837 research outputs found
Franck: Father of the Organ Symphony
No full textNew light on the performance of Frabnck's Organ Works, explained and demonstrated by Joris Verdin at the organ of Royaumont (F). Commentaries and Performance of harmonium pieces by Franck, at the Mustel 1874 harmonium d'art.status: Publishe
Characterization of a complex of necroviruses involved in a necrotic disease of corn salad (Valerianella locusta)
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Histone Deacetylase 7 Licenses Innate Effector Development in iNKT Cells
No full textInnate effector lymphocytes, including invariant natural killer T-cells (iNKT), are conserved and integral components of the vertebrate immune system that orchestrate the early host response to infection, yet the mechanisms by which developing thymocytes acquire either a naïve or innate effector identity remain unclear. Here we report that histone deacetylase 7 (HDAC7), a highly conserved signal-dependent transcriptional corepressor abundantly expressed in thymocytes, is a crucial regulatory factor that licenses innate effector development in iNKT cells. In a gain-of-function setting where HDAC7 is constitutively nuclear localized, innate effector development is blocked and iNKT cells become diverted to extremely rare, naïve-like T-cells with limited cytokine production and propensity to recirculate. Conversely, in a loss-of-function setting where HDAC7 is removed via conditional genetic deletion, naïve T-cell development is impeded and more thymocytes acquire an innate effector identity, particularly in an Eomesodermin-expressing CD8 peripheral subset that resembles so-called “innate memory” T-cells. Regulation of this fate decision hinges on the ability of HDAC7 to antagonize the transcriptional activity of Promyelocytic Leukemia Zinc Finger (PLZF), a signature innate effector transcription factor of innate effector development, which we demonstrate occurs in part through upstream transcriptional repression and direct physical binding. Finally, we find that in mice with a gain-of-function HDAC7 transgene which spontaneously develop tissue-specific autoimmunity directed mainly against the hepatobiliary tissues and gastrointestinal mucosa, restoring iNKT cells in vivo can mitigate tissue destruction and reduce mortality rate. These studies identify HDAC7 as an important epigenetic licensing factor that controls naïve versus innate effector development in thymocytes and implicates a heretofore underappreciated role for innate effectors in protecting against autoimmune disease
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Elucidating Molecular Changes in CD8+ T cells During Aging
No full textOne of the consequences of human aging is an overall decline in immune function. A hallmark of this aging process, termed immunosenescence, is the downregulation of co-receptor CD28 from the surface of CD8+ T cells. This population of terminally differentiated CD8+CD28– T cells accumulates during aging and chronic infections, and is linked to many age-related diseases observed in elderly individuals. In this thesis, we explore the molecular factors regulating CD8+CD28– T cell fate and function. In Chapter III, we find that resting CD8+CD28– T cells possess a unique glycolytic profile that is associated with their enhanced cytotoxicity and decreased expression of NAD+-dependent protein deacetylase SIRT1. Global gene–expression profiling identified the transcription factor FoxO1 as a SIRT1-target involved in the transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in CD8+CD28– T cells, and inhibiting its activity in CD8+CD28+ T cells recapitulates the metabolic and cytotoxic phenotype of resting CD8+CD28– T cells. In Chapter IV, we explore the signaling and functional consequences of IL-15, a pro-memory cytokine that serves as a TCR-independent activation signal for CD8+CD28– T cells. We find that IL-15 signals through mTOR to upregulate a metabolic program conducive for effector T cell function. Targeting CD8+CD28– T cells with a SIRT1 activator or glucose-starvation suppresses IL-15-induced cytotoxicity and proliferation. Altogether, this body of work identifies new molecular pathways that regulate the function of human CD8+CD28– T cells—providing deeper insight into the mechanisms of immune aging, as well as novel therapeutic opportunities to target it
The intragenic enhancer of human immunodeficiency virus type 1 contains functional AP-1 binding sites.
