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Type III Secretion Systems (T3SS) deliver subunits from the bacterial cytosol to nascent cell surface flagella. Early flagellar subunits that form the rod and hook substructures are unchaperoned and contain their own export signals. A gate recognition motif (GRM) docks them at the FlhBc component of the FlhAB-FliPQR export gate, but the gate must then be opened and subunits must be unfolded to pass through the flagellar channel. This induced us to seek further signals on the subunits. Here, we identify a second signal at the extreme N-terminus of flagellar rod and hook subunits and determine that key to the signal is its hydrophobicity. We show that the two export signal elements are recognised separately and sequentially, as the N-terminal signal is recognised by the flagellar export machinery only after subunits have docked at FlhBC via the GRM. The position of the N-terminal hydrophobic signal in the subunit sequence relative to the GRM appeared to be important, as a FlgD deletion variant (FlgDshort), in which the distance between the N-terminal signal and the GRM was shortened, 'stalled' at the export machinery and was not exported. The attenuation of motility caused by FlgDshort was suppressed by mutations that destabilised the closed conformation of the FlhAB-FliPQR export gate, suggesting that the hydrophobic N-terminal signal might trigger opening of the flagellar export gate., University of Cambridge John Lucas Walker studentship

Neurodegeneration is a feature of many debilitating, incurable diseases that are rapidly rising in prevalence, such as Parkinson's disease. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases. Models – from cell-based systems, to unicellular organisms, to complex animals – have proven to be a useful tool to help the research community shed light on the mechanisms underlying neurodegenerative diseases, and these advances have now begun to provide promising therapeutic avenues. In this themed issue of Disease Models & Mechanisms, a special collection of articles focused on neurodegenerative diseases is introduced. The collection includes original research articles that provide new insights into the complex pathophysiology of such diseases, revealing candidate biomarkers or therapeutic targets. Some of the articles describe a new disease model that enables deeper exploration of key mechanisms. We also present a series of reviews that highlight some of the recent translational advances made in studies of neurodegenerative diseases. In this Editorial, we summarize the articles featured in this collection, emphasizing the impact that model-based studies have made in this exciting area of research., Summary: This Editorial introduces a new Special Collection, ‘Neurodegeneration: from models to mechanisms to therapies’, providing a summary of the research and review articles published in this launch issue, as well as highlighting some of DMM's most-read neurodegeneration-related articles from recent issues.

Gerald (Gerry) Rubin, pioneer in Drosophila genetics, is Founding Director of the HHMI-funded Janelia Research Campus. In this interview, Gerry recounts key events and collaborations that have shaped his unique approach to scientific exploration, decision-making, management and mentorship – an approach that forms the cornerstone of the model adopted at Janelia to tackle problems in interdisciplinary biomedical research. Gerry describes his remarkable journey from newcomer to internationally renowned leader in the fly field, highlighting his contributions to the tools and resources that have helped establish Drosophila as an important model in translational research. Describing himself as a ‘tool builder’, his current focus is on developing approaches for in-depth study of the fly nervous system, in order to understand key principles in neurobiology. Gerry was interviewed by Ross Cagan, Senior Editor of Disease Models & Mechanisms., Drosophila Collection: Ross Cagan spoke to Gerry Rubin about his career path and the story behind some of his key breakthroughs, as well as his unique and successful approach to management and mentorship.

Drosophila melanogaster has been adopted as one of the most-used model systems since it was first introduced by Thomas Morgan for the study of heredity in the early 20th century. Its experimental tractability and similarity of its biological pathways to those of humans have placed the model at the forefront of research into human development and disease. With the ongoing accumulation of genetic tools and assays, the fly community has at its fingertips the resources to generate diverse Drosophila disease models for the study of genes and pathways involved in a wide range of disorders. In recent years, the fly has also been used successfully for drug screening. In this Editorial, we introduce a Special Collection of reviews, interviews and original research articles that highlight some of the many ways that Drosophila has made, and continues to make, an impact on basic biological insights and translational science., Drosophila Collection: This Editorial introduces a new Special Collection, ‘Spotlight on Drosophila: Translational Impact’, providing a summary of its contents so far and highlighting the impact of Drosophila as a model for human diseases.

