3α,7-dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic acids display neuroprotective properties in common forms of Parkinson’s disease

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

Objective A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. Design By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. Results HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. Conclusions Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure

Web Search Clickstreams

Search engines are a vital part of the Web and thus the Internet infrastructure. Therefore understanding the behavior of users searching the Web gives insights into trends, and enables enhancements of future search capabilities. Possible data sources for studying Web search behavior are either server-side logs or client-side logs. Unfortunately, current server-side logs are hard to obtain as they are considered proprietary by the search engine operators. Therefore we in this paper present a methodology for extracting client-side logs from the traffic exchanged between a large user group and the Internet. The added benefit of our methodology is that we do not only extract the search terms, the query sequences, and search results of each individual user but also the full \textit{clickstrea}, i.e., the result pages users view and the subsequently visited hyperlinked pages. We propose a finite-state Markov model that captures the user web searching and browsing behavior and allows us to deduce users' prevalent search patterns. To our knowledge, this is the first such detailed client-side analysis of clickstreams

Glycine Dissolution Behavior under Forced Convection

The integration of a flow-through cell into a Mach–Zehnder interferometer offers the possibility to study the dissolution of crystals in detail. The influence of flow on the displacement velocity of a specific crystal facet and the distribution of the solute concentration around the crystal are measured simultaneously in a time-resolved manner. The disintegration from the crystal surface and the mass transfer into the solvent can be separated. We aim to establish an in vitro experiment that improves the quality of prediction for the bioavailability of active pharmaceutical ingredients. In the presented feasibility study, glycine was used as a model substance. It was successfully demonstrated that the set-up is suitable for observing disintegration and mass transfer separately. The description of the dissolution rate in terms of the Sherwood number as a function of Reynolds, Schmidt and Grashof numbers clearly shows that with increasing flow rate there is a transition from natural to forced convection as the dominant mass transfer mechanism. Temporal and spatial resolved concentration fields visualize the convective mass transfer and also show the influence of convection on the diffusive boundary layer. No limitation of the dissolution by surface disintegration could be found in the examined range of flow rates