👤 Haichen Chu

The key to proper implant integration in bone replacement is to orchestrate the complex interactions between materials and tissues. Moreover, due to the rapid demographic shift towards aging societies and the increase in elderly and osteoporotic patients, it is of great importance that implant materials are osteointegrative in not only healthy but also compromised bone tissues. Here, titanium (Ti) scaffolds were subjected to shifted laser surface texturing (sLST) using a nanosecond pulsed laser to create an open pore macrotopography with micro-and nano-Ti droplets. In contrast to conventional laser texturing, which leads to high heat accumulation; in sLST, the frequency of laser pulses is low, allowing for resolidification, thereby creating a surface with abundant coverage micro-/nanodroplets. The main objective was to compare the cellular responses of human mesenchymal stromal cells (hMSCs) on sLST-textured Ti surfaces (LT-Ti) for the first time with standard sand-blasted, acid-etched surfaces (SLA-Ti). In-depth analyses of cell survival, proliferation, shape, mineralization, and gene expression were performed. Cell survival/proliferation was found to be similar on both surfaces; however, SEM imaging revealed differences in hMSC morphology. On LT-Ti, cells adopted well-rounded shapes, whereas on SLA-Ti they assumed more planar shapes. Bulk RNA sequencing performed after short-term culture on both surfaces disclosed expression changes in genes such as Show less

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases. Show less

Oxymatrine is an alkaloid with the property of immunomodulation. Recent studies have demonstrated that oxymatrine inhibits experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by promoting the production of interferon-β (IFN-β). However, the mechanism through which oxymatrine regulates the production of IFN-β remains unclear. The aim of this study was to investigate the pharmacological effects and related molecular mechanisms of oxymatrine in the treatment of EAE through in vivo and in vitro experiments. Oxymatrine alleviated neurological dysfunction, demyelination, and inflammation in EAE mice. It reduced microglia/macrophage infiltration and polarization, lowered pro-inflammatory cytokine levels (iNOS, TNF-α), and enhanced the expression of IL-10 and IL-27. Additionally, oxymatrine upregulated the STING/TBK1/IRF3 signaling pathway in EAE mice, promoting IFN-β production by microglia. Similarly, in LPS-induced BV2 cells, oxymatrine suppressed inflammatory factors and activated the STING/TBK1/IRF3 pathway to enhance IFN-β production. Notably, treatment with the STING inhibitor, C176, reversed these effects in both EAE mice and LPS-induced BV2 cells, confirming the pathway's critical role in the mechanism of oxymatrine therapy. Oxymatrine promotes IFN-β production in microglia by upregulating the STING/TBK1/IRF3 signaling pathway, thereby alleviating the neurological dysfunction of EAE and reducing pathological and inflammatory events. This study identifies a novel anti-EAE mechanism of oxymatrine: promoting IFN-β production in microglia by activating the STING/TBK1/IRF3 pathway. However, it lacks clinical sample verification. If validated later, oxymatrine may provide a more economical, convenient endogenous IFN-β induction regimen for MS patients. Show less

Although the human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from both cerebellum and frontal cortex of AD/ADRD patients and normal controls. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we pinpointed two likely causal genes, Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and three-dimensional (3D) genome data. Via CRISPRi experiments, we found that perturbation of rs4788201 and rs62056801 significantly inhibited the expression of their target genes, SEZ6L2 and KANSL1, in human iPSC-derived neurons. This cell subtype-specific regulatory landscape in the human cerebellum identified here offers novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less

Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysis (LPA) and Association Rule Mining (ARM) to identify distinct sleep quality subgroups and uncover key factor combinations, thereby informing targeted intervention strategies. A total of 1,686 nurses from 123 hospitals in Shandong Province were recruited through multistage stratified sampling. LPA was used to classify participants based on seven sleep dimensions from the Pittsburgh Sleep Quality Index (PSQI), while ARM was applied to identify frequent itemsets of sleep disorder triggers. Key influencing factors were further examined using univariate analysis and multivariate logistic regression. Three latent sleep profiles were identified: high (63.11%), moderate (34.10%), and low (2.79%) sleep quality. The low-sleep subgroup was characterized by higher proportions of being unmarried/divorced (42.55%), low monthly income (≤ 3,000 CNY, 42.55%), non-permanent employment (76.60%), and severe psychological distress (44.68%). In contrast, the high-sleep subgroup featured higher rates of being married (85.62%), moderate income (3,001–7,000 CNY, 73.03%), and low psychological distress (51.32%). Key determinants included marital status (OR = 2.153/2.252), income (OR = 9.098), employment type (OR = 1.475), and psychological state (OR = 0.060–0.555). ARM revealed distinct risk combinations: “low income + non-permanent employment” (lift = 3.895) for the low-sleep group; “married + moderate income + non-permanent employment + patient conflict” for the moderate group; and “high income + low psychological distress” buffering night-shift effects in the high-sleep group. By integrating LPA and ARM, this study reveals the multidimensional heterogeneity and interactive mechanisms underlying clinical nurses’ sleep quality. The findings support a stratified intervention framework combining institutional safeguards with precision strategies to enhance sleep health management in nursing populations. Show less

Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to be established. This study investigated the relationship between Lp(a) concentrations and cardiovascular outcomes in Taiwanese individuals, stratified by pre-existing ASCVD status. We conducted a retrospective analysis of 51,934 subjects from the Chang Gung Research Database (January 2004 to June 2019), comprising 49,363 individuals without ASCVD and 2,571 with established ASCVD. The primary outcome was major adverse cardiovascular events (MACEs), encompassing acute myocardial infarction, ischemic stroke, revascularization procedures, peripheral arterial interventions, and cardiovascular mortality. Individuals were followed until their last visit to our institutions or December 31, 2019. During a mean follow-up of 6.6 years (standard deviation: 5.0 years), the study population demonstrated a median Lp(a) of 9.6 mg/dL (interquartile range: 4.6-18.5). In ASCVD-free individuals, Lp(a) concentrations ≥30 mg/dL were associated with increased MACE risk (adjusted subdistribution hazard ratio [aSHR]: 1.24; 95% confidence interval [CI]: 1.07-1.43). Similarly, in the ASCVD cohort, elevated Lp(a) predicted higher MACE occurrence (aSHR: 1.36; 95% CI: 1.07-1.74). Restricted cubic spline analysis confirmed a progressive risk elevation beyond the 30 mg/dL threshold in both groups. Lp(a) levels ≥30 mg/dL independently predicted adverse cardiovascular outcomes, regardless of baseline ASCVD status. This threshold appears suitable for cardiovascular risk stratification in both primary and secondary prevention settings. Show less

Although molecular tests developed for a growing list of oncogenic alterations have significantly aided in the classification of head and neck carcinomas, tumours in which prototypical histologic and immunophenotypic features are lacking or only partially developed continue to pose diagnostic challenges. Searching for known diagnostic and therapeutic targets by clinical next-generation sequencing (NGS) assays can often lead to new discoveries. We present our institutional experience in applying targeted RNA NGS in 36 head and neck carcinomas that were morphologically difficult to classify between 2016 and 2023. The patients ranged in age from 5 to 83 years (median, 64), with the majority of tumors occurring in the major salivary glands and the sinonasal tract. Overall, seven (19%) cases showed unusual gene rearrangements, including five novel alterations: MON2::STAT6 in a hard palate adenocarcinoma with mucinous features, POC5::RAF1 in apocrine intraductal carcinoma of the lacrimal gland, EWSR1::CDADC1 fusion in a basaloid carcinoma of the submandibular gland, NFATC2::NUTM2B in myoepithelial carcinoma, and NSD3::NCOA2 fusion in a peculiar high-grade carcinoma with a peritheliomatous growth pattern, and focal myogenic differentiation. Potential therapeutic actionability was identified in three cases (RAF1 and FGFR2 fusions). These findings broaden the current spectrum of gene rearrangements in head and neck carcinomas and support the utility of clinical NGS in identifying unusual, actionable alterations in diagnostically challenging cases. Show less

