Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer\u27s Disease

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer\u27s disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically activated phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure

Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF

Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics

BACKGROUND: Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. While the association of mutant-FUS with stress granules is well established, the effect of the mutant protein on stress granules has not been examined. Here we investigated the effect of mutant-FUS on stress granule formation and dynamics under conditions of oxidative stress. RESULTS: We found that expression of mutant-FUS delays the assembly of stress granules. However, once stress granules containing mutant-FUS are formed, they are more dynamic, larger and more abundant compared to stress granules lacking FUS. Once stress is removed, stress granules disassemble more rapidly in cells expressing mutant-FUS. These effects directly correlate with the degree of mutant-FUS cytoplasmic localization, which is induced by mutations in the nuclear localization signal of the protein. We also determine that the RGG domains within FUS play a key role in its association to stress granules. While there has been speculation that arginine methylation within these RGG domains modulates the incorporation of FUS into stress granules, our results demonstrate that this post-translational modification is not involved. CONCLUSIONS: Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response

Nonlinear interaction of Alfv\'enic instabilities and turbulence via the modification of the equilibrium profiles

Nonlinear simulations of Alfv\'en modes (AM) driven by energetic particles (EP) in the presence of turbulence are performed with the gyrokinetic particle-in-cell code ORB5. The AMs carry a heat flux, and consequently they nonlinearly modify the plasma temperature profiles. The isolated effect of this modification on the dynamics of turbulence is studied, by means of electrostatic simulations. We find that turbulence is reduced when the profiles relaxed by the AM are used, with respect to the simulation where the unperturbed profiles are used. This is an example of indirect interaction of EPs and turbulence. First, an analytic magnetic equilibrium with circular concentric flux surfaces is considered as a simplified example for this study. Then, an application to an experimentally relevant case of ASDEX Upgrade is discussed

Towards formal modelling and verification of pervasive computing systems

Smart systems equipped with emerging pervasive computing technologies enable people with limitations to live in their homes independently. However, lack of guarantees for correctness prevent such system to be widely used. Analysing the system with regard to correctness requirements is a challenging task due to the complexity of the system and its various unpredictable faults. In this work, we propose to use formal methods to analyse pervasive computing (PvC) systems. Firstly, a formal modelling framework is proposed to cover the main characteristics of such systems (e.g., context-awareness, concurrent communications, layered architectures). Secondly, we identify the safety requirements (e.g., free of deadlocks and conflicts) and specify them as safety and liveness properties. Furthermore, based on the modelling framework, we propose an approach of verifying reasoning rules which are used in the middleware for perceiving the environment and making adaptation decisions. Finally, we demonstrate our ideas using a case study of a smart healthcare system. Experimental results show the usefulness of our approach in exploring system behaviours and revealing system design flaws such as information inconsistency and conflicting reminder services.No Full Tex

Microservice Transition and its Granularity Problem: A Systematic Mapping Study

Microservices have gained wide recognition and acceptance in software industries as an emerging architectural style for autonomic, scalable, and more reliable computing. The transition to microservices has been highly motivated by the need for better alignment of technical design decisions with improving value potentials of architectures. Despite microservices' popularity, research still lacks disciplined understanding of transition and consensus on the principles and activities underlying "micro-ing" architectures. In this paper, we report on a systematic mapping study that consolidates various views, approaches and activities that commonly assist in the transition to microservices. The study aims to provide a better understanding of the transition; it also contributes a working definition of the transition and technical activities underlying it. We term the transition and technical activities leading to microservice architectures as microservitization. We then shed light on a fundamental problem of microservitization: microservice granularity and reasoning about its adaptation as first-class entities. This study reviews state-of-the-art and -practice related to reasoning about microservice granularity; it reviews modelling approaches, aspects considered, guidelines and processes used to reason about microservice granularity. This study identifies opportunities for future research and development related to reasoning about microservice granularity.Comment: 36 pages including references, 6 figures, and 3 table

Detectability of Plasmodium falciparum clones

BACKGROUND: In areas of high transmission people often harbour multiple clones of Plasmodium falciparum, but even PCR-based diagnostic methods can only detect a fraction (the detectability, q) of all clones present in a host. Accurate measurements of detectability are desirable since it affects estimates of multiplicity of infection, prevalence, and frequency of breakthrough infections in clinical drug trials. Detectability can be estimated by typing repeated samples from the same host but it has been unclear what should be the time interval between the samples and how the data should be analysed. METHODS: A longitudinal molecular study was conducted in the Kassena-Nankana district in northern Ghana. From each of the 80 participants, four finger prick samples were collected over a period of 8 days, and tested for presence of different Merozoite Surface Protein (msp) 2 genotypes. Implications for estimating q were derived from these data by comparing the fit of statistical models of serial dependence and over-dispersion. RESULTS: The distribution of the frequencies of detection for msp2 genotypes was close to binomial if the time span between consecutive blood samples was at least 7 days. For shorter intervals the probabilities of detection were positively correlated, i.e. the shorter the interval between two blood collections, the more likely the diagnostic results matched for a particular genotype. Estimates of q were rather insensitive to the statistical model fitted. CONCLUSIONS: A simple algorithm based on analysing blood samples collected 7 days apart is justified for generating robust estimates of detectability. The finding of positive correlation of detection probabilities for short time intervals argues against imperfect detection being directly linked to the 48-hour periodicity of P. falciparum. The results suggest that the detectability of a given parasite clone changes over time, at an unknown rate, but fast enough to regard blood samples taken one week apart as statistically independent

Backbone-functionalised ruthenium diphosphine complexes for catalytic upgrading of ethanol and methanol to iso-butanol †

Efficient catalysts for Guerbet-type ethanol/methanol upgrading to iso-butanol have been developed via Michael addition of a variety of amines to ruthenium-coordinated dppen (1,1-bis(diphenylphosphino)ethylene). All catalysts produce over 50% iso-butanol yield with >90% selectivity in 2 h with catalyst 1 showing the best activity (74% yield after this time). The selectivity and turnover number approach 100% and 1000 respectively using catalyst 6. The presence of uncoordinated functionalised donor groups in these complexes results in a more stable catalyst compared to unfunctionalised analogues

Design, development and field evaluation of a Spanish into sign language translation system

This paper describes the design, development and field evaluation of a machine translation system from Spanish to Spanish Sign Language (LSE: Lengua de Signos Española). The developed system focuses on helping Deaf people when they want to renew their Driver’s License. The system is made up of a speech recognizer (for decoding the spoken utterance into a word sequence), a natural language translator (for converting a word sequence into a sequence of signs belonging to the sign language), and a 3D avatar animation module (for playing back the signs). For the natural language translator, three technological approaches have been implemented and evaluated: an example-based strategy, a rule-based translation method and a statistical translator. For the final version, the implemented language translator combines all the alternatives into a hierarchical structure. This paper includes a detailed description of the field evaluation. This evaluation was carried out in the Local Traffic Office in Toledo involving real government employees and Deaf people. The evaluation includes objective measurements from the system and subjective information from questionnaires. The paper details the main problems found and a discussion on how to solve them (some of them specific for LSE)

Effect of a brief intervention on evidence-based medicine skills of pediatric residents

BACKGROUND: While Evidence-Based Medicine (EBM) skills are increasingly being taught in medical schools, teaching quality has been insufficient, so that incoming pediatric residents lack adequate EBM skills required for patient care. The objective of this study was to evaluate the effectiveness of a brief teaching module developed to improve EBM skills of pediatric residents. METHODS: With-in subjects study design with pre- and post-test evaluation was performed in a large urban pediatric residency training program in Brooklyn, New York. We included PGY-1s during intern orientation, while second and third year pediatric residents were selected based on schedule availability. Sixty-nine residents were enrolled into the study, 60 (87%) completed the training. An EBM training module consisting of three or four weekly two-hour seminars was conducted. The module was designed to teach core EBM skills including (1) formulating answerable clinical questions, (2) searching the evidence, (3) critical appraisal skills including validity and applicability, and (4) understanding levels of evidence and quantitative results for therapy articles. A portion of the Fresno test of competence in EBM was used to assess EBM skills. The test presented a clinical scenario that was followed by nine short answer questions. One to three questions were used to assess EBM skills for each of the four core skills. The κ co-efficient for inter-rater reliability was 0.74 (95% CI: 0.56–0.92). RESULTS: Prior to the training module, the residents achieved a mean score of 17% correct overall. Post intervention, the mean score increased to 63% with improvement in each EBM category. A mean of 4.08 more questions (out of 9) were answered correctly after the training (95% CI of 3.44–4.72). CONCLUSION: A brief training module was effective in improving EBM skills of pediatric residents