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Loss-of-function mutations in multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes lead to decreased sperm motility and impaired male fertility. As an MMAF gene, the function of fibrous sheath-interacting protein 2 (FSIP2) remains largely unknown. In this work, we identified a homozygous truncating mutation of FSIP2 in an infertile patient. Accordingly, we constructed a knock-in (KI) mouse model with this mutation. In parallel, we established an Fsip2 overexpression (OE) mouse model. Remarkably, KI mice presented with the typical MMAF phenotype, whereas OE mice showed no gross anomaly except for sperm tails with increased length. Single-cell RNA sequencing of the testes uncovered altered expression of genes related to sperm flagellum, acrosomal vesicle and spermatid development. We confirmed the expression of Fsip2 at the acrosome and the physical interaction of this gene with Acrv1, an acrosomal marker. Proteomic analysis of the testes revealed changes in proteins sited at the fibrous sheath, mitochondrial sheath and acrosomal vesicle. We also pinpointed the crucial motifs of Fsip2 that are evolutionarily conserved in species with internal fertilization. Thus, this work reveals the dosage-dependent roles of Fsip2 in sperm tail and acrosome formation.

Background:Myostatin (MSTN) is related to growth and development. MSTN gene-mutated animals are prone to dystocia and fetus enlargement, but there is no report of pancreatitis. Pancreatitis is a disease of the pancreas caused by the self-digesting effect of trypsin. In animals, pancreatitis often occurs in dogs or cats and manifests as edema, congestion, bleeding, or necrosis of the pancreas. Clinically, symptoms such as abdominal pain, bloating, nausea, vomiting, and fever appear. Elevated levels of amylase in blood and urine. Pancreatitis is very dangerous to the survival of animals. We must pay attention to it.Case presentation: This is a fatal case report of a myostatin (MSTN) gene-mutated calf diagnosed with pancreatitis. Analyses of the blood biochemistry, blood routine, postmortem anatomy and tissue section of the 2-month old calf showed that the pancreatitis indexes α-amylase and serum lipase were higher than those of normal MSTN gene-mutated and wild-type cattle. The pancreas was found to be swollen, dark red and bloody. The structure of the acinar cells of the pancreas was unidentifiable, and massive coagulation necrosis and lysis necrosis filled in the lobules of the pancreas. The interlobular spaces became enlarged, the vessels among the lobules were dilated and congested with obvious edema and blood stasis.Conclusions: Evidence from anatomy, histology, blood physiology, and biochemistry parameters indicate that the myostatin mutated calf died of pancreatitis. There are few reports on the pathology of gene-mutated animals. This is the first case of MSTN gene-mutated bovine pancreatitis.

Radioresistance is a major cause of treatment failure in tumor radiation therapy, and the underlying mechanisms of radioresistance are still elusive. Golgi phosphoprotein 3 (GOLPH3) has been reported to associate tightly with cancer progression and chemoresistance. Herein, we explored whether GOLPH3 mediated radioresistance of lung adenocarcinoma (LUAD) and whether targeted suppression of GOLPH3 sensitized LUAD to radiation therapy.The aberrant expression of GOLPH3 was evaluated by immunohistochemistry in LUAD clinical samples. To evaluate the association between GOLPH3 and radioresistance, colony formation and apoptosis were assessed in control and GOLPH3 knockdown cells. γ-H2AX foci and level determination and micronucleus test were used to analyze DNA damage production and repair. The rescue of GOLPH3 knockdown was then performed by exogenous expression of small interfering RNA-resistant mutant GOLPH3 to confirm the role of GOLPH3 in DNA damage repair. Mechanistically, the effect of GOLPH3 on regulating stability and nuclear accumulation of epidermal growth factor receptor (EGFR) and the activation of DNA-dependent protein kinase (DNA-PK) were investigated by quantitative real-time polymerase chain reaction, western blot, immunofluorescence, and coimmunoprecipitation. The role of GOLPH3 in vivo in radioresistance was determined in a xenograft model.In tumor tissues of 33 patients with LUAD, the expression of GOLPH3 showed significant increases compared with those in matched normal tissues. Knocking down GOLPH3 reduced the clonogenic capacity, impaired double-strand break (DSB) repair, and enhanced apoptosis after irradiation. In contrast, reversal of GOLPH3 depletion rescued the impaired repair of radiation-induced DSBs. Mechanistically, loss of GOLPH3 accelerated the degradation of EGFR in lysosome, causing the reduction in EGFR levels, thereby weakening nuclear accumulation of EGFR and attenuating the activation of DNA-PK. Furthermore, adenovirus-mediated GOLPH3 knockdown could enhance the ionizing radiation response in the LUAD xenograft model.GOLPH3 conferred resistance of LUAD to ionizing radiation via stabilizing EGFR, and targeted suppression of GOLPH3 might be considered as a potential therapeutic strategy for sensitizing LUAD to radiation therapy.

RAPGEF1 is a guanine nucleotide exchange factor responsible for transmitting extracellular signals to the Ras family of GTPase located at the inside of membrane. Here, we report for the first time a homozygous mutation of RAPGEF1 in a consanguineous family with two siblings affected by neuropsychiatric disorder. To confirm the correlation of the mutation and the phenotype, we utilized in silico analysis and established a zebrafish model. Survival rate was reduced in the rapgef1a-knockdown model, and the zebrafish showed global morphological abnormalities, particularly of brain and blood vessels. Co-application of human RAPGEF1 wildtype mRNA effectively rescued the abnormal phenotype, while that of RAPGEF1 mRNA carrying the human mutation did not. This work is the first report of a human Mendelian disease associated with RAPGEF1 and the first report of a zebrafish model built for this gene. The phenotype of zebrafish model provides further evidence that defective RAPGEF1 may lead to global developmental delay in human patients.

