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Identification of hub genes involved in early-onset schizophrenia using genetically predicted regulated gene-expression risk score for schizophrenia
No full text[[abstract]]Background: Genome-wide association studies (GWAS) have unveiled the polygenic architecture of schizophrenia (SZ). Early-onset SZ (EOS), a more homogeneous SZ subtype, may aid in dissecting the genetic etiology of SZ and further understanding its genetic architecture. Gene-expression imputation enabled the translation of GWAS results into regulatory mechanisms and made it possible to construct genetically regulated gene-expression risk scores for SZ (SZ-GeRS). We utilized a rich collection of SZ patients with varying familial loadings and applied the GeRS approach to assess the association between SZ-GeRS and EOS. This study aims to (1) assess SZ-GeRS utility in distinguishing EOS from late-onset SZ (LOS), (2) determine if SZ-GeRS adds additional value over SZ-PRS in differentiating EOS from LOS, and (3) identify potential hub genes linked to EOS. Methods: Participants in this study included 595 SZ patients from 314 multiplex families and 595 sex- and onset age-matched SZ patients from simplex families. Initially, genetically regulated gene expressions were predicted by integrating GWAS-based genotype data in our samples with an existing SNP-expression prediction model of DLPFC brain tissue. SZ-GeRS was then calculated for each gene by weighting its genetically predicted expression with the corresponding effect size of transcriptome-wide association studies of SZ. Additionally, module-based SZ-GeRS was calculated by summing SZ-GeRS for each gene within psychiatric disorder-related modules from a previous study. Associations between each module-based SZ-GeRS and EOS were assessed by mixed-effects logistic regression model, with significant modules validated by another independent sample. Hub genes within the EOS-related module were identified through network analysis using Ingenuity Pathway Analysis software, exploring their biological functions. Finally, the effectiveness of two types of module-based SZ-GeRS, i.e., SZ-GeRS based on all genes and hub genes in EOS-related module, and SZ-PRS in distinguishing EOS from LOS was compared in samples with different familial loading. Results: Among 595 SZ patients, 223 were EOS and the remaining 372 were LOS. We found one module-based SZ-GeRS, i.e., module 10 (M10-GeRS), was associated with EOS in both discovery and replication samples. Subjecting genes in module 10 to IPA network analysis, six hub genes were identified, which include RUVBL2, COPS6, TUBA4A, PSMB5, PSMB2, and LRPPRC. The module-based SZ-GeRS based on these hub genes, dubbed as M10hub-GeRS, remained the direction of effect on EOS in both samples. Furthermore, both M10-GeRS and M10hub-GeRS explained more variance than the conventional SZ-PRS in both discovery and replication samples, accounting for additional variance in EOS (2.5% and 0.7 %, respectively). Discussion: Our results suggest incorporating SZ-GeRS into SZ-PRS enhances the ability to distinguish EOS from LOS. Also, we identified hub genes for EOS that have been reported to be related to neurological diseases in previous studies, potentially serving as 'mixed genes' for SZ, influencing susceptibility and early-onset status. Understanding genetically regulated gene expression in EOS will enrich potential pathway research, enhancing psychiatric classification in personalized medicine. Our study reveals the value of integrating large genetic study results with a rich collection of SZ patients with different familial loading to explore the biological functions of EOS and identify hub genes
Electronegative ApoCIII-Rich HDL promotes cellular damage and vascular aging
No full text[[abstract]]Background: Experimental studies attributing HDL a cardioprotective effect are challenged by well-designed randomized controlled trials showing largely neutral results, which might be related to more recent observations that certain HDL particles exert detrimental effects. This study explores the effects of electronegative HDL on cellular damage and vascular aging. Using anion-exchange chromatography, HDL was divided into five subclasses (H1 to H5) based on increasing electronegativity. Compared to the health-promoting H1, the most electronegative subclass, H5 contains significantly higher levels of ApoCIII and triglycerides (TG). Purpose: Herein, we aim to explore the cellular and molecular mechanisms underpinning H5-induced pathology in human umbilical vein vascular endothelial cells (HUVECs), which may accelerate vascular aging preceding the development of atherosclerotic cardiovascular disease (ASCVD). Methods: H1 and H5 were isolated from patients with metabolic syndrome (MetS). To gauge the impact of H5 on vascular integrity, HUVECs were treated with solvent, H1, or H5 at concentrations of 25, 50, or 100 µg/mL. Cell viability and apoptosis were evaluated using the MTT assay and PI/Calcein fluorescent staining, respectively. Immunofluorescence staining and immunoblotting, focusing on 8-oxodG, P53, and β-gal, proxies of DNA damage and cellular senescence, were performed. Senescence-associated secretory phenotype (SASP) analysis was done to elucidate the senescent mechanism. By harnessing Mitosox imaging reactive oxygen species (ROS) synthesis was monitored. Finally, unbiased lipid- and transcriptomics were used to identify lipid components potentially involved in H5 signaling. Results: As compared to controls, MetS patients exhibited more electronegative HDL particles, as indicated by increased H5 (1.604±0.410% vs 4.598±4.712%, P=0.0016). Remarkable elevations were noted in individuals with severe clinical complications, as shown in the representative patient with left ventricular hypertrophy, chronic coronary syndrome, and heart failure (Fig. 1). In HUVECs, H5 but not H1 reduced cell viability and increased apoptosis in a concentration-dependent manner. In parallel, H5 but not H1 induced cell aging, ROS production, and DNA damage, with SASP cytokines including IL-1β, IL-6, CCL2, TNF-α, and γH2AX (Fig. 1). Notably, compared to H1, H5 exhibited high contents of various TG species, impairing H5’s anti-inflammatory and antioxidant capacities, along with reductions in several phosphatidylcholines that may constitute essential cell membrane structural components, as evidenced by lipidomic studies (Fig. 2). Conclusion: H5, the most electronegative and dysfunctional HDL subfraction, is capable of inducing DNA damage, oxidative stress, and senescence in vascular ECs. Its notable elevation in patients with MetS highlights a previously unrecognized etiology, shedding light on how electronegative HDL may contribute to and expedite ASCVD
Bioinformatic analyses to identify osteogenic robustness in tissue-specific human mesenchymal stem cells (MSCS) and 3D in vitro platforms for rapid functional validation
No full text[[abstract]]Objective: Progress in precision medicine has dramatically improved outcomes for oncology and related cell therapies, but allogeneic mesenchymal stem cell (MSC) therapy, which holds the most promise for regeneration of bone, is complex with its many available tissue sources, lags in establishing molecular and high-resolution criteria to predict and improve therapeutic outcomes. In addition, while in vivo validation is the gold standard for osteogenesis, the long time period required (4–8 weeks) and the need for immunocompromised mice when testing human cellular products make use of this assay difficult and costly for clinical application. Methods: We assess the use of whole transcriptomic information followed by rapid functional validation in a 3D in vitro platform to identify robust osteogenic capacity between commonly used sources of human MSCs. Results: Transcriptomic analysis revealed similar enrichment for osteogenic-related pathways adult bone marrow (BM) MSCs compared to fetal placental MSCs (PMSCs). Interestingly, mitochondrial-related pathways were significantly more enriched in PMSCs than BMMSCs. Functional assessment of mitochondrial membrane potential and respiration validated the transcriptomic findings. Functional osteogenic differentiation in 3D in vitro culture demonstrated more robust osteogenesis with PMSCs compared to BMMSCs. Moreover, 3D culture further enhanced the mitochondrial functions of PMSCs in a significant fashion, which was not consistently seen with BMMSCs. Inhibiting mitochondrial function in 3D-cultured PMSCs resulted in a significant decrease in osteogenesis at both transcriptomic and functional levels, demonstrating the importance of mitochondrial health in MSC osteogenesis. Conclusion: Bioinformatics analyses of whole transcriptomes is therapeutically useful for identification of functional osteogenic capacity between difference sources of human MSCs. Moreover, the state of mitochondrial health is strongly aligned with MSC osteogenic capacity and can be modulated by 2D vs. 3D in vitro culture. Our data implicates additional therapeutically relevant strategies to improve regeneration of bone, an organ which undergo age-related as well as pathologic decline, through modulating mitochondrial health and 3D in vitro culture systems
Enhancing osteoporosis care in rural settings: A comprehensive intervention approach and its impact on treatment rates
No full text[[abstract]]Objective: To evaluate the impact of a comprehensive intervention on enhancing both the hospital arrival and treatment rate of anti-osteoporosis medication (AOM) within a rural community. Methods: In this randomized controlled trial, 567 patients were allocated to three groups: Comprehensive Care (CC), Osteoporosis Care Only (OC), and Delayed Care (DC). The CC and OC groups received five interventions, encompassing professional and specialist support, increasing disease awareness, transportation assistance, peer support, and case management; the DC group received only the first two interventions. Results: In the CC group, 73.3% (85 individuals) of the 116 participants recommended for hospital treatment successfully arrived, with 58.6% (68 individuals) receiving AOM. Conversely, in the DC group, only 4.1% (6 individuals) out of 146 recommended for hospitalization reached the hospital and received AOM after screening. Significantly divergent proportions were observed between the CC and DC groups concerning hospital arrival (P < 0.001) and AOM receipt (P < 0.01). Similar significant outcomes were noted in the OC group in comparison with DC group. In the OC group, 81% (124 individuals) of the 153 recommended for hospitalization arrived after intervention, and 69.3% (106 individuals) received AOM. The results were also significant when compared to the DC group (P < 0.001, P < 0.001, respectively). Conclusion: The findings underscore the imperative for a comprehensive intervention to enhance osteoporosis treatment rates in rural regions. The notable increase in hospital arrival and treatment rates observed in both the CC and OC groups contrast with those in the DC group. These results emphasize the significance of incorporating healthcare professionals and specialists, increasing disease awareness, and offering supportive measures to facilitate rural patients in accessing healthcare services
Role of air pollution in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues
No full text[[abstract]]Background and Aims: To investigate the association between air pollution and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues. Methods: We enrolled 1298 CHB patients treated with nucleotide/nucleoside analogues and analysed the incidence and risk factors for HCC. Daily estimates of air pollutants were estimated since the previous year from the enrolment date. Results: The annual incidence of HCC was 2.1/100 person-years after a follow-up period of over 4840.5 person-years. Factors with the strongest association with HCC development were liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 3.00/1.55-5.81; p = 0.001), male sex (2.98/1.51-5.90; p = 0.02), body mass index (1.11/1.04-1.18; p = 0.002) and age (1.06/1.04-1.09; p < 0.001). Among patients with cirrhosis, the factors associated with HCC development were male sex (HR/95% CI: 2.10/1.00-4.25; p = 0.04) and NO2 (per one-unit increment, parts per billion; 1.07/1.01-1.13; p = 0.01). Moreover, patients with the highest quartile of annual NO2 exposure had more than a three-fold risk of HCC than those with the lowest quartile of annual exposure (HR/95% CI: 3.26/1.34-7.93; p = 0.01). Among patients without cirrhosis, the strongest factors associated with HCC development were male sex (HR/95% CI: 5.86/1.79-19.23; p = 0.004), age (1.12/1.07-1.17; p < 0.001) and platelet count (0.99/0.98-1.00; p = 0.04). Conclusions: Air pollution influences HCC development in CHB patients who receive nucleotide/nucleoside analogue therapy. Long-term NO2 exposure might accelerate HCC development in CHB patients with cirrhosis receiving nucleotide/nucleoside analogue treatment
Generation of quaternary carbons in cycloalkanones and lactones with arynes through a domino process
No full text[[abstract]]A synthetic method was developed for the generation of a quaternary carbon center in carbonyl compounds. This innovative process involved the reaction of alpha-thiolate lactones and cycloalkanones with two equivalents of arynes in acetonitrile to give alpha,alpha-diarylated products in 63-85% yields at 25 degrees C. The reaction unfolds through an unconventional domino process, encompassing sequential 1,2-elimination, 1,2-nucleophilic addition, 1,4-proton transfer, the second 1,2-nucleophilic addition, interrupted Pummerer rearrangement, intramolecular spirocyclization, and sulfonium ring-opening. The potential of this "single-flask" reaction was systematically investigated and found well-suited to generate diarylated carbonyl compounds, incorporating naphthalene, pyridine, quinoline, or isoquinoline rings adorned with various substituents
Serial changes in metabolic dysfunction-associated steatotic liver disease after sleeve gastrectomy and their associations with abdominal adiposity: A prospective cohort study
No full text[[abstract]]Background: Little is known about the associations between changes in hepatic steatosis and changes in abdominal adiposity after metabolic bariatric surgery. Objectives: To evaluate the serial changes in hepatic steatosis and abdominal adiposity following sleeve gastrectomy (SG). Setting: University hospital, Taiwan. Methods: In this prospective study, patients who underwent SG and intraoperative liver biopsy were enrolled. Magnetic resonance imaging (MRI) was performed to assess the liver fat fraction (LFF), visceral adipose tissue (VAT) area, and subcutaneous adipose tissue (SAT) area. Liver fibrosis was assessed preoperatively via biopsy and the fibrosis-4 index (FIB-4) and postoperatively with the FIB-4. Results: Seventy-six metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including 67 pure MASLD patients and 9 MASLD patients with combined etiologies, were enrolled. LFF and visceral-to-subcutaneous fat ratio were associated with metabolic dysfunction-associated steatohepatitis, and VAT area was associated with significant fibrosis (≥F2). Twelve months after SG, all MRI measurements significantly improved. The median LFF of pure MASLD patients decreased from 17.4% at baseline to 4.2% and 3.7% at the 6th and 12th postoperative months, respectively. Complete resolution of steatosis was achieved in 97.5% of patients at the 12th postoperative months. Using %VAT and %SAT reductions at the sixth postoperative month as references, LFF decreased more rapidly, with fold ratios of 1.3 and 1.8, respectively. Conclusions: SG resulted in a significant decrease in hepatic steatosis and abdominal adiposity in patients with severe obesity, but hepatic steatosis improved faster than abdominal adiposity. Hepatic steatosis resolved in almost all patients 12 months after SG
Dual-function antibodies targeting VEGFR2 and VEGFR3
No full text[[abstract]]An isolated antibody, comprising heavy chain complementary determining regions CDR1, CDR2, and CDR3 from a heavy chain variable region sequence having SEQ ID NO: 1 or 3; light chain complementary determining regions CDR1, CDR2, and CDR3 from a light chain variable region sequence having SEQ ID NO: 2 or 4; wherein the antibody binds specifically to both vascular endothelial growth factor receptor-2 (VEGFR2) and vascular endothelial growth factor receptor-3 (VEGFR3)
Aminothiazole compounds as protein kinase inhibitors
No full text[[abstract]]FIELD: pharmaceutics. SUBSTANCE: invention relates to a compound of the formula (I) or to its pharmaceutically acceptable salt, where R1 is C1-6alkyl; X is NRa; Y is CRbRc or NRd, in which Rc is H, N(CH3)2, Rb, together with Ra, carbon atom related to Rb, and nitrogen atom related to Ra, is piperidinyl, and Rd, together with Ra and nitrogen atoms related to Rd and Ra, is piperazinyl; R2 is -CH2CH2Re or NRfRg, in which Re is H, halogen or ORh, and each of Rf and Rg is C1-6alkyl, Rh is H, and R3 is pyridyl or pyrimidinil. The invention also relates to a pharmaceutical composition for the treatment of cancer associated with tyrosine kinase, based on the compound of the formula (I). EFFECT: new compounds and a pharmaceutical composition based on them are obtained that can be used in medicine for the treatment of cancer. 13 cl, 1 tbl, 5 e
Aminothiazole compounds as protein kinase inhibitors
No full text[[abstract]]Aminothiazole compounds of Formula (I) shown below and pharmaceutical compositions containing one of such compounds: (I). Also disclosed are methods of inhibiting a tyrosine kinase and treating cancer associated with a tyrosine kinase with one of the aminothiazole compounds