ABSTRACT
Somatic mutations in spliceosome genes are detectable in â¼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.
Subject(s)
Cyclohexylamines/pharmacology , Mutation , RNA Splicing/drug effects , Spiro Compounds/pharmacology , Spliceosomes/drug effects , Splicing Factor U2AF/genetics , Animals , Cell Cycle/drug effects , Cell Proliferation/drug effects , HEK293 Cells , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Transgenic , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Primary Cell Culture , Spliceosomes/genetics , Splicing Factor U2AF/metabolismABSTRACT
The present article attempts to highlight the use of assistive technologies in academic libraries in India, the United Kingdom, the United States, and Canada. It dwells upon the use and importance of assistive technologies in general and their use for visually challenged learners in particular. Further, it gives suggestions for implementing assistive technologies in academic libraries for making visually challenged students self-reliant learners in accomplishing their academic and research pursuits. The present study adopted convenience sampling for collecting the data, which was collected between December 15, 2012 and January 18, 2013.
Subject(s)
Libraries , Self-Help Devices , Canada , Data Collection , Humans , India , United Kingdom , United StatesABSTRACT
The Indian subcontinent is characterized by the ancestral and cultural diversity of its people. Genetic input from several unique source populations and from the unique social architecture provided by the caste system has shaped the current genetic landscape of India. In the present study 200 individuals each from three upper-caste and four middle-caste Hindu groups and from two Muslim populations in North India were examined for 10 polymorphic Alu insertions (PAIs). The investigated PAIs exhibit high levels of polymorphism and average heterozygosity. Limited interpopulation variance and genetic flow in the present study suggest admixture. The results of this study demonstrate that, contrary to common belief, the caste system has not provided an impermeable barrier to genetic exchange among Indian groups.
