C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation

Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD

Aging and memory phenomena in magnetic and transport properties of vortex matter: a brief review

There is mounting experimental evidence that strong off-equilibrium phenomena, such as ``memory'' or ``aging'' effects, play a crucial role in the physics of vortices in type II superconductors. We give a short review, based on a recently introduced schematic vortex model, of current progresses in understanding out of equilibrium vortex behaviours. We develop a unified description of ``memory'' phenomena in magnetic and transport properties, such as magnetisation loops and their ``anomalous'' 2nd peak, logarithmic creep, ``anomalous'' finite creep rate in the limit of vanishing temperature, ``memory'' and ``irreversibility'' in I-V characteristics, time dependent critical currents, ``rejuvenation'' and ``aging'' of the system response.Comment: updated versio

Cochrane rehabilitation: 2020 Annual report

during its fourth year of existence, cochrane rehabilitation went on to promote evidence-informed health decision-making in rehabilitation. in 2020, the outbreak of the coVid-19 pandemic has made it necessary to alter priorities. in these challenging times, cochrane rehabilitation has firstly changed its internal organisation and established a new relevant project in line with pandemic needs: the REH-COVER (Rehabilitation – coVid-19 evidence-based response) action. the aim was to focus on the timely collection, review and dissemination of summarised and synthesised evidence relating to COVID-19 and rehabilitation. Cochrane Rehabilitation REH-COVER action has included in 2020 five main initiatives: 1) rapid living systematic reviews on rehabilitation and coVid-19; 2) interactive living evidence map on rehabilitation and coVid-19; 3) definition of the research topics on “rehabilitation and COVID-19” in collaboration with the World Health Organization (WHO) rehabilitation programme; 4) Cochrane Library special collection on Coronavirus (COVID-19) rehabilitation; and 5) collaboration with COVID-END for the topics “rehabilitation” and “disability.” Furthermore, we are still carrying on five different special projects: Be4rehab; RCTRACK; definition of rehabilitation for research purposes; ebook project; and a prioritization exercise for Cochrane Reviews production. The Review Working Area continued to identify and “tag” the rehabilitation-relevant reviews published in the cochrane library; the publication Working area went on to publish Cochrane Corners, working more closely with the Cochrane Review Groups (CRGs) and Cochrane Networks, particularly with Cochrane Musculoskeletal, oral, skin and sensory Network; the Education Working area, the most damaged in 2020, tried to continue performing educational activities such as workshops in different online meetings; the Methodology Working area organized the third and fourth cochrane Rehabilitation Methodological (CRM) meetings respectively in Milan and Orlando; the Communication Working Area spread rehabilitation evidences through different channels and translated the contents in different languages