In vitro whole-genome analysis identifies a susceptibility locus for HIV-1.

Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1-infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)-anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents.

Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions.

OBJECTIVE: To develop and compare two new technologies for diagnosing a contiguous gene syndrome, the Williams-Beuren syndrome (WBS). METHODS: The first proposed method, named paralogous sequence quantification (PSQ), is based on the use of paralogous sequences located on different chromosomes and quantification of specific mismatches present at these loci using pyrosequencing technology. The second exploits quantitative real time polymerase chain reaction (QPCR) to assess the relative quantity of an analysed locus. RESULTS: A correct and unambiguous diagnosis was obtained for 100% of the analysed samples with either technique (n = 165 and n = 155, respectively). These methods allowed the identification of two patients with atypical deletions in a cohort of 182 WBS patients. Both patients presented with mild facial anomalies, mild mental retardation with impaired visuospatial cognition, supravalvar aortic stenosis, and normal growth indices. These observations are consistent with the involvement of GTF2IRD1 or GTF2I in some of the WBS facial features. CONCLUSIONS: Both PSQ and QPCR are robust, easy to interpret, and simple to set up. They represent a competitive alternative for the diagnosis of segmental aneuploidies in clinical laboratories. They have advantages over fluorescence in situ hybridisation or microsatellites/SNP genotyping for detecting short segmental aneuploidies as the former is costly and labour intensive while the latter depends on the informativeness of the polymorphisms.

Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis.

BACKGROUND: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. METHODS: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.

Educação e colonização no Brasil: as escolas étnicas alemãs

Este artigo apresenta dados de pesquisa sobre a organização escolar e curricular de escolas primárias na colônia catarinense Hansa, fundada em 1897. Foi baseado na análise de documentos da Companhia Colonizadora Hamburguesa. Os resultados mostram peculiaridades como o ensino em alemão e o currículo focalizado no Cálculo e na aprendizagem da língua e cultura alemãs nas disciplinas de Leitura, Escrita, Poesia, Canto, Religião e Latim. Porém, havia matérias como Português e História, que abordavam questões brasileiras. Nos seus primeiros anos, as instituições mantiveram aspectos pedagógicos que as caracterizam como típicas expressões do fenômeno das escolas étnicas: as escolas alemãs [Deutsch Schulen]. Elas atenderam a necessidade de escola, embasadas por um conjunto de práticas educativas de cunho étnico que mesclaram aspectos culturais estrangeiros àqueles do contexto brasileiro. O uso da língua alemã constituiu um indicador étnico essencial. A compreensão dessas instituições escolares na história da educação brasileira é parametrizada pelas relações entre currículo e cultura, considerando a questão étnica como fator central na análise dos processos sociais.

Modeval2 Reference Manual

El Projecte MODEVAL respon a la necessitat detectada en matèria d'avaluació de competències bàsiques de les persones, i tracta de definir quins són els nivells bàsics d'habilitats que garanteixen unes condicions individuals favorables per al desenvolupament de la persona, la ciutadania activa, i la integració social, cultural i professional dels individus. Mentre el projecte MODEVAL 1 tenia com a objectiu realitzar un marc de referència metodològic a nivell europeu per a dur a terme l'avaluació de competències; el projecte MODEVAL 2, és a dir, el present treball, té com a objectiu la creació de mòduls de formació per als diferents interessats (és a dir, formadors d'alfabetització i de formació bàsica, investigadors, coordinadors de centres de formació, els responsables polítics, estadístics, persones que realitzaran enquestes a gran escala sobre el coneixement de base, etc.) per tal d'aplicar les recomanacions del projecte i crear les seves pròpies eines d'avaluació.

Modeval2 Manuel de Reference

El Projecte MODEVAL respon a la necessitat detectada en matèria d'avaluació de competències bàsiques de les persones, i tracta de definir quins són els nivells bàsics d'habilitats que garanteixen unes condicions individuals favorables per al desenvolupament de la persona, la ciutadania activa, i la integració social, cultural i professional dels individus. Mentre el projecte MODEVAL 1 tenia com a objectiu realitzar un marc de referència metodològic a nivell europeu per a dur a terme l'avaluació de competències; el projecte MODEVAL 2, és a dir, el present treball, té com a objectiu la creació de mòduls de formació per als diferents interessats (és a dir, formadors d'alfabetització i de formació bàsica, investigadors, coordinadors de centres de formació, els responsables polítics, estadístics, persones que realitzaran enquestes a gran escala sobre el coneixement de base, etc.) per tal d'aplicar les recomanacions del projecte i crear les seves pròpies eines d'avaluació.

Alterations of the 5'untranslated region of SLC16A12 lead to age-related cataract.

PURPOSE. Knowledge of genetic factors predisposing to age-related cataract is very limited. The aim of this study was to identify DNA sequences that either lead to or predispose for this disease. METHODS. The candidate gene SLC16A12, which encodes a solute carrier of the monocarboxylate transporter family, was sequenced in 484 patients with cataract (134 with juvenile cataract, 350 with age-related cataract) and 190 control subjects. Expression studies included luciferase reporter assay and RT-PCR experiments. RESULTS. One patient with age-related cataract showed a novel heterozygous mutation (c.-17A>G) in the 5'untranslated region (5'UTR). This mutation is in cis with the minor G-allele of the single nucleotide polymorphism (SNP) rs3740030 (c.-42T/G), also within the 5'UTR. Using a luciferase reporter assay system, a construct with the patient's haplotype caused a significant upregulation of luciferase activity. In comparison, the SNP G-allele alone promoted less activity, but that amount was still significantly higher than the amount of the common T-allele. Analysis of SLC16A12 transcripts in surrogate tissue demonstrated striking allele-specific differences causing 5'UTR heterogeneity with respect to sequence and quantity. These differences in gene expression were mirrored in an allele-specific predisposition to age-related cataract, as determined in a Swiss population (odds ratio approximately 2.2; confidence intervals, 1.23-4.3). CONCLUSIONS. The monocarboxylate transporter SLC16A12 may contribute to age-related cataract. Sequences within the 5'UTR modulate translational efficiency with pathogenic consequences.