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Abstract Background The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. Methods We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3 −/− and Cxcl10 −/− ) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3 −/− and Cxcl10 −/− stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3 −/− or Cxcl10 −/− recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Results Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10 −/− stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10 −/− donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. Conclusions The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

Abstract This paper proposes a hybrid model to improve Information Content (IC) related metrics of semantic similarity between words, named IC+SP, based on the essential hypothesis that IC and the shortest path are two relatively independent semantic evidences and have approximately equal influences to the semantic similarity metric. The paradigm of IC+SP is to linearly combine the IC-related metric and the shortest path. Meanwhile, a transformation from the semantic similarity of the concepts to that of the words is presented by maximizing every component of IC+SP. 13 improved IC-related metrics based on IC+SP are formed and implemented on the experimental platform HESML Lastra-Díaz (Inf Syst 66:97–118, 2017). Pearson’s and Spearman’s correlation coefficients on well-accepted benchmarks for the improved metrics compare to those for the original ones to evaluate IC+SP. I introduce the Wilcoxon Signed-Rank Test needing no standard distribution hypothesis, while, this hypothesis is required by T-Test on the sample of small size. T-Test, as well as the Wilcoxon Signed-Rank Test, conduct on the differences of the correlative coefficients for improved and original metrics. It is expected that the improved IC-related metrics could significantly outperform their corresponding original ones, and the experimental results, including the comparisons of mean and maximum of correlation coefficients as well as the p-value and confidence interval of both tests, accomplish the anticipation in the vast majority of cases.

Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and PubMed databases, all global registered clinical trials in the ClinicalTrials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority (89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema (9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development (58.19%). Approximately half of the trials (49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic (40 out of 1830; 2.19%) and diabetic eye disease (3 out of 1830; 0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.

AbstractBackground Poor sleep quality is a common problem among hemodialysis (HD) patients. Dietary fiber is a key component of a healthy diet and is beneficial for a variety of health outcomes; however, evidence of an association between dietary fiber consumption and subjective sleep quality has not been established among HD patients. Therefore, we determined the association between dietary fiber consumption and the subjective sleep quality in Chinese maintenance HD patients, taking into account fiber type and source.Methods Dietary intake was assessed with a validated food frequency questionnaire in a cross-sectional study including 741 maintenance HD patients between December 2021 and January 2022. The daily intake of dietary fiber was categorized into three groups. The lowest tertile was used as the reference category. Sleep quality of patients was accurately calculated using the Pittsburgh sleep quality index standard questionnaire. Multivariable logistic regression model and restricted cubic spline analysis were performed to assess the relationship between dietary fiber consumption and poor sleep quality.Results Compared with the lowest tertile group of dietary fiber intake, the highest tertile group had a lower prevalence of poor sleep quality. After adjustment for potential confounders, a higher intake of total dietary fiber (ORtertile 3 (T3) to tertile 1 (T1)= 0.51, 95% CI: 0.31–0.85), total insoluble dietary fiber (ORT3 to T1 =0.54, 95% CI: 0.33–0.89), and soluble dietary fiber in vegetables (ORT3 to T1 =0.61, 95% CI: 0.40–0.93) were associated with a lower prevalence of poor sleep quality. Furthermore, significant linear trends were also observed (p

Abstract Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation. Among all the affected bacteria, B. coccoides is markedly increased in the feces of leucine‐deprived mice. Moreover, gavage with B. coccoides improves insulin sensitivity and reduces body fat in high‐fat diet (HFD) mice, and singly colonization of B. coccoides increases insulin sensitivity in gnotobiotic mice. The effects of B. coccoides are mediated by metabolizing tryptophan into indole‐3‐acetic acid (I3AA) that activates the aryl hydrocarbon receptor (AhR) in the liver. Finally, this work reveals that reduced fecal B. coccoides and I3AA levels are associated with the clinical metabolic syndrome. These findings suggest that B. coccoides is a newly identified bacterium increased by leucine deprivation, which improves metabolic disorders via metabolizing tryptophan into I3AA.

Impossible differential cryptanalysis is very important in the field of symmetric ciphers. Currently, there are many automatic search approaches to find impossible differentials. However, these methods have two underlying assumptions: Markov cipher assumption and key independence assumption. Actually, these two assumptions are not true in ARX ciphers, especially lightweight ones. In this paper, we study the impossible differentials in ARX cipher under weak keys for the first time. Firstly, we propose several accurate difference propagation properties on consecutive two and three modular additions. Then, these properties are applied to four typical local constructions composed of two consecutive modular additions, two modular additions with a rotation operation, xoring secret key or constant in the middle, to find impossible differentials under weak keys or special constants. What’s more, we propose a more accurate difference propagation property on three consecutive modular additions. It can be used to find impossible differentials on more complex local constructions under weak keys or special constants. In practical ciphers, these impossible differentials on local constructions can be used to find contradictions. Lastly, combining our new findings with traditional automatic search methods for impossible differentials, we propose a framework to find impossible differentials in ARX ciphers under weak keys. As applications, we apply the framework to SPECK-32/64, LEA and CHAM-64/128. As a result, we find two 8-round impossible differentials for SPECK-32/64 under 260 weak keys, and one 11-round impossible differential for LEA under 2k−1 weak keys, where k is the key size. These impossible differentials can start from any round. Furthermore, we find two 22-round impossible differentials for CHAM-64/128 under 2127 weak keys starting from certain rounds. As far as we know, all these impossible differentials are longer than previous ones.

Objective To explore the mechanism of FGFR3⁃TACC3 (F3⁃T3) fusion gene mediating DNA damage repair through promoting pyruvate kinase M2 (PKM2)'s nuclear translocation in glioblastoma. Methods The lentiviral transfection technology was used to constructed stable transitional cell lines U87MG cells and U251MG cells that stably expressing F3 ⁃ T3 and empty vector. In vivo glioblastoma model was constructed by intracranial in situ tumor implantation in athymic mice, and the tumorigenic ability of F3⁃T3 transfected cells in athymic mice of each treatment group was observed by small⁃animal in vivo imaging system. Bioinformatics analysis was performed to analyze gene microarray data exploring the possible biological functions of F3 ⁃ T3 mediating chemoresistance and identify the relationship between survival expectations and PKM2 expression levels in glioblastoma patients from The Cancer Genome Atlas (TCGA) database. Transient transfection of small interference RNA (siRNA) was used to knock down the expression of PKM2 in the F3 ⁃ T3 transfected cells. Proliferative activity of U87MG and U251MG cells treated with different concentrations of temozolomide (TMZ), transfected with siRNA, and TMZ in combination with Compound 3k, a PKM2 inhibitor, was observed in CCK ⁃ 8 cell proliferation assays. Nuclear and cytoplasmic proteins were extracted separately and PKM2 protein expression was observed in whole cell extract, cytoplasmic extract and cytosolic extract after TMZ treatment. Relative expression of PKM2, relative expression of cytosolic phosphorylated histone H2AX (p⁃H2AX) and relative expression of siRNA knockdown PKM2 gene in U87MG and U251MG cells stably expressing the F3 ⁃ T3 fusion gene, detected by Western blotting. Results 1) CCK⁃8 cell proliferation assay showed that the survival rate of U87MG cells in the F3 ⁃ T3 transfected group was higher than that in the empty vector transfected group after treatment with TMZ 640, 320, 160, 80, 40 μmol/L (P = 0.000, 0.000, 0.000, 0.000, 0.004, 0.010), and the survival rate of U251MG cells in the F3 ⁃ T3 transfected group was also higher than that in the empty vector transfected group after TMZ 640, 320, 160, 80, 40, 20, 5 μmol/L (P = 0.000, 0.000, 0.000, 0.002, 0.001, 0.002); the survial rate of U87MG cells in the si⁃PKM2⁃1009 transfected group was lower than that of F3 ⁃ T3 transfected group after TMZ 640, 320, 160, 80, 40, 20, 10, 5, 2.50 μmol/L, the survival rate of U251MG cells in the si⁃PKM2⁃1377 transfected group was also lower than that in F3⁃T3 transfected group after TMZ 640, 320, 160, 80, 40, 20, 5 μmol/L (P = 0.000, 0.000, 0.002, 0.000, 0.002, 0.048, 0.042); and the survival rate of U87MG cells in TMZ + Compound 3k group was lower than TMZ group after TMZ 640, 320, 160, 80, 40, 20 μmol/L (P = 0.000, 0.000, 0.000, 0.000, 0.001, 0.002), and the survival rate of U251MG cells in TMZ + Compound 3k group after treatment with high concentrations of TMZ (640, 320, 160, 80 and 40 μmol/L) was also lower than TMZ group (P = 0.000, 0.000, 0.000, 0.000, 0.003), while the survival rate of U251MG cells in TMZ + Compound 3k group after treatment with low concentrations of TMZ (10, 5 and 2.50 μmol/L) was higher than that of TMZ group (P = 0.000, 0.000, 0.006). 2) An animal model of glioblastoma showed the presence of TMZ resistance in homozygous mice. 3) Bioinformatic analysis showed that the biological function of F3⁃T3 was significantly enriched in the DNA repair pathway (P = 0.000). Survival and overall survival of glioblastoma patients in the TCGA database were lower in the PKM2 high expression group than in the low expression group (P < 0.05). 4) Western blotting showed that the relative expression of p⁃H2AX in U87MG (P = 0.000, 0.000, 0.004) and U251MG (P = 0.000, 0.007, 0.005) cells in the F3 ⁃ T3 transfected group were lower than those in the empty vector transfected group after TMZ treatment for 48 h and then medium change for 24, 36 and 48 h. PKM2 protein incorporation into the nucleus was observed in both U87MG and U251MG cells in the F3⁃T3 transfected group after TMZ treatment, whereas it was not observed in cells in the empty vector transfected group; si⁃PKM2⁃1009 and si⁃ PKM2⁃1377 knocked down the relative expression of p⁃H2AX in U87MG (P = 0.000, 0.001, 0.006) and U251MG (P = 0.000, 0.000, 0.000) cells, respectively. Conclusions In the presence of TMZ, F3 ⁃ T3 promotes PKM2's nuclear translocation and activates DNA damage repair pathways, which in the eventually results resistance of glioblastoma cell to TMZ. PKM2 inhibitors can compromise the resistance glioblastoma cells stably expressing F3⁃T3 fusion gene to TMZ.

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet–induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1–WIPI2 axis may be a novel therapeutic strategy for NASH.

