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Key Points Many aspects of neuronal function are regulated by changes in the concentration of intracellular free Ca 2+ . To fully understand how this occurs, an appreciation is needed of how changes in the concentration of a simple ion can modify neuronal function in various ways, and how the same ion can produce distinct outcomes in the same type of neuron. The diversity of events controlled by Ca 2+ are partly a consequence of distinct types of Ca 2+ signal that differ spatially, temporally and in magnitude. The differing outcomes are due to the actions of various Ca 2+ sensor proteins that transduce the Ca 2+ signals into specific changes in cellular function. A number of Ca 2+ -binding proteins related to calmodulin are enriched in or expressed only in the nervous system, where they have distinct roles in the regulation of neuronal function. These include the neuronal calcium sensor (NCS) protein family, members of which have been implicated in a wide range of Ca 2+ signalling events. During evolution there has been a progressive increase in the size of the NCS family. Mammals have a highly conserved set of 14 NCS genes that encode NCS-1, three visinin-like proteins (VILIPs), hippocalcin, neurocalcin-δ, recoverin, three guanylyl cyclase-activating proteins (GCAPs) and four voltage-gated potassium (Kv) channel-interacting proteins (KchIPs). There are also several alternatively spliced versions of the KChIPs. NCS proteins are in a Ca 2+ -free state under resting conditions and all have a high affinity for Ca 2+ , which allows them to bind Ca 2+ following small increases in concentration above resting levels. Some NCS proteins are cytosolic at resting Ca 2+ and reversibly associate with membranes, but others such as NCS-1 and GCAPs are always associated with membranes. Members of the NCS family have distinct target proteins that they regulate. Many of these do not overlap with calmodulin and so contribute to the specificity of the NCS protein function. The NCS proteins regulate many cellular events in neurons and in retinal photoreceptors. Evidence for these functions originally came from biochemical analyses and studies of the effects of overexpressing the proteins, but in recent years many of these proposed functions have been confirmed in genetic studies. Changes in expression levels of certain NCS proteins in disease states, and initial analyses of single nucleotide polymorphisms in the Ncs-1 gene, have indicated possible links to neurological disorders. NCS-1 is most probably derived from the primordial NCS precursor; it is expressed from yeast to man and has multiple functions due to its ability to interact with and regulate many target proteins. By contrast, some NCS proteins have specific, single functions; recoverin inhibits rhodopsin kinase and the GCAPs regulate guanylyl cyclases in the retina. The KChIPs are a large subfamily with distinct properties, subcellular localization and cell type expression patterns. They are required for the normal traffic and gating properties of Kv4 channels, are involved in the repression of specific gene transcription and interact with presenilin. Genetic studies have demonstrated that individual NCS proteins have essential functions that cannot be compensated for by other Ca 2+ sensors. Differences in Ca 2+ affinity, localization, different cellular dynamics, differential cellular expression and distinct target proteins are factors in the specialization of NCS protein function. Ca 2+ signals in neurons need to be finely tuned in order to trigger the appropriate response. This review discusses the different characteristics and functions of the neuronal calcium sensor protein family members as key components of neuronal Ca 2+ signalling pathways. In neurons, intracellular calcium signals have crucial roles in activating neurotransmitter release and in triggering alterations in neuronal function. Calmodulin has been widely studied as a Ca 2+ sensor that has several defined roles in neuronal Ca 2+ signalling, but members of the neuronal calcium sensor protein family have also begun to emerge as key components in a number of regulatory pathways and have increased the diversity of neuronal Ca 2+ signalling pathways. The differing properties of these proteins allow them to have discrete, non-redundant functions.

Macroautophagy (autophagy) is a crucial cellular stress response for degrading defective macromolecules and organelles, as well as providing bioenergetic intermediates during hypoxia and nutrient deprivation. Here we report a thiol-dependent process that may account for impaired autophagy during aging. This is through direct oxidation of key autophagy-related (Atg) proteins Atg3 and Atg7. When inactive Atg3 and Atg7 are protected from oxidation due to stable covalent interaction with their substrate LC3. This interaction becomes transient upon activation of Atg3 and Atg7 due to transfer of LC3 to phosphatidylethanolamine (lipidation), a process crucial for functional autophagy. However, loss in covalent-bound LC3 also sensitizes the catalytic thiols of Atg3 and Atg7 to inhibitory oxidation that prevents LC3 lipidation, observed in vitro and in mouse aorta. Here findings provide a thiol-dependent process for negatively regulating autophagy that may contribute to the process of aging, as well as therapeutic targets to regulate autophagosome maturation. A dysfunction of autophagy can be detected in aged tissues, but how this is regulated is unclear. Here, the authors show in vitro and in aged mice aorta, that inhibition of LC3 lipidation under conditions of oxidative stress causes oxidation of Atg3 and Atg7, preventing autophagosome maturation.

Migration in the 21st century is one of the pre-eminent issues of our present historical moment, a phenomenon that has acquired new urgency with accelerating climate change, civil wars, and growing economic scarcities. Refugees and Migrants in Contemporary Film, Art and Media consists of eleven essays that explore how artists have imaginatively engaged with this monumental human drama, examining a range of alternative modes of representation that provide striking new takes on the experiences of these precarious populations. Covering prominent art works by Ai Weiwei and Richard Mosse, and extending the spectrum of representation to refugee film workshops on the island of Lésbos as well as virtual reality installations of Alejandro G. Iñárritu and works by Balkan and Turkish directors, such as Melisa Önel, the chapters included here focus on the power of aesthetic engagement to illuminate the stories of refugees and migrants in ways that overturn journalistic clichés.

A look at how post-9/11 cinema captures the new face of war in the twenty-first century While the war film has carved out a prominent space within the history of cinema, the twenty-first century has seen a significant shift in the characteristics that define it. Serving as a roadmap to the genre's contemporary modes of expression, The New American War Film explores how, in the wake of 9/11, both the nature of military conflict and the symbolic frameworks that surround it have been dramatically reshaped. Featuring in-depth analyses of contemporary films like The Hurt Locker , Zero Dark Thirty , Eye in the Sky , American Sniper , and others, The New American War Film details the genre's turn away from previously foundational themes of heroic sacrifice and national glory, instead emphasizing the procedural violence of advanced military technologies and the haptic damage inflicted on individual bodies. Unfolding amid an atmosphere of profound anxiety and disillusionment, the new American war film demonstrates a breakdown of the prevailing cultural narratives that had come to characterize conflict in the previous century. With each chapter highlighting a different facet of war's cinematic representation, The New American War Film charts society's shifting attitudes toward violent conflict and what is broadly considered to be its acceptable repercussions. Drawing attention to changes in gender dynamics and the focus on war's lasting psychological effects within these recent films, Robert Burgoyne analyzes how cinema both reflects and reveals the makeup of the national imaginary.

Age-associated neurodegenerative disorders such as Alzheimer’s disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential.

Histone crotonylation is a newly identified epigenetic modification that has a pronounced ability to regulate gene expression. It belongs to an expanding group of short chain lysine acylations that also includes the extensively studied mark histone acetylation. Emerging evidence suggests that histone crotonylation is functionally distinct from histone acetylation and that competition for sites of modification, which reflects the cellular metabolic status, could be an important epigenetic mechanism that regulates diverse processes. Here, we discuss the enzymatic and metabolic regulation of histone crotonylation, the “reader” proteins that selectively recognise this modification and translate it into diverse functional outcomes within the cell, as well as the identified physiological roles of histone crotonylation, which range from signal-dependent gene activation to spermatogenesis and tissue injury.

Background An array of experimental models have been developed in the small model organisms C. elegans, S. cerevisiae and D. melanogaster for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD) and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap. Results We carried out an integrated analysis using C. elegans as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in C. elegans . In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways) and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapy Conclusions We identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases have, as an underlying feature, protein aggregation phenotypes it was not surprising that some of the overlapping genes encode proteins involved in protein folding and protein degradation. Interestingly, however, some of the overlapping genes encode proteins that have not previously featured in targeted studies of neurodegeneration and this information will form a useful resource to be exploited in further studies of potential drug-targets.

Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q) did not show changes in its affinity for Ca(2+) or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q) with the loss of a Ca(2+) -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.

Calcium signalling plays a crucial role in the control of neuronal function and plasticity. Changes in neuronal Ca 2+ concentration are detected by Ca 2+ -binding proteins that can interact with and regulate target proteins to modify their function. Members of the neuronal calcium sensor (NCS) protein family have multiple non-redundant roles in the nervous system. Here we review recent advances in the understanding of the physiological roles of the NCS proteins and the molecular basis for their specificity.

With the recent release of spectacular blockbuster films from Gladiator to The Lord of the Rings trilogy, the epic has once again become a major form in contemporary cinema. This new volume in the AFI Film Readers series explores the rebirth of the epic film genre in the contemporary period, a period marked by heightened and conflicting appeals to national, ethnic, and religious belonging.The orginal essays in this volume explore the tension between the evolving global context of film production and reception and the particular provenance of the epic as an expression of national mythology and aspirations, challenging our understanding of epics produced in the present as well as our perception of epic films from the past. The contributors will explore new critical approaches to contemporary as well as older epic films, drawing on ideas from cultural studies, historiography, classics, and film studies. Introduction Section 1: Spectacle Chapter 1: Monica Silveira Cyrino, \"'This is Sparta!' The Reinvention of the Epic in Zach Snyder's 300.\" Chapter 2: Kirsten Thompson, \"'Philip Never Saw Babylon:' 360 Degree Vision and the Historical Epic in the Digital Era.\" Chapter 3: Leon Hunt, \"Heroic Chivalry, Heroic Sacrifice: 'Martial Arthouse' as Epic Cinema.\" Chapter 4: Robert Burgoyne, \"Bare Life and Sovereignty in Gladiator .\" Section 2: Center and Periphery Chapter 5: Dina Iordanova, \"'Rise of the Rest:' Globalizing Epic Cinema.\" Chapter 6: Bettina Bildhauer, \"Signs of the Times: The Semiotics of Time and Event in Sirk's Sign of the Pagan .\" Chapter 7: Tom Conley, \" The Fall of the Roman Empire : On Space and Allegory.\" Chapter 8: Mark Jancovich, \"'An Italianmade Spectacle Film Dubbed in English:' Cultural Distinctions, National Cinema and the Critical Reception of the Postwar Historical Epic.\" Chapter 9: Ruby Cheung, \" Red Cliff : The Chinese-Language Epic and Diasporic Chinese Spectators.\" Section 3: Remembering the Nation Chapter 10: Philip Wagner, \"Passing Through Nightmares: Cecil B. DeMille's The Plainsman and the Epic Discourse in New Deal America.\" Chapter 11: Bruce Babington, \"Epos Indigenized: The New Zealand Wars Film From Rudall Hayward to Vincent Ward.\" Section 4: The Family Epic Chapter 12: Bhaskar Sarkar, in \"Epic Melodrama, or Cine-Maps of the Global South.\" Chapter 13: Anne Gselvik, \"Black Blood: There Will Be Blood. \" Section 5: The Body in the Epic Chapter 14: Alison Griffiths, \"The Monstrous Epic: Deciphering Mel Gibson's The Passion of the Christ .\" Chapter 15: Saer Ba, \"Reading the Black Body in Epic Cinema.\" Robert Burgoyne is Professor and Chair of Film Studies at the University of St Andrews. His recent publications include Film Nation: Hollywood Looks at U.S. History , revised and expanded edition (2010), and The Hollywood Historical Film (2008).