Heart failure (HF) is the terminal stage of multiple cardiovascular diseases. However, the pathogenesis of HF remains unclear and prompt; appropriate diagnosis and treatment of HF are crucial. Cardiomyocytes isolated from HF subjects frequently present mitochondrial impairment and dysfunction. Many studies have suggested that the regulation by noncoding RNAs (ncRNAs) of mitochondria can affect the occurrence and progression of HF. The regulation by ncRNAs of myocardial mitochondria during HF and the recent applications of ncRNAs in the diagnosis and treatment of HF are summarized in this review that is intended to gain keen insights into the mechanisms of HF and more effective treatments.

In this paper, we developed a meshless collocation method by using barycentric rational interpolation basis function based on the Chebyshev to deduce the scheme for solving the Helmholtz equation defined in arbitrary domain with complex boundary shapes. Firstly, the spatial variables and their partial derivatives are treated by interpolation basis functions, and the collocation method for solving second order differential equations is established. Then the differential matrix is used to simplify the differential equations on a given test node. Finally, numerical experiments based on three kinds of test nodes show that the proposed method can be used to calculate not only the high wave numbers problems, but also the variable wave numbers problems. Moreover, the algorithm has the advantages of high calculation accuracy, good numerical stability and the less CPU time consuming.

Cerebral palsy (CP), the most prevalent physical disability in children, has long been ignored with regard to its inherent molecular mechanism. In this work, we performed in-depth clinical and molecular analysis on 120 idiopathic CP families, and identified in half of the patients the underlying risk factors. By a compilation of 117 CP-related genes, we recognized the characteristic features in terms of inheritance and function, and proposed a dichotomous classification system according to the expression patterns. In two patients with both CP and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. We developed an algorithm and proved in mice brain that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. In a CP patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of corticospinal tract. We confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocyte, resulting in suppressed astrocyte proliferation and a shortage of lipid contents supplied for oligodendrocyte myelination. This work broadened the scope of understanding of CP etiology and paved a way for innovative therapeutic strategies.

Micheliolide (MCL) has shown promising anti-inflammatory and anti-tumor efficacy. However, whether and how MCL enhances the sensitivity of non-small-cell lung cancer (NSCLC) to radiotherapy are still unknown. In the present paper, we found that MCL exerted a tumor cell killing effect on NSCLC cells in a dose-dependent manner, and MCL strongly sensitized p53-deficient NSCLC cells, but not the cells with wild-type p53 to irradiation (IR). Meanwhile, MCL markedly inhibited the expression of hypoxia-inducible factor-1&alpha, (HIF-1&alpha, ) after IR and hypoxic exposure in H1299 and Calu-1 cells rather than in H460 cells. Consistently, radiation- or hypoxia-induced expression of vascular endothelial growth factor (VEGF) was also significantly inhibited by MCL in H1299 and Calu-1 cells, but not in H460 cells. Therefore, inhibition of the HIF-1&alpha, pathway might, at least in part, contribute to the radiosensitizing effect of MCL. Further study showed that MCL could accelerate the degradation of HIF-1&alpha, through the ubiquitin-proteosome system. In addition, the transfection of wild-type p53 into p53-null cells (H1299) attenuated the effect of MCL on inhibiting HIF-1&alpha, expression. These results suggest MCL effectively sensitizes p53-deficient NSCLC cells to IR in a manner of inhibiting the HIF-1&alpha, pathway via promoting HIF-1&alpha, degradation, and p53 played a negative role in MCL-induced HIF-1&alpha, degradation.

Goats are one of the most widespread farmed animals across the world; however, their migration route to East Asia and local evolutionary history remain poorly understood. Here, we sequenced 27 ancient Chinese goat genomes dating from the Late Neolithic period to the Iron Age. We found close genetic affinities between ancient and modern Chinese goats, demonstrating their genetic continuity. We found that Chinese goats originated from the eastern regions around the Fertile Crescent, and we estimated that the ancestors of Chinese goats diverged from this population in the Chalcolithic period. Modern Chinese goats were divided into a northern and a southern group, coinciding with the most prominent climatic division in China, and two genes related to hair follicle development, FGF5 and EDA2R, were highly divergent between these populations. We identified a likely causal de novo deletion near FGF5 in northern Chinese goats that increased to high frequency over time, whereas EDA2R harbored standing variation dating to the Neolithic. Our findings add to our understanding of the genetic composition and local evolutionary process of Chinese goats.

An anaerobic bacterium Clostridium buturicum QXYZ514 was isolated from a pond soil sample located neighboring to a biodiesel factory. This bacterium possesses excellent metabolic features for converting biodiesel-derived glycerol into various bioproducts, including 1,3-propanediol, butyrate, lactate, and acetate, and fuels, like ethanol and butanol. To further improve the yield of the target products and minimize the production of the by-products, the whole genome sequence of this multipurpose strain might provide necessary genetic information, and hence, the complete genome of QXYZ514 strain was sequenced using the PacBio RS II sequencing method. According to the complete genome sequence, the genome of QXYZ514 consisted of two circular chromosomes with a total of 4,636,461 bp, where GC content was found to be 28.76%. Major predicted features of the genome included a total of 4220 coding sequences (CDS), 87 tRNAs genes, and 36 rRNAs genes, which were annotated with the help of different databases for a better understanding of this strain. Six possible CRISPR components were also predicted in the genome. The exploration of the complete genome sequence of the QXYZ514 strain would have the potential to enrich the diversity of this species, and to recognize some significant hydrolytic enzymes, which could provide the references for overcoming the bottlenecks in the biorefinery usage of this bacterium in the valorization of biodiesel-derived glycerol.

