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991.
Lin Zhang Yiming Chen Fahui Li Lihui Zhang Jinhong Feng Lei Zhang 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1918
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells. 相似文献
992.
993.
David M. Gordon David Cunningham Gloria Zender Patrick J. Lawrence Jacqueline S. Penaloza Hui Lin Sara M. Fitzgerald-Butt Katherine Myers Tiffany Duong Donald J. Corsmeier Jeffrey B. Gaither Harkness C. Kuck Saranga Wijeratne Blythe Moreland Benjamin J. Kelly Baylor-Johns Hopkins Center for Mendelian Genomics Vidu Garg Peter White Kim L. McBride 《PLoS genetics》2022,18(6)
Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant’s effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes. 相似文献
994.
Min Hee Kim Gabriel L. Schwartz Justin S. White M. Maria Glymour Sean F. Reardon Kiarri N. Kershaw Scarlett Lin Gomez Daniel F. Collin Pushkar P. Inamdar Guangyi Wang Rita Hamad 《PLoS medicine》2022,19(6)
BackgroundCardiovascular disease (CVD) disproportionately affects Black adults in the United States. This is increasingly acknowledged to be due to inequitable distribution of health-promoting resources. One potential contributor is inequities in educational opportunities, although it is unclear what aspects of education are most salient. School racial segregation may affect cardiovascular health by increasing stress, constraining socioeconomic opportunities, and altering health behaviors. We investigated the association between school segregation and Black adults’ CVD risk.Methods and findingsWe leveraged a natural experiment created by quasi-random (i.e., arbitrary) timing of local court decisions since 1991 that released school districts from court-ordered desegregation. We used the Panel Study of Income Dynamics (PSID) (1991 to 2017), linked with district-level school segregation measures and desegregation court order status. The sample included 1,053 Black participants who ever resided in school districts that were under a court desegregation order in 1991. The exposure was mean school segregation during observed schooling years. Outcomes included several adult CVD risk factors and outcomes. We fitted standard ordinary least squares (OLS) multivariable linear regression models, then conducted instrumental variables (IV) analysis, using the proportion of schooling years spent in districts that had been released from court-ordered desegregation as an instrument. We adjusted for individual- and district-level preexposure confounders, birth year, and state fixed effects. In standard linear models, school segregation was associated with a lower probability of good self-rated health (−0.05 percentage points per SD of the segregation index; 95% CI: −0.08, −0.03; p < 0.001) and a higher probability of binge drinking (0.04 percentage points; 95% CI: 0.002, 0.07; p = 0.04) and heart disease (0.01 percentage points; 95% CI: 0.002, 0.15; p = 0.007). IV analyses also found that school segregation was associated with a lower probability of good self-rated health (−0.09 percentage points; 95% CI: −0.17, −0.02, p = 0.02) and a higher probability of binge drinking (0.17 percentage points; 95% CI: 0.04, 0.30, p = 0.008). For IV estimates, only binge drinking was robust to adjustments for multiple hypothesis testing. Limitations included self-reported outcomes and potential residual confounding and exposure misclassification.ConclusionsSchool segregation exposure in childhood may have longstanding impacts on Black adults’ cardiovascular health. Future research should replicate these analyses in larger samples and explore potential mechanisms. Given the recent rise in school segregation, this study has implications for policies and programs to address racial inequities in CVD.Min Hee Kim and colleagues investigate the association between exposure to school racial segregation in childhood and long-term cardiovascular health among Black adults in the United States. 相似文献
995.
996.
Jiantong Liu Xinyu Wang Lin Liu Xuefeng Wu Zhichao Xia Qingxue Guo 《Ecology and evolution》2022,12(7)
Deciduous and evergreen trees differ in their responses to drought and nitrogen (N) demand. Whether or not these functional types affect the role of the bacterial community in the N cycle during drought remains uncertain. Two deciduous tree species (Alnus cremastogyne, an N2‐fixing species, and Liquidambar formosana) and two evergreen trees (Cunninghamia lanceolata and Pinus massoniana) were used to assess factors in controlling rhizosphere soil bacterial community and N cycling functions. Photosynthetic rates and biomass production of plants, 16S rRNA sequencing and N‐cycling‐related genes of rhizosphere soil were measured. The relative abundance of the phyla Actinobacteria and Firmicutes was higher, and that of Proteobacteria, Acidobacteria, and Gemmatimondaetes was lower in rhizosphere soil of deciduous trees than that of evergreen. Beta‐diversity of bacterial community also significantly differed between the two types of trees. Deciduous trees showed significantly higher net photosynthetic rates and biomass production than evergreen species both at well water condition and short‐term drought. Root biomass was the most important factor in driving soil bacterial community and N‐cycling functions than total biomass and aboveground biomass. Furthermore, 44 bacteria genera with a decreasing response and 46 taxa showed an increased response along the root biomass gradient. Regarding N‐cycle‐related functional genes, copy numbers of ammonia‐oxidizing bacteria (AOB) and autotrophic ammonia‐oxidizing archaea (AOA), N2 fixation gene (nifH), and denitrification genes (nirK, nirS) were significantly higher in the soil of deciduous trees than in that of the evergreen. Structural equation models explained 50.2%, 47.6%, 48.6%, 49.4%, and 37.3% of the variability in copy numbers of nifH, AOB, AOA, nirK, and nirS, respectively, and revealed that root biomass had significant positive effects on copy numbers of all N‐cycle functional genes. In conclusion, root biomass played key roles in affecting bacterial community structure and soil N cycling. Our findings have important implications for our understanding of plants control over bacterial community and N‐cycling function in artificial forest ecosystems. 相似文献
997.
不同类型拌种剂对花生及其根际微生物的影响 总被引:2,自引:0,他引:2
拌种处理对于花生一播全苗和稳定高产非常重要.选用不同类型的4种拌种剂即哈茨木霉菌剂(真菌拮抗剂)、甲基托布津(杀真菌剂)、适乐时(杀真菌剂)、好安威(化学杀虫剂)处理花生种子,通过测定花生农艺性状、品质指标、根际土壤微生物动态等来评价其对花生和环境的综合效应.结果表明:1)各种杀菌剂拌种均能提高花生成苗率,而好安威略差;各拌种剂促进花生株高、叶绿素含量,而单株叶片数适乐时增多,好安威减少,单株分枝数盛花期有所增多(好安威除外),结果期均略减少;单株烂、虫、芽果数均减少,单株秕果数增加,单株饱果数降低(好安威除外),百果重和百仁重提高(哈茨木霉除外),而饱满度降低;最终荚果产量除哈茨木霉略低,其余拌种剂增产效果极显著,甲基托布津、适乐时、好安威比对照分别增产34.58%、25.90%、22.82%.2)哈茨木霉拌种使蛋白质含量、亚油酸含量增幅最大,油份含量增幅较大,油亚比值降幅最大;甲基托布津处理的蛋白质和油份含量降幅最大;适乐时对提高油份含量、油亚比值效果最佳;好安威对品质指标的影响有限.3)从细菌及放线菌与真菌的比值来看,甲基托布津促细菌、抑真菌的效果好且长,对放线菌/真菌比值影响较小;哈茨木霉在前中期促细菌与放线菌、抑真菌的效果明显,但后期效果趋反;适乐时促细菌、抑真菌的效果短促,且一直强烈抑制放线菌;而好安威相比影响较小.4)好安威对根瘤菌具有显著的抑制作用,而哈茨木霉、适乐时、甲基托布津均极显著增加根瘤数量.结论:各拌种剂对花生产量、品质、根瘤、根际微生物产生了较大差异的综合效应,须因地、因时选用;化学杀菌剂甲基托布津的农艺效应、环境微生物效应均最好,唯蛋白质含量、油份含量略有降低,是一种较理想的综合优良拌种剂. 相似文献
998.
999.
1000.
ChaoChien Chang KeeChin Sia JiaFeng Chang ChiaMo Lin ChuenMao Yang ITa Lee Thi Thuy Tien Vo KuoYang Huang WeiNing Lin 《Journal of cellular and molecular medicine》2022,26(14):3850
Obesity is a world‐wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro‐inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS‐modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase‐2 (COX‐2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS‐stimulated gene expression of COX‐2 together with the phosphorylation of p47phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase‐dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS‐mediated COX‐2 expression and preadipocyte proliferation. Moreover, LPS‐induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX‐2 or PEG2 receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK‐dependent COX‐2 expression. 相似文献