The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses
Joseph D. Buxbaum
Jessica M. Brownfeld
Richard J. L. Anney
Edwin H. Cook,
Christine M. Freitag
Sabine M. Klauck
John I. Nurnberger
Stephen W. Scherer
James S. Sutcliffe
Astrid M. Vicente
- Background: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
Methods: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Results: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children?s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1?M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
Conclusions: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
Microplastics in freshwater ecosystems: what we know and what we need to know
A. Dick Vethaak
- BackgroundWhile the use of plastic materials has generated huge societal benefits, the `plastic age? comes with downsides: One issue of emerging concern is the accumulation of plastics in the aquatic environment. Here, so-called microplastics (MP), fragments smaller than 5?mm, are of special concern because they can be ingested throughout the food web more readily than larger particles. Focusing on freshwater MP, we briefly review the state of the science to identify gaps of knowledge and deduce research needs.State of the scienceEnvironmental scientists started investigating marine (micro)plastics in the early 2000s. Today, a wealth of studies demonstrates that MP have ubiquitously permeated the marine ecosystem, including the polar regions and the deep sea. MP ingestion has been documented for an increasing number of marine species. However, to date, only few studies investigate their biological effects.The majority of marine plastics are considered to originate from land-based sources, including surface waters. Although they may be important transport pathways of MP, data from freshwater ecosystems is scarce. So far, only few studies provide evidence for the presence of MP in rivers and lakes. Data on MP uptake by freshwater invertebrates and fish is very limited.Knowledge gapsWhile the research on marine MP is more advanced, there are immense gaps of knowledge regarding freshwater MP. Data on their abundance is fragmentary for large and absent for small surface waters. Likewise, relevant sources and the environmental fate remain to be investigated. Data on the biological effects of MP in freshwater species is completely lacking. The accumulation of other freshwater contaminants on MP is of special interest because ingestion might increase the chemical exposure. Again, data is unavailable on this important issue.ConclusionsMP represent freshwater contaminants of emerging concern. However, to assess the environmental risk associated with MP, comprehensive data on their abundance, fate, sources, and biological effects in freshwater ecosystems are needed. Establishing such data critically depends on a collaborative effort by environmental scientists from diverse disciplines (chemistry, hydrology, ecotoxicology, etc.) and, unsurprisingly, on the allocation of sufficient public funding.
Treadmill walking during vocabulary encoding improves verbal long-term memory
- Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall.
A multi-resource data integration approach: identification of candidate genes regulating cell proliferation during neocortical development
Cynthia M. Vied
Alexandre A. S. F. Raposo
Richard S. Nowakowski
- Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8–9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2, and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
Semantic mechanisms may be responsible for developing synesthesia
- Currently, little is known about how synesthesia develops and which aspects of synesthesia can be acquired through a learning process. We review the increasing evidence for the role of semantic representations in the induction of synesthesia, and argue for the thesis that synesthetic abilities are developed and modified by semantic mechanisms. That is, in certain people semantic mechanisms associate concepts with perception-like experiences—and this association occurs in an extraordinary way. This phenomenon can be referred to as “higher” synesthesia or ideasthesia. The present analysis suggests that synesthesia develops during childhood and is being enriched further throughout the synesthetes’ lifetime; for example, the already existing concurrents may be adopted by novel inducers or new concurrents may be formed. For a deeper understanding of the origin and nature of synesthesia we propose to focus future research on two aspects: (i) the similarities between synesthesia and ordinary phenomenal experiences based on concepts; and (ii) the tight entanglement of perception, cognition and the conceptualization of the world. Importantly, an explanation of how biological systems get to generate experiences, synesthetic or not, may have to involve an explanation of how semantic networks are formed in general and what their role is in the ability to be aware of the surrounding world.
The limits of model-based regulation
- VigVigIn this paper, we investigate how the introduction of complex, model-based capital regulation affected credit risk of financial institutions. Model-based regulation was meant to enhance the stability of the financial sector by making capital charges more sensitive to risk. Exploiting the staggered introduction of the model-based approach in Germany and the richness of our loan-level data set, we show that (1) internal risk estimates employed for regulatory purposes systematically underpredict actual default rates by 0.5 to 1 percentage points; (2) both default rates and loss rates are higher for loans that were originated under the model-based approach, while corresponding risk-weights are significantly lower; and (3) interest rates are higher for loans originated under the model-based approach, suggesting that banks were aware of the higher risk associated with these loans and priced them accordingly. Further, we document that large banks benefited from the reform as they experienced a reduction in capital charges and consequently expanded their lending at the expense of smaller banks that did not introduce the model-based approach. Counter to the stated objectives, the introduction of complex regulation adversely affected the credit risk of financial institutions. Overall, our results highlight the pitfalls of complex regulation and suggest that simpler rules may increase the efficacy of financial regulation.
Is there a threat of self-reinforcing deflation in the Euro area? A view through the lens of the Phillips curve
- The recent decline in euro area inflation has triggered new calls for additional monetary stimulus by the ECB in order to counter the threat of a self‐reinforcing deflation and recession spiral. This note reviews the available evidence on inflation expectations, output gaps and other factors driving current inflation through the lens of the Phillips curve. It also draws a comparison to the Japanese experience with deflation in the late 1990s and the evidence from Japan concerning the outputinflation nexus at low trend inflation. The note concludes from this evidence that the risk of a selfreinforcing deflation remains very small. Thus, the ECB best await the impact of the long‐term refinancing operations decided in June that have the potential to induce substantial monetary accommodation once implemented for the first time in September.
Neuordnung der Finanzmärkte in Europa durch MiFID II/MiFIR
- Die Anpassung der EU-Richtlinie über Märkte für Finanzinstrumente (MiFID II) und die Einführung einer begleitenden Verordnung (MiFIR) im Jahr 2014 werden erhebliche Auswirkungen auf die Finanzmärkte in Europa haben und zu einer grundlegenden Neuordnung der Finanzmarktstrukturen führen. Ausgehend von einer Diskussion der Zielerreichung der ursprünglichen Richtlinie (MiFID I) aus dem Jahr 2004 werden im vorliegenden Artikel die Zielsetzungen und Maßnahmen der Neuregelung beleuchtet. Wesentliche Elemente im Hinblick auf Marktstrukturen und den Wertpapierhandel sind die Einführung einer neuen Handelsplatzkategorie, des organisierten Handelssystems („Organised Trading Facility“; OTF), sowie die Ausweitung der bislang für Aktien geltenden Transparenzvorschriften auf weitere Finanzinstrumente. Zudem werden eine Handelsverpflichtung für Aktien und Derivate sowie eine Clearingpflicht für Derivate, die auf geregelten Märkten gehandelt werden, neu eingeführt. Schließlich werden der algorithmische Handel und der Hochfrequenzhandel auf europäischer Ebene reguliert, wobei die Regelungen weitgehend dem 2013 eingeführten deutschen Hochfrequenzhandelsgesetz angelehnt sind. Im Ausblick wird zunächst der weitere Prozess der Regulierung skizziert (insbesondere die sog. Level II-Maßnahmen). Abschließend werden mögliche Auswirkungen von MiFID II und MiFIR auf die Marktstruktur und den Wertpapierhandel aufgezeigt.
Effective resolution of banks: problems and solutions
Jan Pieter Krahnen
Thomas von Lüpke
- This essay reviews a cornerstone of the European Banking Union project, the resolution of systemically important banks. The focus is on the inherent conflict between a possible intervention by resolution authorities, conditional on a crisis situation, and effective prevention prior to a crisis. Moreover, the paper discusses the rules for bail-in debt and conversion rules for different layers of debt. Finally, some organizational requirements to achieve effective resolution results will be analyzed.
Wiederbewaldung von beweideten Mooren des Alpenvorlandes
- Der Offenlandcharakter und der FFH-Status vieler bisher extensiv beweideter Niedermoore Oberbayerns sind aktuell durch ein abnehmendes Nutzungsinteresse seitens der Landwirtschaft gefährdet. Bei abnehmendem Beweidungsdruck breiten sich Waldinseln in die bisher vom Weidevieh offen gehaltenen Moorflächen (Caricion davallianae, Caricion lasiocarpae) aus. Da der Zeitbedarf der progressiven Sukzession und Waldentwicklung das Zeitbudget des normalen Vegetationskundlers bei weitem übersteigt, wurden die wichtigsten Sukzessionspfade durch das Verfahren der „time-by-site-substitution“ rekonstruiert. Hierzu wurden Offenland-Wald-Ökotone in noch bestehenden extensiv beweideten, großflächigen Allmendweiden (> 50 ha) auf Anmoor-, Kalkflachmoor- und Zwischenmoorstandorten untersucht. Die Sukzessionen streben über Waldpionierstadien Schwarzerlen-Fichten-Auwäldern, Fichten- Schwarzerlen-Bruchwäldern bzw. Fichten-Moorwäldern entgegen, wobei der Fichte (Picea abies) in den (bisher erreichten) Endstadien der Vegetationsentwicklung gegenüber der in den intermediären Sukzessionsstadien vorherrschenden Schwarzerlen (Alnus glutinosa) und Moorkiefern (Pinus x rotundata) in den voralpinen Standorten eine hohe Bedeutung zukommt. Die Ansiedlung nässeempfindlicher Pflanzenarten, darunter auch der Fichte, wird durch die Bultbildung der Schwarzerle bzw. der Torfmoose (auf den Zwischenmoorstandorten) begünstigt, womit die biogene Bultbildung zu einem entscheidenden sukzessionsbestimmenden Faktor avanciert. Die Beweidung wirkt auf Anmoor- und Kalkflachmoorstandorten sukzessionsbeschleunigend durch die Schaffung von Keimungsnischen für die Schwarzerle, während sie auf Zwischenmoorstandorten die Bultbildung der Torfmoose und damit die Ansiedlung von Moorkiefer und Fichte als späte Sukzessionsarten unterdrückt. Die Artenzahlen (-Diversität) sind in den späten Sukzessionsstadien der verschiedenen Moorwaldgesellschaften aufgrund der bultbedingten Vielfalt an Kleinstandorten signifikant höher als in den frühen (Grasland betonten) Sukzessionsstadien. Trotzdem sollte naturschutzfachlich ein Nebeneinander von frühen und späten Stadien angestrebt werden, weil es sich bei den lichtbedürftigen Offenlandarten und den schattenverträglichen Waldarten um komplementäre Artengruppen handelt, womit auf kleiner Fläche außergewöhnlich hohe Gesamtartenzahlen erreicht werden können.