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The bidirectional cavopulmonary connection (BCPC) is a pivotal stage in the surgical palliation of single-ventricle patients. However, there is ongoing debate regarding the benefits and drawbacks of BCPC with additional or antegrade pulmonary blood flow (AAPBF) in optimizing the subsequent stage-total cavopulmonary connection (TCPC). To determine the influence of BCPC with AAPBF on pulmonary artery growth and hemodynamic outcomes. A retrospective review was conducted of 167 single-ventricle patients who underwent BCPC at Siriraj Hospital between 2006 and 2022. Patients were categorized into two groups based on AAPBF status: group 1 (with AAPBF, Median ages at pre-BCPC assessment were 1.06 years (group 1) and 2.17 years (group 2), and at pre-TCPC assessment were 6.19 and 7.27 years, respectively. Median age at BCPC operation was similar between groups (1.58 BCPC with AAPBF effectively promotes pulmonary artery growth without adversely affecting ventricular volume loading or pulmonary artery pressure. Further investigation into the development of arteriovenous malformations is recommended. Show less

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients living with type 1 diabetes (T1D). Dyslipidemia is a frequent risk factor in this population. Although statin therapy has demonstrated cardiovascular (CV) benefits in diabetes overall, specific evidence in T1D remains limited. This systematic review aims to evaluate the impact of statins on clinical and surrogate atherosclerosis-related outcomes in patients with T1D without established ASCVD. Statin use was associated with a significant reduction in the risk of major adverse cardiovascular events (MACE), with a pooled hazard ratio (HR) of 0.77 (95% CI: 0.70-0.84; low certainty), and a mean low-density lipoprotein cholesterol (LDL-C) reduction of 30.3 mg/dL (95% CI: -47.02 to -13.58; moderate certainty). Reductions in ApoB and non-HDL cholesterol were also reported. We conducted a systematic review following PRISMA guidelines. Searches were performed in PubMed, EMBASE, and Epistemonikos from inception to June 2025 using terms related to T1D, statins, and primary prevention. Eleven studies were included-nine randomized controlled trials (RCTs) and two cohort studies. Six (four RCTs and two cohorts) were eligible for meta-analysis of two primary outcomes; the remaining were summarized narratively. Statin use in T1D patients without ASCVD was associated with improved lipid profiles and reduced MACE. These findings support considering statins as a preventive strategy in this population, although prospective studies with hard outcomes are needed to better identify patients most likely to benefit. Show less

Lanthanides-doped luminescent materials have gathered considerable attention due to their application potential in stress sensing, lighting and display, anti-counterfeiting technology and so forth. However, existing materials mainly cover the 380-1540 nm range, with slight extension to the UV region, impeding their applications in solar-blind imaging, background-free tracking, concealed communication, etc. To address this challenge, here we propose guidelines for far-UVC (200-230 nm) optical design. Accordingly, we achieve multi-stimulated far-UVC luminescence at ~222 nm in Pr Show less

Early recognition of a risk of Alzheimer's disease (AD) remains a global challenge, and blood proteomic markers are of particular interest for wide-scale diagnostic use. Quantitative multiple reaction monitoring (MRM) approach demonstrates good reproducibility in the characteristic changes in the levels of reported candidate biomarkers (CBs) in different cohorts in AD. Following up on our previous study, we performed a joint analysis of 331 blood plasma samples from two different clinical cohorts of participants, comprising a total of 95 samples from patients with AD, 136 samples from patients with mild cognitive impairment (MCI), and 100 samples from controls. The obtained results confirm the significance of 37 CBs. A logistic regression-based algorithm was used to build protein classifiers, and a total of 21 important proteins were selected, 13 of which (ORM1, APOA4, LBP, HP, FN1, BCHE, APOE, PZP, A1BG, TF, SERPINA7, TTR, and F12) formed a universal panel that demonstrated strong classification performance in distinguishing AD patients from controls (ROC-AUC = 0.90) and in separating stable and progressing patients with MCI (ROC-AUC = 0.81). Overall, the analysis confirms the high potential of the MRM method for validating CBs in independent cohorts. Show less

Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less

Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather were HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation. Show less

