Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective

Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS

Earth-like Habitats in Planetary Systems

Understanding the concept of habitability is related to an evolutionary knowledge of the particular planet-in-question. Additional indications so-called "systemic aspects" of the planetary system as a whole governs a particular planet's claim on habitability. Here we focus on such systemic aspects and discuss their relevance to the formation of an 'Earth-like' habitable planet. We summarize our results obtained by lunar sample work and numerical models within the framework of the Research Alliance "Planetary Evolution and Life". We consider various scenarios which simulate the dynamical evolution of the Solar System and discuss the likelihood of forming an Earth-like world orbiting another star. Our model approach is constrained by observations of the modern Solar System and the knowledge of its history. Results suggest that the long-term presence of terrestrial planets is jeopardized due to gravitational interactions if giant planets are present. But habitability of inner rocky planets may be supported in those planetary systems hosting giant planets. Gravitational interactions within a complex multiple-body structure including giant planets may supply terrestrial planets with materials which formed in the colder region of the proto-planetary disk. During these processes, water, the prime requisite for habitability, is delivered to the inner system. This may occur either during the main accretion phase of terrestrial planets or via impacts during a post-accretion bombardment. Results for both processes are summarized and discussed with reference to the lunar crater record. Starting from a scenario involving migration of the giant planets this contribution discusses the delivery of water to Earth, the modification of atmospheres by impacts in a planetary system context and the likelihood of the existence of extrasolar Earth-like habitable worlds.Comment: 36 Pages, 6 figures, 2014, Special Issue in Planetary and Space Science on the Helmholtz Research Alliance on Planetary Evolution and Lif

Disentangling AGN and Star Formation in Soft X-rays

We have explored the interplay of star formation and AGN activity in soft X-rays (0.5-2 keV) in two samples of Seyfert 2 galaxies (Sy2s). Using a combination of low resolution CCD spectra from Chandra and XMM-Newton, we modeled the soft emission of 34 Sy2s using power law and thermal models. For the 11 sources with high signal-to-noise Chandra imaging of the diffuse host galaxy emission, we estimate the luminosity due to star formation by removing the AGN, fitting the residual emission. The AGN and star formation contributions to the soft X-ray luminosity (i.e. L$_{x,AGN}$ and L$_{x,SF}$) for the remaining 24 Sy2s were estimated from the power law and thermal luminosities derived from spectral fitting. These luminosities were scaled based on a template derived from XSINGS analysis of normal star forming galaxies. To account for errors in the luminosities derived from spectral fitting and the spread in the scaling factor, we estimated L$_{x,AGN}$ and L$_{x,SF}$ from Monte Carlo simulations. These simulated luminosities agree with L$_{x,AGN}$ and L$_{x,SF}$ derived from Chandra imaging analysis within a 3\sigma\ confidence level. Using the infrared [NeII]12.8\mu m and [OIV]26\mu m lines as a proxy of star formation and AGN activity, respectively, we independently disentangle the contributions of these two processes to the total soft X-ray emission. This decomposition generally agrees with L$_{x,SF}$ and L$_{x,AGN}$ at the 3\sigma\ level. In the absence of resolvable nuclear emission, our decomposition method provides a reasonable estimate of emission due to star formation in galaxies hosting type 2 AGN.Comment: accepted for publication in ApJ; 34 pages, 9 tables, 4 figure

Muscle Satellite Cells: Exploring the Basic Biology to Rule Them

Adult skeletal muscle is a postmitotic tissue with an enormous capacity to regenerate upon injury. This is accomplished by resident stem cells, named satellite cells, which were identified more than 50 years ago. Since their discovery, many researchers have been concentrating efforts to answer questions about their origin and role in muscle development, the way they contribute to muscle regeneration, and their potential to cell-based therapies. Satellite cells are maintained in a quiescent state and upon requirement are activated, proliferating, and fusing with other cells to form or repair myofibers. In addition, they are able to self-renew and replenish the stem pool. Every phase of satellite cell activity is highly regulated and orchestrated by many molecules and signaling pathways; the elucidation of players and mechanisms involved in satellite cell biology is of extreme importance, being the first step to expose the crucial points that could be modulated to extract the optimal response from these cells in therapeutic strategies. Here, we review the basic aspects about satellite cells biology and briefly discuss recent findings about therapeutic attempts, trying to raise questions about how basic biology could provide a solid scaffold to more successful use of these cells in clinics

