Le rôle de la protéine interagissant avec hedgehog (Hhip) dans la formation rénale modulée par le diabète maternel et dans la néphropathie diabétique

Nous avons précédemment rapporté que le diabète maternel altère la néphrogenèse chez la progéniture diabétique de notre modèle murin de diabète maternel. Notre analyse par puce à ADN réalisée sur les reins néonatals de ces descendants de grossesse diabétique a révélé que l'expression de la protéine interagissant avec hedgehog (Hhip) était significativement surexprimée par rapport au groupe contrôle. En tant qu'antagoniste de Sonic hedgehog (Shh) qui joue un rôle essentiel dans la différenciation cellulaire, la croissance et le modelage tissulaire pendant le développement des reins et la fibrose rénale, Hhip se lie à Shh et atténue sa bioactivité. Il a été rapporté que la protéine Hhip est principalement exprimée dans les cellules endothéliales vasculaires et les cellules adjacentes à celles exprimant Shh. Cependant, le rôle fonctionnel de l'expression de Hhip dans les reins en développement et matures est à peine connu. Nous avons tout d'abord établi le profil d'expression de Hhip dans les reins embryonnaires. Dans notre modèle murin de diabète maternel, nous avons observé que l'expression du gène Hhip est différemment surexprimée dans le mésenchyme métanéphrique différencié et l'épithélium du bourgeon urétérique de la progéniture. En utilisant des cellules mésenchymateuses métanéphriques en culture (cellules MK4), nous avons démontré que le D-glucose élevé (25 mM D-glucose) stimulait spécifiquement l'expression de Hhip de façon dépendante du temps, puis ciblait la signalisation TGFβ1. De plus, la surexpression de Hhip augmentait l'expression des gènes pro-apoptotiques [NF-kB (P50/p65) et p53] et inhibait l'expression des gènes prolifératifs (i.e. Shh, Pax2, N-myc et p27Kip1). Finalement, nous avons démontré que le diabète maternel qui altère le développement des reins pourrait jouer un rôle dans les interactions de la voie Hhip et TGFβ1-SMAD (Diabetologia 2014). Après la naissance, dans le rein normal non-diabétique, l'expression de Hhip est quiescente; une expression basale et limitée de Hhip (ARNm et protéine) est détectable dans les cellules endothéliales glomérulaires matures, les podocytes et les cellules épithéliales tubulaires rénales. Alors que les lésions des cellules épithéliales glomérulaires (GECs) et des podocytes sont la caractéristique de la lésion rénale précoce de la néphropathie diabétique (DN), nous avons examiné plus en détail le rôle de l'expression rénale de Hhip dans certains modèles de diabète murin—e.g. souris Akita, souris db/db et souris Hhip hétérozygote (Hhip +/−) rendus diabétiques avec de faibles doses de streptozotocine (LDSTZ). Nos données révèlent que l'hyperglycémie (ou un taux élevé de glucose in vitro) active l'expression du gène Hhip dans les cellules endothéliales glomérulaires et les podocytes. En particulier, l'hétérozygosité de Hhip protège l'intégrité glomérulaire avec moins de pertes de podocytes et améliore les paramètres rénaux [c.-à-d., une diminution du ratio albumine/créatinine urinaire (ACR, une caractéristique de l'apparition de la maladie rénale) et les caractéristiques de la DN (hypertrophie rénale, augmentation du taux de filtration glomérulaire, glomérulosclérose et fibrose)]. Prises dans leur ensemble, nos données suggèrent que l’augmentation de l'expression rénale de Hhip due aux concentrations élevées de glucose peut déclencher directement le processus d'apoptose et de fibrose des cellules endothéliales glomérulaires observé dans le diabète et qu’elle joue un rôle clé dans le développement et la progression de la DN (Sci. Report 2018). Mots-clés : Expression des gènes de Hhip, diabète maternel, néphrogenèse, néphropathie diabétique, dérivé réactif de l'oxygèneWe previously reported that maternal diabetes impairs nephrogenesis in diabetic progeny in our maternal diabetes murine model. Our gene-array performed in neonatal kidneys of those affected offspring revealed that hedgehog interacting protein (Hhip) expression was significantly upregulated, as compared to the control group. As an antagonist of sonic hedgehog (Shh) which plays an essential role in cell differentiation, growth and tissue patterning during kidney development and kidney fibrosis, Hhip binds to Shh and attenuates its bioactivity. It is reported that Hhip is predominantly expressed in vascular endothelial cells and cells adjacent to those expressing Shh. However, the functional role of Hhip expression in the developing and mature kidney is barely known. We first established the expression pattern of Hhip in embryonic kidneys. We observed in our murine model of maternal diabetes that Hhip gene expression is differentially up-regulated in differentiated metanephric mesenchyme and ureteric bud epithelium of the offspring. Using cultured metanephric mesenchymal cells (MK4 cells), we demonstrated that high D-glucose (25 mM D-Glucose) specifically stimulated Hhip expression in a time-/dose-dependent manner, and then targeted TGFβ1 signaling. In addition, overexpression of Hhip increased the expression of pro-apoptotic genes [NF-kB (p50/p65) and p53] and inhibited the expression of proliferative genes (i.e., Shh, Pax2, N-myc, and p27kip1). Finally, we demonstrated that maternal diabetes impairing kidney development might mediate the interactions of Hhip and TGFβ1-Smad pathway (Diabetologia 2014). After birth, in normal non-diabetic state, Hhip expression is quiescent; a limited basal Hhip expression (mRNA and protein) is detectable in mature glomerular endothelial cells, podocytes and renal tubular epithelial cells. While glomerular epithelial cells (GECs) and podocyte injury is the hallmark of early renal injury in diabetic nephropathy (DN), we further examined the role of renal Hhip expression in murine diabetes models--e.g., Akita mice, db/db mice and heterozygous Hhip deficiency (Hhip+/−) mice rendered diabetic with low-dose streptozotocin (LDSTZ). Our data revealed that hyperglycemia (or high glucose in vitro) activates Hhip gene expression in glomerular endothelial cells and podocytes. In particular, Hhip heterozygosity protects glomerular integrity with less podocyte loss and improved renal outcomes [i.e., decreased urinary albumin/Creatinine (Cre) ratio (ACR, a hallmark of onset of kidney disease) and DN-features (renal hypertrophy, increased glomerular filtration rate, glomerulosclerosis and fibrosis)]. Taken together, our data suggest that high glucose-elevated renal Hhip expression may directly trigger the process of apoptosis and fibrosis in glomerular endothelial cells in diabetes and it plays a key role in the development and progression of DN (Sci. Report 2018). Keywords: Hhip gene expression, maternal diabetes, nephrogenesis, diabetic nephropathy, reactive oxygen specie

