Belrose G.,Center Hospitalier University Of Fort Of France |
Gross A.,Montpellier University |
Olindo S.,Center Hospitalier University Of Fort Of France |
Lezin A.,Center Hospitalier University Of Fort Of France |
And 8 more authors.
A determinant of human T-lymphotropic virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) development is the HTLV-1-infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of the pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4+-T cell clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of provirus-positive CD4+ T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax-positive-infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and Gag-mRNA levels peaked spontaneously, before declining concomitantly to HBZ-mRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome ofVPAtreatment on HTLV-1-infected-cell proliferation and survival. © 2011 by The American Society of Hematology. Source
Davenport N.R.,Cellular and Molecular Biology |
Sonnemann K.J.,Laboratory of Cell and Molecular Biology |
Eliceiri K.W.,Laboratory of Cell and Molecular Biology |
Eliceiri K.W.,Laboratory for Optical and Computational Instrumentation |
And 3 more authors.
Molecular Biology of the Cell
Cells rapidly reseal after damage, but how they do so is unknown. It has been hypothesized that resealing occurs due to formation of a patch derived from rapid fusion of intracellular compartments at the wound site. However, patching has never been directly visualized. Here we study membrane dynamics in wounded Xenopus laevis oocytes at high spatiotemporal resolution. Consistent with the patch hypothesis, we find that damage triggers rampant fusion of intracellular compartments, generating a barrier that limits influx of extracellular dextrans. Patch formation is accompanied by compound exocytosis, local accumulation and aggregation of vesicles, and rupture of compartments facing the external environment. Subcellular patterning is evident as annexin A1, dysferlin, diacylglycerol, active Rho, and active Cdc42 are recruited to compartments confined to different regions around the wound. We also find that a ring of elevated intracellular calcium overlaps the region where membrane dynamics are most evident and persists for several minutes. The results provide the first direct visualization of membrane patching during membrane repair, reveal novel features of the repair process, and show that a remarkable degree of spatial patterning accompanies damage-induced membrane dynamics. © 2016 van Gent and Kanaar. Source
Piserchio A.,City College of New York |
Warthaka M.,University of Texas at Austin |
Devkota A.K.,Cellular and Molecular Biology |
Kaoud T.S.,University of Texas at Austin |
And 6 more authors.
The mitogen-activated protein (MAP) kinase ERK2 contains recruitment sites that engage canonical and noncanonical motifs found in a variety of upstream kinases, regulating phosphatases and downstream targets. Interactions involving two of these sites, the D-recruitment site (DRS) and the F-recruitment site (FRS), have been shown to play a key role in signal transduction by ERK/MAP kinases. The dynamic nature of these recruitment events makes NMR uniquely suited to provide significant insight into these interactions. While NMR studies of kinases in general have been greatly hindered by their large size and complex dynamic behavior leading to the suboptimal performance of standard methodologies, we have overcome these difficulties for inactive full-length ERK2 and obtained an acceptable level of backbone resonance assignments. This allowed a detailed investigation of the structural perturbations that accompany interactions involving both canonical and noncanonical recruitment events. No crystallographic information exists for the latter. We found that the chemical shift perturbations in inactive ERK2, indicative of structural changes in the presence of canonical and noncanonical motifs, are not restricted to the recruitment sites but also involve the linker that connects the N- and C-lobes and, in most cases, a gatekeeper residue that is thought to exert allosteric control over catalytic activity. We also found that, even though the canonical motifs interact with the DRS utilizing both charge-charge and hydrophobic interactions, the noncanonical interactions primarily involve the latter. These results demonstrate the feasibility of solution NMR techniques for a comprehensive analysis of docking interactions in a full-length ERK/MAP kinase. © 2011 American Chemical Society. Source
Freed D.,Cellular and Molecular Biology |
Freed D.,Kennedy Krieger Institute |
Stevens E.L.,Kennedy Krieger Institute |
Stevens E.L.,U.S. Food and Drug Administration |
And 2 more authors.
Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny. These mutations affect varying genomic sizes ranging from single nucleotides to entire chromosomes and have been implicated in disease, most prominently cancer. The phenotypic consequences of somatic mosaicism are dependent upon many factors including the developmental time at which the mutation occurs, the areas of the body that are affected, and the pathophysiological effect(s) of the mutation. The advent of second-generation sequencing technologies has augmented existing array-based and cytogenetic approaches for the identification of somatic mutations. We outline the strengths and weaknesses of these techniques and highlight recent insights into the role of somatic mosaicism in causing cancer, neurodegenerative, monogenic, and complex disease. © 2014 by the authors; licensee MDPI, Basel, Switzerland. Source
Leading Indian scientists have voiced concerns during the past week over religious intolerance and the killings of three noted advocates of rational thinking. The action is an unusual occurrence in a country where scientists rarely step out of their research domains to comment on social or political issues. It follows an outcry by leading writers, who since September have been returning their national awards in protest against what they see as the government's failure to curb religious intolerance in India. Anti-superstition activist Narendra Dabholkar was killed in 2013, communist politician Govind Pansare in February of this year and literature scholar Malleshappa Kalburgi in August. All three killings have been blamed on members of extreme right-wing Hindu groups. The killing of Kalburgi triggered the protests from the writers, which intensified early this month after a mob in a town near New Delhi killed a Muslim man who was rumoured to have slaughtered a cow (Hinduism considers cows to be sacred animals). On 22 October, a group of scientists followed up the writers' protest by launching an online petition to India's president, Pranab Mukherjee, protesting against the killings. It gathered 268 signatories. The petition was followed on 27 October by a statement from the Inter-Academy Panel on Ethics in Science, a body set up by the Indian National Science Academy, New Delhi; the Indian Academy of Sciences, Bangalore; and the National Academy of Sciences, Allahabad. The statement pointed out that the Indian constitution mandated that “its citizens abide by and uphold reason and scientific temper”. “Yet,” it continued, ”we note with sadness and growing anxiety several of [sic] statements and actions which run counter to this constitutional requirement of every citizen of India,” and which should be “nipped in the bud”. Indira Nath, a member of the panel and an immunologist at the Indian National Science Academy in New Delhi, says that the panel wants to: “bring back rationality and scientific thinking to the mainstream. It is an apolitical statement and not directed against the government of the day.” A day later, more than 100 scientists from leading Indian science institutes, including national award winners, three fellows of the UK Royal Society and a foreign associate of the US National Academy of Sciences, signed a second statement expressing deep concern over the “climate of intolerance and the ways in which science and reason are being eroded in the country”. The scientists lamented what they called “active promotion of irrational and sectarian thought by important functionaries of the government”. Thiagarajan Jayaraman, who is chair of the Centre for Science, Technology and Society at the Tata Institute of Social Sciences in Mumbai and a lead signatory on the second statement, mentioned the example of a statement made by Prime Minister Narendra Modi in October 2014. Modi said that the Hindu elephant-headed deity Ganesha was an example of knowledge of transplantation in ancient India, and that the birth of some mythological characters in the ancient Indian text Mahabharata reflected knowledge of advanced genetics and stem cells. Naresh Dadhich, a physicist at the Inter-University Centre for Astronomy and Astrophysics in Pune, India, and one of the petitioners to the Indian president, says that “the government has failed to check or discourage the anti-rational environment”. All three advocates who were killed were “widely regarded by the scientific community as part of efforts to promote science among the public”, Jayaraman adds. Pushpa Mittra Bhargava, former director of the Centre for Cellular and Molecular Biology, says that he plans to return a national award in protest. “Science is about reason and rationality. If three rationalists can be killed, scientists too can be killed.” On 29 October, a group of Indian historians joined the fray by releasing their own statement protesting against religious superstition. Groups of artists and sociologists have also issued similar statements.