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The MAPK/ERK pathway plays a critical role in the regulation of milk production by controlling cellular processes such as proliferation, differentiation and survival, which are essential for lactogenesis and mammary gland function. Bubalus bubalis (Water buffalo), known for its unique physiological and ecological characteristics, serves as an ideal model to explore the evolutionary and molecular roles of MAPK/ERK pathway genes. This study presents the first comprehensive computational analysis of MAPK/ERK genes in B. bubalis, identifying 21 key genes involved in the pathway. Phylogenetic analysis clustered these genes into 13 distinct clades, such as MST1, GRB2, RAS, ETS1, JUN and FOS, and revealed close evolutionary relationships with Bos taurus and Camelus bactrianus. Structural characterization identified 10 conserved motifs, including essential domains like protein kinase, ETS and RAS, reflecting their functional significance. Gene structure analysis revealed substantial variation in exon-intron patterns, while synteny analysis confirmed collinearity with human orthologs, indicating genomic conservation. Physicochemical analysis highlighted a broad range of molecular weights and isoelectric points, with most proteins classified as hydrophilic and thermostable. Gene duplication and selection analyses revealed seven segmentally duplicated gene pairs, with the JUN-ETS1 and DUSP6-MST1 pairs showing evidence of positive selection, suggesting functional divergence. These findings establish a foundational understanding of MAPK/ERK pathway genes in B. bubalis and provide valuable insights into potential targets for genetic improvement, selective breeding and sustainable dairy management strategies aimed at enhancing milk production and quality. Show less

Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation. DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S. Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival. The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets. Show less

The Saccharomyces cerevisiae Cell Wall Integrity (CWI) pathway responds to cell wall stress and is composed of MAP3K Bck1, MAP2Ks Mkk1 and Mkk2 and MAPK Slt2. Although human ERK5 has been considered the functional orthologue of Slt2, our results indicate that human ERK1 and ERK2 exhibit a much greater ability than ERK5 to replace Slt2 under various cell wall stresses. ERK5 is only able to slightly complement an slt2Δ mutant phenotype in the presence of tunicamycin, and the constitutively active truncated version ERK5ΔCt did not improve this complementation ability. Like Slt2, ERK1, ERK2 and ERK5ΔCt are concentrated in the nucleus, and show higher phosphorylation than ERK5 upon CWI pathway stimulation. Expression of a hyperactive version of the human MAP2K MEK5 leads to specific ERK5 and ERK5ΔCt phosphorylation, leading to a partial replacement of the Mkk1/2-Slt2 function under cell wall stress. Expressed in yeast, the human Dual Specificity Phosphatases DUSP3 and DUSP6 reduce the level of ERK5 phosphorylation to a similar extent, whereas DUSP6 shows higher activity than DUSP3 on ERK1 or ERK2. Our results show the different degree of integration of human ERKs and DUSPs into the yeast CWI signalling circuit, which can be exploited for functional analysis or pharmacological screenings. Show less

G-Quadruplexes (G4s) are noncanonical nucleic acid secondary structures enriched in genomic regions critical for transcription and replication. These dynamic scaffolds recruit G4-binding proteins (G4BPs), thereby regulating diverse cellular processes. However, the functional roles of G4BPs in the G4-bound state remain poorly defined. Here, we report the development of G4L-PROTACs-bifunctional small molecules that couple a G4 ligand with an E3 ligase recruiter to achieve selective proteasomal degradation of G4-bound G4BPs. Unlike RNAi or CRISPR-Cas9, which eliminate proteins irrespective of binding state, G4L-PROTACs enable depletion of G4BPs only when associated with G4s. Using model G4 motifs from telomeres and the NRAS 5' UTR, we demonstrated in vitro ternary complex formation. In cells, G4L-PROTAC treatment reduced endogenous levels of the G4-resolving helicase DHX36, resulting in a marked increase in intracellular G4 abundance, as shown by BG4 immunofluorescence. This phenotype highlights the ability of G4L-PROTACs to modulate the G4-protein equilibrium in living cells. Notably, G4L-PROTACs do not induce G4-mediated transcriptional silencing, underscoring their precision in modulating nucleic acid-protein interactions. This strategy offers a powerful platform for probing G4-G4BP functions and holds promise for therapeutic targeting of G4-associated proteins. Show less

