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Showing papers by "University of Freiburg published in 2014"


Journal ArticleDOI
Silvia De Rubeis1, Xin-Xin He2, Arthur P. Goldberg1, Christopher S. Poultney1, Kaitlin E. Samocha3, A. Ercument Cicek2, Yan Kou1, Li Liu2, Menachem Fromer3, Menachem Fromer1, R. Susan Walker4, Tarjinder Singh5, Lambertus Klei6, Jack A. Kosmicki3, Shih-Chen Fu1, Branko Aleksic7, Monica Biscaldi8, Patrick Bolton9, Jessica M. Brownfeld1, Jinlu Cai1, Nicholas G. Campbell10, Angel Carracedo11, Angel Carracedo12, Maria H. Chahrour3, Andreas G. Chiocchetti, Hilary Coon13, Emily L. Crawford10, Lucy Crooks5, Sarah Curran9, Geraldine Dawson14, Eftichia Duketis, Bridget A. Fernandez15, Louise Gallagher16, Evan T. Geller17, Stephen J. Guter18, R. Sean Hill3, R. Sean Hill19, Iuliana Ionita-Laza20, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck21, Alexander Kolevzon1, Irene Lee22, Jing Lei2, Terho Lehtimäki, Chiao-Feng Lin17, Avi Ma'ayan1, Christian R. Marshall4, Alison L. McInnes23, Benjamin M. Neale24, Michael John Owen25, Norio Ozaki7, Mara Parellada26, Jeremy R. Parr27, Shaun Purcell1, Kaija Puura, Deepthi Rajagopalan4, Karola Rehnström5, Abraham Reichenberg1, Aniko Sabo28, Michael Sachse, Stephen Sanders29, Chad M. Schafer2, Martin Schulte-Rüther30, David Skuse22, David Skuse31, Christine Stevens24, Peter Szatmari32, Kristiina Tammimies4, Otto Valladares17, Annette Voran33, Li-San Wang17, Lauren A. Weiss29, A. Jeremy Willsey29, Timothy W. Yu19, Timothy W. Yu3, Ryan K. C. Yuen4, Edwin H. Cook18, Christine M. Freitag, Michael Gill16, Christina M. Hultman34, Thomas Lehner35, Aarno Palotie36, Aarno Palotie3, Aarno Palotie24, Gerard D. Schellenberg17, Pamela Sklar1, Matthew W. State29, James S. Sutcliffe10, Christopher A. Walsh19, Christopher A. Walsh3, Stephen W. Scherer4, Michael E. Zwick37, Jeffrey C. Barrett5, David J. Cutler37, Kathryn Roeder2, Bernie Devlin6, Mark J. Daly3, Mark J. Daly24, Joseph D. Buxbaum1 
13 Nov 2014-Nature
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

2,228 citations


Journal ArticleDOI
TL;DR: A Galaxy based web server for processing and visualizing deeply sequenced data, called deepTools, that enables users with little bioinformatic background to explore the results of their sequencing experiments in a standardized setting and can be used without registration.
Abstract: We present a Galaxy based web server for processing and visualizing deeply sequenced data. The web server’s core functionality consists of a suite of newly developed tools, called deepTools, that enable users with little bioinformatic background to explore the results of their sequencing experiments in a standardized setting. Users can upload pre-processed files with continuous data in standard formats and generate heatmaps and summary plots in a straightforward, yet highly customizable manner. In addition, we offer several tools for the analysis of files containing aligned reads and enable efficient and reproducible generation of normalized coverage files. As a modular and open-source platform, deepTools can easily be expanded and customized to future demands and developments. The deepTools webserver is freely available at http://deeptools.ie-freiburg.mpg. de and is accompanied by extensive documentation and tutorials aimed at conveying the principles of deep-sequencing data analysis. The web server can be used without registration. deepTools can be installed locally either stand-alone or as part of Galaxy.

2,084 citations


Journal ArticleDOI
TL;DR: The open-source C++ software package qpOASES is described, which implements a parametric active-set method in a reliable and efficient way and can be used to compute critical points of nonconvex QP problems.
Abstract: Many practical applications lead to optimization problems that can either be stated as quadratic programming (QP) problems or require the solution of QP problems on a lower algorithmic level. One relatively recent approach to solve QP problems are parametric active-set methods that are based on tracing the solution along a linear homotopy between a QP problem with known solution and the QP problem to be solved. This approach seems to make them particularly suited for applications where a-priori information can be used to speed-up the QP solution or where high solution accuracy is required. In this paper we describe the open-source C++ software package qpOASES, which implements a parametric active-set method in a reliable and efficient way. Numerical tests show that qpOASES can outperform other popular academic and commercial QP solvers on small- to medium-scale convex test examples of the Maros-Meszaros QP collection. Moreover, various interfaces to third-party software packages make it easy to use, even on embedded computer hardware. Finally, we describe how qpOASES can be used to compute critical points of nonconvex QP problems.

