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951.
Natural underlying mtDNA heteroplasmy as a potential source of intra‐person hiPSC variability 下载免费PDF全文
Ester Perales‐Clemente Alexandra N Cook Jared M Evans Samantha Roellinger Frank Secreto Valentina Emmanuele Devin Oglesbee Vamsi K Mootha Michio Hirano Eric A Schon Andre Terzic Timothy J Nelson 《The EMBO journal》2016,35(18):1979-1990
Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high‐quality biorepositories. Beyond inter‐person variability, the root cause of intra‐person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next‐generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non‐mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC‐derived cardiomyocytes with expanded mtDNA mutations non‐related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra‐person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine. 相似文献
952.
Polyploidy: a missing link in the conversation about seed transfer of a commonly seeded native grass in western North America 下载免费PDF全文
The use of local, native plant materials is now common in restoration but testing for polyploidy in seed sources is not. Diversity in cytotypes across a landscape can pose special seed transfer challenges, because the methods used to determine genetically appropriate materials for seed transfer do not account for cytotypic variation. This lack of consideration may result in mixing cytotypes through revegetation, which could reduce long‐term population viability. We surveyed nine populations of a native bunchgrass, Pseudoroegneria spicata, in three EPA Level III Ecoregions in the western United States to determine the frequency of polyploidy, whether there are differences in traits (phenotype, fecundity, and mortality) among plants of different cytotypes, and whether cytotype frequency varies among ecoregions. We assessed trait variation over 2 years in a common garden and determined ploidy using flow cytometry. Polyploidy and mixed cytotype populations were common, and polyploids occurred in all ecoregions. Four of the nine populations were diploid. The other five had tetraploids present: three had only tetraploid individuals whereas two had mixed diploid/tetraploid cytotypes. There was significant variation in traits among cytotypes: plants from tetraploid populations were larger than diploid or mixed populations. The frequency and distribution of cytotypes make it likely that seed transfer in the study area will inadvertently mix diploid and polyploid cytotypes in this species. The increasing availability of flow cytometry may allow ploidy to be incorporated into native plant materials sourcing and seed transfer. 相似文献
953.
Shekhawat P Bennett MJ Sadovsky Y Nelson DM Rakheja D Strauss AW 《American journal of physiology. Endocrinology and metabolism》2003,284(6):E1098-E1105
The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid beta-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. beta-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy. 相似文献
954.
955.
Stephen R. Williams Qiong Yang Fang Chen Xuan Liu Keith L. Keene Paul Jacques Wei-Min Chen Galit Weinstein Fang-Chi Hsu Alexa Beiser Liewei Wang Ebony Bookman Kimberly F. Doheny Philip A. Wolf Michelle Zilka Jacob Selhub Sarah Nelson Stephanie M. Gogarten Bradford B. Worrall Sudha Seshadri Michèle M. Sale the Genomics Randomized Trials Network the Framingham Heart Study 《PLoS genetics》2014,10(3)
956.
Jorge Assis Nelson Castilho Coelho Filipe Alberto Myriam Valero Pete Raimondi Dan Reed Ester Alvares Serr?o 《PloS one》2013,8(7)
The genetic consequences of living on the edge of distributional ranges have been
the subject of a largely unresolved debate. Populations occurring along
persistent low latitude ranges (rear-edge) are expected to retain high and
unique genetic diversity. In contrast, currently less favourable environmental
conditions limiting population size at such range-edges may have caused genetic
erosion that prevails over past historical effects, with potential consequences
on reducing future adaptive capacity. The present study provides an empirical
test of whether population declines towards a peripheral range might be
reflected on decreasing diversity and increasing population isolation and
differentiation. We compare population genetic differentiation and diversity
with trends in abundance along a latitudinal gradient towards the peripheral
distribution range of
Saccorhiza
polyschides
, a large brown
seaweed that is the main structural species of kelp forests in SW Europe.