Objective Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-dependent transcription factor, and rifampicin is a human PXR-specific activator. Rifampicin and isoniazid co-therapy targets porphyrin biosynthesis via PXR and results in hepatic protoporphyrin IX accumulation and subsequent liver injury. The present study aimed to investigate the associations between genetic polymorphisms in NR1I2 and ATDH in an Eastern Chinese Han population. Methods A 1:4 matched case-control study was conducted using 146 ATDH cases and 584 controls. Seven single nucleotide polymorphisms (SNPs) were detected and analysed. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking history and drinking history as covariates. Results Patients carrying the GG genotype of rs7643645 were at a higher risk of ATDH than those carrying the AA genotype (OR = 1.864, 95% CI: 1.106–3.141, P = .020), and significant differences were also found under the recessive model (P = .029) and additive model (P = .021). Patients with a polymorphism at rs2276707 were at a reduced risk of ATDH under the recessive model (OR = 0.600, 95% CI: 0.364–0.988, P = .045). Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the additive model (rs7643645, OR = 1.429, 95% CI: 1.027–1.988, P = .034) and recessive model (rs2276707, OR = 0.478, 95% CI: 0.253–0.902, P = .023). Functional annotation using ENCODE data also indicated that rs2276707 and rs7643645 were located in the histone modification regions targeting enhancers or promoter (H3K4Me1, H3K4Me3 and H3K27Ac). Conclusions Based on this case-control study, SNPs rs7643645 and rs2276707 in NR1I2 may contribute to susceptibility to ATDH in Eastern Chinese Han anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

In the present study, recombinant strains were constructed for xylitol production by cloning and expressing the novel xylitol dehydrogenase (xdh) and alcohol dehydrogenase (adh) genes in E. coli BL21 (DE3) from Gluconobacter thailandicus CGMCC1.3748. The optimum pH, temperature, specific activity and kinetic parameters were further investigated for purified XDH. The co-culture of G. thailandicus (30 g/L), BL21-xdh (20 g/L) and BL21-adh (20 g/L) produced 34.34 g/L of xylitol after 48 h in the presence of 40 g/L d-arabitol and 2% ethanol. The concentration of xylitol produced in this co-biotransformation was found to be 2.7-folds higher than the xylitol yield of G. thailandicus alone, while the yield was increased by 4.8% when compared to that of G. thailandicus mixed with BL21-xdh under the similar experimental conditions.

Scope: Maltol (3-hydroxy-2-methy-4-pyrone), a potent antioxidative agent, typically is used to enhance flavor and preserve food. This study evaluated its effects on preventing diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)-induced diabetic rats and explored its mechanisms. Methods and results: We intraperitoneally injected Sprague-Dawley (SD) rats with STZ (65 mg kg−1, ip) and treated the rats with different doses of maltol after 4 weeks of injection. During treatment, we evaluated motor nerve conduction velocity (MNCV) and thermal and mechanical hyperalgesia and assayed the oxidative stress, Na+–K+-ATPase activity, and apoptosis. Repeated treatment with maltol for 12 weeks significantly improved thermal and mechanical hyperalgesia, increased the MNCV, elevated the Na+–K+-ATPase activity, and ameliorated oxidative stress and apoptosis in STZ-induced diabetic rats. We coincubated RSC96 cells, a Schwann cell line, with maltol and hydrogen peroxide (H2O2, 0.6 mM). Evidently, maltol increased cell viability and inhibited apoptosis after injury by H2O2. Conclusions: Maltol was demonstrated to prevent DPN development and may provide a new alternative for the treatment of DPN.

In this study, a newly strain named Clostridium butyricum YJH-09 were isolated from the sample of pond soil and identified through physiological, biochemical and 16S rDNA analysis. Then, the dhaT gene encoding a novel 1,3-propanediol dehydrogenase (PDOR) was cloned from this strain and expressed in Escherichia coli BL21(DE3). Subsequently, the recombinant PDOR was purified and the optimal pH and temperature, specific activities and kinetic parameter were investigated. Furthermore, the whole cells of Clostridium butyricum YJH-09 mixed with BL21-dhaT were used to produce 1,3-PD through co-biotransformation. As results, 25.88g/L of 1,3-PD was generated with 0.54g/g yield from 50g/L glycerol in 30h, and the 1,3-PD production was increased more than 2-fold compared with wild type strain alone. This research would offer useful information for further development of the biosynthesis of 1,3-PD.

Ethnopharmacological relevance Rhubarb is a natural herbal medicine widely used clinically with numerous pharmacological activities including anti-cancer. Specifically, several studies reported that free anthraquinones from Rhubarb suppressed the proliferation of hepatoma cells. Nonetheless, recent studies revealed that Rhubarb caused hepatotoxicity in vivo, confirming its “two-way” effect on the liver. Therefore, the efficacy and safety of Rhubarb in the in vivo treatment of liver cancer should be further elucidated. Aim of the study: This study investigated the presence of hepatoprotection or hepatotoxicity of Rhubarb in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Material and methods A total of 112 male Sprague-Dawley rats weighing 190–250 g were enrolled. The rats were induced hepatocarcinogenesis using diethylnitrosamine (0.002 g/rat) until 17 weeks. Starting at week 11, Rhubarb granules (4 g/kg and 8 g/kg) were intragastrically administered daily for 7 weeks. All rats were euthanized at week 20 and the livers were analyzed via non-targeted metabolomics analysis. We established hepatic glucose 6 phosphate (6PG) levels and glucose 6 phosphate dehydrogenase (G6PD) activities to assess the pentose phosphate pathway (PPP). And the liver injuries of rats were analyzed via histological changes, hepatic function, as well as hepatic protein levels of alpha-fetoprotein (AFP), pyruvate kinase isozyme type M2 (PKM2), and proliferating cell nuclear antigen (PCNA). Furthermore, polydatin (0.1 g/kg/d) as a specific inhibitor of G6PD was used to treat rats. Notably, their histological changes, hepatic function, hepatic 6PG levels, hepatic G6PD activities, PCNA levels, and PKM2 levels were recorded. Results Non-targeted metabolomics revealed that Rhubarb regulated the PPP in the liver of Rhubarb-DEN-treated rats. Besides, Rhubarb activated the oxidative branch of the PPP by activating G6PD (a rate-limiting enzyme in the oxidative PPP) in the liver of Rhubarb-DEN-treated rats. Meanwhile, Rhubarb promoted DEN-induced hepatocarcinogenesis. Moreover, polydatin attenuated the promoting effect of Rhubarb on DEN-induced hepatocarcinogenesis. Conclusions Rhubarb promoted DEN-induced hepatocarcinogenesis by activating the PPP, indicating that the efficacy and safety of Rhubarb in the treatment of liver cancer deserve to be deliberated.

