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To identify latent profiles of Fear of Progression (FoP) in parents of children with cancer, explore their associated factors, and test the mediating role of Sense of Coherence (SOC) between FoP and psychological distress (PD). A cross-sectional study was conducted with 273 parents of children with cancer in China. We used latent profile analysis (LPA) to identify FoP profiles, multinomial logistic regression to determine associated factors, and mediation analysis to test the role of SOC. Three distinct FoP profiles were identified: medication sensitive with low fear (38%), treatment sensitive with moderate fear (21%), and overall high fear (41%). These profiles were significantly differentiated by disease-related (e.g., treatment history), individual-related, and interpersonal-related (e.g., self-disclosure) factors. Across the sample, higher FoP was associated with greater PD. Importantly, mediation analyses revealed that SOC significantly mediated the relationship between FoP and PD for the moderate and high FoP profiles, but not for the low LoP profile. Parents of children with cancer exhibit heterogeneous FoP profiles. SOC acts as a crucial mediator between FoP and PD, particularly for parents with moderate and high FoP profiles. These findings underscore the importance of screening for specific FoP profiles and suggest that tailored interventions designed to enhance SOC could effectively reduce PD in high-risk parents. Show less

Asymptomatic Alzheimer's Disease (AsymAD) is a preclinical stage of Alzheimer's Disease (AD) identified by amyloid plaques and neurofibrillary tangles in cognitively normal individuals and offers essential understanding for early diagnosis and treatment of AD. To uncover molecular insights into AsymAD, RNA sequencing (RNA-seq) datasets from two different consortia, ROSMAP (Religious Orders Study and Memory and Aging Project) and MSBB (Mount Sinai Brain Bank), were investigated. The individuals in the datasets were grouped into AD and AsymAD based on clinical and neuropathological criteria. Differentially expressed genes (DEGs), differentially expressed transcripts (DETs), and differentially used transcripts (DUTs) were identified between AD and AsymAD samples. The results were interpreted through functional enrichment analysis and compared with the predefined lists of AD-related and learning-memory-cognition-related genes, and genes from an independent mouse dataset. The genes from the list of DEGs, DETs and DUTs were mapped onto a human protein-protein interaction network, revealing subnetworks associated with AsymAD. This led to the discovery of biomarker candidate genes: NRXN3, DGKB, ADAMTS2, GNG4, ENPP5, PCOLCE, COL25A1, COL26A1, MRPL1, and MRPL30. This study introduces an innovative approach by including DETs and DUTs in the analyses, beyond the standard focus on DEGs, pointing out comprehensive insights into the molecular mechanisms of AsymAD. In addition, combining the results of the subnetwork analysis from DEGs, DETs, and DUTs provided a new perspective to AsymAD and resulted in the discovery of further important genes, which can pave the way for early detection and intervention of AD. Show less

Electronic health records will increasingly aggregate longitudinal laboratory results from multiple providers, but availability alone does not guarantee safe interpretation. We present guidance, developed by laboratory professionals with the DGKL medical informatics division, for cumulative displays that are clinically meaningful. The core principle is to group medically comparable analyses while preserving laboratory provenance so that clinicians can follow true patient trends without conflating them with laboratory-induced variation. Comparability is defined algorithmically from Logical Observation Identifiers Names and Codes (LOINC) axis: analyses estimating the same patient property (allowing serum/plasma system equivalence and mathematically convertible properties such as substance vs. mass concentration) are grouped; coding of units is harmonized via Unified Code for Units of Measure (UCUM) with consistent conversion of numeric results and corresponding reference intervals, including inequality qualifiers. Analyte-specific conversion factors should come from authoritative sources; for poorly standardized measurands (e.g., tumor markers) or when conversions are inappropriate (e.g., Lp(a)), results remain separated. Methodological distinctions that affect interpretation - such as screening vs. confirmatory drug testing and point-of-care testing - are displayed independently to signal potential analytical discontinuities. A standardized, medically meaningful default result sequence - derived from LOINC metadata and clinical nomenclatures, with alphabetic naming as a pragmatic fallback - supports cross-laboratory aggregation; rare or novel tests lacking robust standardization remain as free text. The rules-based approach updates seamlessly with LOINC releases and remains compatible with the Nomenclature for Properties and Units (NPU), facilitating cross-border exchange within the European Health Data Space. While harmonized presentation improves trend analysis, true comparability ultimately requires measurement procedures traceable to reference methods and materials. Show less

Alzheimer's disease and related dementias are influenced by genetic and environmental risk factors. We investigated the relationship between contextual exposures and cognitive outcomes, independent of and in interaction with polygenic risk. Using the Multi-Ethnic Study of Atherosclerosis (N = 5687), we assessed the associations of contextual determinants representing the social, chemical, and built environment with incident dementia and late-life cognition using proportional hazards regression and generalized estimating equation models, then evaluated their joint effects stratified by genetic risk via Bayesian kernel machine regression. Neighborhood disadvantage was associated with higher dementia risk and poorer cognitive scores after adjusting for genetic risk and other individual-level covariates. Joint analysis of all contextual determinants indicated that more deleterious mixtures of contextual determinants are associated with lower late-life cognition among apolipoprotein E ɛ4 non-carriers with intermediate polygenic risk. Contextual determinants are associated with dementia and late-life cognition after adjusting for age, sex, education, and genetic risk. Show less

Neurexins (NRXNs) are presynaptic adhesion molecules essential for synaptic organization and the regulation of excitatory-inhibitory balance. The molecular diversity of NRXNs arises from alternative promoters and splicing, particularly at splice site 4 (SS4), which dictates ligand binding. Dysregulation of NRXNs has been linked to substance use disorders, but it remains unclear how the expression of NRXN isoforms responds to physiologically relevant amounts of ethanol. Human IMR-32 neuroblastoma cells were maintained in an undifferentiated (UnDiff) state or differentiated (Diff) with trans-retinoic acid (tRA) to promote an enrichment in parvalbumin (PV) expression. Cells were exposed to physiologically relevant ethanol concentrations (0, 7, or 35 mM) in vapor chambers. Quantitative polymerase chain reaction (qPCR) quantified mRNA levels of major NRXN transcripts (NRXN1, NRXN2, and NRXN3) and SS4 variants (+SS4, -SS4). Immunocytochemistry (ICC) was used to measure protein expression and overlap with neuroligin2 (NLGN2) and PV. Differentiation increased basal expression of several NRXN transcripts, including NRXN2α, NRXN2 +SS4, NRXN3α, NRXN3β, and NRXN3 -SS4. In Diff cells, ethanol-induced dose-dependent downregulation of NRXN2α, NRXN3α, NRXN3β, and NRXN3 -SS4 transcripts, while NRXN1 remained stable. In Diff cells, ICC confirmed isoform-specific protein reductions without changes in other markers (Tuj1 and PV). NRXN3β decreased at 7 and 35 mM; and NRXN1 and NRXN2 at 35 mM. Ethanol significantly reduced overall expression of NRXN3β at 7 and 35 mM; and NRXN1 and NRXN2 at 35 mM, along with NRXN3β-NLGN2 spatial overlap and NRXN1, 2, and 3β signal within PV-positive cells, indicating targeted disruption of inhibitory synaptic organization. Physiologically relevant ethanol exposure alters NRXN expression in an isoform-, splice site-, and differentiation-dependent manner, prominently affecting NRXN3 and the SS4 site. These coordinated transcriptional and proteomic changes suggest that ethanol perturbs NRXN3β-NLGN2 interactions and inhibitory synapse stability, revealing a molecular pathway where alcohol may compromise cortical network excitatory-inhibitory balance. Show less

Intermediate monocytes (IM) exhibit proinflammatory properties and contribute to atherosclerosis. Elevated lipoprotein(a) [Lp(a)] levels modulate monocyte behavior, while proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in inflammatory pathways beyond lipid metabolism. The effects of PCSK9 inhibition on monocyte subset distribution in high-risk coronary artery disease patients remain unclear. To assess the effects of lipoprotein fractions and PCSK9 inhibitor (PCSK9i) therapy on monocyte subset distribution in patients with stable coronary artery disease and highly elevated Lp(a) levels. We followed 100 statin-treated patients in the stable phase after myocardial infarction with highly elevated Lp(a), randomized to PCSK9i or placebo for six months. Biochemical, genetic, and cellular analyses were performed at baseline and follow-up. At baseline, IM levels correlated with total cholesterol (ρ = -0.202, In high-risk patients, PCSK9 inhibition modulates monocyte-lipoprotein interactions without affecting the monocyte subset distribution. PCSK9 may promote vascular inflammation through CCL2 regulation, which appears more closely related to Lp(a) composition than its circulating concentration. NCT04613167; https://www.clinicaltrials.gov/study/NCT04613167, date of registration: 6th of October 2020. Show less

The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships. We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication. We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes. Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings. Show less

The apolipoprotein E ε4 (APOE ε4), a well-established genetic risk factor for Alzheimer's disease (AD), is deeply involved in amyloid-β (Aβ) and tau pathology. Blood-based biomarkers (BBMs), including Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL), offer accessible proxies of AD pathology. Reactive astrocytes, indicated by elevated GFAP, are increasingly recognized as key players in AD progression. However, how astrocyte reactivity interacts with APOE genotype to shape BBMs and Aβ deposition remains unclear. We included 283 participants across the cognitive spectrum including cognitively unimpaired (CU), mild cognitive impairment (MCI), and all-cause dementia (ACD) from Guangzhou health aging and dementia cohort. Primary outcome measures were plasma biomarkers (Aβ42/40 ratio, p-tau181, GFAP, and NfL) and amyloid PET standardized uptake value ratio (SUVR). Participants were stratified by APOE ε4 carrier status and astrocyte activation. Group comparisons, correlation analyses, and sensitivity analyses were performed. Stage-dependent APOE effects were observed: while modulating Aβ42/40 ratios in both CU and MCI, APOE influenced p-Tau181 only in MCI, exclusively under Ast-. SUVR was significantly higher in APOE ε4 + group at MCI stage, particularly in Ast- cases. Intriguingly, p-Tau/Aβ42 showed strong SUVR correlations across all subgroups except APOE ε4- Ast- group. Our findings indicate that astrocyte reactivity is associated with differences in how APOE ε4 relates to both peripheral BBMs and central Aβ deposition, supporting an interplay between genetic risk and neuroinflammatory states in AD pathogenesis. Show less

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the primary indication for heart transplantation. The intricate and poorly elucidated pathogenesis of genetic DCM, coupled with the paucity of effective therapeutic options, imposes a substantial burden on both patients and their families. In this study, we identified a novel MYBPC3 mutation (c.194C > T) in a patient diagnosed with DCM and established a patient-specific human induced pluripotent stem cell (hiPSC) model. Cardiomyocytes derived from these patient-specific hiPSCs (hiPSC-CMs) exhibited hallmark features of DCM, including cell enlargement, aberrant distribution of sarcomeric α-actinin, and dysregulated calcium ion homeostasis, as compared to control hiPSC-CMs derived from a healthy individual. RNA sequencing analysis revealed a significant upregulation of CASQ2, which encodes calsequestrin, a protein that binds to Ryanodine receptor 2 (RyR2). Notably, treatment with the RyR2 inhibitor ryanodine effectively restored the abnormal calcium transients observed in DCM-hiPSC-CMs. In summary, our findings provide compelling evidence that the c.194 C > T mutation of MYBPC3 plays a definitive pathogenic role in DCM, and that modulation of the RyR2 receptor may alleviate calcium dysregulation in affected cardiomyocytes. These insights enhance our understanding of the molecular mechanisms underlying DCM and offer a promising therapeutic strategy for patients with calcium ion dysregulation associated with this condition. Show less

Glaucoma is a leading cause of irreversible blindness, yet the circulating proteins and metabolic pathways that causally contribute to different glaucoma subtypes remain poorly defined. We analyzed baseline plasma proteomics in 1485 glaucoma cases (447 primary open‑angle glaucoma [POAG], 177 primary angle-closure glaucoma [PACG], 120 normal-tension glaucoma [NTG]) in the UK Biobank using Cox models with graded adjustment. We then integrated five independent protein quantitative trait loci resources with FINLAND R12 genome-wide association study data to perform two‑sample Mendelian randomization (MR) and cross‑cohort meta‑analysis for overall glaucoma and each subtype. To prioritize effector genes and pathways, we conducted summary-data-based Mendelian randomization (SMR) using eQTLGen and two‑step mediation MR using metabolite quantitative trait loci data for ∼1400 plasma metabolites from the Canadian Longitudinal Study on Aging cohort. In fully adjusted Cox models, 484 proteins were associated with incident glaucoma, 135 with NTG, 59 with POAG, and 1 with PACG (false discovery rate <0.05). Multicohort MR and meta‑analysis identified eight proteins with robust causal effects: NRP2, TSPAN1, and HAVCR2 for overall glaucoma; NRXN3 for PACG; MANSC4 for NTG; and LTBP2, CD69, and SMAD1 for POAG. SMR supported NRP2 (overall glaucoma) and SMAD1 (POAG) as causal genes. Mediation MR revealed that sphingomyelins, acylcarnitines, and bile acid-related metabolites partially mediated the effects of several proteins, defining shared (e.g., sphingolipid) and subtype‑specific metabolic pathways. By integrating epidemiologic, proteomic, genetic, and metabolomic data, we identify convergent systemic protein and metabolic signatures associated with glaucoma susceptibility and its clinical subtypes. These findings nominate NRP2, SMAD1, and related pathways as promising biomarkers and therapeutic targets and support a systems‑level view of glaucoma pathogenesis beyond intraocular pressure alone. Show less