R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less

Glioblastoma is the most aggressive form of primary brain tumor, characterized with poor prognosis and resistance to conventional therapies. Increasing evidence points to oxidative stress and redox dysregulation as important contributors to glioblastoma progression. Previously, chloride intracellular channel protein 4 (CLIC4), a redox-sensitive protein, has been implicated in cancer biology. However, its roles in glioblastoma remain poorly understood. Here, we found that CLIC4 expression is upregulated in glioblastoma tissues and cell lines, and is positively correlated with tumor malignancy and poor survival outcomes in patients with glioblastoma. Gene silencing of CLIC4 significantly reduces glioblastoma cell viability, migration, and proliferation in vitro and suppress tumor growth in vivo. Mechanistically, CLIC4 appears to maintain redox homeostasis by regulating mitochondrial functions, including membrane potential, mass, ROS production, and the activity of complexes III and IV. Moreover, a G-quadruplex (G4) structure located in CLIC4 promoter region is related to CLIC4 upregulation by oxidative stress in glioblastoma. This G4 structure can be readily oxidized to a parallel conformation, thereby enhancing its binding with DHX36 protein to promote gene transcription. Collectively, these findings position CLIC4 as a pivotal modulator of oxidative stress in glioblastoma and a potential target for developing therapeutic approaches for the treatment of glioblastoma. Show less

Senescence of mesenchymal stem cells in bone tissue (BMSCs), the primary progenitors of osteoblasts, is a key contributor to age-related osteopenia and osteoporosis. Aged cells exhibit elevated cellular stress and abnormal accumulation of stress granules (SGs), which contain G-quadruplex (G4) structured nucleic acids and G4-binding proteins. Dhx36, a helicase that unwinds G4 structure, may play a protective role in this context. In this study, we investigated the function of Dhx36 in BMSCs and bone homeostasis by silencing Dhx36 expression in vitro and in vivo. Dhx36 deficiency increased SG formation and impaired their resolution in BMSCs. This was accompanied by reduced expression of G4-containing autophagyrelated genes and diminished autophagic activity. Loss of Dhx36 also enhanced senescence features and impaired BMSC osteogenic differentiation. Dhx36 expression was significantly lower in bone tissue and BMSCs from aged mice, compared to young mice. Moreover, 8-week-old mice with BMSC-specific Dhx36 knockout exhibited reduced bone volume and trabecular number, indicating premature bone loss. Analysis of public singlecell RNA sequencing data further showed that stress induced by 5-fluorouracil in mice suppressed Dhx36 expression in BMSCs, and downregulated genes related to ossification and osteoblast differentiation. Collectively, our findings identify Dhx36 as a regulator of BMSC aging, linking SG dynamics and autophagy to bone homeostasis, and suggest Dhx36 as a potential therapeutic target to prevent age-related bone loss. [BMB Reports 2025; 58(12): 501-510]. Show less

