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1.
J Exp Med ; 217(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302400

RESUMO

The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.

2.
BMC Genomics ; 20(1): 898, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775605

RESUMO

Following the publication of this article [1], the authors reported that the images of Figs. 1, 2 and 3 were published in the incorrect order, whereby they mismatch with their captions.

3.
Front Immunol ; 10: 2568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781096

RESUMO

CD8+ T cells are important effectors of adaptive immunity against pathogens, tumors, and self antigens. Here, we asked how human cognate antigen-responsive CD8+ T cells and their receptors could be identified in unselected single-cell gene expression data. Single-cell RNA sequencing and qPCR of dye-labeled antigen-specific cells identified large gene sets that were congruently up- or downregulated in virus-responsive CD8+ T cells under different antigen presentation conditions. Combined expression of TNFRSF9, XCL1, XCL2, and CRTAM was the most distinct marker of virus-responsive cells on a single-cell level. Using transcriptomic data, we developed a machine learning-based classifier that provides sensitive and specific detection of virus-responsive CD8+ T cells from unselected populations. Gene response profiles of CD8+ T cells specific for the autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein differed markedly from virus-specific cells. These findings provide single-cell gene expression parameters for comprehensive identification of rare antigen-responsive cells and T cell receptors.

4.
Cell Rep ; 27(4): 1307-1318.e3, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018142

RESUMO

The neural stem cell (NSC) reservoir can be harnessed for stem cell-based regenerative therapies. Zebrafish remarkably regenerate their brain by inducing NSC plasticity in a Amyloid-ß-42 (Aß42)-induced experimental Alzheimer's disease (AD) model. Interleukin-4 (IL-4) is also critical for AD-induced NSC proliferation. However, the mechanisms of this response have remained unknown. Using single-cell transcriptomics in the adult zebrafish brain, we identify distinct subtypes of NSCs and neurons and differentially regulated pathways and their gene ontologies and investigate how cell-cell communication is altered through ligand-receptor pairs in AD conditions. Our results propose the existence of heterogeneous and spatially organized stem cell populations that react distinctly to amyloid toxicity. This resource article provides an extensive database for the molecular basis of NSC plasticity in the AD model of the adult zebrafish brain. Further analyses of stem cell heterogeneity and neuro-regenerative ability at single-cell resolution could yield drug targets for mobilizing NSCs for endogenous neuro-regeneration in humans.

5.
Nat Metab ; 1(1): 111-124, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30886999

RESUMO

Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2 knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signaling and decreases expression of the Wnt inhibitor sclerostin specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2 knockout mice. We further show that the extracellular domain of Tfr2 binds BMPs and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signaling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in a complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.

6.
Nat Metab ; 1(5): 584, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-32694850

RESUMO

In the version of this article initially published, affiliation 14 was incorrect, and Deutsche Forschungsgemeinschaft grants SFB1036 and SFB1118 were missing from the Acknowledgements. The errors have been corrected in the HTML and PDF versions of the article.

7.
Nat Commun ; 9(1): 4737, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413698

RESUMO

Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Evolutionary theory predicts that changes in cis-regulatory elements are important for morphological changes. We combined genome sequencing, functional genomics and genome-wide comparative analyses to investigate regulatory elements in lineages that lost morphological traits. We first show that limb loss in snakes is associated with widespread divergence of limb regulatory elements. We next show that eye degeneration in subterranean mammals is associated with widespread divergence of eye regulatory elements. In both cases, sequence divergence results in an extensive loss of transcription factor binding sites. Importantly, diverged regulatory elements are associated with genes required for normal limb patterning or normal eye development and function, suggesting that regulatory divergence contributed to the loss of these phenotypes. Together, our results show that genome-wide decay of the phenotype-specific cis-regulatory landscape is a hallmark of lost morphological traits.


