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Axons are the long and slender processes of neurons constituting the biological cables that wire the nervous system. The growth and maintenance of axons require bundles of microtubules that extend through their entire length. Understanding microtubule regulation is therefore an essential aspect of axon biology. Key regulators of neuronal microtubules are the spectraplakins, a well-conserved family of cytoskeletal cross-linkers that underlie neuropathies in mouse and humans. Spectraplakin deficiency in mouse orDrosophilacauses severe decay of microtubule bundles and axon growth inhibition. The underlying mechanisms are best understood forDrosophilaShort stop (Shot) and believed to involve cytoskeletal cross-linkage: the N-terminal calponin homology (CH) domains bind to F-actin, and the C-terminus to microtubules and Eb1. Here we have gained new understanding by showing that the F-actin interaction must be finely balanced: altering the properties of F-actin networks or deleting/exchanging Shot’s CH domains induces changes in Shot function - with a Lifeact-containing Shot variant causing remarkable remodelling of neuronal microtubules. In addition to actin-MT cross-linkage, we find strong indications that Shot executes redundant MT bundle-promoting roles that are F-actin-independent. We argue that these likely involve the neuronal Shot-PH isoform, which is characterised by a large, unexplored central plakin repeat region (PRR). Work on PRRs might therefore pave the way towards important new mechanisms of axon biology and architecture that might similarly apply to central PRRs in mammalian spectraplakins.

Axons are the slender, up to meter-long projections of neurons that form the biological cables wiring our bodies. Most of these delicate structures must survive for an organism’s lifetime, meaning up to a century in humans. Axon maintenance requires life-sustaining motor protein-driven transport distributing materials and organelles from the distant cell body. It seems logic that impairing this transport causes systemic deprivation linking to axon degeneration. But the key steps underlying these pathological processes are little understood. To investigate mechanisms triggered by motor protein aberrations, we studied more than 40 loss- and gain-of-function conditions of motor proteins, cargo linkers or further genes involved in related processes of cellular physiology. We used one standardised Drosophila primary neuron system and focussed on the organisation of axonal microtubule bundles as an easy to assess readout reflecting axon integrity. We found that bundle disintegration into curled microtubules is caused by the losses of Dynein heavy chain and the Kif1 and Kif5 homologues Unc-104 and Kinesin heavy chain (Khc). Using point mutations of Khc and functional loss of its linker proteins, we studied which of Khc’s sub-functions might link to microtubule curling. One cause was emergence of harmful reactive oxygen species through loss of Milton/Miro-mediated mitochondrial transport. In contrast, loss of the Kinesin light chain linker caused microtubule curling through an entirely different mechanism appearing to involve increased mechanical challenge to microtubule bundles through de-inhibition of Khc. The wider implications of our findings for the understanding of axon maintenance and pathology are discussed.

Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to serve as their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how these factors functionally integrate to regulate axon biology. As an attempt to bridge between molecular mechanisms and their cellular relevance, we explain here the model of local axon homeostasis, based on our own experiments inDrosophilaand published data primarily from vertebrates/mammals as well asC. elegans. The model proposes that (1) the physical forces imposed by motor protein-driven transport and dynamics in the confined axonal space, are a life-sustaining necessity, but pose a strong bias for MT bundles to become disorganised. (2) To counterbalance this risk, MT-binding and -regulating proteins of different classes work together to maintain and protect MT bundles as necessary transport highways. Loss of balance between these two fundamental processes can explain the development of axonopathies, in particular those linking to MT-regulating proteins, motors and transport defects. With this perspective in mind, we hope that more researchers incorporate MTs into their work, thus enhancing our chances of deciphering the complex regulatory networks that underpin axon biology and pathology.

The formation and maintenance of microtubules requires their polymerisation, but little is known about how this polymerisation is regulated in cells. Focussing on the essential microtubule bundles in axons of Drosophila and Xenopus neurons, we show that the plus-end scaffold Eb1, the polymerase XMAP215/Msps and the lattice-binder Tau co-operate interdependently to promote microtubule polymerisation and bundle organisation during axon development and maintenance. Eb1 and XMAP215/Msps promote each other’s localisation at polymerising microtubule plus-ends. Tau outcompetes Eb1-binding along microtubule lattices, thus preventing depletion of Eb1 tip pools. The three factors genetically interact and show shared mutant phenotypes: reductions in axon growth, comet sizes, comet numbers and comet velocities, as well as prominent deterioration of parallel microtubule bundles into disorganised curled conformations. This microtubule curling is caused by Eb1 plus-end depletion which impairs spectraplakin-mediated guidance of extending microtubules into parallel bundles. Our demonstration that Eb1, XMAP215/Msps and Tau co-operate during the regulation of microtubule polymerisation and bundle organisation, offers new conceptual explanations for developmental and degenerative axon pathologies., Author summary Axons are the up-to-meter-long processes of nerve cells that form the cables wiring our nervous system. Once established, they must survive for a century in humans. Improper extension of axons leads to neurodevelopmental defects, and age- or disease-related neurodegeneration usually starts in axons. Axonal architecture and function depend on bundles of filamentous polymers, called microtubules. These bundles run all along the axonal core, and their disruption correlates with axon decay. How these axonal microtubule bundles are formed and dynamically maintained is little understood. We bridge this knowledge gap by studying how different classes of microtubule-binding proteins may regulate these processes. Here we show how three proteins of very different function, Eb1, XMAP215 and Tau, cooperate intricately to promote the polymerisation processes that form new microtubules during axon development and maintenance. If either protein is dysfunctional, polymerisation is slowed down and newly forming microtubules fail to align into proper bundles. These findings provide new explanations for the decay of microtubule bundles, hence axons. To unravel these mechanisms, we used the fruit fly as a powerful organism for biomedical discoveries. We then showed that the same mechanisms act in frog axons, suggesting they might apply also to humans.

The number of acquired or inherited conditions leading to axon degeneration (from now on referred to as axonopathies) is vast. To diagnose patients, clinicians use a range of indicators including physiology, morphology, family and patient history, as well as genetics, with the specific location of the lesion within the nervous system being a prominent feature. For the neurobiologist, these criteria are often unsatisfactory, and key questions remain unanswered. For example, does it make sense that different axonopathies affect distinct neuron groups through distinct mechanisms? Would it not be more likely that there are common routes to axon degeneration? In this opinion piece, I shall pose this fundamental question and try to find answers that are hopefully thought-provoking and trigger some conceptual rethinking in the field. I will conclude by describing the "dependency cycle of axon homeostasis" as a new approach to make sense of the intricate connections of axon biology and physiology, also suggesting that different axonopathies might share common paths to axon degeneration.

Anhand eines von Drudel 11 e. V. entwickelten digitalen Trainings zum Abbau von Gewalt und Hass beleuchtet der Beitrag grundlegende Gestaltungsprinzipien wie Interaktivitat, Multimedialitat und Gamification. Insbesondere geht es dabei um die Frage, welche Rolle dem Beziehungsaspekt bei der padagogischen Arbeit im digitalen Raum zukommt. Neben konzeptionellen Uberlegungen auf der Basis von zentralen Forschungsergebnissen zu Online-Interventionen bundelt der Beitrag Praxiserfahrungen aus einer funfjahrigen Entwicklungs- und Erprobungsphase.

Five decades of ultrastructural studies of axons are reviewed and reinterpreted on the basis of current mechanistic knowledge, revealing microtubule bundles as the essential common architectural element of vertebrate and invertebrate axons., The maintenance of axons for the lifetime of an organism requires an axonal cytoskeleton that is robust but also flexible to adapt to mechanical challenges and to support plastic changes of axon morphology. Furthermore, cytoskeletal organization has to adapt to axons of dramatically different dimensions, and to their compartment-specific requirements in the axon initial segment, in the axon shaft, at synapses or in growth cones. To understand how the cytoskeleton caters to these different demands, this review summarizes five decades of electron microscopic studies. It focuses on the organization of microtubules and neurofilaments in axon shafts in both vertebrate and invertebrate neurons, as well as the axon initial segments of vertebrate motor- and interneurons. Findings from these ultrastructural studies are being interpreted here on the basis of our contemporary molecular understanding. They strongly suggest that axon architecture in animals as diverse as arthropods and vertebrates is dependent on loosely cross-linked bundles of microtubules running all along axons, with only minor roles played by neurofilaments.

Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the Arf activator Efa6 inC. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function ofDrosophilaEfa6 in experimentally and genetically amenable fly neurons. First, we show thatDrosophilaEfa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT elimination domain/MTED) that binds tubulin and inhibits microtubule growthin vitroand cells. If N-terminal MTED-containing fragments are in the cytoplasm they abolish entire microtubule networks of mouse fibroblasts and whole axons of fly neurons. Full-length Efa6 is membrane-attached, hence primarily blocks MTs in the periphery of fibroblasts, and explorative MTs that have left axonal bundles in neurons. Accordingly, loss of Efa6 causes an increase of explorative MTs: in growth cones, they enhance axon growth, in axon shafts, explorative MTs cause excessive branching, as well as atrophy through perturbations of MT bundles. Efa6 over-expression causes the opposite phenotypes. Taken together, our work conceptually links molecular and sub-cellular functions of cortical collapse factors to axon growth regulation and reveals new roles in axon branching and in the prevention of axonal atrophy. Furthermore, the MTED delivers a promising tool that can be used to inhibit MTs in a compartmentalised fashion when fusing it to specifically localising protein domains.Summary statementThe cortical collapse factor Efa6 inhibits microtubule polymerising outside axonal bundles. Thereby it limits axon growth and branching, but preserves microtubule bundle organisation crucial for axon maintenance.

Drosophila genetics is combined with high-resolution microscopy and a number of functional readouts to demonstrate key factors required for the presence of regularly spaced rings of cortical actin in axons. The data suggest important roles for the actin rings in microtubule regulation, most likely by sustaining their polymerization., Axons are cable-like neuronal processes wiring the nervous system. They contain parallel bundles of microtubules as structural backbones, surrounded by regularly spaced actin rings termed the periodic membrane skeleton (PMS). Despite being an evolutionarily conserved, ubiquitous, highly ordered feature of axons, the function of PMS is unknown. Here we studied PMS abundance, organization, and function, combining versatile Drosophila genetics with superresolution microscopy and various functional readouts. Analyses with 11 actin regulators and three actin-targeting drugs suggest that PMS contains short actin filaments that are depolymerization resistant and sensitive to spectrin, adducin, and nucleator deficiency, consistent with microscopy-derived models proposing PMS as specialized cortical actin. Upon actin removal, we observed gaps in microtubule bundles, reduced microtubule polymerization, and reduced axon numbers, suggesting a role of PMS in microtubule organization. These effects become strongly enhanced when carried out in neurons lacking the microtubule-stabilizing protein Short stop (Shot). Combining the aforementioned actin manipulations with Shot deficiency revealed a close correlation between PMS abundance and microtubule regulation, consistent with a model in which PMS-dependent microtubule polymerization contributes to their maintenance in axons. We discuss potential implications of this novel PMS function along axon shafts for axon maintenance and regeneration.

The aim of this special issue on science communication is to inspire and help scientists who are taking part or want to take part in science communication and engage with the wider public, clinicians, other scientists or policy makers. For this, some articles provide concise and accessible advice to individual scientists, science networks, or learned societies on how to communicate effectively; others share rationales, objectives and aims, experiences, implementation strategies and resources derived from existing long-term science communication initiatives. Although this issue is primarily addressing scientists working in the field of biomedical research, much of it similarly applies to scientists from other disciplines. Furthermore, we hope that this issue will also be used as a helpful resource by academic science communicators and social scientists, as a collection that highlights some of the major communication challenges that the biomedical sciences face, and which provides interesting case studies of initiatives that use a breadth of strategies to address these challenges. In this editorial, we first discuss why we should communicate our science and contemplate some of the different approaches, aspirations and definitions of science communication. We then address the specific challenges that researchers in the biomedical sciences are faced with when engaging with wider audiences. Finally, we explain the rationales and contents of the different articles in this issue and the various science communication initiatives and strategies discussed in each of them, whilst also providing some information on the wide range of further science communication activities in the biomedical sciences that could not all be covered here.

Spectraplakins are evolutionarily well conserved cytoskeletal linker molecules that are true members of three protein families: plakins, spectrins and Gas2-like proteins. Spectraplakin genes encode at least 7 characteristic functional domains which are combined in a modular fashion into multiple isoforms, and which are responsible for an enormous breadth of cellular functions. These functions are related to the regulation of actin, microtubules, intermediate filaments, intracellular organelles, cell adhesions and signalling processes during the development and maintenance of a wide variety of tissues. To gain a deeper understanding of this enormous functional diversity, invertebrate genetic model organisms, such as the fruit fly Drosophila, can be used to develop concepts and mechanistic paradigms that can inform the investigation in higher animals or humans. Here we provide a comprehensive overview of our current knowledge of the Drosophila spectraplakin Short stop (Shot). We describe its functional domains and isoforms and compare them with those of the mammalian spectraplakins dystonin and MACF1. We then summarise its roles during the development and maintenance of the nervous system, epithelia, oocytes and muscles, taking care to compare and contrast mechanistic insights across these functions in the fly, but especially also with related functions of dystonin and MACF1 in mostly mammalian contexts. We hope that this review will improve the wider appreciation of how work on Drosophila Shot can be used as an efficient strategy to promote the fundamental concepts and mechanisms that underpin spectraplakin functions, with important implications for biomedical research into human disease.

In our research of biological systems at the sub-cellular scale we focus on the cytoskeleton, particularly its components actin-filaments and microtubules, which are key mediators of axon growth and maintenance. Knowing how filaments and microtubules are regulated enhances our understanding of neural development, ageing, degeneration and regeneration. In the cytoskeletal machinery, finger-like, extremely narrow and long, membrane protrusions called filopodia act as sensors, facilitating proper cellular navigation and directed growth. Since explanations of dynamical and mechanical aspects of filopodia, centred in diffusion and transport processes, are being studied, we investigate the displacement of actins in the filopodia and discuss compensatory G-actin drift and diffusion towards the filopodia tip to supply the polymerisation of actins into filaments moving backwards. We conclude, through some simple calculations, that diffusion alone cannot provide the necessary actins to the polymerisation processes in all situations. Therefore, advection processes and Stokes equation need to be added to diffusion models to better simulate the colloidal fluid dynamics in filopodia cell-membrane protrusions.

Spectraplakins are evolutionarily well conserved cytoskeletal linker molecules that are true members of three protein families: plakins, spectrins and Gas2-like proteins. Spectraplakin genes encode at least 7 characteristic functional domains which are combined in a modular fashion into multiple isoforms, and which are responsible for an enormous breadth of cellular functions. These functions are related to the regulation of actin, microtubules, intermediate filaments, intracellular organelles, cell adhesions and signalling processes during the development and maintenance of a wide variety of tissues. To gain a deeper understanding of this enormous functional diversity, invertebrate genetic model organisms, such as the fruit flyDrosophila, can be used to develop concepts and mechanistic paradigms that can inform the investigation in higher animals or humans. Here we provide a comprehensive overview of our current knowledge of theDrosophilaspectraplakin Short stop (Shot). We describe its functional domains and isoforms and compare them with those of the mammalian spectraplakins dystonin and MACF1. We then summarise its roles during the development and maintenance of the nervous system, epithelia, oocytes and muscles, taking care to compare and contrast mechanistic insights across these functions in the fly, but especially also with related functions of dystonin and MACF1 in mostly mammalian contexts. We hope that this review will improve the wider appreciation of how work onDrosophilaShot can be used as an efficient strategy to promote the fundamental concepts and mechanisms that underpin spectraplakin functions, with important implications for biomedical research into human disease.

Science communication is becoming an increasingly important part of a scientist's remit, and engaging with primary and secondary schools is one frequently chosen strategy. Here we argue that science communication in schools will be more effective if based on good understanding of the realities of school life, which can be achieved through structured participation and/or collaboration with teachers. For example, the Manchester Fly Facility advocates the use of the fruit fly Drosophila as an important research strategy for the discovery processes in the biomedical sciences. To communicate this concept also in schools, we developed the 'droso4schools' project as a refined form of scientist-teacher collaboration that embraces the expertise and interests of teachers. Within this project, we place university students as teaching assistants in university partner schools to collaborate with teachers and develop biology lessons with adjunct support materials. These lessons teach curriculum-relevant biology topics by making use of the profound conceptual understanding existing in Drosophila combined with parallel examples taken from human biology. By performing easy to implement experiments with flies, we bring living organisms into these lessons, thus endeavouring to further enhance the pupil's learning experience. In this way, we do not talk about flies but rather work with flies as powerful teaching tools to convey mainstream curriculum biology content, whilst also bringing across the relevance of Drosophila research. Through making these lessons freely available online, they have the potential to reach out to teachers and scientists worldwide. In this paper, we share our experiences and strategies to provide ideas for scientists engaging with schools, including the application of the droso4schools project as a paradigm for long-term school engagement which can be adapted also to other areas of science.

Science communication is increasingly important for scientists, although research, teaching and administration activities tend to eat up our time already, and budgets for science communication are usually low. It appears impossible to combine all these tasks and, in addition, to develop engagement activities to a quality and impact that would make the efforts worth their while. Here we argue that these challenges are easier addressed when centering science communication initiatives on a long-term vision with a view to eventually forming outreach networks where the load can be shared whilst being driven to higher momentum. As one example, we explain the science communication initiative of the Manchester Fly Facility. It aims to promote public awareness of research using the model organism Drosophila, which is a timely, economic and most efficient experimental strategy to drive discovery processes in the biomedical sciences and must have a firm place in the portfolios of funding organisations. Although this initiative by the Manchester Fly Facility is sustained on a low budget, its long-term vision has allowed gradual development into a multifaceted initiative: (1) targeting university students via resources and strategies for the advanced training in fly genetics; (2) targeting the general public via science fairs, educational YouTube videos, school visits, teacher seminars and the droso4schools project; (3) disseminating and marketing strategies and resources to the public as well as fellow scientists via dedicated websites, blogs, journal articles, conference presentations and workshops - with a view to gradually forming networks of drosophilists that will have a greater potential to drive the science communication objective to momentum and impact. Here we explain the rationales and implementation strategies for our various science communication activities - which are similarly applicable to other model animals and other areas of academic science - and share our experiences and resources to provide ideas and readily available means to those who are actively engaging or intend to do so.

