quantified deletion events and found that CBE did not induce large deletions when targeting a single LPA site and produced only a small fraction (<4%) of large deletions when editing across multiple sites. In contrast, CRISPR-Cas9 cutting of LPA resulted primarily in large deletions. These findings demonstrate that CBE enables sustained reduction of circulating apolipoprotein(a) in an LPA-transgenic mouse model while largely preserving genomic integrity. Show less

Clutch length is a key determinant of reproductive efficiency in geese and strongly positively correlates with egg production. We recorded daily egg production in 280 individually housed Zi geese, calculated clutch-related indices, and selected 12 geese to form long-clutch (LC) and short-clutch (SC) groups for ovarian transcriptomic, proteomic, and metabolomic analyses. The results showed that egg number, large clutch length, large clutch number, average clutch length, and average clutch number were significantly higher in LC than in SC groups (P < 0.0001). Transcriptomic analysis identified 885 differentially expressed genes enriched in oocyte development and ovarian steroidogenesis, with APOB, PLA2G4C, MMP2, MMP9, and NOBOX as key genes; proteomic analysis identified 437 differentially abundant proteins enriched in arachidonic acid metabolism and mitophagy, with CXCL12, RARB, and MAD2L1 as key proteins; and metabolomic analysis identified 35 differentially abundant metabolites enriched in glycolysis/gluconeogenesis, with lactic acid, guanidinoacetic acid, and 3-hydroxybutyrylcarnitine as key metabolites. Integration of multi-omics datasets highlighted a lactate-associated cross-omics signature supported by YWHAZ at the protein level and by the lactate transporter SLC16A3. Collectively, these findings deepen our understanding of the molecular basis underlying clutch-length variation in goose ovaries and highlight candidate genes, proteins, and metabolites for future functional validation. Show less

Familial dysbetalipoproteinemia (FDB) is a lipid disorder characterized by defective clearance of triglyceride-rich lipoprotein remnants. Definitive diagnosis has relied on genetic markers, lipid profiles, and specialized lipid assays including gel electrophoresis that demonstrates the characteristic beta-band consistent with enriched small VLDL and IDL. We present a case of a 51-year-old female with progressive hyperlipidemia despite a stable plant-based diet and regular exercise. Her lipid profile met many of the diagnostic criteria for FDB (ApoB < 120 mgd/L, TG > 133 mg/dL [1.5 mmol/L], and TG/ApoB ratio < 8.8). However, advanced lipid testing failed to demonstrate hallmark lipid remnant accumulation, likely due to statin therapy initiation prior to the time of testing. Genetic testing revealed heterozygosity for the ApoE2 variant (Arg176Cys) and another novel variant of unknown significance (VUS), 593 G > A (Arg198His), on the same allele (herein termed ApoE2-Wolverine). The ApoE2-Wolverine variant may be contributing to the patient's dyslipidemia; however, further investigation into its functional significance and cardiovascular implications is needed. Her treatment with rosuvastatin 10 mg, 2 g of daily eicosapentaenoic acid (EPA), and lifestyle modifications contributed to improvements in her lipid levels. This case highlights the diagnostic challenges in FDB, especially when novel genetic variants are involved. While many criteria for FDB were met, confirmatory gel electrophoresis and genetic testing were inconclusive. This case underscores the need for multimodal assessment in FDB diagnosis, incorporating genetic analysis, lipid profiles, and therapeutic response. Show less

Familial hypercholesterolemia (FH) is a heritable condition that disrupts the body's ability to clear low-density lipoprotein cholesterol (LDL-C), commonly known as "bad cholesterol" from the bloodstream. This leads to persistently elevated LDL levels from birth, significantly increasing the risk of premature atherosclerosis and cardiovascular events, such as heart attack and stroke. This occurs due to variations in genes such as low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). The treatments that are available for FH include pharmacological interventions, microbiome-based treatments, molecular approaches, nanotechnology methods, surgical procedures, nutraceuticals, herbal therapy, yoga and physical fitness methods, along with lifestyle management. This review discusses the adverse effects associated with various conventional treatment methods for hypercholesterolemia and the need for a safe and effective approach for the treatment of this genetic condition. An integrated approach combining pharmacological, molecular, and lifestyle interventions has emerged as a pragmatic solution. Yoga and fitness-based therapies positively impact lipid profiles, offering non-pharmacological and holistic adjunctive options. This comprehensive approach addresses the multifaceted aspects of FH management, considering genetic factors, socioeconomic considerations, and individualized patient needs. Show less

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ Show less

This study aims to elucidate the role of Enterococcusin the progression from inflammatory bowel disease to colorectal cancer (CRC), with a focus on identifying key metabolites and host genes regulated by Enterococcusand their influence on CRC development. Using the database gutMGene, gutMDisorder and MACdb, we mined the key metabolites and human genes. We acquired the activated genes (panel 1) and inhibited genes (panel 2), and metabolite associated genes (MAGs, panel 3). Subsequent analyses included protein-protein interaction (PPI) network construction, functional enrichment, differential expression and survival analysis in CRC, and immune infiltration assessment. We screened 12 activated genes (Panel1: Show less

PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8 Show less

Although recommended for cardiovascular (CV) risk stratification in adults, the role of lipoprotein(a) [Lp(a)] in hypertension is not fully established. To evaluate Lp(a) levels in adult outpatients with essential arterial hypertension. A retrospective, observational study was conducted in outpatients of both sexes, aged ≥ 18 years, with treated or untreated essential hypertension, who were consecutively evaluated at the Hypertension Unit, Excellence Hypertension Center, Sant'Andrea Hospital, Rome, Italy. Participants underwent office and out-of-office blood pressure (BP) measurements, as well as assessment of hypertension-mediated organ damage (HMOD). BP measurements were performed, and hypertension phenotypes were classified according to 2023 European hypertension guidelines. Lp(a) levels were measured, and the study population was stratified according to a Lp(a) cut-off value of ≥50 mg/dl. Due to the non-uniform distribution, absolute Lp(a) values were logarithmically transformed. A total of 230 patients with available Lp(a) values were included (42.6% women, mean age 66.3 ± 11.5 years, BMI 27.1 ± 4.5 kg/m2, office BP 137.1 ± 18.1/83.7 ± 11.0 mmHg, 24-hour BP 129.8 ± 14.5/79.6 ± 9.8 mmHg, Lp(a) 51.4 ± 65.3 mg/dL), among whom 32.2% had Lp(a) ≥50 mg/dl. There were significantly higher proportions of men (74.3% vs. 49.4%; P < 0.001), dyslipidaemia (97.3% vs. 75.0%; P < 0.001) and comorbidities (55.4% vs. 30.8%; P < 0.001) in patients with high Lp(a) than in those with normal Lp(a), who also received more frequently lipid lowering therapies (P < 0.001) and aspirin (P = 0.003). However, lower office systolic BP values (133.5±18.8 vs. 138.8±17.6 mmHg: P = 0.036) were observed in patients with Lp(a) ≥50 mg/dL than in those with < 50 mg/dl. Also, no significant differences for Lp(a) levels were observed among various hypertension phenotypes, as defined by office (P = 0.156) or out-of-office BP values (P = 0.065). No significant correlations were found between Lp(a) and office or out-of-office BP levels, both in treated and untreated hypertensive outpatients. In our population, Lp(a) levels were not associated with either office or out-of-office BP values, irrespective of antihypertensive treatment status. The role of Lp(a) in hypertension warrants further investigation. Show less

Atherosclerotic cardiovascular disease (ASCVD) continues to be a major global health burden, with substantial residual cardiovascular risk remaining. Growing evidence highlights the liver’s pivotal role in the onset and development of ASCVD through multiple interconnected pathways. As the metabolic center of the body, the liver regulates the synthesis, secretion, and clearance of several atherogenic lipoproteins while simultaneously serving as a systemic inflammation amplifier, producing cytokines, acute-phase proteins, and coagulation factors. Traditional liver-targeted therapies, such as statins, have demonstrated that regulating liver metabolism can confer significant cardiovascular benefits. Subsequently, advances in nucleic acid-based drugs and in vivo gene-editing tools have broadened this strategy, enabling accurate and durable modulation of hepatic gene expression. However, recent clinical trials suggest that improvements in laboratory biomarkers do not always translate into proportional reductions in major adverse cardiovascular events. Moreover, the long-term safety and durability of lipid nanoparticles and gene-editing platforms remain ongoing concerns. Future research should focus on the classification of patients based on multiple omics data, and distinguish those whose main problem is metabolic disorder from those who are mainly at high risk of inflammation, thereby facilitating personalized therapeutic targeting. Overall, current evidence indicates that the liver represents a convergent therapeutic target for modulating both lipid metabolism and inflammation, offering a promising opportunity for deeper and more durable cardiovascular risk reduction. Show less

Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering or antidiabetic therapy and advanced atherosclerosis. Proteomics enables the identification of biomarkers and molecular pathways related to atherogenesis in prediabetes. To investigate the relationship between prediabetes and preclinical atherosclerosis in apparently healthy individuals using a comprehensive proteomic approach. This cross-sectional, population-based study included 389 participants (mean age 49 ± 10 years; 47% males) from the Białystok PLUS cohort in Poland. Individuals with known diabetes, major cardiovascular, inflammatory, or malignant diseases, or those receiving steroidal or lipid-lowering therapy were excluded. Carotid ultrasound was used to assess preclinical atherosclerosis, and prediabetes was defined as impaired fasting glucose, impaired glucose tolerance, or HbA1c 5.7–6.4%. Proteomic profiling was performed using the Olink® Reveal platform, enabling deep profiling of 1050 proteins with the Proximity Extension Assay and next-generation sequencing readout, yielding log2-scaled NPX (Normalized Protein eXpression) values. In preliminary analyses, we identified proteins associated with prediabetes and then linked them to early atherosclerotic lesions. A block-sPLS-DA model integrating clinical and proteomic data revealed clear separation between participants with and without prediabetes. The clinical block comprised eight variables reflecting cardiometabolic status, whereas the proteomic block retained 45 proteins across two components. The heatmap shows pairwise Pearson correlations between selected serum proteins and clinical variables (Fig. 1). Vascular and age measures cluster together and share correlation patterns distinct from those of BMI and glycaemic parameters. A protein module including the ectodysplasin A2 receptor (EDA2R) and leiomodin 1 (LMOD1) correlates positively with age and vascular parameters, and inversely with GFR and HDL-C. Multivariable linear regression analyses were performed with selected vascular parameters as dependent variables and clinical covariates, together with proteins identified in Component 2, which are weakly related to clinical parameters and thus may represent novel biomarkers associated with prediabetes (Fig. 2). Expression of EDA2R (B = 0.05; An integrative block-sPLS-DA approach separated individuals with prediabetes from those without and revealed a proteomic signature independent of clinical covariates. Within this signature, the expression of LMOD1, EDA2R, and C16orf89 showed robust associations with atherosclerosis-related vascular traits. Enrichment analyses highlighted proteins involved in neuronal processes as candidate pathways linking early glucose disturbances with preclinical atherosclerosis. The online version contains supplementary material available at 10.1186/s12933-026-03128-w. Show less

Acute ischemic stroke (AIS) poses a substantial risk of permanent disability and death globally, with neuroinflammation being a key driver of secondary brain damage post-stroke. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond its well-accepted role in cholesterol metabolism through low-density lipoprotein receptor (LDLR) degradation, has emerged as an important mediator of neuroinflammation, making it an attractive new therapeutic target. This has sparked broader discussions about the potential pleiotropic effects of PCSK9 inhibitors on brain function. Proprotein convertase subtilisin/kexin type 9 mediates inflammation post-ischemia directly and indirectly by disrupting mTOR pathways. This stimulates signaling cascades associated with inflammation. For example, the nuclear factor-κB (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinase (MAPK) pathways in microglia activation. It also brings about reaction in astrocytes and increases the release of cytokines like interleukin-1β, interleukin-6, and tumor necrosis factor-α. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein E receptor 2 (ApoER2) present on neurons cells, leading to further inflammatory effects. Proprotein convertase subtilisin/kexin type 9 indirectly increases lipoprotein(a) [Lp(a)], which promotes inflammation through the Lp(a)-TLR4 axis and induces endothelial dysfunction. Monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (siRNA) agents (inclisiran) are examples of PCSK9 inhibitors. According to preclinical studies, these inhibitors can mitigate neuroinflammation by blocking the M1 polarization of microglia and downregulating key pro-inflammatory factors while preserving the blood-brain barrier (BBB). They also inhibit neuronal apoptosis via the Bcl-2/Bax-caspase cascade and reduce the aggregation of β-amyloid (Aβ). Evidently, the findings from cardiac ischemia-reperfusion models show that pretreatment with PCSK9 inhibitors is effective with optimal neuroprotection. Recent clinical data support these mechanisms: PCSK9 inhibitors not only lower LDL-C and Lp(a) but also reduce systemic inflammatory markers (e.g., high-sensitivity C-reactive protein [hs-CRP], interleukin-6). Early adjunctive use of evolocumab in AIS is associated with reduced early neurological deterioration, highlighting that its effects extend beyond lipid lowering to modulating immune pathways in both the central and peripheral systems. As a promising multitarget therapeutic strategy for AIS, PCSK9 inhibitors target the interconnected pathways of lipid metabolism and neuroinflammation. Future studies should address critical challenges such as defining the optimal therapeutic time window, improving BBB penetrability, and refining patient stratification to translate their neuroprotective effects into clinical benefits for stroke patients. Show less

The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via Show less

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of early onset atherosclerosis. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3)-inhibiting monoclonal antibody, lowers LDL-C independently of LDL receptor activity. However, its effects on other lipid-related markers remain poorly investigated in real-world clinical practice. We herein report a 54-year-old Japanese woman with genetically confirmed compound heterozygous familial hypercholesterolemia (FH) treated with evinacumab in combination with other lipid-lowering agents. Lipoprotein apheresis was continued every two weeks throughout the treatment. Serum sampling before and after evinacumab administration found that, following evinacumab initiation, LDL-C decreased from 324 to 205 mg/dL (reduction of 119 mg/dL, -36.7%) and triglycerides from 155 to 51 mg/dL (reduction of 103 mg/dL, -66.8%). Notably, atherosclerosis-related markers showed substantial reductions, with remnant-like particle cholesterol (RLP-C) decreasing from 10.5 to ＜2.0 mg/dL, small dense LDL-C (sdLDL-C) from 80.2 to 22.1 mg/dL, and malondialdehyde-modified LDL (MDA-LDL) from 105 to 87 mg/dL. Apolipoproteins (ApoB, ApoC2, ApoC3, ApoE, and ApoA5) decreased as well. No significant changes were observed in lipoprotein (a), free fatty acids, interleukin-6, or high-sensitivity C-reactive protein levels. This is the first clinical report to comprehensively evaluate the lipid-modifying effects of evinacumab in a Japanese HoFH patient. In this case, evinacumab was highly efficacious against atherosclerosis-related markers and apolipoproteins, beyond simple LDL-C reduction, suggesting additional cardiovascular benefits. These findings provide mechanistic insights that may inform therapeutic strategies for the management of HoFH. Show less

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with 'normal' LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in Among participants, 31.2 % had LDL-C <100 mg/dL (normal), 39.5 % had LDL-C 100-129 mg/dL, and 29.3 % had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3 %, 6.9 %, and 7.6 % of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5 % in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( Individuals with 'normal' LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles. Show less

Although the specific reasons for exercise motivation and the emotions felt during it are both important for physical activity (PA), little is known about how they combine to form distinct psychological profiles. This study used a person-centered approach to identify these latent profiles based on specific exercise motives and exercise-induced emotions among Chinese college students, and examined their associations with gender and PA. We recruited 1,586 undergraduates from a university in southern China ( Show less

To use compositional data analysis to examine the associations of daily movement behaviors with body composition, and to predict changes in body composition after reallocating time among behaviors in preschool-aged children. 268 preschoolers were included in the cross-sectional study. An accelerometer was used to assess sedentary behavior (SB), light and moderate-to-vigorous physical activity (LPA and MVPA). A parental report was used to collect sleep time. Bioelectrical impedance analysis was employed to assess body composition. Compositional linear regression analysis was employed to explore how daily movement behaviors were associated with body composition. Compositional isotemporal substitution analysis was employed to estimate changes in body composition after reallocating time among behaviors. 24-h movement behaviors composition significantly predicted fat-free mass index (FFMI), soft lean mass index (SLMI), and skeletal muscle mass index (SMMI), but not fat mass index, percent body fat, and bone mineral content index. The compositional isotemporal substitution analyses consistently showed that increasing MVPA at the expenses of SB was positively associated with FFMI (+0.328 kg/m The findings highlight the importance of MVPA in improving preschoolers' body composition. Increasing MVPA at the expenses of SB may be a strategy to improve body composition in preschoolers. Show less

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less