Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral shRNA-mediated reduction of PRMT5 significantly decreased PI3K/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation, but boosted the expression of PPARalpha and PGC-1alpha with a concomitant increase of mitochondrial biogenesis. Moreover, by overexpressing an exogenous wild-type or enzyme-dead mutant PRMT5, or by inhibiting PRMT5 enzymatic activity with a small molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARalpha and PGC-1alpha expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for treatment of fatty liver. Biology, Inc

A Selective Small Molecule DNA2 Inhibitor for Sensitization of Human Cancer Cells to Chemotherapy

Cancer cells frequently up-regulate DNA replication and repair proteins such as the multifunctional DNA2 nuclease/helicase, counteracting DNA damage due to replication stress and promoting survival. Therefore, we hypothesized that blocking both DNA replication and repair by inhibiting the bifunctional DNA2 could be a potent strategy to sensitize cancer cells to stresses from radiation or chemotherapeutic agents. We show that homozygous deletion of DNA2 sensitizes cells to ionizing radiation and camptothecin (CPT). Using a virtual high throughput screen, we identify 4-hydroxy-8-nitroquinoline-3-carboxylic acid (C5) as an effective and selective inhibitor of DNA2. Mutagenesis and biochemical analysis define the C5 binding pocket at a DNA-binding motif that is shared by the nuclease and helicase activities, consistent with structural studies that suggest that DNA binding to the helicase domain is necessary for nuclease activity. C5 targets the known functions of DNA2 in vivo: C5 inhibits resection at stalled forks as well as reducing recombination. C5 is an even more potent inhibitor of restart of stalled DNA replication forks and over-resection of nascent DNA in cells defective in replication fork protection, including BRCA2 and BOD1L. C5 sensitizes cells to CPT and synergizes with PARP inhibitors

Tailoring of polar and nonpolar ZnO planes on MgO (001) substrates through molecular beam epitaxy

Polar and nonpolar ZnO thin films were deposited on MgO (001) substrates under different deposition parameters using oxygen plasma-assisted molecular beam epitaxy (MBE). The orientations of ZnO thin films were investigated by in situ reflection high-energy electron diffraction and ex situ X-ray diffraction (XRD). The film roughness measured by atomic force microscopy evolved as a function of substrate temperature and was correlated with the grain sizes determined by XRD. Synchrotron-based X-ray absorption spectroscopy (XAS) was performed to study the conduction band structures of the ZnO films. The fine structures of the XAS spectra, which were consistent with the results of density functional theory calculation, indicated that the polar and nonpolar ZnO films had different electronic structures. Our work suggests that it is possible to vary ZnO film structures from polar to nonpolar using the MBE growth technique and hence tailoring the electronic structures of the ZnO films

Potential interaction between the oral microbiota and COVID-19: a meta-analysis and bioinformatics prediction

ObjectivesThe purpose of this study was to evaluate available evidence on the association between the human oral microbiota and coronavirus disease 2019 (COVID-19) and summarize relevant data obtained during the pandemic.MethodsWe searched EMBASE, PubMed, and the Cochrane Library for human studies published up to October 2022. The main outcomes of the study were the differences in the diversity (α and β) and composition of the oral microbiota at the phylum and genus levels between patients with laboratory-confirmed SARS-CoV-2 infection (CPs) and healthy controls (HCs). We used the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA) database, Protein−protein interaction (PPI) network (STRING) and Gene enrichment analysis (Metascape) to evaluate the expression of dipeptidyl peptidase 4 (DPP4) (which is the cell receptor of SARS CoV-2) in oral tissues and evaluate its correlation with viral genes or changes in the oral microbiota.ResultsOut of 706 studies, a meta-analysis of 9 studies revealed a significantly lower alpha diversity (Shannon index) in CPs than in HCs (standardized mean difference (SMD): -0.53, 95% confidence intervals (95% CI): -0.97 to -0.09). Subgroup meta-analysis revealed a significantly lower alpha diversity (Shannon index) in older than younger individuals (SMD: -0.54, 95% CI: -0.86 to -0.23/SMD: -0.52, 95% CI: -1.18 to 0.14). At the genus level, the most significant changes were in Streptococcus and Neisseria, which had abundances that were significantly higher and lower in CPs than in HCs based on data obtained from six out of eleven and five out of eleven studies, respectively. DPP4 mRNA expression in the oral salivary gland was significantly lower in elderly individuals than in young individuals. Spearman correlation analysis showed that DPP4 expression was negatively correlated with the expression of viral genes. Gene enrichment analysis showed that DPP4-associated proteins were mainly enriched in biological processes, such as regulation of receptor-mediated endocytosis of viruses by host cells and bacterial invasion of epithelial cells.ConclusionThe oral microbial composition in COVID-19 patients was significantly different from that in healthy individuals, especially among elderly individuals. DPP4 may be related to viral infection and dysbiosis of the oral microbiome in elderly individuals

Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants

Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome. Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set. We find that the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity. These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes

Effects of continuous positive airway pressure on depression and anxiety symptoms in patients with obstructive sleep apnoea: results from the sleep apnoea cardiovascular Endpoint randomised trial and meta-analysis

Background: Whether continuous positive airway pressure (CPAP) treatment can improve depression or anxiety symptoms in obstructive sleep apnoea (OSA) patients remains uncertain. Methods: Secondary analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial, combined with a systematic review of randomised evidence. The SAVE secondary analyses involved 2410 patients with co-existing moderate–severe OSA and established cardiovascular disease randomly allocated to CPAP treatment plus usual care or usual care alone and followed up for 3·7 (SD 1·6) years. We evaluated the effect of CPAP treatment on depression and anxiety caseness (scores ≥8 on the Hospital Anxiety and Depression Scale depression and anxiety subscales [HADS-D and HADS-A]) for OSA patients. Findings: CPAP treatment was associated with reduced odds of depression caseness (adjusted odds ratio [OR] 0·80, 95% confidence interval [CI] 0·65–0·98, P = 0·031) compared to usual care in the SAVE trial and the treatment effect was greater in those with pre-existing depression symptoms. A systematic review of 20 randomised trials including 4255 participants confirmed a benefit of CPAP in reducing depression symptoms in OSA patients: the overall effect (standardisedmean difference)was−0·18 (95% CI−0·24 to−0·12). No effect of CPAP treatment on anxiety caseness was found both in patients of the SAVE study (adjusted OR 0·98, 95% CI 0·78–1·24, P = 0·89) and the systematic review. Interpretation: CPAP reduces depression symptoms in patients with co-existing OSA and CVD independently of improvements in sleepiness

Host–Guest Cocrystallization of Phenanthrene[2]arene Macrocycles Facilitating Structure Determination of Liquid Organic Molecules

Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern