Cognitive health in persons with human immunodeficiency virus: the impact of early treatment, comorbidities, and aging

With the advent of virally suppressive antiretroviral therapy (ART), life expectancy for persons with human immunodeficiency virus (HIV) with access to ART now approaches that of the general population. As persons with HIV age, noninfectious comorbidities occur more frequently compared with persons without HIV. Such comorbidities are likely to affect cognitive health, which may also be affected by lifestyle factors that may differ in persons with HIV. At the National Institutes of Health–supported meeting on Biotypes of Central Nervous System (CNS) Complications in persons with HIV, a session was devoted to early HIV treatment, noninfectious comorbidities, and aging as each pertains to cognitive health. Areas of consideration included acute and early HIV infection (presentation by Phillip Chan), drugs of abuse (Scott Letendre), stroke and cerebrovascular disease (Felicia Chow), mental health (John Joska), and aging (Julian Falutz). These presentations were followed by a discussion session led by Woody Lin, Jose A. Muñoz-Moreno, Paola Cinque, and Jeff Taylor. Alan Winston and Bruce Brew chaired the meeting with Jasmini Alagaratnam and Htein Linn Aung acting as rapporteurs. Here we present the main topics covered in the presentations, and the associated discussions highlighting knowledge gaps and future directions

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin

Epicardial epithelial-mesenchymal transition (EMT) is hypothesized to generate cardiovascular progenitor cells that differentiate into various cell types, including coronary smooth muscle and endothelial cells, perivascular and cardiac interstitial fibroblasts and cardiomyocytes. Here we show that an epicardial-specific knockout of Wt1 leads to a reduction of mesenchymal progenitor cells and their derivatives. We demonstrate that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during Embryonic Stem (ES) cell differentiation, through direct transcriptional regulation of Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages fail to form in Wt1 null embryoid bodies but this effect is rescued by the expression of Snai1, underlining the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell based therapies

Mu-Opioid Receptors Transiently Activate the Akt-nNOS Pathway to Produce Sustained Potentiation of PKC-Mediated NMDAR-CaMKII Signaling

BACKGROUND: In periaqueductal grey (PAG) matter, cross-talk between the Mu-opioid receptor (MOR) and the glutamate N-methyl-D-Aspartate receptor (NMDAR)-CaMKII pathway supports the development of analgesic tolerance to morphine. In neurons, histidine triad nucleotide binding protein 1 (HINT1) connects the regulators of G protein signaling RGSZ1 and RGSZ2 to the C terminus of the MOR. In response to morphine, this HINT1-RGSZ complex binds PKCgamma, and afterwards, the interplay between PKCgamma, Src and Gz/Gi proteins leads to sustained potentiation of NMDAR-mediated glutamate responses. METHODOLOGY/PRINCIPAL FINDINGS: Following an intracerebroventricular (icv) injection of 10 nmol morphine, Akt was recruited to the synaptosomal membrane and activated by Thr308 and Ser473 phosphorylation. The Akt activation was immediately transferred to neural Nitric Oxide Synthase (nNOS) Ser1417. Afterwards, nitric oxide (NO)-released zinc ions recruited PKCgamma to the MOR to promote the Src-mediated phosphorylation of the Tyr1325 NMDAR2A subunit. This action increased NMDAR calcium flux and CaMKII was activated in a calcium-calmodulin dependent manner. CaMKII then acted on nNOS Ser847 to produce a sustained reduction in NO levels. The activation of the Akt-nNOS pathway was also reduced by the binding of these proteins to the MOR-HINT1 complex where they remained inactive. Tolerance to acute morphine developed as a result of phosphorylation of MOR cytosolic residues, uncoupling from the regulated G proteins which are transferred to RGSZ2 proteins. The diminished effect of morphine was prevented by LNNA, an inhibitor of nNOS function, and naltrindole, a delta-opioid receptor antagonist that also inhibits Akt. CONCLUSIONS/SIGNIFICANCE: Analysis of the regulatory phosphorylation of the proteins included in the study indicated that morphine produces a transient activation of the Akt/PKB-nNOS pathway. This activation occurs upstream of PKCgamma and Src mediated potentiation of NMDAR activity, ultimately leading to morphine tolerance. In summary, the Akt-nNOS pathway acts as a primer for morphine-triggered events which leads to the sustained potentiation of the NMDAR-CaMKII pathway and MOR inhibition

Characterization of Microbialites and Microbial Mats of the Laguna Negra Hypersaline Lake (Puna of Catamarca, Argentina)

