Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.

INTRODUCTION: Our aim was to study the prevalence of frailty and its associated factors in a subacute geriatric ward. METHODS: This was a cross-sectional study of 167 participants between June 2018 and June 2019. Baseline demographics and participants' Mini Nutritional Assessment, Geriatric Depression Scale, Mini Mental State Examination, Charlson's Comorbidity Index and LACE index scores were obtained. Functional measurements such as modified Barthel's Index scores and hand grip strength (HGS) were taken. Frailty was assessed using the Clinical Frailty Scale (CFS) and the FRAIL scale. Data on history of healthcare utilisation, medications, length of stay, selected blood investigations and presence of geriatric syndromes were also collected. RESULTS: The prevalence of pre-frailty (CFS 4) and frailty (CFS ≥ 5) was 16.2% and 63.4%, respectively. There were significant associations between CFS and age (pre-frail vs. non-frail: odds ratio [OR] 1.14, 95% confidence interval [CI] 1.04-1.25, P = 0.006; frail vs. non-frail: OR 1.08, 95% CI 1.01-1.15, P = 0.021), HGS at discharge (frail vs. non-frail: OR 0.90, 95% CI 0.82-0.99, P = 0.025), serum albumin (frail vs. non-frail: OR 0.90, 95% CI 0.82-0.99, P = 0.035) and the presence of urinary incontinence (frail vs. non-frail: OR 3.03, 95% CI 1.19-7.77, P = 0.021). CONCLUSION Frailty is highly prevalent in the subacute geriatric setting and has many associated factors. In this study, independent factors associated with frailty were age, HGS at discharge, serum albumin and urinary incontinence. This has implications for future resource allocation for frail older inpatients and may help direct further research to study the effectiveness of frailty-targeted interventions.
Humans ; Aged ; Frailty/epidemiology* ; Frail Elderly ; Hand Strength ; Prevalence ; Singapore/epidemiology* ; Cross-Sectional Studies ; Fatigue Syndrome, Chronic ; Geriatric Assessment ; Urinary Incontinence ; Serum Albumin

Although somatic cells can be reprogrammed to pluripotent stem cells (PSCs) with pure chemicals, authentic pluripotency of chemically induced pluripotent stem cells (CiPSCs) has never been achieved through tetraploid complementation assay. Spontaneous reprogramming of spermatogonial stem cells (SSCs) was another non-transgenic way to obtain PSCs, but this process lacks mechanistic explanation. Here, we reconstructed the trajectory of mouse SSC reprogramming and developed a five-chemical combination, boosting the reprogramming efficiency by nearly 80- to 100-folds. More importantly, chemical induced germline-derived PSCs (5C-gPSCs), but not gPSCs and chemical induced pluripotent stem cells, had authentic pluripotency, as determined by tetraploid complementation. Mechanistically, SSCs traversed through an inverted pathway of in vivo germ cell development, exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts. Besides, SSC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5C-gPSCs, which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles. Our work sheds light on the unique regulatory network underpinning SSC reprogramming, providing insights to understand generic mechanisms for cell-fate decision and epigenetic-related disorders in regenerative medicine.
Male ; Mice ; Animals ; Cellular Reprogramming/genetics* ; Tetraploidy ; Pluripotent Stem Cells/metabolism* ; Induced Pluripotent Stem Cells/metabolism* ; DNA Methylation ; Spermatogonia/metabolism* ; Germ Cells/metabolism*

Animals ; Epithelial Cells ; Epithelial-Mesenchymal Transition/genetics* ; MicroRNAs/genetics* ; Rats ; Rats, Inbred SHR ; Transforming Growth Factor beta/genetics* ; Transforming Growth Factor beta1/pharmacology*

Humans ; COVID-19/epidemiology* ; Pandemics ; Orthopedics ; Orthopedic Procedures ; Telemedicine

Synechocystis sp.PCC 6803(hereafter:Synechocystis)is a model organism for studying photosynthesis,energy metabolism,and environmental stress.Although known as the first fully sequenced phototrophic organism,Synechocystis still has almost half of its proteome without func-tional annotations.In this study,by using co-fractionation coupled with liquid chromatography-tandem mass spectrometry(LC-MS/MS),we define 291 multi-protein complexes,encompassing 24,092 protein-protein interactions(PPIs)among 2062 distinct gene products.This information not only reveals the roles of photosynthesis in metabolism,cell motility,DNA repair,cell division,and other physiological processes,but also shows how protein functions vary from bacteria to higher plants due to changes in interaction partners.It also allows us to uncover the functions of hypothetical proteins,such as S110445,S110446,and S110447 involved in photosynthesis and cell motility,and Sill 334 involved in regulation of fatty acid biogenesis.Here we present the most exten-sive PPI data for Synechocystis so far,which provide critical insights into fundamental molecular mechanisms in cyanobacteria.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Adenocarcinoma of Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Squamous Cell/genetics* ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/genetics* ; Polymorphism, Single Nucleotide

Background/Aims: Gastroparesis is identified as a subject that is understudied in Asia. The scientific committee of the Asian Neurogastroenterology and Motility Association performed a Knowledge, Attitude, and Practices survey on gastroparesis among doctors in Asia. Methods: The questionnaire was created and developed through a literature review of current gastroparesis works of literature by the scientific committee of Asian Neurogastroenterology and Motility Association. Results: A total of 490 doctors from across Asia (including Bangladesh, China, Hong Kong, Indonesia, Japan, Malaysia, Myanmar, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam) participated in the survey. Gastroparesis is a significant gastrointestinal condition. However, a substantial proportion of respondents was unable to give the correct definition and accurate diagnostic test. The main reason for lack of interest in diagnosing gastroparesis was “the lack of reliable diagnostic tests” (46.8%) or “a lack of effective treatment” (41.5%). Only 41.7% of respondents had access to gastric emptying scintigraphy. Most doctors had never diagnosed gastroparesis at all (25.2%) or diagnosed fewer than 5 patients a year (52.1%). Conclusions Gastroparesis can be challenging to diagnose due to the lack of instrument, standardized method, and paucity of research data on normative value, risk factors, and treatment studies in Asian patients. Future strategies should concentrate on how to disseminate the latest knowledge of gastroparesis in Asia. In particular, there is an urgent need to estimate the magnitude of the problems in high risk and idiopathic patients as well as a standardized diagnostic procedure in Asia.

The mammalian epididymis not only plays a fundamental role in the maturation of spermatozoa, but also provides protection against various stressors. The foremost among these is the threat posed by oxidative stress, which arises from an imbalance in reactive oxygen species and can elicit damage to cellular lipids, proteins, and nucleic acids. In mice, the risk of oxidative damage to spermatozoa is mitigated through the expression and secretion of glutathione peroxidase 5 (GPX5) as a major luminal scavenger in the proximal caput epididymidal segment. Accordingly, the loss of GPX5-mediated protection leads to impaired DNA integrity in the spermatozoa of aged Gpx5