Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the ...DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.
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•Caspase-8 tDED assembles into filaments through quasi-equivalent contacts•The assembly of caspase-8 filaments is nucleated by the upstream Fas/FADD complex•cFLIP tDED also forms filaments, which interact with caspase-8 by comingling•MC159 inhibits caspase-8 filament assembly by a unique capping mechanism
How caspase-8 is activated has been a long-standing question. Fu et al. show that its tDED forms filaments using quasi-equivalent interactions. Cryo-EM structure of the filament reveals mechanisms of caspase-8 activation and its regulation by cFLIP and MC159.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled "Sudden Unexpected Death in Fetal Life Through Early Childhood: New ...Opportunities." Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term "SIDS" in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and "omics" approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of "SIDS" as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research.
Deathscapes Maddrell, Avril, Dr; Sidaway, James D, Professor
2010, 20160513, 2010-12-01, 2016-05-18, 20100101
eBook
Death is at once a universal and everyday, but also an extraordinary experience in the lives of those affected. Death and bereavement are thereby intensified at (and frequently contained within) ...certain sites and regulated spaces, such as the hospital, the cemetery and the mortuary. However, death also affects and unfolds in many other spaces: the home, public spaces and places of worship, sites of accident, tragedy and violence. Such spaces, or Deathscapes, are intensely private and personal places, while often simultaneously being shared, collective, sites of experience and remembrance; each place mediated through the intersections of emotion, body, belief, culture, society and the state. Bringing together geographers, sociologists, anthropologists, cultural studies academics and historians among others, this book focuses on the relationships between space/place and death/ bereavement in 'western' societies. Addressing three broad themes: the place of death; the place of final disposition; and spaces of remembrance and representation, the chapters reflect a variety of scales ranging from the mapping of bereavement on the individual or in private domestic space, through to sites of accident, battle, burial, cremation and remembrance in public space.
The book also examines social and cultural changes in death and bereavement practices, including personalisation and secularisation. Other social trends are addressed by chapters on green and garden burial, negotiating emotion in public/ private space, remembrance of violence and disaster, and virtual space. A meshing of material and 'more-than-representational' approaches consider the nature, culture, economy and politics of Deathscapes - what are in effect some of the most significant places in human society.
Terror management theory (TMT) highlights the motivational impact of thoughts of death in various aspects of everyday life. Since its inception in 1986, research on TMT has undergone a slight but ...significant shift from an almost exclusive focus on the manipulation of thoughts of death to a marked increase in studies that measure the accessibility of death-related cognition. Indeed, the number of death-thought accessibility (DTA) studies in the published literature has grown substantially in recent years. In light of this increasing reliance on the DTA concept, the present article is meant to provide a comprehensive theoretical and empirical review of the literature employing this concept. After discussing the roots of DTA, the authors outline the theoretical refinements to TMT that have accompanied significant research findings associated with the DTA concept. Four distinct categories (mortality salience, death association, anxiety-buffer threat, and dispositional) are derived to organize the reviewed DTA studies, and the theoretical implications of each category are discussed. Finally, a number of lingering empirical and theoretical issues in the DTA literature are discussed with the aim of stimulating and focusing future research on DTA specifically and TMT in general.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
18.
PD‐1/PD‐L1‐dependent immune response in colorectal cancer Payandeh, Zahra; Khalili, Saeed; Somi, Mohammad Hossein ...
Journal of cellular physiology,
July-August 2020, 2020-07-00, 20200701, Volume:
235, Issue:
7-8
Journal Article
Peer reviewed
Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main ...contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1.
Schematic representation of different strategies to the modulation of the expression and function of the programmed cell death‐1 (PD‐1) in colorectal cancer (CRC). This protein is involved in multiple aspects of CRC development and PD‐1‐based therapies are promising therapeutic strategies for patients suffering from CRC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Heart failure (HF) with preserved ejection fraction (HFpEF) represents half of HF patients, who are more likely older, women, and hypertensive. Mortality rates in HFpEF are higher compared with age- ...and comorbidity-matched non-HF controls and lower than in HF with reduced ejection fraction (HFrEF); the majority (50–70%) are cardiovascular (CV) deaths. Among CV deaths, sudden death (SD) (~ 35%) and HF-death (~ 20%) are the leading cardiac modes of death; however, proportionally, CV deaths, SD, and HF-deaths are lower in HFpEF, while non-CV deaths constitute a higher proportion of deaths in HFpEF (30–40%) than in HFrEF (~ 15%). Importantly, the underlying mechanism of SD has not been clearly elucidated and non-arrhythmic SD may be more prominent in HFpEF than in HFrEF. Furthermore, there is no specific strategy for identifying high-risk patients, probably due to wide heterogeneity in presentation and pathophysiology of HFpEF and a plethora of comorbidities in this population. Thus, the management of HFpEF remains problematic due to paucity of data on the clinical benefits of current therapies, which focus on symptom relief and reduction of HF-hospitalization by controlling fluid retention and managing risk-factors and comorbidities. Matching a specific pathophysiology or mode of death with available and novel therapies may improve outcomes in HFpEF. However, this still remains an elusive target, as we need more information on determinants of SD. Implantable cardioverter-defibrillators (ICDs) have changed the landscape of SD prevention in HFrEF; if ICDs are to be applied to HFpEF, there must be a coordinated effort to identify and select high-risk patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core ...FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIP
into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.
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