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Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a common complication after carbon monoxide poisoning. This study focused on the role and mechanism of Axin-1 regulating ferroptosis in DEACMP. Nissl staining, immunohistochemistry, immunofluorescence and Prussian blue were used to evaluate the histopathology and iron distribution of DEACMP rats. The N6-methyladenosine (m The expression of Axin-1 in DEACMP rats was increased, and its up-regulation was related to IGF2BP2-mediated m IGF2BP2-mediated m Show less

This study employs latent profile analysis (LPA) to identify distinct profiles of positive youth development (PYD) based on the 5C model (connection, competence, confidence, character, and caring). While extensive research has established associations between PYD indicators and adolescent mental health, well-being, and behavioral outcomes, a person-centered approach allows for a deeper exploration of how different patterns of PYD characteristics are related to these distal outcomes. Unlike previous studies, this research uses 15 PYD indicators, capturing all subdimensions of each of the four Cs, with caring treated as a unidimensional construct. The study was conducted on a national cross-sectional sample of 3,559 first-year high school students (aged 15.1 years). Latent profiles were identified via maximum likelihood estimation, and model fit was evaluated through multiple fit indices. The BCH method was used to assess profile associations with distal outcomes. Six distinct profiles were identified along with their relationships with distal outcomes (Vulnerable Youth: Distressed and Risk Behaving, Caring but Struggling: Distressed but Reserved, Balanced Achievers: Resilient Contributors, Self-Centred Underachievers: Risk Behaving, Confident but Detached: High-Performing Rebels, and Thriving Stars: Thriving and Contributing). The results highlight how strengths in one area (e.g., confidence, competence, and caring) can coexist with significant risks (e.g., binge drinking, antisocial behaviour, and mental health), whereas adolescents with poor mental health or risk behaviour may possess very different internal and external resources. Among the below-average PYD groups, students with very low levels of character and caring but preserved confidence are prone to risk behaviors while being somewhat protected from mental health issues. Others, characterized by high diversity and caring but very low confidence, show vulnerability to mental health challenges without risk behaviors. Additionally, high-risk behaviors can either cooccur with mental health issues in extremely low-PYD students or emerge independently in confident, competent adolescents lacking character, caring, and school connections. By revealing unique developmental pathways, this study enhances the understanding of youth development diversity, emphasizing the necessity of examining both observable behaviors and underlying developmental traits for developing targeted interventions that support strengths and address challenges within distinct adolescent subgroups. Show less

Persistent monocyte activation and altered cytokine responses are reported in PWH despite ART. How prior HIV-1 infection status and timing of ART initiation relate to monocyte pattern-recognition receptor crosstalk between TLR8 and RLRs remains uncertain. We conducted a comparative cohort study in adult males enrolled from two Dutch HIV-cohorts. Participants included HIV-negative participants, PWH who initiated ART during chronic HIV infection, and PWH who initiated ART during acute HIV infection, with sampling at 24 and 156 weeks after ART initiation for the acute group. PBMCs were stimulated with an RLR agonist, a TLR8 agonist, or both. Monocyte surface markers were assessed by flow cytometry and pro-inflammatory cytokines were analysed with qPCR and ELISA. Across groups, RLR stimulation induced IL-12p70 and IL-27, TLR8 stimulation induced IL-6 and IL-12p70 and combined TLR8 + RLR co-stimulation synergistically increased IL-12p70 and IL-27 while restricting IL-6. Compared with controls, CHI showed reduced IL-12p70 and IL-27 and higher IL-6. In AHI at 24 weeks, cytokine patterns and co-stimulation effects resembled HIV-negative participants; by 156 weeks, responses were attenuated and approximated CHI. In this male cohort, TLR8-RLR crosstalk was preserved early after ART initiation during acute infection but diminished over time, approaching profiles observed in chronically treated infection. These observations emphasise a potential early window after ART initiation for interventions aiming to preserve monocyte function and motivate studies to characterise underlying mechanisms. Funding for this study was obtained through a ZonMW/Aidsfonds grant NL4Cure: Bridging shock and kill strategies (446002508). Show less

Myeloid/Lymphoid Neoplasms with eosinophilia and involvement of Tyrosine Kinase gene fusions (MLN-TK) is a WHO disease category including a diverse group of malignancies characterised by recurrent genomic rearrangements of tyrosine kinase (TK) genes such as PDGFRA, PDGFRB, FGFR1, JAK2, ETV6 and FLT3. Identification of these TK rearrangements is important for the accurate diagnosis of MLN-TK and allows targeted therapy with TK inhibitors. In this study, we validated the use of optical genome mapping (OGM) retrospectively by analysing 11 samples from 10 cases with suspected or known TK rearrangements, previously analysed by current standard of care (SOC) methodologies, i.e., chromosome banding analysis (CBA), FISH and/or PCR-based techniques. In six abnormal cases, OGM was able to detect the rearrangements previously determined by SOC methods. Furthermore, OGM identified the fusion partner in the JAK2- and PDGFRB-rearranged cases and elucidated the mechanism underlying the BCR::FGFR1 and ETV6::SYK rearrangement. In two cases with a normal karyotype, OGM detected two cryptic FIP1L1::PDGFRA and TNIP1::PDGFRB rearrangements. In the two remaining cases, no abnormalities were detected either by OGM or SOC methods. We demonstrate that OGM is a valid technique for the diagnostic workflow of MLN-TK, able to detect TK rearrangements and to identify unknown TK fusion partners. Show less

Chronic exposure to second-hand smoke (SHS) contributes to the development of health issues, including cancer and cardiovascular diseases. Molecular mechanisms underlying SHS-related diseases remain poorly understood, highlighting the need for reliable risk assessment biomarkers. Herein, we demonstrate that the plasma proteome of individuals exposed to SHS undergoes significant modulation. Butyrylcholinesterase (BChE) and Vitamin D-binding protein (GC) that are involved in the physiological response to circulating toxic substances, as well as key mediators of systemic inflammation, including Complement C1r subcomponent (C1R), Complement C1q subcomponent subunit C (C1QC), Histidine-rich glycoprotein (HRG), and Vitamin K-dependent protein S (PROS1), were found to be significantly modulated in SHS-exposed individuals. Moreover, strong indicators of a pro-atherothrombotic response such Apolipoprotein A-IV (APOA4) and Alpha-2-antiplasmin (SERPINF2), were also differentially expressed. These findings provide novel insights into the biological pathways linking SHS-exposure to cardiovascular risks, and suggest a panel of candidate proteins with potential utility as SHS-risk assessment biomarkers. Show less

in the last decades, social networking sites (SNSs) use among adolescents has dramatically increased, feeding the adolescents' needs. However, younger users might be more vulnerable to problematic social networking. Scholar research increasingly highlighted the need to explore the underlying mechanisms of problematic use of SNSs. Difficulties in emotion regulation, general distress, experiences of shame, and specific motivations for SNSs use might represent risk factors for problematic social networking. On the contrary, other variables adolescence-related and potentially involved in problematic SNSs use (emptiness, boredom, emotional autonomy, and self-concept clarity) need further exploration. the present person-centered study aimed at profiling SNSs teen users (13-19 years) based on their (problematic) social networking, by comparing their SNSs-related behaviors and motivations, emotional dysregulation, distress symptoms, emptiness, boredom, shame, self-concept clarity, and emotional autonomy. the study involved 774 Italian adolescents (57% females; mean age = 15.74 ± 1.62 years) and four different profiles characterized by unique patterns of (problematic) social networking were identified through the latent profile analysis (LPA): (1) non-problematic SNSs users, (2) at-risk SNSs users, (3) problematic SNSs users, and (4) defended SNSs users (ntp=218; AIC=39125.44; BIC=39988.37; SSABIC=39296.00; entropy=.97; LMP-LRT p <.05; BLRT p <.05). concerning the emerging profiles, problematic and non-problematic SNSs users displayed the highest and lower levels of risk factors related to social networking, respectively. The so-called "Defended" profile might include participant adolescents who defensively avoided thinking about the psychological and emotional experiences of SNSs use, showing very low levels in all the variables exploring SNSs-related behaviors and motivations, and psychological risk. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression. Show less

Atherosclerotic CVD is a major cause of death in individuals with type 1 diabetes mellitus (T1DM). However, conventional risk factors do not fully account for the increased risk. This study aimed to investigate whether serum proteins associate with diabetes status and the occurrence of CVD in T1DM. We used isotope dilution-MS/MS to quantify 28 serum proteins in 228 subjects participating in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used linear regression to analyze the association between serum protein levels and T1DM status using 47 healthy controls and 134 T1DM patients without CVD and Cox proportional hazards regression to assess their prediction for incident CVD by a case-cohort study using a subcohort of 145 T1DM subjects and a total of 47 CVD events. Of the 28 serum proteins studied, five of them-alpha-2-macroglobulin (A2M), apolipoprotein A-IV, apolipoprotein L1, insulin-like growth factor 2, and phospholipid transfer protein-were significantly associated with T1DM status, with A2M being 1.6-fold higher in T1DM. After adjusting for potential confounders, A2M independently predicted incident CVD, with a mean hazard ratio of 3.3 and 95% CI of 1.8-6.1. In our study, A2M showed the largest increase in serum levels when comparing patients with T1DM to control subjects. A2M also predicted incident CVD, suggesting that it could serve as both a marker and possibly a mediator of atherosclerosis in T1DM. These findings emphasize the importance of specific serum proteins in assessing and managing CVD risk in T1DM. Show less

