115 research outputs found
Partial Restoration of Mutant Enzyme Homeostasis in Three Distinct Lysosomal Storage Disease Cell Lines by Altering Calcium Homeostasis
A lysosomal storage disease (LSD) results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulumāassociated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamilāboth US Food and Drug Administrationāapproved hypertension drugsāpartially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patientāderived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely Ī±-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety
Healing in the Wake of Sexual Violence
This special event recognized the voices of those who have been impacted by violence and shared solutions for healing the devastating effects of violence. This event showed how the transformative influence of restorative justice can empower survivors and facilitate the healing process for survivors, professionals in the field, and anyone whose life has been affected by violence.
Recognized speakers in restorative justice as well as survivors of violence shared information, research, and personal stories.
Speakers Included:
Msgr. Charles Chaffman, Judicial Vicar of the Los Angeles Archdiocese
Justice Janine Geske, Marquette Law School
Mimi Lind, Director of Mental Health and Domestic Violence Intervention Program, The Venice Family Clinic
āLupeā, Survivor of Human Trafficking
Dr. Jaime Romo, Author, Healing the Sexually Abused Heart: A Workbook for Survivors, Thrivers, and Supporters, Parents Preventing Abuse, and Teachers Preventing Abus
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