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Aplastic anemia (AA) is a bone marrow failure disease characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Bone marrow adiposity represents a typical pathological manifestation observed in AA. The aim of this study was to establish a murine model of AA using immune-mediated methods and assess the impact of rapamycin (Rapa) and cyclosporin A (CsA) on bone marrow adiposity. The AA murine model was induced by 137Cs γ-ray irradiation and allogeneic lymphocyte infusion. Rapamycin and cyclosporine were administered intraperitoneally. Hematological parameters, bone marrow adiposity, and lipidomic profiles were evaluated. Gene and protein expression related to adipogenesis were analyzed. The Hematoxylin and Eosin (HE) and BODIPY staining results revealed an increase in adipocyte area and a decrease in hematopoietic area in AA murine. Relative expression levels of PPAR-γ, LPL, and Ap2 mRNA were significantly elevated in bone marrow mononuclear cells (BMMNCs) from the AA group. Lipidomics analysis indicated notable differences between the AA group and the normal group regarding lipid metabolism, particularly concerning glycerolphospholipids. Following treatment with Rapa and CsA, not only did the hematological profile of AA murine recover, but there was also a reduction in bone marrow adiposity in HE and BODIPY staining and a decrease in the gene and protein expression of PPAR-γ, LPL, and Ap2. The lipidomic analysis revealed a reduction in the lipid metabolism of AA murine following Rapa and CsA treatment in AA murine, particularly acylcarnitin (ACar), phosphatidylserine (PS) and phosphatidylethanolamine (PE). The enrichment results of the KEGG pathway analysis demonstrated a statistically significant role of C42H82N010P in glycerophospholipid metabolism. Our study used lipidomics for the first time to investigate lipid metabolism in AA murine, revealing that Rapa and CsA primarily downregulate glycerophospholipid metabolism as a means to alleviate bone marrow adiposity in AA murine. Show less

Lipoprotein(a) [Lp(a)] is a novel biomarker for Atherosclerotic cardiovascular disease prediction. Yet, given the scarcity in high-quality evidence, its use in routine primary prevention screening is lacking. For this reason, we aimed to assess Lp(a) prognostic utility during routine screening. A retrospective cohort of adults with available Lp(a) measurement, taken during a screening program (2008-2024) in a tertiary care center. Major adverse cardiovascular events (MACE) was the study primary outcome. The optimal Lp(a) threshold was evaluated using spline curve analysis and validated by Cox regression models adjusted for clinical and laboratory covariates. Subgroup analyses were performed in patients with SCORE2 and PCE data. 3052 people were included with a median (IQR) follow-up of 6.4 (3.5-12) years. Lp(a) threshold of 50 mg/dL was identified as a risk inflection point. High Lp(a) (> 50 mg/dL) was associated with increased MACE risk, independent of clinical data (HR 1.55, 95% CI 1.10-2.17, p = 0.011) or different laboratory variables (HR 1.62, 95% CI 1.07-2.46). High Lp(a) remained a predictor for MACE in models incorporating the SCORE2 and PCE scores, and its incorporation into these scores improved their performance in high-risk patients. In people with cardiovascular comorbidities, the optimal Lp(a) threshold for MACE prediction was 61 mg/dL, while it was 48.4 mg/dL in those without (n = 2778). In a large ambulatory and mostly healthy cohort, Lp(a) showed a strong predictive utility for cardiovascular events. These findings support the integration of Lp(a) into primary cardiovascular risk assessment and role in guiding emerging targeted therapies. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for myocardial infarction and stroke. Elevated Lp(a) >50 mg/dL (>125 nmol/L) is common and present in about 1 in 5 individuals. Although Lp(a) may be a cause of young ischemic stroke (age ≤60), limited data on national testing trends in this population are available, testing in the general population remains low overall, and different organizations have varying guidelines for testing. By determining the degree to which this population is tested, information on national testing trends of Lp(a) in young ischemic stroke patients may influence future guideline recommendations to increase Lp(a) testing. This study aims to use a large, real-world dataset to assess trends of Lp(a) testing in young ischemic stroke