Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer`s Disease: New Data and Meta-Analysis

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (RDNF) confer susceptibility to Alzheimer`s disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD. (C) 2009 Wiley-Liss, Inc.

Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27

Background. Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum chagasi. Genome-wide linkage studies from Sudan and Brazil identified a putative susceptibility locus on chromosome 6q27. Methods. Twenty-two single-nucleotide polymorphisms (SNPs) at genes PHF10, C6orf70, DLL1, FAM120B, PSMB1, and TBP were genotyped in 193 VL cases from 85 Sudanese families, and 8 SNPs at genes PHF10, C6orf70, DLL1, PSMB1, and TBP were genotyped in 194 VL cases from 80 Brazilian families. Family-based association, haplotype, and linkage disequilibrium analyses were performed. Multispecies comparative sequence analysis was used to identify conserved noncoding sequences carrying putative regulatory elements. Quantitative reverse-transcription polymerase chain reaction measured expression of candidate genes in splenic aspirates from Indian patients with VL compared with that in the control spleen sample. Results. Positive associations were observed at PHF10, C6orf70, DLL1, PSMB1, and TBP in Sudan, but only at DLL1 in Brazil (combined P = 3 x 10(-4) at DLL1 across Sudan and Brazil). No functional coding region variants were observed in resequencing of 22 Sudanese VL cases. DLL1 expression was significantly (P = 2 x 10(-7)) reduced (mean fold change, 3.5 [SEM, 0.7]) in splenic aspirates from patients with VL, whereas other 6q27 genes showed higher levels (1.27 x 10(-6) < P < .01) than did the control spleen sample. A cluster of conserved noncoding sequences with putative regulatory variants was identified in the distal promoter of DLL1. Conclusions. DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene.

Reactive nitrogen intermediate susceptibility of Mycobacterium tuberculosis genotypes in an urban setting

BACKGROUND: Mycobacterium tuberculosis genotypes resistant to reactive nitrogen intermediates (RNI) predominate in certain urban communities, suggesting that this phenotype influences disease transmission. OBJECTIVE: To compare different M. tuberculosis genotypes for resistance to RNI generated in vitro. DESIGN: We genotyped 420 M. tuberculosis isolates from a neighborhood in Sao Paulo, Brazil, and analyzed them for susceptibility to RNI generated in acidified sodium nitrite (ASN) solution. RESULTS: Seventy-one (43%) of 167 recent-infection strains and 68 (43%) of 158 endogenous infection strains showed moderate- to high-level ASN resistance. CONCLUSION: ASN resistance of M. tuberculosis is not necessarily a determining factor for enhanced transmission.

EFFECT OF COLD FRONTS ON THE BENTHIC MACROFAUNA OF EXPOSED SANDY BEACHES WITH CONTRASTING MORPHODYNAMICS

The aim of this study was to determine the short-term environmental changes caused by the simultaneous passage of a high energy event on two sandy beaches with different morphodynamic states and their influence on the richness, abundance and distribution of the benthic macrofauna. Two microtidal exposed sandy beaches with contrasting morphodynamics were simultaneously sampled before, during and after the passage of two cold fronts in Santa Catarina. The reflective beach showed a higher susceptibility to the increase in wave energy produced by the passage of cold fronts and was characterized by rapid and intense erosive processes in addition to a capacity for rapid restoration of the beach profile. As regards the dissipative beach, erosive processes operated more slowly and progressively, and it was characterized further by a reduced capacity for the recovery of its sub-aerial profile. Although the intensity of the environmental changes was distinct as between the morphodynamic extremes, changes in the composition, richness and abundance of macrobenthos induced by cold fronts were not evident for either of the beaches studied. On the other hand, alterations in the distribution pattern of the macrofauna were observed on the two beaches and were related to variations in sea level, position of the swash zone and moisture gradient, suggesting that short-term accommodations in the spatial structure of the macrobenthos occur in response to changes in environmental conditions in accordance with the temporal dynamics characteristic of each morphodynamic state.

Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This `experiment of nature` indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.

Alveolar macrophages from susceptible mice are more competent than those of resistant mice to control initial Paracoccidioides brasiliensis infection

Alveolar macrophages ( AM) are the first host cells to interact with Paracoccidioides brasiliensis (Pb), a primary human pathogen that causes severe pulmonary infections in Latin America. To better understand innate immunity in pulmonary paracoccidioidomycosis, we decided to study the fungicidal and secretory abilities of AM from resistant (A/J) and susceptible (B10.A) mice to infection. Untreated, IFN-gamma and IL-12 primed AM from B10. A and A/J mice were challenged with P. brasiliensis yeasts and cocultured for 72 h. B10. A macrophages presented an efficient fungicidal ability, were easily activated by both cytokines, produced high levels of nitric oxide ( NO), IL-12, and MCP-1 associated with low amounts of IL-10 and GM-CSF. In contrast, A/J AM showed impaired cytokine activation and fungal killing, secreted high levels of IL- 10 and GM-CSF but low concentrations of NO, IL- 12, and MCP-1. The fungicidal ability of B10. A but not of A/J macrophages was diminished by aminoguanidine treatment, although only the neutralization of TGF-beta restored the fungicidal activity of A/J cells. This pattern of macrophage activation resulted in high expression of MHC class II antigens by A/J cells, while B10. A macrophages expressed elevated levels of CD40. Unexpectedly, our results demonstrated that susceptibility to a fungal pathogen can be associated with an efficient innate immunity, while a deficient innate response can ultimately favor the development of a resistant pattern to infection. Moreover, our data suggest that different pathogen recognition receptors are used by resistant and susceptible hosts to interact with P. brasiliensis yeasts, resulting in divergent antigen presentation, acquired immunity, and disease outcomes.

Naturally Acquired Antibodies to Plasmodium vivax Duffy Binding Protein (DBP) in Rural Brazilian Amazon

Duffy binding protein (DBP), a leading malaria vaccine candidate, plays a critical role ill Plasmodium vivax erythrocyte invasion. Sixty-eight of 366 (18.6%) subjects had IgG anti-DBP antibodies by enzyme-linked immunosorbent assay (ELISA) in a community-based cross-sectional survey ill the Brazilian Amazon Basin. Despite Continuous exposure to low-level malaria transmission, the overall seroprevalence decreased to 9.0% when the Population was reexamined 12 months later. Antibodies from 16 of 50 (360%) Subjects who were ELISA-positive at the baseline were able to inhibit erythrocyte binding to at least one of two DBP variants tested. Most (13 of 16) of these subjects still had inhibitory antibodies when reevaluated 12 months later. Cumulative exposure to malaria was the strongest predictor of DBP seropositivity identified by Multiple logistic regression models in this population. The poor antibody recognition of DBP elicited by natural exposure to P. vivax in Amazonian populations represents a challenge to be addressed by vaccine development strategies.

In vitro sensitivity of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis Brazilian isolates to meglumine antimoniate and amphotericin B

Resistance of Leishmania parasites to specific chemotherapy has become a well-documented problem in the Indian subcontinent in recent years but only a few studies have focused on the susceptibility of American Leishmania isolates. Our susceptibility assays to meglumine antimoniate were performed against intracellular amastigotes after standardizing an in vitro model of macrophage infection appropriate for Leishmania (Viannia) braziliensis isolates. For the determination of promastigote susceptibility to amphotericin B, we developed a simplified MTT-test. The sensitivity in vitro to meglumine antimoniate and amphotericin B of 13 isolates obtained from Brazilian patients was determined. L. (V.) braziliensis isolates were more susceptible to meglumine antimoniate than Leishmania (Leishmania) amazonensis. EC(50), EC(90) and activity indexes (calculated over the sensitivity of reference strains), suggested that all isolates tested were susceptible in vitro to meglumine antimoniate, and did not show association with the clinical outcomes. Isolates were also uniformly susceptible in vitro to amphotericin B.

OntoMap: an ontology-based architecture to perform the semantic mapping between an interlingua and software components

This paper is about the use of natural language to communicate with computers. Most researches that have pursued this goal consider only requests expressed in English. A way to facilitate the use of several languages in natural language systems is by using an interlingua. An interlingua is an intermediary representation for natural language information that can be processed by machines. We propose to convert natural language requests into an interlingua [universal networking language (UNL)] and to execute these requests using software components. In order to achieve this goal, we propose OntoMap, an ontology-based architecture to perform the semantic mapping between UNL sentences and software components. OntoMap also performs component search and retrieval based on semantic information formalized in ontologies and rules.

Thermo luminescence of natural and synthetic diopside

Diopside, a natural silicate mineral of formula CaMgSi2O6, has been investigated concerning its thermoluminescence (TL) and electron paramagnetic resonance (EPR) properties. Glow curves and TL vs. gamma-dose were obtained irradiating natural samples to additional dose varying from 50 to 10,000Gy. Except for a 410 degrees C peak found in the Al-doped artificial diopside, all the other peaks grow linearly with radiation dose, but saturate beyond -1 kGy. To investigate high-temperature effect before irradiation, measurements of TL intensity in samples annealed at 500-900 degrees C and then irradiated to I kGy gamma-dose were carried out. Also the TL emission spectrum has been obtained. To compare with natural diopside, a synthetic pure polycrystal was produced and further those doped with iron, aluminum and manganese were also produced. (c) 2007 Elsevier B.V. All rights reserved.

XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility

Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of similar to 26 months and a nearly identical maximal life expectancy of similar to 37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.