Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a th Show more
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a three-wave longitudinal study was designed to explore the heterogeneity of parent-child attachment networks using latent profile analysis (LPA) and random intercept latent transition analysis (RI-LTA). Participants included 2116 adolescents (ages 14-21; 53.8% girls). Results identified five stable parent-child attachment network profiles, each showing moderate but decreasing stability. Notably, adolescents who were grouped into an attachment network characterized by secure maternal attachment but insecure paternal attachment, similar to those in attachment networks with both insecure maternal and paternal attachment, scored higher levels of problematic mobile phone use than those who were grouped into attachment networks with both secure maternal and paternal attachment. Our findings fill empirical gaps and provide strong evidence supporting attachment-based interventions to reduce problematic mobile phone use. Show less
While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a seri Show more
While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC Show less
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with d Show more
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with diabetic macular edema (DME) underwent optical coherence tomography (OCT) imaging to examine the changes of HEs before and after intravitreal conbercept injection (IVC). The area of HEs showed minimal change after the first IVC (1.39±1.41 to 1.38±1.3 mm Conbercept reduces HEs in DR by enhancing Müller glia phagocytosis possibly through activating PPARγ-CD36 axis, which is mediated by inhibition of VEGF signaling. Modulation of Müller glia phagocytic capacity might provide a novel therapeutic strategy to treat DR and DME. Show less
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic mo Show more
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic modalities to revolutionize clinical management and enhance patient outcomes. The recent seminal discovery by Swamynathan et al. has unveiled menadione, a vitamin K precursor, as a potent inducer of triaptosis-a novel regulated cell death pathway mediated through the oxidative modulation of phosphatidylinositol 3-kinase PIK3C3/VPS34. This mechanistically distinct cell death paradigm, characterized by its intimate association with endosomal dysfunction and oxidative stress-induced cellular catastrophe, has demonstrated remarkable therapeutic efficacy in preclinical prostate cancer models, outperforming conventional therapeutic regimens and emerging as a potential paradigm-shifting strategy in oncology. This comprehensive review provides a critical synthesis of the triaptosis discovery landscape, elucidating its molecular intricacies and pathophysiological implications. We systematically examine the multifaceted roles of endosomal biology in oncogenesis and tumor progression, while offering a nuanced perspective on redox homeostasis in malignant cells and the therapeutic potential of oxidative stress modulation. Furthermore, we address the inherent dichotomy of oxidative stress induction in cancer therapy, balancing its therapeutic promise against potential adverse effects. Looking toward the horizon of cancer research, we explore transformative therapeutic strategies leveraging triaptosis induction and its potential applications beyond oncology, aiming to catalyze a new era of precision medicine that ultimately enhances patient survival and quality of life. Show less
High-abundance serum proteins, mostly modified by N-glycans, are usually depleted from human sera to achieve in-depth analyses of serum proteome and sub-proteomes. In this study, we show that these hi Show more
High-abundance serum proteins, mostly modified by N-glycans, are usually depleted from human sera to achieve in-depth analyses of serum proteome and sub-proteomes. In this study, we show that these high-abundance glycoproteins (HAGPs) can be used as valuable standard glycopeptide resources, as long as the structural features of their glycans have been well defined at the glycosite-specific level. By directly analyzing intact glycopeptides enriched from serum, we identified 1322 unique glycopeptides at 48 N-glycosites from the top 12 HAGPs (19 subclasses). These HAGPs could be further classified into four major groups based on the structural features of their attached N-glycans. Immunoglobins including IGHG1/2/3/4, IGHA1/2 and IGHM were mostly modified by core fucosylated and bisected N-glycans with rarely sialic acids. Alpha-1-acid glycoproteins (ORM1/2) and haptoglobins (HP) were mainly modified by tri-and tetra-antennary (40 %) N-glycans with antenna-fucoses and sialic acids. Complement components C3 and C4A/B were highly modified by oligo-mannose glycans. The other HAGPs including SERPINA1, A2M, TF, FGB/G and APOB mainly contain bi-antennary complex glycans with the common core structure and (sialyl-) LacNAc branch structures. These HAGPs are easily detected by LC-MS analysis and therefore could be used as standard glycopeptides for glycoproteomic methodology studies as well as possible clinical utilities. Show less
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Show more
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Disease Neuroimaging Initiative. Edge time series (ETS) were obtained based on resting-state functional magnetic resonance data. The top 10% co-fluctuation signals of all time points in ETS were extracted to construct the high-amplitude frame networks, and the co-fluctuation signals from the remaining time points were used to construct the low-amplitude frame networks. In both network states, the graph theory and network-based statistics (NBS) analyses were used to compare SCD and HC. The correlation of the imaging indicators with cognitive scores and apolipoprotein E (APOE) ε4 genes was performed by Spearman correlation analysis. SCD exhibited lower peak amplitude and longer trough-to-trough duration (TTD) compared to HC. In both network states, the normalized clustering coefficient, normalized characteristic path length, small-worldness, and global efficiency of SCD were significantly reduced, and the altered nodal centralities of SCD predominantly exhibited a decreasing trend. However, the high-amplitude frame network identified more altered brain regions compared to the low-amplitude frame network. Furthermore, a SCD-related subnetwork was found in the high-amplitude frame network, which was composed of 11 brain regions and 13 edges. TTD was positively related to the number of APOE ε4 genes; the normalized characteristic path length, the betweenness centrality of right postcentral gyrus, and the connection between bilateral angular gyrus were correlated with cognitive scores. Our findings demonstrate that the edge-centric network framework reveals details of brain network alterations in SCD through different perspectives, and these alterations hold potential as novel biomarkers for SCD. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty Show more
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Show less
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safet Show more
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safety of treatment with pemigatinib, an oral, potent, selective FGFR1-3 inhibitor, in patients with advanced FGFR-altered CNS tumors. FIGHT-207 was a single-arm, open-label, phase 2 study of pemigatinib in patients with advanced solid tumors harboring FGFR fusions/rearrangements or other mutations. Patients received pemigatinib 13.5 mg once daily until disease progression or unacceptable toxicity. Endpoints included tumor response and safety. Of the 13 patients with CNS tumors in FIGHT-207, 10 had glioblastoma. Fibroblast growth factor receptor alterations were FGFR3-TACC3 fusions (n = 9), FGFR1 K656E mutations (n = 2), FGFR1 N546K mutation (n = 1), and FGFR1-MITF fusion (n = 1). Three patients (23%) displayed objective responses (1 complete, 2 partial). Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors. Show less
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute config Show more
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC Show less
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a m Show more
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a multifaceted role in the progression of cardiac hypertrophy and HF. Here, it is identified that a lncRNA forkhead box O6, opposite strand (Foxo6os) is significantly downregulated in murine HF model induced using transverse aortic constriction (TAC). Knockdown of Foxo6os accelerates cardiomyocyte hypertrophy, reflects as elevated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7). Conversely, Foxo6os overexpression can improve cardiac function and alleviate adverse cardiac remodeling. Mechanistically, Foxo6os directly interacts with myosin-binding protein-C (MYBPC3), which then recruits protein kinase C alpha (PKC-α) to facilitate MYBPC3 phosphorylation, resulting in maintaining myocardial contractility and postponing HF progression. Therefore, these findings underscore the critical role of Foxo6os in preserving cardiomyocyte contractile function, suggesting a potential for Foxo6os as a novel therapeutic target of HF. Show less
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfuncti Show more
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfunction in endothelial cells (ECs). Endothelial cell-specific molecule 1 (ESM1), has been identified as a marker for activated ECs. Nevertheless, the mechanisms underlying ESM1-induced endothelial cell proliferation remain elusive. The expression of ESM1, ANGPTL4 and autophagy related protein were confirmed by western blot. Proliferation ability was tested by MTT and EdU. Lipids level was confirmed by Oil red staining. Autophagic flux was confirmed by Monodansylcadaverine (MDC) staining and pCMV-mCherry-GFP-LC3B fluorescence staining assay. The mouse model of AS was used to observe the effect of PA on the ESM1-ANGPTL4-autophagy signaling axis. This study elucidates ESM1-ANGPTL4 axis in maintaining proliferation of ECs and lipid reprogramming. Furthermore, it has been observed that PA has the ability to stimulate EC to autonomously increase the expression of ESM1, which in turn can counteract the detrimental effects of PA on ECs. Conversely, when ESM1 is suppressed, the damaging effects of PA on ECs are exacerbated. Mechanistically, our findings indicate that ESM1 facilitates EC proliferation and lipids homeostasis by up-regulating autophagy through ANGPTL4. This effect of ESM1 on ECs can be attenuated by ATG7 inhibiting. Additionally, the serum levels of ESM1 were found to be elevated in AS mice. ESM1 was found to enhance ECs proliferation and mitigate endothelial cell injury induced by PA through the upregulation of autophagy. This mechanism potentially serves as a protective factor against atherosclerosis progression. Show less
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic A Show more
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a Show more
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to the hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation, histological observation of testicular tissues from two sheep breeds was carried out using haematoxylin-eosin (HE) conventional staining. A total of 103 differentially expressed genes (DEGs) were authenticated in high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 50 up-regulated genes and 53 down-regulated genes. Functional analyses revealed several terms and pathways that were closely related to testis adaptation to the plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes, and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep. Show less
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive Show more
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE Show less
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing Show more
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate Show more
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate the mechanism of regulating rice leave color. To investigate the molecular mechanism that triggers the purple color in rice leaf, phenotypic characterization and genome-wide transcriptome analysis were conducted using the japonica rice cultivar nipponbare (Nip) and its two purple leaf mutants, A total of 2247, 5484, 4525, 2103, 4375 and7029DEGs (differentially expressed genes) were identified in nip-a vs These results not only revealed the molecular mechanism triggering leaf purple color in the rice mutants Show less
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to ass Show more
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to assess the impact of EO blends (oregano, cinnamon and lemon oils) on growth performance, meat physicochemical parameters, intestinal health and lipid metabolism in the small intestine of weaned Bamei (a kind of obese-type pig) piglets. One hundred and forty-four male 60-day-old weaned Bamei piglets were randomly assigned to three groups of six replicates each: CON (basal diet), T1 (basal diet + 250 mg/kg EO), and T2 (basal diet + 500 mg/kg EO) over 28 days. The results showed that T1 trended to improve the average daily gain and feed intake to body gain ratio (p < 0.1), reduced water loss (p < 0.05), and increased the redness of meat (p < 0.05) compared to the CON. In addition, a significant change in the proportion of C17:0 and C20:1 was observed in the meat of T1 (p < 0.05). Improved intestinal health was evidenced by the reduced crypt depth, improved villi-to-crypt length ratio, and better superoxide dismutase activity in T1 (p < 0.05). Further study on intestinal lipid metabolism showed that duodenal lipase activity and the mRNA expression levels of lipid transport-related genes in the jejunum (FABPs, APOA1, APOB and ACSL3) were significantly reduced, alongside diminished serum lipid metabolites (Total protein and triglyceride) in the groups fed with EO (p < 0.05). In short, EO supplementation especially at 250 mg/kg improved intestinal health and inhibited lipid metabolism, which had a positive effect on the overall performance of Bamei piglets. This new evidence contributes to understanding the early regulatory role of EO in obese pigs and their potential to alleviate adolescent obesity. Show less
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of le Show more
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less
The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) gene polymorphism (rs638405) has been widely reported to be associated with Alzheimer's disease (AD) risk. However, studies on the relati Show more
The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) gene polymorphism (rs638405) has been widely reported to be associated with Alzheimer's disease (AD) risk. However, studies on the relationship between BACE1 gene polymorphism (rs638405), brain volume, and cognition in AD patients remain scarce. To investigate the effect of genetic polymorphism in BACE1 on gray matter volume (GMV) and cognition in AD, this study recruited 111 cognitively unimpaired (CU) controls and 144 AD patients. The effect of BACE1 rs638405 polymorphism on cognition was explored in CU and AD groups. Then the interaction effect of the diagnosis and BACE1 rs638405 polymorphism on GMV was performed, following the post-hoc analysis of regions of interest (ROIs) in interaction analysis. Mediation analysis was used to elucidate the relationship among genotypes, ROIs and cognition. BACE1 rs638405 G carriers (BACE1 G+) showed significantly lower scores in global cognition and memory function than noncarriers (BACE1 G-) in AD group. Genotypes (G+/G-) and diagnosis (CU/AD) have interaction on GMV of medial temporal lobe (MTL) including the left parahippocampus and right hippocampus. Post-hoc analysis revealed that BACE1 G+ exhibited significantly lower GMV in ROIs compared to BACE1 G- in AD. Finally, mediation analysis further demonstrated that the GMV of ROIs mediated the effect of BACE1 rs638405 polymorphism on cognition in AD. Our results emphasize the BACE1 rs638405 gene polymorphisms may affect the GMV of MTL and cognition in AD, deepening the understanding of AD pathogenesis. Show less
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers a Show more
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment. This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into "penumbra freezing" and "non-penumbra freezing" groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with "penumbra freezing." Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes. Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the "penumbra freezing" group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the "non-penumbra freezing" group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the "penumbra freezing" group (304.63 ± 52.44 mg/L) than in the "non-penumbra freezing" group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of "non-penumbra freezing" beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers. ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology. ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for "penumbra freezing," suggesting the potential to extend the treatment window. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
Qianzhu Jiang, Huiting Li · 2025 · Journal of bioenergetics and biomembranes · Springer · added 2026-04-24
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific Show more
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less
Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulde Show more
Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulder function. Therefore, we aimed to explore the diagnostic biomarkers and potential mechanisms of FS from a transcriptomics perspective. Total RNA was extracted from tissue samples of 15 FS and 11 controls. At the outset, we conducted differential expression analysis, weighted gene co-expression network analysis (WGCNA), and utilized the cytoHubba plugin, complemented by two machine learning algorithms, receiver operating characteristic (ROC) analysis, and expression level evaluation to identify biomarkers for FS. Subsequently, a nomogram was constructed based on the biomarkers. Additionally, we conducted enrichment and immune infiltration analyses to explore the mechanisms associated with these biomarkers. Finally, we confirmed the expression patterns of the biomarkers at the clinical level through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This study established a link between FS biomarkers that have strong diagnostic potential and specific immune responses, highlighting possible targets for diagnosing and treating FS. Show less
Relying on a single biomarker in biomedical analysis is often insufficient for accurate disease or pathogen determination. A recent trend is using simultaneous multiplex detection of multiple biomarke Show more
Relying on a single biomarker in biomedical analysis is often insufficient for accurate disease or pathogen determination. A recent trend is using simultaneous multiplex detection of multiple biomarkers to improve diagnostic accuracy and throughput. To enable multiplex detection, we developed a series of surface-enhanced Raman scattering (SERS) nanoprobes, referred to as nanoaggregate-embedded beads (NAEBs). These NAEBs were synthesized using three distinct Raman reporter molecules: Safranin O, ethyl violet, and cresyl violet acetate. By integrating the NAEBs with magnetic nanoparticles and a simple capillary magnetofluidic device, we developed a rapid and simultaneous multiplex detection platform for genetic analysis of an aquacultural pathogen Vibrio parahaemolyticus (VP) for pirA, pirB, and ompA and genotyping of Alzheimer's disease's risk factor biomarker Apoliproprotein E (ApoE). For VP detection, a limit of detection (LOD) as low as ~ 10 Show less
Jessica Blumenfeld, Yaqiao Li, Min Joo Kim+12 more · 2025 · bioRxiv : the preprint server for biology · Cold Spring Harbor Laboratory · added 2026-04-24
Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathologica Show more
Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target. Show less
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in A Show more
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis. First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking. According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy. Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients. Show less