patients in the United States from 2015-2024. We performed a retrospective analysis of Lp(a) testing in young ischemic stroke patients across the United States from January 1, 2015 to December 31, 2024 using Epic Cosmos, a nationwide, de-identified electronic health record (EHR) dataset comprising over 300 million patient records from over 1,715 hospitals and 41,000 clinics, including from all 50 states, Washington D.C., Lebanon, and Saudi Arabia. The current count values for patients, hospitals, and clinics are available on the Epic Cosmos website. Although the Epic Cosmos data dictionary includes Lebanon and Saudi Arabia as standardized site locations, no patients from these countries were present in our analytic cohort; thus, all analyses were restricted to individuals within the United States. We evaluated the number of young ischemic stroke patients, defined as age ≤60 with history of an ischemic cerebrovascular accident (CVA), who had ever undergone Lp(a) testing, the testing rate per annual young ischemic stroke patients, geographical variation, and percentages of patients tested stratified by age, sex, ethnicity, race, and diagnosis of coronary artery disease (CAD). Testing rates were calculated as the number of distinct patients tested per year and as the testing rate per annual patient population. For each stratum we calculated the proportion tested with Wilson 95 % confidence intervals and assessed between-group differences using chi square or Fisher exact tests as appropriate. Annual trends in the testing proportion were modeled using a binomial generalized linear model with a logit link, treating the annual number tested as the numerator and the annual young ischemic stroke population as the denominator, and we report the odds ratio per calendar year with robust standard errors. Geographical variation was visualized using a heat map of testing by state. All analyses were descriptive and intended to characterize population-level patterns of ischemic stroke within the Cosmos network rather than infer causal associations. Given the exploratory design, no additional model-based adjustment for confounding was performed. All data are de-identified in compliance with HIPAA standards and governed under Epic's "Rules of the Road" for institutional data use. From 2015 to 2024, out of a total of 188,305 distinct young ischemic stroke patients, 9,226 (4.9 %) underwent Lp(a) testing. Additionally, the annual number of tested patients increased significantly from 179 in 2015 to 1,992 in 2024 (p<0.001), and the annual percentage of patients undergoing Lp(a) testing increased from 4.3 % in 2015 to 9.3 % in 2024. The states with the largest number of tested patients were Ohio (10.4 %), Texas (7.4 %), and Pennsylvania (5.5 %). The rates of testing were significantly different between sexes, with a larger percentage of young women with ischemic strokes tested compared to young men. Analyzing patients with reported racial data, patients who identified as Black or African American underwent testing for Lp(a) at the highest rate, compared with patients who identified as Asian, "None of the above", White, or Other Race. Among patients undergoing testing with reported ethnic identity, a higher percentage of patients who identified as Hispanic or Latino were tested compared to those who identified as non-Hispanic. Stratifying the total tested patients by age, adults between the ages of 50-60 years made up the largest percentage of patients (4,460; 48.3 %); however, the highest rate of testing occurred in patients aged 5-18. In addition, a higher rate of the young ischemic stroke patients who had ever had a diagnosis of CAD underwent testing compared to patients without CAD. Lp(a) testing among young ischemic stroke patients has increased significantly over the past decade, likely reflecting growing clinical recognition of its causal role in atherosclerotic disease. The rise parallels key updates in lipid management and stroke prevention guidelines, including the 2019 European Society of Cardiology and 2024 National Lipid Association recommendations advocating at least once-in-a-lifetime Lp(a) measurement. Increasing assay availability and heightened awareness of the causal relationship of Lp(a) with atherosclerotic disease may also have contributed to the observed upward trend. Despite this, only about one in twenty young ischemic stroke patients had ever been tested, underscoring a substantial implementation gap between evidence and clinical practice. Show less

