129 research outputs found

    Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.

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    Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate toward the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.This work was supported by NIH awards F32HL106989 and K01DK098315 to E.M.P, grants from Leukaemia and Lymphoma Research, Cancer Research UK and core support by the Wellcome Trust to B.G.; and NIH grant R01HL092471, Rita Allen Scholar Award and Leukemia Lymphoma Society Scholar Award to E.P.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier/Cell Press

    Remote Estimation of Net Ecosystem CO2 Exchange in Crops: Principles, Technique Calibration and Validation

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    Accurate and synoptic estimation of spatially distributed CO2 fluxes is of great importance for regional and global studies of carbon balance. A technique solely based on remotely sensed data was developed and tested for estimating net ecosystem CO2 exchange (NEE) in maize and soybean. The model is based on the reflectance in two spectral channels: the near-infrared and either the green or red-edge around 700 nm. The technique provides accurate estimations of mid-day NEE in both crops under either rainfed or irrigated conditions, explaining more than 85% of NEE variation in maize and more than 81% in soybean, and shows great potential for remotely tracking crop NEE

    Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

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    To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trial

    A dynamic leaf gas-exchange strategy is conserved in woody plants under changing ambient CO2: evidence from carbon isotope discrimination in paleo and CO2 enrichment studies

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    Rising atmospheric [CO2 ], ca , is expected to affect stomatal regulation of leaf gas-exchange of woody plants, thus influencing energy fluxes as well as carbon (C), water and nutrient cycling of forests. Researchers have proposed various strategies for stomatal regulation of leaf gas-exchange that include maintaining a constant leaf internal [CO2 ], ci , a constant drawdown in CO2 (ca - ci ), and a constant ci /ca . These strategies can result in drastically different consequences for leaf gas-exchange. The accuracy of Earth systems models depends in part on assumptions about generalizable patterns in leaf gas-exchange responses to varying ca . The concept of optimal stomatal behavior, exemplified by woody plants shifting along a continuum of these strategies, provides a unifying framework for understanding leaf gas-exchange responses to ca . To assess leaf gas-exchange regulation strategies, we analyzed patterns in ci inferred from studies reporting C stable isotope ratios (δ(13) C) or photosynthetic discrimination (∆) in woody angiosperms and gymnosperms that grew across a range of ca spanning at least 100 ppm. Our results suggest that much of the ca -induced changes in ci /ca occurred across ca spanning 200 to 400 ppm. These patterns imply that ca - ci will eventually approach a constant level at high ca because assimilation rates will reach a maximum and stomatal conductance of each species should be constrained to some minimum level. These analyses are not consistent with canalization towards any single strategy, particularly maintaining a constant ci . Rather, the results are consistent with the existence of a broadly conserved pattern of stomatal optimization in woody angiosperms and gymnosperms. This results in trees being profligate water users at low ca , when additional water loss is small for each unit of C gain, and increasingly water-conservative at high ca , when photosystems are saturated and water loss is large for each unit C gain. This article is protected by copyright. All rights reserved.Rising atmospheric [CO2], c(a), is expected to affect stomatal regulation of leaf gas-exchange of woody plants, thus influencing energy fluxes as well as carbon (C), water, and nutrient cycling of forests. Researchers have proposed various strategies for stomatal regulation of leaf gas-exchange that include maintaining a constant leaf internal [CO2], c(i), a constant drawdown in CO2 (c(a)-c(i)), and a constant c(i)/c(a). These strategies can result in drastically different consequences for leaf gas-exchange. The accuracy of Earth systems models depends in part on assumptions about generalizable patterns in leaf gas-exchange responses to varying c(a). The concept of optimal stomatal behavior, exemplified by woody plants shifting along a continuum of these strategies, provides a unifying framework for understanding leaf gas-exchange responses to c(a). To assess leaf gas-exchange regulation strategies, we analyzed patterns in c(i) inferred from studies reporting C stable isotope ratios (C-13) or photosynthetic discrimination () in woody angiosperms and gymnosperms that grew across a range of c(a) spanning at least 100ppm. Our results suggest that much of the c(a)-induced changes in c(i)/c(a) occurred across c(a) spanning 200 to 400ppm. These patterns imply that c(a)-c(i) will eventually approach a constant level at high c(a) because assimilation rates will reach a maximum and stomatal conductance of each species should be constrained to some minimum level. These analyses are not consistent with canalization toward any single strategy, particularly maintaining a constant c(i). Rather, the results are consistent with the existence of a broadly conserved pattern of stomatal optimization in woody angiosperms and gymnosperms. This results in trees being profligate water users at low c(a), when additional water loss is small for each unit of C gain, and increasingly water-conservative at high c(a), when photosystems are saturated and water loss is large for each unit C gain

    A review of the dodo and its ecosystem: insights from a vertebrate concentration Lagerstätte in Mauritius

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    The dodo Raphus cucullatus Linnaeus, an extinct and flightless, giant pigeon endemic to Mauritius, has fascinated people since its discovery, yet has remained surprisingly poorly known. Until the mid-19th century, almost all that was known about the dodo was based on illustrations and written accounts by 17th century mariners, often of questionable accuracy. Furthermore, only a few fragmentary remains of dodos collected prior to the bird's extinction exist. Our understanding of the dodo's anatomy was substantially enhanced by the discovery in 1865 of subfossil bones in a marsh called the Mare aux Songes, situated in southeastern Mauritius. However, no contextual information was recorded during early excavation efforts, and the majority of excavated material comprised larger dodo bones, almost all of which were unassociated. Here we present a modern interdisciplinary analysis of the Mare aux Songes, a 4200-year-old multitaxic vertebrate concentration Lagerstätte. Our analysis of the deposits at this site provides the first detailed overview of the ecosystem inhabited by the dodo. The interplay of climatic and geological conditions led to the exceptional preservation of the animal and associated plant remains at the Mare aux Songes and provides a window into the past ecosystem of Mauritius. This interdisciplinary research approach provides an ecological framework for the dodo, complementing insights on its anatomy derived from the only associated dodo skeletons known, both of which were collected by Etienne Thirioux and are the primary subject of this memoir.publishedVersio

    KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

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    The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology
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