Upregulation of α-ENaC induces pancreatic β-cell dysfunction,ER stress,and SIRT2 degradation

Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels inβ-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.

Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes

Diabetes mellitus(DM)is still one of the most common diseases worldwide,and its prevalence is still increasing globally.According to the American and European recommendations,metformin is considered a first-line oral hypoglycemic drug for controlling type 2 DM(T2DM)patients.Metformin is the ninth most often prescribed drug in the world,and at least 120 million diabetic people are estimated to receive the drug.In the last 20 years,there has been increasing evidence of vitamin B12 deficiency among metformin-treated diabetic patients.Many studies have reported that vitamin B12 deficiency is related to the malabsorption of vitamin B12 among metformin-treated T2DM patients.Vitamin B12 deficiency may have a very bad complication for the T2DM patient.In this review,we will focus on the effect of metformin on the absorption of vitamin B12 and on its proposed mechanisms in hindering vitamin B12 absorption.In addition,the review will describe the clinical outcomes of vitamin B12 deficiency in metformintreated T2DM.

SARS-CoV-2 Delta变异株:从结构变异到强传染力

严重急性呼吸综合征冠状病毒2(SARS-CoV-2)变体Delta变异株(B.1.617.2毒株),以极强的传播力迅速成为了目前世界范围的2019冠状病毒病(COVID-19)主要致病毒株。刺突蛋白作为冠状病毒的关键结构蛋白质,介导了SARS-CoV-2与靶细胞识别、结合及融合过程,与Delta变异株的高传染性密切相关。Delta变异株中刺突蛋白基因突变位点从其空间构象、表面亲水性与自由能等方面加以改变,影响了刺突蛋白与靶细胞膜的识别与融合过程,加速了结合进程。Delta变异株的分子结构及其功能研究对于COVID-19的预防及治疗至关重要。本文简述了SARS-CoV-2 Delta变异株相较于野生株的分子结构特点,着重以冠状病毒刺突蛋白为基础,回顾了中和抗体与血清之于Delta变异株的效力改变,并总结了SARS-CoV-2 Delta变异株的病毒动力学及临床特征,以期为拓宽Delta变异株分子结构功能变异研究方向,为未来COVID-19疫苗设计与应用提供思路。

CsIPT1b and CsUGT85A2 delay female corolla opening in cucumber by regulating the content of cytokinins

Corolla opening is essential for the propagation of unisexual flowering plants,meanwhile commodity fruits with opening corolla have higher commodity value in cucumber fresh food market.Until now,there is little research on the mechanism of corolla opening in cucumber.In a previous paper,we identified a unique cucumber(Cucumis sativus)line(‘6457’)that possesses super ovaries and shows delayed corolla opening when nutrient supplies are abundant.We also previously showed that the expression of CsIPT1b(isopentenyl transferase)and CsUGT85A2(cytokinin glycosyltransferase)is correlated with the delayed opening of the female corolla.Here,we investigated the mechanism of delayed female corolla opening in cucumber by conducting transgenic experiments,hormone assays,and yeast one-hybrid assays.CsIPT1b and CsUGT85A2 positively and negatively regulated delayed female corolla opening,respectively.In CsIPT1b-overexpressing plants and CsUGT85A2 knockout plants,the content of the trans-zeatin riboside,trans-zeatin,and N6-isopentenyladenosine was increased.Overall,our findings indicate that CsIPT1b and CsUGT85A2 were important regulators of the timing of female corolla opening.These genes could thus be targets to cucumber molecular breeding of fruit with flowers remaining on the tip.

DUSP2 deletion with CRISPR/Cas9 promotes Mauthner cell axonal regeneration at the early stage of zebrafish

Axon regeneration of central neurons is a complex process that is tightly regulated by multiple extrinsic and intrinsic factors.The expression levels of distinct genes are changed after central neural system(CNS)injury and affect axon regeneration.A previous study identified dusp2 as an upregulated gene in zebrafish with spinal cord injury.Here,we found that dual specificity phosphatase 2(DUSP2)is a negative regulator of axon regeneration of the Mauthner cell(M-cell).DUSP2 is a phosphatase that mediates the dephosphorylation of JNK.In this study,we knocked out dusp2 by CRISPR/Cas9 and found that M-cell axons of dusp2(-/-)zebrafish had a better regeneration at the early stage after birth(within 8 days after birth),while those of dusp2^(+/-)zebrafish did not.Overexpression of DUSP2 in Tg(Tol 056)zebrafish by single-cell electroporation retarded the regeneration of M-cell axons.Western blotting results showed that DUSP2 knockout slightly increased the levels of phosphorylated JNK.These findings suggest that knocking out DUSP2 promoted the regeneration of zebrafish M-cell axons,possibly through enhancing JNK phosphorylation.

Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

Background: Pancreatic ductal adenocarcinoma(PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type(WT) PDAC cells(cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ m RNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Positive Correlation between PMS2 Deficiency and PD-L1 Expression in Pancreatic Cancer

Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P < 0.05), T stage (T3 vs T4: P = 0.039), and MSH3 expression was related to T stage (P < 0.05). Besides, both MSH2 expression (P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.

Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

To date,metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile.Indeed,metformin is the most widely used oral insulinsensitizing agent,being prescribed to more than 100 million people worldwide,including patients with prediabetes,insulin resistance,and polycystic ovary syndrome.However,over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency.Of note,evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status.Vitamin B12(also referred to as cobalamin)is a water-soluble vitamin that is mainly obtained from animal-sourced foods.At the cellular level,vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection.Thus,vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities(e.g.,megaloblastic anemia and formation of hypersegmented neutrophils),progressive axonal demyelination and peripheral neuropathy.Nevertheless,no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy,and vitamin B12 deficiency remains frequently unrecognized in such individuals.Therefore,in this“field of vision”article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients,which could serve as a practical guide for identifying individuals at high risk for this condition.Moreover,we discuss additional relevant topics related to this field,including:(1)The lack of consensus about the exact definition of vitamin B12 deficiency;(2)The definition of reliable biomarkers of vitamin B12 status;(3)Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis;and(4)Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency.Finally,we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency,particularly when this condition is induced by metformin.

Some Results on Type 2 Degenerate Poly-Fubini Polynomials and Numbers

In this paper,we introduce type 2 degenerate poly-Fubini polynomials and derive several interesting characteristics and properties.In addition,we define type 2 degenerate unipoly-Fubini polynomials and establish some certain identities.Furthermore,we give some relationships between degenerate unipoly polynomials and special numbers and polynomials.In the last section,certain beautiful zeros and graphical representations of type 2 degenerate poly-Fubini polynomials are shown.

Preparation of polythiophene/WO_3 organic-inorganic hybrids and their gas sensing properties for NO_2 detection at low temperature

Polythiophene/WO3（PTP/WO3）organic-inorganic hybrids were synthesized by an in situ chemical oxidative polymerization method,and char- acterized by X-ray diffraction（XRD）,transmission electron microscopy（TEM）and thermo-gravimetric analysis（TGA）.The Polythiophene/ WO3 hybrids have higher thermal stability than pure polythiophene,which is beneficial to potential application as chemical sensors.Gas sensing measurements demonstrate that the gas sensor based on the Polythiophene/WO3 hybrids has high response and good selectivity for de- tecting NO2 of ppm level at low temperature.Both the operating temperature and PTP contents have an influence on the response of PTP/WO3 hybrids to NO2.The 10 wt%PTP/WO3 hybrid showed the highest response at low operating temperature of 70-C.It is expected that the PTP/WO3 hybrids can be potentially used as gas sensor material for detecting the low concentration of NO2 at low temperature.

Calculation of the CO2 Degassing during Contact Metamorphism and Its Geological Significance:The Model and Example from the Shuanshan Area of the South Tan-Lu Fault Belt

The paper studies CO2 degassing and controlling factors under the condition of contact metamorphism in the Shuangshan area, southern Tan-Lu fault belt and the method of calculating the amount of CO2 degassing. The results show that the amount of CO2 degassing is controlled by the characteristics of the country rocks, including the thermal conductivity, penetrability, porosity and connectivity. Compositions, size and depth of intrusive rock also have an important influence on CO2 degassing, i.e., they generated numerous cracks in the country rocks, and thus allowed the easy flow and accumulation of fluids. The amount of CO2 flux in contact metamorphism is calculated quantitatively based on the metamorphic reaction and time-integrated fluid flux. The value （0.729- 2.446×10^4 mol/cm^2） of CO2 flux suggests that CO2 was provided mainly by the contact metamorphic reaction. The generation and releasing of CO2 are positively correlated with the degree of metamorphism, and XCO2 in fluids gradually increases from dolomite zone to calcite zone, but in the zone of grossular, fluid flux is the largest and XCO2 sharply decreases due to involvement of magmatic water. This study presents evidence that a large amount of industrial-scale CO2 can be produced during contact metamorphism. On the basis of theoretical and practical studies, a cone model has been proposed to response CO2 degassing for the contact metamorphism, and it can be used to explore CO2 accumulations beyond the oil-gas basins. This model can also be applied to the study of inorganic genesis of CO2 accumulations.