5-(Pyridin-2-yl)-3,3′-bi(1H-1,2,4-triazole)

In the title mol­ecule, C9H7N7, the two triazole rings are twisted by an angle of 3.8 (5)°; the central triazole ring is twisted by 32.3 (6)° with respect to the pyridyl ring. The crystal packing consists of layers generated by inter­molecular N—H⋯N hydrogen bonds

A Blue Native-PAGE analysis of membrane protein complexes in Clostridium thermocellum

Background Clostridium thermocellum is a Gram-positive thermophilic anaerobic bacterium with the unusual capacity to convert cellulosic biomass into ethanol and hydrogen. Identification and characterization of protein complexes in C. thermocellum are important toward understanding its metabolism and physiology. Results A two dimensional blue native/SDS-PAGE procedure was developed to separate membrane protein complexes of C. thermocellum. Proteins spots were identified by MALDI-TOF/TOF Mass spectrometry. 24 proteins were identified representing 13 distinct protein complexes, including several putative intact complexes. Interestingly, subunits of both the F1-F0-ATP synthase and the V1-V0-ATP synthase were detected in the membrane sample, indicating C. thermocellum may use alternative mechanisms for ATP generation. Conclusion Two dimensional blue native/SDS-PAGE was used to detect membrane protein complexes in C. thermocellum. More than a dozen putative protein complexes were identified, revealing the simultaneous expression of two sets of ATP synthase. The protocol developed in this work paves the way for further functional characterization of these protein complexes

Secreted Acb1 Contributes to the Yeast-to-Hypha Transition in Cryptococcus neoformans