This study aims to investigate the molecular differences and commonalities between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) by analyzing RNA-sequencing (RNA-seq) data. By focusing on differentially expressed genes and enriched pathways, the investigation seeks to identify unique biomarkers, shared pathways, and potential therapeutic targets for these autoimmune diseases. This study involved 10 patients with SSc and 24 with SLE who did not receive immunosuppressants. RNA-seq data from patients with SSc and SLE were analyzed using DESeq2 to identify differentially expressed genes. Functional and pathway enrichment analyses were conducted and comparative analyses were performed. We identified 2055 differentially expressed genes (DEGs) between patients with SSc and controls. Notably, the expression of the shared gene RGS5 was significantly downregulated in both SLE and SSc, with a more pronounced downregulation in SSc. Additionally, the expression of the key transcription factor EGR1 was upregulated in SSc, whereas that of BLK, ITGAM, and IFNG was upregulated in SLE. Network analysis identified hub genes-AP3D1, FTX, USP47, CUX1, ZC3H4, CAND1, INTS1, TRNT1, MTERF1, and SETD1B-that may play critical roles in the progression of both SLE and SSc. These findings suggest that RGS5 could serve as a shared biomarker for vascular dysfunction, while EGR1 and BLK may represent therapeutic targets in SSc and SLE. Overall, this analysis enhances understanding of distinct and overlapping gene expression signatures in SSc and SLE, providing a foundation for future targeted treatment strategies and requiring further validation in larger cohorts. Show less

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14 Show less

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC Show less

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Show less

Salvia miltiorrhiza, a prominent traditional Chinese medicinal resource, has been extensively employed in the management of cardiovascular and cerebrovascular ailments. Ensuring the consistency of S. miltiorrhiza raw materials revolves around the imperative task of maintaining stable tanshinones content and composition. An effective approach in this regard involves the utilization of endophytic fungi as inducers. Within this context, our study spotlights an endophytic fungus, Penicillium steckii DF33, isolated from the roots of S. miltiorrhiza. Remarkably, this fungus has demonstrated a significant capacity to boost the biosynthesis and accumulation of tanshinones. The primary objective of this investigation is to elucidate the underlying regulatory mechanism by which DF33 enhances and regulates the biosynthesis and accumulation of tanshinones. This is achieved through its influence on the differential expression of crucial CYP450 genes within the S. miltiorrhiza hairy roots system. The results revealed that the DF33 elicitor not only promotes the growth of hairy roots but also enhances the accumulation of tanshinones. Notably, the content of cryptotanshinone was reached 1.6452 ± 0.0925 mg g Show less