1,076 citations


Journal ArticleDOI
TL;DR: The vulnerability of microglia to dysfunction is described and it is proposed that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.
Abstract: Mononuclear phagocytic cells in the CNS used to be defined according to their anatomical location and surface marker expression. Recently, this concept has been challenged by the results of developmental and gene expression profiling studies that have used novel molecular biological tools to unravel the origin of microglia and to define their role as specialized tissue macrophages with long lifespans. Here, we describe how these results have redefined microglia and helped us to understand how different myeloid cell populations operate in the CNS based on their cell-specific gene expression signatures, distinct ontogeny and differential functions. Moreover, we describe the vulnerability of microglia to dysfunction and propose that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.

1,047 citations


Posted Content
TL;DR: In this paper, the authors re-evaluate the state-of-the-art for object recognition from small images with convolutional networks, questioning the necessity of different components in the pipeline.
Abstract: Most modern convolutional neural networks (CNNs) used for object recognition are built using the same principles: Alternating convolution and max-pooling layers followed by a small number of fully connected layers. We re-evaluate the state of the art for object recognition from small images with convolutional networks, questioning the necessity of different components in the pipeline. We find that max-pooling can simply be replaced by a convolutional layer with increased stride without loss in accuracy on several image recognition benchmarks. Following this finding -- and building on other recent work for finding simple network structures -- we propose a new architecture that consists solely of convolutional layers and yields competitive or state of the art performance on several object recognition datasets (CIFAR-10, CIFAR-100, ImageNet). To analyze the network we introduce a new variant of the "deconvolution approach" for visualizing features learned by CNNs, which can be applied to a broader range of network structures than existing approaches.

1,008 citations



Journal ArticleDOI
TL;DR: By stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthetic.
Abstract: Hand loss is a highly disabling event that markedly affects the quality of life. To achieve a close to natural replacement for the lost hand, the user should be provided with the rich sensations that we naturally perceive when grasping or manipulating an object. Ideal bidirectional hand prostheses should involve both a reliable decoding of the user's intentions and the delivery of nearly "natural" sensory feedback through remnant afferent pathways, simultaneously and in real time. However, current hand prostheses fail to achieve these requirements, particularly because they lack any sensory feedback. We show that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthesis. This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and "life-like" quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands.

791 citations


Journal ArticleDOI
TL;DR: A novel mapping system that robustly generates highly accurate 3-D maps using an RGB-D camera that applies to small domestic robots such as vacuum cleaners, as well as flying robotssuch as quadrocopters.
Abstract: In this paper, we present a novel mapping system that robustly generates highly accurate 3-D maps using an RGB-D camera. Our approach requires no further sensors or odometry. With the availability of low-cost and light-weight RGB-D sensors such as the Microsoft Kinect, our approach applies to small domestic robots such as vacuum cleaners, as well as flying robots such as quadrocopters. Furthermore, our system can also be used for free-hand reconstruction of detailed 3-D models. In addition to the system itself, we present a thorough experimental evaluation on a publicly available benchmark dataset. We analyze and discuss the influence of several parameters such as the choice of the feature descriptor, the number of visual features, and validation methods. The results of the experiments demonstrate that our system can robustly deal with challenging scenarios such as fast camera motions and feature-poor environments while being fast enough for online operation. Our system is fully available as open source and has already been widely adopted by the robotics community.

781 citations


Journal ArticleDOI
TL;DR: In this article, the impact of guidance on the efficacy of Internet-based interventions was systematically reviewed and a systematic search of MEDLINE, CENTRAL and PsycINFO, PsycARTICLES and Psyndex (search date 4th June 2013) was conducted.

753 citations


Proceedings Article
08 Dec 2014
TL;DR: This paper presents an approach for training a convolutional neural network using only unlabeled data and trains the network to discriminate between a set of surrogate classes, finding that this simple feature learning algorithm is surprisingly successful when applied to visual object recognition.
Abstract: Current methods for training convolutional neural networks depend on large amounts of labeled samples for supervised training. In this paper we present an approach for training a convolutional neural network using only unlabeled data. We train the network to discriminate between a set of surrogate classes. Each surrogate class is formed by applying a variety of transformations to a randomly sampled 'seed' image patch. We find that this simple feature learning algorithm is surprisingly successful when applied to visual object recognition. The feature representation learned by our algorithm achieves classification results matching or outperforming the current state-of-the-art for unsupervised learning on several popular datasets (STL-10, CIFAR-10, Caltech-101).

