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Find video protocols related to scientific articles indexed in Pubmed.
Alternative polyadenylation regulates CELF1/CUGBP1 target transcripts following T cell activation.
Gene
PUBLISHED: 08-11-2014
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Alternative polyadenylation (APA) is an evolutionarily conserved mechanism for regulating gene expression. Transcript 3' end shortening through changes in polyadenylation site usage occurs following T cell activation, but the consequences of APA on gene expression are poorly understood. We previously showed that GU-rich elements (GREs) found in the 3' untranslated regions of select transcripts mediate rapid mRNA decay by recruiting the protein CELF1/CUGBP1. Using a global RNA sequencing approach, we found that a network of CELF1 target transcripts involved in cell division underwent preferential 3' end shortening via APA following T cell activation, resulting in decreased inclusion of CELF1 binding sites and increased transcript expression. We present a model whereby CELF1 regulates APA site selection following T cell activation through reversible binding to nearby GRE sequences. These findings provide insight into the role of APA in controlling cellular proliferation during biological processes such as development, oncogenesis and T cell activation.
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Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.
N. Engl. J. Med.
PUBLISHED: 06-26-2014
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Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.
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Human papillomavirus vaccine acceptance among young men in Bangalore, India.
Int. J. Dermatol.
PUBLISHED: 06-25-2014
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Human papillomavirus (HPV) is the most common sexually transmitted infection in the world. It can lead to anogenital, cervical, and head and neck cancer, with higher risk of malignant disease in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. In India, 73,000 of the 130,000 women diagnosed with cervical cancer die annually. Gardasil(®) , a vaccine available against HPV types 6, 11, 16, and 18, is approved for use in women in India but not men. A backlash to post-licensure trials has created a negative public opinion of the vaccine for women. Vaccinating boys and men is an alternate approach to prevent cervical cancer in women. This study gauges facilitators and barriers to vaccination acceptance among men in Bangalore, India.
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Post-transcriptional regulation of cytokine signaling by AU-rich and GU-rich elements.
J. Interferon Cytokine Res.
PUBLISHED: 04-05-2014
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Cytokines are necessary for cell communication to enable responses to external stimuli that are imperative for the survival and maintenance of homeostasis. Dysfunction of the cytokine network has detrimental effects on intra- and extracellular environments. Thus, it is critical that the expression of cytokines and the signals transmitted by cytokines to target cells are tightly regulated at numerous levels, including transcriptional and post-transcriptional levels. Here, we briefly summarize the role of AU-rich elements (AREs) in the regulation of cytokine gene expression at the post-transcriptional level and describe a role for GU-rich elements (GREs) in coordinating the regulation of cytokine signaling. GREs function as post-transcriptional regulators of proteins that control cellular activation, growth, and apoptosis. GREs and AREs work in concert to coordinate cytokine signal transduction pathways. The precise regulation of cytokine signaling is particularly important, because its dysregulation can lead to human diseases.
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AIDS-related mycoses: the way forward.
Trends Microbiol.
PUBLISHED: 03-04-2014
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The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
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CELFish ways to modulate mRNA decay.
Biochim. Biophys. Acta
PUBLISHED: 01-03-2013
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The CELF family of RNA-binding proteins regulates many steps of mRNA metabolism. Although their best characterized function is in pre-mRNA splice site choice, CELF family members are also powerful modulators of mRNA decay. In this review we focus on the different modes of regulation that CELF proteins employ to mediate mRNA decay by binding to GU-rich elements. After starting with an overview of the importance of CELF proteins during development and disease pathogenesis, we then review the mRNA networks and cellular pathways these proteins regulate and the mechanisms by which they influence mRNA decay. Finally, we discuss how CELF protein activity is modulated during development and in response to cellular signals. We conclude by highlighting the priorities for new experiments in this field. This article is part of a Special Issue entitled: RNA Decay mechanisms.
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Regulation of CUG-binding protein 1 (CUGBP1) binding to target transcripts upon T cell activation.
J. Biol. Chem.
PUBLISHED: 11-23-2011
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The RNA-binding protein, CUG-binding protein 1 (CUGBP1), regulates gene expression at the levels of alternative splicing, mRNA degradation, and translation. We used RNA immunoprecipitation followed by microarray analysis to identify the cytoplasmic mRNA targets of CUGBP1 in resting and activated primary human T cells and found that CUGBP1 targets were highly enriched for the presence of GU-rich elements (GREs) in their 3-untranslated regions. The number of CUGBP1 target transcripts decreased dramatically following T cell activation as a result of activation-dependent phosphorylation of CUGBP1 and decreased ability of CUGBP1 to bind to GRE-containing RNA. A large percentage of CUGBP1 target transcripts exhibited rapid and transient up-regulation, and a smaller percentage exhibited transient down-regulation following T cell activation. Many of the transiently up-regulated CUGBP1 target transcripts encode important regulatory proteins necessary for transition from a quiescent state to a state of cellular activation and proliferation. Overall, our results show that CUGBP1 binding to certain GRE-containing target transcripts decreased following T cell activation through activation-dependent phosphorylation of CUGBP1.