Atherosclerosis (AS) and Non-alcoholic fatty liver disease (NAFLD) are chronic metabolic disorders with high prevalence and significant health impacts. Both conditions share common pathophysiological pathways including abnormal lipid metabolism and inflammation. Berberine (BBR), an isoquinoline alkaloid, is known for its beneficial effects on various metabolic and cardiovascular disorders. This study investigates BBR's impact on AS and NAFLD through bioinformatics analysis and experimental models. This study utilized various bioinformatics methods, including transcriptome analysis, weighted gene co-expression network analysis (WGCNA), machine learning, and molecular docking, to identify key genes and pathways involved in AS and NAFLD. Subsequently an animal model of AS combined with NAFLD was established using ApoE-/- mice fed a high-fat diet. The efficacy and mechanism of action of BBR were verified using methods such as hematoxylin and eosin (HE) staining, Oil Red O staining, and real-time quantitative PCR (RTqPCR). Through transcriptome analysis, WGCNA, and machine learning, this study identified 48 key genes involved in both AS and NAFLD. Function analysis revealed that the implicated genes were significantly involved in pathways like cytokine-cytokine receptor interaction, chemokine signaling, and IL-17 signaling pathway, suggesting their role in inflammation and immune responses. Single cell validation identified six key genes: dual specificity phosphatase 6 (DUSP6), chemokine ligand 3 (CCL3), complement component 5a receptor 1 (C5AR1), formyl peptide receptor 1 (FPR1), myeloid nuclear differentiation antigen (MNDA), and proviral integration site of murine 2(PIM2). Finally, molecular docking and animal experiments showed that BBR significantly reduced lipid deposits and inflammatory markers in liver and aortic tissues. In conclusion, BBR can improve AS combined with NAFLD by regulating genes like MNDA, PIM2, DUSP6, CCL3, C5AR1, and FPR1, with the mechanism related to inflammation control. The findings suggest potential clinical benefits of BBR in reducing the progression of both AS and NAFLD, warranting further investigation. Show less

Early evaluation and intervention for post-stroke cognitive impairment are crucial for improving the prognosis of acute ischemic stroke. The search for specific diagnostic markers and feasible therapeutic targets is extremely urgent.The characteristics of circular RNAs make them promising candidates. To screen circular RNAs as novel biomarkers and therapeutic targets for post-stroke cognitive impairment in large-artery atherosclerosis anterior circulation cerebral infarction patients. In this prospective observational study, patients with first-ever large-artery atherosclerosis anterior circulation cerebral infarction were recruited. The Montreal Cognitive Assessment was used to assess the cognitive statuses of patients. Venous blood samples were collected on the seventh day after stroke onset. A circRNA microarray was used to identify differentially expressed circular RNAs in the discovery cohort (four patients with post-stroke cognitive impairment and four patients with post-stroke cognitive normal characteristics), and validation was performed in the validation cohorts (45 patients with post-stroke cognitive impairment and 30 patients with post-stroke cognitive normal characteristics) using quantitative real-time polymerase chain reaction. Receiver operating characteristic curves of the validated circular RNAs and the NIHSS score were constructed, and the area under the curve, sensitivity, and specificity were calculated. Correlation analysis was performed to explore the relationship between the copy number of circular RNAs and the cognitive status. The functions of the differentially expressed circular RNAs were predicted using bioinformatics analysis. CircRNA microarray analysis revealed 189 human circular RNAs (152 upregulated and 37 downregulated) that were differentially expressed in the plasma samples of patients with post-stroke cognitive impairment and PSCN characteristics. The expression of hsa_circ₀₀₈₉₇₆₃, hsa_circ₀₀₆₄₆₄₄, and hsa_circ₀₀₈₉₇₆₂ was validated using quantitative real-time polymerase chain reaction. The area under the curve, sensitivity, and specificity of hsa_circ₀₀₈₉₇₆₂ in post-stroke cognitive impairment diagnosis were 0.993, 97.8%, and 96.7%, respectively, and the correlation coefficient between hsa_circ₀₀₈₉₇₆₂ expression and the Montreal Cognitive Assessment score was -0.693 (p < 0.001), which made it an ideal biomarker. Bioinformatic analysis revealed that the targeted mRNAs of the three circular RNAs were enriched in pathologically related signaling pathways of post-stroke cognitive impairment, such as the MAPK and PI3K-Akt signaling pathways. Based on the circRNA-miRNA-mRNA network, the three circular RNAs play a crucial role in numerous pathological processes of acute ischemic stroke and post-stroke cognitive impairment by sponging miRNAs such as MiR-335, MiR-424, and MiR-670. By building the protein-protein interaction network, we identified cluster 1 according to the MCODE score; cluster 1 was composed of ERBB4, FGFR1, CACNA2D1, NRG1, PPP2R5E, CACNB4, CACNB2, CCND1, NTRK2, and PTCH. Hsa_circ₀₀₈₉₇₆₂, hsa_circ₀₀₆₄₆₄₄, and hsa_circ₀₀₈₉₇₆₃ are potential novel biomarkers and focal points for exploring intervention targets in post-stroke cognitive impairment of large-artery atherosclerosis anterior circulation cerebral infarction patients. ChiCTR2000035074. Show less

Oncogenic FGFR1/2/3 rearrangements are found in various cancers. Reported cases in head and neck (HN) are mainly squamous cell carcinomas (SCCs) with FGFR3::TACC3 fusions, a subset of which also harbour high-risk human papillomavirus (HPV). However, the knowledge of the clinicopathological spectrum of FGFR-rearranged head and neck carcinomas (FHNC) is limited. A retrospective MSK-fusion clinical sequencing cohort 2016-23 was searched to identify malignant tumours in the HN region harbouring FGFR1/2/3 fusion. FHNC were characterised by histological examination, immunohistochemistry and molecular analysis. Electronic medical records were reviewed. Three FHNC were identified. Two cases (cases 1 and 2) involved sinonasal tract and were high-grade carcinomas with squamous, basaloid, glandular and/or ductal-myoepithelial features. Case 1 arose in a 79-year-old man and harboured FGFR2::KIF1A fusion. Case 2 arose in a 58-year-old man, appeared as HPV-related multiphenotypic sinonasal carcinoma (HMSC), and was positive for FGFR2::TACC2 fusion and concurrent high-risk HPV, non-type 16/18. Case 3 was FGFR3::TACC3 fusion-positive keratinising SCCs arising in the parotid of a 60-year-old man. All three cases presented at stage T4. Clinical follow-up was available in two cases; case 1 remained disease-free for 41 months post-treatment and case 3 died of disease 2 months after the diagnosis. FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high-risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV-positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high-risk HPV. Show less

Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling. Show less

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less

Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD. Statistically, the random-effects inverse-variance-weighted (IVW) model was used as main analysis and several methods were conducted for sensitivity analysis to test the robustness of our results. Our findings revealed reduced risks of AD related to genetically proxied subtilisin/kexin type 9 (PCSK9) inhibition and lipoprotein lipase (LPL) agonist, while an increased AD risk associated with Niemann-Pick C1-like 1 (NPC1L1) inhibition. Circulating lipids and other drug targets did not show significant associations with AD risk. These results were replicated in the validation cohort; sensitivity analyses confirmed the robustness. This MR study suggests that, independent of circulating lipids, the use of PCSK9 inhibitors and LPL agonists may be associated with a decreased risk of AD, while inhibition of NPC1L1 is implicated in an increased risk. These findings may help optimize personalized selection of lipid-lowering drugs for AD patients and those at risk of AD. Show less

Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke . Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes ( The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation. Show less

Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%-27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT-M) could be used to prevent the potential birth of CMS-affected children is unclear. Application of WES (whole-exome sequencing) for carrier testing and guidance for the PGT-M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy. The clinical phenotypes of stillborn fetuses were also assessed. The family carried two likely pathogenic variants in RAPSN(NM₀₀₅₀₅₅.5): c.133G>A (p.V45M) and c.280G>A (p.E94K). And the potential birth of CMS-affected child was successfully prevented, allowing the family to have offspring devoid of disease-associated variants and exhibiting a normal phenotype. This report constitutes the first documented case of achieving a CMS-free offspring through PGT-M in a CMS-affected family. By broadening the known variant spectrum of RAPSN in the Chinese population, our findings underscore the feasibility and effectiveness of PGT-M for preventing CMS, offering valuable insights for similarly affected families. Show less

