RNAi-Mediated c-Rel Silencing Leads to Apoptosis of B Cell Tumor Cells and Suppresses Antigenic Immune Response In Vivo

c-Rel is a member of the Rel/NF-κB transcription factor family and is predominantly expressed in lymphoid and myeloid cells, playing a critical role in lymphocyte proliferation and survival. Persistent activation of the c-Rel signal transduction pathway is associated with allergies, inflammation, autoimmune diseases, and a variety of human malignancies. To explore the potential of targeting c-Rel as a therapeutic agent for these disorders, we designed a small interfering RNA (siRNA) to silence c-Rel expression in vitro and in vivo. C-Rel-siRNA expression via a retroviral vector in a B cell tumor cell line leads to growth arrest and apoptosis of the tumor cells. Silencing c-Rel in primary B cells in vitro compromises their proliferative and survival response to CD40 activation signals, similar to the impaired response of c-Rel knockout B cells. Most important, in vivo silencing of c-Rel results in significant impairment in T cell-mediated immune responses to antigenic stimulation. Our study thus validates the efficacy of c-Rel-siRNA, and suggests the development of siRNA-based therapy, as well as small molecular inhibitors for the treatment of B cell tumors as well as autoimmune diseases

Neuromechanical response of the upper body to unexpected perturbations during gait initiation in young and older adults

Background: Control of upper body motion deteriorates with ageing leading to impaired ability to preserve balance during gait, but little is known on the contribution of the upper body to preserve balance in response to unexpected perturbations during locomotor transitions, such as gait initiation. Aim: To investigate differences between young and older adults in the ability to modify the trunk kinematics and muscle activity following unexpected waist lateral perturbations during gait initiation. Methods: Ten young (25 ± 2 years) and ten older adults (73 ± 5 years) initiated locomotion from stance while a lateral pull was randomly applied to the pelvis. Two force plates were used to define the feet centre-of-pressure displacement. Angular displacement of the trunk in the frontal plane was obtained through motion analysis. Surface electromyography of cervical and thoracic erector spinae muscles was recorded bilaterally. Results: A lower trunk lateral bending towards the stance leg side in the preparatory phase of gait initiation was observed in older participants following perturbation. Right thoracic muscle activity was increased in response to the perturbation during the initial phase of gait initiation in young (+ 68%) but not in older participants (+ 7%). Conclusions: The age-related reduction in trunk movement could indicate a more rigid behaviour of the upper body employed by older compared to young individuals in response to unexpected perturbations preceding the initiation of stepping. Older adults’ delayed activation of thoracic muscles could suggest impaired reactive mechanisms that may potentially lead to a fall in the early stages of the gait initiation

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk