Оптимизация вычисления обратного БПФ на многоядерном процессоре

The article describes the method of calculating the inverse FFT N-point sequence with a N-point complex FFT, also the implementation of similar approach for computing on multi-core computing architecture. The main quality parameters of similar organization such as speedup and efficiency of computing resources were analyzed

Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology

Untersuchung von krankheitsassoziierten Gerüstproteinen in der postsynaptischen Dichte

Connector Enhancer of Kinase Suppressor of Ras (CNK2) is a disease-associated scaffold protein that is expressed specifically in nervous tissue. Patients with CNK2 mutations exhibit an array of neurocognitive symptoms, ranging from mild intellectual disability (ID) and language delay to more severe and general delayed cognitive and motor development. Seizures are also present in most patients (Damiano et al., 2017; Vaags et al., 2014). Understanding the molecular details of the function of CNK2 during development of nervous tissue will contribute to our knowledge about how CNK2 alterations can cause neurodevelopmental disorders. To explore the function of CNK2, we first examined its specific localisation in cultured rat hippocampal neurons and validated that CNK2 is expressed in neurons and enriched at postsynaptic sites (Iida et al., 2002). We next utilised an shRNA-mediated knockdown approach to explore the effects of loss of CNK2 function at these postsynaptic sites, i.e. in dendritic spines of glutamatergic neurons, and observed a reduction in PSD size. Next, we explored the effect of truncated CNK2 variants in neurons. In neurons expressing a disease-associated CNK2 variant (CNK2-P1), we saw an increase in PSD size and a reduced exchange rate in dendritic spines compared to that for wild-type CNK2. We also took advantage of several other CNK2 variants and comparatively investigated their properties in heterologous cells and in dendritic spines. Expression of EGFP-CNK2-PH, a CNK2 variant which lacks the ability to attach to the membrane, caused a reduction in PSD size, which resembles the phenotype we observed in CNK2-knockdown neurons. Further studies revealed a set of novel binding partners for CNK2. Taking advantage of a yeast-two-hybrid approach to screen for brain-expressed CNK2 interaction partners, we identified several binding partners that may participate in the execution of CNK2-mediated regulatory functions in neurons. Interestingly, the proteins identified were not structural proteins that have been previously shown to participate in regulating PSD size. Instead, our list of interacting proteins consisted predominantly of regulatory proteins, including, for example the Rho-GTPase activating protein Vilse/ARHGAP39, which has previously been investigated for its role in mediating CNK2 function (Lim et al., 2014), and the regulatory kinases MINK1 and TNIK. Subsequent studies explored the new link between CNK2 and the kinases of the MINK1/TNIK family, for which we discovered a specific interaction with CNK2; these proteins do not interact with CNK1, for example. We focussed specifically on the new CNK2-interacting kinase TNIK, which, like CNK2, was recently implicated in cognitive disorders (Anazi et al., 2016). TNIK is a well-characterised signalling molecule that plays a decisive role in the activation of multiple signal cascades (Larhammar et al., 2017; Wang et al., 2016). More recently, it has been shown that it is concentrated in dendritic spines (Burette et al., 2015), and that it plays a role, together with MINK1, in the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking (Hussain et al., 2010). We observed a clear functional interdependency between CNK2 and TNIK: subcellular localisation of TNIK is regulated by CNK2 in heterologous cells and in neurons. We confirmed that CNK2 and TNIK exhibit overlapping expression in dendrites and at postsynaptic sites, and taking advantage of TNIK binding CNK2 variants that exhibit aberrant subcellular localisation, we demonstrated that CNK2 directly modulates neuronal TNIK, and thus provide strong support for the idea that TNIK and CNK2 participate in common pathways that may be critical for the observed CNK2-mediated regulation of PSD size. In summary, our data provide evidence supporting the idea that CNK2 and TNIK/MINK1 family kinases work together in the neuronal environment to ensure proper development and regulation of dendritic spines.Connector Enhancer