Abstract Background The association between serum β2-microglobulin (β2M) levels and the risk of all-cause and cardiovascular disease (CVD) mortality and the incidence of cardiovascular events (CVEs) in patients undergoing maintenance hemodialysis (MHD) is inconclusive. Furthermore, no study has been performed in China on the significance of serum β2M levels in MHD patients. Therefore, this study investigated the aforementioned association in MHD patients. Methods In this prospective cohort study, 521 MHD patients were followed at Dalian Municipal Central Hospital affiliated with Dalian University of Technology from December 2019 to December 2021. The serum β2M levels were categorized into three tertiles, and the lowest tertile served as the reference group. Survival curves were calculated by the Kaplan–Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Sensitivity analysis was performed by excluding patients with CVD at baseline. Results During the follow-up period of 21.4 ± 6.3 months, there were 106 all-cause deaths, of which 68 were caused by CVD. When excluding CVD patients at baseline, there were 66 incident CVEs. Kaplan–Meier analysis revealed that the risk of all-cause and CVD mortality in the highest tertile of serum β2M levels was significantly higher than that in the lowest tertile (P 0.05). After adjusting for potential confounders, serum β2M levels were positively associated with the risk of all-cause (HR = 2.24, 95% CI = 1.21–4.17) and CVD (HR = 2.54, 95% CI = 1.19–5.43) mortality, and a linear trend was evident (P 0.05). Conclusion The serum β2M level may be a significant predictor of the risk of all-cause and CVD mortality in MHD patients. Further studies are needed to confirm this finding.

Summary: Background: Liver disease is linked to series of extrahepatic multisystem manifestations. However, little is known about the associations between liver and eye diseases, especially cataract, the global leading cause of blindness. We aimed to investigate whether severe liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, and liver fibrosis and cirrhosis, were associated with an increased risk of the cataract. Methods: A total of 326,558 participants without cataract at baseline enrolled in the UK Biobank between 2006 and 2010 were included in this prospective study. The exposures of interest were severe liver diseases (defined as hospital admission), including NAFLD, ALD, viral hepatitis and liver fibrosis and cirrhosis. The outcome was incident cataract. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Each liver disease was first treated as a binary time-varying variable to investigate its association with cataract, and then was treated as a ternary time-varying variable to examine the recent (liver disease within 0–5 years) vs. long-term (liver disease > 5 years) state associations with the risk of cataract. Findings: After a median follow-up of 13.3 years (interquartile range, 12.5–14.0 years), 37,064 individuals were documented as developing cataract. Higher risk of cataract was found in those with severe NAFLD (HR, 1.47; 95% CI, 1.33–1.61), ALD (HR, 1.57; 95% CI, 1.28–1.94) and liver fibrosis and cirrhosis (HR, 1.58; 95% CI, 1.35–1.85), but not in individuals with viral hepatitis when exposure was treated as a binary time-varying variable (P = 0.13). When treating exposure as a ternary time-varying variable, an association between recently diagnosed viral hepatitis and cataract was also observed (HR, 1.55; 95% CI, 1.07–2.23). Results from the combined model suggested they were independent risk factors for incident cataract. No substantial changes were found in further sensitivity analyses. Interpretation: Severe liver diseases, including NAFLD, ALD, liver fibrosis and cirrhosis and recently diagnosed viral hepatitis, were associated with cataract. The revelation of liver-eye connection suggests the importance of ophthalmic care in the management of liver disease, and the intervention precedence of patients with liver disease in the early screening and diagnosis of cataract. Funding: National Natural Science Foundation of China, Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission, Clinical Research Plan of Shanghai Shenkang Hospital Development Center, Shanghai Municipal Key Clinical Specialty Program, the Guangdong Basic and Applied Basic Research Foundation and Shenzhen Science and Technology Program.

Helicobacter pylori (H. pylori) infection is thought to impact various extragastric diseases, including nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease. Meanwhile, the pathogenesis of NAFLD needs further research, and effective treatment for this disease remains elusive. In this mini-review, we enumerate and ponder on the evidence demonstrating an association between H. pylori infection and NAFLD. Primarily, we delve into high-quality meta-analyses and clinical randomized controlled trials focusing on the association studies between the two. We also discuss clinical studies that present opposite conclusions. In addition, we propose a mechanism through which H. pylori infection aggravates NAFLD: inflammatory cytokines and adipocytokines, insulin resistance, lipid metabolism, intestinal barrier and microbiota, H. pylori outer membrane vesicles and H. pylori-infected cell-extracellular vesicles. This mini-review aims to further explore NAFLD pathogenesis and extragastric disease mechanisms caused by H. pylori infection.

Food-borne antibiotic-resistant Campylobacter poses a serious threat to public health. To understand the prevalence and genetic characteristics of Campylobacter in Chinese local dual-purpose (meat and eggs) chickens, the genomes of 30 Campylobacter isolates, including 13 C. jejuni and 17 C. coli from Jianghan-chickens in central China, were sequenced and tested for antibiotic susceptibility. The results showed that CC-354 and CC-828 were the dominant clonal complexes of C. jejuni and C. coli, respectively, and a phylogenetic analysis showed that three unclassified multilocus sequence types of C. coli were more closely genetically related to C. jejuni than to other C. coli in this study. Of the six antibiotics tested, the highest resistance rates were to ciprofloxacin and tetracycline (100%), followed by lincomycin (63.3%), erythromycin (30.0%), amikacin (26.7%), and cefotaxime (20.0%). The antibiotic resistance rate of C. coli was higher than that of C. jejuni. The GyrA T86I mutation and 15 acquired resistance genes were detected with whole-genome sequencing (WGS). Among those, the GyrA T86I mutation and tet(O) were most prevalent (both 96.7%), followed by the blaOXA-type gene (90.0%), ant(6)-Ia (26.7%), aac(6’)-aph(3’’) (23.3%), erm(B) (13.3%), and other genes (3.3%). The ciprofloxacin and tetracycline resistance phenotypes correlated strongly with the GyrA T86I mutation and tet(O)/tet(L), respectively, but for other antibiotics, the correlation between genes and resistance phenotypes were weak, indicating that there may be resistance mechanisms other than the resistance genes detected in this study. Virulence gene analysis showed that several genes related to adhesion, colonization, and invasion (including cadF, porA, ciaB, and jlpA) and cytolethal distending toxin (cdtABC) were only present in C. jejuni. Overall, this study extends our knowledge of the epidemiology and antibiotic resistance of Campylobacter in local Chinese dual-purpose chickens.

Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 μmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 (BRG1). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1–TERT axis. MLT might be used as a complimentary agent for alcoholics.

Objective Histological morphology, immunophenotype and molecular diagnosis of gliomas were reported and classified according to fifth edition of the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5). Methods Total 60 glioma patients with a clear diagnosis through genetic testing were collected in General Hospital of Southern Theatre Command of Chinese PLA from July 2019 to July 2021. All of them were diagnosed based on histopathology and molecular alterations by HE staining, immunohistochemical staining, and genetic screening and were classified according to the WHO CNS5. Results A total of 60 gliomas, according to WHO CNS5, were classified into one with pilocytic astrocytoma (1.67%), one with ganglioglioma (1.67%), 15 with astrocytomas, IDH⁃mutant (25%), 11 with oligodendrogliomas, IDH⁃mutant and 1p/19q co⁃deleted (18.33%), one with pleomorphic xanthoastrocytoma (1.67%), 21 with glioblastomas, IDH⁃wildtype (35%), 3 with diffuse midline glioma, H3 K27⁃altered (5%) and 7 with glioma, NEC (11.67%). The 7 patients with glioma, NEC were respectively diagnosed based on histopathology as anaplastic astrocytoma in one case, oligodendrogliomas in 2 cases, diffuse astrocytomas in 2 cases, ganglioglioma in one case, and anaplastic oligodendroglioma in one case, with only one case with methylguanine⁃DNA methyltransferase (MGMT) promoter methylation and one case with BRAF V600E mutation by genetic screening. The 21 patients with glioblastoma, IDH⁃wildtype were respectively diagnosed based on histopathology as glioblastoma in 15 cases, oligodendroglioma in one case, anaplastic oligodendroglioma in 2 cases, diffuse astrocytoma in 2 cases and anaplastic astrocytoma in one case, while TERT promoter mutation in 15 cases (71.43%), EGFR amplification in 7 cases (33.33%), MGMT promoter methylation in 5 patients (23.81%) and amplification of chromosome 7 in one case (4.76%). The 15 patients with astrocytoma, IDH⁃mutant, CNS WHO grade 2-4 were diagnosed based on histopathology as glioblastoma in 3 cases, oligodendroglioma in 2 cases, anaplastic oligodendroglioma in one case, diffuse astrocytoma in 8 cases and anaplastic astrocytoma in one case, with MGMT promoter methylation in 11 cases, homozygous deletion of cyclin⁃dependent kinase inhibitor 2A/B (CDKN2A/B) in 2 cases. Conclusions This article is the first pathological diagnosis report of single⁃center glioma since the publication of WHO CNS5, suggesting the WHO CNS5 could more accurately classify gliomas. However, the proportion of glioma, NEC diagnosed is still relatively high. Even well⁃classified gliomas have many differences in genetic signature. The molecular features of gliomas still require further deeply exploration.

Objective To evaluate the improvement of superficial temporal artery⁃middle cerebral artery (STA⁃MCA) bypass combined with encephalo⁃myo⁃synangiosis (EMS) on cognitive function in patients with moyamoya disease (MMD). Methods Total 37 patients with MMD treated with STA⁃MCA+EMS in Tianjin Medical University General Hospital from July 2017 to June 2020 were reviewed. Mini⁃Mental State Examination (MMSE), Auditory Verbal Learning Test (AVLT), Trail Making Test⁃A (TMT⁃A), Trail Making Test⁃B (TMT⁃B), Verbal Fluency Test (VFT) and Rey⁃Osterrieth Complex Figure Test (ROCFT) were used to evaluate overall cognitive function, memory, attention, executive function, language function and visuospatial function in all patients one week before surgery and 6 months after surgery. Results Compared with one week before surgery, the MMSE score [24 (23, 26) score vs. 25.00 (23.50, 27.00) score; Z=⁃4.201, P=0.000] and ROCFT score [28 (23, 30) score vs. 31.00 (28.50, 32.00) score; Z=⁃3.968, P=0.004] increased, while the TMT⁃A test [69.00 (56.00, 87.50) s vs. 42 (37, 48) s; Z=⁃5.144, P=0.002] and TMT⁃B test [177 (168, 190) s vs. 138 (133, 144) s; Z=⁃5.309, P=0.001] decreased at 6 months after surgery. There was no statistic difference of AVLT⁃1R (Z=⁃1.595, P=0.113), AVLT⁃5R (Z=⁃1.573, P=0.121) and VFT (Z=⁃1.616, P=0.124) before and after surgery. Conclusions STA⁃MCA+EMS can improve the overall cognitive function, attention, executive function and visuospatial ability of patients with MMD, but has no significant effect on short⁃term memory, long⁃term memory and language function, and can improve cognitive function and the quality of life.