728 citations


Journal ArticleDOI
TL;DR: Taking together, mutations in CTLA4 resulting inCTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
Abstract: The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.

Journal ArticleDOI
TL;DR: The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.
Abstract: In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. While ischaemic events dominate the cardiac complications of diabetes, it is widely recognised that the risk for developing heart failure is also increased in the absence of overt myocardial ischaemia and hypertension or is accelerated in the presence of these comorbidities. These diabetes-associated changes in myocardial structure and function have been called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed to contribute to the development of diabetic cardiomyopathy following analysis of various animal models of type 1 or type 2 diabetes and in genetically modified mouse models. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms. The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.

Journal ArticleDOI
TL;DR: Mapping of motifs in NTCPs have increased the understanding of the species specificities of HBV and HDV, and could lead to small animal models for studies of viral infection and replication.

Journal ArticleDOI
TL;DR: This paper demonstrates that motion will be exploited most effectively, if it is regarded over larger time windows, and suggests working with a paradigm that starts with semi-dense motion cues first and that fills up textureless areas afterwards based on color.
Abstract: Motion is a strong cue for unsupervised object-level grouping. In this paper, we demonstrate that motion will be exploited most effectively, if it is regarded over larger time windows. Opposed to classical two-frame optical flow, point trajectories that span hundreds of frames are less susceptible to short-term variations that hinder separating different objects. As a positive side effect, the resulting groupings are temporally consistent over a whole video shot, a property that requires tedious post-processing in the vast majority of existing approaches. We suggest working with a paradigm that starts with semi-dense motion cues first and that fills up textureless areas afterwards based on color. This paper also contributes the Freiburg-Berkeley motion segmentation (FBMS) dataset, a large, heterogeneous benchmark with 59 sequences and pixel-accurate ground truth annotation of moving objects.

Journal ArticleDOI
TL;DR: A revision of the ESTS guidelines was needed because more evidence of the different mediastinal staging technique has become available and both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging.
Abstract: Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours ≤ 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours >3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.

Journal ArticleDOI
TL;DR: The impact of climate change on karst aquifers has been studied in this article, where the authors explore different conceptual models and how they can be translated into numerical models of varying complexity and therefore varying data requirements.
Abstract: Karst regions represent 7–12% of the Earth's continental area, and about one quarter of the global population is completely or partially dependent on drinking water from karst aquifers. Climate simulations project a strong increase in temperature and a decrease of precipitation in many karst regions in the world over the next decades. Despite this potentially bleak future, few studies specifically quantify the impact of climate change on karst water resources. This review provides an introduction to karst, its evolution, and its particular hydrological processes. We explore different conceptual models of karst systems and how they can be translated into numerical models of varying complexity and therefore varying data requirements and depths of process representation. We discuss limitations of current karst models and show that at the present state, we face a challenge in terms of data availability and information content of the available data. We conclude by providing new research directions to develop and evaluate better prediction models to address the most challenging problems of karst water resources management, including opportunities for data collection and for karst model applications at so far unprecedented scales.

Journal ArticleDOI
27 Feb 2014
TL;DR: In this paper, the authors highlight some of the underlying issues in the modeling of risk-weighted assets (RWAs), and frame this discussion in the context of two recent regulatory documents referred to as Basel 3.5.
Abstract: Recent crises in the financial industry have shown weaknesses in the modeling of Risk-Weighted Assets (RWAs). Relatively minor model changes may lead to substantial changes in the RWA numbers. Similar problems are encountered in the Value-at-Risk (VaR)-aggregation of risks. In this article, we highlight some of the underlying issues, both methodologically, as well as through examples. In particular, we frame this discussion in the context of two recent regulatory documents we refer to as Basel 3.5.

Journal ArticleDOI
TL;DR: The findings provide evidence for the strong need for psycho-oncological interventions in cancer populations using a proportional stratified random sample based on the nationwide cancer incidence in Germany.
Abstract: Purpose To provide the 4-week prevalence estimates of mental disorders in cancer populations. Patients and Methods We enrolled adult patients with cancer from in- and outpatient care facilities, using a proportional stratified random sample based on the nationwide cancer incidence in Germany. Patients who scored 9 or above on the Patient Health Questionnaire (PHQ-9) were administered to the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). A random sample of those with a PHQ-9 score that was less than 9 were selected for a CIDI-O. Results A total of 5,889 patients were identified, which led to 4,020 participants (a 68.3% response rate); of those, 2,141 patients were interviewed. The 4-week total prevalence for any mental disorder was 31.8% (95% CI, 29.8% to 33.8%); this included any anxiety disorder (11.5%; 95% CI, 10.2% to 12.9%), any adjustment disorder (11.1%; 95% CI, 9.7% to 12.4%), any mood disorder (6.5%; 95% CI, 5....

Journal ArticleDOI
TL;DR: For the first time a high-precision prediction for the mass of the light CP-even Higgs boson in the MSSM is possible all the way up to the multi-TeV region of the relevant supersymmetric particles.
Abstract: For the interpretation of the signal discovered in the Higgs searches at the LHC it will be crucial in particular to discriminate between the minimal Higgs sector realized in the standard model (SM) and its most commonly studied extension, the minimal supersymmetric standard model (MSSM). The measured mass value, having already reached the level of a precision observable with an experimental accuracy of about 500 MeV, plays an important role in this context. In the MSSM the mass of the light C P -even Higgs boson, M h , can directly be predicted from the other parameters of the model. The accuracy of this prediction should at least match the one of the experimental result. The relatively high mass value of about 126 GeV has led to many investigations where the scalar top quarks are in the multi-TeV range. We improve the prediction for M h in the MSSM by combining the existing fixed-order result, comprising the full one-loop and leading and subleading two-loop corrections, with a resummation of the leading and subleading logarithmic contributions from the scalar top sector to all orders. In this way for the first time a high-precision prediction for the mass of the light C P -even Higgs boson in the MSSM is possible all the way up to the multi-TeV region of the relevant supersymmetric particles. The results are included in the code FeynHiggs .

Journal ArticleDOI
TL;DR: In this article, the authors investigated the effect of three different types of nano-fillers on fracture toughness and failure mechanism of epoxy-based polymer nano-composites, including thermally reduced graphene oxide (TRGO), graphite nano-platelets (GNP), and multi-wall carbon nano-tubes (MWCNT).

Journal ArticleDOI
TL;DR: In this article, the authors analyzed the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe for Common Variable Immunodeficiency (CVID) patients.
Abstract: Background Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. Objective This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results Early disease onset ( Conclusion Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