Signatures of recent bottleneck events were also evaluated to determine whether
the recently recorded distributional shifts had a negative influence on
effective population size. Our findings show decreasing population density and
increasing spatial fragmentation and local extinctions towards the southern
edge. Genetic data revealed two well supported groups with a central contact
zone. As predicted, higher differentiation and signs of bottlenecks were found
at the southern edge region. However, a decrease in genetic diversity associated
with this pattern was not verified. Surprisingly, genetic diversity increased
towards the edge despite bottlenecks and much lower densities, suggesting that
extinctions and recolonizations have not strongly reduced diversity or that
diversity might have been even higher there in the past, a process of shifting
genetic baselines. 相似文献
957.
Reuben S.E. Young Andrew P. Bowman Kaylyn D. Tousignant Berwyck L.J. Poad Jennifer H. Gunter Lisa K. Philp Colleen C. Nelson Shane R. Ellis Ron M.A. Heeren Martin C. Sadowski Stephen J. Blanksby 《Journal of lipid research》2022,63(6):100223
The cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular FAs and their de novo synthesis. Given that oxidation of de novo synthesized FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates; however, hitherto, all FAs have been considered part of a common pool. To probe potential metabolic partitioning of cellular FAs, cancer cells were supplemented with stable isotope-labeled FAs. Structural analysis of the resulting glycerophospholipids revealed that labeled FAs from uptake were largely incorporated to canonical (sn-) positions on the glycerol backbone. Surprisingly, labeled FA uptake also disrupted canonical isomer patterns of the unlabeled lipidome and induced repartitioning of n-3 and n-6 PUFAs into glycerophospholipid classes. These structural changes support the existence of differences in the metabolic fates of FAs derived from uptake or de novo sources and demonstrate unique signaling and remodeling behaviors usually hidden from conventional lipidomics. 相似文献
958.
Kaposi's sarcoma-associated herpesvirus-induced upregulation of the c-kit proto-oncogene,as identified by gene expression profiling,is essential for the transformation of endothelial cells 下载免费PDF全文
Moses AV Jarvis MA Raggo C Bell YC Ruhl R Luukkonen BG Griffith DJ Wait CL Druker BJ Heinrich MC Nelson JA Früh K 《Journal of virology》2002,76(16):8383-8399
Kaposi's sarcoma (KS), the most frequent malignancy afflicting AIDS patients, is characterized by spindle cell formation and vascularization. Infection with KS-associated herpesvirus (KSHV) is consistently observed in all forms of KS. Spindle cell formation can be replicated in vitro by infection of dermal microvascular endothelial cells (DMVEC) with KSHV. To study the molecular mechanism of this transformation, we compared RNA expression profiles of KSHV-infected and mock-infected DMVEC. Induction of several proto-oncogenes was observed, particularly the receptor tyrosine kinase c-kit. Consistent with increased c-Kit expression, KHSV-infected DMVEC displayed enhanced proliferation in response to the c-Kit ligand, stem cell factor (SCF). Inhibition of c-Kit activity with either a pharmacological inhibitor of c-Kit (STI 571) or a dominant-negative c-Kit protein reversed SCF-dependent proliferation. Importantly, inhibition of c-Kit signal transduction reversed the KSHV-induced morphological transformation of DMVEC. Furthermore, overexpression studies showed that c-Kit was sufficient to induce spindle cell formation. Together, these data demonstrate an essential role for c-Kit in KS tumorigenesis and reveal a target for pharmacological intervention. 相似文献
959.
The solubilities of zinc, iron, copper, magnesium, calcium, inorganic phosphate, and citrate in milk decreased when acidic milk preparations were neutralized. In decaseinated bovine milk soluble zinc, iron, and copper were reduced 90%, 60%, and 50%, respectively, as the pH was raised from 4 to 7. Simultaneous precipitation of minerals and citrate was confirmed by analysis of washed precipitate. We propose that the diminished solubilities of zinc, iron, copper, magnesium, and citrate are linked to the precipitation of calcium phosphate through one or more mechanisms of coprecipitation. Such control on mineral solubility may have an impact upon mineral absorption from milk. 相似文献
960.