Abstract Dialysis adequacy is a known risk factor for mortality in maintenance hemodialysis (MHD) patients. However, the optimal dialysis dose remains controversial. Therefore, we aimed to explore the relationship between dialysis dose and all-cause and cardiovascular disease (CVD) mortality among MHD. We examined the associations of dialysis dose with mortality in a cohort (n = 558) of MHD patients from 31 December 2015 to 31 December 2020. Dialysis adequacy was assessed using baseline Single-pool Kt/Vurea (spKt/V), which was categorized into three groups, and the lowest dose group was used as the reference category. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 214 patients died (64.5% for CVD). Compared with the low-dose group, high-dose group could reduce the risk of all-cause mortality by 33% (HR = 0.67, 95% CI: 0.47–0.98). Of note, when stratification by age, high-dose group was associated with both lower all-cause (HR = 0.46, 95% CI: 0.26–0.81) and CVD mortality (HR = 0.42, 95% CI: 0.20–0.88) among patients with age below 65 years. When stratification by dialysis age, high-dose group was associated with decreased risk of CVD mortality (HR = 0.43, 95% CI: 0.20–0.91) among patients with dialysis age over 60 months. spKt/V is a simple index of hemodialysis dose used in clinical practice and a useful modifiable factor in predicting the risk of death, especially in MHD patients under 65 years old or dialysis age more than 60 months.

ObjectiveTo explore the mRNA differential expressions and the sequential change pattern in acute myocardial infarction （AMI） mice.MethodsThe AMI mice relevant dataset GSE4648 was downloaded from Gene Expression Omnibus （GEO）. In the dataset， 6 left ventricular myocardial tissue samples were selected at 0.25， 1， 4， 12， 24 and 48 h after operation in AMI group and sham control group， and 6 left ventricular myocardial tissue samples were selected in blank control group， a total of 78 samples were analyzed. Differentially expressed genes （DEGs） were analyzed by R/Bioconductor package limma， functional pathway enrichment analysis was performed by clusterProfiler， protein-protein interaction （PPI） network was constructed by STRING database and Cytoscape software， the key genes were identified by Degree topological algorithm， cluster sequential changes on DEGs were analyzed by Mfuzz.ResultsA total of 1 320 DEGs were associated with the development of AMI. Functional enrichment results included cellular catabolic process， regulation of inflammatory response， development of muscle system and vasculature system， cell adhesion and signaling pathways mainly enriched in mitogen-activated protein kinase （MAPK） signaling pathway. The key genes of AMI included MYL7， TSC22D2， HSPA1A， BTG2， NR4A1， RYR2 were up-regulated or down-regulated at 0.25-48 h after the occurrence of AMI.ConclusionThe functional signaling pathway of DEGs and the sequential expression of key genes in AMI may provide a reference for the forensic identification of AMI.

Abstract Background The association between serum total indoxyl sulfate (tIS), and cardiovascular disease (CVD) and all-cause mortality is a matter of debate. In the current study we sought to determine the association, if any, between serum tIS, and all-cause and CVD-associated mortality in patients on maintenance hemodialysis (MHD). Methods A prospective cohort study was conducted involving 500 MHD patients at Dalian Municipal Central Hospital from 31 December 2014 to 31 December 2020. Serum tIS levels were measured at baseline and classified as high (≥44.16 ng/ml) or low (

Abstract Background Higher serum galectin-3 levels are related to adverse outcomes in different disease states. However, the association of galectin-3 with mortality in the maintenance hemodialysis (HD) population has not been fully described. Thus, we aimed to assess the predictive significance of galectin-3 for all-cause and cardiovascular (CV) mortality through a Chinese maintenance HD population. Methods A prospective cohort study was conducted in five hundred and six patients with end-stage renal disease who underwent hemodialysis at Dalian Central Hospital before December 31, 2014. Serum galectin-3 levels were measured at baseline and classified as high (> 8.65 ng/ml) or low (≤ 8.65 ng/ml) according to the “X-tile” program. Primary and secondary outcomes were all-cause and CV mortality, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by the Cox proportional hazards regression models. Results During the median follow-up of 60 months, there were 188 all-cause deaths and 125 CV deaths. Compared with maintenance HD population with galectin-3 ≤ 8.65 ng/ml, the adjusted HR for all-cause mortality among those with galectin-3 > 8.65 ng/ml was 1.59 (CI: 0.96–2.65, p = 0.07). Furthermore, multivariable analysis showed that maintenance HD patients with galectin-3 > 8.65 ng/ml had a 2.13-fold higher risk of CV death than those with galectin-3 ≤ 8.65 ng/ml (HR = 2.13, 95% CI 1.07–4.26). Conclusion Galectin-3 is an independent predictor of CV mortality in maintenance HD patients.

BackgroundPostoperative nausea and vomiting (PONV) are common after laparoscopic sleeve gastrectomy (LSG), affecting patient satisfaction and postoperative recovery. The purpose of this study was to investigate the incidence and severity of PONV after LSG and the relationship between Helicobacter pylori (HP) and PONV.MethodsPatients undergoing LSG in our center from June 1, 2018, to May 31, 2022, were divided into HP-positive and HP-negative groups for retrospective analysis. The independent risk factors of PONV were determined by univariate and binary logistic regression analysis using a 1:1 propensity score matching (PSM) method.ResultsA total of 656 patients was enrolled, and 193 pairs of HP-positive and negative groups were matched after PSM. Both groups of patients had similar clinical features and surgical procedures. PONV occurred in 232 patients (60.1%) after LSG, and the incidence of PONV in HP-positive patients was 61.10%. The incidence and severity of PONV were statistically similar in both groups (P=0.815). Multivariate analysis showed that the female sex (OR=1.644, P=0.042), postoperative pain (OR=2.203, P=0.001) and use of postoperative opioid (OR=2.229, P=0.000) were independent risk factors for PONV after LSG, whereas T2DM (OR=0.510, P=0.009) and OSAS (OR=0.545, P=0.008) independently reduced the incidence rate of PONV. There was no difference either in smoking (P=0.255) or alcohol drinking (P=0.801). HP infection did not affect PONV (P=0.678).ConclusionsThe incidence of PONV following LSG was relatively high. Female sex, postoperative pain and use of postoperative opioid predicted a higher incidence of PONV. Patients with T2DM and OSAS were less likely to have PONV. There was no clear association between HP infection and PONV after LSG.

Diagnosis of central precocious puberty (CPP) in girls remains a huge challenge. The current study was to measure the serum expression of methyl-DNA bind protein 3 (MBD3) in CPP girls and assess its diagnostic efficacy. To begin with, we enrolled 109 CPP girls and 74 healthy pre-puberty girls. Then, MBD3 expression in their serum samples was measured via reverse transcription-quantitative polymerase chain reaction, and its diagnostic efficacy on CPP was assessed via the receiver operating characteristic (ROC) curve, followed by correlation analysis between serum MBD3 and patient age, gender, bone age, weight, height, body mass index, basal luteinizing hormone (LH), peak LH, basal follicle-stimulating hormone (FSH), peak FSH, and ovarian size using bivariate correlations method. Finally, independent predictors of MBD3 expression were confirmed using multivariate linear regression analysis. MBD3 was highly expressed in sera of CPP patients. The area under the ROC curve of MBD3 diagnosing CCP was 0.9309, with 1.475 cut-off value (92.66% sensitivity and 86.49% specificity). MBD3 expression positively correlated with basal LH, peak LH, basal FSH, and ovarian size, among which basal LH was considered the strongest independent predictor of MBD3, followed by basal FSH and peak LH. In summary, serum MBD3 could act as a biomarker in aiding CPP diagnosis.

Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the “sexual dimorphism” is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.

End-stage liver disease is one of the leading causes of death around the world. Since insufficient sources of transplantable liver and possible immune rejection severely hinder the wide application of conventional liver transplantation therapy, artificial three-dimensional (3D) liver culture and assembly from stem cells have become a new hope for patients with end-stage liver diseases, such as cirrhosis and liver cancer. However, the induced differentiation of single-layer or 3D-structured hepatocytes from stem cells cannot physiologically support essential liver functions due to the lack of formation of blood vessels, immune regulation, storage of vitamins, and other vital hepatic activities. Thus, there is emerging evidence showing that 3D organogenesis of artificial vascularized liver tissue from combined hepatic cell types derived from differentiated stem cells is practical for the treatment of end-stage liver diseases. The optimization of novel biomaterials, such as decellularized matrices and natural macromolecules, also strongly supports the organogenesis of 3D tissue with the desired complex structure. This review summarizes new research updates on novel differentiation protocols of stem cell-derived major hepatic cell types and the application of new supportive biomaterials. Future biological and clinical challenges of this concept are also discussed.

Background & Aims: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. Methods: ALD-associated liver injury were induced in TLR2 knockout (TLR2–/–), TLR3–/–, TLR2–/– bone marrow transplanted (BMT), TLR3–/– BMT, IL-10–/– mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD. Results: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG’s actions. Conclusions: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production. Keywords: Alcoholic Liver Disease, Kupffer Cell, Toll-like Receptor, EGCG

Abstract Mobile crowd sensing (MCS) is a novel emerging paradigm that leverages sensor-equipped smart mobile terminals (e.g., smartphones, tablets, and intelligent wearable devices) to collect information. Compared with traditional data collection methods, such as construct wireless sensor network infrastructures, MCS has advantages of lower data collection costs, easier system maintenance, and better scalability. However, the limited capabilities make a mobile crowd terminal only support limited data types, which may result in a failure of supporting high-dimension data collection tasks. This paper proposed a task allocation algorithm to solve the problem of high-dimensional data collection in mobile crowd sensing network. The low-cost and balance-participating algorithm (LCBPA) aims to reduce the data collection cost and improve the equality of node participation by trading-off between them. The LCBPA performs in two stages: in the first stage, it divides the high-dimensional data into fine-grained and smaller dimensional data, that is, dividing an m-dimension data collection task into k sub-task by K-means, where (k

Supercapacitors, also called electrochemical capacitors or ultracapacitors, have attracted increasing attention owing to their high specific capacitance, high power density, long lifecycle, fast charge-discharge ability, wide working temperature range, and environmental friendliness for mobile electronics, power grids, and hybrid electric vehicles. The electrode is the most important part of supercapacitors; therefore, the electrode material is the chief factor that determines the properties of supercapacitors. To enhance the performance of a supercapacitor, particularly its specific energy while retaining its intrinsic high specific power, several researchers have focused mainly on improving the properties of electrode materials. The major classes of materials applied for supercapacitors include various forms of carbon, transition metal oxides, and conductive polymers. Compared to the carbon materials and conducting polymer materials, transition metal oxides can achieve a much higher specific capacitance because of their high theoretical capacitance, well-defined electrochemical redox activity, low cost, and abundant resources. In particular, binary metal oxides, such as NiMoO4, MnMoO4, and CoMoO4, have been extensively studied as pseudocapacitor electrode materials because of their good electronic conductivity and rich redox reactions. In this study, pinecone-like NiMoO4/MnO2 composite materials were successfully synthesized using a facile hydrothermal method. Na2MoO4·2H2O, NiSO4·6H2O, and MnO2 were used as raw materials. The as-products were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), galvanostatic charge-discharge, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). The results show that when the optimal content of MnO2 reaches 10%, the obtained NiMoO4/MnO2 composite materials exhibits a pinecone-like porous morphology, with the particle size ranging from 200 to 600 nm. The results show that NiMoO4/MnO2 composite materials have excellent electrochemical properties. The discharge specific capacitance of NM0, NM5, NM10, NM15, and NM20 composites with corresponding MnO2 contents of 0%, 5%, 10%, 15%, and 20% are 260, 248, 650, 420, and 305 F·g-1, respectively, at a current density of 1 A·g-1. When the current density is up to 10 A·g-1, the initial discharge specific capacitance is 102 F·g-1. After 100-week cycles, the discharge specific capacitance of the NM10 sample is still 147 F·g-1. The improvements can be mainly attributed to the introduction of MnO2 in the NiMoO4/MnO2 composite materials to overcome the shortcomings of single NiMoO4.