Microtubule organization plays a central role in cell differentiation, orchestrating essential processes such as cell polarization, mechanotransduction, organelle positioning and intracellular transport. A hallmark of many differentiated cells is the transition from a centrosomal to a non-centrosomal microtubule-organizing center (MTOC). Here, we demonstrate that both centrosomal and nuclear envelope (NE)-associated MTOCs coexist in osteoclasts. We show that the key players for NE-MTOC formation, the AKAP6 and nesprin-1 (SYNE1) isoforms AKAP6β and nesprin-1α, previously considered muscle specific, are upregulated during osteoclast differentiation, suggesting a conserved role in NE-MTOC assembly across cell types. Targeted depletion of AKAP6 in RAW264.7-derived osteoclasts led to the displacement of the Golgi and MTOC-associated proteins PCM1, pericentrin and CDK5RAP2 from the NE, while their centrosomal localization remained intact. This selectively impaired microtubule nucleation from the NE without disrupting centrosomal microtubule activity, enabling a functional dissection of the two MTOCs. Loss of NE-MTOC activity, through AKAP6 depletion, impaired podosome formation and significantly reduced bone resorption capacity, highlighting the distinct and essential role of NE-derived microtubules in osteoclast function. Show less

Cardiac damage predicts poor outcomes in polytrauma (PT). In older patients, cardiovascular risk factors may predispose to post-traumatic cardiac dysfunction. This study examined whether cardiovascular risk correlates with cardiac damage and influences clinical outcomes in PT. This study at a German Level 1 Trauma Centre enrolled 59 polytrauma patients upon ER admission. Blood samples were taken at ER, 24h, 48h, 72h, 96h & 10d to assess cardiac damage via Troponin T & NT-proBNP. Transthoracic echocardiography (TTE) was performed at 24h/48h. Cardiovascular risk was evaluated using the SCORE2 algorithm. Subgroup analysis compared cardiac damage in patients with high (SCORE2 >7.5%) vs low risk, & assessed the additional impact of chest trauma. Arrhythmias were observed in 39% of patients, whereas acute repolarization disorder occurred in nearly 19%. TTE revealed wall motion abnormalities in 12%, diastolic dysfunction in 10% & right ventricular dysfunction in 5%. SCORE2 and Lp(a) significantly correlated with serum levels of TnT & NT-proBNP. SCORE2 values were associated with non-survival, wall motion disorders, diastolic dysfunction and relaxation disorders (p<0.05). A higher incidence of arrhythmias, diastolic dysfunction and relaxation disorders was observed in the subgroup of high-risk patients with chest trauma. Patients in the high-risk group without chest trauma showed higher non-survival rates (50%), which may be strongly influenced by a history of myocardial infarction. Cardiovascular risk was significantly associated with cardiac damage markers, TTE abnormalities & increased mortality. A history of myocardial infarction was associated with higher mortality in PT-patients with an elevated SCORE2 risk. Show less

Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely symptomatic, with limited efficacy and significant side effects. Microglia act as pivotal mediators of DNP through RAGE/TLR4/NLRP3-driven IL-1β and BDNF release that amplifies spinal pain signaling. Microglia respond directly to hyperglycemia-induced cues such as advanced glycation end-products, reactive oxygen species, ATP, and pro-inflammatory signals, becoming activated and releasing cytokines, chemokines, and neuromodulators including BDNF that amplify spinal pain signaling. This review synthesizes recent insights into the molecular triggers of microglial activation such as RAGE, TLRs, purinergic receptors, and inflammasomes and the downstream intracellular pathways including NF-κB, MAPK, PI3K/Akt, and BDNF-TrkB that drive neuroinflammation. We further examine neuroimmune crosstalk, including bidirectional microglia-neuron and microglia-astrocyte signaling, which sustains central sensitization. Translational studies linking these pathways to human DNP are evaluated, along with novel technologies that illuminate microglial phenotypes. Emerging therapeutic strategies focus on inhibition of these pathways, including RAGE antagonists and purinergic receptor blockers. However, a critical translational gap persists owing to insufficient human validation of microglial biomarkers and the limited fidelity of current animal models. By integrating basic and clinical findings, we underscore the promise of microglia-focused interventions to complement traditional analgesics and ultimately improve outcomes in DNP patients. Show less

Cascade screening can identify individuals with elevated lipoprotein(a) [Lp(a)], a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study is to explore the effectiveness of cascade screening with asymptomatic children as index cases to identify family members with elevated Lp(a). In this retrospective study we used our database consisting of all children referred for a tentative diagnosis of hereditary dyslipidemia to the Amsterdam University Medical Centers pediatric lipid clinic (1989-2023). Elevated Lp(a) was defined as ≥30 mg/dL or ≥75 nmol/L. We evaluated two cascade screening approaches (opportunistic and systematic), calculated the number needed to screen (NNS) and repeated the analysis exclusively in children with FH as subgroup with particularly high cardiovascular risk. A total of 1,931 children were included (732 indexes, mean age (SD) 11.7 (4.5) years; 1,199 relatives, mean age (SD) 10.1 (4.4) years). In total, 480 (25%) of all children had elevated Lp(a) concentrations (≥30 mg/dL or ≥75 nmol/L). Both opportunistic (732 indexes) and systematic (316 indexes) cascade screening identified relatives with elevated Lp(a). The NNS was of 3.7 (95% CI 3.3-4.3) for the systematic approach and 4.1 (95% CI 3.8-4.6) for the opportunistic approach. In the FH subgroup, NNS were 3.9 (95% CI 3.4-4.5) and 4.3 (95% CI 3.9-4.8), respectively. Our findings suggest that cascade screening using children as index cases is an effective strategy to identify asymptomatic relatives at risk. Cardiovascular risk assessment should include Lp(a), especially in patients with FH who face an even higher cardiovascular risk. Until effective therapies become available, management should focus on modifiable risk factors. Show less

Blood-based biomarkers could improve the precision of Alzheimer's disease (AD) clinical diagnosis and expand access to targeted treatments. Therefore, we evaluated the diagnostic accuracy of plasma Elecsys p-tau217 (Roche) and compared it with Elecsys p-tau181 (Roche) and Lumipulse p-tau217 (Fujirebio). We also assessed the added value of APOE-ε4 carrier status, plasma Aβ42 and Aβ42/40 in a memory-clinic cohort and evaluated associations with longitudinal cognition. A total of 187 patients from the Cognitive Centre Ghent University (CCUG) biobank, classified as AD (n = 103) or non-AD cognitive disorders (n = 84) based on CSF biomarkers (CSF Aβ42/40 ratio, total tau and p-tau181), were included. Plasma Elecsys p-tau181, p-tau217, and APOE-ε4 were measured on the Roche cobas Elecsys plasma p-tau217 showed high discriminative performance for AD versus non-AD (AUC 0.939), comparable to Lumipulse p-tau217 (AUC 0.950; p = 0.485). Elecsys p-tau181 performed lower than Elecsys p-tau217 (AUC 0.903; p = 0.043). Using a two-cut-off strategy, the intermediate proportion was 19.9% for Elecsys p-tau217, 11.9% for Lumipulse p-tau217, and 33.2% for Elecsys p-tau181. Adding APOE-ε4 to Elecsys p-tau217 improved discriminative performance (AUC 0.970, p = 0.02) and reduced intermediates to 11.0%. Adjustment for Aβ42 on the Fujirebio platform did not significantly increase the AUC (0.950 vs. 0.957; p = 0.322) and modestly reduced intermediate classifications (11.9% to 10.0%). Higher baseline Elecsys p-tau217 was associated with lower baseline MoCA and a trend towards faster MoCA decline (p = 0.07). Age, sex, renal function, Fazekas score, and CAA were not significantly associated with Elecsys p-tau217 concentrations. Plasma Elecsys p-tau217 measured on an automated high-throughput platform shows excellent diagnostic accuracy for AD. Incorporating APOE-ε4 further improves classification, while Aβ42 adjustment had only limited additional impact. Baseline p-tau217 also reflects cognitive severity and may relate to subsequent cognitive decline in the memory-clinic setting. Show less

Olive pomace (OP), a by-product of olive oil production, is a sustainable resource rich in bioactive compounds with potential applications in cosmetics and pharmaceuticals. This study investigates the protective effects of olive pomace juice (OPJ) against H Show less

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality, particularly among high-risk patients. Despite the availability of multiple lipid lowering therapies, many patients fail to achieve the guideline recommended low-density lipoprotein cholesterol (LDL-C) targets. Obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor optimizes lipid profile by blocking the exchange of cholesterol esters from high-density lipoprotein cholesterol (HDL-C) to Apolipoprotein B (ApoB) containing lipoproteins. This study evaluates the efficacy and safety of obicetrapib as an adjunctive therapy in high-risk ASCVD patients. Online databases were searched. Outcomes included percentage changes in LDL-C, HDL-C, non-HDL-C, total cholesterol, triglyceride, ApoB, lipoprotein (a) [Lp(a)] and risk of any adverse events (AE), AE leading to discontinuation, acute kidney injury (AKI), transaminase or creatine kinase (CK) elevation and hypertension. Risk ratio (RR) for categorical outcomes and mean difference (MD) for continuous outcomes were reported using 95% confidence intervals (CI). Three studies with 3088 patients (mean age 64 ± 11, 37% female) were selected. Obicetrapib significantly reduced LDL-C (-31.75%), non-HDL-C (-29.35%), triglyceride (-5.61%), Lp(a) (-35.67%), ApoB (-19.37%), and increased HDL-C (+125.94%) with no difference in total cholesterol levels. Obicetrapib was not associated with increased risk for any AE, AE leading to discontinuation, AKI, transaminase or CK elevation, and hypertension. Obicetrapib substantially improved lipid profiles in high-risk ASCVD patients on maximally tolerated lipid lowering therapy, without increased short-term adverse events. However, further long-term randomized studies are needed to confirm sustained efficacy, long-term safety, and potential impacts on clinical cardiovascular outcomes. Show less

This study integrates fluorescence resonance energy transfer (FRET) and small-angle X-ray scattering (SAXS) to elucidate, in real time, how triacylglycerol (TAG) self-assembly dynamics in human milk regulate digestion and absorption. Among three major human milk TAGs-1-oleoyl-2-palmitoyl-3-linoleoyl-glycerol (OPL), 1,3-dioleoyl-2-palmitoyl-glycerol (OPO), and 1,3-dilinoleoyl-2-palmitoyl-glycerol (LPL)-OPL showed ∼20% faster lipolysis and more rapid micelle formation (I Show less

Coronary microvascular dysfunction (CMD) constitutes an increasingly acknowledged aspect of coronary artery disease. Even though traditional cardiovascular risk factors have been implicated in CMD pathogenesis, data on lipoprotein (a) [Lp(a)] is limited. This cross-sectional study aimed to investigate whether Lp(a) levels are associated with CMD in patients with angina and nonobstructive coronary arteries. Coronary physiology assessment was performed with the standard bolus thermodilution technique, allowing for coronary flow reserve (CFR) and index of microvascular resistance estimation. Participants were categorized into 3 groups based on Lp(a) levels (<30, [30 to 50], and ≥50 mg/dl) as well as into 2 groups based on the presence of CMD. CMD was defined as CFR ≤2.5 and/or index of microvascular resistance ≥25. A total of 127 patients were recruited. No significant differences in baseline characteristics were observed between the groups. In unadjusted analysis, no significant associations were found. In multivariable analysis adjusting for age and sex, participants with Lp(a) values ≥50 mg/dl displayed a trend for a 4.25 increased CMD risk when compared to participants with Lp(a) values <30 mg/dl (odds ratio 4.25, confidence interval 0.81 to 22.28, p = 0.087). The same group of patients tended to have lower CFR than controls with Lp(a) <30 mg/dl, with a median CFR that was 1.05 units lower (p = 0.086). In conclusion, patients with high Lp(a) levels tended to display a higher prevalence of CMD and lower CFR. More studies are needed in order to better elucidate the relationship between Lp(a) and CMD. Show less