GW002 is a recombinant protein engineered by fusing the C-terminal region of human glucagon-like peptide-1 (GLP-1) to the N-terminal region of human serum albumin (HSA) with a peptide linker. This study aims to evaluate its anti-diabetic effects both in vitro and vivo. The GLP-1 receptor-dependent luciferase reporter plasmid was transiently transfected in NIT-1 cells to calculate the half-maximal concentration (EC50) for GLP-1 receptor activation, and normal ICR mice and diabetic KKAy mice were acutely injected with GW002 (1, 3 and 9 mg/kg) subcutaneously to evaluate the hypoglycemic action, while the diabetic KKAy and db/db mice were treated with GW002 once daily for 7 weeks to evaluate the effects on glucose metabolism. The results showed that GW002 activated GLP-1 receptor in NIT-1 cells with higher EC50 versus exendin-4 (46.7 vs. 7.89 nM), and single subcutaneous injection of GW002 at doses of 1, 3 and 9 mg/kg efficiently restrained the glycemia variation after oral glucose loading in ICR mice for at least 4 days, as well as reducing the non-fasting blood glucose in KKAy mice for about 2 days, while repeated injections of GW002 significantly improved abnormal glycaemia, HbA1c levels, oral glucose intolerance and β-cell function in diabetic db/db mice. These results suggested that GW002 showed prolonged hypoglycemic action by activating its cognate receptor and provided efficient control of glucose metabolism. Thus GW002 may be a potential treatment for the management of type 2 diabetes.

In order to explore subsistence patterns in northern Shaanxi Province around 4,000 yr BP, 28 human and 24 animal bones from the Shengedaliang site were sampled for stable carbon and nitrogen isotope ratio analysis. The results show that most people primarily subsisted on C4 resources, e.g. millet and millet-related animal products, despite the fact that there was some intake of C3 plants by some individuals. Stable nitrogen isotope values indicate that there were differences in meat consumption between individuals at the site. Pigs were mainly foddered with millet and millet byproducts, as well as some cattle, according to their high δ 13C values. However, most cattle and the sheep/goats consumed wild C3 plants at Shengedaliang. Our above findings indicates that subsistence patterns in northern Shaanxi around 4,000 yr BP were characterized by millet farming, while the grassland animal husbandry, e.g. cattle and sheep/goats raising, displayed very little contribution to local economy. The intensive millet farming in northern Shaanxi provided enough food for population growth, ensured the accumulation of wealth, and consequently accelerated social differentiation and complexity.

The aim of this work was to study the random mutagenesis of Clostridium butyricum strain. A high 1,3-PD tolerant mutant strain, designated as C. butyricum YP855, was developed from the wild strain C. butyricum XYB11, using combined chemical (NTG, N-methyl-N′-nitro-N-nitrosoguanidine,) and plasma-based mutagenesis (ARTP, atmospheric and room temperature plasma). The YP855 showed a maximum tolerance of 85 g/L to 1,3-PD (up to 30.8% increase) when compared with the tolerance exhibited by the wild strain. Under the optimum conditions as established by the response surface methodology (RSM), the mutant strain produced 37.20 g/L of 1,3-PD, which is 29.48% higher than the concentration obtained from the wild strain (28.73 g/L). This research would offer information for further development of the biosynthesis of 1,3-PD by the mutant strain of C. butyricum.

Objective. To study oral pharmacokinetics of Aconitum extract in randomized Sprague-Dawley (SD) rats and observe the profile change in vivo between plasma concentration and time with an aim to disclose relevant delivery rule for total components from Aconitum extract and finally to evaluate the research of Aconitum sustained-release preparation. Methods. Randomized rats were administered orally with the single and multiple dose of Aconitum extract based on the clinical use of Aconitum injection. Blood samples were collected at predetermined interval time from an eye of rats. The concentration of total components in those samples was determined by a new analytic method of area under absorbance-wavelength curve, the data were analyzed by Drug and Statistics software, and then the pharmacokinetic parameters and compartment model were acquired and compared, respectively. Results. The pharmacokinetic parameters of single and multiple doses were similar, and both of them showed characteristics of the one-compartment model. Cav, DF, and AUCss were (2.075 ± 0.282) µg/ml, (2.405 ± 0.175), and (24.901 ± 0.422) µg/ml/h, respectively. However, the concentrations of total components in the fifth and sixth day were 0.32 and 0.44 µg/ml, which were lower than the value of Cav. Conclusion. The method of AUAWC is feasible for the pharmacokinetics study in vivo analysis on total components of Aconitum with good sensitivity, specificity, and repeatability. The results demonstrated that both absorption and elimination of total components from Aconitum extract in rats were rapid and pharmacokinetic behavior was consistent at the level of single and multiple doses, which confirms that Aconitum injection is available to transform the oral sustained-release preparation. This will bring a good instruction to the research of sustained-release preparation of traditional Chinese medicine (TCM), which still lacks of an evaluation method available for total components in vivo analysis.