Addressing cultural, racial and ethnic discrepancies in guideline discordant gestational weight gain: a systematic review and meta-analysis

Objective To systematically review the literature and describe the discrepancies in achieving the 2009 Institute of Medicine (IOM) gestational weight gain (GWG) guidelines across cultures. Methods Ten databases were searched from inception to April 2018. Observational cohort studies were included that examined adult women; reported on a measure of culture; compared cultural groups, and reported on GWG. Articles were broken down into papers that used the current 2009 IOM GWG guidelines and those that used others. A meta-analysis was conducted for studies using the 2009 guidelines examining the prevalence of discordant GWG across cultural groups. Results The review included 86 studies. Overall, 69% of women experienced discordant GWG irrespective of culture. White women experienced excessive GWG most often, and significantly more than Asian and Hispanic women; Black women had a higher prevalence of excessive GWG than Hispanic and Asian women; however, this difference was not significant. Conclusions The majority of women experience excessive GWG, with White women experiencing this most often. Culturally diverse GWG guidelines are needed to individualize antenatal care and promote optimal maternal-fetal health outcomes across cultural groups

Aedes fluviatilis cell lines as new tools to study metabolic and immune interactions in mosquito‑Wolbachia symbiosis

In the present work, we established two novel embryonic cell lines from the mosquito Aedes fluviatilis containing or not the naturally occurring symbiont bacteria Wolbachia, which were called wAflu1 and Aflu2, respectively. We also obtained wAflu1 without Wolbachia after tetracycline treatment, named wAflu1.tet. Morphofunctional characterization was performed to help elucidate the symbiont-host interaction in the context of energy metabolism regulation and molecular mechanisms of the immune responses involved. The presence of Wolbachia pipientis improves energy performance in A. fluviatilis cells; it affects the regulation of key energy sources such as lipids, proteins, and carbohydrates, making the distribution of actin more peripheral and with extensions that come into contact with neighboring cells. Additionally, innate immunity mechanisms were activated, showing that the wAflu1 and wAflu1.tet cells are responsive after the stimulus using Gram negative bacteria. Therefore, this work confirms the natural, mutually co-regulating symbiotic relationship between W. pipientis and A. fluviatilis, modulating the host metabolism and immune pathway activation. The results presented here add important resources to the current knowledge of Wolbachia-arthropod interactions

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. Methods: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. Results: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. Conclusions: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders

Federated Identity Management for Research Collaborations

This white-paper expresses common requirements of Research Communities seeking to leverage Identity Federation for Authentication and Authorisation. Recommendations are made to Stakeholders to guide the future evolution of Federated Identity Management in a direction that better satisfies research use cases. The authors represent research communities, Research Services, Infrastructures, Identity Federations and Interfederations, with a joint motivation to ease collaboration for distributed researchers. The content has been edited collaboratively by the Federated Identity Management for Research (FIM4R) Community, with input sought at conferences and meetings in Europe, Asia and North America

Machine learning in marine ecology: an overview of techniques and applications

Machine learning covers a large set of algorithms that can be trained to identify patterns in data. Thanks to the increase in the amount of data and computing power available, it has become pervasive across scientific disciplines. We first highlight why machine learning is needed in marine ecology. Then we provide a quick primer on machine learning techniques and vocabulary. We built a database of ∼1000 publications that implement such techniques to analyse marine ecology data. For various data types (images, optical spectra, acoustics, omics, geolocations, biogeochemical profiles, and satellite imagery), we present a historical perspective on applications that proved influential, can serve as templates for new work, or represent the diversity of approaches. Then, we illustrate how machine learning can be used to better understand ecological systems, by combining various sources of marine data. Through this coverage of the literature, we demonstrate an increase in the proportion of marine ecology studies that use machine learning, the pervasiveness of images as a data source, the dominance of machine learning for classification-type problems, and a shift towards deep learning for all data types. This overview is meant to guide researchers who wish to apply machine learning methods to their marine datasets.Machine learning in marine ecology: an overview of techniques and applicationspublishedVersio