ALBERT

Description: Energy poverty is high up on national and European Union policy agendas. A number of possible indicators to measure the issue have been identified in the literature, but comparable data with European coverage is scarce. The EU Commission thus proposes four independent indicators on the "EU Energy Poverty Observatory" based on self-reported items from the pan-European surveys on income and living conditions (SILC) and household budgets (HBS). It is of increasing public interest to analyse social impacts of energy policies, and quantify energy poverty indicators also from modelling. This paper first shortly outlines how the expenditure-based indicators using HBS micro data may be directly linked to existing macroeconomic models through their defining variables (energy expenditure and income). As endogenous modelling based on micro data is difficult, the link may be country-specific elasticities. The main contribution of the paper is a systematic in-depth sensitivity analysis of the two indicators to changes in income and energy expenditure following varying patterns in the underlying distributions of the micro data. The results may be used by future soft links to models. The results display sometimes counterintuitive effects. We find that whether these indicators increase/decrease after a change of income or energy expenditure largely depends on the specific country-wise income and energy expenditure distribution between households on a micro-level. Due to their definition, the examined indicators are especially sensitive, when income changes alter the indicator threshold values, which in these cases are the median values in underlying distributions. We discuss these findings and relate them to several indicator shortcomings and potential remedies through changes in indicator definition.

Description: In order to calculate the financial return of energy efficiency measures, a cost-benefit analysis (CBA) is a proven tool for investors. Generally, however, most CBAs for investors have a narrow focus, which is - simply speaking - on investment costs compared with energy cost savings over the life span of the investment. This only provides part of the full picture. Ideally, a comprehensive or extended CBA would take additional benefits as well as additional costs into account. The objective of this paper is to reflect upon integrating into a CBA two important cost components: transaction costs and energy efficiency services - and how they interact. Even though this concept has not been carried out to the knowledge of the authors, we even go a step further to try to apply this idea. In so doing, we carried out a meta-analysis on relevant literature and existing data and interviewed a limited number of energy experts with comprehensive experience in carrying out energy services. Even though data is hardly available, we succeeded in constructing three real-world cases and applied an extended CBA making use of information gathered on transaction costs and energy services costs. We were able to show that, despite these additional cost components, the energy efficiency measures are economically viable. Quantitative data was not available on how energy services reduce transaction costs; more information on this aspect could render our results even more positive. Even though empirical and conceptual research must intensify efforts to design an even more comprehensive CBA, these first-of-its-kind findings can counterargue those that believe energy efficiency is not worth it (in monetary terms) due to transaction costs or energy services costs. In fact, this is good news for energy efficiency and for those that seek to make use of our findings to argue in favor of taking up energy efficiency investments in businesses.

Description: This chapter turns to the measurement of performance in delivering corporate and ecosystem purposes. The metrics are designed to capture the pain points in the ecosystem that need to be addressed and the success of the intervention in addressing them. This requires measures of non-financial as well as financial performance. The chapter provides an overview of measurements of non-financial forms of capital: natural, human, and social. In examining natural capital, it contrasts input measures that record the amount of natural resources that are used in the production process and output measures that examine the impact of the inputs on products, emissions, waste, etc. It notes that measuring inputs is in general more straightforward than outputs and it therefore argues that natural capital metrics should be constructed around inputs rather than outputs.

Description: Unser Papier entwickelt Maßnahmen für eine "Just transition"-Governance als Grundlage einer Politischen Ökonomie im Strukturwandel. Für eine Fallstudie im Rheinischen Braunkohlerevier wurden sechs Experteninterviews mit Bürgerinitiativen, Gewerkschaften und Vertretern des Landes Nordrhein-Westfalen durchgeführt. Die Ergebnisse zeigen den Bedarf an politischen Maßnahmen in verschiedenen Bereichen auf: Während für die Traditionsfirmen der Braunkohleindustrie und deren Beschäftigten eine Vielzahl von Förderpolitiken entwickelt wurde und wird, erhalten Beschäftigte von Subunternehmen kaum Unterstützung im Strukturwandel. Letztere sind daher einem hohen Risiko ausgesetzt, durch den Ausstieg aus der Kohleförderung ihren Arbeitsplatz zu verlieren. Die Interviews zeigten auch, dass im Rheinischen Braunkohlerevier aufgrund des geltenden Bergbaugesetzes Flächen zu einer knappen Ressource werden könnten. Der Akteurszentrierte Institutionalismus wird genutzt, um Maßnahmen abzuleiten, die den Bedürfnissen der verschiedenen Interessengruppen entsprechen. Abschließend werden Bezüge sowohl zum Transition Management als auch zur Politischen Ökonomie hergestellt.

Description: The data centre industry (DCI) has grown from zero in the 1980s, to enabling 60% of the global population to be connected in 2021 via 7.2 million data centres. The DCI is based on a linear economy and there is an urgent need to transform to a Circular Economy to establish a secure supply chain and ensure an economically stable and uninterrupted service, which is particularly difficult in an industry that is comprised of ten insular subsectors. This paper describes the CEDaCI project which was established to address the challenge in this unique sector; this ground-breaking project employs a whole systems approach, Design Thinking and the Double Diamond methods, which rely on people/stakeholder engagement throughout. The paper reviews and assesses the impact of these methods and project to date, using quantitative and qualitative research, via an online sectoral survey and interviews with nine data centre and IT industry experts. The results show that the project is creating positive impact and initiating change across the sector and that the innovative output (designs, business models, and a digital tool) will ensure that sectoral transformation continues; the project methods and structure will also serve as an exemplar for other sectors.

Description: The rising popularity and strong increase in the number of electric bicycles make it necessary to consider the built-in resources as well as possible treatments after the use phase. The time lag between the purchase and the occurrence of relevant defects suggests significant increases in defective components. Especially the great dynamics of the market due to regular innovations, product renewals, and the lack of spare parts availability for older models make the long-term use by customers much more difficult than for conventional bicycles. Therefore, it is necessary to analyze circular business models for the electric bicycle market. In this way, the required structures for a sustainable electric bicycle industry can be created so that valuable materials do not go into disposal but undergo a new use phase. Based on the results of "AddRE-Mo-Value Preservation Scenarios for Urban Electromobility of Persons and Loads through Additive Manufacturing and Remanufacturing," a research project funded by the German Federal Ministry of Education and Research, this paper addresses four circular business models, two sales models, and two service models. The guiding research interest of this paper is the combination of remanufacturing and additive manufacturing from a business model perspective, analyzing the extent to which additive remanufacturing can be considered a solution for electric bicycles' circularity. After describing the approach and methods used to develop these four circular business models the business models are described and analyzed using the Business Model Canvas. Based on this analysis, it is shown that the combination of remanufacturing and additive manufacturing can be applied to the electric bicycle market and be integrated into both sales and service models. The description of these business models will help managers design viable business models in the context of sustainable electric bicycles. It also shows that the individual partners within the value chain must collaborate more closely. In the electric bicycle industry, a single company will probably not be able to close the product cycle completely. Further research is needed to develop concepts of the business models and examine their practical feasibility in technical and organizational operations to achieve a circular economy.

Description: Reuse is still seen as a "niche phenomenon" and consumers seem to waste economic opportunities linked to buying and selling second-hand products. For this reason, this paper focuses on incentives and barriers to sell and buy second-hand products, as indicated in the literature, and applies a theoretical framework of transaction costs to explain the existing consumption patterns. For this paper, a representative online survey was conducted in which 1023 consumers in Germany participated, age 16 and older. The data were analyzed for statistically significant deviations between different groups of economic actors selling or buying second-hand products. Results show that valuable unused products exist in households, but barriers such as uncertainties about the reliability of the buyer or the quality of the product hinder the transition into sustainable consumption. Different forms of transaction costs are important explanatory variables to explain why consumers nevertheless predominantly buy new products, although they are aware that second-hand would save money and make an individual contribution to climate protection.

Description: This paper argues that, although Japan's and Germany's energy transition paths differ in detail, a trend towards decentralisation is clearly evident in both countries. Based on comprehensive screening, own stocktaking and the results of a stakeholder dialogue, this paper highlights the motivation for different local actors to enter the energy market in both countries. Although there are challenges to success in a market dominated by large energy companies, this paper argues that the benefits to local communities outweigh the efforts. Overall, it is shown that democratisation and the decentralisation of the energy system are suitable to facilitate a successful transformation process in both countries.

Description: More and more companies are announcing their intention to become climate-neutral and numerous companies already offer climate-neutral products or services: From climate-neutral parcel delivery to air travel. But what exactly do the companies' net-zero targets mean? Is the target set ambitious? And what role does offsetting play, i.e., purchasing carbon credits that are accounted against the company's own climate target? The approaches behind the proclaimed targets are often difficult to understand. Against this background, this Zukunftsimpuls provides ten recommendations for the definition and implementation of neutrality targets. Among other things, the authors advocate the use of a robust database as the basis for net-zero targets, emphasize the importance of transparent communication, and highlight the role that offsetting should play. Purchased carbon credits should make as limited a contribution as possible for meeting climate targets and should only be used to offset emissions that cannot be reduced or avoided. More generally, net-zero targets should not be made the sole criterion for ambitious climate strategies. Rather, they are a building block of a much more comprehensive strategy of corporate climate action.

Description: Als Herausforderung der Verkehrswende werden häufig die möglicherweise wegfallenden Arbeitsplätze diskutiert. Denn die Beschäftigung der Automobilindustrie in Deutschland gilt als wichtiges Argument für einen sozialverträglichen Strukturwandel. Aber auch die Wirtschaftszweige des Umweltverbunds bieten viele Arbeitsplätze. Vor diesem Hintergrund untersucht die vorliegende Studie des Wuppertal Instituts und des Instituts Arbeit und Technik der Westfälischen Hochschule die Beschäftigtenzahlen in Teilmärkten der Fahrradwirtschaft sowie deren Umsatzentwicklung.

Description: The European Union (EU) has established that the goal of achieving climate neutrality by 2050 as a key driver of innovation and growth for industry and the economy in the EU. In addition to offering great opportunities, this also poses considerable challenges for the European economy and, for the most part, for basic industries, which are particularly emission-intensive and face strong international competition. An integrated climate and industry strategy is of central importance to protecting the climate, since the production of steel, cement, basic chemicals, glass, paper, and other materials in the EU and worldwide accounts for roughly one fifth of total greenhouse gas emissions. Even in a greenhouse gas-neutral future, we will not be able to fully eliminate our need for these materials. At the same time, it is particularly challenging to produce these materials without creating emissions given the state of technology and the necessary infrastructures. This applies above all to the question of how large amounts of green energy, including electricity and hydrogen, can be produced at competitive prices. Analyses show that despite the considerable costs involved in process changeover, the costs of transforming the raw materials industry are acceptable to society as a whole, given that the additional costs usually only increase the price of the end products by a few percentage points. However, in the case of crude steel or cement, the price would increase by between one third and 100 per cent. Since almost all raw materials manufacturers face strong global market competition, in most cases they are not able to bankroll the investments in climate-neutral production and the required energy infrastructure without outside support. This paper outlines an integrated climate industrial policy package that allows the EU to utilise its existing technological leadership in many of these industries to build a greenhouse gas-neutral raw materials industry.

Description: In the light of Germany's chosen path towards the energy transition, the regulatory framework has changed considerably. New players have succeeded in entering the market, and renewable energies have become increasingly competitive. Greater electrification of the transport and heating sectors will be needed in the future to achieve national climate targets. Against this background, Germany's big energy companies need to be sure that their sales will increase. However, they were unable to anticipate this development, and made strategic mistakes in the past. The development of sustainable business models in line with the energy transition failed to materialize. Now it is becoming increasingly clear that companies must create new business models to survive in the long term. These business models have to keep with the tradition, whilst meeting the needs of low-carbon power supplies. In this paper, we will examine the past and future challenges of the four energy companies and develop a proposal for evaluating sustainable business models. For this purpose, we use the multi-level perspective to categorize developments in the electricity market over the last 50 years, and then apply a multi-criteria analysis to derive five suitable business models from the results.

Description: In this paper, we aim to present a comprehensive analysis on the emerging phenomenon of distributed innovation in commons-based peer production (CBPP) platforms. Starting with the exploration of the widely held belief on value-creation confined to industrial settings, we raise several questions regarding the feasibility of, and a need for, an inclusive innovation process that can tap grassroots capacity into both traditional (industrial research and development) and emerging (peer-to-peer) innovation models to yield sustainable solutions. In particular, we explore the emergence and structuration of digital innovations in the maker movement, as it presents an alternative construct of innovation wherein access to and sharing of knowledge is predominantly distributed. With innovation outcomes often freely revealed, its very structuration could pose a principal challenge to our conceptualizations of value creation and competitive advantage in the current economic model. Drawing from responses received from 200 collaborative innovation platforms, six semi‐structured interviews focusing on socio-technical innovation cases, as well as four in-depth narrative interviews with maker turned entrepreneurs, we present a detailed analysis on the topology of network, typology of actors, as well as the underlying innovation ecosystem in CBPP networks in Germany. In doing so, we contribute to the conceptualization of peer-to-peer distributed innovations in collaborative platforms.

Description: The concept Material Input per Service Unit (MIPS) was developed 20 years ago as a measure for the overall natural resource use of products and services. The material intensity analysis is used to calculate the material footprint of any economic activities in production and consumption. Environmental assessment has developed extensive databases for life cycle inventories, which can additionally be adopted for material intensity analysis. Based on practical experience in measuring material footprints on the micro level, this paper presents the current state of research and methodology development: it shows the international discussions on the importance of accounting methodologies to measure progress in resource efficiency. The MIPS approach is presented and its micro level application for assessing value chains, supporting business management, and operationalizing sustainability strategies is discussed. Linkages to output-oriented Life Cycle Assessment as well as to Material Flow Analysis (MFA) at the macro level are pointed out. Finally we come to the conclusion that the MIPS approach provides relevant knowledge on resource and energy input at the micro level for fact-based decision-making in science, policy, business, and consumption.

Description: Increasing concerns regarding the world's natural resources and sustainability continue to be a major issue for global development. As a result several political initiatives and strategies for green or resource-efficient growth both on national and international levels have been proposed. A core element of these initiatives is the promotion of an increase of resource or material productivity. This dissertation examines material productivity developments in the OECD and BRICS countries between 1980 and 2008. By applying the concept of convergence stemming from economic growth theory to material productivity the analysis provides insights into both aspects: material productivity developments in general as well as potentials for accelerated improvements in material productivity which consequently may allow a reduction of material use globally.The results of the convergence analysis underline the importance of policy-making with regard to technology and innovation policy enabling the production of resource-efficient products and services as well as technology transfer and diffusion.​

Description: In globalen Energieszenarien spielt die Windenergie eine wichtige Rolle für den zukünftigen Strommix. Die Technologie hat sich bewährt und die Windbranche entwickelt sich zu einer reifen Industrie. Während der bisherige Ausbau der Windenergie stark von deutschen und europäischen Unternehmen bestimmt wurde, sind nun chinesische und amerikanische Unternehmen auf dem Weltmarkt weitgehend führend. Das vorliegende Buch untersucht daher maßgebende Erfolgsfaktoren der deutschen Windbranche auf dem internationalen Markt und konzentriert sich auf zwei Bereiche: Zum einen wird die Anwendbarkeit der Erfolgsfaktorenforschung - ein Konzept aus dem strategischen Management - einer kritischen Prüfung unterzogen. Zum anderen werden in einer qualitativen Analyse Erfolgsfaktoren diskutiert, die für die vergleichsweise junge Branche wichtig sind. Entscheidend ist es demnach, Lösungen, Strategien oder Technologieentwicklungen aus anderen Branchen zu transferieren (Transferkompetenz) und eine gemeinsame Technologieentwicklung in der Wertschöpfungskette (Joint Development) zu etablieren.

Description: Die systematisch-intentionale Förderung von innovativen Unternehmensgründungen aus Universitäten und Forschungseinrichtungen bedarf einer ergänzenden Neuausrichtung, will sie sich zukünftig als noch legitimierter und effizienter erweisen. Dabei wird im Rahmen einer integrativen Gründungs- und Innovationsförderung aus Universitäten und Forschungseinrichtungen eine Programmatik entworfen, die sich insbesondere in Prototypen komplexer Zukunftsinnovationen manifestiert.

Description: Aufgrund der Reform des Erneuerbare-Energien-Gesetzes soll die Förderhöhe für Strom aus Photovoltaik-Freiflächenanlagen nun wettbewerblich über Ausschreibungen ermittelt werden. Dafür muss eine entsprechende Rechtsverordnung geschaffen werden. Für die Eckpunkte eines solchen Ausschreibungsdesigns hat das Bundeswirtschaftsministerium eine öffentliche Konsultation in Gang gesetzt, zu der auch das Wuppertal Institut zusammen mit dem Fraunhofer-Institut für Solare Energiesysteme ISE und weiteren Unterstützern eine Stellungnahme abgegeben haben. Ihre Empfehlung ist, die Ressourcen-/bzw. Landnutzung von PV-Freiflächenanlagen als wesentliches Kriterium in die Förderung einzubeziehen. Vor dem Hintergrund eines erhöhten Nutzungsdrucks auf den ländlichen Raum weisen sie darauf hin, dass ihr angestrebter Ausbau zu ökonomischen, ökologischen, politischen und gesellschaftlichen Konfliktkonstellationen führen könnte. Zugleich machen sie deutlich, dass es zur herkömmlichen Technologie eine Alternative, die Agrophotovoltaik-Freiflächentechnologie gibt, ein Anbausystem zur Produktion von landwirtschaftlichen Gütern unterhalb von PV-Modulen. Sie ermöglicht die simultane Erzeugung von PV-Strom und die Produktion von Nahrungsmitteln. Folgerichtig wird empfohlen, nicht die PV-Anlagen, sondern Freiflächen-Technologien zum Gegenstand der geplanten Pilotausschreibungen zu machen. Die Ausweitung herkömmlicher Anlagen sollte sich auf unterdurchschnittlich fruchtbare Ackerflächen beschränken.

Description: There are a variety of economic and ecological benefits to increased resource efficiency. Social, institutional and technical innovations can all contribute towards efficiency increases. Companies face different hurdles in fostering such innovation. Small and medium-sized companies are subject to specific constraints that may prevent them from benefiting from innovation-induced resource efficiency improvements. Qualitative interviews were conducted among German small and medium-sized enterprises (SMEs) and intermediaries to identify barriers for resource efficiency innovations and to elaborate a policy mix at the federal level that could help SMEs to overcome these. We found five major barriers to resource efficiency innovations in German SMEs, comprising deficits in innovation culture, inter-firm cooperation along the value chain, finance, awareness and take-up of government funds. We propose a distinct policy mix as a response to this situation. The policy mix comprises the interlocking and synergistic elements of government funding schemes, innovation agents and innovation laboratories.

Description: Although there are already some qualification offers available for enterprises to support resource efficiency innovations, the high potentials that can be identified especially for small and medium sized enterprises (SMEs) have not been activated until now. As successful change lies in the hands of humans, the main aim of vocational education has to be the promotion of organisational and cultural changes in the enterprises. As there is already a small but increasing number of enterprises that perform very well in resource efficiency innovations one question arises: What are typical characteristics of those enterprises? Leaning on a good-practice approach, the project "ResourceCulture" is going to prove or falsify the hypothesis that enterprises being successful with resource efficiency innovations have a specific culture of trust, which substantially contributes to innovation processes, or even initially enables them. Detailed empirical field research will light up which correlations between resource efficiency, innovation and cultures of trust can be found and will offer important aspects for the improvement of management instruments and qualification concepts for workplace training. The project seizes qualification needs that were likewise mentioned by enterprises and consultants, regarding the implementation of resource efficiency. This article - based on first empirical field research results - derives preliminary indications for the design of the qualification module for the target groups resource efficiency consultants and managers. On this basis and in order to implement "ResourceCulture" conceptual and methodological starting points for workplace training are outlined.

Description: Die Krisen der internationalen Finanzmärkte waren 1998 noch nicht Realität, Atomkraft galt in Deutschland unter der Regierung Kohl immer noch als Zukunftsoption für die kommenden Jahrzehnte und für eine Bundespolitik in Richtung Energiewende war weit und breit kein gesellschaftlicher Konsens in Sicht. Dennoch gab es schon vor der Energiewende Projekte, die sich der Steigerung der Energieeffizienz verschrieben hatten. Mit kombinierten Einspar- und Solarkraftwerken, die an Schulen mit finanzieller Bürgerbeteiligungen entstehen, sollte der Weg zu einer umweltverträglichen Energieversorgung für vier Schulen in Nordrhein-Westfalen eingeschlagen werden. Wie der vorliegende Projektbericht zeigt, konnten die Ziele des Vorhabens erreicht werden: Steigerung der Endenergieeffizienz, verstärkte Nutzung erneuerbarer Energien und der Einsatz dezentraler Kraft-Wärme-Kopplung.

Description: The food and agricultural sector will face numerous challenges in the next decades, arising from changing global production and consumption patterns, which currently go along with high resource use, causing ecological and socio-economic impacts. The aim of this paper is to illustrate and evaluate the practical applicability of the Hot Spot Analysis methodology in the context of supply chain management in companies. The HSA is a method to identify social and ecological problems along the entire life cycle of a product. Special emphasis is put on a customized implementation in the value chain beef of McDonald's Germany. The HSA of McDonald's beef value chain shows that the main ecological problems arise in the phase of raw material extraction, whereas the main social problems can be identified in the phase of slaughtering. Finally, the paper shows potentials and shortcomings of such a customized application and how the results can be implemented in the sustainability management of a company.

Description: Critical metals are in great demand by the electrical and electronics industry, so waste electrical and eletronic equipment represents a significant source of secondary raw materials. Owing to low recycling rates and the concomitant supply risks associated with critical metals, the closure of the material cycles is highly relevant to the German economy. Losses of these metals occur from collection until their material recovery, along the entire disposal chain of waste electrical and electronic equipment. This paper develops planning criteria for the design of collection groups to achieve higher recovery amounts of such metals. The aim is to clarify what amounts of metals exist, both product-specific and on the market, how the dismantling of the products is constructed and how collection groups can be arranged with planning criteria oriented towards resource conservation. The analysis is a snapshot using the example of indium and selected products. A procedure is presented and findings identified which are transferable to various critical metals and to waste electrical and electronic equipment. The results show that grouping of products according to resource amounts and the dismantling effort enables forward-looking and resource-efficient planning of the treatment of every single collection group.

Description: This paper reflects the socio-economic power of renewable energy production cooperatives for a wider energy system transformation in Germany. Energy cooperatives have turned into important supporters of renewable and decentralised energy structures, due to their strong growth since the year 2006, their participation in local renewable energy projects and their democratic awareness. The cooperative form of coordinating local renewable energy projects applies to a decentralised energy system that is managed by many smaller firms - a system concept that is preferred by the majority of German citizens. However, there is not enough knowledge to understand to what extent this organisational form is able to unify a broad group of actors in promoting a renewable energy system (societal power) and to gather capital for elaborating renewable energy supply structures (economic power). The reflection is based on an empirical assessment of all energy cooperatives that were registered in Germany before 31st December 2013. Their growth dynamic and their business approaches are discussed. A special focus lies on renewable energy production cooperatives. The study presents the development of their members, their capital, their profit and loss, as well as their investment intensity over a timeframe of three years (2010-2012). The socio-economic potential of renewable energy production cooperatives for supporting a renewable energy system is discussed against the background of empirical results.

Description: Die elektrische Energieversorgung von Kommunen wird nach einer Privatisierungswelle Ende der 1990er Jahren mehr und mehr wieder in kommunale Hand zurückgeholt und Kommunen entdecken Chancen und Möglichkeiten, die sich dadurch ergeben. In Nordhessen ist ein Trend der Rekommunalisierung erkennbar durch die Neugründung von Stadt- und Gemeindewerken zur Elektrizitätsversorgung oder deren Weiterentwicklung. Dieser Prozess wird unter anderem durch die Städtische Werke Aktiengesellschaft, Kassel angetrieben, die als Partner die Kommunen insbesondere beim Rückkauf der Stromnetze, der Gründung von eigenen Stadtwerken und dem Vertrieb von Energieprodukten unterstützen. Gleichzeitig ist seit Mitte Dezember 2013 der Energieversorger E.ON Mitte AG von den nordhessischen und südniedersächsischen Landkreisen (zurück)gekauft und als Energie aus der Mitte GmbH & Co. KG (EAM) wieder in kommunaler Hand. Vor dem Hintergrund dieser Entwicklungen untersucht die vorliegende Arbeit den Prozess der Rekommunalisierung der Energieversorgung in Nordhessen und beschreibt die damit verbundenen Herausforderungen für die Kommunen. Am Beispiel von drei Kommunalwerken in Nordhessen wird die Fragestellung untersucht, wie der Prozess der Rekommunalisierung gestaltet werden kann und welche Teilprozesse wie Netzrückkauf, Vertrieb und Erzeugung mit welchen Herausforderungen verbunden sind. Auch die Frage, welche Bedeutung die Rekommunalisierung von E.ON Mitte AG hat, wird untersucht. Um möglichst viel Wissen über die Rekommunalisierungsvorgänge von beteiligten Personen zu erlangen, wurde das Erhebungsverfahren der leitfadengestützten Experteninterviews ausgewählt. Die Auswertung der erhobenen Daten erfolgte mit der Methodik Grounded Theory.

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cressey, Daniel -- England -- Nature. 2014 Apr 10;508(7495):159. doi: 10.1038/508159a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717487" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cressey, Daniel -- England -- Nature. 2014 Mar 6;507(7490):18. doi: 10.1038/507018a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24598618" target="_blank"〉PubMed〈/a〉

Description: Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bessede, Alban -- Gargaro, Marco -- Pallotta, Maria T -- Matino, Davide -- Servillo, Giuseppe -- Brunacci, Cinzia -- Bicciato, Silvio -- Mazza, Emilia M C -- Macchiarulo, Antonio -- Vacca, Carmine -- Iannitti, Rossana -- Tissi, Luciana -- Volpi, Claudia -- Belladonna, Maria L -- Orabona, Ciriana -- Bianchi, Roberta -- Lanz, Tobias V -- Platten, Michael -- Della Fazia, Maria A -- Piobbico, Danilo -- Zelante, Teresa -- Funakoshi, Hiroshi -- Nakamura, Toshikazu -- Gilot, David -- Denison, Michael S -- Guillemin, Gilles J -- DuHadaway, James B -- Prendergast, George C -- Metz, Richard -- Geffard, Michel -- Boon, Louis -- Pirro, Matteo -- Iorio, Alfonso -- Veyret, Bernard -- Romani, Luigina -- Grohmann, Ursula -- Fallarino, Francesca -- Puccetti, Paolo -- P30 CA056036/CA/NCI NIH HHS/ -- R01 CA109542/CA/NCI NIH HHS/ -- R01 ES007685/ES/NIEHS NIH HHS/ -- R01ES007685/ES/NIEHS NIH HHS/ -- England -- Nature. 2014 Jul 10;511(7508):184-90. doi: 10.1038/nature13323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3]. ; 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2]. ; Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. ; Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy. ; Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy. ; 1] Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany [2] Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany. ; Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan. ; Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan. ; CNRS UMR6290, Institut de Genetique et Developpement de Rennes, Universite de Rennes 1, 35043 Rennes, France. ; Department of Environmental Toxicology, University of California, Davis, 95616 California, USA. ; Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia. ; Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA. ; New Link Genetics Corporation, Ames, 50010 Iowa, USA. ; IMS Laboratory, University of Bordeaux, 33607 Pessac, France. ; Bioceros, 3584 Utrecht, The Netherlands. ; Department of Medicine, University of Perugia, 06132 Perugia, Italy. ; Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24930766" target="_blank"〉PubMed〈/a〉

Description: The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1-8, and removes Nedd8 modifications from target proteins. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pan, Lei -- Wang, Su -- Lu, Tinglin -- Weng, Changjiang -- Song, Xiaoqing -- Park, Joseph K -- Sun, Jin -- Yang, Zhi-Hao -- Yu, Junjing -- Tang, Hong -- McKearin, Dennis M -- Chamovitz, Daniel A -- Ni, Jianquan -- Xie, Ting -- GM64428/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):233-6. doi: 10.1038/nature13562.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China [3]. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA [3]. ; 1] Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [2]. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA. ; 1] Department of Molecular Biology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA. ; Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China. ; Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China. ; Department of Plant Sciences, Tel Aviv University, Tel Aviv 69978, Israel. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119050" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469351/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469351/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geisbert, Thomas W -- UC7 AI070083/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Oct 2;514(7520):41-3. doi: 10.1038/nature13746. Epub 2014 Aug 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Texas Medical Branch at Galveston, Galveston National Laboratory, Galveston, Texas 77550-0610, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25171470" target="_blank"〉PubMed〈/a〉

