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The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divided into two groups with most likely two topographically distinct binding sites. The aim of the current study was to identify the binding site of one such group of ligands, exemplified by three allosteric antagonists, CCR2-RA-[R], JNJ-27141491, and SD-24. We first used a chimeric CCR2/CCR5 receptor approach to obtain insight into the binding site of the allosteric antagonists and additionally introduced eight single point mutations in CCR2 to further characterize the putative binding pocket. All constructs were studied in radioligand binding and/or functional IP turnover assays, providing evidence for an intracellular binding site for CCR2-RA-[R], JNJ-27141491, and SD-24. For CCR2-RA-[R] the most important residues for binding were found to be the highly conserved tyrosine Y 7.53 and phenylalanine F 8.50 of the NPxxYx (5,6) F motif, as well as V 6.36 at the bottom of TM-VI and K 8.49 in helix-VIII. These findings demonstrate for the first time the presence of an allosteric intracellular binding site for CCR2 antagonists. This contributes to an increased understanding of the interactions of diverse ligands at CCR2 and may allow for a more rational design of future allosteric antagonists.

Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of αS directly or indirectly, for example by favoring a pro-inflammatory environment in the gut. Thus, while the development of PD has not yet being associated with a unique microbial species, more data will be necessary to examine potential harmful interactions between the microbiota and the host, and to understand their relevance in PD pathogenesis.

The identification of Leptospira clinical isolates through genotyping and serotyping, besides the recognition of its reservoirs, are important tools for understanding the epidemiology of leptospirosis, and they are also keys for identifying new species and serovars. Fourteen clinical isolates from animals were characterized by means of single enzyme amplified length polymorphism, variable number of tandem repeat analysis, pulsed field gel electrophoresis, and serotyping. All isolates were identified as Leptospira interrogans, serovar Canicola. Infections by this serovar occur in urban regions, where dogs represent the main maintenance hosts, whereas bovine and swine may act as reservoirs of serovar Canicola in rural areas. Both urban and rural aspects of leptospirosis, and the role of domestic animals as maintenance hosts, cannot be neglected in developing and developed countries.

Leptospira interrogans serogroup Icterohaemorrhagiae is the major serogroup infecting humans worldwide, and rodents and dogs are the most significant transmission sources in urban environments. Knowledge of the prevalent serovars and their maintenance hosts is essential to understand the epidemiology of leptospirosis. In this study, 20 Leptospira isolates were evaluated by pulsed-field gel electrophoresis (PFGE), variable number tandem-repeat analysis (VNTR), serotyping, and determination of antimicrobial resistance profile. Isolates, originated from bovine, canine, human, and rodent sources, were characterized by microscopic agglutination test with polyclonal and monoclonal antibodies and were identified as L. interrogans serogroup Icterohaemorrhagiae serovar Copenhageni. MICs of antimicrobials often used in veterinary medicine were determined by broth microdilution test. Most of tested antibiotics were effective against isolates, including penicillin, ampicillin, and ceftiofur. Higher MIC variability was observed for fluoroquinolones and neomycin; all isolates were resistant to trimethoprim/sulfamethoxazole and sulphadimethoxine. Isolates were genotyped by PFGE and VNTR; both techniques were unable to discriminate between serovars Copenhageni and Icterohaemorrhagiae, as expected. PFGE clustered all isolates in 1 pulsotype, indicating that these serovars can be transmitted between species and that bovine, rodent, and dogs can maintain them in the environment endangering the human population.

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To each pair, R, T , consisting of a unitary commutative von Neumann-regular ring, R, where 2 is a unit and T is a preorder on R, we associate a reduced special group, G T (R), which faithfully reflects quadratic form theory, modulo T , over free R-modules and then show, using the representation of R as the ring of global sections of its affine scheme, together with results from [M. Dickmann, F. Miraglia, On quadratic forms whose total signature is zero mod 2 n . Solution to a problem of M. Marshall, Invent. Math. 133 (1998) 243-278; M. Dickmann, F. Miraglia, Lam's Conjecture, Algebra Colloq. 10 (2003) 149-176; M. Dickmann, F. Miraglia, Algebraic K-theory of special groups, J. Pure Appl. Algebra 204 (2006) 195-234], that G T (R) satisfies a powerful K-theoretic property, the [SMC]-property. From this we conclude that quadratic form theory modulo T over free R-modules verifies Marshall's signature conjecture, Lam's conjecture, as well as a reduced version of Milnor's Witt ring conjecture.The main result of this paper is that, if R is a commutative von Neumann-regular ring in which 2 is a unit, then the reduced theory of quadratic forms with invertible coefficients in R,