Delayed reperfusion deficits after experimental stroke account for increased pathophysiology.

Cerebral blood flow and oxygenation in the first few hours after reperfusion following ischemic stroke are critical for therapeutic interventions but are not well understood. We investigate changes in oxyhemoglobin (HbO(2)) concentration in the cortex during and after ischemic stroke, using multispectral optical imaging in anesthetized mice, a remote filament to induce either 30 minute middle cerebral artery occlusion (MCAo), sham surgery or anesthesia alone. Immunohistochemistry establishes cortical injury and correlates the severity of damage with the change of oxygen perfusion. All groups were imaged for 6 hours after MCAo or sham surgery. Oxygenation maps were calculated using a pathlength scaling algorithm. The MCAo group shows a significant drop in HbO(2) during occlusion and an initial increase after reperfusion. Over the subsequent 6 hours HbO(2) concentrations decline to levels below those observed during stroke. Platelets, activated microglia, interleukin-1α, evidence of BBB breakdown and neuronal stress increase within the stroked hemisphere and correlate with the severity of the delayed reperfusion deficit but not with the ΔHbO(2) during stroke. Despite initial restoration of HbO(2) after 30 min MCAo there is a delayed compromise that coincides with inflammation and could be a target for improved stroke outcome after thrombolysis

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Transfer of a major dominant gene for resistance to eyespot disease from a wild grass to hexaploid wheat

Eyespot disease, caused by the fungus Pseudocercosporella herpotrichoides, is responsible for considerable lodging and reductions of yield in extensive areas of wheat cultivation in North and South America, Europe, New Zealand, Australia and Africa1. The level of resistance of wheat cultivars is too low, even among the less susceptible ones (that is, Cappelle Desprez and Cerco) and no genes for resistance have to date been characterized in any species. Sprague2 found a high level of resistance to this disease in the wild grass Aegilops ventricosa and several workers have attempted its transfer to cultivated wheat with only partial success3−5. We report here a major dominant gene for resistance, which has been transferred from tetraploid Ae. ventricosa (genomes DvDvMvMv) to hexaploid wheat, Triticum aestivum (AABBDD), using tetraploid wheat, Triticum turgidum (AABB), as a 'bridge' species

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.

BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3). RESULTS: In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Neutrinoless double beta decay in seesaw models

We study the general phenomenology of neutrinoless double beta decay in seesaw models. In particular, we focus on the dependence of the neutrinoless double beta decay rate on the mass of the extra states introduced to account for the Majorana masses of light neutrinos. For this purpose, we compute the nuclear matrix elements as functions of the mass of the mediating fermions and estimate the associated uncertainties. We then discuss what can be inferred on the seesaw model parameters in the different mass regimes and clarify how the contribution of the light neutrinos should always be taken into account when deriving bounds on the extra parameters. Conversely, the extra states can also have a significant impact, cancelling the Standard Model neutrino contribution for masses lighter than the nuclear scale and leading to vanishing neutrinoless double beta decay amplitudes even if neutrinos are Majorana particles. We also discuss how seesaw models could reconcile large rates of neutrinoless double beta decay with more stringent cosmological bounds on neutrino masses.Comment: 34 pages, 5 eps figures and 1 axodraw figure. Final version published in JHEP. NME results available in Appendi

Validation of 3D neutronic-thermalhydraulic coupled codes RELAP5/PARCSv2.7 and TRACEv5.0P3/PARCSv3.0 against a PWR control rod drop transient

[EN] In nuclear safety field, neutronic and thermalhydraulic codes performance is an important issue. New capabilities implementation, as well as models and tools improvements are a significant part of the community effort in looking for better Nuclear Power Plants (NPP) designs. A procedure to analyze the PWR response to local deviations on neutronic or thermalhydraulic parameters is being developed. This procedure includes the simulation of Incore and Excore neutron flux detectors signals. A control rod drop real plant transient is used to validate the used codes and their new capabilities. Cross-section data are obtained by means of the SIMTAB methodology. Detailed thermalhydraulic models were developed: RELAP5 and TRACE models simulate three different azimuthal zones. Besides, TRACE model is performed with a fully 3D core, thus, the cross-flow can be obtained. A cartesian vessel represents the fuel assemblies and a cylindrical vessel the bypass and downcomer. Simulated detectors signals are obtained and compared with the real data collected during a control rod drop trial at a PWR NPP and also with data obtained with SIMULATE-3K code.The authors would like to acknowledge the economic support provided by Centrales Nucleares Almaraz-Trillo (CNAT) and IBERDROLA Ingeniería y Construcción (Iberinco) for the realization of this work, and express their great appreciation to Arturo López, Juan Antonio Bermejo and Alberto Ortego for their valuable collaboration and their willingness to develop this work. This work has also been supported by the Spanish Ministerio de Economía y Competitividad, through the projects NUC-MULTPHYS (ENE2012-34585) and VALIUN-3D (ENE2011-22823), and the Generalitat Valenciana (GVA), through the project PROMETEO II/2014/008.Garcia-Fenoll, M.; Mesado Melia, C.; Barrachina, T.; Miró Herrero, R.; Verdú Martín, GJ.; Bermejo, JA.; López, A.... (2017). Validation of 3D neutronic-thermalhydraulic coupled codes RELAP5/PARCSv2.7 and TRACEv5.0P3/PARCSv3.0 against a PWR control rod drop transient. Journal of Nuclear Science and Technology. 54(8):908-919. https://doi.org/10.1080/00223131.2017.1329035S90891954