The structure function of the death domain of human IRAK-M.

PubMed

Du, Jiangfeng; Nicolaes, Gerry Af; Kruijswijk, Danielle; Versloot, Miranda; van der Poll, Tom; van 't Veer, Cornelis

2014-12-07

IRAK-M is an inhibitor of Toll-like receptor signaling that acts by re-directing IRAK-4 activity to TAK1 independent NF-κB activation and by inhibition of IRAK-1/IRAK-2 activity. IRAK-M is expressed in monocytes/macrophages and lung epithelial cells. Lack of IRAK-M in mice greatly improves the resistance to nosocomial pneumonia and lung tumors, which entices IRAK-M as a potential therapeutic target. IRAK-M consists of an N-terminal death domain (DD), a dysfunctional kinase domain and unstructured C-terminal domain. Little is known however on IRAK-M's structure-function relationships. Since death domains provide the important interactions of IRAK-1, IRAK-2 and IRAK-4 molecules, we generated a 3D structure model of the human IRAK-M-DD (residues C5-G119) to guide mutagenesis studies and predict protein-protein interaction points. First we identified the DD residues involved in the endogenous capacity of IRAK-M to activate NF-κB that is displayed upon overexpression in 293T cells. W74 and R97, at distinct interfaces of the IRAK-M-DD, were crucial for this endogenous NF-κB activating capacity, as well as the C-terminal domain (S445-E596) of IRAK-M. Resulting anti-inflammatory A20 and pro-inflammatory IL-8 transcription in 293T cells was W74 dependent, while IL-8 protein expression was dependent on R97 and the TRAF6 binding motif at P478. The IRAK-M-DD W74 and R97 binding interfaces are predicted to interact with opposite sides of IRAK-4-DD's. Secondly we identified DD residues important for the inhibitory action of IRAK-M by stable overexpression of mutants in THP-1 macrophages and H292 lung epithelial cells. IRAK-M inhibited TLR2/4-mediated cytokine production in macrophages in a manner that is largely dependent on W74. R97 was not involved in inhibition of TNF production but was engaged in IL-6 down-regulation by IRAK-M. Protein-interactive residues D19-A23, located in between W74 and R97, were also observed to be crucial for inhibition of TLR2/4 mediated cytokine

The GYF domain protein PSIG1 dampens the induction of cell death during plant-pathogen interactions

PubMed Central

Matsui, Hidenori; Nomura, Yuko; Egusa, Mayumi; Hamada, Takahiro; Hyon, Gang-Su; Kaminaka, Hironori; Ueda, Takashi

2017-01-01

The induction of rapid cell death is an effective strategy for plants to restrict biotrophic and hemi-biotrophic pathogens at the infection site. However, activation of cell death comes at a high cost, as dead cells will no longer be available for defense responses nor general metabolic processes. In addition, necrotrophic pathogens that thrive on dead tissue, take advantage of cell death-triggering mechanisms. Mechanisms by which plants solve this conundrum remain described. Here, we identify PLANT SMY2-TYPE ILE-GYF DOMAIN-CONTAINING PROTEIN 1 (PSIG1) and show that PSIG1 helps to restrict cell death induction during pathogen infection. Inactivation of PSIG1 does not result in spontaneous lesions, and enhanced cell death in psig1 mutants is independent of salicylic acid (SA) biosynthesis or reactive oxygen species (ROS) production. Moreover, PSIG1 interacts with SMG7, which plays a role in nonsense-mediated RNA decay (NMD), and the smg7-4 mutant allele mimics the cell death phenotype of the psig1 mutants. Intriguingly, the psig1 mutants display enhanced susceptibility to the hemi-biotrophic bacterial pathogen. These findings point to the existence and importance of the SA- and ROS-independent cell death constraining mechanism as a part of the plant immune system. PMID:29073135

DNA Repair Domain Modeling Can Predict Cell Death and Mutation Frequency for Wide Range Spectrum of Radiation

NASA Technical Reports Server (NTRS)

Viger, Louise; Ponomarev, Artem L.; Plante, Ianik; Evain, Trevor; Penninckx, Sebastien; Blattnig, Steve R.; Costes, Sylvain V.

2017-01-01

Exploration missions to Mars and other destinations raise many questions about the health of astronauts. The continuous exposure of astronauts to galactic cosmic rays is one of the main concerns for long-term missions. Cosmic ionizing radiations are composed of different ions of various charges and energies notably, highly charged energy (HZE) particles. The HZE particles have been shown to be more carcinogenic than low-LET radiation, suggesting the severity of chromosomal aberrations induced by HZE particles is one possible explanation. However, most mathematical models predicting cell death and mutation frequency are based on directly fitting various HZE dose response and are in essence empirical approaches. In this work, we assume a simple biological mechanism to model DNA repair and use it to simultaneously explain the low- and high-LET response using the exact same fitting parameters. Our work shows that the geometrical position of DNA repair along tracks of heavy ions are sufficient to explain why high-LET particles can induce more death and mutations. Our model is based on assuming DNA double strand breaks (DSBs) are repaired within repair domain, and that any DSBs located within the same repair domain cluster into one repair unit, facilitating chromosomal rearrangements and increasing the probability of cell death. We introduced this model in 2014 using simplified microdosimetry profiles to predict cell death. In this work, we collaborated with NASA Johnson Space Center to generate more accurate microdosimetry profiles derived by Monte Carlo techniques, taking into account track structure of HZE particles and simulating DSBs in realistic cell geometry. We simulated 224 data points (D, A, Z, E) with the BDSTRACKS model, leading to a large coverage of LET from 10 to 2,400 keV/µm. This model was used to generate theoretical RBE for various particles and energies for both cell death and mutation frequencies. The RBE LET dependence is in agreement with

Phosphate homeostasis in the yeast Saccharomyces cerevisiae, the key role of the SPX domain-containing proteins.

PubMed

Secco, David; Wang, Chuang; Shou, Huixia; Whelan, James

2012-02-17

In the yeast Saccharomyces cerevisiae, a working model for nutrient homeostasis in eukaryotes, inorganic phosphate (Pi) homeostasis is regulated by the PHO pathway, a set of phosphate starvation induced genes, acting to optimize Pi uptake and utilization. Among these, a subset of proteins containing the SPX domain has been shown to be key regulators of Pi homeostasis. In this review, we summarize the recent progresses in elucidating the mechanisms controlling Pi homeostasis in yeast, focusing on the key roles of the SPX domain-containing proteins in these processes, as well as describing the future challenges and opportunities in this fast-moving field. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Structural basis of death domain signaling in the p75 neurotrophin receptor

PubMed Central

Lin, Zhi; Tann, Jason Y; Goh, Eddy TH; Kelly, Claire; Lim, Kim Buay; Gao, Jian Fang; Ibanez, Carlos F

2015-01-01

Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. Here we report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors. DOI: http://dx.doi.org/10.7554/eLife.11692.001 PMID:26646181

Purification, crystallization and preliminary x-ray crystallographic studies of RAIDD Death-Domain (DD).

PubMed

Jang, Tae-ho; Park, Hyun Ho

2009-06-03

Caspase-2 activation by formation of PIDDosome is critical for genotoxic stress induced apoptosis. PIDDosome is composed of three proteins, RAIDD, PIDD, and Caspase-2. RAIDD is an adaptor protein containing an N-terminal Caspase-Recruiting-Domain (CARD) and a C-terminal Death-Domain (DD). Its interactions with Caspase-2 and PIDD through CARD and DD respectively and formation of PIDDosome are important for the activation of Caspase-2. RAIDD DD cloned into pET26b vector was expressed in E. coli cells and purified by nickel affinity chromatography and gel filtration. Although it has been known that the most DDs are not soluble in physiological condition, RAIDD DD was soluble and interacts tightly with PIDD DD in physiological condition. The purified RAIDD DD alone has been crystallized. Crystals are trigonal and belong to space group P3(1)21 (or its enantiomorph P3(2)21) with unit-cell parameters a = 56.3, b = 56.3, c = 64.9 A and gamma = 120 degrees . The crystals were obtained at room temperature and diffracted to 2.0 A resolution.

Characterization of Calmodulin–Fas Death Domain Interaction: An Integrated Experimental and Computational Study

PubMed Central

2015-01-01

The Fas death receptor-activated death-inducing signaling complex (DISC) regulates apoptosis in many normal and cancer cells. Qualitative biochemical experiments demonstrate that calmodulin (CaM) binds to the death domain of Fas. The interaction between CaM and Fas regulates Fas-mediated DISC formation. A quantitative understanding of the interaction between CaM and Fas is important for the optimal design of antagonists for CaM or Fas to regulate the CaM–Fas interaction, thus modulating Fas-mediated DISC formation and apoptosis. The V254N mutation of the Fas death domain (Fas DD) is analogous to an identified mutant allele of Fas in lpr-cg mice that have a deficiency in Fas-mediated apoptosis. In this study, the interactions of CaM with the Fas DD wild type (Fas DD WT) and with the Fas DD V254N mutant were characterized using isothermal titration calorimetry (ITC), circular dichroism spectroscopy (CD), and molecular dynamics (MD) simulations. ITC results reveal an endothermic binding characteristic and an entropy-driven interaction of CaM with Fas DD WT or with Fas DD V254N. The Fas DD V254N mutation decreased the association constant (Ka) for CaM–Fas DD binding from (1.79 ± 0.20) × 106 to (0.88 ± 0.14) × 106 M–1 and slightly increased a standard state Gibbs free energy (ΔG°) for CaM–Fas DD binding from −8.87 ± 0.07 to −8.43 ± 0.10 kcal/mol. CD secondary structure analysis and MD simulation results did not show significant secondary structural changes of the Fas DD caused by the V254N mutation. The conformational and dynamical motion analyses, the analyses of hydrogen bond formation within the CaM binding region, the contact numbers of each residue, and the electrostatic potential for the CaM binding region based on MD simulations demonstrated changes caused by the Fas DD V254N mutation. These changes caused by the Fas DD V254N mutation could affect the van der Waals interactions and electrostatic interactions between CaM and Fas DD, thereby

Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death.

PubMed

Kasimsetty, Sashi G; Shigeoka, Alana A; Scheinok, Andrew A; Gavin, Amanda L; Ulevitch, Richard J; McKay, Dianne B

2017-08-01

Nucleotide-binding oligomerization domain (Nod)-containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 × 2 -/- mice rapidly underwent cell death upon exposure to alloantigen. The Nod1 × 2 -/- T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 × 2 -/- T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflammatory states, including those associated with bone marrow or solid organ transplantation. Copyright © 2017 by The American Association of Immunologists, Inc.

An approach to predict Sudden Cardiac Death (SCD) using time domain and bispectrum features from HRV signal.

PubMed

Houshyarifar, Vahid; Chehel Amirani, Mehdi

2016-08-12

In this paper we present a method to predict Sudden Cardiac Arrest (SCA) with higher order spectral (HOS) and linear (Time) features extracted from heart rate variability (HRV) signal. Predicting the occurrence of SCA is important in order to avoid the probability of Sudden Cardiac Death (SCD). This work is a challenge to predict five minutes before SCA onset. The method consists of four steps: pre-processing, feature extraction, feature reduction, and classification. In the first step, the QRS complexes are detected from the electrocardiogram (ECG) signal and then the HRV signal is extracted. In second step, bispectrum features of HRV signal and time-domain features are obtained. Six features are extracted from bispectrum and two features from time-domain. In the next step, these features are reduced to one feature by the linear discriminant analysis (LDA) technique. Finally, KNN and support vector machine-based classifiers are used to classify the HRV signals. We used two database named, MIT/BIH Sudden Cardiac Death (SCD) Database and Physiobank Normal Sinus Rhythm (NSR). In this work we achieved prediction of SCD occurrence for six minutes before the SCA with the accuracy over 91%.

Beatquency domain and machine learning improve prediction of cardiovascular death after acute coronary syndrome.

PubMed

Liu, Yun; Scirica, Benjamin M; Stultz, Collin M; Guttag, John V

2016-10-06

Frequency domain measures of heart rate variability (HRV) are associated with adverse events after a myocardial infarction. However, patterns in the traditional frequency domain (measured in Hz, or cycles per second) may capture different cardiac phenomena at different heart rates. An alternative is to consider frequency with respect to heartbeats, or beatquency. We compared the use of frequency and beatquency domains to predict patient risk after an acute coronary syndrome. We then determined whether machine learning could further improve the predictive performance. We first evaluated the use of pre-defined frequency and beatquency bands in a clinical trial dataset (N = 2302) for the HRV risk measure LF/HF (the ratio of low frequency to high frequency power). Relative to frequency, beatquency improved the ability of LF/HF to predict cardiovascular death within one year (Area Under the Curve, or AUC, of 0.730 vs. 0.704, p < 0.001). Next, we used machine learning to learn frequency and beatquency bands with optimal predictive power, which further improved the AUC for beatquency to 0.753 (p < 0.001), but not for frequency. Results in additional validation datasets (N = 2255 and N = 765) were similar. Our results suggest that beatquency and machine learning provide valuable tools in physiological studies of HRV.

The Nuclear Death Domain Protein p84N5; a Candidate Breast Cancer Susceptibility Gene

DTIC Science & Technology

2005-05-01

DATES COVERED ( Leave blank) May 2005 Annual (1 May 04 - 30 Apr 05) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS The Nuclear Death Domain Protein p84N5; a...p84N5 targeted siRNAs effectively reduced the protein levels of p84N5, but did not affect the levels of non- targeted transcripts such as P-actin...p84N5. Cell proliferation and apoptosis (data not shown) was examined using Guava ViaCount and Nexin assays, respectively. Plotted is the number of

Domain-Generality versus Domain-Specificity: The Life and Impending Death of a False Dichotomy.

ERIC Educational Resources Information Center

Sternberg, Robert J.

1989-01-01

Argues that the question of whether information representation and processing are domain-general or domain-specific is neither meaningful nor answerable. Researchers should be asking questions about ways in which representation and processing are domain-general and ways in which they are domain-specific. (RH)

New types of metacaspases in phytoplankton reveal diverse origins of cell death proteases

PubMed Central

Choi, C J; Berges, J A

2013-01-01

Metacaspases are evolutionarily distant homologs of caspases that are found outside the metazoan and are known to have key roles in programmed cell death (PCD). Two types of metacaspases (types I and II) have been defined in plants based on their domain structures; these have similarities to metazoan ‘initiator' and ‘executioner' caspases. However, we know little about metacaspases in unicellular organisms and even less about their roles in cell death. We identified a novel group of metacaspases in sequenced phytoplanktonic protists that show domain architectures distinct from either type I or II enzymes; we designate them as type III. Type III metacaspases exhibit a rearrangement of domain structures between N- and C-terminus. In addition, we found a group of metacaspase-like proteases in phytoplankton that show sequence homology with other metacaspases, but defy classification in conventional schemes. These metacaspase-like proteases exist in bacteria alongside a variant of type I metacaspases and we propose these bacterial metacaspases are the origins of eukaryotic metacaspases. Type II and III metacaspases were not detected in bacteria and they might be variants of bacterial type I metacaspases that evolved in plants and phytoplanktonic protists, respectively, during the establishment of plastids through the primary and secondary endosymbiotic events. A complete absence of metacaspases in protists that lost plastids, such as oömycetes and ciliates indicates the gene loss during the plastid-to-nucleus gene transfer. Taken together, our findings suggest endosymbiotic gene transfer (EGT) is a key mechanism resulting in the evolutionary diversity of cell death proteases. PMID:23412383

Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.