The aim of the study was to identify proteomic signatures from the serum of horses affected by simple obstructive intestinal colic to characterize the pathological process and to assess potential biomarkers for early diagnosis. Seven horses with obstructive colic received venous blood samples for determination of standard hematobiochemical, inflammatory, and lipid profiles at the time of initial clinical examination and after conservative therapy upon recovery. Proteomic profiling was also performed on all samples by means of a within-group analysis (sick horses at discharge vs. sick horses at admission). A validation of expression levels was performed by the Multiple Reaction Monitoring approach. In the within-group comparison, 70 proteins showed a significant difference; The proteins involved in the immune response (C2, FC 2.41; CFB, FC 3.41; HPX, FC 7.36; LTF, FC -0.55; PSMA7, FC-0.55), blood coagulation (VWF, FC -0.54; F13A1, FC-0.54; F13B, FC-0.57; PRDX2, FC-0.41; FBLN1, FC-0.62; KNG1, FC-3.86) and lipid homeostasis (APOA4, FC -0.66; APOA5, FC -0.13; APOE, FC-0.56; LCAT FC-0.58) have changed. The study suggested the coexistence of inflammatory status, the presence of intestinal bacteria that may have triggered the immune response, and hyperlipidemia in horses with obstructive colic. Show less

Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and most CRCs arise from colorectal adenomas. Early detection and removal of precancerous lesions during the adenoma-carcinoma sequence can significantly reduce CRC risk. However, current clinical practice lacks rapid, noninvasive screening tools for reliable adenoma detection. Proteomic analysis was performed on serum samples from patients with inflammatory polyps (non-neoplastic), patients with adenomas, and healthy controls to identify key differentially expressed proteins capable of distinguishing adenoma patients. The alterations in these candidate proteins were further validated by ELISA to evaluate their potential as diagnostic biomarkers for colorectal adenoma. In two independent cohorts, we identified two candidate biomarkers, apolipoprotein A4 (APOA4) and filamin A (FLNA), through a multi-step selection process involving ANOVA p-value screening, sparse partial least squares discriminant analysis (sPLS-DA), and LASSO regression analysis. These candidates were subsequently validated in a third cohort using ELISA. The ELISA results for APOA4 were discordant with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) findings. In contrast, FLNA levels measured by ELISA showed a progressive decrease from healthy controls to patients with inflammatory polyps and further to those with adenomas. We propose FLNA as a potential biomarker for the diagnosis of colorectal adenomas. The areas under the ROC curves exceeded 0.7 for both key clinical comparisons: 0.810 for adenomas versus healthy controls, and 0.734 for adenomas versus inflammatory polyps. Overall, this study not only enhances our understanding of the serum proteome in colorectal adenoma but also identifies FLNA as a promising biomarker for its clinical diagnosis. Show less

Tick infestation is one of the main challenges in tropical beef cattle production, leading to significant economic losses. Knowledge of the molecular factors underlying natural tick resistance in cattle contributes to genetic selection through the identification of biomarkers that can be used to accurately identify animals resistant to ticks. Although several genes associated with resistance to ticks have been identified, the molecular mechanisms underlying tick resistance are yet to be elucidated. This study investigated the biological processes, pathways, and key proteins involved in the resistance to the tick Rhipicephalus (Boophilus) microplus in a tropically adapted beef cattle breed. Tick resistance was evaluated in 162 Caracu cows. Blood samples were collected from a subset of 16 extreme animals, including eight with a high tick load (SUS) and eight with a low tick load (RES), for proteomic analysis by LC-MS/MS. A total of 172 and 34 proteins were exclusively identified in plasma samples from the SUS and RES groups, respectively. In addition, 14,034 proteins were detected in the blood plasma of both groups, of which 51 and 101 proteins were significantly increased in plasma samples of the SUS and RES groups, respectively. Among the top 20 proteins with the highest absolute log-fold change values, those encoded by the RNASE1, TNS2, NOXO1, ZNRF3, APOA4, KMT2B, RPS6KA5, PON1, C4BPA, SETD2, HP, TMEM63A, MAST2, and SETD1B genes were highlighted based on their functions that may contribute to a response to tick infestation. Functional enrichment analysis revealed 36 biological processes, 35 molecular functions, and 16 pathways to be significant (P < 0.05), highlighting those related to hemostasis, vesicular transport, cell proliferation and migration, calcium, actin, lipids, scavenger receptors, hydrogen peroxide, tyrosine, and insulin-like growth factor, which may contribute to tick resistance. In addition, PPI network analysis revealed several proteins involved in complement and coagulation systems, hematopoiesis, and immune response as important nodes, based on their centrality and edges. The identification of differentially abundant proteins between RES and SUS animals, as well as their relationships and roles in key biological processes and molecular pathways detected, contribute to improving our understanding of the mechanisms underlying tick resistance in naturally adapted cattle breeds. Furthermore, the differentially abundant proteins detected in this study are potential biomarkers for the response to R. microplus infestation. Show less

Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duodenal, cecal, hepatic, and cardiac inflammation remains elusive. Specific pathogen-free chicken embryos (n = 72) were allocated to the control, LPS groups (10 μg, 24 μg, 50 μg, 100 μg, 170 μg/egg, respectively). Fifteen day old embryonated eggs were injected abovementioned solutions via the allantoic cavity by disposable syringes. On embryonic day 19, the tissues of the embryos were collected for histopathology, RNA extraction, real-time PCR, and immunohistochemistry investigation. The results demonstrated that there was inflammatory responses (heterophils infiltration or macrophages accumulation) presented in the duodena, ceca, livers, and hearts after LPS induction. The duodenal mRNA expressions of inflammatory-associated mediators (TLR4, IFNγ, IL-1β, IL-6, IL-8, MMP9, MMP3, p38, or NF-κB1) were significantly upregulated after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Duodenal immunopositivity of TLR4, MMP9, and MMP3 significantly increased following LPS induction (24 μg or 50 μg) compared to the control group. Meanwhile, the hepatic mRNA expressions of inflammatory-associated factors (IFNγ, MMP3, IL-1β, IL-10, TNFα, IL-8, or NF-κB1) significantly increased after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Additionally, cardiac mRNA expression of TLR4, IFNγ, IL-1β, IL-8, IL-10, MMP3, MMP9, and TNFα was significantly increased in all five LPS groups compared to the control group. Cardiac protein expressions of TLR4 or IFNγ significantly increased when compared 100 μg LPS group with the control group. Duodenal and cecal mRNA expressions of programmed cell death-related factors presented irregular. The mRNA expression of hepatic pyroptosis-associated gene AMPKα2, Beclin-1, Bcl-2, CASP1, or CASP12 after LPS induction (10 μg, 24 μg, or 50 μg/egg) increased when compared with the control group. Furthermore, the cardiac mRNA expressions of pyroptosis-related gene CASP1 and CASP12 in five LPS groups increased when compared with the control group. Cardiac autophagy-related gene Bcl-2, ATG5, or LC3B enhanced in LPS groups (10 μg, 50 μg, or 100 μg/egg) when compared with the control group, whereas LC3A, CASP1, or Drp1 mRNA expression in five LPS groups reduced when compared with the control group, respectively. The mRNA expressions of duodenal mucosal barrier function-associated mediators Claudin 1 and PEPT1 were upregulated after LPS induction (10 μg or 50 μg/egg) when compared five LPS groups with the control group, respectively; nevertheless, duodenal Mucin 2 and SGLT1 mRNA expression reduced in four groups (24 μg, 50 μg, 100 μg, or 170μg /egg) when compared with the control group, as well as cecal mRNA expressions of Mucin 2, occludin, SGLT1.The mRNA expressions of liver permeability-related gene (claudin 1 and occludin) increased in the five groups when compared with the control group, as well as cardiac permeability and energy metabolism-related gene (AMPKα2, APOA4, PPARα, SGLT, and claudin1). In conclusion, LPS can induce duodenal, hepatic and cardiac inflammation, initiate energy deficiency, autophagy, programmed cell death, enhanced intestinal mucous barrier function, tight junction, and permeability in chicken embryos. Show less

Dysferlin direct protein-protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in the tectorial membrane (TM) co-localizing with FKBP8, consistent with the SPR determination of tight, positively Ca Show less

Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential therapeutic intervention or prevention is still insufficient. The present study aimed to uncover the key pathological molecules by using iTRAQ proteomics. The results identified 2432 candidate proteins in SATR patients using iTRAQ proteomic analysis. A total of 307 differentially expressed proteins (DEPs) were identified and linked to 211 KEGG signaling pathways including Coronavirus disease (COVID-19), focal adhesion, and ribosomes. GO enrichment analysis highlighted significant enrichment in processes such as biological adhesion, ossification, lipid (APOA4) processes, and extracellular matrix (ECM) organization (collagen). PPI network analysis identified hub genes such as serum albumin (ALB), fibronectin (FN1), and actin cytoplasmic 1. The WB analysis confirmed that FN1 and the receptor for activated C kinase (RACK1) were downregulated in the SATR tendon. Immunohistochemical staining revealed that collagen I and III were suppressed, while collagen II and APOA4 expression were higher in the SATR pathological tissue ( Show less

Fibroblast growth factor 2 (FGF2)regulates signal transduction by forming complexes with its receptors, FGF receptors (FGFRs), and heparan sulfate (HS), playing a crucial role in biological systems. Although HS has been suggested to modulate FGF/FGFR signaling as a coreceptor, multiple hypotheses exist regarding how HS affects FGF/FGFR signaling and the mechanism remains unclear. Herein, to highlight the role of FGF2/HS interaction in FGF2/FGFR1 signaling, FGF2 mutants with reduced HS-binding affinity are rationally designed through in silico analysis. These FGF2 mutants exhibit reduced HS affinity by more than two orders of magnitude while maintaining binding affinity to FGFR1. In addition, these mutants retain their thermal stability. Cellular assays using the FGF2 mutant suggest that, contrary to previous reports, the contribution of the FGF2/HS interaction in FGF2/FGFR1 signaling may be limited. The mutant FGFs that specifically alter the interaction with HS, achieved in this study, would contribute to an understanding of the role of FGF/HS interaction in FGF/FGFR signaling. Show less

To describe the prevalence and clinicopathologic associations of FGFR-altered urinary tract carcinomas in institutions incorporating reflex testing. Next-generation sequencing was prospectively performed on urinary tract carcinomas for the detection of FGFR1-4 alterations at 2 tertiary care centers (2021-2025), using the Oncomine Comprehensive Assay (OCA) v3 DNA and OCA Plus RNA. Reflex testing was conducted on metastatic and/or advanced (pT3/4) carcinomas. The cohort included 366 patients (239 lower tract carcinomas, 72 upper tract carcinomas, and 55 metastases). Median age was 72.5 years (range, 36-97). Fifty-nine (16.1%) tumors were FGFR-altered. Forty-nine (13.4%) patients with actionable FGFR alterations (33 FGFR3 mutations, 13 FGFR3 fusions, and 3 FGFR2 mutations) were all 55 years or older (P = .097). The prevalence of actionable FGFR alterations was significantly higher in upper vs lower tract carcinomas (23.8% vs 13.8%, P = .007) and in lung metastases vs other metastatic sites (57.1% vs 10.4%, P = .002). A higher frequency was also seen in metastases vs primary tumors (16.4% vs 12.9%), although this difference did not reach statistical significance (P = .482). Actionable FGFR alterations were observed in urothelial carcinoma not otherwise specified (40/261) and in urothelial carcinoma with squamous differentiation (6/43), micropapillary features (2/11), or nested features (2/7). The detection rate for FGFR1-4 alterations in a real-world, dual-institution cohort of urinary tract carcinomas was reported. Show less

To explore the latent classes and their associated factors of sleep quality among police officers, and to analyze the potential heterogeneity in sleep quality within this population. A total of 1162 police officers were selected using cluster random sampling in the Inner Mongolia Autonomous Region between September and December 2021. Participants completed a basic information questionnaire and the Pittsburgh sleep quality index(PSQI). Latent profile analysis(LPA) was employed to examine heterogeneity in sleep quality, and multinomial Logistic regression was used to identify associated factors of the latent profiles. The mean age of participants was(43.08±8.98) years. The sample comprised 920 males(79.2%) and 242 females(20.8%), 987(84.9%) were married and 175(15.1%) were single, 644(55.4%) had a high school education or below, and 518(44.6%) had college education or above. By department, 607(52.2%) worked in grassroots police stations, 200(17.2%) were criminal police, and 355(30.6%) served in other units. Significant heterogeneity in sleep quality was identified, revealing four distinct latent classes: good sleep group(n=821, 70.6%), moderate sleep group(n=46, 4.0%), sleep-disordered group(n=249, 21.4%), and medication-assisted sleep group(n=46, 4.0%). Using the good sleepers as the reference group, multinomial Logistic regression indicated that older age was a significant risk factor for belonging to the medication-assisted sleep group(OR=1.348, 95%CI 1.078-1.822). Higher education level was a protective factor against membership in the moderate sleep group(OR=4.101, 95%CI 1.304-12.893). Serving as a grassroots police station officer or criminal police officer was a significant risk factor for membership in both the moderate sleep group(OR = 3.329, 95%CI 1.338-8.284; OR=4.188, 95%CI 1.415-12.396) and sleep-disordered group(OR=1.701, 95%CI 1.196-2.420; OR=1.587, 95%CI 1.073-2.533). Sleep quality among police officers demonstrates significant heterogeneity. Age, police department assignment, and educational level are key associated factors of distinct latent classes of sleep quality. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes remains unclear. This study aims to examine the associations of physical activity with the risk of liver cirrhosis, cancer, cardiovascular disease (CVD) incidence and mortality. 32 681 MASLD participants with accelerometer-derived physical activity data from the UK Biobank were analysed. Physical activity intensity was categorised into light (LPA), moderate (MPA) and vigorous (VPA) intensity. Cox proportional hazard and acceleration failure models were employed to assess associations between physical activity duration and outcomes. During a median follow-up of 7.5-7.9 years, 1883 deaths, 151 liver cirrhosis, 3312 cancers and 6657 CVD events were recorded. Physical activity, regardless of intensity, was consistently associated with a reduced risk of liver cirrhosis, CVD and all-cause mortality. Compared with non-MASLD individuals, our analysis indicates that longer duration of physical activity, specifically >1945 min/week of LPA or >383 min/week of MPA may theoretically eliminate the excess risk of mortality associated with MASLD. Among MASLD individuals, longer physical activity duration, regardless of intensity, was associated with reduced risks of liver cirrhosis and mortality. MPA and VPA were associated with lower CVD risk, while VPA was associated with reduced cancer risk, highlighting the potential benefits of increasing the intensity and duration of physical activity in MASLD management. Show less

The PromarkerD test accurately predicts diabetic kidney disease. We aimed to determine whether PromarkerD and/or its constituent biomarkers would also identify an increased risk of distal sensory polyneuropathy (DSPN) complicating type 2 diabetes (T2D). We selected 160 community-based adults without baseline DSPN (mean age 69 years, 56% males), 80 of whom were free of DSPN after four years and 80 who developed DSN based on the vibration perception threshold. Baseline plasma apolipoprotein A-IV (ApoA4), CD5 antigen-like protein (CD5L) and insulin-like growth factor binding protein 3 (IBP3) concentrations were measured and PromarkerD risk scores were generated. Logistic regression modelling assessed associations between PromarkerD risk and its component proteins and incident DSPN. At Year 4, 77 of 151 with valid data (51%) had developed DSPN. The PromarkerD area under the receiver operating characteristic curve was 0.53 (95% CI 0.43-0.62). The odds ratio for the PromarkerD score for identifying incident DSPN was 0.97 (95% CI 0.82-1.16, P = 0.76), with similar non-significant results for plasma ApoA4, CD5L, and IBP3. PromarkerD and its constituent protein concentrations, each with some preclinical or epidemiological evidence of an association with DSPN, did not predict incident DSPN over 4 years of follow-up. These data support microangiopathy-specific pathophysiological mechanisms in T2D. Show less

Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Show less

The potential impact of lifestyle changes such as prolonged fasting on brain health still remains unclear. Neurodegenerative diseases often exhibit two key hallmarks: accumulation of misfolded proteins such as amyloid beta oligomers (AβO) and intracellular cholesterol accumulation. In this study, we investigate how a 36-h fast affects the capacity of isolated high-density lipoproteins (HDLs) to modulate the effects of AβO and excess cholesterol in microglia. HDL from 36-h fasted individuals were significantly more effective in effluxing cholesteryl esters from treated microglia, showing a remarkable 10-fold improvement compared to HDL from the postprandial state. Furthermore, the ability of 36-h fasted HDL to mitigate the reduction of apolipoprotein E secretion in AβO- and cholesterol-loaded microglia surpassed that of postprandial HDL. In exploring differences among HDL parameters from postprandial, overnight fasted, and 36-h fasted individuals, we observed that plasma HDL-cholesterol and apolipoprotein A-I concentrations remained unchanged. However, nuclear magnetic resonance (NMR) analysis revealed reduced total HDL particle count, a decrease in the smallest HDL particles (HDL1, 7.4 nm diameter), and an increase in the largest HDL particles (HDL7, 12 nm) after the 36-h fast. Transmission electron microscopy (TEM) analysis further found an increase in even larger HDL particles (12-14 nm) in 36-h fasted individuals. Targeted mass spectrometry (MS)-based proteomics and glycoproteomics unveiled a reduction in HDL-associated apolipoprotein A-IV and disialylated apolipoprotein C-III content following the 36-h fast. These findings collectively suggest that prolonged fasting induces structural, compositional, and functional alterations in HDL particles, and influences their capacity to attenuate the effects of excess cholesterol and AβO in microglia. Show less

The MetaboHealth score is an indicator of physiological frailty in middle aged and older individuals. The aim of the current study was to explore which molecular pathways co-vary with the MetaboHealth score. Using a Luminex cytokine assay and liquid chromatography-mass spectrometry-based proteomics we explored the plasma proteins associating with the difference in 100 extreme scoring individuals selected from two large population cohorts, the Leiden Longevity Study (LLS) and the Rotterdam Study (RS), and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR). In addition, we estimated the heritability of the score using 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs. In the contrasting extreme scoring individuals from LLS and RS, we uncovered significant differences in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 (out of 289) plasma proteins. The high, poor health related, score associated with 42 increased inflammatory and immune related protein levels (CRP, LBP, HPT) and lowered levels of 71 HDL remodeling and cholesterol transport related proteins (e.g. APOA1, APOA2, APOA4, and TETN). Using the NTR twins, we subsequently showed that the MetaboHealth score is moderately heritable (h Show less

Amyloidosis is a group of protein misfolding diseases and a well-recognized disorder in avian species. However, the knowledge of wild avian amyloid proteome is scarce. We report here gross, histopathological, ultrastructural, immunohistochemical and proteomic findings of systemic amyloidosis in seven Eurasian stone-curlews (Burhinus oedicnemus) necropsied in the Canary Islands. Spleen (5/6-83.33%), liver (3/5-60%), kidney (3/5-60%), proventricle (3/5-60%) and intestine (3/6-50%) were the more severely affected organs. All cases underwent chronic inflammatory processes associated to helminth, bacteria or fungi infection. Verminous chronic ventriculitis was the most frequent associated pathology in 5/7 (71.43%) followed by bumblefoot in 2/7 (28.57%) cases. Electron microscopy revealed a predominantly amorphous substance with 10 nm diameter non-branching amyloid fibrils. AA amyloidosis was characterized by immunohistochemistry and mass spectrometry analysis. By mass spectrometry three amyloid signature proteins were also identified: vitronectin, apolipoprotein A-IV and apolipoprotein A-I in 6/7 (85.71%), 4/7 (57.14%), and 3/7 (42.86%) cases, respectively, contributing with new knowledge about the amyloid proteome of amyloidosis in wild avian species. Show less

Global warming exacerbates heatstroke, increasing its severity and associated health risks, including fatal kidney damage. Predicting post-heatstroke organ injury remains difficult, delaying timely medical intervention. This study aims to identify potential blood biomarkers that reflect organ stress and recovery status following heatstroke. Plasma samples (n = 12) from clinically diagnosed classical (non-exertional) heatstroke patients were collected at diagnosis and recovery. Two-dimensional gel electrophoresis was used to analyze protein expression, identifying 359 protein spots. Selected proteins showing differential expression were validated by Western blotting. Here, five proteins-alpha-1 antitrypsin, alpha-1 microglobulin/bikunin precursor, apolipoprotein A-IV, clusterin, and complement component 2-show significant changes between the two timepoints. These proteins are linked to inflammatory, coagulation, and lipid metabolism pathways. Alpha-1 antitrypsin, alpha-1 microglobulin, and complement component 2 may reflect the resolution of inflammation, while apolipoprotein A-IV and clusterin indicate renal stress. The alpha-1 microglobulin-IgA complex may exert anti-inflammatory effects. Complement component 2, an initiator of the complement cascade, has not been previously reported to be associated with heat stress. The findings suggest that these proteins may serve as blood biomarkers to assess heatstroke severity and monitor recovery. Their clinical application could improve early detection of organ damage and guide intervention strategies. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging. Show less

Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment. Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models. Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin ( OMD ), apolipoprotein A4 ( APOA4 ), and insulin like growth factor binding protein 6 ( IGFBP6 ) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells. Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD , APOA4 , and IGFBP6  may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

The quality of eggshells holds substantial economic significance and serves as a critical selection criterion in poultry breeding. Eggshell translucency significantly impairs their aesthetic quality, which is structurally attributed to the thinning of the eggshell membrane or reduced tensile strength. In this study, 836 dwarf white hens were selected, with 45 hens each assigned to the opaque group and the translucent group. Grading for eggshell translucency was conducted at 75, 80, and 85 weeks of age. Based on the results from these three gradings, 35 hens that consistently produced translucent eggs and 35 hens that consistently produced opaque eggs were reclassified into the translucent group and the opaque group, respectively. The thickness of the eggshell membrane, latitudinal and longitudinal tensile force and length, and other indicators related to eggshell membrane quality were measured. Correlation analysis was performed using RNA-seq genomics and DIA proteomics based on the relationships among these indicators. Transcriptome analysis revealed 179 significantly differentially expressed genes, indicating that the causes of translucent eggshells are associated with metabolism, signal transduction, the immune system, molecular binding, transport, and catabolism. Seven potential candidate genes, including Show less

Chronic renal allograft injury (CRAI) is a major cause of allograft loss in kidney transplant recipients (KTRs). The aim of this study was to evaluate the associations of urinary apolipoprotein A4 (ApoA-IV) levels with renal function and rapid renal function decline in KTRs. This study included 50 KTRs. Proteomic analysis via liquid chromatography‒mass spectrometry and tandem mass spectrometry (LC-MS/MS) was performed to identify potential urinary biomarkers. The SWATH (sequential window acquisition of all theoretical mass spectra) method was used for protein quantification. Urinary ApoA-IV levels were validated by enzyme-linked immunosorbent assay (ELISA). Rapid renal function decline was defined as an estimated glomerular filtration rate (GFR) decrease of >3 mL/min/1.73 m2 per year or initiation of dialysis. The log-transformed urinary ApoA-IV levels measured by ELISA had a significantly inverse correlation with the estimated GFR (r = -0.72, P < 0.001). Moreover, urinary ApoA-IV levels were higher in patients with rapid renal function decline than in those with stable renal function (215.4 ± 181.8 μg/mL vs. 42.5 ± 72.4 μg/mL, P = 0.001). Univariate logistic regression analysis revealed that log-transformed urinary ApoA-IV levels were significantly associated with rapid renal function decline (odds ratio [OR] 6.70, 95% confidence interval [CI] 2.56-22.83; P < 0.001). Multiple logistic regression showed urinary ApoA-IV levels remained a significant risk factor for rapid renal function decline (OR 4.10, 95% CI 1.10-19.55; P = 0.047). ROC curve analysis revealed the area under the curve (AUC) of 0.834 (95% CI 0.722-0.945, P < 0.001) for urinary ApoA-IV levels in predicting rapid renal function decline. Our results suggest that urinary ApoA-IV levels might be a potential biomarker for renal allograft function and could be used as a predictor for rapid renal function decline in KTRs. Show less