Experiments that use the mouse as a model for disease have recently come under scrutiny because of the repeated failure of data, particularly derived from preclinical studies, to be replicated or translated to humans. The usefulness of mouse models has been questioned because of irreproducibility and poor recapitulation of human conditions. Newer studies, however, point to bias in reporting results and improper data analysis as key factors that limit reproducibility and validity of preclinical mouse research. Inaccurate and incomplete descriptions of experimental conditions also contribute. Here, we provide guidance on best practice in mouse experimentation, focusing on appropriate selection and validation of the model, sources of variation and their influence on phenotypic outcomes, minimum requirements for control sets, and the importance of rigorous statistics. Our goal is to raise the standards in mouse disease modeling to enhance reproducibility, reliability and clinical translation of findings., Summary: Raising standards for carrying out and reporting mouse model studies will improve reproducibility and relevance to human disease research.

Owen Sansom, Deputy Director of the Cancer Research UK Beatson Institute, began his research career investigating the molecular mechanisms of apoptosis. Over the course of his work he has moved progressively into a more translational arena, and the current focus of his lab is to understand the signalling pathways underlying colorectal and pancreatic cancers. The Sansom lab uses mouse models to pinpoint how mutations that commonly occur in these frequently deadly cancers co-operate to promote tumorigenesis in vivo. This work has provided many important insights into the molecular changes associated with intestinal and pancreatic neoplasia and has revealed new targets for drug development. Here, Owen tells the stories behind some of his most exciting breakthroughs, describes the experiences and mentors that shaped his research interests and style of running a lab, and discusses the challenges of recapitulating the complexity of cancer as well as translating preclinical evidence to patient therapies.

The Bohmann lab, based at the University of Rochester Medical Center in New York, uses Drosophila to explore the cross-talk between stress and metabolic regulation, with the goal of understanding how the signaling pathways involved can drive aging, cancer and other degenerative pathologies. In this interview, Dirk Bohmann describes his motives for moving into the fly field, explains how the study of aging can give important insights into complex disease mechanisms, and advocates using a systems-biology approach to advance drug discovery.

Future prospects continue to be strong for research using the rat as a model organism. New technology has enabled the proliferation of many new transgenic and knockout rat strains, the genomes of more than 40 rat strains have been sequenced, publications using the rat as a model continue to be produced at a steady rate, and discoveries of disease-associated genes and mechanisms from rat experiments abound, frequently with conservation of function between rats and humans. However, advances in genome technology have led to increasing insights into human disease directly from human genetic studies, pulling more and more researchers into the human genetics arena and placing funding for model organisms and their databases under threat. This, therefore, is a pivotal time for rat-based biomedical research – a timely moment to review progress and prospects – providing the inspiration for a new Special Collection focused on the impact of the model on translational science, launched in this issue of Disease Models & Mechanisms. What disease areas are most appropriate for research using rats? Why should the rat be favoured over other model organisms, and should the present levels of funding be continued? Which approaches should we expect to yield biologically and medically useful insights in the coming years? These are key issues that are addressed in the original Research Articles and reviews published in this Special Collection, and in this introductory Editorial. These exemplar articles serve as a landmark for the present status quo after a decade of major advances using the rat model and could help to guide the direction of rat research in the coming decade., Summary: This Editorial introduces a new Special Collection, ‘Spotlight on Rat: Translational Impact’, providing a summary of the articles published in this launch issue and a flavour of what's to come, as well as highlighting the impact rat models have made and continue to make on understanding human disease.

In recent years, the zebrafish has emerged as an increasingly prominent model in biomedical research. To showcase the translational impact of the model across multiple disease areas, Disease Models & Mechanisms has compiled a Special Issue that includes thought-provoking reviews, original research reporting new and important insights into disease mechanisms, and novel resources that expand the zebrafish toolkit. This Editorial provides a summary of the issue’s contents, highlighting the diversity of zebrafish disease models and their clinical applications. Special Issue: Spotlight on Zebrafish One aim of a Disease Models & Mechanisms (DMM) ‘Special Issue’ is to highlight how emerging disease models can lead to exceptional growth in particular areas of translational research. This is especially true for this issue, Spotlight on Zebrafish: Translational Impact. The zebrafish has traditionally been used to study developmental biology. Its optical transparency for the first few weeks, high fecundity and ex vivo fertilization have meant that the fundamental processes and mechanisms of vertebrate embryo development from a single cell through to a swimming fish can be studied in exquisite detail. Over the past decade these same features have enabled the zebrafish to become a preeminent disease model and tool for studying disease mechanisms. Importantly, discoveries EDITORIAL