No full textAn intragenic enhancer in the pol gene of human immunodeficiency virus type 1 has previously been identified (Verdin et al. Proc. Natl. Acad. Sci. USA 87:4874-4878, 1990). This element is composed of two subdomains both exhibiting phorbol ester-inducible enhancing activity on the viral thymidine kinase promoter in HeLa cells. Examination of the nucleotide sequence of one of these domains (nucleotides 4079 to 4342, HXB2 isolate) revealed the presence of three short DNA regions highly homologous to the recognition site for cellular transcription factor AP-1. Two short oligonucleotides containing these AP-1 sites each functioned as a phorbol ester-inducible enhancer when cloned upstream of the thymidine kinase promoter and transfected into HeLa cells. Gel mobility shift assays and competition experiments using the same two oligonucleotides demonstrated that they bound affinity-purified AP-1 or AP-1 present in uninduced and 12-O-tetradecanoylphorbol-13-acetate-induced HeLa nuclear extracts. Footprinting experiments confirmed that all three predicted sites bound purified AP-1. These results suggest that the AP-1 factor could play a role in the transcriptional regulation of human immunodeficiency virus type 1 gene expression.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
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BCL6 maintains thermogenic capacity of brown adipose tissue during dormancy
No full textDuring exposure to environmental cold, brown adipocytes protect against hypothermia by generating heat (thermogenesis). In warm environments, brown adipocytes become inactive or dormant, but still maintain their identity and thermogenic capacity, allowing rapid reactivation of thermogenesis upon subsequent cold exposure. Our understanding of the dormant state and its regulation is very limited. Here, we show that the transcription factor B cell leukemia/lymphoma 6 (BCL6) is specifically required for maintenance of thermogenic capacity during dormancy in mouse brown adipocytes. By a combination of both direct and indirect transcriptional mechanisms, BCL6 promotes uncoupled respiration, fatty acid oxidation, and survival in dormant brown adipocytes. In part, BCL6 achieves this by remodeling the epigenome of brown adipocytes to enforce brown and oppose white adipocyte cellular identity. Thus, unlike other transcription factors that regulate cold-induced thermogenesis, BCL6 is specifically required for maintenance of thermogenic fitness during adaptation to environmental warmth
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Transcriptional Regulation of the Synaptic Plasticity-Related Gene Arc
No full textHigher order mental processes, such as learning, memory, and cognition, are built upon the brain's remarkable capacity to convert everyday, transient experiences into stored memories that can last a lifetime. Specific biochemical and structural changes at synapses, the highly specialized points of communication between neurons, are thought to serve as the molecular basis for these processes. However, the underlying mechanisms that regulate these synaptic modifications are poorly understood. For example, it remains unclear how synaptic activity regulates specific patterns of gene expression required to maintain these long-term adaptive synaptic changes. To gain insight into these mechanisms, this study investigated the transcriptional regulation of Arc, a neuronal immediate-early gene (IEG) essential for synaptic plasticity. Several powerful techniques, which had not previously been used in combination to study the transcription of a neuronal IEG, were used here to identify and characterize the genomic regulatory regions directly involved in Arc transcription. The DNaseI hypersensitivity assay was first applied in primary rat cortical neuron cultures to screen the endogenous chromatin structure flanking the Arc gene locus for discrete "open" nucleosome-depleted regions. A novel reporter gene driven by these putative regulatory regions was then used to identify two transcriptional enhancer regions located ~6.5 kilobase pairs (Kb) and ~850-950 base pairs (bp) upstream of Arc. Bioinformatic analysis was then used to help identify an evolutionarily and functionally conserved serum response element (SRE) within the distal enhancer, as well as a conserved, yet non-canonical binding site for a putative novel neuronal transcription factor within the proximal enhancer. Biochemical binding studies confirmed that the serum response factor binds to this SRE in vivo at the endogenous Arc promoter, and that some unknown nuclear protein(s) binds in vitro to the proximal enhancer region. Finally, two additional regulatory regions, located ~9.3 Kb and ~700-850 bp upstream of Arc, with apparent repressor activity were also identified. Thus, this investigation provides novel insights into the molecular mechanisms underlying the regulation of Arc gene expression
Sequencing viral siRNAs to identify previously undescribed viruses and viroids in a panel of ornamental plant samples structured as a matrix of pools
No full textOrnamental plants constitute a largely unknown and potentially important source of pathogens affecting not only ornamental plants, but also major crop species. We have carried out studies using high-throughput sequencing of 21-24 nt RNAs from potentially virus-infected ornamental plants, followed by assembly of sequence scaffolds, to identify the virus and viroid genomes present in a panel of 67 plant samples representing 46 species belonging to the main sectors of the ornamental plant industry (cut flowers, pot plants, bulbs). A pilot study demonstrated that samples could be pooled (5 samples per pool), and the overall process simplified without loss of detection of important known pathogens. In a full-scale study, pools of 5 samples were organized in a 5 × 5 matrix to facilitate attribution of a sequence to a precise sample directly from analysis of the matrix. In the total of 67 samples analyzed in the two studies, partial sequences suggesting the presence of 25 previously unknown viruses and viroids were detected, including all types of virus and viroid genomes, and also showed four cases of known viruses infecting previously undescribed hosts. Furthermore, two types of potential mis-assembly were analyzed, and were shown to not affect the conclusions regarding the presence of the pathogens identified, but show that mis-assembly can affect the results when the objective is determining complete bona fide viral genome sequences. These results clearly confirm that ornamental plants constitute a potential source of unknown viruses and viroids that could have a major impact on agriculture, and that sequencing siRNAs of potentially virus- or viroid-infected ornamental plants is an effective means for screening for the presence of potentially important pathogens
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INVESTIGATING THE ROLE OF T CELL ACTIVATION ON THE ESTABLISHMENT OF HIV LATENCY IN PRIMARY CD4+ T CELLS USING A DUAL-REPORTER VIRUS
No full textAcquired Immunodeficiency virus (AIDS) has killed 36 million people since the first cases were reported in 1981, and is considered a worldwide pandemic. AIDS is caused by the human immunodeficiency virus (HIV), which first originated in Africa in the early 1900s, and by the 1980s had spread around the globe. HIV is a lentivirus that slowly destroys the immune system by infecting and killing CD4+ T cells. There is currently no cure or vaccine for HIV. However, drug therapy exists that is capable of controlling HIV infection, and prevents the progression to AIDS. Drug therapy cannot eradicate HIV because the virus can become transcriptionally silent after integrating its genetic material into the host cell's genome, resulting in latent infection. HIV latency is a reversible state, and allows the virus to remain within an infected individual for the entirety of their life-span. The study of HIV latency has been ongoing since 1986, but has been hindered by two major problems: 1) latently infected cells are extremely rare, in vivo; and 2) latently infected cells are indistinguishable from uninfected cells. The work of this dissertation focused on the development and utilization of an HIV dual-reporter virus that could identify latently infected cells, and distinguish them from productively infected and uninfected cells. The HIV dual-reporter viruses utilize two different fluorescent proteins. One fluorescent protein is under the control of the HIV LTR promoter, and identifies cells that are productively infected, while the other fluorescent protein is under the control of a constitutive promoter, independent of the viral promoter, and identifies cells that have integrated provirus. Infection of Jurkat cells and primary CD4+ T cells with these dual-reporter viruses allows for the identification and purification of latently infected cells. This isolated latent population which only expresses the fluorescent protein that is under the control of the constitutive promoter, is devoid of viral transcripts and viral proteins. One of these dual-reporter viruses, HIV Duo-Fluo I, was used to study the role of T cell activation on the establishment of HIV latency in primary CD4+ T cells. Resting primary CD4+ T cells are capable of supporting productive HIV infection, but show a propensity towards latent infection, while activated primary CD4+ T cells are capable of supporting latent infection, but show a propensity towards productive infection. Further, activated primary CD4+ T cells are capable of supporting latent infection without the need to return to a resting state. Our findings suggest that HIV latency is not completely dependent on T cell activation and that infection of both resting and activated primary CD4+ T cells can contribute to the HIV latent reservoir
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