Oral leukoplakia and proliferative verrucous leukoplakia represent oral potentially malignant disorders. Oral leukoplakia typically presents as solitary lesions, while proliferative verrucous leukoplakia manifests as multifocal lesions with higher malignant potential. This study aimed to investigate the genetic heterogeneity between these disorders through differential gene expression, genetic variants, and microRNA profiling to identify potential biomarkers for diagnosis and prognosis. Biopsies and peripheral blood samples were obtained from 20 patients. Subsequently, RNA extraction, RNA-Seq libraries preparation, and bioinformatic analyses were conducted to ascertain differential gene expression, genetic variants, and microRNA expression. In mRNA analysis, overexpressed genes in proliferative verrucous leukoplakia are primarily associated with inflammation and immune regulation, while underexpressed genes relate to skin barrier maintenance. Pathway analysis reveals underexpressed genes related to impaired keratinization in proliferative verrucous leukoplakia and with keratin envelope formation in oral leukoplakia, while overexpressed genes are linked to synaptic processes and protein-protein interactions. Somatic mutation drivers in proliferative verrucous leukoplakia include variants in NRXN3, SRGAP2B, INIP, MYO18A, and ATF7IP genes. Regarding variant analysis, two variants in the Syndecan 3 (SDC3) gene identified in proliferative verrucous leukoplakia have demonstrated enormous value and indicate an important biomarker for a differential diagnosis and to predict prognosis. Proliferative verrucous leukoplakia shows in miRNA analysis MIR1246 and MIR767 overexpression, with MIR135B being the most underexpressed. Our findings emphasize the intricate transcriptomic profiles in oral leukoplakia and proliferative verrucous leukoplakia development, laying the groundwork for future studies to enhance clinical management and patient outcomes in oral oncology. Syndecan 3 gene polymorphisms may represent a key point in proliferative verrucous leukoplakia differential diagnosis and prognostic prediction. Show less

Atherosclerosis (AS) is a cardiovascular disorder accompanied by endothelial dysfunction and vascular inflammation. We aim to investigate the effects of Ras guanine nucleotide-releasing protein 3 (RasGRP3), a guanine nucleotide exchange factor in AS. Decreased RasGRP3 protein expression was observed in the endothelium of high-fat diet-fed ApoE The online version contains supplementary material available at 10.1007/s10753-026-02473-y. Show less

Apolipoprotein A-IV amyloidosis (AApoA-Ⅳ) is a rare subtype of cardiac amyloidosis (CA) and is often overlooked because of its clinical similarity to transthyretin (ATTR) CA. An 82-year-old man presented with heart failure with preserved ejection fraction. His clinical features, including grade 1 uptake on Although the pathologic significance of the unique histologic features remains unclear, they may represent distinguishing characteristics of AApoA-IV amyloidosis. AApoA-IV CA typically presents with elderly-onset heart failure with preserved ejection fraction and may show positive uptake on bone scintigraphy. Differentiation from ATTR CA is possible based on characteristic histopathologic findings and mass spectrometry-based proteomic analysis. Show less

Cerebral ischemia/reperfusion injury (CI/RI) is a common complication of cerebrovascular diseases such as stroke, characterized by mitochondrial dysfunction. This study investigates the function of proliferation-associated protein 2G4 (PA2G4) released by neural stem cells (NSCs)-derived exosomes (NSC-Exo) in treating middle cerebral artery occlusion/reperfusion (MCAO/R) by regulating mitophagy. NSC-Exo were extracted and identified. Treatment of NSC-Exo alleviated neurofunctional impairments in MCAO/R-induced mice, reduced oxidative stress and inflammatory responses in hippocampal tissues, and decreased neuronal apoptosis. We analyzed the alteration of molecular mechanisms under the effect of NSC-Exo treatment using bioinformatics analysis and RNA sequencing. PA2G4 was enriched in NSC-Exo, and the absence of PA2G4 in neurons impaired the mitigating effect of NSC-Exo on hippocampal neuronal injury and inhibited mitophagy. NSC-Exo delivered PA2G4 to recruit WW domain-containing protein 2 (WWP2), thereby mediating ubiquitination and degradation of Annexin A2 (ANXA2), and overexpression of PA2G4 or WWP2 reversed the accentuating effect of ANXA2 overexpression on MCAO injury. These findings indicate that PA2G4 delivered by NSC-Exo recruits WWP2 to mediate ubiquitination of ANXA2, thereby activating mitophagy to alleviate oxidative stress in hippocampal neurons in MCAO/R. This study offers a novel target for the treatment of CI/RI. Show less

In a previous study, we showed that oral supplementation with lysophosphatidylcholine (LPC)-bound omega-3 fatty acids (n-3) increases cortical eicosapentaenoic acid (EPA, C20:5n-3) but not docosahexaenoic acid (DHA, C22:6n-3) in an apolipoprotein E (APOE)- and duration-dependent manner. This may reflect DHA retention in blood-brain interfaces, such as microvessels (MV) and choroid plexus (ChP). To assess whether LPC n-3 intake over two or four months modulates the lipid composition of MV and ChP in APOE3 and APOE4 mice. APOE3 and APOE4 mice received daily gavage of LPC-bound EPA (21.5 mg/day) and DHA (10.4 mg/day) or sunflower oil (control) for two or four months (n=5-8 mice per genotype and treatment). Lipids from plasma, frontal cortex (FCx), ChP, and MV were analyzed by liquid chromatography-tandem mass spectrometry. Principal component analysis indicated that phospholipid levels in plasma, ChP, MV and FCx were modulated more by the type of oil administered by gavage (LPC n-3-enriched oil vs. sunflower oil) than by APOE genotype or gavage duration. The ChP was the most responsive tissue to n-3 supplementation. Total DHA increased in the FCx of APOE3 mice receiving LPC n-3, but not in APOE4 mice. In contrast, EPA levels were significantly higher across genotypes and biological compartments in n-3-supplemented mice. This study reports higher DHA and EPA concentrations in the brain of APOE3 mice supplemented with LPC n‑3 and reinforces evidence of lower DHA accretion in APOE4 mice. It also identifies the ChP as a major site of n‑3 response. Show less

Pregnant women have a high incidence of perinatal mood and anxiety disorders (PMADs). To explore the influence factor on perinatal psychology, we analysed the SCFAs, lipids, cognition, emotion, and cytokines in the late pregnant women. The mood, cognition, SCFAs of the non-pregnant group were compared to those in the late pregnancy. The differences in SCFAs, lipids, cognition, and cytokines between the high-risk and low-risk groups for affective disorders among women in the late pregnancy were analysed, and the risk factors were sought. Compared with the non-pregnant group, the pregnant group scored lower on the SDMT (P < 0.001), DST (P = 0.035), VRT (P = 0.001), and VFT (P < 0.001), and took longer on the TMTA (P = 0.004). Acetate (P = 0.001) and butyrate (P = 0.002) were higher, while propionate (P < 0.001) and isobutyrate (P = 0.001) were lower in the pregnant group than in the non-pregnant group. Among the pregnant women, CRP was higher in the high-risk group for mood disorders than in the low-risk group (P = 0.048). Meanwhile, HDL was positively associated with DST (P = 0.000), VRT (P = 0.015), and VFT (P < 0.001). Longer TMTA completion times were associated with reduced propionate (P = 0.072) and LPa (P = 0.022). Longer TMTB completion time was associated with lower life satisfaction (P = 0.037), as well as decreased cholesterol (P = 0.026). Pregnant women experience changes in cognition and SCFAs. CRP is a sensitive indicator for monitoring affective disorder. Regulation of SCFAs and lipids may be beneficial for cognition and affect. Show less

Phthalates are ubiquitous environmental contaminants and endocrine-disrupting chemicals used as plasticizers in consumer products, medical devices, and industrial materials. Evidence from in vitro experiments, animal models, and epidemiological studies suggests that phthalate exposure, particularly to di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP), may induce neurotoxicity through multiple interconnected mechanisms. The developing brain is especially vulnerable, with prenatal and early-life exposures linked to cognitive deficits, behavioral abnormalities, and neurodevelopmental disorders. Conventional therapeutic options remain limited, highlighting the need for effective neuroprotective strategies. Natural bioactive compounds such as polyphenols, flavonoids, carotenoids, and other phytochemicals have been investigated as potential neuroprotective candidates in preclinical models owing to their multi-target mechanisms (e.g., antioxidant, anti-inflammatory, and neurotrophic actions), potent antioxidant capacity, and regulation of cellular signaling pathways. Preclinical studies demonstrate that lycopene, ferulic acid, coenzyme Q10, omega-3 fatty acids, vanillic acid, and Moringa oleifera extracts attenuate phthalate-induced neurotoxicity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, suppressing nuclear factor-kappa B (NF-κB)-mediated inflammation, modulating MAPK/ERK and PI3K/Akt signaling, and restoring brain-derived neurotrophic factor (BDNF)/TrkB support. Despite these promising findings, challenges persist, including poor bioavailability, lack of standardized dosing, and limited human clinical trials. A structured review of experimental and epidemiological studies was conducted using predefined inclusion criteria. This review integrates evidence across in vitro, in vivo, and human studies to identify key mechanisms of phthalate-induced neurotoxicity, including oxidative stress, neuroinflammation, endocrine disruption, epigenetic dysregulation, and impaired neuroplasticity, and evaluates pathway-specific neuroprotective actions of bioactive compounds while highlighting critical translational gaps. Show less

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1-2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications. Show less

Lipoprotein(a) [Lp(a)] is a highly atherogenic particle that significantly increases overall cardiovascular risk. Evidence regarding concentrations of Lp(a) in the Polish general population remains limited, as well as the association between Lp(a) and various clinical characteristics. The aim in this study was to analyze Lp(a) concentration in a Polish population hospitalized in a tertiary referral hospital, compare clinical characteristics between patients with low and high Lp(a) and find the predictors of increased Lp(a) concentrations. This was an observational, cross-sectional study. All patients hospitalized in the Clinical Department of Internal Medicine, Endocrinology, Diabetology, and Nephrology in the Czerniakowski Hospital between 01.03.2024 and 08.10.2024 and with measured Lp(a) concentration were consecutively included. Patients were divided into two groups: those with high Lp(a) (≥ 30 mg/dL) and those with low Lp(a) ( < 30 mg/dL). The groups were compared in terms of multiple clinical characteristics. Multiple logistic regression was used to determine independent predictors of high Lp(a). The p-value below 0.05 was considered statistically significant. Out of 562 patients, 117 had high Lp(a) concentration (20.8%). The groups did not differ in terms of age, sex, or clinical examination findings. In a multiple logistic regression, male sex was associated with a decreased odds ratio of high Lp(a) (OR = 0.2857, 95% CI: 0.1107 to 0.6468, p = 0.01). High Lp(a) is prevalent in the Polish population, and thus it is important to measure it routinely in each individual at least once in a lifetime and control all other known cardiovascular risk factors to decrease the overall risk. Show less

Depression has emerged as a concerning factor in colon cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined. This study aimed to elucidate how depression affects colon cancer progression and chemotherapeutic response, and to explore potential molecular targets and therapeutic interventions involving the traditional Chinese medicine formula Sinisan (SNS) and its bioactive component Quercetin. A mouse model combining depression and colon cancer was established to evaluate behavioral alterations, tumor progression, and pathological features. RNA sequencing was performed to screen the differentially expressed genes. The effects of corticosterone (CORT) on proliferation, colony formation, migration, and GSTM2 expression were examined in HCT116 cells, followed by functional validation through GSTM2 overexpression and inhibition assays. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) were used to validate the binding of Quercetin to GSTM2. The therapeutic efficacy of SNS and Quercetin was assessed with respect to depressive symptoms, serum BDNF levels, NLRP3 inflammasome activity, and the potency of 5-fluorouracil (5-FU) chemotherapy. Mice with depression and colon cancer exhibited aggravated depressive behaviors and accelerated tumor progression. RNA-sequencing and network pharmacology analyses identified GSTM2 as a promising candidate target in colon cancer treatment, which was markedly down-regulated in the DP-CC group. CORT enhanced proliferation, colony formation, and migration of HCT116 cells while simultaneously suppressing GSTM2 expression. Conversely, GSTM2 levels negatively correlated with cell proliferation, colony formation, and chemoresistance in HCT116 cells. Treatment with SNS alleviated depressive symptoms, elevated serum BDNF, reduced NLRP3 inflammasome activity, and potentiated the efficacy of 5-FU chemotherapy. Quercetin, a bioactive component of SNS, bound to GSTM2 through hydrogen-bond and van-der-Waals interactions, up-regulated GSTM2 expression, and mitigated CORT-induced proliferation, colony formation, and chemoresistance. Our findings suggest that depression promotes colon-cancer progression by down-regulating GSTM2, whereas SNS restores GSTM2 expression and enhances chemotherapeutic response. Show less

Allostatic load (AL), an index of cumulative physiological dysregulation from chronic stress, may contribute to Alzheimer's disease (AD) pathophysiology by accelerating brain aging. Higher AL has been associated with AD-related biomarkers, suggesting a mechanistic connection. Lifestyle factors influence both AL and AD vulnerability, but their moderating role in AL-AD biomarker associations remains unclear. We included 111 cognitively unimpaired older adults from the baseline visit of the Age-Well trial. AL was computed as a composite score of 18 biomarkers spanning neuroendocrine, immune, metabolic, cardiovascular-respiratory, and anthropometric systems. Plasma biomarkers included amyloid beta (Aβ)42, Aβ40, phosphorylated-tau (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Physical activity, Mediterranean diet adherence, and cognitive activity were assessed using validated questionnaires. Multiple linear regressions tested associations between AL and (1) AD-related biomarkers and (2) lifestyle factors, as well as their interactions, controlling for age, sex, education, apolipoprotein E ε4 (APOE ε4) status, and glomerular filtration rate (GFR). Higher AL was associated with higher Aβ42/Aβ40 ratio ( Regular physical activity was associated with a weaker relationship between AL and early AD-related biomarkers in this cross-sectional sample. Longitudinal studies should confirm whether maintaining physical activity attenuates stress-related physiological dysregulation and reduces AD vulnerability. Show less

Alzheimer's disease (AD) biomarkers in plasma and cerebrospinal fluid (CSF) are useful for disease diagnosis, prognosis, risk assessment and monitoring therapy response, as well as for uncovering altered disease pathways. Previously, we and others cloned a novel gene, KLK6, which encodes a serine protease of the kallikrein family. The protein (hK6) is highly expressed in the brain, spinal cord and cerebellum. To examine the correlation of hK6 concentration in CSF with various clinicopathological variables in AD, we used a quantitative ELISA system. The variables examined included patient age, sex, MMSE score, APOE status, amyloid β 1-42 (Αβ1-42), phosphorylated Tau 181 (p-Tau181), total Tau (t-Tau). Previously, using a cohort of Swedish and Norwegian patients, we established a positive correlation between CSF hK6 and age as well as the levels of core AD biomarkers in four groups of patients (cognitively normal, MCI without progression to AD, MCI with progression to AD within 2 years and AD dementia). In this investigation, our goal was to validate these previous data with a large and independent patient cohort from Spain. We found that CSF hK6 is minimally or not affected by patient age and sex, but it significantly correlates with MMSE score and CSF Aβ1-42, p-Tau1811 and t-Tau. We conclude that these correlations further support our previous findings and suggest that hK6 may be an additional biomarker for AD and may play some role in the pathogenesis of AD. Show less

Atherosclerosis presents a persistent health challenge, with limited therapies addressing residual cardiovascular risk. Gualou Xiebai Banxia Decoction (GXBD), a classical Chinese herbal formula traditionally used for chest obstruction syndromes, was evaluated as a dietary-style intervention in ApoE Show less

This study examined how different photoperiods affect net energy partitioning and explored the mechanisms via blood biochemistry, gut microbiota, and fecal metabolites. Twelve healthy crossbred pigs (47.7 ± 7.5 kg) were randomly allocated to two groups and subjected to a self-controlled crossover design. Following an 8-day baseline under a normal photoperiod (12L:12D, 12 h light:12 h dark), pigs were assigned to two photoperiod treatment groups: prolonged photoperiod (18L:6D, 18 h light:6 h dark; P group) and shortened photoperiod (6L:18D, 6 h light:18 h dark; S group). Measurements during the baseline (12L:12D) and treatment phases are designated as N1/P (for the P group) and N2/S (for the S group), respectively. The treatment periods were interspersed with the baseline 12L:12D photoperiod and repeated six times. It was observed that, compared to N2, shortened photoperiod (S) had significantly higher net energy deposition, net energy for protein deposition, and net energy for fat deposition ( Show less

