Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation

The human FMR1 gene contains a CGG repeat in its 5′ untranslated region. The repeat length in the normal population is polymorphic (5–55 CGG repeats). Lengths beyond 200 CGGs (full mutation) result in the absence of the FMR1 gene product, FMRP, through abnormal methylation and gene silencing. This causes Fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation, defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: Fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS, FMR1 mRNA levels are elevated and it has been hypothesised that FXTAS is caused by a pathogenic RNA gain-offunction mechanism. We have developed a knock in mouse model carrying an expanded CGG repeat (98 repeats), which shows repeat instability and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. Here, we report further repeat instability, up to 230 CGGs. An expansion bias was observed, with the largest expansion being 43 CGG units and the largest contraction 80 CGG repeats. In humans, this length would be considered a full mutation and would be expected to result in gene silencing. Mice carrying long repeats (∼230 CGGs) display elevated mRNA levels and decreased FMRP levels, but absence of abnormal methylation, suggesting that modelling the Fragile X full mutation in mice requires additional repeats or other genetic manipulation

"When the banks withdraw, slum landlords take over": The structuration of neighbourhood decline through Redlinging, Drug Dealing, Speculation and Immigrant Exploitation

Rather than viewing neighbourhood decline as a natural process resulting from the in-flow of low-income households, this study uses a socio-spatial approach that looks at the structuration of neighbourhood decline by emphasising the power of agents/actors, linking the structure of the real estate industry to the development of the neighbourhood. Landlords and banks are not merely automata of the price mechanism that steer the natural operation of the market, but should be seen as intentionally and unintentionally restructuring the local real estate market and thus possibly producing, or contributing to, processes of neighbourhood decline. This paper presents the Tarwewijk (Rotterdam, the Netherlands) as a case study of neighbourhood decline. Attention is paid to the social and physical decline of the neighbourhood, drug dealing, undocumented immigrants and processes impacting the housing market such as speculation, blockbusting, milking and redlining. It is argued that the retreat of ‘formal’ actors, such as banks and bona fide landlords, stimulates the rise of the underworld in both the housing and drugs markets.status: publishe

Fermentação ruminal e eficiência microbiana em bezerros holandeses alimentados com dietas contendo diferentes níveis de concentrado Ruminal fermentation and microbial efficiency in Holstein calves fed diets with different concentrate levels

RESUMO - Este trabalho foi realizado para avaliar os efeitos de diferentes níveis de concentrado sobre os parâmetros da fermentação ruminal, as digestibilidades aparente, total, ruminal e intestinal de N, a eficiência microbiana e o balanço de N. Cinco bezerros holandeses, inteiros, fistulados no rúmen e abomaso, com idade média inicial de 5,8±0,7 meses e 107,4±11,0 kg PV médio inicial, foram distribuídos em quadrado latino 5x5 (tratamento x período). Os animais foram alojados em baias individuais e alimentados à vontade com dietas contendo 30,0; 45,0; 60;0; 75,0; e 90,0% de concentrado, com base na MS, em rações contendo como volumoso, o feno de capim coast-cross e no concentrado, o farelo de soja, fubá de milho. Os valores de pH foram influenciados pelos níveis de concentrado das rações, e , 11,3 horas após a alimentação, foram estimandos os valores mínimos de 6,10; 5,89; 5,67; 5,46; e 5,24, para as rações com níveis de 30,0; 45,0; 60,0; 75,0; e 90,0%de concentrado nas rações, respectivamente. A concentração de amônia ruminal reduziu linearmente, em função dos tempos pós-alimentação, apresentando comportamento quadrático, com valores mínimos de 6,84; 7,14; 7,63; 7,82; 8,09; e 8,00 mg/dL, para 86,31; 84,86; 83,41; 81,95; 77,59; e 68,86% de concentrado nas rações. O numero de protozoários ruminais reduziu linearmente com o aumento dos níveis de concentrado nas rações. A eficiência de síntese de compostos nitrogenados microbianos aumentou linearmente com os níveis de concentrado nas rações.<br>ABSTRACT - This work was conducted to evaluate the effects of different concentrate levels on the parameters of at ruminal fermentation, the apparent, total, ruminal and intestinal N digestibilities, the microbial efficiency and the N balance. Five rumen and abomasum fistulated bull Holstein calves, with an initial average age of 5.8±0.7 months and initial average of 107.4±11.0 kg LW were allotted to a 5x5 Latin square design (treatment x period). The animals were housed in individual stalls and full fed diets (DM basis) containing 30.0, 45.0, 60.0, 75,0 and 90.0% of concentrate.The diets were based on coast-cross grass hay as forage and soybean meal and corn ground grain in the concentrate. The pH values were affected by the concentrate levels of the diets, and , 11.3 hours post-feeding, the minimum values of 6.10, 5.89, 5.67, 5.46, and 5.24, respectively, were estimated for the diets with 30.0, 45.0, 60.0, 75.0 e 90.0% of concentrate in the diets, respectively. The ruminal ammonia concentration linearly decreased, in function of post-feeding time and showing quadratic behavior, with a minimum values of 6.84, 7.14, 7,40, 7.63, 7.82, 8.09, and 8.00 mg/dL, for 86.31, 84.86, 83.41, 80,50, 81.95, 77.59, and 68.86% of concentrate in the diets. The number of ruminal protozoa linearly reduced as the dietary concentrate levels increased. The efficiency of microbial nitrogenous compound synthesis linearly increased, as the concentrate levels in the diets increased