Journal ArticleDOI
M. Bicer1, H. Duran Yildiz1, I. Yildiz2, G. Coignet3, Marco Delmastro3, Theodoros Alexopoulos4, Christophe Grojean, Stefan Antusch5, Tanaji Sen6, Hong-Jian He7, K. Potamianos8, Sigve Haug9, Asunción Moreno, Arno Heister10, Veronica Sanz11, Guillelmo Gomez-Ceballos12, Markus Klute12, Marco Zanetti12, Lian-Tao Wang13, Mogens Dam14, Celine Boehm15, Nigel Glover15, Frank Krauss15, Alexander Lenz15, Michael Syphers16, Christos Leonidopoulos17, Vitaliano Ciulli, P. Lenzi, Giacomo Sguazzoni, Massimo Antonelli, Manuela Boscolo, Umberto Dosselli, O. Frasciello, C. Milardi, G. Venanzoni, Mikhail Zobov, J.J. van der Bij18, M. De Gruttola19, D. W. Kim20, Michail Bachtis21, A. Butterworth21, C. Bernet21, Cristina Botta21, Federico Carminati21, A. David21, L. Deniau21, David D'Enterria21, Gerardo Ganis21, Brennan Goddard21, Gian F. Giudice21, Patrick Janot21, John Jowett21, Carlos Lourenco21, L. Malgeri21, Emilio Meschi21, Filip Moortgat21, Pasquale Musella21, J. A. Osborne21, Luca Perrozzi21, Maurizio Pierini21, Louis Rinolfi21, A. De Roeck21, Juan Rojo21, G. Roy21, Andrea Sciabà21, A. Valassi21, C. S. Waaijer21, Jorg Wenninger21, H. K. Woehri21, Frank Zimmermann21, A. Blondel22, Michael Koratzinos22, Philippe Mermod22, Yasar Onel23, R. Talman24, E. Castaneda Miranda25, Eugene Bulyak, D. Porsuk, Dmytro Kovalskyi26, Sanjay Padhi26, Pietro Faccioli, John Ellis27, Mario Campanelli28, Yang Bai29, M. Chamizo, Robert Appleby30, Hywel Owen30, H. Maury Cuna31, C. Gracios32, German Ardul Munoz-Hernandez32, Luca Trentadue33, E. Torrente-Lujan34, S. Wang35, David Bertsche36, A. V. Gramolin37, Valery I. Telnov37, Marumi Kado38, P. Petroff38, Patrizia Azzi, Oreste Nicrosini, Fulvio Piccinini, Guido Montagna39, F. Kapusta38, S. Laplace38, W. Da Silva38, Nectaria A. B. Gizani40, Nathaniel Craig41, Tao Han42, Claudio Luci43, Barbara Mele43, Luca Silvestrini43, Marco Ciuchini, R. Cakir44, R. Aleksan, Fabrice Couderc, Serguei Ganjour, Eric Lancon, Elizabeth Locci, P. Schwemling, M. Spiro, C. Tanguy, Jean Zinn-Justin, Stefano Moretti45, M. Kikuchi46, Haruyo Koiso46, Kazuhito Ohmi46, Katsunobu Oide46, G. Pauletta47, Roberto Ruiz de Austri48, Maxime Gouzevitch38, Subhasis Chattopadhyay49 
TL;DR: In this article, the authors present a first appraisal of the salient features of the TLEP physics potential, to serve as a baseline for a more extensive design study, and present a combination of TLEp and the VHE-LHC offers, for a great cost effectiveness, the best precision and the best search reach of all options presently on the market.
Abstract: The discovery by the ATLAS and CMS experiments of a new boson with mass around 125 GeV and with measured properties compatible with those of a Standard-Model Higgs boson, coupled with the absence of discoveries of phenomena beyond the Standard Model at the TeV scale, has triggered interest in ideas for future Higgs factories. A new circular e+e- collider hosted in a 80 to 100 km tunnel, TLEP, is among the most attractive solutions proposed so far. It has a clean experimental environment, produces high luminosity for top-quark, Higgs boson, W and Z studies, accommodates multiple detectors, and can reach energies up to the t-tbar threshold and beyond. It will enable measurements of the Higgs boson properties and of Electroweak Symmetry-Breaking (EWSB) parameters with unequalled precision, offering exploration of physics beyond the Standard Model in the multi-TeV range. Moreover, being the natural precursor of the VHE-LHC, a 100 TeV hadron machine in the same tunnel, it builds up a long-term vision for particle physics. Altogether, the combination of TLEP and the VHE-LHC offers, for a great cost effectiveness, the best precision and the best search reach of all options presently on the market. This paper presents a first appraisal of the salient features of the TLEP physics potential, to serve as a baseline for a more extensive design study.

Journal ArticleDOI
TL;DR: The concept of barriers is increasingly used to describe the obstacles that hinder the planning and implementation of climate change adaptation as mentioned in this paper, and there is a need for research that focuses on the interdependencies between barriers and considers the dynamic ways in which barriers develop and persist.
Abstract: The concept of barriers is increasingly used to describe the obstacles that hinder the planning and implementation of climate change adaptation. The growing literature on barriers to adaptation reveals not only commonly reported barriers, but also conflicting evidence, and few explanations of why barriers exist and change. There is thus a need for research that focuses on the interdependencies between barriers and considers the dynamic ways in which barriers develop and persist. Such research, which would be actor-centred and comparative, would help to explain barriers to adaptation and provide insights into how to overcome them.

Journal ArticleDOI
TL;DR: Induced pluripotent stem cells are generated from subjects with GD and PD harbouring GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration are provided.
Abstract: Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), are the strongest genetic risk factor for Parkinson's disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.

Journal ArticleDOI
TL;DR: It is suggested that SSFs could be integrated with state-space models to classify behavioural states when estimating SSFs, as well as to highlight weak features of this modelling approach that should be developed by further research.
Abstract: Recent progress in positioning technology facilitates the collection of massive amounts of sequential spatial data on animals. This has led to new opportunities and challenges when investigating animal movement behaviour and habitat selection. Tools like Step Selection Functions (SSFs) are relatively new powerful models for studying resource selection by animals moving through the landscape. SSFs compare environmental attributes of observed steps (the linear segment between two consecutive observations of position) with alternative random steps taken from the same starting point. SSFs have been used to study habitat selection, human-wildlife interactions, movement corridors, and dispersal behaviours in animals. SSFs also have the potential to depict resource selection at multiple spatial and temporal scales. There are several aspects of SSFs where consensus has not yet been reached such as how to analyse the data, when to consider habitat covariates along linear paths between observations rather than at their endpoints, how many random steps should be considered to measure availability, and how to account for individual variation. In this review we aim to address all these issues, as well as to highlight weak features of this modelling approach that should be developed by further research. Finally, we suggest that SSFs could be integrated with state-space models to classify behavioural states when estimating SSFs.

Journal ArticleDOI
TL;DR: The algorithm introduced here must be seen as a considerable improvement over the current standard of algorithms for binary networks due to its higher sensitivity and likely to lead to be useful for detecting modules in the typically noisy data of ecological networks.
Abstract: Summary Ecological networks are often composed of different subcommunities (often referred to as modules). Identifying such modules has the potential to develop a better understanding of the assembly of ecological communities and to investigate functional overlap or specialization. The most informative form of networks are quantitative or weighted networks. Here, we introduce an algorithm to identify modules in quantitative bipartite (or two-mode) networks. It is based on the hierarchical random graphs concept of Clauset et al. (2008 Nature 453: 98–101) and is extended to include quantitative information and adapted to work with bipartite graphs. We define the algorithm, which we call QuanBiMo, sketch its performance on simulated data and illustrate its potential usefulness with a case study. Modules are detected with a higher accuracy in simulated quantitative networks than in their binary counterparts. Even at high levels of noise, QuanBiMo still classifies 70% of links correctly as within- or between-modules. Recursively applying the algorithm results in additional information of within-module organization of the network. The algorithm introduced here must be seen as a considerable improvement over the current standard of algorithms for binary networks. Due to its higher sensitivity, it is likely to lead to be useful for detecting modules in the typically noisy data of ecological networks.

Journal ArticleDOI
TL;DR: A comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item, is compiled.
Abstract: Background: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. Methods: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. Results: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. Interpretation: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.

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TL;DR: Flexible perovskite based solar cells with power conversion efficiencies of 7% have been prepared on PET based conductive substrates as discussed by the authors, demonstrating their suitability for roll to roll processing.
Abstract: Flexible perovskite based solar cells with power conversion efficiencies of 7% have been prepared on PET based conductive substrates. Extended bending of the devices does not deteriorate their performance demonstrating their suitability for roll to roll processing.

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TL;DR: Over time, the heart is progressively reconstituted with bone marrow–derived macrophages, even in the absence of inflammation.
Abstract: Cardiac macrophages (cMΦ) are critical for early postnatal heart regeneration and fibrotic repair in the adult heart, but their origins and cellular dynamics during postnatal development have not been well characterized. Tissue macrophages can be derived from embryonic progenitors or from monocytes during inflammation. We report that within the first weeks after birth, the embryo-derived population of resident CX3CR1+ cMΦ diversifies into MHCII+ and MHCII− cells. Genetic fate mapping demonstrated that cMΦ derived from CX3CR1+ embryonic progenitors persisted into adulthood but the initially high contribution to resident cMΦ declined after birth. Consistent with this, the early significant proliferation rate of resident cMΦ decreased with age upon diversification into subpopulations. Bone marrow (BM) reconstitution experiments showed monocyte-dependent quantitative replacement of all cMΦ populations. Furthermore, parabiotic mice and BM chimeras of nonirradiated recipient mice revealed a slow but significant donor contribution to cMΦ. Together, our observations indicate that in the heart, embryo-derived cMΦ show declining self-renewal with age and are progressively substituted by monocyte-derived macrophages, even in the absence of inflammation.

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TL;DR: In this paper, a general framework and examples of approaches for enhancing pollinator richness and abundance, quantity and quality of pollen on stigmas, crop yield, and farmers' profit, including some benefits detected only through longterm monitoring.
Abstract: Recent evidence highlights the value of wild-insect species richness and abundance for crop pollination worldwide. Yet, deliberate physical importation of single species (eg European honey bees) into crop fields for pollination remains the mainstream management approach, and implementation of practices to enhance crop yield (production per area) through wild insects is only just beginning. With few exceptions, studies measuring the impacts of pollinator-supporting practices on wild-insect richness and pollination service success – particularly in relation to long-term crop yield and economic profit – are rare. Here, we provide a general framework and examples of approaches for enhancing pollinator richness and abundance, quantity and quality of pollen on stigmas, crop yield, and farmers' profit, including some benefits detected only through long-term monitoring. We argue for integrating the promotion of wild-insect species richness with single-species management to benefit farmers and society.