Ohmic Contact at Al/TiO_2/n-Ge Interface with TiO_2 Deposited at Extremely Low Temperature

TiO2deposited at extremely low temperature of 120°C by atomic layer deposition is inserted between metal and n-Ge to relieve the Fermi level pinning. X-ray photoelectron spectroscopy and cross-sectional transmission electron microscopy indicate that the lower deposition temperature tends to effectively eliminate the formation of GeOxto reduce the tunneling resistance. Compared with TiO2deposited at higher temperature of 250°C,there are more oxygen vacancies in lower-temperature-deposited TiO2, which will dope TiO2contributing to the lower tunneling resistance. Al/TiO2/n-Ge metal-insulator-semiconductor diodes with 2 nm 120°C deposited TiO2achieves 2496 times of current density at-0.1 V compared with the device without the TiO2interface layer case, and is 8.85 times larger than that with 250°C deposited TiO2. Thus inserting extremely low temperature deposited TiO2to depin the Fermi level for n-Ge may be a better choice.

Dynamics of a ±1/2 defect pair in a confined geometry:A thin hybrid aligned nematic cell

Confined geometry can change the defect structure and its properties.In this paper,we investigate numerically the dynamics of a dipole of ±1/2 parallel wedge disclination lines in a confined geometry：a thin hybrid aligned nematic（HAN） cell,based on the Landau-de Gennes theory.When the cell gap d is larger than a critical value of 12ξ（where ξis the characteristic length for order-parameter change）,the pair annihilates.A pure HAN configuration without defect is formed in an equilibrium state.In the confined geometry of d ≤ 12ξ,the diffusion process is discovered for the first time and an eigenvalue exchange configuration is formed in an equilibrium state.The eigenvalue exchange configuration is induced by different essential reasons.When 10ξ 〈 d ≤ 12ξ,the two defects coalesce and annihilate.The biaxial wall is created by the inhomogeneous distortion of the director,which results in the eigenvalue exchange configuration.When d≤ 10ξ,the defects do not collide and the eigenvalue exchange configuration originates from the biaxial seeds concentrated at the defects.

Electronic and Optical Properties of TiS2 Determined from Generalized Gradient Approximation Study

The electronic and optical properties of TiS2 are studied of density functional theory. A linearized and augmented by using an ab-initio calculation within the frame plane wave basis set with the generalized gradient approximation as proposed by Perdew et al. is used for the energy exchange-correlation determination. The results show a metallic character of TiS2, and the plots of total and partial densities of states of TiS2 show the metallic character of the bonds and a strong hybridization between the states d of Ti and p of S below the Fermi energy. The optical properties of the material such as real and imaginary parts of dielectric constant （ε（w） = ε1（w） ＋ iε2（w））, refractive index n（w）, optical reflectivity R（w）, for E / /x and E / /z are performed for the energy range of 0-.14 eV.

K You 48-2 Developed by Rice and Sorghum Res Inst,Sichuan Acad of Agri Sci

K You 48-2 is a new combination of early hybrid rice with good grain quality and high yield, developed by combining male sterile line K-Qing A having japonica cytoplasm and indica genome and restorer line Ce 48-2. In the regional trial of Hubei Province in 1991, its yield was 4.4% higher than that of the CK Weiyou 48-2, being significant at 0.05 level. In the same year, in another regional trial of Sichuan Province, its yield was 8.9% higher than that of the CK Weiyou 48-2, being significant at 0.01 level. It has the highest yield among all tested varieties in both provincial trials. It has shown good grain quality with 60% head rice recovery and moderate resistance to rice blast.

Robust photocatalytic benzene degradation using mesoporous disk-like N-TiO2 derived from MIL-125(Ti)

N-doped anatase-rutile titanium dioxide(N-TiO2)is a classical semiconductor widely used in environmental remediation.Its photocatalytic performance is typically affected by its morphology,porous structure,and phase composition.Herein,disk-like mesoporous N-TiO2 was prepared by calcining MIL-125(Ti)and melamine matrix at different temperatures in air.The photocatalytic efficiency of the prepared mesoporous N-TiO2 for the photo-oxidation of gaseous benzene under visible-light irradiation was studied.With respect to light absorption and mass transfer,as-prepared N-TiO2 annealed at 500℃(MM-500)showed the best photocatalytic activity with corresponding photodegradation and mineralization efficiencies of 99.1%and 72.0%,respectively.In addition.MM-500 exhibited excellent reusability and stability in cyclic experiments,in which 84.8%of gaseous benzene could still be photodegraded after 10 experimental cycles.Furthermore,electron spin resonance analysis indicated that·OH and·O2-radicals were the dominating reactive oxygen species during the photo-oxidation process.Their excellent performance suggests that the as-prepared N-TiO2 photocatalysts can be used to eliminate volatile organic compounds.