Adaptation to stress by eukaryotic pathogens is often accompanied by a transition in cellular morphology. The human fungal pathogen Cryptococcus neoformans is known to switch between the yeast and the filamentous form in response to amoebic predation or during mating. As in the classic dimorphic fungal pathogens, the morphotype is associated with the ability of cryptococci to infect various hosts. Many cryptococcal factors and environmental stimuli, including pheromones (small peptides) and nutrient limitation, are known to induce the yeast-to-hypha transition. We recently discovered that secreted matricellular proteins could also act as intercellular signals to promote the yeast-to-hypha transition. Here we show that the secreted acyl coenzyme A (acyl-CoA)-binding protein Acb1 plays an important role in enhancing this morphotype transition. Acb1 does not possess a signal peptide. Its extracellular secretion and, consequently, its function in filamentation are dependent on an unconventional GRASP (Golgi reassembly stacking protein)-dependent secretion pathway. Surprisingly, intracellular recruitment of Acb1 to the secretory vesicles is independent of Grasp. In addition to Acb1, Grasp possibly controls the secretion of other cargos, because the graspΔ mutant, but not the acb1Δ mutant, is defective in capsule production and macrophage phagocytosis. Nonetheless, Acb1 is likely the major or the sole effector of Grasp in terms of filamentation. Furthermore, we found that the key residue of Acb1 for acyl binding, Y80, is critical for the proper subcellular localization and secretion of Acb1 and for cryptococcal morphogenesis

Patterns and Determinants of Antibiotic Use Behaviors among Rural Community Residents in Eastern China

Inappropriate antibiotic use may lead to antibiotic resistance, which has become a serious global crisis. Addressing suboptimal antibiotic use in the general population can play a significant role in the fight against antimicrobial resistance. This study aims to describe antibiotic use and sources of acquisition, and to identify factors influencing antibiotic access among rural community residents in Eastern China. A cross-sectional survey was conducted from July to August 2020, and 1494 participants from two villages in Eastern China were enrolled. Information was obtained using face-to-face interviews with a structured electronic questionnaire. Chi-squared and multinominal logistic regression analysis were used to explore possible determinants. In total, 1379 participants were eligible for the analysis. In the past 12 months, nearly half the respondents had taken any antibiotic (48.4%), and this proportion varied across marital status and age group. Two thirds of them (59.9%) obtained antibiotics from medical facilities with a prescription when they last took antibiotics, while 17.7% and 22.4% chose retail pharmacies and other sources, respectively. Multinominal analysis found that a higher proportion obtained antibiotics outside medical facilities among those aged 15 to 44 years, unmarried, non-white collar workers, with more years of education, lower annual household income per capita and lower levels of antibiotic knowledge. The antibiotic use behavior of rural community residents in Eastern China remains suboptimal. Antibiotic use and access behaviors need to be further addressed. Effective antibiotic stewardship in non-medical facility sources and training programs targeted for rural Chinese is warranted in future

Konsep Proses Pemesinan Berkelanjutan

Metal industrial machining usually strongth pressure from all sectors, ether raw material industries or user metal industries. Manufacturint process which offered to all sectors industries or companies that sustainable manufakturing consist of three main factor are efective cost, enviroment and social performance

Macromolecular organization and genetic mapping of a rapidly evolving chromosome-specific tandem repeat family (B77) in cotton (Gossypium)

Isolation and characterization of the most prominent repetitive element families in the genome of tetraploid cotton (Gossypium barbadense L; [39]) revealed a small subset of families that showed very different properties in tetraploids than in their diploid progenitors, separated by 1-2 million years. One element, B77, was characterized in detail, and compared to the well-conserved 5S and 45S rRNA genes. The 572 bp B77 repeat was found to be concentrated in several discontinuous tandem arrays confined to a single 550 kb SalI fragment in tetraploid cotton. Genetic mapping based on the absence of the pentameric ‘rung’ in the G. barbadense ‘ladder’ showed that B77 maps to a D-subgenome chromosome. In situ hybridization supports the contention that the array is confined largely to a single chromosomal site in the D-subgenome. The B77 repeat has undergone a substantial increase in copy number since formation of tetraploid cotton from its diploid relatives. RFLPs observed among tetraploid cotton species suggest that amplification and/or rearrangement of the repeat may have continued after divergence of the five tetraploid cotton species. B77 contains many short direct repeats and shares significant DNA sequence homology with a Nicotiana alata retrotransposon Tna1-2 integrase motif. The recent amplification of B77 on linkage group D04 suggests that the D-subgenome of tetraploid cotton may be subject to different evolutionary constraints than the D-genome diploid chromosomes, which exhibit few genome-specific elements. Further, the abundance of B77 in G. gossypioides supports independent evidence that it may be the closest extant relative of the D-genome ancestor of cotton.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43448/1/11103_2004_Article_183493.pd

Secular trend of the leading causes of death in China from 2003 to 2013

Background: To analyze the epidemiological characteristics and secular trends of the leading causes of death in China.Methods: Data on the leading causes of death was collected from the Statistical Yearbook of China. Data for 11 years, from 2003 to 2013, was analyzed by regression analysis and chi-square test.Results: The top 3 causes of death from 2009 to 2013 were cancer, cerebrovascular disease, and cardiopathy, with the role of cardiopathy increasing over time (P<0.01). The proportion of deaths related to cardio-cerebrovascular diseases in urban and rural areas increased to 41.9% and 44.8%, respectively, in 2013, and was significantly higher than that for cancer, 25.5% and 22.4% (both P<0.01). Injury and poisoning in urban or rural areas represented the fifth leading cause of death. In 2006, endocrine, nutritional, and metabolic diseases were the sixth main cause of death, with 3.3% in urban areas. The role of genito-urinary,respiratory, and digestive system diseases in urban areas and genito-urinary system diseases in rural areas decreased during this period (all P<0.05).Conclusion: Cancer, cerebrovascular disease, and cardiopathy accounted for more than 67% of all deaths from 2007 to 2013 in China, and significantly increased in proportion from 2003 to 2013.Keywords: Causes of death; China; cancer; cardiovascular diseas

Interfacing with silica boosts the catalysis of copper

厦门大学化学化工学院郑南峰教授团队长期致力于研究固体功能材料的表界面化学行为，在分子水平上实现对固体功能材料的化学性能的调控与优化。得益于固体表面物理化学国家重点实验室的多学科合作以及能源材料化学协同创新中心的多单位优势互补，郑南峰教授课题组通过与校内外多个课题组的密切合作，近期在功能材料的可控制备、复杂表界面结构的高分辨表征和表界面过程分子机制的深入理解等方面取得系列重要进展，相关成果近期均在Nature Communications发表。 与厦门大学傅钢、袁友珠教授以及中国科学院物理研究所谷林研究员密切合作，历时五年，在多相催化的金属-载体界面效应研究方面取得重要进展。SiO2被广泛用作工业负载型金属催化剂的载体，多被视为惰性载体，在催化过程中仅起到分散金属的作用。郑南峰教授领衔的合作研究打破这个催化领域的“定式”。他们发现了“惰性”载体SiO2与Cu之间存在可以数量级提升酯基加氢催化性能的活性界面，揭示了相关界面效应的分子作用机制，并应用于指导实用铜催化剂的制备。【Abstract】Metal-support interaction is one of the most important parameters in controlling the catalysis of supported metal catalysts. Silica, a widely used oxide support, has been rarely reported as an effective support to create active metal-support interfaces for promoting catalysis. In this work, by coating Cu microparticles with mesoporous SiO2, we discover that Cu/SiO2 interface creates an exceptional effect to promote catalytic hydrogenation of esters. Both computational and experimental studies reveal that Cu–Hδ− and SiO–Hδ+ species would be formed at the Cu–O–SiOx interface upon H2 dissociation, thus promoting the ester hydrogenation by stablizing the transition states. Based on the proposed catalytic mechanism, encapsulting copper phyllosilicate nanotubes with mesoporous silica followed by hydrogen reduction is developed as an effective method to create a practical Cu nanocatalyst with abundant Cu-O-SiOx interfaces. The catalyst exhibits the best performance in the hydrogenation of dimethyl oxalate to ethylene glycol among all reported Cu catalysts.We thank the National Key R&D Program of China (2017YFA0207302, 2017YFA0207303, 2017YFA0206801), the NNSF of China (21731005, 21420102001, 21721001, 21333008, 21373167, 21573178), and the Fundamental Research Funds for the Central Universities (20720160046) for financial support. 研究工作得到了科技部、国家自然科学基金委和教育部，中科院先导项目，国家重点研发计划，分子反应动力学国家重点实验室开放课题基金等项目的资助