Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals

From efforts to improve the biophysical properties of antisense oligonucleotides by incorporating backbone- or sugar-modified nucleoside analogs, 2'-O-methoxyethyl ribonucleosides 8b were identified as building blocks for a second generation of antisense oligonucleotides. Compounds containing these modifications were demonstrated to combine the benefit of a high binding affinity to the RNA complement with a large increase in nuclease resistance, allowing the use of regular phosphodiester linkages. Chimeric oligonucleotides with 2'-O-methoxyethyl ribonucleosides, 8b, in the wings and a central DNA-phosphorothioate window were shown to efficiently downregulate C-'raf' kinase and PKC-α messenger-RNA in tumor cell lines resulting in a profound inhibition of cell proliferation. The same compounds were able to effectively reduce the growth of tumors in animal models at low concentrations indicating the potential utility of these second generation antisense oligonucleotides for therapeutic applications

Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients

International audienceBackground: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. Results: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. Conclusion: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs

Elevated Pontine and Putamenal GABA Levels in Mild-Moderate Parkinson Disease Detected by 7 Tesla Proton MRS

Background: Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding: To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. c-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p,0.001 for pons and p,0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance: The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of th

Desempenho produtivo de tambacus alimentados com dietas suplementadas com vitamina E

O objetivo deste trabalho foi avaliar os efeitos da suplementação da dieta de tambacus com concentrações de vitamina E sobre variáveis de desempenho e hematológicas, bem como determinar a relação da atividade da glutationa peroxidase com a inclusão de vitamina E e selênio na dieta. Foram utilizados 250 juvenis de tambacu, divididos em 25 aquários. A dieta basal constituiu-se de ração peletizada com 32% de proteína bruta e 3.300 kcal kg-1 de energia digestível, e inclusão de 0,40 mg kg-1 de Se. As dietas-teste - isoprotéicas e isoenergéticas - foram compostas da dieta basal com diferentes concentrações de vitamina E (0, 100, 200, 300, 400 mg kg-1), em delineamento inteiramente ao acaso, com cinco tratamentos e cinco repetições. Não foi observado efeito significativo da suplementação com vitamina E sobre o comprimento total, volume corpuscular médio, concentração de hemoglobina corpuscular média e número de eritrócitos, nem sobre a atividade da glutationa peroxidase. Peso final e conversão alimentar aparente, no entanto, sofreram efeito dos tratamentos suplementados. O teor de 400 mg kg-1 de vitamina E melhorou o comprimento padrão e ganho de peso. A suplementação da dieta com vitamina E resulta em melhor desempenho produtivo de tambacus