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Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease
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Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state
Highlights: • We designed and synthesized 24 SSO sequences to skip exon 3 in CSB mRNA. • SSO generated an additional nonsense mutation at the upstream region of PGBD3. • Such SSO up-regulated several gene expression levels in CS cells. • SSO treatment might allow CS cells to mimic UV{sup S}S cell. Cockayne syndrome (CS) is a severe disorder with no effective treatment. The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UV{sup S}S), a disorder that causes mild symptoms. How the CSB gene determines a patient's fate is unknown, but one intriguing point is that in UV{sup S}S patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region. In contrast, in CS patient cells, there is at least one allele with several mutations downstream of the PGBD3 inserted region, or there are homozygous mutations in exon 1. Here, we designed and synthesized 24 splice switching oligonucleotides (SSOs) to skip exon 3 in CSB mRNA. Use of these SSOs induced a frame shift in order to generate an alternative stop codon at the upstream region of the PGBD3 invasion site. As a result, a reduction of mitochondrial membrane potential following H{sub 2}O{sub 2} treatment in CS cell was recovered. It was demonstrated that up-regulation of several gene expression brought about by SSOs are related to mitochondrial dysfunction in CS cells.
Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies
The ‘neurotrophic sesquiterpenes’ refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABA A receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other ‘cage convulsant’ compounds such as TETS and picrotoxin. We hypothesize here that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.
Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer’s Disease
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Integrated LAMP and immunoassay platform for diarrheal disease detection
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Purine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors for autoimmune diseases
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
Multifaceted assessment of the APP/PS1 mouse model for Alzheimer’s disease: Applying MRS, DTI, and ASL
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