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101.
Tao Tan Jun Wu Chenyang Si Shaoxing Dai Youyue Zhang Nianqin Sun E Zhang Honglian Shao Wei Si Pengpeng Yang Hong Wang Zhenzhen Chen Ran Zhu Yu Kang Reyna Hernandez-Benitez Llanos Martinez Martinez Estrella Nuñez Delicado W. Travis Berggren Juan Carlos Izpisua Belmonte 《Cell》2021,184(8):2020-2032.e14
102.
Miller AL Webb MS Copik AJ Wang Y Johnson BH Kumar R Thompson EB 《Molecular endocrinology (Baltimore, Md.)》2005,19(6):1569-1583
103.
Force generation in striated muscle is coupled with inorganic phosphate (Pi) release from myosin, because force falls with increasing Pi concentration ([Pi]). However, it is unclear which steps in the cross-bridge cycle limit loaded shortening and power output. We examined the role of Pi in determining force, unloaded and loaded shortening, power output, and rate of force development in rat skinned cardiac myocytes to discern which step in the cross-bridge cycle limits loaded shortening. Myocytes (n = 6) were attached between a force transducer and position motor, and contractile properties were measured over a range of loads during maximal Ca2+ activation. Addition of 5 mM Pi had no effect on maximal unloaded shortening velocity (Vo) (control 1.83 ± 0.75, 5 mM added Pi 1.75 ± 0.58 muscle lengths/s; n = 6). Conversely, addition of 2.5, 5, and 10 mM Pi progressively decreased force but resulted in faster loaded shortening and greater power output (when normalized for the decrease in force) at all loads greater than 10% isometric force. Peak normalized power output increased 16% with 2.5 mM added Pi and further increased to a plateau of 35% with 5 and 10 mM added Pi. Interestingly, the rate constant of force redevelopment (ktr) progressively increased from 0 to 10 mM added Pi, with ktr 360% greater at 10 mM than at 0 mM added Pi. Overall, these results suggest that the Pi release step in the cross-bridge cycle is rate limiting for determining shortening velocity and power output at intermediate and high relative loads in cardiac myocytes. muscle mechanics; force-velocity relationship; cross-bridge cycle 相似文献
104.
Qayyum R Snively BM Ziv E Nalls MA Liu Y Tang W Yanek LR Lange L Evans MK Ganesh S Austin MA Lettre G Becker DM Zonderman AB Singleton AB Harris TB Mohler ER Logsdon BA Kooperberg C Folsom AR Wilson JG Becker LC Reiner AP 《PLoS genetics》2012,8(3):e1002491
Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N?=?16,388) with p<5×10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p?=?9.1×10(-9)), 7q11 (rs13236689, CD36, p?=?2.8×10(-9)), 10q21 (rs7896518, JMJD1C, p?=?2.3×10(-12)), 11q13 (rs477895, BAD, p?=?4.9×10(-8)), and 20q13 (rs151361, SLMO2, p?=?9.4×10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N?=?14,909) and one (11q13) in Hispanic Americans (N?=?3,462). For MPV (N?=?4,531), genetic variants in 3 regions were significant at p<5×10(-8), two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis. 相似文献
105.
106.
Aaron M. Bender Rebecca L. Weiner Vincent B. Luscombe Sonia Ajmera Hyekyung P. Cho Sichen Chang Xiaoyan Zhan Alice L. Rodriguez Colleen M. Niswender Darren W. Engers Thomas M. Bridges P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(15):3576-3581
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp = 2.1, Kp,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. 相似文献
107.
Disentangling environmental and host sources of fungal endophyte communities in an experimental beachgrass study 下载免费PDF全文
Disentangling the ecological factors that contribute to the assembly of the microbial symbiont communities within eukaryotic hosts is an ongoing challenge. Broadly speaking, symbiont propagules arrive either from external sources in the environment or from internal sources within the same host individual. To understand the relative importance of these propagule sources to symbiont community assembly, we characterized symbiotic fungal endophyte communities within the roots of three species of beachgrass in a field experiment. We manipulated two aspects of the external environment, successional habitat and physical disturbance. To determine the role of internal sources of propagules for endophyte community assembly, we used beachgrass individuals with different pre‐existing endophyte communities. Endophyte species richness and community composition were characterized using culture‐based and next‐generation sequencing approaches. Our results showed that external propagule sources associated with successional habitat, but not disturbance, were particularly important for colonization of most endophytic taxa. In contrast, internal propagule sources played a minor role for most endophytic taxa but were important for colonization by the dominant taxon Microdochium bolleyi. Our findings highlight the power of manipulative field experiments to link symbiont community assembly to its underlying ecological processes, and to ultimately improve predictions of symbiont community assembly across environments. 相似文献
108.
Yanwen Jiang David Redmond Kui Nie Ken W Eng Thomas Clozel Peter Martin Leonard HC Tan Ari M Melnick Wayne Tam Olivier Elemento 《Genome biology》2014,15(8)
Background
Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.Results
We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events.Conclusions
Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0432-0) contains supplementary material, which is available to authorized users. 相似文献109.
110.