Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type

IntroductionClinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic currents, and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. However, emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are among others that the translation from this binary characterization to neuronal firing is currently not well-understood—especially when considering different neuronal cell types. In this study, we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations.MethodsTo this end, we simulated a diverse collection of single-compartment, conductance-based neuron models that differed in their composition of ionic currents. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of known mutations in KCNA1 gene encoding the KV1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1).ResultsThese simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability depends on neuron type, i.e., the properties and expression levels of the unaffected ionic currents.DiscussionConsequently, neuron-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and are an important step toward improving the efficacy and precision of personalized medicine approaches

Validation of the Exoplanet Kepler-21b using PAVO/CHARA Long-Baseline Interferometry

We present long-baseline interferometry of the Kepler exoplanet host star HD179070 (Kepler-21) using the PAVO beam combiner at the CHARA Array. The visibility data are consistent with a single star and exclude stellar companions at separations ~1-1000 mas (~ 0.1-113 AU) and contrasts < 3.5 magnitudes. This result supports the validation of the 1.6 R_{earth} exoplanet Kepler-21b by Howell et al. (2012) and complements the constraints set by adaptive optics imaging, speckle interferometry, and radial velocity observations to rule out false-positives due to stellar companions. We conclude that long-baseline interferometry has strong potential to validate transiting extrasolar planets, particularly for future projects aimed at brighter stars and for host stars where radial velocity follow-up is not available.Comment: 5 pages, 3 figures, accepted for publication in MNRAS Letters; v2: minor changes added in proo

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants

Nordic LifeWatch cooperation, final report: A joint initiative from Denmark, Iceland, Finland, Norway and Sweden

The main goal of the present report is to outline the possibilities for an enhanced cooperation between the Nordic countries within eScience and biodiversity. LifeWatch is one of several ESFRI projects which aim to establish eInfrastructures and databases in the field of biodiversity and ecosystem research. Similarities between Nordic countries are extensive in relation to a number of biodiversity related issues. Most species in Nordic countries are common, and frequently the same challenges concerning biodiversity and ecosystem services are addressed in the different countries. The present report has been developed by establishing a Nordic LifeWatch network with delegates from each of the Nordic countries. The report has been written jointly by the delegates, and the work was organized by establishing working groups with the following themes: strategic issues, technical development, legal framework and communication. Written during two workshops, Skype meetings and emailing, the following main issues are discussed in the present report: * Scientific needs for improved access to biodiversity data and advanced eScience research infrastructure in the Nordic countries. * Future challenges and priorities facing the international biodiversity research community. * Scientific potential of openly accessible biodiversity and environmental data for individual researchers and institutions. * Spin-off effects of open access for the general public. * Internationally standardized Nordic metadata inventory. * Legal framework and challenges associated with environmental-, climate-, and biodiversity data sharing, communication, training and scientific needs. * Finally, some strategic steps towards realizing a Nordic LifeWatch construction and operational phase are discussed. Easy access to open data on biodiversity and the environment is crucial for many researchers and research institutions, as well as environmental administration. Easy access to data from different fields of science creates an environment for new scientific ideas to emerge. This potential of generating new, interdisciplinary approaches to pre-existing problems is one of the key features of open-access data platforms that unify diverse data sources. Interdisciplinary elements, access to data over larger gradients, compatible eSystems and eTools to handle large amounts of data are extremely important and, if further developed, represent significant steps towards analysis of biological effects of climate change, human impact and development of operational ecosystem service assessment techniques. It is concluded that significant benefits regarding both scientific potential, technical developments and financial investments can be obtained by constructing a common Nordic LifeWatch eInfrastructure. Several steps concerning organizing and funding of a future Nordic LifeWatch are discussed, and an action plan towards 2020 is suggested. To analyze the potential for future Nordic LifeWatch in detail, our main conclusion is to arrange a Nordic LifeWatch conference as soon as possible. This conference should involve Nordic research councils, scientists and relevant stakeholders. The national delegates from the participating countries in the Nordic LifeWatch project are prepared to present details from the report and developments so far as a basis for further development of Nordic LifeWatch. The present work is financed by NordForsk and in-kind contributions from participating institutions