Post traumatic epilepsy （PTE） is a serious complication of traumatic brain injury and a difficult problem in forensic justice practice. In recent years, many biomarkers have been applied to the diagnosis, treatment and prognosis of injuries and diseases. There have been many studies on the biomarkers of PTE in the field of epilepsy. This paper reviews the progress in research on biomarkers of PTE in recent years in order to provide reference for the forensic identification of PTE.

Background: Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Despite an increasing appreciation that such white matter disconnectivity is linked to social behavior deficits, virtually no etiologically meaningful myelin-related genes have been identified in oligodendrocytes, the key myelinating cells in the CNS, to furnish an account on the causes. The impact of neurodevelopmental perturbations during pregnancy such as maternal immune activation (MIA) on these genes in memory-related neural networks has not been experimentally scrutinized.Methods: In this study, a mouse model of MIA by the viral dsRNA analog poly(I:C) was employed to mimic the effects of inflammation during pregnancy. Transcriptional expression levels of selected myelin- or oligodendroglia-related genes implicated in schizophrenia or ASD development were analyzed by in situ hybridization (ISH) and quantitative real-time PCR (qRT-PCR) with brain samples from MIA and control groups. The analysis focused on SOX-10 (SRY-related HMG-box 10), MAG (myelin-associated glycoprotein), and Tf (transferrin) expression in the hippocampus and the surrounding memory-related cortical regions in either hemisphere.Results: Specifically, ISH reveals that in the brain of prenatal poly(I:C)-exposed mouse offspring in the MIA model (gestation day 9), mRNA expression of the genes SOX10, MAG and Tf were generally reduced in the limbic system including the hippocampus, retrosplenial cortex and parahippocampal gyrus on either side of the hemispheres. qRT-PCR further confirms the reduction of SOX10, MAG, and Tf expression in the medial prefrontal cortex, sensory cortex, amygdala, and hippocampus.Conclusions: Our present results provide direct evidence that prenatal exposure to poly(I:C) elicits profound and long-term changes in transcript level and spatial distribution of myelin-related genes in multiple neocortical and limbic regions, notably the hippocampus and its surrounding memory-related neural networks. Our work demonstrates the potential utility of oligodendroglia-related genes as biomarkers for modeling neurodevelopmental disorders, in agreement with the hypothesis that MIA during pregnancy could lead to compromised white matter connectivity in ASD.

Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator 200 (PA200) associates with 20S core particle to form proteasome complex that catalyzes polyubiquitin-independent degradation of acetylated histones, thus playing a pivotal role in DNA repair and spermatogenesis. Here, we present cryo-electron microscopy (cryo-EM) structures of the human PA200-20S complex and PA200 at 2.72 Å and 3.75 Å, respectively. PA200 exhibits a dome-like architecture that caps 20S and uses its C-terminal YYA (Tyr-Tyr-Ala) to induce the α-ring rearrangements and partial opening of the 20S gate. Our structural data also indicate that PA200 has two openings formed by numerous positively charged residues that respectively bind (5,6)-bisdiphosphoinositol tetrakisphosphate (5,6[PP]2-InsP4) and inositol hexakisphosphate (InsP6) and are likely to be the gates that lead unfolded proteins through PA200 and into the 20S. Besides, our structural analysis of PA200 found that the bromodomain (BRD)-like (BRDL) domain of PA200 shows considerable sequence variation in comparison to other human BRDs, as it contains only 82 residues because of a short ZA loop, and cannot be classified into any of the eight typical human BRD families. Taken together, the results obtained from this study provide important insights into human PA200-induced 20S gate opening for substrate degradation and the opportunities to explore the mechanism for its recognition of H4 histone in acetylation-mediated proteasomal degradation.

Whether and how garlic-derived S-allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of β-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface. KEY WORDS: S-allylmercaptocysteine, HCC, Wnt, LRP6, Human, Nude mice

Abstract Background One of the major obstacles facing stem cell therapy is the limited number of functional stem cells available after transplantation due to the harsh microenvironment surrounding the damaged tissue. The aim of this study was to delineate the mechanistic involvement of lysophosphatidic acid receptors (LPARs) and sphingosine-1-phosphate receptors (S1PRs) in the regulation of anti-stress and transplantation efficacy of stem cells. Methods Human adipose-derived mesenchymal stem cells (hADMSCs) were treated with chemical toxin or ethanol to induce cell stress. Lysophosphatidic acid (LPA) and/or sphingosine-1-phosphate (S1P) were co-treated to examine their protective effects and mechanisms on stem cell damage. Acute liver failure and alcoholic liver disease murine models were also established to test the transplantation efficacy of hADMSCs with or without LPA/S1P pre-incubation. Results Co-stimulation of LPAR1 by LPA and S1PR1/3 by S1P synergistically enhanced the anti-stress ability of hADMSCs induced by chemical or ethanol incubation in vitro. Downstream pathways involved in this process included the Gi protein (but not the G12/13 proteins), the RAS/ERK pathway, and the PI3K/Akt pathway. Upon cell injury, the nuclear translocation of nuclear factor-kappa B (NF-κB) was promoted to facilitate the activation of downstream pro-inflammatory gene transcription, which was ameliorated by co-treatment with LPA and/or S1P. Increased secretion of interleukin (IL)-10 from stem cells by LPA and/or S1P seemed to be one of the major protective mechanisms since blocking IL-10 expression significantly aggravated stress-induced cell damage. In a drug-induced acute liver failure model and a chronic alcoholic liver disease model, pre-conditioning with LPA and/or S1P significantly enhanced the survival ratio and the therapeutic efficacy of hADMSCs in mice, including ameliorating histological damage, oxidative stress, inflammation, fibrosis, lipid metabolism dysfunction, and enhancing alcohol metabolizing enzyme activity. Importantly, supplementing LPA and/or S1P did not alter the basic characteristics of the hADMSCs nor induce tumour formation after cell transplantation. Conclusions Co-use of LPA and S1P represents a novel and safe strategy to enhance stem cell transplantation efficacy for future drug- and alcoholic-related liver disease therapies.

Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while over-expression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3β in HCC. Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.

Long non-coding mRNAs play important roles in muscle development and regeneration. Here the authors identify a long non-coding mRNA that promotes myogenesis by sequestering miR-125b, leading to increased expression of insulin-like growth factor 2.

Four new dicaffeoylspermidine derivatives, lycibarbarspermidines P–S (1–4), were isolated from the fruit of Lycium barbarum (wolfberry). The structures were determined by extensive spectroscopic (HRESIMS, 1D NMR, and 2D NMR) analyses and chemical methods. Dicaffeoylspermidine derivatives are a kind of major bioactive and characteristic constituents in wolfberry, and the discovery of 1–4 added new members of this family.

The severe shortage of donor liver organs requires the development of alternative methods to provide transplantable liver tissues such as stem cell-derived organoids. Despite several studies describing the generation of vascularized and functional liver tissues, none have succeeded in assembling human liver buds containing hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). Here, we report a reproducible, easy-to-follow, and comprehensive self-assembly protocol to generate three-dimensional (3D) human liver buds from naïve mesenchymal stem cells (MSCs), MSC-derived hepatocytes, and HSC- and LSEC-like cells. By optimizing the ratio between these different cell lineages, the cell mixture self-assembled into 3D human liver buds within 72 h in vitro , and exhibited similar characteristics with early-stage murine liver buds. In a murine model of acute liver failure, the mesenteric transplantation of self-assembled human liver buds effectively rescued animal death, and triggered hepatic ameliorative effects that were better than the ones observed after splenic transplantation of human hepatocytes or naïve MSCs. In addition, transplanted human liver buds underwent maturation during injury alleviation, after which they exhibited a gene expression profile signature similar to the one of adult human livers. Collectively, our protocol provides a promising new approach for the in vitro construction of functional 3D human liver buds from multiple human MSC-derived hepatic cell lineages; this new technique would be useful for clinical transplantation and regenerative medicine research.

Aiming at the problems such as low CBM utilization rate caused by low concentration CBM with methane content less than 8% extracted from a small coal mine in Hancheng mining area, Shaanxi Province, and serious environmental pollution caused by coal-fired hot blast stove for heating, the heat storage and oxidation heating technology of ultra-low concentration gas in small coal mine was studied by combining field investigation and heat balance calculation. This technology replaces the coal-fired hot blast stove, realizes “coal and CBM mining and sharing” in the coal mine, and constructs a virtuous cycle development of “promoting drainage by using and promoting safety by drainage”. The research shows that: the scheme improves the utilization rate of CBM in the mining area, cancels the consumption of coal combustion, and can use 2.59 million Nm3 of pure CBM every year, generating 1.95 million yuan of economic benefits. And the emissions reduction of CO2 equivalent is 36000 tons. The benefits of safety, economy and environmental protection are remarkable. This technology is especially suitable for the utilization of ultra-low concentration CBM whose concentration is less than 8%, which has practical significance to improve the CBM utilization rate and promote the realization of the goal of “zero emission”.

In coal mining industry, equipment safety and reliability during operation are essential in the production process. In recent years, along with the continuous improvement of intelligent coal mining equipment, reliable production requirements have simultaneously increased. Therefore, this article aims to study the maintenance decision making method that considers the safety inspection of a fully mechanized mining equipment group. The goal is to establish a maintenance decision making model that considers the safety overhaul of fully mechanized mining equipment group in order to minimize the total maintenance, production costs and safety risks. Firstly, the regular safety inspection procedure and the maintenance process were introduced. Then, a model guideline method that considers a fully mechanized mining equipment group's safety inspection was established. Finally, through the comparison of algorithms and maintenance strategies, it is proved that the maintenance decision optimization method proposed in this paper is of great significance for improving equipment reliability, improving comprehensive operation rate, reducing maintenance costs, and ensuring coal mine safety production.

This paper proposes a method to evaluate the level of detail (LoD) of geographic features on digital maps and assess their LoD consistency. First, the contour of the geometry of the geographic feature is sketched and the hierarchy of its graphical units is constructed. Using the quartile measurement method of statistical analysis, outliers of graphical units are eliminated and the average value of the graphical units below the bottom quartile is used as the statistical LoD parameter for a given data sample. By comparing the LoDs of homogeneous and heterogeneous features, we analyze the differences between the nominal scale and actual scale to evaluate the LoD consistency of features on a digital map. The validation of this method is demonstrated by experiments conducted on contour lines at a 1:5K scale and artificial building polygon data at scales of 1:2K and 1:5K. The results show that our proposed method can extract the scale of features on maps and evaluate their LoD consistency.