Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

BACKGROUND: Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. METHODS: To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. RESULTS: Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally, we derived a candidate set of 24 novel genetic modifiers, including histone deacetylase 3 (HDAC3), metabotropic glutamate receptor 1 (GRM1), CDK5 regulatory subunit 2 (CDK5R2), and coactivator 1ß of the peroxisome proliferator-activated receptor gamma (PPARGC1B). CONCLUSIONS: The results of our study give us an intriguing picture of the molecular complexity of HD. Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics

Colorful Niches of Phytoplankton Shaped by the Spatial Connectivity in a Large River Ecosystem: A Riverscape Perspective

Large rivers represent a significant component of inland waters and are considered sentinels and integrators of terrestrial and atmospheric processes. They represent hotspots for the transport and processing of organic and inorganic material from the surrounding landscape, which ultimately impacts the bio-optical properties and food webs of the rivers. In large rivers, hydraulic connectivity operates as a major forcing variable to structure the functioning of the riverscape, and–despite increasing interest in large-river studies–riverscape structural properties, such as the underwater spectral regime, and their impact on autotrophic ecological processes remain poorly studied. Here we used the St. Lawrence River to identify the mechanisms structuring the underwater spectral environment and their consequences on pico- and nanophytoplankton communities, which are good biological tracers of environmental changes. Our results, obtained from a 450 km sampling transect, demonstrate that tributaries exert a profound impact on the receiving river’s photosynthetic potential. This occurs mainly through injection of chromophoric dissolved organic matter (CDOM) and non-algal material (tripton). CDOM and tripton in the water column selectively absorbed wavelengths in a gradient from blue to red, and the resulting underwater light climate was in turn a strong driver of the phytoplankton community structure (prokaryote/eukaryote relative and absolute abundances) at scales of many kilometers from the tributary confluence. Our results conclusively demonstrate the proximal impact of watershed properties on underwater spectral composition in a highly dynamic river environment characterized by unique structuring properties such as high directional connectivity, numerous sources and forms of carbon, and a rapidly varying hydrodynamic regime. We surmise that the underwater spectral composition represents a key integrating and structural property of large, heterogeneous river ecosystems and a promising tool to study autotrophic functional properties. It confirms the usefulness of using the riverscape approach to study large-river ecosystems and initiate comparison along latitudinal gradients

Cosmology with the Laser Interferometer Space Antenna

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational wave observations by LISA to probe the universe

Remote detection of invasive alien species

The spread of invasive alien species (IAS) is recognized as the most severe threat to biodiversity outside of climate change and anthropogenic habitat destruction. IAS negatively impact ecosystems, local economies, and residents. They are especially problematic because once established, they give rise to positive feedbacks, increasing the likelihood of further invasions and spread. The integration of remote sensing (RS) to the study of invasion, in addition to contributing to our understanding of invasion processes and impacts to biodiversity, has enabled managers to monitor invasions and predict the spread of IAS, thus supporting biodiversity conservation and management action. This chapter focuses on RS capabilities to detect and monitor invasive plant species across terrestrial, riparian, aquatic, and human-modified ecosystems. All of these environments have unique species assemblages and their own optimal methodology for effective detection and mapping, which we discuss in detail

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis

The impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review

Introduction Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. Methods A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Results Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Conclusions Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients

Magnetic resonance imaging based noninvasive measurements of brain hemodynamics in neonates : A review

Perinatal disturbances of brain hemodynamics can have a detrimental effect on the brain's parenchyma with consequently adverse neurodevelopmental outcome. Noninvasive, reliable tools to evaluate the neonate's brain hemodynamics are scarce. Advances in magnetic resonance imaging have provided new methods to noninvasively assess brain hemodynamics. More recently these methods have made their transition to the neonatal population. The aim of this review is twofold. Firstly, to describe these newly available noninvasive methods to investigate brain hemodynamics in neonates. Secondly, to discuss the results that were obtained with these techniques, identifying both potential clinical applications as well as gaps of knowledge

The impact of the early phase of the COVID-19 pandemic on mental-health services in Europe

The current COVID-19 pandemic confronts psychiatric patients and mental health services with unique and severe challenges. In order to identify these trans-national challenges across Europe, an ad-hoc survey was conducted among 23 experts, each answering for one European or aligned country. A number of important themes and issues were raised for the impact of COVID-19 on mental health and mental health services, barriers to service provision and future consequences. A number of key issues were reported by colleagues across several jurisdictions, even though these were at different stages of their national epidemics. Based on these findings, we articulate some important learnings from the early stages of the COVID-19 European pandemic, and highlight key considerations for all countries’ mental health services as the current pandemic develops and for future pandemics

Cosmology with the Laser Interferometer Space Antenna

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational wave observations by LISA to probe the universe