Design Principles for Ligand-Sensing, Conformation-Switching Ribozymes

Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elements typically fuse a molecular recognition domain (aptamer) with a catalytic signal generator (ribozyme). Although the rational design of aptazymes has begun to be explored, the relationships between the thermodynamics of aptazyme conformational changes and aptazyme performance in vitro and in vivo have not been examined in a quantitative framework. We have therefore developed a quantitative and predictive model for aptazymes as biosensors in vitro and as riboswitches in vivo. In the process, we have identified key relationships (or dimensionless parameters) that dictate aptazyme performance, and in consequence, established equations for precisely engineering aptazyme function. In particular, our analysis quantifies the intrinsic trade-off between ligand sensitivity and the dynamic range of activity. We were also able to determine how in vivo parameters, such as mRNA degradation rates, impact the design and function of aptazymes when used as riboswitches. Using this theoretical framework we were able to achieve quantitative agreement between our models and published data. In consequence, we are able to suggest experimental guidelines for quantitatively predicting the performance of aptazyme-based riboswitches. By identifying factors that limit the performance of previously published systems we were able to generate immediately testable hypotheses for their improvement. The robust theoretical framework and identified optimization parameters should now enable the precision design of aptazymes for biotechnological and clinical applications

Merging paleobiology with conservation biology to guide the future of terrestrial ecosystems

Conservation of species and ecosystems is increasingly difficult because anthropogenic impacts are pervasive and accelerating. Under this rapid global change, maximizing conservation success requires a paradigm shift from maintaining ecosystems in idealized past states toward facilitating their adaptive and functional capacities, even as species ebb and flow individually. Developing effective strategies under this new paradigm will require deeper understanding of the long-term dynamics that govern ecosystem persistence and reconciliation of conflicts among approaches to conserving historical versus novel ecosystems. Integrating emerging information from conservation biology, paleobiology, and the Earth sciences is an important step forward on the path to success. Maintaining nature in all its aspects will also entail immediately addressing the overarching threats of growing human population, overconsumption, pollution, and climate change.Peer reviewe

Influenza A virus replicates productively in primary human kidney cells and induces factors and mechanisms related to regulated cell death and renal pathology observed in virus-infected patients

IntroductionInfluenza A virus (IAV) infection can cause the often-lethal acute respiratory distress syndrome (ARDS) of the lung. Concomitantly, acute kidney injury (AKI) is frequently noticed during IAV infection, correlating with an increased mortality. The aim of this study was to elucidate the interaction of IAV with human kidney cells and, thereby, to assess the mechanisms underlying IAV-mediated AKI.MethodsTo investigate IAV effects on nephron cells we performed infectivity assays with human IAV, as well as with human isolates of either low or highly pathogenic avian IAV. Also, transcriptome and proteome analysis of IAV-infected primary human distal tubular kidney cells (DTC) was performed. Furthermore, the DTC transcriptome was compared to existing transcriptomic data from IAV-infected lung and trachea cells.ResultsWe demonstrate productive replication of all tested IAV strains on primary and immortalized nephron cells. Comparison of our transcriptome and proteome analysis of H1N1-type IAV-infected human primary distal tubular cells (DTC) with existing data from H1N1-type IAV-infected lung and primary trachea cells revealed enrichment of specific factors responsible for regulated cell death in primary DTC, which could be targeted by specific inhibitors.DiscussionIAV not only infects, but also productively replicates on different human nephron cells. Importantly, multi-omics analysis revealed regulated cell death as potential contributing factor for the clinically observed kidney pathology in influenza

The economics of debt clearing mechanisms

We examine the evolution of decentralized clearinghouse mechanisms from the 13th to the 18th century; in particular, we explore the clearing of non- or limitedtradable debts like bills of exchange. We construct a theoretical model of these clearinghouse mechanisms, similar to the models in the theoretical matching literature, and show that specific decentralized multilateral clearing algorithms known as rescontre, skontrieren or virement des parties used by merchants were efficient in specific historical contexts. We can explain both the evolutionary self-organizing emergence of late medieval and early modern fairs, and its robustness during the 17th and 18th century

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder