Following fusion of the human immunodeficiency virus type-1 (HIV-1) with host cells' membrane and reverse transcription of the viral RNA, the resulted cDNA is integrated into the host genome by the viral integrase enzyme (IN). Quantitative estimations have revealed that only 1–2 copies are integrated per infected cell, although many copies of the viral RNA are reverse-transcribed. The molecular mechanism that restricts the integration degree has not, so far, been elucidated. Following integration, expressed partially spliced and unspliced transcripts are exported from the nuclei by the viral Rev protein. Here, we show that in virally infected cells, the Rev interacts with the IN forming a Rev–IN complex and consequently limits the number of integration events. Disruption of the Rev–IN complex by selected IN-derived peptides or infection by a Rev-deficient virus stimulate integration resulting in large numbers of integration event/cell. Conversely, infection of Rev-expression cells blocks integration and inhibits virus production. Increased integration appears to correlate with increased cell death of infected cultures. Our results thus demonstrate a new regulatory function of Rev and probably establish a link between Rev restriction of HIV-1 integration and protection of HIV-1-infected cells from premature cell death.
Cocaine-induced modifications of glutamatergic synaptic transmission in the mesolimbic system play a key role in adaptations that promote addictive behaviors. In particular, the activation of ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) in the ventral tegmental area (VTA) is critical for both cocaine-induced synaptic plasticity induced by a single cocaine injection and for the initiation of cocaine psychomotor sensitization. In this study, we set to determine whether the NR2 subunits of the NMDAR play a specific role in triggering cocaine-induced alterations in synaptic plasticity and the development of psychomotor sensitization. We found that inhibition of NR2A-containing NMDARs by NVP-AAM077, or NR2B-containing receptors by ifenprodil, blocked cocaine-induced increase in the AMPAR/NMDAR currents ratio, a measure of long-term potentiation (LTP) in vivo, in VTA neurons 24h following a single cocaine injection. Furthermore, inhibition of the NR2A subunit during the development of psychomotor sensitization attenuated the enhanced locomotor activity following repeated cocaine injections. Together, these results suggest that NR2-containing NMDA receptors play an important role in the machinery that triggers synaptic and behavioral adaptations to drugs of abuse such as cocaine.
Miron Prokocimer, Davidovich, Maya , Nissim-Rafinia, Malka , Wiesel-Motiuk, Naama , Bar, Daniel Z, Barkan, Rachel , Meshorer, Eran , ו Gruenbaum, Yosef . 2009. “Nuclear Lamins: Key Regulators Of Nuclear Structure And Activities.”. J Cell Mol Med, 13, 6, Pp. 1059-85. doi:10.1111/j.1582-4934.2008.00676.x. תקציר
The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies’. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases.
Eran Meshorer ו Gruenbaum, Yosef . 2009. “Nurd Keeps Chromatin Young.”. Nat Cell Biol, 11, 10, Pp. 1176-7. doi:10.1038/ncb1009-1176.
It is often assumed that Testimony and Autobiography are clearly distinct genres. On this view Testimony conveys eye-witness reports of particular tragic events, whether momentary or of longer duration (e.g. years in a concentration camp), while Autobiography is seen as more chronologically extended and more introspective. However, since many Holocaust narratives incorporate “testimony” into a larger life-narrative which, among other things, traces the psychological effects of trauma in later years, it seems reasonable to see Testimony, at least in some instances, as an aspect of Autobiography. As always, such generic markers should be seen as heuristic indicators, not as inflexible taxonomic categories. Most serious writers agentially deploy, develop and combine generic possibilities. One such writer is Jacob G. Rosenberg, Australia’s finest Jewish autobiographer and a world class figure in Holocaust writing. Born into a Bundist family in Lodz in 1922, Rosenberg is the author of two award-winning autobiographical volumes, East of Time (2005) and Sunrise West (2007), that narrate his life in the Lodz Ghetto, Auschwitz and Ebensee, and Australia. His is a hybrid art fusing scriptural and folk materials with influences from Yiddish literature and Western modernity. His signature technique -- the imaginatively charged vignette -- is equally attuned to the description of horror and of redemptive, sometimes visionary, enchantment. Though the psychological dimension of his writing owes more to Yiddish sources than to Freudian modernity, his tracing of trauma’s aftermath down the years constitutes full-blown autobiographical writing which powerfully incorporates and extends the act of testimony. Rosenberg writes: “Once you have been tortured, you are forever tortured.”
Professor of English and Director of the Unit for Studies in Biography and Autobiography at La Trobe University, Melbourne, and is currently Tong Tin Sun Chair Professor and Head, Department of English, at Lingnan University, Hong Kong. He has published books on the English and American novel, relations between literary theory and philosophy, ethics and life-writing. His books include Threads of Life: Autobiography and the Will (Chicago, 2001); a memoir, Shadow of Doubt: My Father and Myself (Bystander, 2003), and This Crazy Thing a Life: Australian Jewish Autobiography (University of Western Australia Press, 2007).
Over the past several decades, economists, psychologists, and neuroscientists have conducted experiments in which a subject, human or animal, repeatedly chooses between alternative actions and is rewarded based on choice history. While individual choices are unpredictable, aggregate behavior typically follows Herrnstein's matching law: the average reward per choice is equal for all chosen alternatives. In general, matching behavior does not maximize the overall reward delivered to the subject, and therefore matching appears inconsistent with the principle of utility maximization. Here we show that matching can be made consistent with maximization by regarding the choices of a single subject as being made by a sequence of multiple selves-one for each instant of time. If each self is blind to the state of the world and discounts future rewards completely, then the resulting game has at least one Nash equilibrium that satisfies both Herrnstein's matching law and the unpredictability of individual choices. This equilibrium is, in general, Pareto suboptimal, and can be understood as a mutual defection of the multiple selves in an intertemporal prisoner's dilemma. The mathematical assumptions about the multiple selves should not be interpreted literally as psychological assumptions. Human and animals do remember past choices and care about future rewards. However, they may be unable to comprehend or take into account the relationship between past and future. This can be made more explicit when a mechanism that converges on the equilibrium, such as reinforcement learning, is considered. Using specific examples, we show that there exist behaviors that satisfy the matching law but are not Nash equilibria. We expect that these behaviors will not be observed experimentally in animals and humans. If this is the case, the Nash equilibrium formulation can be regarded as a refinement of Herrnstein's matching law.
Organic‐inorganic sol‐gel composite incorporating highly emitting CdSe/ZnS quantum dots and CdSe/CdS/ZnS quantum rods is reported. Optical gain measurements conducted on a quantum rod/sol‐gel composite film show stable room temperature amplified spontaneous emission under ambient conditions.
Peripheral blood monocytes play a central role in the mononuclear phagocyte system by providing a critical link between the bone marrow (BM), as major site of adult hematopoiesis, and peripheral, terminally differentiated mononuclear phagocyte populations, as represented macrophages and dendritic cells. Moreover, recent experimental evidence highlights the plasticity of these ephemeral mobile cells and their direct involvement in the establishment and resolution of inflammatory reactions. Here we summarize the recent advance in our understanding of monocyte origins, subset dynamics and monocyte fates. In particular, we will focus on emerging evidence for monocyte recirculation to the BM and discuss its potential implications in health and disease.
The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.