of Kinase Suppressor of Ras2 (CNK2) ist ein krankheits-assoziiertes Gerüstprotein das spezifisch in neuronalem Gewebe exprimiert wird. Patienten, die eine Mutation im CNK2 Gen haben, leiden an einer Reihe neurokognitiver Symptome, die von milder geistiger Behinderung und verzögerter Sprachentwicklung bis hin zu schwerer und weitreichender Verzögerung in der geistigen und motorischen Entwicklung reichen. In manchen Patienten treten auch Krampfanfälle auf (Damiano et al., 2017; Vaags et al., 2014). Ein Verständnis über die molekularen Feinheiten der Funktion von CNK2 während der Entwicklung würde zu unserem Wissen darüber beitragen, wie Veränderungen in CNK2 neuronale Entwicklungsstörungen verursachen können. Um die Funktion von CNK2 zu erforschen, haben wir erst die genaue Lokalisation in kultivierten Neuronen aus dem Hippokampus von Ratten untersucht und bestätigt, dass CNK2 in Neuronen exprimiert und in der Postsynapse angereichert ist. Als nächstes nutzten wir einen shRNA vermittelten knockdown Ansatz, um die Auswirkungen des Funktionsverlustes von CNK2 in der Postsynapse, insbesondere in den dendritischen Dornfortsätzen glutamaterger Neurone, zu untersuchen. Hierbei stellten wir eine Größenminderung der postsynaptischen Dichte fest. Anschließend untersuchten wir die Auswirkung verkürzter CNK2 Varianten in Neuronen. In Neuronen, die die krankheits-assoziierte CNK2 Variante (CNK2-P1) exprimierten, sahen wir eine Vergrößerung der postsynaptischen Dichte und eine geringere Austauschrate im Vergleich zu CNK2 im Wildtyp. Wir nutzten auch mehrere CNK2 Varianten und verglichen ihre Eigenschaften in heterologen Zellen und in dendritischen Dornfortsätzen. Expression von EGFP-CNK2-PH, einer CNK2 Variante die ihre Fähigkeit an die Membran zu binden, verloren hat, verursachte eine Größenminderung der postsynaptischen Dichte, was dem Phänotyp ähnelt, den wir bei CNK2 knockdown beobachten. Anschließende Untersuchungen lieferten eine Reihe neuer Interaktionspartner von CNK2. Wir zogen Nutzen aus der Methode des Hefe-zwei-Hybrid-Systems um nach neuartigen CNK2 Interaktionspartnern zu suchen, die im Gehirn exprimiert sind, und identifizierten mehrere Bindepartner, die an der Ausführung CNK2-vermittelter, regulatorischer Funktion in Neuronen beteiligt sein könnten. Interessanterweise waren die identifizierten Proteine nicht Strukturproteine, von denen bereits bekannt war, dass sie an der Größenregulierung der PSD beteiligt sind. Stattdessen bestand unsere Liste von interagierenden Proteinen überwiegend aus regulatorischen Proteinen. Darunter zum Beispiel das Rho-GTPase aktivierende Protein Vilse/ARHGAP39, dessen Rolle bei der Funktionsvermittlung von CNK2 schon vorher untersucht wurde (Lim et al., 2014), sowie die regulatorischen Kinasen MINK1 und TNIK. Die folgenden Studien untersuchten den neuen Zusammenhang zwischen CNK2 und den Kinasen der MINK1/TNIK Familie und fanden heraus, dass diese spezifisch mit CNK2 interagieren; diese Proteine interagieren zum Beispiel nicht mit CNK1. Wir fokussierten uns gezielt auf die neue, CNK2-bindende Kinase TNIK, die, genau wie CNK2, kürzlich mit kognitiven Störungen in Verbindung gebracht wurde (Anazi et al., 2016). TNIK ist ein gut-charakterisiertes Signalmolekül, das eine maßgebliche Rolle bei der Aktivierung mehrerer Signalkaskaden spielt (Larhammar et al., 2017; Wang et al., 2016). Erst kürzlich wurde gezeigt, dass es in dendritischen Dornfortsätzen konzentriert ist (Burette et al., 2015), und dass es zusammen mit MINK1 eine Rolle bei der Regulation des Austauschs von AMPA Rezeptoren spielt (Hussain et al., 2010). Wir beobachteten eine eindeutige Wechselbeziehung zwischen CNK2 und TNIK: subzelluläre Lokalisation von TNIK ist in heterologen Zellen sowie in Neuronen von CNK2 reguliert. Wir bestätigten, dass CNK2 und TNIK überschneidende Expression in Dendriten und der Postsynapse aufweisen. Wenn wir uns TNIK-bindende CNK2 Varianten zu Nutze machten, die eine anomale subzelluläre Lokalisation aufweisen, konnten wir zeigen, dass CNK2 neuronales TNIK direkt moduliert, und bieten somit nachdrückliche Unterstützung für die Idee, dass TNIK und CNK2 an gemeinsamen Signalwegen beteiligt sind, die für die beobachtete, CNK2-vermittelte Größenregulierung der PSD kritisch sein könnten. Zusammenfassend liefern unsere Daten Beweise, die die Idee unterstützen, dass CNK2 und die Kinasen der MINK1/TNIK Familie gemeinsam im neuronalen Umfeld wirken um die einwandfreie Entwicklung und Regulation dendritischer Dornfortsätze zu gewährleisten

A discrete presynaptic vesicle cycle for neuromodulator receptors

A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning

International audienceRegulation of synaptic neurotransmitter receptor content is a fundamental mechanism for tuning synaptic efficacy during experience-dependent plasticity and behavioral adaptation. However, experimental approaches to track and modify receptor movements in integrated experimental systems are limited. Exploiting AMPA-type glutamate receptors (AMPARs) as a model, we generated a knock-in mouse expressing the biotin acceptor peptide (AP) tag on the GluA2 extracellular N-terminal. Cell-specific introduction of biotin ligase allows the use of monovalent or tetravalent avidin variants to respectively monitor or manipulate the surface mobility of endogenous AMPAR containing biotinylated AP–GluA2 in neuronal subsets. AMPAR immobilization precluded the expression of long-term potentiation and formation of contextual fear memory, allowing target-specific control of the expression of synaptic plasticity and animal behavior. The AP tag knock-in model offers unprecedented access to resolve and control the spatiotemporal dynamics of endogenous receptors, and opens new avenues to study the molecular mechanisms of synaptic plasticity and learning

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.The Nordic Centre of Excellence CRAICC (CRyosphere-Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, was the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic Region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual Centre with the objectives to identify and quantify the major processes controlling Arctic warming and related feedback mechanisms, to outline strategies to mitigate Arctic warming and to develop Nordic Earth System modelling with a focus on the short-lived climate forcers (SLCF), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special-issue of the journal Atmospheric Chemistry and Physics. This manuscript presents an overview on the main scientific topics investigated in the Centre and provides the reader a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Facing the vast amount of outcomes we are not claiming to cover all results from CRAICC in this manuscript but concentrate here on the main results which are related to the feedback loops in the climate change-cryosphere interaction scheme affecting the Arctic amplification.Peer reviewe

Interactions between the atmosphere, cryosphere, and ecosystems at northern high latitudes

The Nordic Centre of Excellence CRAICC (Cryosphere–Atmosphere Interactions in a Changing Arctic Climate), funded by NordForsk in the years 2011–2016, is the largest joint Nordic research and innovation initiative to date, aiming to strengthen research and innovation regarding climate change issues in the Nordic region. CRAICC gathered more than 100 scientists from all Nordic countries in a virtual centre with the objectives of identifying and quantifying the major processes controlling Arctic warming and related feedback mechanisms, outlining strategies to mitigate Arctic warming, and developing Nordic Earth system modelling with a focus on short-lived climate forcers (SLCFs), including natural and anthropogenic aerosols. The outcome of CRAICC is reflected in more than 150 peer-reviewed scientific publications, most of which are in the CRAICC special issue of the journal Atmospheric Chemistry and Physics. This paper presents an overview of the main scientific topics investigated in the centre and provides the reader with a state-of-the-art comprehensive summary of what has been achieved in CRAICC with links to the particular publications for further detail. Faced with a vast amount of scientific discovery, we do not claim to completely summarize the results from CRAICC within this paper, but rather concentrate here on the main results which are related to feedback loops in climate change–cryosphere interactions that affect Arctic amplification