Type 2 diabetes (T2D) is a complex metabolic disorder driven by genetic and environmental factors. While genome-wide association studies (GWAS) have identified numerous T2D-associated variants, many remain functionally uncharacterized. Integration of GWAS with molecular phenotyping offers a path to revealing biological relevance. We investigated the influence of GWAS-variants, including sub-threshold T2D-associated variants (GWAS p-value ≤ 0.0001), on gene and protein expression to assign functional relevance. Genetic variants associated with T2D in the GWAS Catalog and present in our whole-genome sequencing (WGS) data were used to perform expression quantitative trait loci (eQTL) analysis in 242 whole-blood mRNA-sequenced samples. The same variants were used to perform protein quantitative trait loci (pQTL) analysis in a set of 362 plasma samples profiled on the Olink platform. For each analysis, the datasets were randomly split into discovery and validation subsets. Associations between variants and mRNA or protein levels were tested by multiple linear regression, and only QTLs that reached a false discovery rate adjusted p-value ≤ 0.05 in the discovery dataset and replicated in the validation dataset (p ≤ 0.05) with same direction of effect were carried forward. QTL-linked mRNAs and proteins were subsequently evaluated for their relationship with T2D status to connect them with T2D pathophysiology. We identified 1,291 eQTLs linked to 97 mRNAs and 1,273 pQTLs linked to 22 proteins. Among these, 10 mRNAs and 5 proteins were differentially expressed between non-diabetic and diabetic individuals. Notably, LPL, APOBR, APOM (lipid metabolism), NOTCH2, TREH (β-cell/endocrine regulation), and HLA-A, OAS3 (immune response) converged on three biological axes central to T2D pathophysiology. The directionality of molecular effects was consistent with known disease mechanisms, including insulin resistance (LPL, APOBR), β-cell stress (TREH, NOTCH2), and chronic inflammation (OAS3). Our findings indicate that variants falling below conventional GWAS significance thresholds can have demonstrable effects on gene expression and protein levels. This underscores the importance of prioritizing biological relevance alongside statistical significance, rather than relying solely on rigid p-value cutoffs. Show less

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Lipid biomarkers, including direct low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and apolipoprotein A1 (ApoA1), are essential tools for cardiovascular risk assessment. Monitoring patient-derived median values over time may provide insights into population health and analytical performance. This study provides a descriptive analysis of population-level lipid results spanning nearly two decades. While trends in patient medians may support quality assurance, these data do not constitute a validated approach to risk prediction or definitive analytical monitoring due to the absence of outcome and treatment information. We retrospectively analyzed routine clinical laboratory data from Uppsala University Hospital, Sweden, covering January 2006-December 2024. A total of 890,948 LDL-C, 867,446 HDL-C, 64,787 ApoB, and 65,500 ApoA1 results were included. Measurements were performed on Abbott Architect systems until 2021, after which assays were transferred to Roche Cobas Pro platforms. Statistical analyses included trend evaluation, variability assessment, and seasonal pattern analysis. Women had modestly higher LDL-C and HDL-C levels compared to men, while ApoB values were similar between sexes. ApoA1 was notably higher in women. Over the 19-year period, median LDL-C declined from 3.18 to 2.62 mmol/L, consistent with improved lipid management. HDL-C remained stable (1.36-1.45 mmol/L), while ApoB and ApoA1 concentrations showed minimal change. Variability was highest for LDL-C (median CV 6.4%) and lowest for ApoA1 (median CV 2.6%). Seasonal variation was negligible across all analytes. Testing volumes increased substantially for LDL-C and HDL-C, whereas ApoB and ApoA1 requests peaked around 2010 and later declined. Long-term monitoring of median patient values demonstrates declining LDL-C, stable HDL-C, and consistent ApoB/ApoA1 ratios with minimal seasonal effects. These findings highlight the potential utility of patient medians as supplementary quality indicators and for population-level lipid surveillance. Show less

Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin-binding protein C ( To elucidate the common and distinctive pathological pathways across species and foster a greater understanding of the concordance of mouse HCM models to clinical These common biological processes across species are consistent with known phenotypic aspects of HCM such as hypertrophy, hypercontractility, diastolic dysfunction, and altered energy metabolism. Surprisingly, among conserved biological processes within cardiomyocytes across species, the individual genes driving the biological processes were distinct. This work to identify common and species-specific disease-promoting pathway differences will allow development of targeted therapies for both human and veterinary application and will facilitate an understanding of the idiosyncrasies of mouse models. Show less

Cardiomyopathy (CM) is associated with atrial remodeling and atrial fibrillation (AF), often complicating rhythm management. Ventricular dysfunction contributes to AF through pressure and volume overload, while AF worsens ventricular function via tachycardia and irregular activation. Evidence suggests catheter ablation improves outcomes in CM patients, though success is influenced by the extent of atrial and ventricular remodeling. Patients undergoing their first catheter ablation for AF were divided into hypertrophic (HCM), ischemic (ICM), non-ischemic (NICM), and no-CM groups. Pre-ablation late-gadolinium enhancement cardiac magnetic imaging (LGE-MRI) was used to assess left atrial (LA) fibrosis burden and anatomical distribution. Patients were followed prospectively for arrhythmia recurrence. A total of 552 patients, 39 HCM (69% obstructive), 39 ICM, 115 with NICM, and 359 without CM were included between January 2015 and December 2022. LA fibrosis was significantly higher in patients with CM (19.1 ± 7.5% vs. 16.5 ± 6.9%; P = 0.01). HCM and ICM had the greatest LA fibrosis among the different CM subtypes (21.3 ± 8.7% and 21.9 ± 9.1%, respectively). There was no significant difference in the regional distribution of fibrosis among the various groups. AF recurrence was observed in 321 (58.2%) after 456 (175-1204) days. Multivariate analysis revealed that compared to no CM, HCM was associated with a three-fold increase in AF recurrence (HR = 3.07, 95% CI 2.06-4.58, P < 0.001), followed by ICM (HR 1.61, 95%, CI 0.95-2.72; P = 0.07) and NICM (HR of 1.53, 95% CI 1.14-2.06; P = 0.05). LA fibrosis and volume index were independently associated with recurrence (HR = 1.03, 95% CI 1.01-1.06, P = 0.01 and HR = 1.02, 95% CI 1.01-1.03, P = 0.01). Genetic testing revealed key distinctions between HCM and NICM, with MYBPC3 and MYH7 as prominent genes in HCM and a heterogeneous genetic basis in NICM. Hypertrophic cardiomyopathy is associated with the highest risk of AF recurrence followed by ischemic and non-ischemic cardiomyopathy after catheter ablation. LA fibrosis regional patterns did not differ between cardiomyopathy types, while overall fibrosis and volume predicted recurrence. Show less

Post-stroke cognitive impairment (PSCI) is a prevalent and disabling condition with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive neuromodulation therapy. This review synthesizes recent advances in rTMS for PSCI, focusing on its mechanisms, therapeutic effects across cognitive domains, and safety profile. We summarize evidence indicating that rTMS exerts its effects by modulating cortical excitability, promoting neuroplasticity via BDNF signaling, and regulating dysfunctional brain networks, particularly the central executive and default mode networks. Clinical studies demonstrate that high-frequency stimulation, primarily targeting the dorsolateral prefrontal cortex (DLPFC), can significantly improve memory, executive function, attention, and activities of daily living (ADLs) in patients with PSCI. A favorable safety profile is reported, with mild and transient adverse effects being most common. However, significant heterogeneity in stimulation parameters (e.g., frequency, intensity, pulses) exists across studies. Current evidence suggests that ensuring a sufficient number of stimulation pulses and duration may be necessary. rTMS represents a promising therapeutic tool for PSCI, demonstrating benefits in key cognitive and functional domains. Future research must prioritize large-scale, standardized randomized controlled trials to optimize stimulation protocols, confirm long-term efficacy, and explore synergistic combinations with other rehabilitation strategies. Show less