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Dimethylation of histone H3 lysine 9 （H3K9me2） is an important epigenetic mark associated with transcription repression. Here, we identified PHF8, a JmjC-domain-containing protein, as a histone demethylase specific for this repressing mark. Recombinant full-length wild type protein could remove methylation from H3K9me2, but mutation of a conserved histidine to alanine H247A abolished the demethylase activity. Overexpressed exogenous PHF8 was colocalized with B23 staining. Endogenous PHF8 was also colocalized with B23 and fibrillarin, two well-established nucleolus proteins, suggesting that PHF8 is localized in the nucleolus and may regulate rRNA transcription. Indeed, PHF8 bound to the promoter region of the rDNA gene. Knockdown of PHF8 reduced the expression of rRNA, and overexpression of the gene resulted in upregulation of rRNA transcript. Concomitantly, H3K9me2 level was elevated in the promoter region of the rDNA gene in PHF8 knockdown cells and reduced significantly when the wild type but not the catalytically inactive H247A mutant PHF8 was overexpressed. Thus, our study identified a histone demethylase for H3K9me2 that regulates rRNA transcription.

HnRNPE2 decoy RNA恢复C/EBPα活性诱导32D-P210的细胞粒系分化

目的:采用核不均一核糖核蛋白E2(hnRNP E2)decoy RNA靶向阻断CCAAT增强子结合蛋白alpha(C/EBPα)基因的异常翻译,诱导小鼠白血病样32D-P210细胞株向粒系分化,并进一步探讨其分子机制.方法:电穿孔法分别将野生型和突变型hnRNP E2 decoy RNA表达质粒转染入32D-P210细胞,经G418筛选出稳定株后,RT-PCR检测C/EBPa,粒细胞集落刺激因子受体(G-CSFR)与髓过氧化物酶(MPO)基因的mRNA水平;WesternBlot检测C/EBPa,G-CSFR的蛋白表达水平;瑞氏染色观察粒细胞集落刺激因子(G-CSF)刺激前后细胞形态;流式细胞仪检测分化抗原Gr-1,CD11b的表达.结果:筛选到分别稳定表达野生型或突变型hnRNP E2 decoy RNA的TG细胞株和TGA细胞株.与未转染组32D-P210细胞相比,TG细胞株C/EBPa mRNA水平无改变,但42ku-C/EBPa蛋白、G-CSFR mRNA和MPO mRNA水平分别升高了(43.8±4.9)%,(69.1±3.2)%和(37.8±4.2)%(P<0.05);G-CSF刺激后,TG细胞出现中、晚幼粒细胞甚至成熟粒细胞形态学特征;同时Gr-1分化抗原的表达率上升至40.3%,未转染组32D-P210细胞的Gr-1表达率5.5%(P<0.05);然而CD11b在3组细胞都是高表达,没有明显的变化(P>0.05);以上各参数在TGA细胞株与未转染组32D-P210细胞株间均无显著性差异(P>0.05).结论:hnRNP E2 decoy RNA能够诱导32D-P210细胞向粒系分化,其机制可能与decoy RNA特异性阻断hnRNAE2与C/EBPα mRNA非翻译区结合,调节C/EBPα mRNA翻译,恢复42ku-C/EBPα表达,上调其下游G-CSFR和MPO等分化基因的表达有关.G-CSF可加速这一作用从而促进32D-P210细胞的分化过程.

The radiation response of androgen-refractory prostate cancer cell line C4-2 derived from androgen-sensitive cell line LNCaP

Radiation therapy is a relatively effective therapeutic method for localized prostate cancer （PCa） patients. However, radioresistance occurs in nearly 30% of patients treated with potentially curative doses. Therapeutic synergy between radiotherapy and androgen ablation treatment provides a promising strategy for improving the clinical outcome. Accordingly, the androgen deprivation-induced signaling pathway may also mediate radiosensitivity in PCa cells. The C4-2 cell line was derived from the androgen-sensitive LNCaP parent line under androgen-depleted condition and had acquired androgen-refractory characteristics. In our study, the response to radiation was evaluated in both LNCaP and C4-2. Results showed that C4-2 cells were more likely to survive from irradiation and appeared more aggressive in their resistance to radiation treatment compared with LNCaP, as measured by clonogenic assays and cell viability and cell cycle analyses. Gene expression analyses revealed that a set of genes involved in cell cycle arrest and DNA repair were differentially regulated in LNCaP and C4-2 in response to radiation, which was also consistent with the radiation-resistant property observed in C4-2 cells. These results strongly suggested that the radiation-resistant property may develop with progression of PCa to androgen- independent status. Not only can the LNCaP and C4-2 PCa progression model be applied for investigating androgen-refractory progression, but it can also be used to explore the development of radiation resistance in PCa.