Description: The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pancera, Marie -- Zhou, Tongqing -- Druz, Aliaksandr -- Georgiev, Ivelin S -- Soto, Cinque -- Gorman, Jason -- Huang, Jinghe -- Acharya, Priyamvada -- Chuang, Gwo-Yu -- Ofek, Gilad -- Stewart-Jones, Guillaume B E -- Stuckey, Jonathan -- Bailer, Robert T -- Joyce, M Gordon -- Louder, Mark K -- Tumba, Nancy -- Yang, Yongping -- Zhang, Baoshan -- Cohen, Myron S -- Haynes, Barton F -- Mascola, John R -- Morris, Lynn -- Munro, James B -- Blanchard, Scott C -- Mothes, Walther -- Connors, Mark -- Kwong, Peter D -- AI0678501/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P01 GM056550/GM/NIGMS NIH HHS/ -- P01-GM56550/GM/NIGMS NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- R01 GM098859/GM/NIGMS NIH HHS/ -- R01-GM098859/GM/NIGMS NIH HHS/ -- R21 AI100696/AI/NIAID NIH HHS/ -- R21-AI100696/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- ZIA AI005023-13/Intramural NIH HHS/ -- ZIA AI005024-13/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa. ; Departments of Medicine, Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina 27710, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa [2] University of the Witwatersrand, Braamfontein, Johannesburg 2000, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban 4041, South Africa. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296255" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, Nicola -- England -- Nature. 2014 Feb 6;506(7486):16-7. doi: 10.1038/506016a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499897" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cressey, Daniel -- England -- Nature. 2014 Feb 27;506(7489):419-20. doi: 10.1038/506419a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572404" target="_blank"〉PubMed〈/a〉

Description: Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited. Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180099/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180099/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mancias, Joseph D -- Wang, Xiaoxu -- Gygi, Steven P -- Harper, J Wade -- Kimmelman, Alec C -- GM070565/GM/NIGMS NIH HHS/ -- GM095567/GM/NIGMS NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- R01 CA157490/CA/NCI NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- R01CA157490/CA/NCI NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):105-9. doi: 10.1038/nature13148. Epub 2014 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Radiation Oncology Program, Boston, Massachusetts 02115, USA [4] Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695223" target="_blank"〉PubMed〈/a〉

Description: The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals, suggesting that several somatic mutations may be required for their development. To address this, here we characterize 197 anti-stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pappas, Leontios -- Foglierini, Mathilde -- Piccoli, Luca -- Kallewaard, Nicole L -- Turrini, Filippo -- Silacci, Chiara -- Fernandez-Rodriguez, Blanca -- Agatic, Gloria -- Giacchetto-Sasselli, Isabella -- Pellicciotta, Gabriele -- Sallusto, Federica -- Zhu, Qing -- Vicenzi, Elisa -- Corti, Davide -- Lanzavecchia, Antonio -- U19 AI-057266/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):418-22. doi: 10.1038/nature13764. Epub 2014 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. ; Department of Infectious Diseases and Vaccines MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, USA. ; Viral Pathogens and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland. ; Unit of Preventive Medicine, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland [3]. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Insitute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296253" target="_blank"〉PubMed〈/a〉

Description: During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process. Re-initiation is thought to involve the same factors as standard initiation. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134322/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134322/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schleich, Sibylle -- Strassburger, Katrin -- Janiesch, Philipp Christoph -- Koledachkina, Tatyana -- Miller, Katharine K -- Haneke, Katharina -- Cheng, Yong-Sheng -- Kuchler, Katrin -- Stoecklin, Georg -- Duncan, Kent E -- Teleman, Aurelio A -- 260602/European Research Council/International -- England -- Nature. 2014 Aug 14;512(7513):208-12. doi: 10.1038/nature13401. Epub 2014 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany. ; 1] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2]. ; 1] Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany [2]. ; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany. ; 1] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Zentrum fur Molekulare Biologie der Universitat Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043021" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Oct 9;514(7521):140. doi: 10.1038/514140a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25297398" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mallapaty, Smriti -- England -- Nature. 2014 Feb 20;506(7488):279. doi: 10.1038/506279a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553222" target="_blank"〉PubMed〈/a〉

Description: Genome instability is central to ageing, cancer and other diseases. It is not only proteins involved in DNA replication or the DNA damage response (DDR) that are important for maintaining genome integrity: from yeast to higher eukaryotes, mutations in genes involved in pre-mRNA splicing and in the biogenesis and export of messenger ribonucleoprotein (mRNP) also induce DNA damage and genome instability. This instability is frequently mediated by R-loops formed by DNA-RNA hybrids and a displaced single-stranded DNA. Here we show that the human TREX-2 complex, which is involved in mRNP biogenesis and export, prevents genome instability as determined by the accumulation of gamma-H2AX (Ser-139 phosphorylated histone H2AX) and 53BP1 foci and single-cell electrophoresis in cells depleted of the TREX-2 subunits PCID2, GANP and DSS1. We show that the BRCA2 repair factor, which binds to DSS1, also associates with PCID2 in the cell. The use of an enhanced green fluorescent protein-tagged hybrid-binding domain of RNase H1 and the S9.6 antibody did not detect R-loops in TREX-2-depleted cells, but did detect the accumulation of R-loops in BRCA2-depleted cells. The results indicate that R-loops are frequently formed in cells and that BRCA2 is required for their processing. This link between BRCA2 and RNA-mediated genome instability indicates that R-loops may be a chief source of replication stress and cancer-associated instability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhatia, Vaibhav -- Barroso, Sonia I -- Garcia-Rubio, Maria L -- Tumini, Emanuela -- Herrera-Moyano, Emilia -- Aguilera, Andres -- England -- Nature. 2014 Jul 17;511(7509):362-5. doi: 10.1038/nature13374. Epub 2014 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centro Andaluz de Biologia Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Americo Vespucio s/n, 41092 Seville, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24896180" target="_blank"〉PubMed〈/a〉

Description: Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082311/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082311/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Genovese, Pietro -- Schiroli, Giulia -- Escobar, Giulia -- Di Tomaso, Tiziano -- Firrito, Claudia -- Calabria, Andrea -- Moi, Davide -- Mazzieri, Roberta -- Bonini, Chiara -- Holmes, Michael C -- Gregory, Philip D -- van der Burg, Mirjam -- Gentner, Bernhard -- Montini, Eugenio -- Lombardo, Angelo -- Naldini, Luigi -- 249845/European Research Council/International -- TGT11D02/Telethon/Italy -- England -- Nature. 2014 Jun 12;510(7504):235-40. doi: 10.1038/nature13420. Epub 2014 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] Vita Salute San Raffaele University, 20132 Milan, Italy. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia. ; Experimental Hematology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Sangamo BioSciences Inc., Richmond, California 94804, USA. ; Department of Immunology Erasmus MC, University Medical Center, 3015 Rotterdam, The Netherlands. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] Vita Salute San Raffaele University, 20132 Milan, Italy [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870228" target="_blank"〉PubMed〈/a〉

Description: The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to approximately 40% of breast cancers. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF2 (also known as RING1B) is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumour suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A. However, unlike RNF2, which is a subunit of polycomb repressive complex 1 (PRC1), we find that TRIM37 associates with polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to specific target genes, resulting in their transcriptional silencing. RNA-interference-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantially decreases tumour growth in mouse xenografts. Conversely, ectopic expression of TRIM37 renders non-transformed cells tumorigenic. Collectively, our results reveal TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumour suppressors and other genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269325/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhatnagar, Sanchita -- Gazin, Claude -- Chamberlain, Lynn -- Ou, Jianhong -- Zhu, Xiaochun -- Tushir, Jogender S -- Virbasius, Ching-Man -- Lin, Ling -- Zhu, Lihua J -- Wajapeyee, Narendra -- Green, Michael R -- R01 GM033977/GM/NIGMS NIH HHS/ -- R01GM033977/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 4;516(7529):116-20. doi: 10.1038/nature13955. Epub 2014 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; CEA/DSV/iRCM/LEFG, Genopole G2, and Universite Paris Diderot, 91057 Evry, France. ; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. ; 1] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470042" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Noorden, Richard -- England -- Nature. 2014 Feb 6;506(7486):17. doi: 10.1038/506017a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499898" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Oct 2;514(7520):6. doi: 10.1038/514006a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25279880" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mansell, Warren -- Carey, Timothy A -- England -- Nature. 2014 Sep 11;513(7517):172. doi: 10.1038/513172e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Manchester, UK. ; Centre for Remote Health, Alice Springs, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209790" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhutta, Zulfiqar Ahmed -- England -- Nature. 2014 Jul 17;511(7509):285-7. doi: 10.1038/511285a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center of Excellence in Women and Child Health at the Aga Khan University in Karachi, Pakistan, and co-director of the Sick Kids Center for Global Child Health in Toronto, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030151" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geraedts, Joep -- England -- Nature. 2014 Jun 19;510(7505):340. doi: 10.1038/510340d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Maastricht University, the Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24943949" target="_blank"〉PubMed〈/a〉

Description: A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Hugo J -- Bronner, Marianne E -- Krumlauf, Robb -- R01 DE017911/DE/NIDCR NIH HHS/ -- R01 NS086907/NS/NINDS NIH HHS/ -- R01DE017911/DE/NIDCR NIH HHS/ -- R01NS086907/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):490-3. doi: 10.1038/nature13723. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; 1] Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA [2] Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City, Kansas 66160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219855" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crooks, Richard M -- England -- Nature. 2014 Jan 9;505(7482):165-6. doi: 10.1038/505165a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402276" target="_blank"〉PubMed〈/a〉

Description: The phylogeny of Allotheria, including Multituberculata and Haramiyida, remains unsolved and has generated contentious views on the origin and earliest evolution of mammals. Here we report three new species of a new clade, Euharamiyida, based on six well-preserved fossils from the Jurassic period of China. These fossils reveal many craniodental and postcranial features of euharamiyidans and clarify several ambiguous structures that are currently the topic of debate. Our phylogenetic analyses recognize Euharamiyida as the sister group of Multituberculata, and place Allotheria within the Mammalia. The phylogeny suggests that allotherian mammals evolved from a Late Triassic (approximately 208 million years ago) Haramiyavia-like ancestor and diversified into euharamiyidans and multituberculates with a cosmopolitan distribution, implying homologous acquisition of many craniodental and postcranial features in the two groups. Our findings also favour a Late Triassic origin of mammals in Laurasia and two independent detachment events of the middle ear bones during mammalian evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bi, Shundong -- Wang, Yuanqing -- Guan, Jian -- Sheng, Xia -- Meng, Jin -- England -- Nature. 2014 Oct 30;514(7524):579-84. doi: 10.1038/nature13718. Epub 2014 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Key Laboratory of Vertebrate Evolution and Human Origins of Chinese Academy of Sciences, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, Beijing 100044, China [2] Department of Biology, Indiana University of Pennsylvania, Indiana, Pennsylvania 15705, USA. ; Key Laboratory of Vertebrate Evolution and Human Origins of Chinese Academy of Sciences, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, Beijing 100044, China. ; Beijing Natural History Museum, 126 Tianqiao Street, Dongcheng District, Beijing 100050, China. ; Paleontological Museum of Liaoning, Shenyang Normal University, Shenyang, Liaoning 110034, China. ; Division of Paleontology, American Museum of Natural History, Central Park West at 79th Street, New York, New York 10024, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209669" target="_blank"〉PubMed〈/a〉

Description: Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schneider, David M -- Nelson, Anders -- Mooney, Richard -- NS079929/NS/NINDS NIH HHS/ -- R01 DC013826/DC/NIDCD NIH HHS/ -- R21 NS079929/NS/NINDS NIH HHS/ -- T32 GM008441/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Sep 11;513(7517):189-94. doi: 10.1038/nature13724. Epub 2014 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA [2]. ; Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25162524" target="_blank"〉PubMed〈/a〉

Description: Fertilization occurs when sperm and egg recognize each other and fuse to form a new, genetically distinct organism. The molecular basis of sperm-egg recognition is unknown, but is likely to require interactions between receptor proteins displayed on their surface. Izumo1 is an essential sperm cell-surface protein, but its receptor on the egg has not been described. Here we identify folate receptor 4 (Folr4) as the receptor for Izumo1 on the mouse egg, and propose to rename it Juno. We show that the Izumo1-Juno interaction is conserved within several mammalian species, including humans. Female mice lacking Juno are infertile and Juno-deficient eggs do not fuse with normal sperm. Rapid shedding of Juno from the oolemma after fertilization suggests a mechanism for the membrane block to polyspermy, ensuring eggs normally fuse with just a single sperm. Our discovery of an essential receptor pair at the nexus of conception provides opportunities for the rational development of new fertility treatments and contraceptives.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998876/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998876/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bianchi, Enrica -- Doe, Brendan -- Goulding, David -- Wright, Gavin J -- 098051/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 24;508(7497):483-7. doi: 10.1038/nature13203. Epub 2014 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. ; Mouse Production Team, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. ; Electron and Advanced Light Microscopy Suite, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739963" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crous, Casparus J -- England -- Nature. 2014 Sep 4;513(7516):7. doi: 10.1038/513007a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186869" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bianco, Paolo -- Cattaneo, Elena -- De Luca, Michele -- Pani, Luca -- England -- Nature. 2014 Feb 27;506(7489):434. doi: 10.1038/506434c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sapienza University of Rome, Italy. ; University of Milan, Italy. ; University of Modena and Reggio Emilia, Modena, Italy. ; Italian Medicines Agency (AIFA), Rome, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572414" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biller-Andorno, Nikola -- England -- Nature. 2014 Jul 10;511(7508):155. doi: 10.1038/511155a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25008510" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biba, Erin -- England -- Nature. 2014 Nov 20;515(7527):S124-5. doi: 10.1038/515S124a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25407711" target="_blank"〉PubMed〈/a〉

Description: Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine gamma-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349202/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349202/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paul, Bindu D -- Sbodio, Juan I -- Xu, Risheng -- Vandiver, M Scott -- Cha, Jiyoung Y -- Snowman, Adele M -- Snyder, Solomon H -- MH18501/MH/NIMH NIH HHS/ -- R01 MH018501/MH/NIMH NIH HHS/ -- T32 GM007309/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):96-100. doi: 10.1038/nature13136. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670645" target="_blank"〉PubMed〈/a〉

Description: Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca(2+)) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation-contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 A. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended alpha-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the alpha-solenoid scaffold, suggesting a mechanism for channel gating by Ca(2+).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300236/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300236/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zalk, Ran -- Clarke, Oliver B -- des Georges, Amedee -- Grassucci, Robert A -- Reiken, Steven -- Mancia, Filippo -- Hendrickson, Wayne A -- Frank, Joachim -- Marks, Andrew R -- P01 HL081172/HL/NHLBI NIH HHS/ -- R01 AR060037/AR/NIAMS NIH HHS/ -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 HL061503/HL/NHLBI NIH HHS/ -- R01 HL083418/HL/NHLBI NIH HHS/ -- R01AR060037/AR/NIAMS NIH HHS/ -- R01GM29169/GM/NIGMS NIH HHS/ -- R01HL061503/HL/NHLBI NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 1;517(7532):44-9. doi: 10.1038/nature13950. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; 1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA. ; 1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; 1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA [3] Department of Biological Sciences, Columbia University, New York, New York 10027, USA. ; 1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA [3] Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470061" target="_blank"〉PubMed〈/a〉