Liver diseases are a major contributor to both morbidity and mortality. Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal. The use of floxed rat resource has rapidly increased, but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited, especially in a spatially and temporally restricted manner. RNA sequencing and real-time polymerase chain reaction (PCR) were used to screen and confirm the presence of liver-specific genes. Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin. Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats. The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tissue sections. Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes. The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats. Apoa4 and Cyp2c11 were identified as two liver-specific genes. Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats. The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats. All the blood biochemical parameters except low-density lipoprotein (LDL) did not change significantly in the Cre rats. No histological alterations were detected in the livers of the Cre rats. Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout, specifically in juvenile and adult liver. Show less

The aim of the present study was to investigate the dietary effects of replacing corn with different proportions of fermented straw on the growth performance and intestinal health of finishing pigs. A total of 275 healthy commercial finishing pigs aged 126 days (average body weight, 82.96 ± 3.07 kg) were randomly allocated into three groups: the control (CTR, basal diet) group, the 5% fermented straw (FJJG5, replacing 5% of the corn) group, and the 10% fermented straw (FJJG10, replacing 10% of the corn) group. There were six replicates in each group and 14-16 pigs per replicate. On day 39 of the experiment, one animal from each replicate was slaughtered for sampling and for further analysis. The results showed that the finishing pigs in the FJJG10 group had a reduced average daily weight gain and an increased feed-to-gain ratio. The FJJG5 group had reduced total cholesterol, high-density lipoprotein, and low-density lipoprotein in their serum, while the FJJG5 and FJJG10 groups had reduced contents of lactate dehydrogenase. In addition, the FJJG5 group exhibited increased T-SOD activity and MDA content in the colon, while the FJJG10 group also showed increased T-AOC activity in their serum and increased contents of MDA in the colon. The FJJG5 group exhibited increased activities of jejunal disaccharidase and lipase, while the FJJG10 group exhibited decreased jejunal crypt depths. Moreover, the FJJG5 group presented an increased relative expression of Show less

Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in circulation after six weeks of consuming a high-fat diet in humans. However, the impact of dietary changes in regulating apoA-IV, and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established. We investigated the regulation of circulating fasting concentrations of apoA-IV in humans in response to diets enriched in either fat or carbohydrates. Moreover, to study the whole-body and tissue-specific glucose and lipid metabolic effects of apoA-IV, we administrered apoA-IV recombinant protein to mice and isolated pancreatic islets. We demonstrate that in healthy human individuals high-fat intake increased fasting plasma apoA-IV concentrations by up to 54%, while high-carbohydrate intake suppressed plasma apoA-IV concentrations. In mice, administration of apoA-IV acutely lowered blood glucose levels both in lean and obese mice. Interestingly, this was related to a dual mechanism, involving both inhibition of hepatic glucose production and increased glucose uptake into white and brown adipose tissues. In addition to an effect on hepatic glucose production, the apoA-IV-induced liver proteome revealed increased capacity for lipoprotein clearance. The effects of apoA-IV in the liver and adipose tissues were concomitant with increased whole-body fatty acid oxidation. Upon glucose stimulation, an improvement in glucose tolerance by apoA-IV administration was related to potentiation of glucose-induced insulin secretion, while apoA-IV inhibited glucagon secretion ex vivo in islets. We find that apoA-IV is potently increased by intake of fat in humans, and that several beneficial metabolic effects, previously associated with high fat intake in humans, are mimicked by administration of apoA-IV protein to mice. Show less

Apolipoprotein A-IV (apoA-IV) is an abundant lipid-binding protein in blood plasma. We previously reported that apoA-IV, as an endogenous inhibitor, competitively binds platelet αIIbβ3 integrin from its N-terminal residues, reducing the potential risk of thrombosis. This study aims to investigate how the apoA-IV Show less