PubMed

Twomey, Edward C; Cordasco, Dana F; Kozuch, Stephen D; Wei, Yufeng

2013-01-01

Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.

The Chloroplastic Protein THF1 Interacts with the Coiled-Coil Domain of the Disease Resistance Protein N′ and Regulates Light-Dependent Cell Death1[OPEN

PubMed Central

Sekine, Ken-Taro; Wallon, Thérèse; Sugiwaka, Yuji; Kobayashi, Kappei

2016-01-01

One branch of plant immunity is mediated through nucleotide-binding/Leu-rich repeat (NB-LRR) family proteins that recognize specific effectors encoded by pathogens. Members of the I2-like family constitute a well-conserved subgroup of NB-LRRs from Solanaceae possessing a coiled-coil (CC) domain at their N termini. We show here that the CC domains of several I2-like proteins are able to induce a hypersensitive response (HR), a form of programmed cell death associated with disease resistance. Using yeast two-hybrid screens, we identified the chloroplastic protein Thylakoid Formation1 (THF1) as an interacting partner for several I2-like CC domains. Co-immunoprecipitations and bimolecular fluorescence complementation assays confirmed that THF1 and I2-like CC domains interact in planta and that these interactions take place in the cytosol. Several HR-inducing I2-like CC domains have a negative effect on the accumulation of THF1, suggesting that the latter is destabilized by active CC domains. To confirm this model, we investigated N′, which recognizes the coat protein of most Tobamoviruses, as a prototypical member of the I2-like family. Transient expression and gene silencing data indicated that THF1 functions as a negative regulator of cell death and that activation of full-length N′ results in the destabilization of THF1. Consistent with the known function of THF1 in maintaining chloroplast homeostasis, we show that the HR induced by N′ is light-dependent. Together, our results define, to our knowledge, novel molecular mechanisms linking light and chloroplasts to the induction of cell death by a subgroup of NB-LRR proteins. PMID:26951433

Challenging patient deaths in pediatric oncology.

PubMed

Granek, Leeat; Bartels, Ute; Scheinemann, Katrin; Barrera, Maru

2015-08-01

Pediatric oncologists look after patients and their families for extended periods of time when they are diagnosed and treated for cancer. Twenty percent of these children will die while under their care. The purpose of this study was to explore what makes patient deaths challenging for pediatric oncologists. Twenty-one Canadian pediatric oncologists were interviewed about their experiences with patient death and were probed about the factors that make patient deaths particularly challenging. Data were analyzed using the grounded theory method. Challenging factors pertaining to patient death were categorized into three main domains. Relational factors included dealing with families perceived as challenging; identifying with parents; and having long-term relationships and special connections with patients and their caregivers. The second domain captured the process of death and dying and included death after curative treatment was stopped; death caused by complications; and unexpected deaths. The third domain encompassed patient factors that included suffering of the child, and the sense that no child should die. The types of relationships pediatric oncologists have with patients and caregivers, and the process by which children die affects pediatric oncologists' perceived level of difficulty in coping with the death. The findings point to the complexity of working with children where parents are included in the decision-making processes around a child's treatment. Implementation of structured review opportunities around patient death and associated decision-making within a multidisciplinary healthcare team may alleviate some of the emotional burden associated with patient deaths.

A Key Claudin Extracellular Loop Domain is Critical for Epithelial Barrier Integrity

PubMed Central

Mrsny, Randall J.; Brown, G. Thomas; Gerner-Smidt, Kirsten; Buret, Andre G.; Meddings, Jon B.; Quan, Clifford; Koval, Michael; Nusrat, Asma

2008-01-01

Intercellular tight junctions (TJs) regulate epithelial barrier properties. Claudins are major structural constituents of TJs and belong to a large family of tetra-spanning membrane proteins that have two predicted extracellular loops (ELs). Given that claudin-1 is widely expressed in epithelia, we further defined the role of its EL domains in determining TJ function. The effects of several claudin-1 EL mimetic peptides on epithelial barrier structure and function were examined. Incubation of model human intestinal epithelial cells with a 27-amino acid peptide corresponding to a portion of the first EL domain (Cldn-153–80) reversibly interfered with epithelial barrier function by inducing the rearrangement of key TJ proteins: occludin, claudin-1, junctional adhesion molecule-A, and zonula occludens-1. Cldn-153–80 associated with both claudin-1 and occludin, suggesting both the direct interference with the ability of these proteins to assemble into functional TJs and their close interaction under physiological conditions. These effects were specific for Cldn-153–80, because peptides corresponding to other claudin-1 EL domains failed to influence TJ function. Furthermore, the oral administration of Cldn-153–80 to rats increased paracellular gastric permeability. Thus, the identification of a critical claudin-1 EL motif, Cldn-153–80, capable of regulating TJ structure and function, offers a useful adjunct to treatments that require drug delivery across an epithelial barrier. PMID:18349130

Remodelling of lace plant leaves: antioxidants and ROS are key regulators of programmed cell death.

PubMed

Dauphinee, Adrian N; Fletcher, Jacob I; Denbigh, Georgia L; Lacroix, Christian R; Gunawardena, Arunika H L A N

2017-07-01

Antioxidants and reactive oxygen species are integral for programmed cell death signaling during perforation formation in the lace plant ( Aponogeton madagascariensis ). The lace plant is an excellent model system for studying developmentally regulated programmed cell death (PCD). During early lace plant leaf development, PCD systematically deletes cells resulting in a perforated leaf morphology that is unique in planta. A distinct feature in young lace plant leaves is an abundance of anthocyanins, which have antioxidant properties. The first sign of PCD induction is the loss of anthocyanin pigmentation in cells that are targeted for destruction, which results in a visible gradient of cell death. The cellular dynamics and time course of lace plant PCD are well documented; however, the signals involved in the pathway remain elusive. This study investigates the roles of antioxidants and ROS in developmental PCD signaling during lace plant perforation formation. The involvement of antioxidants and ROS in the pathway was determined using a variety of techniques including pharmacological whole plant experimentation, long-term live cell imaging, the 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid anti-radical activity assay, and western blot analysis. Results indicate that antioxidants and ROS are key regulators of PCD during the remodelling of lace plant leaves.

Folding and stability of the isolated Greek key domains of the long-lived human lens proteins γD-crystallin and γS-crystallin

PubMed Central

Mills, Ishara A.; Flaugh, Shannon L.; Kosinski-Collins, Melissa S.; King, Jonathan A.

2007-01-01

The transparency of the eye lens depends on the high solubility and stability of the lens crystallin proteins. The monomeric γ-crystallins and oligomeric β-crystallins have paired homologous double Greek key domains, presumably evolved through gene duplication and fusion. Prior investigation of the refolding of human γD-crystallin revealed that the C-terminal domain folds first and nucleates the folding of the N-terminal domain. This result suggested that the human N-terminal domain might not be able to fold on its own. We constructed and expressed polypeptide chains corresponding to the isolated N- and C-terminal domains of human γD-crystallin, as well as the isolated domains of human γS-crystallin. Both circular dichroism and fluorescence spectroscopy indicated that the isolated domains purified from Escherichia coli were folded into native-like monomers. After denaturation, the isolated domains refolded efficiently at pH 7 and 37°C into native-like structures. The in vitro refolding of all four domains revealed two kinetic phases, identifying partially folded intermediates for the Greek key motifs. When subjected to thermal denaturation, the isolated N-terminal domains were less stable than the full-length proteins and less stable than the C-terminal domains, and this was confirmed in equilibrium unfolding/refolding experiments. The decrease in stability of the N-terminal domain of human γD-crystallin with respect to the complete protein indicated that the interdomain interface contributes of 4.2 kcal/mol to the overall stability of this very long-lived protein. PMID:17905830

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

PubMed

Thevenon, Julien; Bourredjem, Abderrahmane; Faivre, Laurence; Cardot-Bauters, Catherine; Calender, Alain; Murat, Arnaud; Giraud, Sophie; Niccoli, Patricia; Odou, Marie-Françoise; Borson-Chazot, Françoise; Barlier, Anne; Lombard-Bohas, Catherine; Clauser, Eric; Tabarin, Antoine; Parfait, Béatrice; Chabre, Olivier; Castermans, Emilie; Beckers, Albert; Ruszniewski, Philippe; Le Bras, Morgane; Delemer, Brigitte; Bouchard, Philippe; Guilhem, Isabelle; Rohmer, Vincent; Goichot, Bernard; Caron, Philippe; Baudin, Eric; Chanson, Philippe; Groussin, Lionel; Du Boullay, Hélène; Weryha, Georges; Lecomte, Pierre; Penfornis, Alfred; Bihan, Hélène; Archambeaud, Françoise; Kerlan, Véronique; Duron, Françoise; Kuhn, Jean-Marc; Vergès, Bruno; Rodier, Michel; Renard, Michel; Sadoul, Jean-Louis; Binquet, Christine; Goudet, Pierre

2013-05-15

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling.

PubMed

D'Cruz, Akshay A; Kershaw, Nadia J; Chiang, Jessica J; Wang, May K; Nicola, Nicos A; Babon, Jeffrey J; Gack, Michaela U; Nicholson, Sandra E

2013-12-01

TRIM (tripartite motif) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 [also known as Efp (oestrogen-responsive finger protein)] has been implicated in the regulation of oestrogen receptor α signalling and in the regulation of innate immune signalling via RIG-I (retinoic acid-inducible gene-I). RIG-I senses cytosolic viral RNA and is subsequently ubiquitinated by TRIM25 at its N-terminal CARDs (caspase recruitment domains), leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein-interaction domain composed of the PRY and SPRY tandem sequence motifs. In the present study we describe the 1.8 Å crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal α-helices, thirteen β-strands arranged into two β-sheets and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp(488) and Trp(621)) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARDs.

Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling

PubMed Central

D'Cruz, Akshay A.; Kershaw, Nadia J.; Chiang, Jessica J.; Wang, May K.; Nicola, Nicos A.; Babon, Jeffrey J.; Gack, Michaela U.; Nicholson, Sandra E.

2014-01-01

TRIM (tripartite motif) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 [also known as Efp (oestrogen-responsive finger protein)] has been implicated in the regulation of oestrogen receptor α signalling and in the regulation of innate immune signalling via RIG-I (retinoic acid-inducible gene-I). RIG-I senses cytosolic viral RNA and is subsequently ubiquitinated by TRIM25 at its N-terminal CARDs (caspase recruitment domains), leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein-interaction domain composed of the PRY and SPRY tandem sequence motifs. In the present study we describe the 1.8 Å crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal α-helices, thirteen β-strands arranged into two β-sheets and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp488 and Trp621) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARDs. PMID:24015671

Comparative analysis of programmed cell death pathways in filamentous fungi.

PubMed

Fedorova, Natalie D; Badger, Jonathan H; Robson, Geoff D; Wortman, Jennifer R; Nierman, William C

2005-12-08

Fungi can undergo autophagic- or apoptotic-type programmed cell death (PCD) on exposure to antifungal agents, developmental signals, and stress factors. Filamentous fungi can also exhibit a form of cell death called heterokaryon incompatibility (HI) triggered by fusion between two genetically incompatible individuals. With the availability of recently sequenced genomes of Aspergillus fumigatus and several related species, we were able to define putative components of fungi-specific death pathways and the ancestral core apoptotic machinery shared by all fungi and metazoa. Phylogenetic profiling of HI-associated proteins from four Aspergilli and seven other fungal species revealed lineage-specific protein families, orphan genes, and core genes conserved across all fungi and metazoa. The Aspergilli-specific domain architectures include NACHT family NTPases, which may function as key integrators of stress and nutrient availability signals. They are often found fused to putative effector domains such as Pfs, SesB/LipA, and a newly identified domain, HET-s/LopB. Many putative HI inducers and mediators are specific to filamentous fungi and not found in unicellular yeasts. In addition to their role in HI, several of them appear to be involved in regulation of cell cycle, development and sexual differentiation. Finally, the Aspergilli possess many putative downstream components of the mammalian apoptotic machinery including several proteins not found in the model yeast, Saccharomyces cerevisiae. Our analysis identified more than 100 putative PCD associated genes in the Aspergilli, which may help expand the range of currently available treatments for aspergillosis and other invasive fungal diseases. The list includes species-specific protein families as well as conserved core components of the ancestral PCD machinery shared by fungi and metazoa.

Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants

PubMed Central

Malkesman, O; Austin, DR; Tragon, T; Henter, ID; Reed, JC; Pellecchia, M; Chen, G; Manji, HK

2011-01-01

The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression—the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm—as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders. PMID:21727899

Structural studies of the protein endostatin in fusion with BAX BH3 death domain, a hybrid that presents enhanced antitumoral activity.

PubMed

Chura-Chambi, Rosa Maria; Arcuri, Helen Andrade; Lino, Felipe; Versati, Natan; Palma, Mario Sergio; Favaro, Denize C; Morganti, Ligia

2017-05-01

Endostatin (ES) is an antiangiogenic protein that exhibits antitumor activity in animal models. However, the activity observed in animals was not observed in human clinical trials. ES-BAX is a fusion protein composed of two functional domains: ES, which presents specificity and is internalized by activated endothelial cells and the proapoptotic BH3 domain of the protein BAX, a peptide inductor of cellular death when internalized. We have previously shown (Chura-Chambi et al., Cell Death Dis, 5, e1371, 2014) that ES-BAX presents improved antitumor activity in relation to wild-type ES. Secondary and tertiary structures of ES-BAX are similar to ES, as indicated by homology-modeling studies and molecular dynamics simulations. Tryptophan intrinsic fluorescence and circular dichroism spectroscopy corroborate these data. 15 N HSQC NMR indicates that ES-BAX is structured, but some ES residues have suffered chemical shift perturbations, suggesting that the BH3 peptide interacts with some parts of the ES protein. ES and ES-BAX present similar stability to thermal denaturation. The production of stable hybrid proteins can be a new approach to the development of therapeutic agents presenting specificity for tumoral endothelium and improved antitumor effect. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Deaths: Leading Causes for 2014.

PubMed

Heron, Melonie

2016-06-01

Objectives-This report presents final 2014 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2014," the National Center for Health Statistics' annual report of final mortality statistics. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Emerging roles for lipids in non-apoptotic cell death

PubMed Central

Magtanong, L; Ko, P J; Dixon, S J

2016-01-01

Non-apoptotic regulated cell death (RCD) is essential to maintain organismal homeostasis and may be aberrantly activated during certain pathological states. Lipids are emerging as key components of several non-apoptotic RCD pathways. For example, a direct interaction between membrane phospholipids and the pore-forming protein mixed lineage kinase domain-like (MLKL) is needed for the execution of necroptosis, while the oxidative destruction of membrane polyunsaturated fatty acids (PUFAs), following the inactivation of glutathione peroxidase 4 (GPX4), is a requisite gateway to ferroptosis. Here, we review the roles of lipids in the initiation and execution of these and other forms of non-apoptotic cell death. We also consider new technologies that are allowing for the roles of lipids and lipid metabolism in RCD to be probed in increasingly sophisticated ways. In certain cases, this new knowledge may enable the development of therapies that target lipids and lipid metabolic processes to enhance or suppress specific non-apoptotic RCD pathways. PMID:26967968

Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

PubMed Central

Lee, Boyeon; Clarke, Douglas; Al Ahmad, Abraham; Kahle, Michael; Parham, Christi; Auckland, Lisa; Shaw, Courtney; Fidanboylu, Mehmet; Orr, Anthony Wayne; Ogunshola, Omolara; Fertala, Andrzej; Thomas, Sarah A.; Bix, Gregory J.

2011-01-01

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5β1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment. PMID:21747167

A "good death": perspectives of Muslim patients and health care providers.

PubMed

Tayeb, Mohamad A; Al-Zamel, Ersan; Fareed, Muhammed M; Abouellail, Hesham A

2010-01-01

Twelve "good death" principles have been identified that apply to Westerners. This study aimed to review the TFHCOP good death perception to determine its validity for Muslim patients and health care providers, and to identify and describe other components of the Muslim good death perspective. Participants included 284 Muslims of both genders with different nationalities and careers. We used a 12-question questionnaire based on the 12 principles of the TFHCOP good death definition, followed by face-to-face interviews. We used descriptive statistics to analyze questionnaire responses. However, for new themes, we used a grounded theory approach with a "constant comparisons" method. On average, each participant agreed on eight principles of the questionnaire. Dignity, privacy, spiritual and emotional support, access to hospice care, ability to issue advance directives, and to have time to say goodbye were the top priorities. Participants identified three main domains. The first domain was related to faith and belief. The second domain included some principles related to self-esteem and person's image to friends and family. The third domain was related to satisfaction about family security after the death of the patient. Professional role distinctions were more pronounced than were gender or nationality differences. Several aspects of "good death," as perceived by Western communities, are not recognized as being important by many Muslim patients and health care providers. Furthermore, our study introduced three novel components of good death in Muslim society.

Operational Details of the Five Domains Model and Its Key Applications to the Assessment and Management of Animal Welfare

PubMed Central

Mellor, David J.

2017-01-01

Simple Summary The Five Domains Model is a focusing device to facilitate systematic, structured, comprehensive and coherent assessment of animal welfare; it is not a definition of animal welfare, nor is it intended to be an accurate representation of body structure and function. The purpose of each of the five domains is to draw attention to areas that are relevant to both animal welfare assessment and management. This paper begins by briefly describing the major features of the Model and the operational interactions between the five domains, and then it details seven interacting applications of the Model. These underlie its utility and increasing application to welfare assessment and management in diverse animal use sectors. Abstract In accord with contemporary animal welfare science understanding, the Five Domains Model has a significant focus on subjective experiences, known as affects, which collectively contribute to an animal’s overall welfare state. Operationally, the focus of the Model is on the presence or absence of various internal physical/functional states and external circumstances that give rise to welfare-relevant negative and/or positive mental experiences, i.e., affects. The internal states and external circumstances of animals are evaluated systematically by referring to each of the first four domains of the Model, designated “Nutrition”, “Environment”, “Health” and “Behaviour”. Then affects, considered carefully and cautiously to be generated by factors in these domains, are accumulated into the fifth domain, designated “Mental State”. The scientific foundations of this operational procedure, published in detail elsewhere, are described briefly here, and then seven key ways the Model may be applied to the assessment and management of animal welfare are considered. These applications have the following beneficial objectives—they (1) specify key general foci for animal welfare management; (2) highlight the foundations of

Birdsong dialect patterns explained using magnetic domains

NASA Astrophysics Data System (ADS)

Burridge, James; Kenney, Steven

2016-06-01

The songs and calls of many bird species, like human speech, form distinct regional dialects. We suggest that the process of dialect formation is analogous to the physical process of magnetic domain formation. We take the coastal breeding grounds of the Puget Sound white crowned sparrow as an example. Previous field studies suggest that birds of this species learn multiple songs early in life, and when establishing a territory for the first time, retain one of these dialects in order to match the majority of their neighbors. We introduce a simple lattice model of the process, showing that this matching behavior can produce single dialect domains provided the death rate of adult birds is sufficiently low. We relate death rate to thermodynamic temperature in magnetic materials, and calculate the critical death rate by analogy with the Ising model. Using parameters consistent with the known behavior of these birds we show that coastal dialect domain shapes may be explained by viewing them as low-temperature "stripe states."

A Key Evolutionary Mutation Enhances DNA Binding of the FOXP2 Forkhead Domain.

PubMed

Morris, Gavin; Fanucchi, Sylvia

2016-04-05

Forkhead box (FOX) transcription factors share a conserved forkhead DNA binding domain (FHD) and are key role players in the development of many eukaryotic species. Their involvement in various congenital disorders and cancers makes them clinically relevant targets for novel therapeutic strategies. Among them, the FOXP subfamily of multidomain transcriptional repressors is unique in its ability to form DNA binding homo and heterodimers. The truncated FOXP2 FHD, in the absence of the leucine zipper, exists in equilibrium between monomeric and domain-swapped dimeric states in vitro. As a consequence, determining the DNA binding properties of the FOXP2 FHD becomes inherently difficult. In this work, two FOXP2 FHD hinge loop mutants have been generated to successfully prevent both the formation (A539P) and the dissociation (F541C) of the homodimers. This allows for the separation of the two species for downstream DNA binding studies. Comparison of DNA binding of the different species using electrophoretic mobility shift assay, fluorescence anisotropy and isothermal titration calorimetry indicates that the wild-type FOXP2 FHD binds DNA as a monomer. However, comparison of the DNA-binding energetics of the monomer and wild-type FHD, reveals that there is a difference in the mechanism of binding between the two species. We conclude that the naturally occurring reverse mutation (P539A) seen in the FOXP subfamily increases DNA binding affinity and may increase the potential for nonspecific binding compared to other FOX family members.

Exceptionally tight membrane-binding may explain the key role of the synaptotagmin-7 C 2 A domain in asynchronous neurotransmitter release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voleti, Rashmi; Tomchick, Diana R.; Südhof, Thomas C.

Synaptotagmins (Syts) act as Ca2+ sensors in neurotransmitter release by virtue of Ca2+-binding to their two C2 domains, but their mechanisms of action remain unclear. Puzzlingly, Ca2+-binding to the C2B domain appears to dominate Syt1 function in synchronous release, whereas Ca2+-binding to the C2A domain mediates Syt7 function in asynchronous release. Here we show that crystal structures of the Syt7 C2A domain and C2AB region, and analyses of intrinsic Ca2+-binding to the Syt7 C2 domains using isothermal titration calorimetry, did not reveal major differences that could explain functional differentiation between Syt7 and Syt1. However, using liposome titrations under Ca2+ saturatingmore » conditions, we show that the Syt7 C2A domain has a very high membrane affinity and dominates phospholipid binding to Syt7 in the presence or absence of L-α-phosphatidylinositol 4,5-diphosphate (PIP2). For Syt1, the two Ca2+-saturated C2 domains have similar affinities for membranes lacking PIP2, but the C2B domain dominates binding to PIP2-containing membranes. Mutagenesis revealed that the dramatic differences in membrane affinity between the Syt1 and Syt7 C2A domains arise in part from apparently conservative residue substitutions, showing how striking biochemical and functional differences can result from the cumulative effects of subtle residue substitutions. Viewed together, our results suggest that membrane affinity may be a key determinant of the functions of Syt C2 domains in neurotransmitter release.« less

Constructing a Cross-Domain Resource Inventory: Key Components and Results of the EarthCube CINERGI Project.

NASA Astrophysics Data System (ADS)

Zaslavsky, I.; Richard, S. M.; Malik, T.; Hsu, L.; Gupta, A.; Grethe, J. S.; Valentine, D. W., Jr.; Lehnert, K. A.; Bermudez, L. E.; Ozyurt, I. B.; Whitenack, T.; Schachne, A.; Giliarini, A.

2015-12-01

While many geoscience-related repositories and data discovery portals exist, finding information about available resources remains a pervasive problem, especially when searching across multiple domains and catalogs. Inconsistent and incomplete metadata descriptions, disparate access protocols and semantic differences across domains, and troves of unstructured or poorly structured information which is hard to discover and use are major hindrances toward discovery, while metadata compilation and curation remain manual and time-consuming. We report on methodology, main results and lessons learned from an ongoing effort to develop a geoscience-wide catalog of information resources, with consistent metadata descriptions, traceable provenance, and automated metadata enhancement. Developing such a catalog is the central goal of CINERGI (Community Inventory of EarthCube Resources for Geoscience Interoperability), an EarthCube building block project (earthcube.org/group/cinergi). The key novel technical contributions of the projects include: a) development of a metadata enhancement pipeline and a set of document enhancers to automatically improve various aspects of metadata descriptions, including keyword assignment and definition of spatial extents; b) Community Resource Viewers: online applications for crowdsourcing community resource registry development, curation and search, and channeling metadata to the unified CINERGI inventory, c) metadata provenance, validation and annotation services, d) user interfaces for advanced resource discovery; and e) geoscience-wide ontology and machine learning to support automated semantic tagging and faceted search across domains. We demonstrate these CINERGI components in three types of user scenarios: (1) improving existing metadata descriptions maintained by government and academic data facilities, (2) supporting work of several EarthCube Research Coordination Network projects in assembling information resources for their domains

Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

PubMed Central

Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F.

2015-01-01

Summary Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets. PMID:25046161

Cell Death in C. elegans Development.

PubMed

Malin, Jennifer Zuckerman; Shaham, Shai

2015-01-01

Cell death is a common and important feature of animal development, and cell death defects underlie many human disease states. The nematode Caenorhabditis elegans has proven fertile ground for uncovering molecular and cellular processes controlling programmed cell death. A core pathway consisting of the conserved proteins EGL-1/BH3-only, CED-9/BCL2, CED-4/APAF1, and CED-3/caspase promotes most cell death in the nematode, and a conserved set of proteins ensures the engulfment and degradation of dying cells. Multiple regulatory pathways control cell death onset in C. elegans, and many reveal similarities with tumor formation pathways in mammals, supporting the idea that cell death plays key roles in malignant progression. Nonetheless, a number of observations suggest that our understanding of developmental cell death in C. elegans is incomplete. The interaction between dying and engulfing cells seems to be more complex than originally appreciated, and it appears that key aspects of cell death initiation are not fully understood. It has also become apparent that the conserved apoptotic pathway is dispensable for the demise of the C. elegans linker cell, leading to the discovery of a previously unexplored gene program promoting cell death. Here, we review studies that formed the foundation of cell death research in C. elegans and describe new observations that expand, and in some cases remodel, this edifice. We raise the possibility that, in some cells, more than one death program may be needed to ensure cell death fidelity. © 2015 Elsevier Inc. All rights reserved.

The pepper cysteine/histidine-rich DC1 domain protein CaDC1 binds both RNA and DNA and is required for plant cell death and defense response.

PubMed

Hwang, In Sun; Choi, Du Seok; Kim, Nak Hyun; Kim, Dae Sung; Hwang, Byung Kook

2014-01-01

Plant defense against microbial pathogens is coordinated by a complex regulatory network. Cysteine/histidine-rich DC1 domain proteins mediate a variety of cellular processes involved in plant growth, development and stress responses. We identified a pepper (Capsicum annuum) cysteine/histidine-rich DC1 domain protein gene, CaDC1, which positively regulates plant defense during microbial infection, based on gene silencing and transient expression in pepper, as well as ectopic expression in Arabidopsis. Induction of CaDC1 by avirulent Xanthomonas campestris pv vesicatoria (Xcv) infection was pronounced at both transcriptional and translational levels in pepper leaves. Purified CaDC1 protein bound to both DNA and RNA in vitro, especially in the presence of Zn(2+). CaDC1 was localized to both the nucleus and the cytoplasm, which was required for plant cell death signaling. The nuclear localization of CaDC1 was dependent on the divergent C1 (DC1) domain. CaDC1 silencing in pepper conferred increased susceptibility to Xcv infection, which was accompanied by reduced salicylic acid accumulation and defense-related gene expression. Ectopic expression of CaDC1 in Arabidopsis enhanced resistance to Hyaloperonospora arabidopsidis. CaDC1 binds both RNA and DNA and functions as a positive regulator of plant cell death and SA-dependent defense responses. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Key apoptotic pathways for heat-induced programmed germ cell death in the testis.

PubMed

Hikim, Amiya P Sinha; Lue, Yanhe; Yamamoto, Cindy M; Vera, Yanira; Rodriguez, Susana; Yen, Pauline H; Soeng, Kevin; Wang, Christina; Swerdloff, Ronald S

2003-07-01

Short-term exposure (43 C for 15 min) of the rat testis to mild heat results within 6 h in stage- and cell-specific activation of germ cell apoptosis. Initiation of apoptosis was preceded by a redistribution of Bax from a cytoplasmic to paranuclear localization in heat-susceptible germ cells. Here we show that the relocation of Bax is accompanied by cytosolic translocation of cytochrome c and is associated with activation of the initiator caspase 9 and the executioner caspases 3, 6, and 7 and cleavage of poly(ADP) ribose polymerase. Furthermore, early in apoptosis, a significant amount of Bax also accumulates in endoplasmic reticulum, as assessed by Western blot analyses of fractionated testicular lysates. In additional studies using the FasL-defective gld mice, we have shown that heat-induced germ cell apoptosis is not blocked, thus providing evidence that the Fas signaling system may be dispensable for heat-induced germ cell apoptosis in the testis. Taken together, these results demonstrate that the mitochondria- and possibly also endoplasmic reticulum-dependent pathways are the key apoptotic pathways for heat-induced germ cell death in the testis.