Objective Alzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort. Methods Detailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule‐associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next‐generation sequencing on 53 dementia‐associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence. Results PSEN1 p.L226R was found in an early‐onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal‐temporal dementia gene, TANK‐binding kinase 1 (TBK1) with a typical AD phenotype in a late‐onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients. Conclusions Thus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients.

Uridine 5’-diphospho-glucuronosyl-transferase 1A1 (UGT1A1) plays an important role in the biliary excretion of bilirubin, suggesting genetic polymorphisms of UGT1A1 may have an impact on bile acid metabolism, which may be related to the development of anti-tuberculosis drug-induced liver injury (ATLI). This study explores the associations between genetic polymorphisms of UGT1A1 and ATLI in a Chinese anti-tuberculosis population. A 1:2 matched case–control study was conducted among 290 ATLI cases and 580 controls, of which causality assessment of ATLI cases was based on the updated Roussel Uclaf Causality Assessment Method (RUCAM). Conditional logistic regression was applied to calculate odds ratio (OR) and 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. The Bonferroni correction was used to adjust P values for multiple testing. Compared with those carrying rs6719561 TT genotype, patients with TC genotype had lower risk of ATLI (adjusted OR = 0.723, 95% CI: 0.531–0.985, P = 0.040). The haplotype TAG (rs3755319-rs2003569-rs4148323) could marginally significantly increase the risk of ATLI (adjusted OR = 5.071, 95% CI: 1.007–25.531, P = 0.049), while haplotype TC (rs4148329-rs6719561) could reduce the risk of ATLI (adjusted OR = 0.719, 95% CI: 0.527–0.982, P = 0.038). Patients with polymorphisms at rs4148328 or rs3755319 were at a reduced risk of moderate and severe liver injury under different genetic models. Based on this case–control study, genetic polymorphisms of UGT1A1 may be associated with susceptibility to ATLI in the Chinese anti-tuberculosis population.

GPAM (glycerol-3-phosphate acyltransferase 1) is a mitochondrial enzyme that catalyze an essential step in glycerolphospholipids and triacylglycerol biosynthesis process. Loss-of-function mutation of GPAM has been shown to lead to hypomyelination of corticospinal tract in cerebral palsy patient. To model this rare disease with human brain organoid, we generated a GPAM knockout human embryonic stem cell line SYSUe-008-A by CRISPR/cas9. The GPAM knockout cell line maintains a normal karyotype and shows comparable level of pluripotent stem cell marker expression and differentiation potential as wild-type human embryonic stem cells.

Text-oriented emotion recognition research has made significant research progress, however, very few works pay attention to learn the highquality long-distance contextual information for the utterance emotion recognition. In this paper, we proposed a context-aware gated recurrent units with self-attention for emotion recognition. The two bidirectional gated recurent units can obtain the sequence ralationship between words and utterances. Compared with the self-attention mechanism that cannot capture long-distance contextual information, three contexts are used in the self-attention mechanism, namely global, deep and deep-global context, which can capture the highquality long-distance contextual information. And the connection mechanism can enhance the embedding information of words and utterances. Experimental results on public Friends and EmotionPush datasets demonstrate that the three contexts in the self-attention mechanism outperforms several baselines on some emotion types recognition and indicate the effectiveness of the designed model, especially the deep-global context increased by 1% and 0.2% on UWA compared with all models.

Physical layer security is a way to realize the secure transmission of information by employing the characteristics of wireless channels. Thanks to its spatial and temporal focusing property, the time-reversal (TR) transmission can achieve effective secure communications even when the transmitter is only equipped with one antenna. This paper studies the design and optimization of the security scheme based on artificial noise (AN) with or without the eavesdropper's channel state information (ECSI) in a TR multi-user downlink multiple access system. The null-space AN is adopted when ECSI is unavailable, and the corresponding optimization problem is to minimize the signal power under each user's signal-to-interference-plus-noise ratio (SINR) target constraint, so that the power used to send AN is maximized and the interception rate of the eavesdropper is minimized. The problem is solved by transforming it into a semidefinite program (SDP) with semidefinite relaxation (SDR). The pre-processing filter and AN are jointly optimized to maximize the sum secrecy rate when ECSI is available. The problem is solved by transforming it into a convex program by using SDR and the first-order Taylor approximation. Simulation results show that the sum secrecy rate of the proposed scheme is significantly higher than that of the conventional TR transmission system with or without AN.

Cerebral ischemia/reperfusion (I/R) is a major cause of severe disability and death all worldwide. However, therapeutic options to minimize the detrimental effects of cerebral I/R injury are limited. Recent research has demonstrated that quercetin mediates neuroprotective effects associated with the activation of the Akt signaling pathway in the cerebral I/R brain. Therefore, the aim of this study was to further investigate the mechanisms of cognitive deficits induced by cerebral I/R injury and the effects of quercetin on these mechanisms. First, we assessed anxiety-like behavioral and cognitive impairment using the open field test and the Morris water maze test, respectively. Next, we examined the severity of apoptosis by staining hippocampal neurons by the Cresyl violet method. Third, we used western blot analysis to investigate the expression of total and phosphorylated Akt, ASK1, JNK3, c-Jun and caspase-3 after I/R injury. Our results revealed that mice subjected to bilateral common carotid occlusion exhibited severe anxiety-like behavior, learning and memory impairment, cell damage and apoptosis. These severe effects were attenuated by administration of quercetin. Further, western blot analysis revealed that quercetin increased p-Akt expression and decreased p-ASK1, p-JNK3 and cleaved caspase-3 expression after cerebral I/R injury and led to inhibition of neuronal apoptosis. Conversely, treatment with LY294002 (a selective inhibitor of Akt1) reversed the effects of quercetin. In conclusion, these findings highlight the important role of quercetin in protecting against cognitive deficits and inhibiting neuronal apoptosis via the Akt signaling pathway. We believe that quercetin might prove to be a useful therapeutic component in treating cerebral I/R diseases in the near future.

The aim of this paper was to investigate the existence of radial solutions for a Kirchhoff-type problem driven by the fractional Laplacian, that iswhere is the fractional Laplacian operator with and , and are constants, is a parameter and without the Ambrosetti–Rabinowitz condition. The existence of nontrivial nonnegative radial solutions is obtained using variational methods combined with a cut-off function technique.

International audience; The relatively low cost and mild toxicity of vanadium makes it an alternative to commercially applied Pt and Cr based catalysts in propane dehydrogenation (PDH). Conventional VOx/Al2O3 catalyst shows high initial activity, but deactivates fast due to severe coke formation, which requires frequent regeneration by coke combustion and causes massive CO2 emissions. In this context, we report on the phosphine (PH3) surface modification of VOx/Al2O3 catalyst leading to substantial improvement of its stability. The phosphorus considerably modifies the properties of the VOx/Al2O3 catalyst: (i) tunes surface acidity, (ii) separates polymerized vanadium oxide species and (iii) weakens interaction between vanadium species with alumina support. Synergy among all these factors facilitate desorption of produced propylene and inhibit the oligomerization of coke precursors, which contributed to the enhancement of the catalyst stability during propane dehydrogenation.

Camptothecin (CPT) is considered one of the most important antitumor agents in the treatment of colon cancer. We synthesized a series of novel CPT (irinotecan, CPT-11) derivatives, which have impressive effects in various tumors. This study investigated the antitumor mechanism of one representative compound, ZBH-01 in colon cancer both in vitro and in vivo. The antiproliferative effect of ZBH-01 on tumor cells was evaluated by MTT assay. Topoisomerase I (Topo I) function and expression were assessed using DNA relaxation assay,qRT-PCR and western blot. Different gene expression among ZBH-01, CPT-11, and SN38 group was analyzed by RNA-seq and verified using qRT-PCR. GO and KEGG pathway analysis of DEmRNAs was performed by “R”. Protein-protein interaction (PPI) networks were constructed by STRING. The screened out mRNAs were functionally annotated. Cell cycle progression and cell apoptosis were assessed by flow cytometry. ZBH-01's inhibition of tumor growth was assessed using xenografts models established from SW1116 cells and colon cancer tissue samples. The results showed that ZBH-01 has comparable or superior antitumor activity against multiple tumor cell lines as compare with CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin). It reduced colon tumor growth superior to CPT-11 in vivo with lower toxicity. ZBH-01 showed a similar mechanism but weaker inhibitory activity on Topo I compared to CPT-11 or SN38. The screening criteria for DEmRNAs are P-value < 0.05 and |log2 fold change | > 1. A total of 100 DEmRNAs (62 downregulated and 38 upregulated mRNAs) have the same expression pattern in the three drug groups. Notably, there are 1769 DEmRNAs (842 downregulated and 927 upregulated mRNAs) specifically expressed in ZBH-01 group as compare with CPT-11 and SN38 group. GO analysis stratified these DEmRNAs in BP (sister chromatid segregation, DNA-dependent DNA replication), MF (catalytic activity, acting on DNA), CC (chromosomal region, condensed chromosome) classifications. The most significantly enriched KEGG pathways for the DEmRNAs in ZBH-01 group were DNA replication, P53 signaling pathway, and cell cycle etc. PPI network construction identified a significant cluster containing 73 genes, which include 14 genes involved in cell cycle process that were verified by qRT-PCR. More precisely, 50 nmol/L ZBH-01 significantly induced cell cycle arrest and apoptosis of colon cancer cells with the changes in gene expression such as p53, CDK2, CCNA2, Bax, Bcl-2, caspase 3, PARP. The further significant result is that ZBH-01 can rapidly exert cytotoxicity after 4 hours of dosing. In contrast, CPT-11 and SN38 had no detectable effect on tumor cells at this time point. In conclusions, ZBH-01 has higher potency in inhibiting colon tumor growth than CPT-11 and SN38 both in vitro and in vivo. It rapidly induces tumor cell apoptosis and cell cycle arrest through regulation of cell cycle signaling pathway. The more precise mechanism of ZBH-01 need to be further studied. Citation Format: Yongqi Li, Zhengkun Tu, Dawei Zhao, Wenqiu Zhang, Miaomiao Yang, Zhihui Wu, Weiguo Shi, Shijie lan, Zhen Guo, Hong Yu, Di Wu. Antitumor activity of a novel irinotecan analog, ZBH-01 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1835.

The roughened-bed stilling basin, serving as one new type of energy dissipator, has been analyzed both theoretically and experimentally in the literature. This study deduces the calculation formula of the length of the curve C0 between the flow-depth contraction section (i.e. hc) and the section just before the hydraulic jump (i.e. h1) when the same elevation is employed for both the bottom of roughened-bed stilling basin and the river-bed surface in the downstream. Further, by approximately assuming the equation of the resistance force exerted on the flow and caused by the bed roughness, this study obtains the expression of the ratio between the flow depth before the hydraulic jump and that behind the hydraulic jump, namely h1/h2. With the aid of the experimental results in the existing literature, it can be concluded that, when compared with the traditional smooth-bed hydraulic jump, the sequent depth and the length of the rolling hydraulic jump can be reduced by about 20∼30% and 20∼50%, respectively, in the condition of the chopping roughness riverbed. Additionally, by combining with the hydraulic model tests, this study indicates that adding the bed-roughness can eliminate the secondary hydraulic jump, improve the flow regime and (under the circumstance of the sill-roughness stilling basin) decrease the length of the stilling basin up to about 40%∼50%. Keywords: Stilling Basin; Hydraulic Jump; Hydraulic Characteristics; Roughened Bed; Sequent Depth; Energy Dissipation

Objective To investigate the expression of Mitofusin-2 (MFN2) in HCC tissues and its role in the development of HCC. Methods A total of 107 HCC specimens were collected for tissue microarray analysis and immunohistochemistry (IHC) analysis. The relationship between MFN2 expression and clinical features of patients with HCC was analyzed. Results Expression level of MFN2 in HCC tissues was 0.92 ± 0.78, significantly lower than that of matched paracancerous liver tissues (1.25 ± 0.75). Patients with low expression of MFN2 had significantly higher rates of cirrhosis than those with high expression of MFN2 (P = 0.049). Kaplan-Meier survival analysis showed that HCC patients with low expression of MFN2 had a worse prognosis in overall survival than HCC patients with high expression of MFN2 (P = 0.027). Patients with high expression of MFN2 had a better prognosis in disease-free survival compared with HCC patients with low expression of MFN2 (P = 0.047). Vascular invasion and MFN2 expression were shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis showed that vascular invasion (P

Antituberculosis (anti-TB) drug-induced hepatotoxicity may be related to the excessive reactive oxygen species induced by hepatotoxic metabolites. Antioxidant activity involves the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The BTB domain and CNC homologue 1 (Bach1) may compete with Nrf2 for binding to transcriptional enhancers. Elimination of Bach1-mediated transcriptional repression depends on nuclear exporter exportin 1 (Xpo1). Thus, Xpo1 may indirectly affect antioxidant activity. The present study aimed to examine the role of tag single-nucleotide polymorphisms in XPO1 in Chinese anti-TB treatment patients. A 1:2 matched case-control study was conducted using 314 anti-TB drug-induced hepatotoxicity cases and 628 controls. After correcting for weight and hepatoprotectant use, conditional logistic regression analysis showed that patients carrying the AA genotype of rs4430924 in XPO1 were at higher risk of anti-TB drug-induced hepatotoxicity than those carrying the GG genotype based on the subgroup of probable cases (adjusted OR, 1.938; 95%CI, 1.035-3.628; P = .039), and marginally significant differences were also found under the recessive model (P = .048) and the additive model (P = .047). Based on this 1:2 matched case-control study, the AA genotype of rs4430924 in XPO1 may be associated with higher risk of anti-TB drug-induced hepatotoxicity in Chinese anti-TB treatment patients. Further studies in larger and more varied populations are required to validate this relationship.

BACKGROUND Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. The slow acetylator status of N-acetyl transferase 2 (NAT2) is a well-established risk factor for ATDH. One novel tagging single nucleotide polymorphism (tagging SNP), rs1495741, in NAT2 has been found to be highly predictive of the NAT2 phenotype. The present study aimed to validate the relationships between tagging SNP rs1495741 and ATDH in a Chinese Han population. METHODS A 1:2 matched case-control study was conducted using 235 ATDH cases and 470 controls. Conditional or unconditional logistic regression analysis was used to estimate the association between genotypes and the risk of ATDH according to the odds ratio (OR) with a 95% confidence interval (CI). RESULTS Patients carrying the AA genotype of tagging SNP rs1495741 were at higher risk of ATDH than those carrying the GG genotype (OR = 1.653, 95% CI = 1.050-2.601; p = 0.030). Subgroup analysis suggested that the AA genotype was a risk factor for ATDH in patients aged older than 50 years (OR = 2.486, 95% CI = 1.313-4.706; p = 0.005), weighing over 50 kg (OR = 1.757, 95% CI = 1.016-3.038; p = 0.044) or using a hepatoprotectant (OR = 1.611, 95% CI = 1.009-2.572; p = 0.046). Tagging SNP rs1495741 was not a significant risk factor for moderate and severe hepatotoxicity but appears to be relevant to risk of mild hepatotoxicity specifically. CONCLUSIONS The present study is the first to validate the relationships between the tagging SNP rs1495741 and ATDH in a Chinese population. Based on this case-control study, the NAT2 rs1495741 polymorphism is a risk factor for mild but not more severe ATDH in Chinese Han patients.

Objective Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is related to hepatotoxic intermediaries, which are detoxified by glutathione S-transferases (GSTs). GSTM1 and GSTT1 are regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway, and the BTB domain and CNC homologue 1 (Bach1) could compete with Nrf2 for binding to the DNA. Thus, bach1 may indirectly affect GSTs expression. The present study aimed to examine the role of tagSNPs in BACH1 in a Chinese population-based cohort. Methods A nested case-control study was conducted. Each ATDH case was matched with two controls by age, gender, treatment history, etc. Seven tagSNPs were detected and analysed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using a conditional logistic regression model. Results A total of 290 ATDH cases and 580 controls were included in the present study. Patients carrying GG genotype of rs372883 were at a lower risk of ATDH than with AA genotype (OR = 0.553, 95%CI: 0.357–0.857, P = .008), and significant differences were also found under recessive model (P = .021) and additive model (P = .009). Similar results were also found in the polymorphism of rs1153285 (AA vs. GG, OR = 0.574, 95%CI: 0.360–0.914, P = .019), and under its recessive model (P = .033) and additive model (P = .026). Two haplotypes of A-G-T and C-T-G were identified to be associated with ATDH development. Further subgroup analysis also suggested significant association between BACH1 polymorphisms and ATDH among certain and probable hepatotoxicity cases. Conclusions This is the first study to explore the relationship between tagSNPs of BACH1 and ATDH in a Chinese cohort. Based on this cohort, genetic polymorphisms of BACH1 may be associated with susceptibility to ATDH in the Chinese population.

Crude glycerol is the main by-product of biodiesel production. A few microorganisms can transfer crude glycerol to 1,3-propanediol (1,3-PD) that is an important chemical material. There exist many limitations such as substrate inhibition, product inhibition when wild strains are used in 1,3-PD biosynthesis. In this review, based on the microbial transformation of 1,3-propanediol from glycerol and its limitations, some strategies using genetic engineering such as knockout or gene overexpression were summarized. The latest research progresses in biosynthesis of 1,3-propanediol from glycerol by genetically engineered strains are discussed.粗甘油是生物柴油生产中的主要副产物，一些微生物可将甘油转化为重要化工原料1,3-丙二醇 (1,3-PD)，而利用这些微生物野生菌株生物合成1,3-PD 会存在一些局限性，如底物抑制、产物抑制等。文中从1,3-丙二醇的甘油生物转化途径与这些局限性出发，总结了生物合成中存在的问题，并针对这些问题提出了一些基于基因敲除或基因过表达等基因工程技术的改造方法，综述了利用基因工程菌生物转化甘油生成1,3-丙二醇的最新研究进展。.

Recently, SIRT5 was reported to be a predominant desuccinylase and demalonylase in mitochondria. Ablation of SIRT5 enhances the systemic succinylation and malonylation of mitochondrial proteins, including various metabolic enzymes; however, its function in pancreatic β cells has not yet been clarified. In this study, we evaluated the effects of SIRT5 overexpression on glucolipotoxicity-induced apoptosis in β cell lines. Full-length SIRT5, which preferentially targeted to mitochondria and partially to the nucleus and cytoplasm, was overexpressed in NIT-1 cells. Chronic exposure to excess palmitate and glucose (High-PA-G) induced apoptosis and suppressed glucose-stimulated insulin secretion in β cells. SIRT5 overexpression significantly alleviated apoptosis under the High-PA-G condition, accompanied by suppressed Caspase 3 activity and reduced malondialdehyde levels. SIRT5 overexpression also improved β cell secretory capacity in response to glucose under the High-PA-G condition, suggesting its protective role in β cell function. Furthermore, SIRT5 overexpression reversed the decreasing trend of anti-apoptotic factors BCL-2 and BCL-XL expression under High-PA-G condition. Further regulation mechanisms between SIRT5 and these anti-apoptotic factors remains to be explored in future studies. Our data reveal that SIRT5 is a potentially protective factor for pancreatic β cells against glucolipotoxicity-induced apoptosis and cell dysfunction.

1,3-Propanediol (1,3-PD) is one of the most important chemicals widely used as monomers for synthesis of some commercially valuable products, including cosmetics, foods, lubricants and medicines. Although 1,3-PD can be synthesized both chemically and biosynthetically, the latter offers more merits over chemical approach as it is economically viable, environmentally friendly and easy to carry out. The biosynthesis of 1,3-PD can be done by transforming glycerol or other similar substrates using some bacteria, such as Clostridium butyricum and Klebsiella pneumoniae. However, these natural microorganisms pose some bottlenecks like low productivity and metabolite inhibition. To overcome these problems, recent research efforts have been focused more on the development of new strains by modifying the genome through different techniques, such as mutagenesis and genetic engineering. Genetically engineered strains obtained by various strategies cannot only gain higher yield than wild types, but also overcome some of the barriers in production by the latter. This review paper presents an overview on the recent advances in the technological approaches to develop genetically engineered microorganisms for efficient biosynthesis of 1,3-PD.

The growing demand for biotechnological products against limited metabolic capacity of industrially used microorganisms has led to an increased interest on strain-improvement over the last several decades, which aimed to enhance metabolite yield, substrate uptake and tolerance of the strains. Among a few techniques of strain-improvement, genome shuffling is the most recent and promising approach used for rapid strain-improvement that can yield a new strain by combining whole genomes of multi-parental microorganisms using the principles of protoplast fusion. Genome shuffling has brought a major breakthrough in the strain-improvement concept as it is found to be effective and reliable for expressing complex phenotypes. This review will discuss the technical aspects and applications of genome shuffling for various industrial strains to present its current status and recent progress. In the concluding remarks, a summary will be presented focusing on the major challenges and future outlooks of this technology.

Based on proxy re-signature technology and Merkel Hash tree, a new public auditing scheme for cloud data is proposed to solve the problems of dynamic data updating and user revocation. The proxy re-signature key is generated by the current data manager's private key and the public key of the revoked user, which cannot leak any information and realizes transferring of ownership data securely. By using the random masking technique, it can prevent the curious third-party auditor from restoring raw data blocks and ensures privacy of cloud data. In addition, a simple authentication structure is constructed by Merkel Hash tree, which simplifies the data update process and supports the update operations such as inserting, modifying and deleting the cloud data. The analysis results show that the proposed scheme satisfies existential unforgeability, and can resist replay attack and deletion attack.

Based on linear secret sharing and digital signature, a new multi-authority attribute-based encryption scheme is proposed. In our scheme, a signature on a user's identity is embedded in the user's private key. The third party can directly trace the identity of the owner of the private key according to the leaked private key, and can verify the correctness of the user's identity publicly. Moreover, multiple authority centers jointly generate the private key of the user, which effectively solves the security problem existing in an authority center. The storage performance analysis results show that our scheme is very suitable for cloud computing environment.

In order to solve problems of providing mobile payment services safely and maximizing the benefits of users, we use attribute-based encryption to propose a joint payment mechanism. Multiple users can get together to obtain one or more services with using pseudonyms, and protect its privacy and decrease the cost. Since the user's attribute key is distributed by multiple authorization centers, it can effectively solve the performance bottlenecks of a single authorized organization. With the help of decryption outsourcing and fixed ciphertext encryption technology, the new scheme greatly reduces the user's computing overhead and storage overhead. In addition, linear secret sharing matrix is introduced to achieve a flexible resource access control policy for users. Analysis results show that the proposed scheme has lower computational complexity and realizes secure communication than the existing similar scheme.

A formulation of regenerated silk fibroin solution that can be easily functionalized and inkjet printed on numerous surfaces is developed. As an example, the inks can be printed on laboratory gloves that change color when exposed to bacteria.