Gbdmr: identifying differentially methylated CpG regions in the human genome via generalized beta regressions.

BACKGROUND: DNA methylation is a biochemical process in which a methyl group is added to the cytosine-phosphate-guanine (CpG) site on DNA molecules without altering the DNA sequence. Multiple CpG sites in a certain genome region can be differentially methylated across phenotypes. Identifying these differentially methylated CpG regions (DMRs) associated with the phenotypes contributes to disease prediction and precision medicine development. RESULTS: We propose a novel DMR detection algorithm, gbdmr. In contrast to existing methods under a linear regression framework, gbdmr assumes that DNA methylation levels follow a generalized beta distribution. We compare gbdmr to alternative approaches via simulations and real data analyses, including dmrff, a new DMR detection approach that shows promising performance among competitors, and the traditional EWAS that focuses on single CpG sites. Our simulations demonstrate that gbdmr is superior to the other two when the correlation between neighboring CpG sites is strong, while dmrff shows a higher power when the correlation is weak. We provide an explanation of these phenomena from a theoretical perspective. We further applied the three methods to multiple real DNA methylation datasets. One is from a birth cohort study undertaken on the Isle of Wight, United Kingdom, and the other two are from the Gene Expression Omnibus database repository. Overall, gbdmr identifies more DMR CpGs linked to phenotypes than dmrff, and the simulated results support the findings. CONCLUSIONS: Gbdmr is an innovative method for detecting DMRs based on generalized beta regression. It demonstrated notable advantages over dmrff and traditional EWAS, particularly when adjacent CpGs exhibited moderate to strong correlations. Our real data analyses and simulated findings highlight the reliability of gbdmr as a robust DMR detection tool. The gbdmr approach is accessible and implemented by R on GitHub: https://github.com/chengzhouwu/gbdmr .

Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism.

Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.

Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases.

Oxidative stress is associated with many acute and chronic inflammatory diseases, yet limited treatment is currently available clinically. The development of enzyme-mimicking nanomaterials (nanozymes) with good reactive oxygen species (ROS) scavenging ability and biocompatibility is a promising way for the treatment of ROS-related inflammation. Herein we report a simple and efficient one-step development of ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with multiple enzyme-mimicking and broad-spectrum ROS scavenging ability for the treatment of ROS-related diseases. Cu5.4O USNPs simultaneously possessing catalase-, superoxide dismutase-, and glutathione peroxidase-mimicking enzyme properties exhibit cytoprotective effects against ROS-mediated damage at extremely low dosage and significantly improve treatment outcomes in acute kidney injury, acute liver injury and wound healing. Meanwhile, the ultrasmall size of Cu5.4O USNPs enables rapid renal clearance of the nanomaterial, guaranteeing the biocompatibility. The protective effect and good biocompatibility of Cu5.4O USNPs will facilitate clinical treatment of ROS-related diseases and enable the development of next-generation nanozymes.

Sequential Phosphine-Catalyzed [4 + 2] Annulation of ß'-Acetoxy Allenoates: Enantioselective Synthesis of 3-Ethynyl-Substituted Tetrahydroquinolines.

The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α-ß', 1,2-dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

Plasma YKL-40 and NGAL are useful in distinguishing ACO from asthma and COPD.

BACKGROUND: Asthma-chronic obstructive pulmonary disorder (COPD) overlap (ACO) is characterized by the coexistence of features of both asthma and COPD and is associated with rapid progress and a poor prognosis. Thus, the early recognition of ACO is crucial. OBJECTIVES: We sought to explore the plasma levels of biomarkers associated with asthma (periostin, TSLP and YKL-40), COPD (NGAL) and their possible correlation with lung function, the bronchodilator response and radiographic imaging in patients with asthma, COPD and with features of ACO. METHODS: We enrolled 423 subjects from 6 clinical centers. All participants underwent blood collection, lung function measurements, bronchodilator response tests and high-resolution CT. Correlations of the plasma biomarkers with lung function, the bronchodilator response and percentemphysema were calculated by Spearman's rank correlation and multivariate stepwise regressionanalysis. RESULTS: 1) Patients with features of ACO had lower plasma YKL-40 than COPD patients and a moderate elevated plasma level of NGAL compared with asthma patients. 2) Patients with features of ACO had an intermediate degree of airflow obstruction, the bronchodilator response and emphysema between patients with COPD and asthma. 3) Plasma YKL-40 was negatively correlated with lung function and with the bronchodilator response, and plasma NGAL was positively correlated with the extent of emphysema. CONCLUSIONS: Plasma YKL-40 is a promising candidate for distinguishing between patients with features of ACO and COPD patients, while plasma NGAL may be a valuable biomarker for differentiating between patients with features of ACO and asthma patients. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009221.

Recent advances of on-demand dissolution of hydrogel dressings.

Wound management is a major global challenge and a big financial burden to the healthcare system due to the rapid growth of chronic diseases including the diabetes, obesity, and aging population. Modern solutions to wound management include hydrogels that dissolve on demand, and the development of such hydrogels is of keen research interest. The formation and subsequent on-demand dissolution of hydrogels is of keen interest to scientists and clinicians. These hydrogels have excellent properties such as tissue adhesion, swelling, and water absorption. In addition, these hydrogels have a distinctive capacity to form in situ and dissolve on-demand via physical or chemical reactions. Some of these hydrogels have been successfully used as a dressing to reduce bleeding in hepatic and aortal models, and the hydrogels remove easily afterwards. However, there is an extremely wide array of different ways to synthesize these hydrogels. Therefore, we summarize here the recent advances of hydrogels that dissolve on demand, covering both chemical cross-linking cases and physical cross-linking cases. We believe that continuous exploration of dissolution strategies will uncover new mechanisms of dissolution and extend the range of applications for hydrogel dressings.

Recent review of the effect of nanomaterials on stem cells.

The field of stem-cell-therapy offers considerable promise as a means of delivering new treatments for a wide range of diseases. Recent progress in nanotechnology has stimulated the development of multifunctional nanomaterials (NMs) for stem-cell-therapy. Several clinical trials based on the use of NMs are currently underway for stem-cell-therapy purposes, such as drug/gene delivery and imaging. However, the interactions between NMs and stem cells are far from being completed, and the effects of the NMs on cellular behavior need critical evaluation. In this review, the interactions between several types of mostly used NMs and stem cells, and their associated possible mechanisms are systematically discussed, with specific emphasis on the possible differentiation effects induced by NMs. It is expected that the enhanced understanding of NM-stem cell interactions will facilitate biomaterial design for stem-cell-therapy and regenerative medicine applications.

One-Pot Synthesis of Polysubstituted Benzenes through a N,N-dimethyl-4-aminopyridine (DMAP)-Catalyzed [4+2] Benzannulation of 1,3-Bis(sulfonyl)butadienes and γ-Substituted Allenoates.

A new strategy for the one-pot synthesis of polysubstituted benzenes through a N,N-dimethyl-4-aminopyridine (DMAP)-catalyzed [4+2] benzannulation from readily prepared 1,3-bis(sulfonyl)butadienes and γ-substituted allenoates is described. This method provides a facile, metal-free and general route to highly substituted benzenes under mild conditions in moderate-to-good yields with complete regioselectivity.

[Spatial distribution and risk assessment of insecticides in surface soil from a rapidly urbanizing region].

To examine the distribution patterns of organic contaminants in rapidly urbanizing regions, the levels and spatial distributions of 19 overlooked insecticides, i. e., phenyl-pyrazole class (fipronil), chlordane, endosulfan, nonachlor, hexachlorobenzene, heptachlor, dieldrin, aldrin, endrin, methoxychlor and their metabolites, were examined in 229 soil samples collected from the Pearl River Delta (PRD) and surrounding areas. The results indicated that higher insecticide levels distributed in the central PRD, while lower levels congested in the surrounding areas. The similar spatial patterns between the levels of insecticides and economic prosperity or population density demonstrated that social-economic factors may have dictated the spatial patterns of insecticides. In addition, the changing of land-use types during urbanization processes, e.g., historical plowlands have been converted into residential landscapes, resulted in high concentrations of banned insecticides in metropolis of the central PRD. Source diagnostics indicated that new inputs of technical chlordane products existed in the PRD and surrounding areas. Fipronil was degraded into fipronil sulfone and fipronil sulfide in most soil samples because of its low half-life in soil. Finally, a risk assessment of 19 insecticides in soil for human health suggested that six samples collected from the major administrative districts with dense population had potential cancer or non-cancer risk to human health. Therefore, these overlooked insecticides should be concerned in future environmental research.