ApoA-IV amyloidosis is a rare disease that involves the deposition of ApoA-IV protein aggregates in tissues. It commonly presents as cardiac or renal disease, but can, in rare cases, cause small bowel perforation. This study describes a case of ApoA-IV type amyloidosis causing small bowel perforation after conversion of a sleeve gastrectomy (SG) into a RYGB in a Crohn's disease (CD) and rheumatoid arthritis (RA) patient. It also considers the indications for bariatric and anti-reflux surgery in the setting of co-morbid inflammatory bowel disease (IBD), gastro-oesophageal reflux disease (GORD), and obesity. Obesity can reduce the efficacy of IBD medications and drives a pro-inflammatory state that may worsen IBD, however IBD patients present an operative challenge due to risk of more intestinal adhesions, potential intolerance to intestinal bypass, and risk of affecting options for future bowel resections if required. SG is often chosen over RYGB for CD patients due to limited short-term complications. However, when considering co-morbid GORD, the long-term risk of medication resistant GORD, erosive oesophagitis, and Barrett's oesophagus with SG is significant, especially given that SG is an irreversible procedure. There is growing evidence that bariatric surgery in IBD patients is both safe and effective, however the decision to perform bariatric surgery in an IBD patient involves consideration of the intricate interplay between obesity and IBD. Show less

Accurate diagnosis of Crohn's disease (CD) is paramount due to its resemblance to other inflammatory bowel diseases. Early and precise diagnosis plays a pivotal role in tailoring personalized treatments, thereby enhancing the quality of life for CD patients. Differential gene expression analysis was conducted to identify genes from the mRNA expression profiles of CD samples, followed by pathway enrichment analysis. The immune cell infiltration levels of each CD patient sample were assessed. Using weighted gene co-expression network analysis, key gene modules linked to CD were found. Hub gene identification was made easier by the construction of protein-protein interaction networks. Next, utilizing the Least Absolute Shrinkage and Selection Operator on the hub genes in the training set, a diagnostic model was created. The accuracy of the model was then confirmed using a different validation set. Our analysis revealed 651 differentially expressed genes, enriched in leukocyte chemotaxis and inflammation-related pathways. Immunization results showed a higher abundance of T cells CD4 memory resting, macrophages M2, and plasma cells in CD patients. Weighted gene co-expression network analysis linked the turquoise module with macrophages M2. Eight hub genes (APOA1, APOA4, CYP2C8, CYP2C9, CYP2J2, EPHX2, HSD3B1, and LPL) formed the diagnostic model, exhibiting excellent diagnostic performance with area under curve values of 0.94 (training set) and 0.941 (validation set). The CD diagnostic model, based on hub genes, shows exceptional diagnostic accuracy, providing a valuable reference for CD diagnosis. Show less

Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive and specific liquid-biopsy methods have yet to achieve satisfactory clinical goals. We enrolled three cohorts and a total of 185 patients diagnosed with benign (BE) and malignant (MA) pulmonary nodules. Utilizing data-independent acquisition (DIA) mass spectrometry, we quantified plasma proteome from these patients. We then performed logistic regression analysis to classify benign from malignant nodules, using cohort 1 as discovery data set and cohort 2 and 3 as independent validation data sets. We also developed a targeted multi-reaction monitoring (MRM) method to measure the concentration of the selected six peptide markers in plasma samples. We quantified a total of 451 plasma proteins, with 15 up-regulated and 5 down-regulated proteins from patients diagnosed as having malignant nodules. Logistic regression identified a six-protein panel comprised of APOA4, CD14, PFN1, APOB, PLA2G7, and IGFBP2 that classifies benign and malignant nodules with improved accuracy. In cohort 1, the area under curve (AUC) of the training and testing reached 0.87 and 0.91, respectively. We achieved a sensitivity of 100%, specificity of 40%, positive predictive value (PPV) of 62.5%, and negative predictive value (NPV) of 100%. In two independent cohorts, the 6-biomarker panel showed a sensitivity, specificity, PPV, and NPV of 96.2%, 35%, 65.8%, and 87.5% respectively in cohort 2, and 91.4%, 54.2%, 74.4%, and 81.3% respectively in cohort 3. We performed a targeted LC-MS/MS method to quantify plasma concentration of the six peptides and applied logistic regression to classify benign and malignant nodules with AUC of the training and testing reached 0.758 and 0.751, respectively. Our study identified a panel of plasma protein biomarkers for distinguishing benign from malignant pulmonary nodules that worth further development into a clinically valuable assay. Show less

As the most common primary malignant bone tumor, further investigation into risk stratification for osteosarcoma (OS) prognosis is of significant clinical importance. Copper is essential for bone metabolism; however, its specific role in OS remains unclear. The expression characteristics of copper metabolism related genes (CORGs) in OS were revealed by single cell sequencing. Prognosis-associated CORGs were identified, and a CORG-related scoring system and risk model were established using bioinformatics approaches, including univariate and multivariate Cox regression analyses and LASSO analysis. We further analyzed immune microenvironment infiltration, molecular subtypes and clinicopathological characteristics. The impact of selected CORG with high-risk coefficient on OS cells was tested by qRT-PCR, western blot, siRNA, colony formation analysis and Transwell in vitro. We successfully developed an OS scoring system related to copper metabolism and validated its independent prognostic value in patients with OS. The potential clinical value of CORG scoring system was analyzed. APOA4 was selected for in vitro experiments and its effect on the proliferation and invasion ability of OS cells was verified. We established a copper metabolism-related scoring system to effectively stratify the risk of OS patients. Our results provide a new basis for the role of copper metabolism in OS and provide new potential targets for the treatment of OS. Show less

Cholesterol synthesis and gallstone formation are promoted by trimethylamine-N-oxide (TMAO), a derivative of trimethylamine, which is a metabolite of gut microbiota. However, the underlying mechanisms of TMAO-induced lithogenesis remain incompletely understood. This study aimed to explore the specific molecular mechanisms through which TMAO promotes gallstone formation. Enzyme-linked immunosorbent assays were used to compare serum concentrations of TMAO, apolipoprotein A4 (APOA4), and proprotein convertase subtilisin/kexin type 9 (PCSK9) between patients with cholelithiasis and normal controls. A murine model of TMAO-induced cholelithiasis was employed, incorporating assays of gallstone weight and bile cholesterol content, along with RNA sequencing of murine hepatic tissue. A TMAO-induced AML12 hepatocyte line was constructed and transfected with targeted small interfering RNAs and overexpression plasmids. Serum TMAO and PCSK9 levels were elevated, whereas APOA4 levels were reduced in patients with cholelithiasis. Furthermore, our murine model demonstrated that TMAO upregulated hepatic expression of PCSK9, 3-hydroxy-3-methylglutaryl-CoA reductase, and ATP-binding cassette sub-family G member 5/8, while reducing APOA4 expression, thereby modulating cholesterol metabolism and promoting lithogenesis. TMAO upregulated hepatic Show less

Apolipoprotein A-IV (apoA-IV), the largest member of the exchangeable apolipoprotein family, is a common constituent of amyloid deposits in renal and cardiac amyloidosis. In this study, we characterized the aggregation propensity of the apoA-IV N-terminal fragment to form amyloid fibrils using a variety of biophysical techniques. Thioflavin T fluorescence assay, circular dichroism measurement, and microscopic observations revealed that the N-terminal 1-70 amino acid fragment of apoA-IV readily forms amyloid fibrils by a transition from a random coil to a β-sheet-rich structure. Sequence-based analysis indicated that residues 7-16 and 38-42 are the major aggregation-prone segments within the N-terminal 1-70 residues of apoA-IV. Consistent with this, deletion of these residues strongly inhibited the β-transition and fibril formation of apoA-IV 1-70. Kinetic and thermodynamic analyses of fibril formation by the apoA-IV 1-70 fragment demonstrated that primary nucleation is the dominant step in fibril formation, for which the activation energy barrier is entirely entropic. In addition, we found that the presence of heparin, a representative glycosaminoglycan, accelerated fibril formation kinetics and enhanced the yield of apoA-IV 1-70 fibrils, and the positively charged residues K58-K59 play a critical role in heparin interaction. Overall, our results suggest that the strong amyloid-forming propensity of the N-terminal fragment of apoA-IV may play a key role in amyloid deposition associated with apoA-IV amyloidosis. Show less

Diabetic retinopathy (DR) is one of the major complications of diabetes, resulting in severe vision loss. Traction retinal detachment (TRD) is the main factor affecting the effect of proliferative diabetic retinopathy (PDR) surgery. Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) was adopted to analyze the proteomes of the vitreous in the TRD, vitreous hemorrhage (VH) and macular hole (MH) groups. By employing bioinformatics tools for GO and KEGG pathway annotation, as well as conducting protein-protein interaction(PPI) network analysis, we investigated the functional enrichment of proteins in the TRD vitreous and their associated pathways. Additionally, peptide center analysis was performed on the proteomic data to identify key differentially expressed proteins based on screening results. Bioinformatics analysis showed that DEPs is mainly enriched in the complement, the coagulation cascade systems and regulation of actin cytoskeleton. The protein interaction network analysis showed that the central proteins were mainly related to sphingolipid metabolism. APOA4, CHI3L1, LTBP2 were significantly up-regulated in TRD, which were related to the complement system, coagulation cascade and platelet activation, sphingolipid metabolism and other pathways. APOA4 and CHI3L1 protein in patients with TRD group raised significantly in the vitreous humor, shows the potential biomarkers for TRD. 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

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

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

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 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

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

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

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

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

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