Low physical activity (LPA) is associated with cardiovascular and cerebrovascular pathologies. This study aimed to assess the prevalence of several noncommunicable diseases relating to LPA. Using the 2021 Global Burden of Disease data set, we modelled LPA-related disease burdens across 204 countries and territories, quantifying mortality counts, age-standardised mortality rates, and disability-adjusted life years (DALYs) for five noncommunicable diseases. We conducted multivariable stratification analyses to assess variations by gender, age, and sociodemographic index (SDI) quintiles. We used age-period-cohort modelling to project burden trajectories, while applying counterfactual decomposition frameworks to delineate synergistic interactions between LPA and risk factors. We found that LPA accounted for 555 101 related deaths globally in 2021 across the five studied pathologies, mostly among individuals aged 60-94 years. Association between LPA-related disease burden and SDI followed a U-shaped distribution across regions and diseases. Among individuals aged 60-89 years, LPA-related deaths were significantly higher in women than in men, indicating a disproportionate burden on elderly females. Ischaemic heart disease (IHD) trends stabilised in low- and middle-SDI regions but declined significantly in high-SDI regions, underscoring global health disparities. From 2007 to 2011, LPA DALYs and mortality risk ratios for IHD, stroke, and lower extremity peripheral arterial disease declined from >1 to <1, whereas diabetes mellitus exhibited an opposite trend, highlighting LPA's persistent and significant impact on diabetes-related morbidity. Demographic shifts and epidemiological transitions were primary drivers of LPA-related disease burden across five pathologies. In high-SDI regions, epidemiological changes predominated, whereas population growth was a key factor in low- and middle-SDI regions. Synergistic interaction of these factors with LPA is projected to substantially amplify future disease burden. Physical activity should be increased among elderly women to address health risks associated with LPA. Likewise, urgent public health interventions are needed for LPA-related diabetes. As IHD burden rises in low- and middle-SDI regions, vascular disease care strategies require optimisation. Moreover, high-SDI regions should strengthen nationwide physical activity promotion, while low- and middle-SDI areas must enhance healthcare infrastructure and manage population growth to reduce LPA-related disease burdens. Show less

Centrioles undergo marked transformations during spermatogenesis that are essential for sperm motility and male fertility. Despite their importance, the molecular mechanisms and ultrastructural dynamics underlying these transformations remain largely unknown. Here, we apply ultrastructure expansion microscopy and reveal previously unrecognized centriolar architectural changes in mouse male germ cells, including geometry switching between the two centrioles and stage-specific removal of distal tip proteins such as centrin and SFI1. We further identify the centrin-POC5 inner scaffold as a key structure selectively augmented at the distal centriole, which directly forms and anchors the flagellum. Functional analyses of Show less

Evaluating prognostic performance of Alzheimer's biomarkers, multi-modal physiological measures, and clinical history in asymptomatic individuals versus established risk factors in asymptomatic individuals is can inform efficient screening strategies. To determine and compare the prognostic performance of amyloid biomarkers, multi-modal physiological measures, and clinical/modifiable risk factors We used clinical trials (A4/LEARN), longitudinal cohorts (ADNI, AIBL, HABS, NACC, OASIS), and the UK Biobank spanning 2004-2025 (median follow-up time range: 1.8-13.72 years) in time-varying survival and binary classification analyses. Settings included a United States clinical trial, longitudinal cohort studies spread across medical centers in the United States and Australia, and the volunteer-based UK Biobank. Patients were cognitively asymptomatic and age 65+ at baseline, and potentially progressed to either clinical impairment, clinical AD diagnosis, or incurred AD ICD-codes. Patients were volunteer or convenience samples. PTau-217, amyloid-PET, CSF markers (AB1-42, pTau-181, total-Tau), plasma proteomics, multi-modal brain-imaging, and cognitive tests were evaluated as predictors, along with demographics (age, sex, education), APOE genotype, and modifiable risk factors in the 2024 Lancet report PTau-217 and amyloid-PET from A4/LEARN were used to predict clinical impairment (CDR score of 0.5+ on two consecutive visits). PTau-217, amyloid-PET imaging across five cohorts, and CSF markers were used to predict clinical AD diagnosis. Plasma proteomics, multimodal neuroimaging, and cognitive assessments from the UK Biobank were used to predict AD ICD-codes. Sample-sizes ranged from 356-28,533 (31-519 cases; female percentages: 48.45-67.39). Models of demographics, APOE genotype, and risk-factors as predictors did not show statistically significant differences in time-dependent area under the receiver operating characteristic curve (AUROC) compared to separate models using amyloid biomarkers. Predicting cognitive impairment in A4/LEARN, pTau-217 improved AUROC by 0.045-0.084 (best: 0.616 (CI: 0.51-0.723) vs. 0.7 (CI: 0.609-0.793)). Amyloid-PET improved AD prediction (maximum AUROC increase 0.074; 0.561 (CI: 0.468-0.653) vs. 0.635 (CI: 0.537-0.733)), and CSF biomarkers showed slightly larger gains (maximum AUROC increase 0.127; 0.627 (CI: 0.438-0.816) vs. 0.754 (CI: 0.577-0.931)). In UK Biobank analyses, mean AUROC improvements were minor across proteomics (0.044), neuroimaging (0.143, with 99.8%/0.2% class-balance), and cognitive tests (0.064). In cognitively asymptomatic populations, biomarkers offer limited advantage over demographics, APOE genotype, and modifiable risk factors, supporting their importance in early AD screening strategies. Show less

Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less

The size of fat globules in ruminant milk to some extent affects the nutritional quality of dairy products and plays potential roles in infant and adult health. Lipid droplets (LD) in mammary epithelial cells are the precursors of milk fat globules (MFG). However, it is unclear what happens to proteins during the transformation process from LD to MFG, and little is known about the regulation of LD diameter in vivo. In this study, 12 mid-lactation Saanen dairy goats were randomly divided into 2 groups: a control group fed a basal diet and an experimental group fed a basal diet supplemented with CLA at 90 g/d. Goat milk was collected for analysis of composition and MFG size. Mammary gland tissue was collected for analysis of LD diameter and proteins. The size of MFG was found to depend on LD diameter in the mammary glands of dairy goats. The regression equations for MFG size (Y) and LD diameter (x) were Y Show less

Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM This study aimed to investigate PM In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM These findings suggested that PM Show less

The Epstein-Barr virus (EBV) infection status varies among BL subtypes. There are unresolved questions regarding the contribution of EBV, which is strongly associated with Burkitt lymphoma, to BL pathogenesis. Differences between EBV-positive and EBV-negative BL have been previously reported. A long-debated and studied topic is the differing origins of EBV-positive and EBV-negative BL cells. Studies have suggested that miRNAs, which are post-transcriptional elements involved in many pathways, play a role in this process. In our study, in silico analyses and a literature review were used to identify miRNAs potentially involved in lymphoma and B lymphocyte development pathways. Three miRNAs (miR-182, miR-320a, miR-144) targeting the Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β Show less

Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yolk percentage, we performed integrated transcriptome and metabolome analyses on the liver, ovary, and magnum tissues of Rhode Island Red chickens with high and low yolk percentages. A total of 322 differentially expressed genes (DEGs) and 128 significantly differential metabolites (SDMs) (VIP>1, P < 0.05) were identified in the liver, whereas 419 DEGs and 215 SDMs were detected in the ovary, and 238 DEGs along with 47 SDMs were found in the magnum. In the liver, genes such as HMGCR, DHCR7, MSMO1, and CYP7A1 were linked to cholesterol metabolism, essential for steroid hormone synthesis and yolk formation, while ACACB, ACSL1, ACSL4, LPL, and SGPP2 were involved in fatty acid biosynthesis, a key process for supplying energy and structural components of the yolk. In the ovary, COL6A6, COMP, CHAD, ITGA7, THBS2, and TNC contributed to extracellular matrix-receptor interactions, which are fundamental for follicle development and oocyte maturation. In the magnum, UGT1A1, MAOB, and ALDH3B2 participated in drug metabolism-cytochrome P450 and amino acid metabolism, ensuring a proper environment for egg white formation and potentially influencing nutrient allocation to the yolk. Metabolic pathway enrichment revealed that steroid hormone biosynthesis, glycerophospholipid metabolism, and betaine metabolism were predominant in the liver; pyruvate, taurine, and hypotaurine metabolism in the ovary; and phenylalanine metabolism in the magnum. Moreover, integrated analysis highlighted key metabolites and genes potentially regulating yolk deposition, including 7,8-dihydroneopterin and Pg 38:4 in the liver (related to immune modulation and lipid metabolism, respectively), thalsimine in the ovary, as well as DL-glutamine in the magnum, all of which may be crucial for maintaining metabolic homeostasis and supporting egg formation. Collectively, these findings deepen our understanding of how distinct molecular and metabolic pathways in the liver, ovary, and magnum orchestrate yolk proportion and deposition. Such insights may advance future strategies to improve egg quality and productivity in poultry breeding programs. Show less

Cardiovascular diseases (CVDs) remain a leading global cause of mortality and disability, with significant disparities observed across countries. This is particularly true in Central and Eastern Europe (CEE), where populations are primarily at high and very high CVD risk. Highlighting modifiable risk factors underscores the urgent need for effective prevention programs. This paper introduces the European Program for Prevention (EPP), an initiative by the International Lipid Expert Panel (ILEP), designed to address these challenges. The EPP aims to enhance awareness and knowledge of validated preventive healthcare solutions implemented in CEE countries, showcase the region's potential for innovative strategies, and evaluate the adaptability of successful programs for broader implementation. The EPP strongly supports the EU Cardiovascular Health Plan, as well as initiatives by the World Heart Federation (WHF) and World Health Organization (WHO), by promoting best practices, early detection, integrated prevention frameworks, training, cross-border cooperation, and policy development. It advocates shifting healthcare priorities towards pre-disease prevention, thus reducing reliance on resource-intensive treatments. The program proposes an optimal CVD prevention system that includes mandatory health education, screening programs for familial hypercholesterolemia and universal Lp(a) screening, and comprehensive check-ups, notably integrated, comprehensive care programs. By leveraging existing validated programs and fostering collaboration, the EPP seeks to reduce the burden of CVD, improve outcomes, and promote cardiovascular health across Europe and beyond. Show less

Osteoarthritis (OA) is a progressive joint disease with no disease-modifying therapies. Incretin-related signaling pathways, including GLP1R, GIPR, ADCY3, and CREB1, may influence cartilage homeostasis and inflammation, but their transcriptional profiles across cohorts remain unclear. To evaluate the expression, diagnostic potential, and functional context of GLP1R, GIPR, ADCY3, and CREB1 in OA cartilage through an integrative meta-analysis of public transcriptomic datasets. We systematically searched the GEO database, identifying 147 records. After screening and applying inclusion criteria, four datasets were included (GSE114007, GSE117999, GSE169077, GSE220243; total N = 83). Expression data were normalized within each dataset, converted to per-gene z-scores, and analyzed using random-effects meta-analysis. Machine learning classifiers (logistic regression, random forest, XGBoost) were trained with leave-one-dataset-out validation. Functional enrichment was performed using g:Profiler. Protocol registration: PROSPERO CRD420251177348. CREB1 (pooled mean difference +0.459, p = 0.036) and GLP1R (+0.518, p = 0.016) were significantly upregulated in OA cartilage, ADCY3 was downregulated (-0.552, p = 0.010), while GIPR showed no significant change. Heterogeneity was low (I A multi-cohort transcriptomic analysis suggests the involvement of a GLP1R-ADCY3-cAMP-CREB1 axis in OA cartilage, with reproducible upregulation of CREB1 and GLP1R. Although sample-level classification was modest, pathway-level signals and experimental evidence support CREB1 as a biomarker candidate and therapeutic target. These findings provide a rationale for prospective validation studies and translational exploration of incretin-pathway modulation in OA. Show less

E3 ubiquitin ligases play a crucial role in modulating receptor stability and signaling at the cell surface, yet the mechanisms governing their substrate specificity remain incompletely understood. Mahogunin Ring Finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitination and degradation. Unlike cytosolic E3 ligases, membrane-tethered E3s require transmembrane adapters to selectively recognize and regulate surface receptors, yet few such ligases have been studied in detail. While MGRN1 is known to regulate the receptor Smoothened (SMO) within the Hedgehog pathway through its interaction with the transmembrane adapter Multiple Epidermal Growth Factor-like 8 (MEGF8), the broader scope of its regulatory network has been speculative. Here, we identify Attractin (ATRN) and Attractin-like 1 (ATRNL1) as additional transmembrane adapters that recruit MGRN1 and regulate cell surface receptor turnover. Through co-immunoprecipitation, we show that ATRN and ATRNL1 likely interact with the RING domain of MGRN1. Functional assays reveal that MGRN1 requires these transmembrane adapters to ubiquitinate and degrade the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, with the latter resulting in enhanced eumelanin production. These findings expand the repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to dictate substrate receptor specificity. By elucidating how MGRN1 selectively engages with surface receptors, this work establishes a broader framework for understanding how this unique class of E3 ligases fine-tunes receptor homeostasis and signaling output. Show less

Lipoprotein lipase (LPL) is a key enzyme that hydrolyzes triglycerides (TGs) into free fatty acids. Several genetic variants of LPL are directly or indirectly associated with variations in lipid levels, causing different lipid metabolic disorders. Previous studies on the LPL gene have shown that exons and introns are essential for gene expression and regulation. However, mechanisms through which introns regulate gene expression and function remain unclear. In this study, we successfully designed a protocol to assess the function of LPL intron 3 in LPL regulation. This was accomplished by constructing luciferase reporter vectors, containing full and partial intron 3 fragments from a healthy human DNA sample. These recombinant constructs facilitated the analysis of transcriptional activity using dual-luciferase reporter assays in cell lines. The results showed that the luciferase activity of the chimeric firefly luciferase reporter construct containing the full-length LPL intron 3 was higher than that of other constructs. In this study, a successful protocol was developed to assess the function of LPL intron 3 in regulation of the LPL gene. This protocol provides a novel method for functional analysis of introns and intronic variants that can be applied to other genes. Show less

s: Cholesteryl ester transfer protein (CETP) inhibition has long been attracting a lot of attention if it could reduce the risk for coronary artery disease (CAD). A previous study has demonstrated that protein-truncating variants (PTVs) were associated with lower risk for CAD, which was dependent on lower LDL cholesterol in general population. We tested this hypothesis among Japanese heterozygous FH (HeFH) patients whose CAD risk was extremely high. We investigated the clinical data of 2344 patients diagnosed with HeFH (mean age = 50 years, males = 1,174, median LDL cholesterol = 244 mg/dL) who were examined for their genotype of CETP and phenotypes, including the presence of CAD from 1990 to 2024 at Kanazawa University Hospital. We investigated whether PTVs of the CETP were associated with plasma lipid levels and CAD among patients with HeFH. We identified 42 patients (1.8 %) with a PTV of CETP in HeFH patients. Compared with non-carriers, carriers of a PTV of CETP had higher HDL cholesterol (effect size, 17.6 mg/dL; 95 % confidence interval [CI], 11.4 to 23.8; P < 0.001), lower LDL cholesterol (-15.4 mg/dL; 95 % CI, -24.5 to -6.3; P < 0.001), and lower lipoprotein (a) [Lp(a)] (-7.8 mg/dL; 95 % CI, -12.5 to -2.5; P < 0.001). CETP PTV carrier status was associated with reduced risk for CAD (odds ratio, 0.64; 95 % CI, 0.38 to 0.90; P < 0.001). PTVs of CETP were significantly associated with higher HDL cholesterol, lower LDL cholesterol, lower Lp(a), and lower risk for CAD among patients with HeFH. Show less