The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer’s disease., This work was made possible through funding by the BBSRC (BB/M007456/1) to NSS, by the BBSRC (BB/I002448/1) and Wellcome Trust ISSF (105610/Z/14/Z) to AP, and the German Science Foundation (DFG; VO 2071/1-1) to AV. The Bioimaging Facility microscopes used in this study were purchased with grants from the BBSRC, The Wellcome Trust and the University of Manchester Strategic Fund, and the Manchester Fly Facility where flies were kept and genetic crosses performed has been supported by funds from The University of Manchester and the Wellcome Trust (087742/Z/08/Z).

Extracellular matrix (ECM) and matrix receptors are intimately involved in most biological processes. The ECM plays fundamental developmental and physiological roles in health and disease, including processes underlying the development, maintenance, and regeneration of the nervous system. To understand the principles of ECM-mediated functions in the nervous system, genetic model organisms like Drosophila provide simple, malleable, and powerful experimental platforms. This article provides an overview of ECM proteins and receptors in Drosophila. It then focuses on their roles during three progressive phases of neural development: (1) neural progenitor proliferation, (2) axonal growth and pathfinding, and (3) synapse formation and function. Each section highlights known ECM and ECM-receptor components and recent studies done in mutant conditions to reveal their in vivo functions, all illustrating the enormous opportunities provided when merging work on the nervous system with systematic research into ECM-related gene functions.

The cytoskeleton is a dynamic network of filamentous protein polymers required for virtually all cellular processes. It consists of three major classes, filamentous actin (F-actin), intermediate filaments, and microtubules, all displaying characteristic structural properties, functions, cellular distributions, and sets of interacting regulatory proteins. One unique class of proteins, the spectraplakins, bind, regulate, and integrate the functions of all three classes of cytoskeleton proteins. Spectraplakins are giant, evolutionary conserved multidomain proteins (spanning up to 9000 aa) that are true members of the plakin, spectrin, and Gas2-like protein families. They have OMIM-listed disease links to epidermolysis bullosa and hereditary sensory and autonomic neuropathy. Their role in disease is likely underrepresented since studies in model animal systems have revealed critical roles in polarity, morphogenesis, differentiation and maintenance, migration, signaling, and intracellular trafficking in a variety of tissues. This enormous diversity of spectraplakin function is consistent with the numerous isoforms produced from single genomic loci that combine different sets of functional domains in distinct cellular contexts. To study the broad range of functions and complexity of these proteins, Drosophila is a powerful model. Thus, the fly spectraplakin Short stop (Shot) acts as an actin-microtubule linker and plays important roles in many developmental processes, which provide experimentally amenable and relevant contexts in which to study spectraplakin functions. For these studies, a versatile range of relevant experimental resources that facilitate genetics and transgenic approaches, highly refined genomics tools, and an impressive set of spectraplakin-specific genetic and molecular tools are readily available. Here, we use the example of Shot to illustrate how the various tools and strategies available for Drosophila can be employed to decipher and dissect cellular roles and molecular mechanisms of spectraplakins.

An dieser Stelle sollte normalerweise ein methodologischer Rahmen dargestellt werden, mit dessen Hilfe das zu untersuchende Phanomen erklart werden konnte. Wie nahert man sich aber einem Phanomen wie es die amokartige Gewalt darstellt? Wahrend anderswo von Postempirismus die Rede ist (vgl. Whitebook 2006, S. 1021), scheint in der Kriminologie, wie bereits Fritz Sack (2003, S. 76) konstatierte, das empiristische Paradigma ungebrochen attraktiv. Muss aber eine strikte Methodik nicht zwangslaufig das Wesentliche verfehlen, indem sie den Schrecken in das Prokrustesbett des immer schon Bekannten einsperrt? Solche Versuche hat es gegeben; Mobbing, Computerspiele, psychische Storungen, die Verfugbarkeit von Waffen waren die schnell herbeizitierten Kandidaten einer Kausalerklarung.

In der vornehmlich amerikanisch gepragten Kriminologie lasst sich die erziehungsgenerierte Spaltung von Denken und Verhalten (unter Ausblendung des Erlebens), also die vor allem kognitivistische, aber auch behavioristische Matrix ebenfalls erkennen, zumal wo es um die Frage der Devianzmotivation geht. Solche gelaufigen Konzepte beschreibt etwa Robert Agnew, der sich auf Kriminalitatsphanomene insgesamt bezieht. Nach Agnew ist die Kriminologie von kognitivistischen Motivationstheorien beherrscht, die auf die moralische oder rationale Bewertung von kriminalisierten Handlungen (soziale Lerntheorien) sowie Handlungsfreiheit (Kontrolltheorien) abstellen (und damit der Management-Logik entgegenkommen) (Agnew 1995, S. 376 ff.).

Voranstehend habe ich mich dafur ausgesprochen, die Frage der Selbstkontrolle und der Gewalt weder in den Konnex burgerlicher Erziehungspraktiken noch in den desubjektivierender Hirnmythen zu stellen, sondern in den des Subjekts, des Ichs. Sozialforschung im Sinne der Sozial-Behavioral Sciences versteht sich als »angewandte Wissenschaft«, das heist, als Problemloseverfahren. Gesucht werden also technische Routinen zur Bewaltigung sozialer Probleme.

Wie gezeigt, ist es nicht so einfach, eine Art typologische Klammer der exzessiven Gewaltausbruche zu finden. Auffallig ist indessen die Wucht, die diese Taten entfalten, nachdem ihnen eine mehr oder weniger lange Zeit der Klausur, der Vorbereitung vorausgegangen war. Letzteres unterscheidet sie von spontanen Gewalttaten und es stellt sich die Frage, was es mit dieser Vorbereitungszeit auf sich hat.

Sehr fruhe Traumen gerieten erst spat in den Fokus der Psychoanalyse, die sich bekanntlich zunachst mit dem sexuellen Trauma spaterer Zeit befasste. Gerade die Sexualitat ist bei den Amoklaufern, soweit es daruber Zeugnisse gibt, der neuralgische Punkt. Auf diesbezugliche Selbstaussagen von Amoklaufern bin ich in der Einleitung eingegangen.

Im Anschluss an das Vorstehende stellt sich nun die Frage, inwiefern die Aversion der christlich gepragten burgerlichen Kultur gegen insbesondere weibliche Sexualitat mit dieser Desintegration des Trieblebens in Verbindung zu bringen ist. Bohme und Bohme in ihrer Auseinandersetzung mit Kant erklaren in diesem Sinne die hysterische Frau zur kulturellen Gefahr des burgerlichen Mannes. Denn der unkontrollierbare Leib dieser Frauen verkorpere genau das, »was die vernunftigen, moralisch und leiblich zusammengenommenen Manner des Burgertums furchten: die Einbildungskraft und die Sympathie, die betroffen machen«.

The cytoskeleton is a dynamic network of filamentous protein polymers required for virtually all cellular processes. It consists of three major classes, filamentous actin (F-actin), intermediate filaments and microtubules, all displaying characteristic structural properties, functions, cellular distributions and sets of interacting regulatory proteins. One unique class of proteins, the spectraplakins, bind, regulate, and integrate the functions of all three classes of cytoskeleton proteins. Spectraplakins are giant, evolutionary conserved multidomain proteins (spanning up to 9000 aa) that are true members of the plakin, spectrin and Gas2-like protein families. They have OMIM-listed disease links to epidermolysis bullosa and hereditary sensory and autonomic neuropathy (HSAN). Their role in disease is likely underrepresented since studies in model animal systems have revealed critical roles in polarity, morphogenesis, differentiation and maintenance, migration, signalling and intracellular trafficking in a variety of tissues. This enormous diversity of spectraplakin function is consistent with the numerous isoforms produced from single genomic loci that combine different sets of functional domains in distinct cellular contexts. To study the broad range of functions and complexity of these proteins, Drosophila is a powerful model. Thus, the fly spectraplakin Short stop (Shot) acts as an actin-microtubule linker and plays important roles in many developmental processes, which provide experimentally amenable and relevant contexts in which to study spectraplakin functions. For these studies, a versatile range of relevant experimental resources that facilitate genetics and transgenic approaches, highly refined genomics tools, and an impressive set of spectraplakin-specific genetic and molecular tools is readily available. Here we use the example of Shot to illustrate how the various tools and strategies available for Drosophila can be employed to decipher and dissect cellular roles and molecular mechanisms of spectraplakins.

Actin and microtubules are components of the cytoskeleton, and are key mediators of neuron growth and maintenance. Knowing how they are regulated enhances our understanding of neural development, ageing, degeneration, and regeneration. However, biological investigation alone will not unravel the complex cytoskeletal machinery. We expect that inquiries about the cytoskeleton can be significantly enhanced if their physico-chemical behavior is concealed and summarized in mathematical and computational models that can be coupled to concepts of biological regulation. Our computational modeling concerns the mechanical aspects associated with the dynamics of relatively simple, finger-like membrane protrusions called filopodia. Here we propose an alternative approach for representing the displacement of molecules and cytoplasmic fluid in the extremely narrow and long filopodia and discuss strategies to couple the particle-in-cell method with algorithms for laminar flow to model the two phases of actin dynamics: polymerization into filaments which are pulled back into the cell and compensatory G-actin drift towards its tip to supply polymerization. We use nerve cells of the fruit fly Drosophila as an effective, genetically amenable biological system to generate experimental data as the basis for the abstract models and their validation.

Da der (methodische) Empirismus auf der Subjekt-Objekt-Spaltung beruht, sie voraussetzt, sind ihm wie bereits vermerkt die Probleme, die mit der Konstitution von Subjekt und Objekt verbunden sind, notwendig verschlossen. Daher kann er nur einen quantitativen Unterschied zwischen Aggression und Gewalt ausmachen, wahrend ein verstehender Zugang den Schluss auf einen qualitativen zulasst, namlich im Hinblick auf die Differenzierung von Subjekt und Objekt – und das heist, der Transformation des primaren Narzissmus – in der individuellen Entwicklung.

Science outreach has become increasingly important for researchers and needs to be of ever improving quality, although the time available aside our science, teaching and administration activities is steadily decreasing. To square this circle, effective strategies are required. Here we argue that this can be achieved by setting simple but ambitious overarching objectives for comprehensive outreach initiatives which target multiple audiences, supported by cumulative build-up of shared high-quality resources, as well as the exchange and collaboration amongst scientists with a common outreach aim. To exemplify this strategy, we explain the low-budget, yet high-quality outreach initiative of the Manchester Fly Facility which aims to promote public awareness of the importance of the model organism Drosophila for biomedical research. (1) This initiative targets the general public at science fairs, through public videos, or through extracurricular activities in schools as well as the development of curriculum-relevant sample lessons for teachers - all supported by a dedicated website. (2) The initiative targets university students: by adapting the public outreach resources for their teaching, and through newly developed advanced training strategies that amalgamate the outreach objectives. (3) It targets fellow scientists through blogs, conference presentations and a second website that provides a one-stop-shop for resources, arguments and strategies. As will be explained, this multi-pronged approach is time-saving in the long run and it is powerful because it reaches a wide range of audiences, helps to gain momentum, to build resource, and to gradually improve quality through cross-fertilisation between different activities, and through exchange within the science community. This helps to build communities, and high-quality outreach will have further important added value: arguments that impress the public, tend to be most effective also with reviewers and grant panel members, and often help to readjust aspects of your own scientific work.

Usually, CLIPs promote microtubule growth by binding their plus ends. However, in neurons, mouse CLIP-170 and fly CLIP-190 are weak end binders, instead forming actin/myosin VI–dependent patches in the center of growth cones. Total CLIP-190 loss, even together with four other plus end binders, reveals no role in neuronal MT regulation., Axons act like cables, electrically wiring the nervous system. Polar bundles of microtubules (MTs) form their backbones and drive their growth. Plus end–tracking proteins (+TIPs) regulate MT growth dynamics and directionality at their plus ends. However, current knowledge about +TIP functions, mostly derived from work in vitro and in nonneuronal cells, may not necessarily apply to the very different context of axonal MTs. For example, the CLIP family of +TIPs are known MT polymerization promoters in nonneuronal cells. However, we show here that neither Drosophila CLIP-190 nor mammalian CLIP-170 is a prominent MT plus end tracker in neurons, which we propose is due to low plus end affinity of the CAP-Gly domain–containing N-terminus and intramolecular inhibition through the C-terminus. Instead, both CLIP-190 and CLIP-170 form F-actin–dependent patches in growth cones, mediated by binding of the coiled-coil domain to myosin-VI. Because our loss-of-function analyses in vivo and in culture failed to reveal axonal roles for CLIP-190, even in double-mutant combinations with four other +TIPs, we propose that CLIP-190 and -170 are not essential axon extension regulators. Our findings demonstrate that +TIP functions known from nonneuronal cells do not necessarily apply to the regulation of the very distinct MT networks in axons.

The advent of “omic” technologies has revolutionized genetics and created a demand to focus classical genetics on its present-day applications (Redfield, 2012, PLoS Biol 10: e1001356). This demand can be met by training students in Drosophila mating scheme design, which is an important problem-solving skill routinely applied in many modern research laboratories. It promotes a thorough understanding and application of classical genetics rules and introduces to transgenic technologies and the use of model organisms. As we show here, such training can be implemented as a flexible and concise module (~1-day home study, ~8-hour course time) on university courses by using our previously published training package designed for fly researchers (Roote and Prokop, 2013, G3 (Bethesda) 3: 353−358). However, assessing this training to make it an accredited course element is difficult, especially in large courses. Here, we present a powerful assessment strategy based on a novel hybrid concept in which students solve crossing tasks initially on paper and then answer automatically marked questions on the computer (1.5 hours total). This procedure can be used to examine student performance on more complex tasks than conventional e-assessments and is more versatile, time-saving, and fairer than standard paper-based assignments. Our evaluation shows that the hybrid assessment is effective and reliably detects varying degrees of understanding among students. It also may be applicable in other disciplines requiring complex problem solving, such as mathematics, chemistry, physics, or informatics. Here, we describe our strategies in detail and provide all resources needed for their implementation.

Adhesion between epithelial cells and extracellular substrates is normally mediated through basal adhesion complexes. However, some cells also possess comparable junctions on their apical surface. Here, we describe two new Drosophila proteins, Piopio and Papillote, that are required for the link between the apical epithelial surface and the overlying apical extracellular matrix (aECM). The two proteins share a zona pellucida (ZP) domain with mammalian aECM components, including the tectorins found in the vertebrate inner ear. Tagged versions of both proteins localized to the apical epithelial surface. Mutations in piopio, papillote and dumpy (another gene encoding a ZP-domain protein) cause defects in the innermost layer of the aECM and its detachment from the epidermis. Loss of Piopio, but not Papillote or Dumpy, causes the absence of specialized microtubule bundles from pupal wings, suggesting that Piopio plays a role in microtubule organization. Thus, ZP domain-containing proteins may have shared functions within the aECM, while also exhibiting specific interactions with the cytoskeleton.

The phenomenon of pioneer neurons has been known for almost a century, but so far we have little insights into mechanisms and molecules involved. Here, we study the formation of theDrosophilaintersegmental motor nerve (ISN). We show that aCC/RP2 and U motor neurons grow together at the leading front of the ISN. Nevertheless, aCC/RP2 neurons are the pioneers, and U neurons are the followers, because only aCC/RP2 neurons effectively influence growth of the ISN. We also show that this influence depends on the neural cell adhesion molecule homolog FasciclinII. First, ablation of aCC/RP2 has a stronger impact on ISN growth than U ablation. Second, strong growth-influencing capabilities of aCC/RP2 are revealed with a stalling approach we used: when aCC/RP2 motor axons are stalled specifically, the entire ISN (including the U neurons) coarrests, demonstrating that aCC/RP2 neurons influence the behavior of U growth cones. In contrast, stalled U neurons do not have the same influence on other ISN motor neurons. The influence on ISN growth requires FasciclinII: targeted expression of FasciclinII in U neurons increases their influence on the ISN, whereas a FasciclinII loss-of-function background reduces ISN coarrest with stalled aCC/RP2 axons. The qualitative differences of both neuron groups are confirmed through our findings that aCC/RP2 growth cones are wider and more complex than those of U neurons. However, U growth cones adopt aCC/RP2-like wider shapes in a FasciclinII loss-of-function background. Therefore, FasciclinII is to a degree required and sufficient for pioneer-follower interactions, but its mode of action cannot be explained merely through an equally bidirectional adhesive interaction.

Neuronal plasticity relies on tightly regulated control of protein levels at synapses. One mechanism to control protein abundance is the ubiquitin-proteasome degradation system. Recent studies have implicated ubiquitin-mediated protein degradation in synaptic development, function, and plasticity, but little is known about the regulatory mechanisms controlling ubiquitylation in neurons. In contrast, ubiquitylation has long been studied as a central regulator of the eukaryotic cell cycle. A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase. Although the APC/C has been detected in several differentiated cell types, a functional role for the complex in postmitotic cells has been elusive. We describe a novel postmitotic role for the APC/C at Drosophila neuromuscular synapses: independent regulation of synaptic growth and synaptic transmission. In neurons, the APC/C controls synaptic size via a downstream effector Liprin-α; in muscles, the APC/C regulates synaptic transmission, controlling the concentration of a postsynaptic glutamate receptor.