Glycosaminoglycan profile in macrophages exposed to Candida albicans and interleukins

Glycosaminoglycans (GAG), are extracellular matrix macromolecules that affect the phagocytic properties of macrophages. In order to assess whether the interaction between macrophages and Candida albicans (iCa) provokes changes in the phenotype, we analyzed the GAG profiles in two macrophage lines, ANA-1 (from murine bone-marrow) and BV-2 (from murine brain). We also investigated GAG modulation by interleukin-1alpha (IL-1alpha) and interleukin-6 (IL-6). During iCa treatment and even after the addition of ILs, ANA-1 accumulated less total GAG compared to controls. IL-1 treatment, combined with iCa exposure, induced a decrease in heparan sulfate and chondroitin sulfate chains, and an increase in the hyaluronic acid percentage. IL-6 treatment, with or without iCa, decreased the hyaluronic acid/sulfated GAG ratio. The GAG pattern in BV-2 appears to be different to ANA-1 and iCa exposure does not induce any difference in total GAG. The inhibitory effect induced by ILs on GAG synthesis is less than that observed in ANA-1 and the GAG elution profile is modulated to a lesser extent by treatment with ILs and/or iCa compared to the ANA-1. We suggest that the observed changes in the expression of the individual GAG classes may be responsible for the macrophage functional heterogeneity

Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis

Toll-like receptors (TLRs) are important components of innate immunity. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes and susceptibility to noninvasive forms of pulmonary aspergillosis. A significant association was observed between allele G on Asp299Gly (TLR4) and chronic cavitary pulmonary aspergillosis (odds ratio [OR], 3.46; P =.003). Susceptibility to allergic bronchopulmonary aspergillosis was associated with allele C on T-1237C (TLR9) (OR, 2.49; P =. 043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis.Fundação para a Ciência e Tecnologia, Portugal (POCI/SAU-ESP/61080/ 2004 and fellowship to A.C., contract SFRH/BD/11837/2003); CAPES (Brazilian government) (grant to A.P); and the Fungal Research Trust, United Kingdom

Geraniol Treatment for Irritable Bowel Syndrome: A Double-Blind Randomized Clinical Trial

Geraniol is an acyclic monoterpene alcohol with well-known anti-inflammatory and antimicrobial properties which has shown eubiotic activity towards gut microbiota (GM) in patients with irritable bowel syndrome (IBS). Methods: Fifty-six IBS patients diagnosed according to Rome III criteria were enrolled in an interventional, prospective, multicentric, randomized, double-blinded, placebo-controlled trial. In the treatment arm, patients received a low-absorbable geraniol food supplement (LAGS) once daily for four weeks. Results: Patients treated with LAGS showed a significant reduction in their IBS symptoms severity score (IBS-SSS) compared to the placebo (195 vs. 265, p = 0.001). The rate of responders according to IBS-SSS (reduction ≥ 50 points) was significantly higher in the geraniol vs placebo group (52.0% vs. 16.7%, p = 0.009) mainly due to the IBS mixed subtype. There were notable differences in the microbiota composition after geraniol administration, particularly a significant decrease in a genus of Ruminococcaceae, Oscillospira (p = 0.01), a decreasing trend for the Erysipelotrichaceae and Clostridiaceae families (p = 0.1), and an increasing trend for other Ruminococcaceae taxa, specifically Faecalibacterium (p = 0.09). The main circulating proinflammatory cytokines showed no differences between placebo and geraniol arms. Conclusion: LAGS was effective in treating overall IBS symptoms, together with an improvement in the gut microbiota profile, especially for the IBS mixed subtype

The structure of glutamate transporters shows channel-like features

AbstractNeuronal and glial glutamate transporters remove the excitatory neurotransmitter glutamate from the synaptic cleft and thus prevent neurotoxicity. The proteins belong to a large family of secondary transporters, which includes transporters from a variety of bacterial, archaeal and eukaryotic organisms. The transporters consist of eight membrane-spanning α-helices and two pore-loop structures, which are unique among secondary transporters but may resemble pore-loops found in ion channels. Another distinctive structural feature is the presence of a highly amphipathic membrane-spanning α-helix that provides a hydrophilic path through the membrane. The unusual structural features of the transporters are discussed in relation to their function

