The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation.

Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation.

Laser speckle imaging of the hippocampus.

Research on hippocampal blood flow is essential for gaining insight into its involvement in learning and memory and its role in age-related cognitive impairment and dementia. In this study, we applied laser speckle contrast imaging (LSCI) and dynamic light scattering imaging (DLSI) to monitor perfusion in mouse hippocampus via a chronic, optically transparent window. LSCI scans showed hippocampal blood vessels appear more out of focus than similar caliber vessels in the mouse cortex. We hypothesize that it is caused by the inverse vascular topology and increased contribution of multiply-scattered photons detected from the upper layers of the hippocampus. We support the hypothesis with DLSI, showing a 1300% increased contribution of multiple-scattering unordered dynamics regime in large hippocampal vessels.

Mortality Reduction in Septic Shock by Plasma Adsorption (ROMPA): a protocol for a randomised clinical trial.

INTRODUCTION: There is a lack of evidence in the efficacy of the coupled plasma filtration adsorption (CPFA) to reduce the mortality rate in septic shock. To fill this gap, we have designed the ROMPA study (Mortality Reduction in Septic Shock by Plasma Adsorption) to confirm whether treatment with an adequate dose of treated plasma by CPFA could confer a clinical benefit. METHODS AND ANALYSIS: Our study is a multicentric randomised clinical trial with a 28-day and 90-day follow-up and allocation ratio 1:1. Its aim is to clarify whether the application of high doses of CPFA (treated plasma ≥0.20 L/kg/day) in the first 3 days after randomisation, in addition to the current clinical practice, is able to reduce hospital mortality in patients with septic shock in intensive care units (ICUs) at 28 and 90 days after initiation of the therapy. The study will be performed in 10 ICUs in the Southeast of Spain which follow the same protocol in this disease (based on the Surviving Sepsis Campaign). Our trial is designed to be able to demonstrate an absolute mortality reduction of 20% (α=0.05; 1-ß=0.8; n=190(95×2)). The severity of the process, ensuring the recruitment of patients with a high probability of death (50% in the control group), will be achieved through an adequate stratification by using both severity scores and classical definitions of severe sepsis/septic shock and dynamic parameters. Our centres are fully aware of the many pitfalls associated with previous medical device trials. Trying to reduce these problems, we have developed a training programme to improve the CPFA use (especially clotting problems). ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committees of all the participant centres. The findings of the trial will be disseminated through peer-reviewed journals, as well as national and international conference presentations. TRIAL REGISTRATION NUMBER: NCT02357433; Pre-results.

Robustness of trans-European gas networks.

Here, we uncover the load and fault-tolerant backbones of the trans-European gas pipeline network. Combining topological data with information on intercountry flows, we estimate the global load of the network and its tolerance to failures. To do this, we apply two complementary methods generalized from the betweenness centrality and the maximum flow. We find that the gas pipeline network has grown to satisfy a dual purpose. On one hand, the major pipelines are crossed by a large number of shortest paths thereby increasing the efficiency of the network; on the other hand, a nonoperational pipeline causes only a minimal impact on network capacity, implying that the network is error tolerant. These findings suggest that the trans-European gas pipeline network is robust, i.e., error tolerant to failures of high load links.

[Characterization of muscarinic receptors in undifferentiated thyroid cells in Fisher rats]. / Caracterización de receptores muscarínicos en células indiferenciadas tiroideas de ratas Fisher.

INTRODUCTION: The parasympathetic autonomous nervous system exerts control over thyroid function by activation of the muscarinic receptors in follicular cells. Various pharmacological and molecular subtypes of muscarinic receptors (M(1), M(2), M(3), M(4), M(5)) have been identified in central nervous system and peripheral tissues. Controversy surrounds receptor characterization in thyroid cells. MATERIALS AND METHODS: Undifferentiated Fisher rat thyroid epithelial cells (FRT) were cultured. Association and dissociation kinetics assays and antagonist competition studies of the binding of (3)H-N-methylscopolamine ((3)H-NMS) to muscarinic receptors were performed to demonstrate the presence of muscarinic receptors. RESULTS: Specific muscarinic receptors in the plasma membrane of FRT cells were observed with an equilibrium dissociation constant (K(d)) of 0.44 nmol. The order of affinities obtained fitting the data to one binding site model in competition experiments with the muscarinic receptor antagonist was: dicyclomine > hexahydrosiladifenidol (HHSD) = 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > pirenzepine > himbacine = 11-[[2-[(diethylamino)methyl]- 1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido (414)benzodiazepine (AF-DX 116). CONCLUSIONS: The results obtained indicate the existence of specific (3)H-NMS muscarinic binding sites located in the plasma membrane of FRT cells. The results obtained in competition experiments suggest that the receptors present in FRT cells belong to the M(3) subtype.

Specialized hepatocyte-like cells regulate Drosophila lipid metabolism.

Lipid metabolism is essential for growth and generates much of the energy needed during periods of starvation. In Drosophila, fasting larvae release large quantities of lipid from the fat body but it is unclear how and where this is processed. Here we identify the oenocyte as the principal cell type accumulating lipid droplets during starvation. Tissue-specific manipulations of the Slimfast amino-acid channel, the Lsd2 fat-storage regulator and the Brummer lipase indicate that oenocytes act downstream of the fat body. In turn, oenocytes are required for depleting stored lipid from the fat body during fasting. Hence, lipid-metabolic coupling between the fat body and oenocytes is bidirectional. When food is plentiful, oenocytes have critical roles in regulating growth, development and feeding behaviour. In addition, they specifically express many different lipid-metabolizing proteins, including Cyp4g1, an omega-hydroxylase regulating triacylglycerol composition. These findings provide evidence that some lipid-processing functions of the mammalian liver are performed in insects by oenocytes.

Determinación de los valores de secreción gástrica basal y estimulada de una muestra poblacional sana de Valencia Edo. Carabobo / Determination the values basal gastric secretion and stimulated in a healthy population sample of the city of Valencia state Carabobo

Determinar los valores patrones normales de secreción ácida basal (BAO), estimulada (MAO) y pico (PAO) en una muestra poblacional sana de la ciudad de Valencia. La muestra esta representada por 309 individuos sanos con edades entre 16 y 21 años, de ambos sexos y a quienes se les realizó un estudio de secreción ácida basal durante una hora y de secreción ácida máxima (MAO) durante una hora bajo estimulación con Histología o Pentagastrina. El pico de secreción (PAO) fue considerado el nivel más alto, de las cuatro muestras de 15 minutos de la secreción bajo estimulación. Como los datos no siguieron una distribución normal se utilizaron pruebas estadísticas no paramétricas. Se determino la mediana, valor máximo y mínimo de los resultados e intervalo intercuartilar y se aplicaron estudios de correlación. Los limites de normalidad se obtuvieron determinando los percentiles 2.5 y 97.5. Se obtuvo valores para el BAO = 0 – 5.07 mEq/h; MAO = 12 – 37,74 mEq/h y PAO = 20,7 – 58,19 mEq/h. El BAO no es una prueba discriminativa del funcionalismo secretor gástrico. El MAO y el PAO al depender directamente de la masa de células parietales nos da una mejor información de la secreción gástrica ácida. Los valores obtenidos por nosotros, coinciden bien con la mayoría de los autores