Microbial carbonates provide an invaluable tool to understand biogeochemical processes in aqueous systems, especially in lacustrine and marine environments. Lakes are strongly sensitive to climatically driven environmental changes, and microbialites have recently been shown to provide a record of these changes. Unraveling physicochemical and microbiological controls on carbonates textures and geochemistry is necessary to correctly interpret these signals and the microbial biosphere record within sedimentary carbonates. The Laguna Negra is a high-altitude hypersaline Andean lake (Puna of Catamarca, Argentina), where abundant carbonate precipitation takes place and makes this system an interesting example that preserves a spectrum of carbonate fabrics reflecting complex physical, chemical, and biological interactions. The extreme environmental conditions (high UV radiation, elevated salinity, and temperature extremes) make the Laguna Negra a good analogue to some Precambrian microbialites (e.g., Tumbiana Fm., Archean, Australia). In addition, the discovery of ancient evaporating playa-lake systems on Mars’ surface (e.g., ShalbatanaVallis, Noachian, Mars) highlights the potential of Laguna Negra to provide insight into biosignature preservation in similar environments, in both terrestrial and extraterrestrial settings, given that microbial processes in the Laguna Negra can be studied with remarkable detail.Fil: Boidi, Flavia Jaquelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Mlewski, Estela Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Gomez, Fernando Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Gérard, Emmanuelle. Centre National de la Recherche Scientifique; Franci

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold

Fire and brief human occupations in Iberia during MIS 4: Evidence from Abric del Pastor (Alcoy, Spain)

There is a relatively low amount of Middle Paleolithic sites in Europe dating to MIS 4. Of the few that exist, several of them lack evidence for anthropogenic fire, raising the question of how this period of global cooling may have affected the Neanderthal population. The Iberian Peninsula is a key area to explore this issue, as it has been considered as a glacial refugium during critical periods of the Neanderthal timeline and might therefore yield archaeological contexts in which we can explore possible changes in the behaviour and settlement patterns of Neanderthal groups during MIS 4. Here we report recent data from Abric del Pastor, a small rock shelter in Alcoy (Alicante, Spain) with a stratified deposit containing Middle Palaeolithic remains. We present absolute dates that frame the sequence within MIS 4 and multi-proxy geoarchaeological evidence of in situ anthropogenic fire, including microscopic evidence of in situ combustion residues and thermally altered sediment. We also present archaeostratigraphic evidence of recurrent, functionally diverse, brief human occupation of the rock shelter. Our results suggest that Neanderthals occupied the Central Mediterranean coast of the Iberian Peninsula during MIS 4, that these Neanderthals were not undergoing climatic stress and they were habitual fire users.This research was funded by a Leakey Foundation General Grant, Spanish Ministry of Science, Innovation and Universities Projects HAR2008-06117/HIST and HAR2015-68321-P, Junta de Castilla y León-FEDER Project BU235P18, the LabEx Sciences Archéologiques de Bordeaux (LaScArBx ANR-10-LABX-52) and ERC Consolidator Grant ERC-CoG-2014. Archaeological excavations at Abric del Pastor are supported by the Archaeological Museum of Alcoy and the Government of Valencia Cultural Heritage Department

Territoriality and the organization of technology during the Last Glacial Maximum in southwestern Europe

Climate changes that occurred during the Last Glacial Maximum (LGM) had significant consequences in human eco-dynamics across Europe. Among the most striking impacts are the demographic contraction of modern humans into southern refugia and the potential formation of a population bottleneck. In Iberia and southern France transformations also included the occurrence of significant technological changes, mostly marked by the emergence of a diverse set of bifacially-shaped stone projectiles. The rapid dissemination of bifacial technologies and the geographical circumscription of specific projectile morphologies within these regions have been regarded as evidence for: (1) the existence of a system of long-distance exchange and social alliance networks; (2) the organization of human groups into cultural facies with well-defined stylistic territorial boundaries. However, the degree and modes in which cultural transmission have occurred within these territories, and how it may have influenced other domains of the adaptive systems, remains largely unknown. Using southern Iberia as a case-study, this paper presents the first quantitative approach to the organization of lithic technology and its relationship to hunter-gatherers' territorial organization during the LGM. Similarities and dissimilarities in the presence of morphological and metric data describing lithic technologies are used as a proxy to explore modes and degrees of cultural transmission. Statistical results show that similarities in technological options are dependent on the chronology and geographical distance between sites and corroborate previous arguments for the organization of LGM settlement in Southern Iberia into discrete eco-cultural facies.STSM COST action (ref. COST-STSM-TD0902-10855); FCT, contract ref. DL 57/2016/CP1361/ CT0026. Work at Vale Boi is funded by the project ALG-01-0145-FEDER-27833 - PTDC/HAR-ARQ/27833/2017.info:eu-repo/semantics/publishedVersio

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis