Attenuation of Toll-Like Receptor Expression and Function in Latent Tuberculosis by Coexistent Filarial Infection with Restoration Following Antifilarial Chemotherapy

Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen–stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans

Pharmacogenetics Meets Metabolomics: Discovery of Tryptophan as a New Endogenous OCT2 Substrate Related to Metformin Disposition

Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Clrenal, Clsec, Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2

A bacterial glycan core linked to surface (S)-layer proteins modulates host immunity through Th17 suppression

Tannerella forsythia is a pathogen implicated in periodontitis, an inflammatory disease of the tooth-supporting tissues often leading to tooth loss. This key periodontal pathogen is decorated with a unique glycan core O-glycosidically linked to the bacterium's proteinaceous surface (S)-layer lattice and other glycoproteins. Herein, we show that the terminal motif of this glycan core acts to modulate dendritic cell effector functions to suppress T-helper (Th)17 responses. In contrast to the wild-type bacterial strain, infection with a mutant strain lacking the complete S-layer glycan core induced robust Th17 and reduced periodontal bone loss in mice. Our findings demonstrate that surface glycosylation of this pathogen may act to ensure its persistence in the host likely through suppression of Th17 responses. In addition, our data suggest that the bacterium then induces the Toll-like receptor 2–Th2 inflammatory axis that has previously been shown to cause bone destruction. Our study provides a biological basis for pathogenesis and opens opportunities in exploiting bacterial glycans as therapeutic targets against periodontitis and a range of other infectious diseases

Use of Spatial Information and Search Strategies in a Water Maze Analog in Drosophila melanogaster

Learning the spatial organization of the environment is crucial to fitness in most animal species. Understanding proximate and ultimate factors underpinning spatial memory is thus a major goal in the study of animal behavior. Despite considerable interest in various aspects of its behavior and biology, the model species Drosophila melanogaster lacks a standardized apparatus to investigate spatial learning and memory. We propose here a novel apparatus, the heat maze, conceptually based on the Morris water maze used in rodents. Using the heat maze, we demonstrate that D. melanogaster flies are able to use either proximal or distal visual cues to increase their performance in navigating to a safe zone. We also show that flies are actively using the orientation of distal visual cues when relevant in targeting the safe zone, i.e., Drosophila display spatial learning. Parameter-based classification of search strategies demonstrated the progressive use of spatially precise search strategies during learning. We discuss the opportunity to unravel the mechanistic and evolutionary bases of spatial learning in Drosophila using the heat maze

Planejamento tridimensional para radioterapia de tumores de esôfago: comparação de técnicas de tratamento e análise de probabilidade de complicações Three-dimensional radiotherapy planning system for esophageal tumors: comparison of treatment techniques and analysis of probability of complications

Para comparar diversas técnicas de irradiação para o câncer de esôfago, foi utilizado sistema de planejamento tridimensional. Em um paciente com carcinoma espinocelular de esôfago médio, foram estudadas as seguintes técnicas de tratamento: dois campos ântero-posteriores e dois campos látero-laterais paralelos e opostos, três campos em "Y" e em "T" e quatro campos em "X". Foram obtidos os histogramas dose-volume, considerando como órgãos de risco medula espinhal e pulmões. Os resultados foram analisados de acordo com as recomendações da Normal Tissue Complication Probability (NTCP) e Tumor Control Probability (TCP). Quanto às doses de irradiação em pulmão, a melhor opção foi a técnica em dois campos ântero-posteriores paralelos e opostos. A medula foi mais poupada quando se utilizaram campos látero-laterais. Sugerimos a combinação de pelo menos duas técnicas de tratamento: ântero-posterior e as técnicas com campos em "Y", "T" ou látero-laterais, para o balanceamento das doses em pulmões e medula espinhal. Ou, ainda, a utilização de técnicas de três campos durante todo o tratamento.<br>Radiotherapy techniques for esophageal cancer were compared using a three-dimensional planning system. We studied the following treatment techniques used for a patient with squamous cell carcinoma of the middle third of the esophagus: two antero-posterior and two latero-lateral parallel opposed fields, three fields ("Y" and "T"), and four fields ("X"). Dose-volume histograms were obtained considering spinal cord and lungs as organs at risk. Analysis was performed comparing doses in these organs as recommended by the Normal Tissue Complication Probability (NTCP) and Tumor Control Probability (TCP). When only the lungs were considered the best technique was two antero-posterior parallel opposed fields. The spinal cord was best protected using latero-lateral fields. We suggest the combination of at least two treatment techniques: antero-posterior fields with "Y" or "T" techniques, or latero-lateral fields in order to balance the doses in the lungs and the spinal cord. Another option may be the use of any of the three-field techniques during the whole treatment