Assuntos
Evolução Biológica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Variação Genética , Animais , Sítios de Ligação , Sequência Conservada/genética , DNA Intergênico/genética , Extremidades/embriologia , Olho/patologia , Genoma , Lagartos/genética , Mamíferos/genética , Anotação de Sequência Molecular , Fenótipo , Análise de Sequência de DNA , Serpentes/genética , Fatores de Transcrição/metabolismo
8.
Elife ; 72018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29916805

RESUMO

Hematopoietic stem cells require MLL1, which is one of six Set1/Trithorax-type histone 3 lysine 4 (H3K4) methyltransferases in mammals and clinically the most important leukemia gene. Here, we add to emerging evidence that all six H3K4 methyltransferases play essential roles in the hematopoietic system by showing that conditional mutagenesis of Setd1b in adult mice provoked aberrant homeostasis of hematopoietic stem and progenitor cells (HSPCs). Using both ubiquitous and hematopoietic-specific deletion strategies, the loss of Setd1b resulted in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis in the spleen, and lethality. By transplantation experiments and expression profiling, we determined that Setd1b is autonomously required in the hematopoietic lineages where it regulates key lineage specification components, including Cebpa, Gata1, and Klf1. Altogether, these data imply that the Set1/Trithorax-type epigenetic machinery sustains different aspects of hematopoiesis and constitutes a second framework additional to the transcription factor hierarchy of hematopoietic homeostasis.


Assuntos
Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Histona-Lisina N-Metiltransferase/genética , Homeostase/genética , Linfopenia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Trombocitopenia/genética , Animais , Transplante de Medula Óssea , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem da Célula/genética , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genes Letais , Células-Tronco Hematopoéticas/citologia , Histona-Lisina N-Metiltransferase/deficiência , Isoenzimas/deficiência , Isoenzimas/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Linfopenia/metabolismo , Linfopenia/patologia , Camundongos , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/deficiência , Baço/metabolismo , Baço/patologia , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Irradiação Corporal Total
9.
Oncotarget ; 9(26): 18099-18114, 2018 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-29719593

RESUMO

Intrinsic and acquired resistances are major obstacles in cancer therapy. Genetic characterization is commonly used to identify predictive or prognostic biomarker signatures and potential cancer targets in samples from therapy-naïve patients. By far less common are such investigations to identify specific, predictive and/or prognostic gene signatures in patients or cancer cells refractory to a specific molecular-targeted intervention. This, however, might have a great value to foster the development of tailored, personalized cancer therapy. Based on our identification of a differential radiosensitization by single and combined ß1 integrin (AIIB2) and EGFR (Cetuximab) targeting in more physiological, three-dimensional head and neck squamous cell carcinoma (HNSCC) cell cultures, we performed comparative whole exome sequencing, phosphoproteome analyses and RNAi knockdown screens in responder and non-responder cell lines. We found a higher rate of gene mutations with putative protein-changing characteristics in non-responders and different mutational profiles of responders and non-responders. These profiles allow stratification of HNSCC patients and identification of potential targets to address treatment resistance. Consecutively, pharmacological inhibition of mTOR and KEAP1 effectively diminished non-responder insusceptibility to ß1 integrin and EGFR targeting for radiosensitization. Our data pinpoint the added value of genetic biomarker identification after selection for cancer subgroup responsiveness to targeted therapies.

10.
Cell ; 172(1-2): 147-161.e12, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29328910

RESUMO

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of ß-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.


Assuntos
Imunidade Inata , Memória Imunológica , Células Progenitoras Mieloides/imunologia , Animais , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Progenitoras Mieloides/efeitos dos fármacos , Mielopoese/imunologia , beta-Glucanas/farmacologia
11.
BMC Genomics ; 18(1): 693, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874118

RESUMO

BACKGROUND: The short-lived fish Nothobranchius furzeri is the shortest-lived vertebrate that can be cultured in captivity and was recently established as a model organism for aging research. Small non-coding RNAs, especially miRNAs, are implicated in age dependent control of gene expression. RESULTS: Here, we present a comprehensive catalogue of miRNAs and several other non-coding RNA classes (ncRNAs) for Nothobranchius furzeri. Analyzing multiple small RNA-Seq libraries, we show most of these identified miRNAs are expressed in at least one of seven Nothobranchius species. Additionally, duplication and clustering of N. furzeri miRNAs was analyzed and compared to the four fish species Danio rerio, Oryzias latipes, Gasterosteus aculeatus and Takifugu rubripes. A peculiar characteristic of N. furzeri, as compared to other teleosts, was a duplication of the miR-29 cluster. CONCLUSION: The completeness of the catalogue we provide is comparable to that of the zebrafish. This catalogue represents a basis to investigate the role of miRNAs in aging and development in this species.


Assuntos
Ciprinodontiformes/genética , Ciprinodontiformes/fisiologia , Biblioteca Gênica , Longevidade/genética , MicroRNAs/genética , RNA não Traduzido/genética , Envelhecimento/genética , Animais , Duplicação Gênica , Anotação de Sequência Molecular
15.
Faraday Discuss ; 200: 229-249, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28574551

RESUMO

IAGOS (In-service Aircraft for a Global Observing System) performs long-term routine in situ observations of atmospheric chemical composition (O3, CO, NOx, NOy, CO2, CH4), water vapour, aerosols, clouds, and temperature on a global scale by operating compact instruments on board of passenger aircraft. The unique characteristics of the IAGOS data set originate from the global scale sampling on air traffic routes with similar instrumentation such that the observations are truly comparable and well suited for atmospheric research on a statistical basis. Here, we present the analysis of 15 months of simultaneous observations of relative humidity with respect to ice (RHice) and ice crystal number concentration in cirrus (Nice) from July 2014 to October 2015. The joint data set of 360 hours of RHice-Nice observations in the global upper troposphere and tropopause region is analysed with respect to the in-cloud distribution of RHice and related cirrus properties. The majority of the observed cirrus is thin with Nice < 0.1 cm-3. The respective fractions of all cloud observations range from 90% over the mid-latitude North Atlantic Ocean and the Eurasian Continent to 67% over the subtropical and tropical Pacific Ocean. The in-cloud RHice distributions do not depend on the geographical region of sampling. Types of cirrus origin (in situ origin, liquid origin) are inferred for different Nice regimes and geographical regions. Most importantly, we found that in-cloud RHice shows a strong correlation to Nice with slightly supersaturated dynamic equilibrium RHice associated with higher Nice values in stronger updrafts.

16.
Cell Rep ; 19(8): 1698-1709, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28538186

RESUMO

Adenoviruses (Ads) are large human-pathogenic double-stranded DNA (dsDNA) viruses presenting an enormous natural diversity associated with a broad variety of diseases. However, only a small fraction of adenoviruses has been explored in basic virology and biomedical research, highlighting the need to develop robust and adaptable methodologies and resources. We developed a method for high-throughput direct cloning and engineering of adenoviral genomes from different sources utilizing advanced linear-linear homologous recombination (LLHR) and linear-circular homologous recombination (LCHR). We describe 34 cloned adenoviral genomes originating from clinical samples, which were characterized by next-generation sequencing (NGS). We anticipate that this recombineering strategy and the engineered adenovirus library will provide an approach to study basic and clinical virology. High-throughput screening (HTS) of the reporter-tagged Ad library in a panel of cell lines including osteosarcoma disease-specific cell lines revealed alternative virus types with enhanced transduction and oncolysis efficiencies. This highlights the usefulness of this resource.


Assuntos
Adenoviridae/genética , Biblioteca Gênica , Engenharia Genética , Vetores Genéticos/metabolismo , Sequência de Bases , Clonagem Molecular , Genes Reporter , Genoma Viral , Ensaios de Triagem em Larga Escala , Humanos
17.
Cell ; 163(6): 1527-38, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26638077

RESUMO

The killifish Nothobranchius furzeri is the shortest-lived vertebrate that can be bred in the laboratory. Its rapid growth, early sexual maturation, fast aging, and arrested embryonic development (diapause) make it an attractive model organism in biomedical research. Here, we report a draft sequence of its genome that allowed us to uncover an intra-species Y chromosome polymorphism representing-in real time-different stages of sex chromosome formation that display features of early mammalian XY evolution "in action." Our data suggest that gdf6Y, encoding a TGF-ß family growth factor, is the master sex-determining gene in N. furzeri. Moreover, we observed genomic clustering of aging-related genes, identified genes under positive selection, and revealed significant similarities of gene expression profiles between diapause and aging, particularly for genes controlling cell cycle and translation. The annotated genome sequence is provided as an online resource (http://www.nothobranchius.info/NFINgb).


Assuntos
Evolução Biológica , Peixes Listrados/genética , Cromossomos Sexuais , Envelhecimento , Animais , Feminino , Genoma , Peixes Listrados/fisiologia , Masculino , Dados de Sequência Molecular , Processos de Determinação Sexual
18.
DNA Res ; 21(1): 27-39, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24122896

RESUMO

Alternative splicing (AS) is a cellular process that increases a cell's coding capacity from a limited set of genes. Although AS is common in higher plants and animals, its prevalence in other eukaryotes is mostly unknown. In fungi the involvement of AS in gene expression and its effect on multi-cellularity and virulence is of great medical and economic interest. We present a genome-wide comparative study of AS in 23 informative fungi of different taxa, based on alignments of public transcript sequences. Random sampling of expressed sequence tags allows for robust and comparable estimations of AS rates. We find that a greater fraction of fungal genes than previously expected is associated with AS. We estimate that on average, 6.4% of the annotated genes are affected by AS, with Cryptococcus neoformans showing an extraordinary rate of 18%. The investigated Basidiomycota show higher average AS rates (8.6%) than the Ascomycota (6.0%), although not significant. We find that multi-cellular complexity and younger evolutionary age associate with higher AS rates. Furthermore, AS affects genes involved in pathogenic lifestyle, particularly in functions of stress response and dimorphic switching. Together, our analysis strongly supports the view that AS is a rather common phenomenon in fungi and associates with higher multi-cellular complexity.


Assuntos
Processamento Alternativo , Fungos/genética , Genoma Fúngico , Animais , Fungos/patogenicidade , Íntrons , Especificidade da Espécie , Virulência/genética
19.
Environ Sci Technol ; 47(18): 10397-404, 2013 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-23844612

RESUMO

Aircraft black carbon (BC) emissions contribute to climate forcing, but few estimates of BC emitted by aircraft at cruise exist. For the majority of aircraft engines the only BC-related measurement available is smoke number (SN)-a filter based optical method designed to measure near-ground plume visibility, not mass. While the first order approximation (FOA3) technique has been developed to estimate BC mass emissions normalized by fuel burn [EI(BC)] from SN, it is shown that it underestimates EI(BC) by >90% in 35% of directly measured cases (R(2) = -0.10). As there are no plans to measure BC emissions from all existing certified engines-which will be in service for several decades-it is necessary to estimate EI(BC) for existing aircraft on the ground and at cruise. An alternative method, called FOX, that is independent of the SN is developed to estimate BC emissions. Estimates of EI(BC) at ground level are significantly improved (R(2) = 0.68), whereas estimates at cruise are within 30% of measurements. Implementing this approach for global civil aviation estimated aircraft BC emissions are revised upward by a factor of ~3. Direct radiative forcing (RF) due to aviation BC emissions is estimated to be ~9.5 mW/m(2), equivalent to ~1/3 of the current RF due to aviation CO2 emissions.


Assuntos
Poluentes Atmosféricos/análise , Aviação , Modelos Teóricos , Fuligem/análise , Fumaça
20.
BMC Evol Biol ; 13: 77, 2013 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-23551990

RESUMO

BACKGROUND: Early evolutionary theories of aging predict that populations which experience low extrinsic mortality evolve a retarded onset of senescence. Experimental support for this theory in vertebrates is scarce, in part for the difficulty of quantifying extrinsic mortality and its condition- and density-dependent components that -when considered- can lead to predictions markedly different to those of the "classical" theories. Here, we study annual fish of the genus Nothobranchius whose maximum lifespan is dictated by the duration of the water bodies they inhabit. Different populations of annual fish do not experience different strengths of extrinsic mortality throughout their life span, but are subject to differential timing (and predictability) of a sudden habitat cessation. In this respect, our study allows testing how aging evolves in natural environments when populations vary in the prospect of survival, but condition-dependent survival has a limited effect. We use 10 Nothobranchius populations from seasonal pools that differ in their duration to test how this parameter affects longevity and aging in two independent clades of these annual fishes. RESULTS: We found that replicated populations from a dry region showed markedly shorter captive lifespan than populations from a humid region. Shorter lifespan correlated with accelerated accumulation of lipofuscin (an established age marker) in both clades. Analysis of wild individuals confirmed that fish from drier habitats accumulate lipofuscin faster also under natural conditions. This indicates faster physiological deterioration in shorter-lived populations. CONCLUSIONS: Our data provide a strong quantitative example of how extrinsic mortality can shape evolution of senescence in a vertebrate clade. Nothobranchius is emerging as a genomic model species. The characterization of pairs of closely related species with different longevities should provide a powerful paradigm for the identification of genetic variations responsible for evolution of senescence in natural populations.


Assuntos
Envelhecimento , Longevidade , Smegmamorpha/classificação , Smegmamorpha/genética , Animais , Clima , Ecossistema , Lipofuscina/análise , Smegmamorpha/fisiologia
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