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Global assessment of GU-rich regulatory content and function in the human transcriptome.
RNA Biol
PUBLISHED: 07-01-2011
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Unlike AU-rich elements (AREs) that are largely present in the 3UTRs of many unstable mammalian mRNAs, the function and abundance of GU-rich elements (GREs) are poorly understood. We performed a genome-wide analysis and found that at least 5% of human genes contain GREs in their 3UTRs with functional over-representation in genes involved in transcription, nucleic acid metabolism, developmental processes, and neurogenesis. GREs have similar sequence clustering patterns with AREs such as overlapping GUUUG pentamers and enrichment in 3UTRs. Functional analysis using T-cell mRNA expression microarray data confirms correlation with mRNA destabilization. Reporter assays show that compared to AREs the ability of GREs to destabilize mRNA is modest and does not increase with the increasing number of overlapping pentamers. Naturally occurring GREs within U-rich contexts were more potent in destabilizing GFP reporter mRNAs than synthetic GREs with perfectly overlapping pentamers. Overall, we find that GREs bear a resemblance to AREs in sequence patterns but they regulate a different repertoire of genes and have different dynamics of mRNA decay. A dedicated resource on all GRE-containing genes of the human, mouse and rat genomes can be found at brp.kfshrc.edu.sa/GredOrg.
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Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death.
J. Infect. Dis.
PUBLISHED: 05-20-2011
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Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups.
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Coordinate regulation of mRNA decay networks by GU-rich elements and CELF1.
Curr. Opin. Genet. Dev.
PUBLISHED: 03-16-2011
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The GU-rich element (GRE) was identified as a conserved sequence enriched in the 3 UTR of human transcripts that exhibited rapid mRNA turnover. In mammalian cells, binding to GREs by the protein CELF1 coordinates mRNA decay of networks of transcripts involved in cell growth, migration, and apoptosis. Depending on the context, GREs and CELF1 also regulate pre-mRNA splicing and translation. GREs are highly conserved throughout evolution and play important roles in the development of organisms ranging from worms to man. In humans, abnormal GRE-mediated regulation contributes to disease states and cancer. Thus, GREs and CELF proteins serve critical functions in gene expression regulation and define an important evolutionarily conserved posttranscriptional regulatory network.
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Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions.
Lancet Infect Dis
PUBLISHED: 10-30-2010
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Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
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Antiretroviral therapy down-regulates innate antiviral response genes in patients with AIDS in sub-saharan Africa.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 09-15-2010
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HIV pathogenesis is characterized by destructive imbalances between virus-mediated immune damage, antiviral immune responses, and immune activation. We characterized the effects of successful antiretroviral therapy (ART) to identify the breadth and patterns of HIV-associated gene expression.
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Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome.
J. Infect. Dis.
PUBLISHED: 08-04-2010
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Cryptococcal meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20%-40% of ART-naive persons with AIDS and prior CM. Pathogenesis is unknown.
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Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings.
Clin. Infect. Dis.
PUBLISHED: 07-06-2010
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Cryptococcal meningitis (CM) remains a common AIDS-defining illness in Africa and Asia. Subclinical cryptococcal antigenemia is frequently unmasked with antiretroviral therapy (ART). We sought to define the cost-effectiveness of serum cryptococcal antigen (CRAG) screening to identify persons with subclinical cryptococcosis and the efficacy of preemptive fluconazole therapy.
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Analysis of CUGBP1 targets identifies GU-repeat sequences that mediate rapid mRNA decay.
Mol. Cell. Biol.
PUBLISHED: 06-14-2010
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CUG-repeat binding protein 1 (CUGBP1) mediates selective mRNA decay by binding to GU-rich elements (GREs) containing the sequence UGUUUGUUUGU found in the 3 untranslated region (UTR) of short-lived transcripts. We used an anti-CUGBP1 antibody to immunoprecipitate CUGBP1 from HeLa cytoplasmic extracts and analyzed the associated transcripts using oligonucleotide microarrays. We identified 613 putative mRNA targets of CUGBP1 and found that the UGUUUGUUUGU GRE sequence and a GU-repeat sequence were both highly enriched in the 3 UTRs of these targets. We showed that CUGBP1 bound specifically to the GU-repeat sequence and that insertion of this sequence into the 3 UTR of a beta-globin reporter transcript conferred instability to the transcript. Based on these results, we redefined the GRE to include this GU-repeat sequence. Our results suggest that CUGBP1 coordinately regulates the mRNA decay of a network of transcripts involved in cell growth, cell motility, and apoptosis.
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Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study.
PLoS Med.
PUBLISHED: 05-25-2010
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Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.
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Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory.
J. Immunol.
PUBLISHED: 07-10-2009
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A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of approximately 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-alpha, or histone deacetylase inhibitors. Thus, IL-12 and IFN-alpha/beta enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.
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Tristetraprolin mediates interferon-gamma mRNA decay.
J. Biol. Chem.
PUBLISHED: 03-03-2009
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Tristetraprolin (TTP) regulates expression at the level of mRNA decay of several cytokines, including the T cell-specific cytokine, interleukin-2. We performed experiments to determine whether another T cell-specific cytokine, interferon-gamma (IFN-gamma), is also regulated by TTP and found that T cell receptor-activated T cells from TTP knock-out mice overproduced IFN-gamma mRNA and protein compared with activated T cells from wild-type mice. The half-life of IFN-gamma mRNA was 23 min in anti-CD3-stimulated T cells from wild-type mice, whereas it was 51 min in anti-CD3-stimulated T cells from TTP knock-out mice, suggesting that the overexpression of IFN-gamma mRNA in TTP knock-out mice was due to stabilization of IFN-gamma mRNA. Insertion of a 70-nucleotide AU-rich sequence from the murine IFN-gamma 3-untranslated region, which contained a high affinity binding site for TTP, into the 3-untranslated region of a beta-globin reporter transcript conferred TTP-dependent destabilization on the beta-globin transcript. Together these results suggest that TTP binds to a functional AU-rich element in the 3-untranslated region of IFN-gamma mRNA and mediates rapid degradation of the IFN-gamma transcript. Thus, TTP plays an important role in turning off IFN-gamma expression at the appropriate time during an immune response.
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Long term 5-year survival of persons with cryptococcal meningitis or asymptomatic subclinical antigenemia in Uganda.
PLoS ONE
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Data presented previously as an abstract at the 2011 CUGH Global Health Conference in Montreal, Canada on 15 Nov 2011. The long-term survival of HIV-infected persons with symptomatic cryptococcal meningitis and asymptomatic, subclinical cryptococcal antigenemia (CRAG+) is unknown. We prospectively enrolled 25 asymptomatic, antiretroviral therapy (ART)-naïve CRAG+ Ugandans with CD4<100 cells/mcL who received pre-emptive fluconazole treatment (CRAG+ cohort) and 189 ART-naïve Ugandans with symptomatic cryptococcal meningitis treated with amphotericin (CM cohort). The 10-week survival was 84% (95%CI: 70-98%) in the CRAG+ cohort and 57% (95%CI: 50%-64%) in the CM cohort. The CRAG+ cohort had improved five-year survival of 76% (95%CI: 59%-93%) compared to 42% (95%CI: 35%-50%) in the CM cohort (P = 0.001). The two cohorts had similar immunosuppression pre-ART with median CD4 counts of 15 vs. 21 CD4/mcL in the CRAG+ and CM cohorts, respectively (P = 0.45). Despite substantial early mortality, subsequent 5-year survival of persons surviving 6-months was excellent (>88%), demonstrating that long term survival is possible in resource-limited settings. Pre-ART CRAG screening with preemptive fluconazole treatment and improved CM treatment(s) are needed to reduce AIDS-attributable mortality due to cryptococcosis which remains 20-25% in sub-Saharan Africa.
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Cryptococcal genotype influences immunologic response and human clinical outcome after meningitis.
MBio
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In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality.
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Perspectives on the ARE as it turns 25 years old.
Wiley Interdiscip Rev RNA
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The AU-rich element (ARE) was discovered in 1986 as a conserved mRNA sequence found in the 3 untranslated region of the TNF-? transcript and other transcripts encoding cytokines and inflammatory mediators. Shortly thereafter, the ARE was shown to function as a regulator of mRNA degradation, and AREs were later shown to regulate other posttranscriptional mechanisms such as translation and mRNA localization. AREs coordinately regulate networks of chemokine, cytokine, and growth regulatory transcripts involved in cellular activation, proliferation, and inflammation. ARE-mediated regulation is carried out by a host of ARE-binding proteins, whose activity is regulated in a cell type and activation-dependent manner. The last 25 years of ARE research has offered insight into the mechanisms and regulation of ARE-mediated mRNA decay, and has provided a road map for the discovery of additional mRNA regulatory motifs. The future of ARE research will transition from a discovery phase to a phase focused on translating basic biological findings into novel therapeutic targets. Our understanding of ARE-mediated gene regulation and posttranscriptional control has implications for many fields of study including developmental biology, neuroscience, immunobiology, and cancer biology.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.