Germline Stem Cell Gene PIWIL2 Mediates DNA Repair through Relaxation of Chromatin

DNA damage response (DDR) is an intrinsic barrier of cell to tumorigenesis initiated by genotoxic agents. However, the mechanisms underlying the DDR are not completely understood despite of extensive investigation. Recently, we have reported that ectopic expression of germline stem cell gene PIWIL2 is associated with tumor stem cell development, although the underlying mechanisms are largely unknown. Here we show that PIWIL2 is required for the repair of DNA-damage induced by various types of genotoxic agents. Upon ultraviolet (UV) irradiation, silenced PIWIL2 gene in normal human fibroblasts was transiently activated after treatment with UV light. This activation was associated with DNA repair, because Piwil2-deficienct mouse embryonic fibroblasts (mili-/- MEFs) were defective in cyclobutane pyrimidine dimers (CPD) repair after UV treatment. As a result, the UV-treated mili-/- MEFs were more susceptible to apoptosis, as characterized by increased levels of DNA damage-associated apoptotic proteins, such as active caspase-3, cleaved Poly (ADP-ribose) polymerase (PARP) and Bik. The impaired DNA repair in the mili-/- MEFs was associated with the reductions of histone H3 acetylation and chromatin relaxation, although the DDR pathway downstream chromatin relaxation appeared not to be directly affected by Piwil2. Moreover, guanine–guanine (Pt-[GG]) and double strand break (DSB) repair were also defective in the mili-/- MEFs treated by genotoxic chemicals Cisplatin and ionizing radiation (IR), respectively. The results indicate that Piwil2 can mediate DNA repair through an axis of Piwil2 → histone acetylation → chromatin relaxation upstream DDR pathways. The findings reveal a new role for Piwil2 in DNA repair and suggest that Piwil2 may act as a gatekeeper against DNA damage-mediated tumorigenesis

The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID‐19

Background Although type 2 diabetes mellitus (T2DM) patients with coronavirus disease 2019 (COVID‐19) develop a more severe condition compared to those without diabetes, the mechanisms for this are unknown. Moreover, the impact of treatment with antihyperglycemic drugs and glucocorticoids is unclear. Methods From 1584 COVID‐19 patients, 364 severe/critical COVID‐19 patients with clinical outcome were enrolled for the final analysis, and patients without preexisting T2DM but elevated glucose levels were excluded. Epidemiological data were obtained and clinical status evaluation carried out to assess the impact of T2DM and its management on clinical outcomes. Results Of 364 enrolled severe COVID‐19 inpatients, 114 (31.3%) had a history of T2DM. Twenty‐seven (23.7%) T2DM patients died, who had more severe inflammation, coagulation activation, myocardia injury, hepatic injury, and kidney injury compared with non‐DM patients. In severe COVID‐19 patients with T2DM, we demonstrated a higher risk of all‐cause fatality with glucocorticoid treatment (adjusted hazard ratio [HR], 3.61; 95% CI, 1.14‐11.46; P = .029) and severe hyperglycemia (fasting plasma glucose ≥11.1 mmol/L; adjusted HR, 11.86; 95% CI, 1.21‐116.44; P = .034). Conclusions T2DM status aggravated the clinical condition of COVID‐19 patients and increased their critical illness risk. Poor fasting blood glucose (≥ 11.1 mmol/L) and glucocorticoid treatment are associated with poor prognosis for T2DM patients with severe COVID‐19

Identification of Piwil2-Like (PL2L) Proteins that Promote Tumorigenesis

PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G0/1 into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development

Relations of lipid parameters, other variables with carotid intima-media thickness and plaque in the general Chinese adults: an observational study

