gene-expression-based diagnostics for presymptomatic diagnosis of hospital-acquired infections

Funding Information: LFM—None to declare. TES—employee of and shareholder in Inflammatix, Inc. PP—received fees for lecture from Gilead and Pfizer, consulting from MSD and Sanofi and unrestricted research grant from Abionic.publishersversionpublishe

In Vivo Identification of Novel Regulators and Conserved Pathways of Phagocytosis in A. gambiae

SummaryAnopheles gambiae uses effective immune responses, including phagocytosis, to fight microbial infection. We have developed a semiquantitative phagocytosis test and used it in conjunction with dsRNA gene silencing to test the in vivo roles of 71 candidate genes in phagocytosis of Escherichia coli and Staphylococcus aureus. Here, we show that inactivation of 26 genes changes the phagocytic activity by more than 45% and that two pathways similar to those that mediate apoptotic cell removal in Caenorhabditis elegans are used in A. gambiae for phagocytosis of microorganisms. Simultaneous inactivation of the identified regulators of phagocytosis and conserved components defining each signaling pathway permitted provisional assignment of the novel regulators to one or the other pathway. Pathway inactivation enhances at least three times the ability of E. coli and S. aureus to proliferate in the mosquito. Interestingly, mosquito survival is not compromised even if both pathways are perturbed simultaneously

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15 -/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies

Deletion of iRhom2 protects against diet-inducedobesity by increasing thermogenesis

Objective:Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energydissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Herewe evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in thepathophysiology of metabolic syndrome.Methods:We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared theirmetabolic phenotypes. We also carried outex vivoassays with primary and immortalized mouse brown adipocytes to establish the autonomy ofthe effect of loss of iRhom2 on thermogenesis and respiration.Results:Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improvedinsulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beigeadipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced ther-mogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.Conclusion:Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasisduring metabolic diseaseWellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/

Variação espacial de cátions, ânions e variáveis físico-químicas no rio Solimões-Amazonas entre Manaus e Jutaí, bacia amazônica

Cátions e ânions majoritários são espécies químicas de grande importância nos diversos compartimentos aquáticos, porém, pouco abordados de forma exclusiva na bacia amazônica. Neste sentido, o objetivo deste estudo foi avaliar a dinâmica espacial de Na+, Ca2+, K+, Mg2+, Cl- e SO4 2- em um trecho do rio Solimões-Amazonas, levando-se em consideração a alcalinidade, potencial hidrogeniônico (pH), condutividade elétrica (CE), sólidos totais em suspensão (STS) e carbono orgânico total (COT). As coletas foram realizadas em maio, julho e setembro de 2012 em sete pontos na calha principal do rio Solimões-Amazonas e na foz de alguns dos principais tributários: rios Jutaí, Juruá, Japurá e Purus. Os cátions e ânions foram analisados por cromatografia de íons, STS por gravimetria, pH por potenciometria, alcalinidade por titulação potenciométrica, CE por condutimetria e o COT por oxidação catalítica por combustão. As concentrações médias dos cátions seguiram esta ordem Ca2+>Na+>Mg2+>K+ e dos ânions SO4 2->Cl-. De montante à jusante a tendência foi diminuição nas concentrações de cátions e ânions, das variáveis pH, CE, STS e alcalinidade, além do aumento das concentrações de COT. O presente estudo evidenciou mudanças nas características químicas sofridas pelo rio Solimões em seu curso. O aporte dos tributários pode ser apontado como um dos fatores responsáveis por essas modificações

Comparative and Functional Genomics The cadherin superfamily in Anopheles gambiae: a comparative study with Drosophila melanogaster

Abstract The cadherin superfamily is a diverse and multifunctional group of proteins with extensive representation across genomes of phylogenetically distant species that is involved in cell-cell communication and adhesion. The mosquito Anopheles gambiae is an emerging model organism for the study of innate immunity and host-pathogen interactions, where the malaria parasite induces a profound rearrangement of the actin cytoskeleton at critical stages of infection. We have used bioinformatics tools to retrieve present sequence knowledge about the complete repertoire of cadherins in A. gambiae and compared it to that of the fruit fly, Drosophila melanogaster. In A. gambiae, we have identified 43 genes coding for cadherin extracellular domains that were re-annotated to 38 genes and represent an expansion of this gene family in comparison to other invertebrate organisms. The majority of Drosophila cadherins show a 1 : 1 Anopheles orthologue, but we have observed a remarkable expansion in some groups in A. gambiae, such as N-cadherins, that were recently shown to have a role in the olfactory system of the fruit fly. In vivo dsRNA silencing of overrepresented genes in A. gambiae and other genes showing expression at critical tissues for parasite infection will likely advance our understanding of the problems of host preference and host-pathogen interactions in this mosquito species

Fiber Bragg grating sensors integrated in polymeric foils

Optical sensors have hit their maturity and a new kind of systems is being developed. This paper deals with the development of a new sensing structure based on polymeric foils and optic fiber sensors, namely the Fiber Bragg Grating sensors. Sensor integration in polymeric foils, using industrial process is the proposed goal. To achieve this goal, Finite Element Analysis was used for prototype modeling and simulation. The model was subjected to loads and restraints in order to retrieve information about stress distribution and displacement of specific points. From the simulation was possible to predict the sections where the sensor should be positioned. A prototype was then fabricated using industrial processes. Tests indicate that the polymeric foil influence on the sensor performance may exist. However, the prototype was able of transferring the full deformation to the optical sensor. Moreover, the optical sensor, which is incorporated in the polymeric foil, is fully functional with high sensitivity, 0.6 picometer by microstrain, allowing deformation measurements, up to 1.2 millimeter.Alexandre Ferreira da Silva is supported by Portuguese Foundation for Science and Technology (SFRH/BD/39459/2007). This work is also sponsored by FCT/MIT-Pt/EDAM-SI/0025/2008