Description: T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORgammat, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORgammat in response to TGF-beta signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rutz, Sascha -- Kayagaki, Nobuhiko -- Phung, Qui T -- Eidenschenk, Celine -- Noubade, Rajkumar -- Wang, Xiaoting -- Lesch, Justin -- Lu, Rongze -- Newton, Kim -- Huang, Oscar W -- Cochran, Andrea G -- Vasser, Mark -- Fauber, Benjamin P -- DeVoss, Jason -- Webster, Joshua -- Diehl, Lauri -- Modrusan, Zora -- Kirkpatrick, Donald S -- Lill, Jennie R -- Ouyang, Wenjun -- Dixit, Vishva M -- England -- Nature. 2015 Feb 19;518(7539):417-21. doi: 10.1038/nature13979. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470037" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bollen, Mathieu -- England -- Nature. 2015 Jan 1;517(7532):29-30. doi: 10.1038/nature14080. Epub 2014 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487157" target="_blank"〉PubMed〈/a〉

Description: Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5' untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353651/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353651/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Shifeng -- Tian, Siqi -- Fujii, Kotaro -- Kladwang, Wipapat -- Das, Rhiju -- Barna, Maria -- 7DP2OD00850902/OD/NIH HHS/ -- DP2 OD008509/OD/NIH HHS/ -- R01 GM102519/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jan 1;517(7532):33-8. doi: 10.1038/nature14010. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Developmental Biology, Stanford University, Stanford, California 94305, USA [2] Department of Genetics, Stanford University, Stanford, California 94305, USA [3] Tetrad Graduate Program, University of California, San Francisco, San Francisco, California 94158, USA. ; Department of Biochemistry, Stanford University, Stanford, California 94305, USA. ; 1] Department of Developmental Biology, Stanford University, Stanford, California 94305, USA [2] Department of Genetics, Stanford University, Stanford, California 94305, USA. ; 1] Department of Biochemistry, Stanford University, Stanford, California 94305, USA [2] Department of Physics, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409156" target="_blank"〉PubMed〈/a〉

Description: Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition. This pathway is prominent at the leading edges of cells where phosphatidylinositol-3,4-bisphosphate-produced by the dephosphorylation of phosphatidylinositol-3,4,5-triphosphate by SHIP1 and SHIP2-recruits lamellipodin, which in turn engages endophilin. This pathway mediates the ligand-triggered uptake of several G-protein-coupled receptors such as alpha2a- and beta1-adrenergic, dopaminergic D3 and D4 receptors and muscarinic acetylcholine receptor 4, the receptor tyrosine kinases EGFR, HGFR, VEGFR, PDGFR, NGFR and IGF1R, as well as interleukin-2 receptor. We call this new endocytic route fast endophilin-mediated endocytosis (FEME).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boucrot, Emmanuel -- Ferreira, Antonio P A -- Almeida-Souza, Leonardo -- Debard, Sylvain -- Vallis, Yvonne -- Howard, Gillian -- Bertot, Laetitia -- Sauvonnet, Nathalie -- McMahon, Harvey T -- U105178805/Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jan 22;517(7535):460-5. doi: 10.1038/nature14067. Epub 2014 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK [2] Institute of Structural and Molecular Biology, University College London &Birkbeck College, London WC1E 6BT, UK. ; Institute of Structural and Molecular Biology, University College London &Birkbeck College, London WC1E 6BT, UK. ; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; 1] Institute of Structural and Molecular Biology, University College London &Birkbeck College, London WC1E 6BT, UK [2] Department of Biology, Ecole Normale Superieure de Cachan, 94235 Cachan, France. ; Institut Pasteur, Unite de Pathogenie Moleculaire Microbienne, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517094" target="_blank"〉PubMed〈/a〉

Description: The manufacture of geometric engravings is generally interpreted as indicative of modern cognition and behaviour. Key questions in the debate on the origin of such behaviour are whether this innovation is restricted to Homo sapiens, and whether it has a uniquely African origin. Here we report on a fossil freshwater shell assemblage from the Hauptknochenschicht ('main bone layer') of Trinil (Java, Indonesia), the type locality of Homo erectus discovered by Eugene Dubois in 1891 (refs 2 and 3). In the Dubois collection (in the Naturalis museum, Leiden, The Netherlands) we found evidence for freshwater shellfish consumption by hominins, one unambiguous shell tool, and a shell with a geometric engraving. We dated sediment contained in the shells with (40)Ar/(39)Ar and luminescence dating methods, obtaining a maximum age of 0.54 +/- 0.10 million years and a minimum age of 0.43 +/- 0.05 million years. This implies that the Trinil Hauptknochenschicht is younger than previously estimated. Together, our data indicate that the engraving was made by Homo erectus, and that it is considerably older than the oldest geometric engravings described so far. Although it is at present not possible to assess the function or meaning of the engraved shell, this discovery suggests that engraving abstract patterns was in the realm of Asian Homo erectus cognition and neuromotor control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joordens, Josephine C A -- d'Errico, Francesco -- Wesselingh, Frank P -- Munro, Stephen -- de Vos, John -- Wallinga, Jakob -- Ankjaergaard, Christina -- Reimann, Tony -- Wijbrans, Jan R -- Kuiper, Klaudia F -- Mucher, Herman J -- Coqueugniot, Helene -- Prie, Vincent -- Joosten, Ineke -- van Os, Bertil -- Schulp, Anne S -- Panuel, Michel -- van der Haas, Victoria -- Lustenhouwer, Wim -- Reijmer, John J G -- Roebroeks, Wil -- England -- Nature. 2015 Feb 12;518(7538):228-31. doi: 10.1038/nature13962. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Faculty of Archaeology, Leiden University, PO Box 9515, 2300RA, Leiden, The Netherlands [2] Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081HV, Amsterdam, The Netherlands. ; 1] Universite de Bordeaux, CNRS UMR 5199, Allee Geoffroy Saint-Hilaire, 33615 Pessac, France [2] Institute of Archaeology, History, Cultural Studies and Religion, University of Bergen, Oysteinsgate 3PO Box 7805, Bergen, Norway. ; Naturalis Biodiversity Center, Darwinweg 2, PO Box 9517, 2300RA, Leiden, The Netherlands. ; 1] School of Archaeology and Anthropology, Australian National University, Australian Capital Territory, 0200 Canberra, Australia [2] National Museum of Australia, Australian Capital Territory 2601, Canberra, Australia. ; 1] Wageningen University, Soil Geography and Landscape Group &Netherlands Centre for Luminescence Dating, PO Box 47, 6700AA, Wageningen, The Netherlands [2] Delft University of Technology, Faculty of Applied Sciences, Mekelweg 15, 2629JB, Delft, The Netherlands. ; Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081HV, Amsterdam, The Netherlands. ; 1] Faculty of Archaeology, Leiden University, PO Box 9515, 2300RA, Leiden, The Netherlands [2] Prinses Beatrixsingel 21, 6301VK, Valkenburg, The Netherlands. ; Universite de Bordeaux, CNRS UMR 5199, Allee Geoffroy Saint-Hilaire, 33615 Pessac, France. ; 1] Museum National d'Histoire Naturelle, UMR 7205, Institut de Systematique, Evolution, Biodiversite, CP51, 55 Rue Buffon, 75005 Paris, France [2] Biotope Recherche et Developpement, 22 Boulevard Marechal Foch, 34140 Meze, France. ; Cultural Heritage Agency of the Netherlands, PO Box 1600, 3800BP, Amersfoort, The Netherlands. ; 1] Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081HV, Amsterdam, The Netherlands [2] Naturalis Biodiversity Center, Darwinweg 2, PO Box 9517, 2300RA, Leiden, The Netherlands [3] Natuurhistorisch Museum Maastricht, De Bosquetplein 7, 6211KJ, Maastricht, The Netherlands. ; 1] Faculte de Medecine, Universite d'Aix-Marseille, EFS, CNRS UMR 7268, Boulevard Pierre Dramard, 13344 Marseille, France [2] Department of Medical Imaging Hopital Nord, Assistance Publique - Hopitaux de Marseille, Chemin de Bourrellys, 13915 Marseille, France. ; Faculty of Archaeology, Leiden University, PO Box 9515, 2300RA, Leiden, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470048" target="_blank"〉PubMed〈/a〉

Description: The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jihye -- Ishiguro, Kei-ichiro -- Nambu, Aya -- Akiyoshi, Bungo -- Yokobayashi, Shihori -- Kagami, Ayano -- Ishiguro, Tadashi -- Pendas, Alberto M -- Takeda, Naoki -- Sakakibara, Yogo -- Kitajima, Tomoya S -- Tanno, Yuji -- Sakuno, Takeshi -- Watanabe, Yoshinori -- England -- Nature. 2015 Jan 22;517(7535):466-71. doi: 10.1038/nature14097. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1Yayoi, Tokyo 113-0032, Japan. ; Instituto de Biologia Molecular y Celular del Cancer (CSIC-USAL), 37007 Salamanca, Spain. ; Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 Japan. ; Laboratory for Chromosome Segregation, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533956" target="_blank"〉PubMed〈/a〉

Description: Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport, and is implicated in viral infections and neurodegenerative diseases. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate. The structure reveals a closure of the motor's ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1-AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Helgo -- Zalyte, Ruta -- Urnavicius, Linas -- Carter, Andrew P -- 100387/Wellcome Trust/United Kingdom -- MC_UP_A025_1011/Medical Research Council/United Kingdom -- WT100387/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Feb 19;518(7539):435-8. doi: 10.1038/nature14023. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470043" target="_blank"〉PubMed〈/a〉

Description: The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7alpha-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buffie, Charlie G -- Bucci, Vanni -- Stein, Richard R -- McKenney, Peter T -- Ling, Lilan -- Gobourne, Asia -- No, Daniel -- Liu, Hui -- Kinnebrew, Melissa -- Viale, Agnes -- Littmann, Eric -- van den Brink, Marcel R M -- Jenq, Robert R -- Taur, Ying -- Sander, Chris -- Cross, Justin R -- Toussaint, Nora C -- Xavier, Joao B -- Pamer, Eric G -- AI95706/AI/NIAID NIH HHS/ -- DP2 OD008440/OD/NIH HHS/ -- DP2OD008440/OD/NIH HHS/ -- K23 AI095398/AI/NIAID NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI042135/AI/NIAID NIH HHS/ -- R01 AI095706/AI/NIAID NIH HHS/ -- R01 AI42135/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32 GM007739/GM/NIGMS NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- U54 CA148967/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):205-8. doi: 10.1038/nature13828. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA [2] Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA. ; Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA. ; Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337874" target="_blank"〉PubMed〈/a〉

Description: Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303590/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303590/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xianqin -- Bogunovic, Dusan -- Payelle-Brogard, Beatrice -- Francois-Newton, Veronique -- Speer, Scott D -- Yuan, Chao -- Volpi, Stefano -- Li, Zhi -- Sanal, Ozden -- Mansouri, Davood -- Tezcan, Ilhan -- Rice, Gillian I -- Chen, Chunyuan -- Mansouri, Nahal -- Mahdaviani, Seyed Alireza -- Itan, Yuval -- Boisson, Bertrand -- Okada, Satoshi -- Zeng, Lu -- Wang, Xing -- Jiang, Hui -- Liu, Wenqiang -- Han, Tiantian -- Liu, Delin -- Ma, Tao -- Wang, Bo -- Liu, Mugen -- Liu, Jing-Yu -- Wang, Qing K -- Yalnizoglu, Dilek -- Radoshevich, Lilliana -- Uze, Gilles -- Gros, Philippe -- Rozenberg, Flore -- Zhang, Shen-Ying -- Jouanguy, Emmanuelle -- Bustamante, Jacinta -- Garcia-Sastre, Adolfo -- Abel, Laurent -- Lebon, Pierre -- Notarangelo, Luigi D -- Crow, Yanick J -- Boisson-Dupuis, Stephanie -- Casanova, Jean-Laurent -- Pellegrini, Sandra -- 1P01AI076210-01A1/AI/NIAID NIH HHS/ -- 309449/European Research Council/International -- 8UL1TR000043/TR/NCATS NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI090935/AI/NIAID NIH HHS/ -- P01AI090935/AI/NIAID NIH HHS/ -- R00 AI106942/AI/NIAID NIH HHS/ -- R00AI106942-02/AI/NIAID NIH HHS/ -- R01 AI035237/AI/NIAID NIH HHS/ -- R37 AI095983/AI/NIAID NIH HHS/ -- R37AI095983/AI/NIAID NIH HHS/ -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- UL1 TR000043/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 1;517(7532):89-93. doi: 10.1038/nature13801. Epub 2014 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. ; 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France. ; 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Microbiology Training Area, Graduate School of Biomedical Sciences of Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA [2] Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy. ; Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, Turkey. ; Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran. ; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK. ; Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha 410013, China. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA. ; BGI-Shenzhen, Shenzhen 518083, China. ; Sangzhi County People's Hospital, Sangzhi 427100, China. ; Genetics Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, Hubei 430070, China. ; 1] Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China [2] Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. ; Institut Pasteur, Bacteria-Cell Interactions Unit, 75724 Paris, France. ; CNRS UMR5235, Montpellier II University, Place Eugene Bataillon, 34095 Montpellier, France. ; Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada. ; Paris Descartes University, 75006 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France. ; 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [3] Paris Descartes University, Imagine Institute, 75015 Paris, France. ; Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; 1] Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 75006 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Howard Hughes Medical Institute, New York, New York 10065, USA [4] Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France [5]. ; 1] Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25307056" target="_blank"〉PubMed〈/a〉

Description: The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes. Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338534/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338534/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grallert, Agnes -- Boke, Elvan -- Hagting, Anja -- Hodgson, Ben -- Connolly, Yvonne -- Griffiths, John R -- Smith, Duncan L -- Pines, Jonathon -- Hagan, Iain M -- 092096/Wellcome Trust/United Kingdom -- A13678/Cancer Research UK/United Kingdom -- A16406/Cancer Research UK/United Kingdom -- C147/A16406/Cancer Research UK/United Kingdom -- C29/A13678/Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jan 1;517(7532):94-8. doi: 10.1038/nature14019. Epub 2014 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; The Gurdon Institute, Tennis Court Road, University of Cambridge, Cambridge, CB2 1QN, UK. ; Biological Mass Spectrometry, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487150" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358788/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358788/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dinman, Jonathan D -- R01 HL119439/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jan 1;517(7532):24-5. doi: 10.1038/nature14069. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409148" target="_blank"〉PubMed〈/a〉