Abstract Background It has been reported that non-high-density lipoprotein cholesterol (non-HDL-C) and lipid ratios, including total cholesterol (TC) / high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) / HDL-C, are better predictors for atherosclerosis than conventional lipid profiles. However, there have been few studies comparing the predictive values of different lipid parameters for early atherosclerosis. The aim of this study was to determine the relevant factors of carotid intima-media thickness (IMT) and plaque in the general Chinese adults and analyze the predictive values of different lipid parameters for carotid IMT and plaque. Methods We collected the demographics, anthropometrics, and laboratory data of 311 Chinese adults without the diagnoses of acute myocardial infarction, stroke, heart failure, peripheral arterial disease, end-stage renal disease or malignant tumor. The carotid IMT and the presence of carotid plaque were evaluated by high-resolution color Doppler ultrasonography. Results Based on the cutoff level of 0.9 mm, the percentage of people with a thickened IMT was 8.4%. And the percentage of people with carotid plaque was 15.8%. Among the lipid parameters, the levels of TC, non-HDL-C and LDL-C were more closely related to carotid IMT and plaque compared with other lipid parameters in the univariate analyses. In multivariate analyses, age, gender and systolic blood pressure (SBP) remained significantly with carotid IMT, whereas age, gender, diastolic blood pressure (DBP) and the TC level remained significantly with carotid plaque. Non-HDL-C level remained significantly with carotid plaque after adjusting for age, gender, waist-hip ratio (WHR), smoking, drinking, SBP and fasting plasma glucose (FPG). Conclusions Age, gender, SBP are important predictors for carotid IMT. Age, gender, DBP and TC are important predictors for carotid plaque. TC, LDL-C and non-HDL-C have greater predictive values for IMT and the presence of carotid plaque compared with other lipid parameters, among which TC has the greatest predictive value for the presence of carotid plaque. The predictive value of non-HDL-C for carotid IMT and plaque is not inferior to that of LDL-C

Construction of cost-effective bimetallic nanoparticles on titanium carbides as a superb catalyst for promoting hydrolysis of ammonia borane

Bimetallic cost-effective CoNi nanoparticles (NPs) are conveniently supported on titanium carbides (MXene) by a simple one-step wet-chemical method. The synthesized CoNi/MXene catalysts are characterized by XPS, TEM, STEM-HAADF and ICP-AES. The as-prepared CoNi NPs with a size of 2.8 nm are well dispersed on the MXene surface. It is found that among the CoNi bimetallic system, Co0.7Ni0.3 shows the best performance toward catalyzing ammonia borane (AB) decomposition with a turnover frequency value of 87.6 molH2 molcat−1 min−1 at 50 °C. The remarkable catalytic performance is attributed to the mild affiliation of MXene to NPs, which not only stabilizes NPs to maintain a good dispersion but also leaves sufficient surface active sites to facilitate the catalytic reaction

Effect of Corn Particle Size on the Particle Size of Intestinal Digesta or Feces and Nutrient Digestibility of Corn–Soybean Meal Diets for Growing Pigs

This study was conducted to evaluate the effect of corn particle size on the particle size of intestinal digesta or feces and nutrient digestibility of corn–soybean meal diets. Twenty-four growing barrows (initial BW: 21.9 ± 1.62 kg) were randomly divided into 4 groups of 6 pigs. A T-cannula was surgically placed in the anterior duodenum (about 50 cm from pylorus) of pigs in Groups 1 and 2 or in the distal ileum of pigs in Groups 3 and 4. Corn used to formulate diets had mean particle size (MPS) of 365 µm (Corn 1) or 682 µm (Corn 2), resulting in diets with MPS of 390 µm (Diet 1) or 511 μm (Diet 2). Diet 1 or 2 were randomly assigned within pig Groups 1 or 2 and 3 or 4. The digestive enzyme activities of duodenal fluid, particle size of intestinal digesta and feces, as well as nutrient digestibility, were determined for each pig as the experiment unit. The MPS of duodenal digesta (181 vs. 287 µm, p < 0.01), ileal digesta (253 vs. 331 µm, p < 0.01), and feces (195 vs. 293 µm, p < 0.01) was significantly reduced for pigs fed Diet 1 vs. Diet 2, respectively. Compared with Diet 2, Diet 1 significantly reduced the proportion of particles above 0.5 mm, but significantly increased the proportion of particles between 0.072 and 0.5 mm (p < 0.01) in digesta and feces (p < 0.01). Diet 1 significantly increased solubles percentage (<0.072 mm) in duodenal digesta (p < 0.05) but did not affect solubles percentage in ileal digesta and feces. The MPS of diet did not affect the activities of amylase, trypsin, and chymotrypsin in the duodenal fluid and the apparent total tract digestibility (ATTD) of dry matter, gross energy, crude protein, ether extract, neutral detergent fiber (NDF) and acid detergent fiber (ADF) in pigs offered Diet 1 compared to Diet 2. The in vitro digestible energy (IVDE) (3706 vs. 3641 kcal/kg; p = 0.03) was greater for Corn 1 vs. Corn 2. However, no significant difference was observed in IVDE (3574 vs. 3561 kcal/kg; p = 0.47) for Diet 1 vs. Diet 2. In conclusion, the particle size of digesta and feces was dependent on the dietary particle size. However, the digestive enzyme activities of duodenal fluid and ATTD of energy and nutrients were not affected by reducing dietary MPS from 511 to 390 µm

A method for characterizing the deformation localization in granular materials using the relative particle motion

The failure location identification of granular materials can be solved by capturing the deformation localization. Considering the relative translation and rotation among particles, a new concept named the relative particle motion (RPM) is proposed to describe the deformation localization of the granular materials. An approach is developed to realize the selection of particles that are used to calculate RPM. The number of particles involved in RPM calculation is controlled by two key parameters, i.e., grid spacing (U) and domain radius (R). Combining the proposed concept and the selection approach of particles, the method that can capture the region of the deformation localization in the granular material is established and implemented in PFC2D.The simulation of a uniaxial compression test is conducted to analyze the effect of parameters U and R on the calculation results of the RPM field, and a reasonable range of U and R is given. Three typical conditions, including the biaxial compression, trapdoor, and particle flow tests, are taken as examples to validate the proposed method under different loading conditions. Regions of the deformation localization characterized by RPM have a good agreement with the shear band presented in the published literature

A prediction method of ground volume loss variation with depth induced by tunnel excavation

A new concept called the transmission ratio of ground volume loss (TRGVL) is proposed to describe the variation law of ground volume loss with depth above the tunnel. Based on the developed Gaussian function, the formula for TRGVL is deduced. Further, the first-order derivative of TRGVL is presented to evaluate the dilation and compression degree of the soil at any depth above the tunnel. A total of 15 cases, involving eight field project cases and seven model test cases, are investigated to validate rationality of the proposed formula. The results of field projects and model test cases indicate variation in TRGVL presents four forms. By analysing the volumetric deformation of the soil above the tunnel, formation mechanism of the each form of TRGVL is revealed. Finally, the evolution of the four forms of TRGVL is used to evaluate the disturbance degree of the soil above the tunnel

Supplementing Glycerol to Inoculum Induces Changes in pH, SCFA Profiles, and Microbiota Composition in In-Vitro Batch Fermentation

Glycerol was generally added to the inoculum as a cryoprotectant. However, it was also a suitable substrate for microbial fermentation, which may produce more SCFAs, thereby decreased pH of the fermentation broth. This study investigated the effect of supplementing glycerol to inoculum on in vitro fermentation and whether an enhanced buffer capacity of medium could maintain the pH stability during in vitro batch fermentation, subsequently improving the accuracy of short chain fatty acids (SCFAs) determination, especially propionate. Two ileal digesta were fermented by pig fecal inoculum with or without glycerol (served as anti-frozen inoculum or frozen inoculum) in standard buffer or enhanced buffer solution (served as normal or modified medium). Along with the fermentation, adding glycerol decreased the pH of fermentation broth (p < 0.05). However, modified medium could alleviate the pH decrement compared with normal medium (p < 0.05). The concentration of total propionic acid production was much higher than that of other SCFAs in anti-frozen inoculum fermentation at 24 and 36 h, thereby increasing the variation (SD) of net production of propionate. The α-diversity analysis showed that adding glycerol decreased Chao1 and Shannon index under normal medium fermentation (p < 0.05) compared to modified medium (p < 0.05) along with fermentation. PCoA showed that all groups were clustered differently (p < 0.01). Adding glycerol improved the relative abundances of Firmicutes, Anaerovibrio, unclassified_f_Selenomonadaceae, and decreased the relative abundance of Proteobacteria (p < 0.05). The relative abundances of Firmicutes, such as Lactobacillus, Blautia and Eubacterium_Ruminantium_group in modified medium with frozen inoculum fermentation were higher than (p < 0.05) those in normal medium at 36 h of incubation. These results showed that adding glycerol in inoculum changed the fermentation patterns, regardless of substrate and medium, and suggested fermentation using frozen inoculum with modified medium could maintain stability of pH, improve the accuracy of SCFA determination, as well as maintain a balanced microbial community