Nat Rev Neurol

Genome-wide association studies (GWAS) have uncovered over two dozen candidate Alzheimer disease susceptibility genes; however, the results of these studies showed limited overlap. Two independently performed GWAS involving cohorts from europe and the US have now identified three additional putative Alzheimer disease genes that show modest but remarkably consistent effects across data sets

Biochem Soc Trans

Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin-proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Abeta (amyloid beta-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration

Truss-like Discrete Element Method Applied to Damage Process Simulation in Quasi-Brittle Materials

This paper discusses the combined application of the lattice discrete element method (LDEM) and the acoustic emission (AE) technique to analyze damage in quasi-brittle materials. These methods were used to study the damage in a concrete slab under pure-shear stress and a pre-fissured sandstone beam subjected to three-point bending. The first test was restricted to simulation results, whereas the second included experimental data. The discrete element method was used to perform the simulations for both tests, whereas the corresponding results and the information from the experiments were assessed using AE analysis tools. It was shown that the synergistic use of these two methods led to a comprehensive understanding of the two analyzed cases and offered an effective, generalizable approach for assessing damage processes in quasi-brittle materials

Developing Effective Alzheimer's Disease Therapies: Clinical Experience and Future Directions

Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease

Quantum liquid droplets in a mixture of Bose-Einstein condensates

Bose-Einstein condensatesquantum mixturesquantum liquidsquantum fluctuationsQuantum droplets are small clusters of atoms self-bound by the balance of attractive and repulsive forces. Here we report on the observation of a novel type of droplets, solely stabilized by contact interactions in a mixture of two Bose-Einstein condensates. We demonstrate that they are several orders of magnitude more dilute than liquid helium by directly measuring their size and density via in situ imaging. Moreover, by comparison to a single-component condensate, we show that quantum many-body effects stabilize them against collapse. We observe that droplets require a minimum atom number to be stable. Below, quantum pressure drives a liquid-to-gas transition that we map out as a function of interaction strength. These ultra-dilute isotropic liquids remain weakly interacting and constitute an ideal platform to benchmark quantum many-body theories.Peer ReviewedPreprin

Explaining Africa’s public consumption procyclicality : revisiting old evidence

This paper compiles a novel dataset of time-varying measures of government consumption cyclicality for a panel of 46 African economies between 1960 and 2014. Government consumption has, generally, been highly procyclical over time in this group of countries. However, sample averages hide serious heterogeneity across countries with the majority of them showing procyclical behavior despite some positive signs of graduation from the “procyclicality trap” in a few cases. By means of weighted least squares regressions, we find that more developed African economies tend to have a smaller degree of government consumption procyclicality. Countries with higher social fragmentation and those are more reliant on foreign aid inflows tend to have a more procyclical government consumption policy. Better governance promotes counter- cyclical fiscal policy whileincreased democracy dampens it. Finally, some fiscal rules are important in curbing the procyclical behavior of government consumption.info:eu-repo/semantics/publishedVersio

Mesenchymal stem cell-derived extracellular vesicles protect human corneal endothelial cells from endoplasmic reticulum stress-mediated apoptosis

Corneal endothelial dystrophy is a relevant cause of vision loss and corneal transplantation worldwide. In the present study, we analyzed the effect of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in an in vitro model of corneal dystrophy, characterized by endoplasmic reticulum stress. The effects of MSC-EVs were compared with those of serum-derived EVs, reported to display a pro-angiogenic activity. MSC-EVs were able to induce a significant down-regulation of the large majority of endoplasmic reticulum stress-related genes in human corneal endothelial cells after exposure to serum deprivation and tunicamycin. In parallel, they upregulated the Akt pathway and limited caspase-3 activation and apoptosis. At variance, the effect of the serum EVs was mainly limited to Akt phosphorylation, with minimal or absent effects on endoplasmic reticulum stress modulation and apoptosis prevention. The effects of MSC-EVs were correlated to the transfer of numerous endoplasmic reticulum (ER)-stress targeting miRNAs to corneal endothelial cells. These data suggest a potential therapeutic effect of MSC-EVs for corneal endothelial endoplasmic reticulum stress, a major player in corneal endothelial dystrophy