Bladder cancer (BLCA) is the most common malignancy of the urinary system. Muscle-invasive bladder cancer (MIBC), which constitutes approximately 25% of all BLCA cases, is characterized by frequent recurrence and early onset of metastasis. Bladder cancer most commonly occurs in elderly patients and is significantly associated with aging. However, the prognostic value of age-related genes in BLCA, especially in MIBC, remains unclear. Training and testing sets were obtained from The Cancer Genome Atlas BLCA project. Differentially expressed genes between BLCA and normal samples intersected with human aging-related genes. Univariate Cox regression and least absolute shrinkage and selection operator regression analyses were used to identify prognostic aging-related signatures, followed by the construction of a risk score model and nomogram. Kaplan-Meier and receiver operating characteristic analyses were conducted to assess the predictive power. An independent BLCA cohort of 165 samples was included for external validation. The CIBERSORT algorithm was used to explore the characteristics of the immune microenvironment. Seven genes ( Collectively, our data provide a 7-gene signature that serves as a potential biomarker for BLCA, especially MIBC. Moreover, this 7-gene signature highlights the role of the tumor immune microenvironment in prognosis and thus might be related to the response to anti-programmed cell death protein 1-based immunotherapy. Show less

Alzheimer's disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitive behavioral abnormalities, we do not know whether TgCtwh6 could also cause host cognitive behavioral changes. So, in this study, we will focus on the effect of TgCtwh6 on mouse cognitive behavior and try in vivo and in vitro to explore the underlying mechanism by which TgCtwh6 give rise to mice cognitive behavior changes at the cellular and molecular level. C57BL/6 mice were infected orally with TgCtwh6 cysts. From day 90 post-infection on, all mice were conducted through the open field test and then Morris water maze test to evaluate cognitive behavior. The morphology and number of cells in hippocampus were examined with hematoxylin-eosin (H&E) and Nissl staining; moreover, Aβ protein in hippocampus was determined with immunohistochemistry and thioflavin S plaque staining. Synaptotagmin 1, apoptosis-related proteins, BACE1 and APP proteins and genes from hippocampus were assessed by western blotting or qRT-PCR. Hippocampal neuronal cell line or mouse microglial cell line was challenged with TgCtwh6 tachyzoites and then separately cultured in a well or co-cultured in a transwell device. The target proteins and genes were analyzed by immunofluorescence staining, western blotting and qRT-PCR. In addition, mouse microglial cell line polarization state and hippocampal neuronal cell line apoptosis were estimated using flow cytometry assay. The OFT and MWMT indicated that infected mice had cognitive behavioral impairments. The hippocampal tissue assay showed abnormal neuron morphology and a decreased number in infected mice. Moreover, pro-apoptotic proteins, as well as BACE1, APP and Aβ proteins, increased in the infected mouse hippocampus. The experiments in vitro showed that pro-apoptotic proteins and p-NF-κBp65, NF-κBp65, BACE1, APP and Aβ proteins or genes were significantly increased in the infected HT22. In addition, CD80, pro-inflammatory factors, notch, hes1 proteins and genes were enhanced in the infected BV2. Interestingly, not only the APP and pro-apoptotic proteins in HT22, but also the apoptosis rate of HT22 increased after the infected BV2 were co-cultured with the HT22 in a transwell device. Neuron apoptosis, Aβ deposition and neuroinflammatory response involved with microglia polarization are the molecular and cellular mechanisms by which TgCtwh6 causes mouse cognitive behavioral abnormalities. Show less

Litter size is an economically important trait in sheep, and it is a complex trait controlled by multiple genes in multiple organs. Among them, the regulation of lamb number trait by the thyroid gland is a very important part. However, the molecular mechanisms of the thyroid gland in sheep reproduction remain unclear. Here, RNA-seq was used to detect transcriptome expression patterns in the thyroid gland between follicular phase (FP) and luteal phase (LP) in Show less

Fibroblast growth factor receptor-3 (FGFR3) gain-of-function mutations are linked to achondroplasia. Infigratinib, a FGFR1-3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro-computed tomography, histology, and immunohistochemistry. Mandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle. High dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies. Show less

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83 Show less