Genetic susceptibility to aspergillosis in allogeneic stem-cell transplantation

Invasive aspergillosis (IA) is a major threat to positive outcomes for allogeneic stem-cell transplantation (allo-SCT) patients. Despite presenting similar degrees of immunosuppression, not all individuals at-risk ultimately develop infection. Therefore, the traditional view of neutropenia as a key risk factor for aspergillosis needs to be accommodated within new conceptual advances on host immunity and its relationship to infection. Polymorphisms in innate immune genes, such as those encoding TLRs, cytokines and cytokine receptors, have recently been associated with susceptibility to IA in allo-SCT recipients. This suggests that understanding host-pathogen interactions at the level of host genetic susceptibility will allow the formulation of new targeted and patient-tailored antifungal therapeutics, including improved donor screening.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/65962/2009, SFRH/BPD/46292/2008Specific Targeted Research Projects MANASP (LSHE-CT-2006), contract number 037899 (FP6), Italian Project PRIN2007KLCKP8_004

Visual Localization in the Presence of Appearance Changes Using the Partial Order Kernel

Visual localization across seasons and under varying weather and lighting conditions is a challenging task in robotics. In this paper, we present a new sequence-based approach to visual localization using the Partial Order Kernel (POKer), a convolution kernel for string comparison, that is able to handle appearance changes and is robust to speed variations. We use multiple sequence alignment to construct directed acyclic graph representations of the database image sequences, where sequences of images of the same place acquired at different times are represented as alternative paths in a graph. We then use the POKer to compute the pairwise similarities between these graphs and the query image sequences obtained in a subsequent traversal of the environment, and match the corresponding locations. We evaluated our approach on a dataset which features extreme appearance variations due to seasonal changes. The results demonstrate the effectiveness of our approach, where it achieves higher precision and recall than two state-of-the-art baseline method

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-?B activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO-dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-?, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-?/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles.We thank Cristina Massi Benedetti for digital art and editing. This work was supported by the Specific Targeted Research Project 'Sybaris' (LSHE-CT-2006), contract number 037899 (FP7) and by the Italian Projects PRIN 2007KLCKP8_004 (to LR) and 2007XYB9T9_001 (to SB). CC and AC were financially supported by fellowships from Fundacao para a Ciencia e Tecnologia, Portugal (contracts SFRH/BD/65962/2009 and SFRH/BPD/46292/2008, respectively)

The endocannabinoid system controls food intake via olfactory processes

Comment in Sensory systems: the hungry sense. [Nat Rev Neurosci. 2014] Inhaling: endocannabinoids and food intake. [Nat Neurosci. 2014]; International audience; Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior

Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection

Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms

DNA has been described as a structural component of the extracellular matrix (ECM) in bacterial biofilms. In Candida albicans, there is a scarce knowledge concerning the contribution of extracellular DNA (eDNA) to biofilm matrix and overall structure. This work examined the presence and quantified the amount of eDNA in C. albicans biofilm ECM and the effect of DNase treatment and the addition of exogenous DNA on C. albicans biofilm development as indicators of a role for eDNA in biofilm development. We were able to detect the accumulation of eDNA in biofilm ECM extracted from C. albicans biofilms formed under conditions of flow, although the quantity of eDNA detected differed according to growth conditions, in particular with regards to the medium used to grow the biofilms. Experiments with C. albicans biofilms formed statically using a microtiter plate model indicated that the addition of exogenous DNA (>160 ng/ml) increases biofilm biomass and, conversely, DNase treatment (>0.03 mg/ml) decreases biofilm biomass at later time points of biofilm development. We present evidence for the role of eDNA in C. albicans biofilm structure and formation, consistent with eDNA being a key element of the ECM in mature C. albicans biofilms and playing a predominant role in biofilm structural integrity and maintenance.National Institute of Dental & Craniofacial ResearchFundação para a Ciência e Tecnologia (FCT) - SFRH/BD/28222/2006National Institute of Allergy and Infectious Disease