Integration of the hepatitis B virus (HBV) genome into the host chromosome of infected patients poses a threat to those with HBV-associated hepatocellular carcinoma (HBV-HCC) due to challenges in early diagnosis and poor prognosis. CircRNAs are known for their oncogenic and biomarker potential in various cancers, including HBV-HCC, by sequestering tumor suppressive miRNAs, which, when free, can silence the expression of oncogenic mRNAs. Therefore, we aimed to develop a bioinformatic model to identify the circRNA-miRNA-mRNA axis in HBV-integrated HCC cell lines and to identify prognostic biomarkers specific to HBV-HCC patients. We identified dysregulated host circRNAs and mRNAs in HBV-negative and HBV-integrated cells using RNA-seq, followed by differential gene expression analysis with DESeq, and performed pathway analysis using Gene Set Enrichment Analysis (GSEA). Junctional sequences of the circRNAs were validated by Sanger sequencing of the amplified products. RT-qPCR further confirmed the dysregulation of 9 randomly selected circRNAs chosen from those with the highest fold-change and adjusted p-values. The miRNA partners for each circRNA were identified using mirDB. miRNA expression validation was performed using the publicly available Gene Expression Omnibus (GEO) database of the same cells, and Empirical Cumulative Distribution Function (ECDF) plots were generated to assess the fold change of mRNAs in potential binding miRNA partners. The mRNA targets for 10 miRNA ECDF plots were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and hub genes were identified using Search Tool for the Retrieval of Interacting Genes (STRING) Cytohubba protein-protein interaction (PPI) analysis. Survival analysis of hub genes was plotted, and a competitive endogenous RNA (ceRNA) network was constructed using Cytoscape. We identified 494 dysregulated circRNAs, 346 dysregulated miRNAs, and 10,419 dysregulated mRNA in HBV-integrated cells through a comprehensive bioinformatic model. circADGRL2 (~ 25-fold) showed the highest upregulation and miR-361-5p acted as a central node of multiple circRNAs: circADGRL2, circPROX1 and circPALS2. BDNF, a target mRNA of miR-361-5p, was identified as the highest risk ratio in HBV-HCC patients, suggesting a possible circADGRL2-miR-361-5p-BDNF axis involved in HBV-HCC. The target mRNAs of miRNAs were predicted to be associated with several cancer pathways, such as MAPK and RAS. Our data suggest a potential dysregulated circRNA-miRNA-mRNA axis in HBV-integrated hepatocytes, which may indicate a poor prognosis for HBV-HCC patients. Show less

Alterations in lipids and apolipoproteins contribute to cardiovascular disease (CVD) and are common in people with HIV. The aim of our study was to compare lipid profiles and body composition between people with and without HIV and to explore whether any associations with HIV could be explained by socio-demographic, clinical characteristics and body composition. Cross-sectional analysis of a cohort study enrolling people with HIV and HIV-negative controls. Apolipoproteins [ApoB-100, ApoA1, Lp(a)] were analysed by immunoturbidimetry. Lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL]), clinical/demographic data and dual-energy X-ray absorptiometry (DXA)-measured body composition parameters were collected. Between-group differences were assessed with Student's T-test. Linear regression models assessed associations of lipids and apolipoproteins with HIV status and associations with socio-demographic, clinical characteristics and body composition. We included 108 people with HIV on treatment (93.5% with viral suppression) and 96 controls. People with HIV were younger, more likely to be male, with obesity, of African ethnicity, smokers and with a higher representation of CVD, hypertension, diabetes and statin use. ApoB-100, TC, HDL and LDL were significantly lower in people with HIV, with no between-group difference in ApoA, Lp(a) and body composition. HIV infection remained independently associated with lower TC and LDL after adjustment for possible confounders. People with HIV from a contemporary cohort had lower pro-atherogenic lipid parameters compared to controls, and no differences in body composition between people with HIV and controls were observed. Traditional risk factors for CVD and chronic inflammation might have a greater impact than dyslipidaemia itself on the increased CVD risk in people with HIV. Show less