Neurophysiology

Contains reports on two research projects.Bell Telephone Laboratories Incorporate

Neurophysiology

Contains research objectives, summary of research and reports on six research objectives.National Institutes of Health (Grant 5 ROl NB-04985-05)National Institutes of Health (Grant NB-07501-02)National Institutes of Health (Grant NB-06251-03)National Institutes of Health (Grant NB-07576-02)U. S. Air Force (Aerospace Medical Division) under Contract AF33(615)-3885Bell Telephone Laboratories IncorporatedNational Institutes of Health (Grant 5 TO1 GM-01555-02

Gyrokinetic simulations in stellarators using different computational domains

In this work, we compare gyrokinetic simulations in stellarators using different computational domains, namely, flux tube, full-flux-surface, and radially global domains. Two problems are studied: the linear relaxation of zonal flows and the linear stability of ion temperature gradient (ITG) modes. Simulations are carried out with the codes EUTERPE, GENE, GENE-3D, and stella in magnetic configurations of LHD and W7-X using adiabatic electrons. The zonal flow relaxation properties obtained in different flux tubes are found to differ with each other and with the radially global result, except for sufficiently long flux tubes, in general. The flux tube length required for convergence is configuration-dependent. Similarly, for ITG instabilities, different flux tubes provide different results, but the discrepancy between them diminishes with increasing flux tube length. Full-flux-surface and flux tube simulations show good agreement in the calculation of the growth rate and frequency of the most unstable modes in LHD, while for W7-X differences in the growth rates are found between the flux tube and the full-flux-surface domains. Radially global simulations provide results close to the full-flux-surface ones. The radial scale of unstable ITG modes is studied in global and flux tube simulations finding that in W7-X, the radial scale of the most unstable modes depends on the binormal wavenumber, while in LHD no clear dependency is found.Comment: submitted to Nuclear Fusio

The Inhibitory Role of miR-486-5p on CSC Phenotype Has Diagnostic and Prognostic Potential in Colorectal Cancer

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second cause of cancer deaths. Increasing evidences supports the idea that the poor prognosis of patients is related to the presence of cancer stem cells (CSCs), a cell population able to drive cancer recurrence and metastasis. The deregulation of microRNAs (miRNAs) plays a role in the formation of CSC. We investigated the role of hsa-miR-486-5p (miR-486-5p) in CRC, CSCs, and metastasis, in order to reach a better understanding of the biomolecular and epigenetic mechanisms mir-486-5p-related. The expression of miR-486-5p was investigated in three di erent matrices from CRC patients and controls and in CSCs obtained from the CRC cell lines HCT-116, HT-29, and T-84. In the human study, miR-486-5p was up-regulated in serum and stool of CRC patients in comparison with healthy controls but down-regulated in tumor tissue when compared with normal mucosa. miR-486-5p was also down-regulated in the sera of metastatic patients. In vitro, miR-486-5p was down-regulated in CSC models and it induced an inhibitory e ect on stem factors and oncogenes in the main pathways of CSCs. Our results provide a step forward in understanding the role of mir-486-5p in CRC and CSC, and suggest that further studies are needed to investigate its diagnostic and prognostic power, possibly in combination with other biomarkers.Instituto de Salud Carlos III PIE16-00045 DTS19/00145Junta de AndalucíaEuropean Union (EU) SOMM17/6109/UGR (UCE-PP2017-3)Chair "Doctors Galera-Requena in cancer stem cell research" CMC-CTS963Fondazione Banco di Sardegn

Nature-based solutions efficiency evaluation against natural hazards: Modelling methods, advantages and limitations

Nature-based solutions (NBS) for hydro-meteorological risks (HMRs) reduction and management are becoming increasingly popular, but challenges such as the lack of well-recognised standard methodologies to evaluate their performance and upscale their implementation remain. We systematically evaluate the current state-of-the art on the models and tools that are utilised for the optimum allocation, design and efficiency evaluation of NBS for five HMRs (flooding, droughts, heatwaves, landslides, and storm surges and coastal erosion). We found that methods to assess the complex issue of NBS efficiency and cost-benefits analysis are still in the development stage and they have only been implemented through the methodologies developed for other purposes such as fluid dynamics models in micro and catchment scale contexts. Of the reviewed numerical models and tools MIKE-SHE, SWMM (for floods), ParFlow-TREES, ACRU, SIMGRO (for droughts), WRF, ENVI-met (for heatwaves), FUNWAVE-TVD, BROOK90 (for landslides), TELEMAC and ADCIRC (for storm surges) are more flexible to evaluate the performance and effectiveness of specific NBS such as wetlands, ponds, trees, parks, grass, green roof/walls, tree roots, vegetations, coral reefs, mangroves, sea grasses, oyster reefs, sea salt marshes, sandy beaches and dunes. We conclude that the models and tools that are capable of assessing the multiple benefits, particularly the performance and cost-effectiveness of NBS for HMR reduction and management are not readily available. Thus, our synthesis of modelling methods can facilitate their selection that can maximise opportunities and refute the current political hesitation of NBS deployment compared with grey solutions for HMR management but also for the provision of a wide range of social and economic co-benefits. However, there is still a need for bespoke modelling tools that can holistically assess the various components of NBS from an HMR reduction and management perspective. Such tools can facilitate impact assessment modelling under different NBS scenarios to build a solid evidence base for upscaling and replicating the implementation of NBS

Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes

The enormous toll on human life during the 1918–1919 Spanish influenza pandemic is a constant reminder of the potential lethality of influenza viruses. With the declaration by the World Health Organization of a new H1N1 influenza virus pandemic, and with continued human cases of highly pathogenic H5N1 avian influenza virus infection, a better understanding of the host response to highly pathogenic influenza viruses is essential. To this end, we compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04. Severe pathology was observed in respiratory tissues from 1918 virus-infected animals as early as 12 hours after infection, and pathology steadily increased at later time points. Although tissues from animals infected with A/Vietnam/1203/04 also showed clear signs of pathology early on, less pathology was observed at later time points, and there was evidence of tissue repair. Global transcriptional profiles revealed that specific groups of genes associated with inflammation and cell death were up-regulated in bronchial tissues from animals infected with the 1918 virus but down-regulated in animals infected with A/Vietnam/1203/04. Importantly, the 1918 virus up-regulated key components of the inflammasome, NLRP3 and IL-1β, whereas these genes were down-regulated by A/Vietnam/1203/04 early after infection. TUNEL assays revealed that both viruses elicited an apoptotic response in lungs and bronchi, although the response occurred earlier during 1918 virus infection. Our findings suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severity of tissue damage

Viral Replication Rate Regulates Clinical Outcome and CD8 T Cell Responses during Highly Pathogenic H5N1 Influenza Virus Infection in Mice

Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans