Brief Report: HIV-1 gp120 T-Cell Responses Correspond to Infection Outcomes in the Global iPrEx Chemoprophylaxis Trial.

Association of HIV-1-specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1β+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8 T-cell responses may help to protect against HIV-1 acquisition

Past millennium hydroclimate variability from Corsican pine tree-ring chronologies

Palaeoclimatic evidence is necessary to place the current warming and drying trends of the Mediterranean region in a long‐term perspective of pre‐industrial variability. Annually resolved and absolutely dated climate proxies that extend back into medieval times are, however, limited to a few sites only. Here we present a network of long ring width chronologies from Pinus nigra tree‐line sites in northern Corsica (France) that cohere exceptionally well over centuries and support the development of a single high‐elevation pine chronology extending back to 974 CE. We apply various detrending methods to these data to retain high‐to‐low frequency ring width variability and scale the resulting chronologies against instrumental precipitation and drought observations to produce hydroclimate reconstructions for the last millennium. Proxy calibration and transfer are challenged by a lack of high‐elevation meteorological data, however, limiting our understanding of precipitation changes in sub‐alpine tree‐line environments. Our new reconstructions extend beyond existing records and provide evidence for low‐frequency precipitation variability in the central‐western Mediterranean from 974–2016 CE. Comparison with a European scale drought reconstruction network shows that regional predictor chronologies are needed to accurately estimate long‐term hydroclimate variability on Corsica

Modernizing and Expanding the NASA Space Geodesy Network to Meet Future Geodetic Requirements

NASA maintains and operates a global network of Very Long Baseline Interferometry (VLBI), Satellite Laser Ranging (SLR), and Global Navigation Satellite System ground stations as part of the NASA Space Geodesy Program. The NASA Space Geodesy Network (NSGN) provides the geodetic products that support Earth observations and the related science requirements as outlined by the US National Research Council (NRC in Precise geodetic infrastructure: national requirements for a shared resource, National Academies Press, Washington, 2010. http://nap.edu/12954, Thriving on our changing planet: a decadal strategy for Earth observation from space, National Academies Press, Washington, 2018. http://nap.edu/24938). The Global Geodetic Observing System (GGOS) and the NRC have set an ambitious goal of improving the Terrestrial Reference Frame to have an accuracy of 1 mm and stability of 0.1 mm per year, an order of magnitude beyond current capabilities. NASA and its partners within GGOS are addressing this challenge by planning and implementing modern geodetic stations colocated at existing and new sites around the world. In 2013, NASA demonstrated the performance of its next-generation systems at the prototype next-generation core site at NASAs Goddard Geophysical and Astronomical Observatory in Greenbelt, Maryland. Implementation of a new broadband VLBI station in Hawaii was completed in 2016. NASA is currently implementing new VLBI and SLR stations in Texas and is planning the replacement of its other aging domestic and international legacy stations. In this article, we describe critical gaps in the current global network and discuss how the new NSGN will expand the global geodetic coverage and ultimately improve the geodetic products. We also describe the characteristics of a modern NSGN site and the capabilities of the next-generation NASA SLR and VLBI systems. Finally, we outline the plans for efficiently operating the NSGN by centralizing and automating the operations of the new geodetic stations

HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications

The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3− fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications

Caveolin-1 and Altered Neuregulin Signaling Contribute to the Pathophysiological Progression of Diabetic Peripheral Neuropathy

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.OBJECTIVE Evaluate if Erb B2 activation and the loss of caveolin-1 (Cav1) contribute to the pathophysiological progression of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS Cav1 knockout and wild-type C57BL/6 mice were rendered diabetic with streptozotocin, and changes in motor nerve conduction velocity (MNCV), mechanical and thermal hypoalgesia, Erb B2 phosphorylation (pErb B2), and epidermal nerve fiber density were assessed. The contribution of Erb B2 to DPN was assessed using the Erb B2 inhibitors PKI 166 and erlotinib and a conditional bitransgenic mouse that expressed a constitutively active form of Erb B2 in myelinated Schwann cells (SCs). RESULTS Diabetic mice exhibited decreased MNCV and mechanical and thermal sensitivity, but the extent of these deficits was more severe in diabetic Cav1 knockout mice. Diabetes increased pErb B2 levels in both genotypes, but the absence of Cav1 correlated with a greater increase in pErb B2. Erb B2 activation contributed to the mechanical hypoalgesia and MNCV deficits in both diabetic genotypes because treatment with erlotinib or PKI 166 improved these indexes of DPN. Similarly, induction of a constitutively active Erb B2 in myelinated SCs was sufficient to decrease MNCV and induce a mechanical hypoalgesia in the absence of diabetes. CONCLUSIONS Increased Erb B2 activity contributes to specific indexes of DPN, and Cav1 may be an endogenous regulator of Erb B2 signaling. Altered Erb B2 signaling is a novel mechanism that contributes to SC dysfunction in diabetes, and inhibiting Erb B2 may ameliorate deficits of tactile sensitivity in DPN. Diabetic peripheral neuropathy (DPN) is a common complication of diabetes (1). Although hyperglycemia is the definitive cause of DPN (2), the vascular, glial, and neuronal damage that underlies the progressive axonopathy in DPN has a complex biochemical etiology involving oxidative stress (3,4), protein glycation (5), protein kinase C activation (6), polyol synthesis (7), and the hexosamine pathway (8). Altered neurotrophic support also contributes to sensory neuron dysfunction in DPN (9), but whether diabetes may alter growth factor signaling in Schwann cells (SCs), which also undergo substantial degeneration in diabetes, is poorly defined. Neuregulins are growth factors that control SC growth, survival, and differentiation via their interaction with Erb B receptors (10). Although Erb B2 signaling promotes developmental myelination and is clearly trophic for SCs, pharmacological evidence supports that pathologic activation of Erb B2 after axotomy (11) or infection with leprosy bacilli (12) is sufficient to induce SC dedifferentiation and demyelination. Additionally, genetic evidence supports that Erb B2 can promote the development of sensory neuropathies independent of diabetes because expression of a dominant-negative Erb B4 in nonmyelinating (13) or myelinating (14) SCs induced a temperature or mechanical sensory neuropathy, respectively. Given the contribution of Erb B2 to the degeneration of SCs, endogenous proteins that regulate Erb B2 activity may influence the development of certain aspects of sensory neuropathies. The interaction of Erb B2 with the protein caveolin-1 (Cav1) inhibits the intrinsic tyrosine kinase activity of the receptor (15). Cav1 is highly expressed in mature, myelinated SCs (16), and we have shown that prolonged hyperglycemia promoted the downregulation of Cav1 in SCs of sciatic nerve (17). Cav1 may regulate Erb B2 signaling in SCs because its forced downregulation was sufficient to enhance neuregulin-induced demyelination of SC–dorsal root ganglion (DRG) neuron cocultures (18). However, it is unknown whether an increase in Erb B2 activity may contribute to the pathophysiological development of DPN and if changes in Cav1 expression may alter Erb B2 activation in diabetic nerve. In the current study, we demonstrate that diabetic Cav1 knockout mice showed an increased activation of Erb B2 and developed greater motor nerve conduction velocity (MNCV) deficits relative to their wild-type counterparts. Inhibition of Erb B2 with two structurally diverse inhibitors corrected the MNCV deficits and mechanical hypoalgesia evident after 6 or 15 weeks of diabetes. Also, induction of a constitutively active Erb B2 in myelinated SCs of adult mice was sufficient to recapitulate the MNCV and mechanical sensitivity deficits observed in the diabetic mice. These studies provide the first evidence that activation of Erb B2 contributes to deficits associated with myelinated fiber function in diabetic nerve and suggest that Cav1 may serve as an endogenous regulator of Erb B2.This work was supported by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health (NS-054847 and DK-073594)

Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabi. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabi. Two main hypotheses can be considered for the origin of c.1187G > A: (i) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and (ii) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabi could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region

Increase Human Metapneumovirus Mediated Morbidity following Pandemic Influenza Infection

Human metapneumovirus (hMPV) is a recently discovered respiratory pathogen, infecting mainly young children. The infected patients suffer from influenza like symptoms (ILS). In Israel the virus is mainly circulating in February to March. Here we report on an increased rate of hMPV infection in the winter season of 2009–10. The 2009–10 infection had several unique characteristics when compared to previous seasons; it started around January and a large number of infants were infected by the virus. Genetic analysis based on the viral L and F genes of hMPV showed that only subtypes A2 and B2 circulated in Israel. Additionally, we have identified a novel variant of hMPV within subgroup A2b, which subdivide it into A2b1 and A2b2. Finally, we showed that the hMPV infection was detected in the country soon after the infection with the pandemic influenza virus had declined, that infection with the pandemic influenza virus was dominant and that it interfered with the infection of other respiratory viruses. Thus, we suggest that the unusual increase in hMPV infection observed in 2009–10 was due to the appearance of the pandemic influenza virus in the winter season prior to 2009–10

Precise date for the Laacher See eruption synchronizes the Younger Dryas

The Laacher See eruption (LSE) in Germany ranks among Europe’s largest volcanic events of the Upper Pleistocene. Although tephra deposits of the LSE represent an important isochron for the synchronization of proxy archives at the Late Glacial to Early Holocene transition, uncertainty in the age of the eruption has prevailed. Here we present dendrochronological and radiocarbon measurements of subfossil trees that were buried by pyroclastic deposits that frmly date the LSE to 13,006 ± 9 calibrated years before present (bp; taken as ad 1950), which is more than a century earlier than previously accepted. The revised age of the LSE necessarily shifts the chronology of European varved lakes relative to the Greenland ice core record, thereby dating the onset of the Younger Dryas to 12,807 ± 12 calibrated years bp, which is around 130 years earlier than thought. Our results synchronize the onset of the Younger Dryas across the North Atlantic–European sector, preclude a direct link between the LSE and Greenland Stadial-1 cooling, and suggest a large-scale common mechanism of a weakened Atlantic Meridional Overturning Circulation under warming condition