The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less

Dyslipidemia is common in people with HIV (PWH) and linked to cardiometabolic disease risk. Subcutaneous adipose tissue (SAT) regulates lipid storage and release, but how SAT cellular composition might influence circulating lipids in PWH on contemporary antiretroviral therapy (ART) is not well defined. Cross-sectional, observational cohort of PWH on long-term contemporary ART with virologic suppression. We performed untargeted fasting plasma lipidomic profiling on 127 individuals with a range of metabolic fitness (non-diabetes, prediabetes, diabetes). Adjusted logistic and linear regression models identified lipid species associated with diabetes status and HOMA2-IR, respectively. Linear regression assessed the relationship between abdominal SAT cell composition from single-cell RNA sequencing with circulating lipid classes (n = 59). The median age was 48 years, body mass index 31.5 kg/m 2 , and 48% self-identified as non-White, with 23% women. Diabetes as a dichotomous outcome had few differences in lipid species. In contrast, HOMA2-IR was associated with higher levels of several species of tri- and diacylglycerols and inversely associated with phosphatidylcholine, phosphatidylethanolamine species, and many of their derivatives among those without diabetes. Adipose tissue microvasculature remodeling, characterized by a reduction in capillary endothelium and decreased expression of key lipid trafficking receptors ( LPL, GPIHBP1 ), was associated with the insulin-resistant lipidomic signature. Adipose tissue microvasculature remodeling in PWH on contemporary ART was associated with changes in several plasma lipid species, which are also linked to insulin resistance. Interventions targeting adipose tissue endothelial dysfunction may improve metabolic health in PWH on long-term ART. Show less

Phytate (phytic acid, or InsP6), the primary phosphorus storage compound in plants, plays essential roles in nutrient homeostasis and cellular signaling. However, its strong metal-chelating properties make cytosolic accumulation cytotoxic, necessitating its sequestration into vacuoles for safe storage. Here, we present the cryo-EM structures of the rice vacuolar phytate transporter, OsMRP5, captured in distinct functional states. These structures reveal the molecular basis of OsMRP5 function as an ATP-binding cassette (ABC) transporter. OsMRP5 employs a specialized substrate-recognition mechanism, uniquely adapted to bind the fully hydrophilic InsP6 through extensive electrostatic and hydrogen-bonding interactions within two distinct, highly polar binding sites in its central cavity. A distinctive electropositive tunnel, positioned above the central cavity, forms a continuous pathway connecting the InsP6-binding pocket to the vacuolar export site. This tunnel likely generates an electrostatic attraction that facilitates the movement of the highly anionic InsP6 through the transporter. By mapping mutations from low-phytic acid (lpa) crop variants onto the OsMRP5 structures, we pinpoint their conserved locations critical for transporter function and validate their impact experimentally. These results reveal how OsMRP5 recognizes and transports the highly charged InsP6 molecules into vacuoles, providing a molecular framework for targeted manipulation of this agriculturally important transporter. Show less

Resilience following combat exposure is an important factor in understanding posttraumatic stress disorder (PTSD), associated risk, and potentially resilience more generally. Identifying underlying genetic factors requires large samples; most biobanks lack extensive resilience assessments, although data regarding trauma and psychiatric symptoms are frequently present that allow computation of a resilience measure. We leveraged the Million Veteran Program (MVP) cohort to calculate discrepancy-based psychiatric resilience (DBPR) scores by regressing PTSD symptoms (PCL-17) onto combat exposure (Deployment Risk and Resilience Inventory-Combat Experiences Scale). We conducted a genome-wide association study (GWAS) of DBPR among European-ancestry (EUR) (n=94,360) and African-ancestry (AFR) participants (n=10,339). We performed conditional analyses with disorders frequently comorbid with PTSD (major depressive disorder, generalized anxiety), examined genetic correlations (r SNP-based heritability was 0.079 (SE=0.007) and three independent genome-wide significant loci were associated with DBPR in EUR; no significant loci were identified in AFR. Trans-ancestry meta-analysis revealed three significant SNPs mapping to RN7SKPP19*rs4650199, MAD1L1*rs12669370, and KANSL1:KANSL1-AS1*rs62060955. In EUR, eight genes were identified in TWAS. One gene (C7orf50) reached a posterior probability >0.90 in TWAS fine mapping. Significant correlations were observed between DBPR and other variables including neuroticism (-0.61), participation in religious groups (0.29) and engaging in sports (0.39, SE = 0.05). The r These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms. Show less

Dyslipidemia remains a major contributor to atherosclerosis and cardiovascular events. While low-density lipoprotein cholesterol (LDL-C) lowering is the primary treatment target, lipoprotein(a) [Lp(a)] has emerged as an independent, genetically determined risk factor, often unaffected by standard treatment. This study aimed to analyze the relationship between body composition parameters and lipid profile, including Lp(a). Clinically stable high cardiovascular risk patients (n = 207) receiving lipid-lowering pharmacotherapy were enrolled in this cross-sectional study. Anthropometric data and body composition were assessed using bioelectrical impedance analysis, including body mass index (BMI), fat mass (FM%) and fat-free mass percentage (FFM%). Lp(a) and lipid profile were measured. Patients were stratified by Lp(a) concentration: <75 nmol/L, 75-125 nmol/L, and >125 nmol/L. Lp(a) levels showed no significant association with body composition, age, and sex. In contrast, HDL-C was significantly inversely correlated with BMI (R = -0.25, p < 0.001) and this relationship was independent of sex (β = -0.68, p < 0.001), while triglycerides were positively correlated with FM% (R = 0.17, p = 0.02) and BMI (R = 0.28, p < 0.001) and negatively with FFM% (R = -0.17, p = 0.02). LDL-C was not associated with body composition. No significant differences in lipid profile or body composition were observed across Lp(a) strata. In high cardiovascular risk patients, Lp(a) appears unrelated to body composition, supporting its role as a non-modifiable, genetically driven risk factor. Conversely, despite pharmacotherapy, HDL-C and triglycerides demonstrated significant associations with body fat distribution. These findings suggest clinical role of body composition assessment in cardiovascular risk management, particularly in addressing residual risk beyond LDL-C. Show less

Patients with chronic kidney disease (CKD) are at a significantly increased risk of developing Alzheimer's disease (AD) and cognitive dysfunction compared to the general population. While recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia in CKD, emerging evidence indicates that it also possesses neuroprotective properties. This study aimed to evaluate the therapeutic impact of rHuEPO on platelet expression of amyloid precursor protein (APP) proteolytic fragments, apolipoprotein E (ApoE), glycogen synthase kinase 3β (GSK3β), total Tau, and phosphorylated Tau species (P-Tau181, P-Tau217, and P-Tau231), along with plasma levels of APP cleaving enzymes, P-Tau217, P-Tau231, inflammatory cytokines, and cholinergic markers in CKD patients with cognitive dysfunction. A total of 60 CKD patients were enrolled, including 30 without cognitive dysfunction and 30 with cognitive dysfunction, as determined by neuropsychological assessment. Platelet protein expression levels of total Tau, P-Tau181, P-Tau217, P-Tau231, and ApoE were analyzed using Western blotting. Gene expression levels of APP-cleaving enzymes, ApoE, GSK3β, and MAPT in platelets were assessed by RT-PCR. Plasma concentrations of APP-cleaving enzymes, inflammatory cytokines, cholinergic markers, P Tau217, and P-Tau231 were quantified. Results were compared with healthy controls, normocytic normochromic anemia, and AD. CKD patients with cognitive dysfunction showed significant alterations in the expression of platelet proteins (total Tau, P-Tau181, P Tau217, P-Tau231, and ApoE) and related genes (APP cleaving enzymes, ApoE, GSK3β, and MAPT), resembling the molecular profile observed in AD. Additionally, plasma levels of APP cleaving enzymes, inflammatory cytokines, cholinergic markers, and phosphorylated Tau species (P-Tau217 and P-Tau231) were significantly altered in these patients. Notably, after 6 months of rHuEPO therapy, these biomarkers showed marked improvement in CKD patients with cognitive dysfunction. These findings suggest that rHuEPO may offer therapeutic benefits beyond anemia correction, potentially serving as a supportive treatment for cognitive dysfunction in CKD by modulating AD-related peripheral biomarkers. Show less

Non-fasting blood lipid indexes and Cystatin C (CysC) are related to coronary artery stenosis, while the predictive value of their combination is unknown. This study aimed to investigate the ability of their combination to predict the degree of coronary artery stenosis. Totally, 194 patients who underwent coronary angiography were included. Data on non-fasting blood lipid indexes, including triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and ApoB/ApoA1, as well as CysC were collected. A degree of coronary artery stenosis ≥ 70% was considered as severe coronary artery stenosis. There were 101 (52.1%) patients with severe coronary artery stenosis. HDL-C ( Non-fasting blood lipid indexes and CysC are associated with severe coronary artery stenosis in patients who undergo coronary angiography, and the combination of ApoB/ApoA1 and CysC is enough to show a promising predictive value for predicting severe coronary artery stenosis. The online version contains supplementary material available at 10.1186/s13019-026-03855-x. Show less

Benign prostatic hyperplasia (BPH) is a common public health problem in ageing men worldwide. Diarylpropionitrile, a selective ERβ agonist, favorably regulates cell proliferation and inflammation, two major hallmarks of BPH pathology. This study aimed to explore the mitigative impact of diarylpropionitrile on testosterone-driven BPH in rats. 40 Sprague Dawley male rats aged 2.5-3 months were randomly divided into 4 groups (n = 10): a normal control group, a testosterone-induced BPH group, a finasteride-treated group, and a diarylpropionitrile-treated group. BPH was induced by daily subcutaneous testosterone injections for 4 weeks, with finasteride and diarylpropionitrile administered orally once daily for the same duration, one hour before each testosterone injection. After 4 weeks of treatment, macroscopic and microscopic features of prostatic hyperplasia and androgenic, proliferative, angiogenic, apoptotic, and inflammatory biomarkers in prostatic tissue homogenates were assessed. Testosterone administration significantly increased prostate weight, prostatic index, and hyperplasia scores, while treatment with either diarylpropionitrile or finasteride effectively ameliorated these testosterone-induced changes. Both treatments significantly lowered elevated prostatic DHT, 5αR2, β-catenin, and PCNA levels, demonstrating a strong anti-proliferative effect. They also attenuated the increased pro-inflammatory cytokines IL-6, IL-27, and PGE2 and growth factors TGF-β and VEGF. Furthermore, both agents inhibited testosterone-induced ERβ upregulation and increased expression of the anti-apoptotic protein BCL2. There were no substantial differences comparing finasteride and diarylpropionitrile in the majority of the tested parameters. Diarylpropionitrile alleviates testosterone-driven BPH in rats by modulating key pathways associated with cellular proliferation and inflammation. Diarylpropionitrile, as an ERβ agonist, represents a promising alternative for the BPH treatment through multi-targeted mechanisms. Show less

Depressive disorders often show recurrent courses that cannot be sufficiently prevented by existing therapeutic protocols. In other affective disorders, recurrence has been linked to three mechanisms -spontaneous recovery, accelerated new/relearning, and reinstatement- which are related to the preservation of disorder-related memory traces even through successful extinction-based interventions. Reconsolidation-interference protocols aim to directly alter such traces by reactivating and destabilizing them before intervention. While this approach has shown benefits in fear, craving, and trauma-related symptoms, its application to depression remains untested. To our knowledge, this study provides the first experimental evidence of its utility in depression-like states. Sixty participants took part in a three-day, three-group, double-blind randomized controlled trial. On day one, helplessness was induced using a modified unsolvable anagram task. On day two, participants were randomized into three groups undergoing different interventions while completing another cognitive demanding task: (1) extinction, where participants experienced success from start to finish; (2) reconsolidation, where participants briefly reexperienced failure before succeeding; or (3) reactivation, where failure repeated. On day three, the helplessness task was presented again to evaluate susceptibility for recurrence across conditions. Behavioral, self-report, and EEG data were collected. Across test days, participants showed reduced motivation and performance, attributing failure to personal ability, confirming successful helplessness induction. However, interventions at day two produced no robust group differences on behavioral, self-report, or EEG measures. Exploratory analyses suggested that brain-derived neurotrophic factor (BDNF) levels may have mediated outcomes. Findings do not confirm reconsolidation-based behavioral interference as effective for depression-like helplessness. Nonetheless, exploratory results highlight BDNF as a potential mediator, warranting further study on its role in postretrieval extinction effects in depression. Show less

The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR. This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway. In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro. SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression. SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment. Show less

Ischemic stroke is one of the leading global causes of disability and death. Despite advances in modern medical technology that improve acute treatment and rehabilitation measures, post-stroke anxiety and depression (PSD) do not receive sufficient attention. To systematically evaluate risk factors and early identification markers for PSD for more precise screening and intervention strategies in clinical practice. This retrospective study analyzed clinical data from 112 patients with ischemic stroke admitted between January 2022 and December 2024. Based on assessments using the Hamilton Rating Scale for Anxiety (HAMA) and Hamilton Rating Scale for Depression (HAMD) at 2 weeks (± 3 days) post-stroke, patients were classified into the PSD group (HAMA ≥ 7 and/or HAMD ≥ 7) and the non-PSD group (HAMA < 7 and HAMD < 7). Observation indicators included psychological assessment, demographic and clinical characteristics, stroke-related clinical indicators, neuroimaging assessments, and laboratory biomarkers. Multivariate logistic regression analysis was used to identify independent risk factors for PSD, and receiver operating characteristic curve analysis was used to evaluate the diagnostic value of potential biomarkers. Of the 112 patients, 46 (41.1%) were diagnosed with PSD. Multivariate analysis identified five independent risk factors: Female gender [Odds ratio (OR) = 2.32, 95% confidence interval (CI): 1.56-3.45], history of mental disorders prior to stroke (OR = 3.17, 95%CI: 1.89-5.32), infarct location in the frontal lobe or limbic system (OR = 2.86, 95%CI: 1.73-4.71), stroke severity with National Institutes of Health Stroke Scale ≥ 8 at admission (OR = 2.54, 95%CI: 1.62-3.99), and low social support (Social Support Rating Scale < 35, OR = 2.18, 95%CI: 1.42-3.36). Subgroup analysis showed that depression patients more commonly had left hemisphere lesions (68.4% PSD is a complex neuropsychiatric consequence of stroke involving disruption of the frontal-limbic circuitry, neuroinflammatory responses, and dysfunction of the hypothalamic-pituitary-adrenal axis. Show less

Ultrasonic calls (USVs) produced by rodents during contacts with group members are poorly studied compared to USVs elicited by isolation, handling, mate exposition or dyad same-sex interactions on a neutral territory. In this study, we apply a procedure for eliciting the USVs accompanying contacts between adult voles living in permanent social groups for two Lasiopodomys vole species. The values of all variables of fundamental and peak frequencies were significantly higher in L. brandtii than in L. mandarinus, the duration of USVs was two times longer in L. brandtii than in L. mandarinus. At the same time, the USVs did not differ between species in the occurrence of different call contours, nonlinear phenomena and note compositions. The USVs emitted during affiliative contacts were acoustically nearly identical to the low-frequency USVs described previously for these two species in the situation of short-term isolation from conspecifics. We discuss that voles can use the same type USVs in two different situations: of short-term isolation from conspecifics and during affiliative contacts in social groups. Call-eliciting procedure applied in this study is easy and potentially appropriate for pilot and comparative studies of USVs across species, including wild-type rodents without long experience of living under laboratory conditions. Show less

Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular-osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron-derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single-cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line-1 in vitro through the FAK-AKT-VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular-mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration. Show less

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are associated with genetic and environmental factors, including exposure to mercury, a heavy metal with neurotoxic effects. To identify and analyze alleles and genes linked to neurodegenerative diseases in relation to mercury exposure in Colombia. Scientific literature and population genotype data from public databases were reviewed, covering 94 Colombian adults genotyped under the CLM (Colombians from Medellín) reference. Data traceability was ensured through ID registration in the 1000 Genomes project database, guaranteeing informed consent and bioethical approval. Eleven genes (GSTP1, ATP7B, BDNF, GCLC, GCLM, MT1A, MT4, ABCC2, ABCB1, GPX1 y GPX4) with 18 polymorphisms distributed across ten chromosomes were analyzed using the SNPstatsTM program. The c² test was applied to evaluate the Hardy-Weinberg equilibrium, considering deviations with p < 0.05 as significant. The results showed a high probability of an association between neurodegenerative diseases such as Alzheimer’s and Parkinson’s and mercury exposure in individuals with genetic variants related to glutathione metabolism and mercury transport and excretion pathways. Genetic alterations or their expression involving mercury bioaccumulation, its crossing of the blood-brain barrier, central nervous system inflammation, and oxidative stress from reactive oxygen and nitrogen species increase the risk of developing Alzheimer’s and Parkinson’s disease. Show less

Resuscitative thoracotomy (RT) is a last-resort intervention for traumatic cardiac arrest or impending cardiovascular collapse. Although outcomes after RT are well described in civilian trauma, data from modern warfare-characterized by high-energy penetrating mechanisms, advanced prehospital care, and rapid evacuation-remain limited. This study evaluated the characteristics and outcomes of RT performed during recent combat operations within a combined military-civilian trauma system. We conducted a retrospective cohort study of all combat casualties who underwent emergency department (ED) RT during the Israel-Hamas conflict (October 27, 2023, to October 27, 2025). Data were extracted from prehospital and ED medical records and postmortem computed tomography reports. RT was defined as a thoracotomy performed in the ED in a pulseless patient with the intent to restore spontaneous circulation. The primary outcome was 30-day survival. Secondary outcomes included return of spontaneous circulation (ROSC) and 24-hour survival. Among 2,335 combat trauma admissions, 27 patients (1.2%) underwent RT. All were young male casualties with penetrating injuries, predominantly from explosive mechanisms (74.1%). Severe trauma was common (ISS ≥25 in 92.6%). Prehospital blood products were administered in 77.8% of patients, and 66.7% arrived at the ED within 60 minutes of injury. ROSC was achieved in 40.7%, of whom 90.9% were transferred to the operating room. Two patients (7.4%) survived to 24 hours and 30 days, both with good neurologic outcomes. No patient who lost pulse before hospital arrival survived. Among modern warfare casualties treated at civilian trauma centers, survival after RT is comparable to that reported in civilian series, despite severe and complex injury patterns. RT should not be considered futile for penetrating abdominal, pelvic, or extremity hemorrhage, even in the presence of associated head injury. In contrast, prehospital circulatory arrest is associated with an extremely poor prognosis.(J Trauma Acute Care Surg. 2026;000:000-000. Copyright © 2026 Wolters Kluwer Health, Inc. All rights reserved.). Show less