Characterization of the Interactions between Calmodulin and Death Receptor 5 in Triple-negative and Estrogen Receptor-positive Breast Cancer Cells

PubMed Central

Fancy, Romone M.; Wang, Lingyun; Zeng, Qinghua; Wang, Hong; Zhou, Tong; Buchsbaum, Donald J.; Song, Yuhua

2016-01-01

Activation of death receptor-5 (DR5) leads to the formation of death inducing signaling complex (DISC) for apoptotic signaling. Targeting DR5 to induce breast cancer apoptosis is a promising strategy to circumvent drug resistance and present a target for breast cancer treatment. Calmodulin (CaM) has been shown to regulate DR5-mediated apoptotic signaling, however, its mechanism remains unknown. In this study, we characterized CaM and DR5 interactions in breast cancer cells with integrated experimental and computational approaches. Results show that CaM directly binds to DR5 in a calcium dependent manner in breast cancer cells. The direct interaction of CaM with DR5 is localized at DR5 death domain. We have predicted and verified the CaM-binding site in DR5 being 354WEPLMRKLGL363 that is located at the α2 helix and the loop between α2 helix and α3 helix of DR5 DD. The residues of Trp-354, Arg-359, Glu-355, Leu-363, and Glu-367 in DR5 death domain that are important for DR5 recruitment of FADD and caspase-8 for DISC formation to signal apoptosis also play an important role for CaM-DR5 binding. The changed electrostatic potential distribution in the CaM-binding site in DR5 DD by the point mutations of W354A, E355K, R359A, L363N, or E367K in DR5 DD could directly contribute to the experimentally observed decreased CaM-DR5 binding by the point mutations of the key residues in DR5 DD. Results from this study provide a key step for the further investigation of the role of CaM-DR5 binding in DR5-mediated DISC formation for apoptosis in breast cancer cells. PMID:27129269

What is a good death? Minority and non-minority perspectives.

PubMed

Tong, Elizabeth; McGraw, Sarah A; Dobihal, Edward; Baggish, Rosemary; Cherlin, Emily; Bradley, Elizabeth H

2003-01-01

While much attention has been directed at improving the quality of care at the end of life, few studies have examined what determines a good death in different individuals. We sought to identify common domains that characterize a good death in a diverse range of community-dwelling individuals, and to describe differences that might exist between minority and non-minority community-dwelling individuals' views. Using data from 13 focus groups, we identified 10 domains that characterize the quality of the death experience: 1) physical comfort, 2) burdens on family, 3) location and environment, 4) presence of others, 5) concerns regarding prolongation of life, 6) communication, 7) completion and emotional health, 8) spiritual care, 9) cultural concerns, 10) individualization. Differences in minority compared to non-minority views were apparent within the domains of spiritual concerns, cultural concerns, and individualization. The findings may help in efforts to encourage more culturally sensitive and humane end-of-life care for both minority and non-minority individuals.

The pepper GNA-related lectin and PAN domain protein gene, CaGLP1, is required for plant cell death and defense signaling during bacterial infection.

PubMed

Kim, Nak Hyun; Lee, Dong Hyuk; Choi, Du Seok; Hwang, Byung Kook

2015-12-01

Carbohydrate-binding proteins, commonly referred to as lectins or agglutinins, function in defense responses to microbial pathogens. Pepper (Capsicum annuum) GNA-related lectin and PAN-domain protein gene CaGLP1 was isolated and functionally characterized from pepper leaves infected with Xanthomonas campestris pv. vesicatoria (Xcv). CaGLP1 contained an amine-terminus prokaryotic membrane lipoprotein lipid attachment site, a Galanthus nivalis agglutinin (GNA)-related lectin domain responsible for the recognition of high-mannose N-glycans, and a carboxyl-terminus PAN/apple domain. RNA gel blot and immunoblot analyses determined that CaGLP1 was strongly induced in pepper by compatible and incompatible Xcv infection. CaGLP1 protein localized primarily to the plasma membrane and exhibited mannose-binding specificity. CaGLP1-silenced pepper plants were more susceptible to compatible or incompatible Xcv infection compared with that of non-silenced control plants. CaGLP1 silencing in pepper leaves did not accumulate H2O2 and induce cell death during incompatible Xcv infection. Defense-related CaDEF1 (defensin) gene expression was significantly reduced in CaGLP1-silenced pepper plants. CaGLP1-overexpression in Arabidopsis thaliana enhanced resistance to Pseudomonas syringae pv. tomato. Defense-related AtPDF1.2 expression was elevated in CaGLP1-overexpression lines. Together, these results suggest that CaGLP1 is required for plant cell death and defense responses through the reactive oxygen species burst and downstream defense-related gene expression in response to bacterial pathogen challenge. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Crystal structure of caspase recruiting domain (CARD) of apoptosis repressor with CARD (ARC) and its implication in inhibition of apoptosis

PubMed Central

Jang, Tae-ho; Kim, Seong Hyun; Jeong, Jae-Hee; Kim, Sunghwan; Kim, Yeun Gil; Park, Hyun Ho

2015-01-01

Apoptosis repressor with caspase recruiting domain (ARC) is a multifunctional inhibitor of apoptosis that is unusually over-expressed or activated in various cancers and in the state of the pulmonary hypertension. Therefore, ARC might be an optimal target for therapeutic intervention. Human ARC is composed of two distinct domains, N-terminal caspase recruiting domain (CARD) and C-terminal P/E (proline and glutamic acid) rich domain. ARC inhibits the extrinsic apoptosis pathway by interfering with DISC formation. ARC CARD directly interacts with the death domains (DDs) of Fas and FADD, as well as with the death effector domains (DEDs) of procaspase-8. Here, we report the first crystal structure of the CARD domain of ARC at a resolution of 2.4 Å. Our structure was a dimer with novel homo-dimerization interfaces that might be critical to its inhibitory function. Interestingly, ARC did not exhibit a typical death domain fold. The sixth helix (H6), which was detected at the typical death domain fold, was not detected in the structure of ARC, indicating that H6 may be dispensable for the function of the death domain superfamily. PMID:26038885

Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity.

PubMed

Pinheiro, Anderson S; Proell, Martina; Eibl, Clarissa; Page, Rebecca; Schwarzenbacher, Robert; Peti, Wolfgang

2010-08-27

The innate immune system provides an initial line of defense against infection. Nucleotide-binding domain- and leucine-rich repeat-containing protein (NLR or (NOD-like)) receptors play a critical role in the innate immune response by surveying the cytoplasm for traces of intracellular invaders and endogenous stress signals. NLRs themselves are multi-domain proteins. Their N-terminal effector domains (typically a pyrin or caspase activation and recruitment domain) are responsible for driving downstream signaling and initiating the formation of inflammasomes, multi-component complexes necessary for cytokine activation. However, the currently available structures of NLR effector domains have not yet revealed the mechanism of their differential modes of interaction. Here, we report the structure and dynamics of the N-terminal pyrin domain of NLRP7 (NLRP7 PYD) obtained by NMR spectroscopy. The NLRP7 PYD adopts a six-alpha-helix bundle death domain fold. A comparison of conformational and dynamics features of the NLRP7 PYD with other PYDs showed distinct differences for helix alpha3 and loop alpha2-alpha3, which, in NLRP7, is stabilized by a strong hydrophobic cluster. Moreover, the NLRP7 and NLRP1 PYDs have different electrostatic surfaces. This is significant, because death domain signaling is driven by electrostatic contacts and stabilized by hydrophobic interactions. Thus, these results provide new insights into NLRP signaling and provide a first molecular understanding of inflammasome formation.

Military Service Member and Veteran Reintegration: A Conceptual Analysis, Unified Definition, and Key Domains

PubMed Central

Elnitsky, Christine A.; Fisher, Michael P.; Blevins, Cara L.

2017-01-01

Returning military service members and veterans (MSMVs) may experience a variety of stress-related disorders and challenges when reintegrating from the military to the community. Facilitating the reintegration, transition, readjustment and coping, and community integration, of MSMVs is a societal priority. To date, research addressing MSMV reintegration has not identified a comprehensive definition of the term or defined the broader context within which the process of reintegration occurs although both are needed to promote valid and reliable measurement of reintegration and clarify related challenges, processes, and their impact on outcomes. Therefore, this principle-based concept analysis sought to review existing empirical reintegration measurement instruments and identify the problems and needs of MSMV reintegration to provide a unified definition of reintegration to guide future research, clinical practice, and related services. We identified 1,459 articles in the health and social sciences literature, published between 1990 and 2015, by searching multiple electronic databases. Screening of abstracts and full text review based on our inclusion/exclusion criteria, yielded 117 articles for review. Two investigators used constant conceptual comparison to evaluate relevant articles independently. We examined the term reintegration and related terms (i.e., transition, readjustment, community integration) identifying trends in their use over time, analyzed the eight reintegration survey instruments, and synthesized service member and veteran self-reported challenges and needs for reintegration. More reintegration research was published during the last 5 years (n = 373) than in the previous 10 years combined (n = 130). The research suggests coping with life stresses plays an integral role in military service member and veteran post-deployment reintegration. Key domains of reintegration include individual, interpersonal, community organizations, and societal factors

Military Service Member and Veteran Reintegration: A Conceptual Analysis, Unified Definition, and Key Domains.

PubMed

Elnitsky, Christine A; Fisher, Michael P; Blevins, Cara L

2017-01-01

Returning military service members and veterans (MSMVs) may experience a variety of stress-related disorders and challenges when reintegrating from the military to the community. Facilitating the reintegration, transition, readjustment and coping, and community integration, of MSMVs is a societal priority. To date, research addressing MSMV reintegration has not identified a comprehensive definition of the term or defined the broader context within which the process of reintegration occurs although both are needed to promote valid and reliable measurement of reintegration and clarify related challenges, processes, and their impact on outcomes. Therefore, this principle-based concept analysis sought to review existing empirical reintegration measurement instruments and identify the problems and needs of MSMV reintegration to provide a unified definition of reintegration to guide future research, clinical practice, and related services. We identified 1,459 articles in the health and social sciences literature, published between 1990 and 2015, by searching multiple electronic databases. Screening of abstracts and full text review based on our inclusion/exclusion criteria, yielded 117 articles for review. Two investigators used constant conceptual comparison to evaluate relevant articles independently. We examined the term reintegration and related terms (i.e., transition, readjustment, community integration) identifying trends in their use over time, analyzed the eight reintegration survey instruments, and synthesized service member and veteran self-reported challenges and needs for reintegration. More reintegration research was published during the last 5 years ( n = 373) than in the previous 10 years combined ( n = 130). The research suggests coping with life stresses plays an integral role in military service member and veteran post-deployment reintegration. Key domains of reintegration include individual, interpersonal, community organizations, and societal factors

Apoptosis in fish: environmental factors and programmed cell death.

PubMed

AnvariFar, Hossein; Amirkolaie, Abdolsamad Keramat; Miandare, Hamed Kolangi; Ouraji, Hossein; Jalali, M Ali; Üçüncü, Sema İşisağ

2017-06-01

Apoptosis, a form of programmed cell death, is a critical component in maintaining homeostasis and growth in all tissues and plays a significant role in immunity and cytotoxicity. In contrast to necrosis or traumatic cell death, apoptosis is a well-controlled and vital process characterized mainly by cytoplasmic shrinkage, chromatin condensation, DNA fragmentation, membrane blebbing and apoptotic bodies. Our understanding of apoptosis is partly based on observations in invertebrates but mainly in mammals. Despite the great advantages of fish models in studying vertebrate development and diseases and the tremendous interest observed in recent years, reports on apoptosis in fish are still limited. Although apoptotic machinery is well conserved between aquatic and terrestrial organisms throughout the history of evolution, some differences exist in key components of apoptotic pathways. Core parts of apoptotic machinery in fish are virtually expressed as equivalent to the mammalian models. Some differences are, however, evident, such as the extrinsic and intrinsic pathways of apoptosis including lack of a C-terminal region in the Fas-associated protein with a death domain in fish. Aquatic species inhabit a complex and highly fluctuating environment, making these species good examples to reveal features of apoptosis that may not be easily investigated in mammals. Therefore, in order to gain a wider view on programmed cell death in fish, interactions between the main environmental factors, chemicals and apoptosis are discussed in this review. It is indicated that apoptosis can be induced in fish by exposure to environmental stressors during different stages of the fish life cycle.

Preliminary identification of key clinical domains for outcome evaluation in fibromyalgia using the Delphi method: the Italian experience.

PubMed

Salaffi, F; Ciapetti, A; Sarzi Puttini, P; Atzeni, F; Iannuccelli, C; Di Franco, M; Cazzola, M; Bazzichi, L

2012-03-19

Fibromyalgia (FM) is a complex syndrome that, in Italy, affects at least 2% of the adult population. It is characterized by chronic widespread musculoskeletal pain often accompanied by multiple other symptoms. The aim of this study was to identify a set of clinical domains for FM considered relevant by both clinicians and patients using a consensus process. Consensus was achieved using the Delphi method based on questionnaires and systematic, controlled opinion feedback. The Delphi exercise involved a panel of 252 rheumatologists and 86 patients with FM as defined by the American College of Rheumatology criteria. All of the patients and clinicians were asked to rank the relative different domains of FM in order of priority. The content validity index (CVI) was used to establish the percentage agreement. The importance of each item was ranked on a 0-3 Likert scale. The frequency, mean relevance scores, and frequency importance product were also calculated. The Delphi exercise showed that the domains ranked highest by patients were similar to those of the clinicians, with the exception of tender point intensity (considered relevant by the clinicians but not by the patients) and environmental sensitivity (considered important by the patients but not by the clinicians). A final 8-item model was developed which was considered to demonstrate adequate validity. The Delphi exercises identified and ranked relevant key clinical domains that need to be assessed in FM research. On the basis of these results, a new patient-reported composite outcome index can be developed and used in clinical trials.

Engineering death receptor ligands for cancer therapy.

PubMed

Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

2013-05-28

CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand-based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

'Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death.

PubMed

Qiu, Shiqiao; Liu, Jing; Xing, Feiyue

2017-04-01

Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.

Conditional disruption of the prolyl hydroxylase domain-containing protein 2 (Phd2) gene defines its key role in skeletal development.

PubMed

Cheng, Shaohong; Xing, Weirong; Pourteymoor, Sheila; Mohan, Subburaman

2014-10-01

We have previously shown that the increase in osterix (Osx) expression during osteoblast maturation is dependent on the activity of the prolyl hydroxylase domain-containing protein 2 (Phd2), a key regulator of protein levels of the hypoxia-inducible factor family proteins in many tissues. In this study, we generated conditional Phd2 knockout mice (cKO) in osteoblast lineage cells by crossing floxed Phd2 mice with a Col1α2-iCre line to investigate the function of Phd2 in vivo. The cKO mice developed short stature and premature death at 12 to 14 weeks of age. Bone mineral content, bone area, and bone mineral density were decreased in femurs and tibias, but not vertebrae of the cKO mice compared to WT mice. The total volume (TV), bone volume (BV), and bone volume fraction (BV/TV) in the femoral trabecular bones of cKO mice were significantly decreased. Cross-sectional area of the femoral mid-diaphysis was also reduced in the cKO mice. The reduced bone size and trabecular bone volume in the cKO mice were a result of impaired bone formation but not bone resorption as revealed by dynamic histomorphometric analyses. Bone marrow stromal cells derived from cKO mice formed fewer and smaller nodules when cultured with mineralization medium. Quantitative RT-PCR and immunohistochemistry detected reduced expression of Osx, osteocalcin, and bone sialoprotein in cKO bone cells. These data indicate that Phd2 plays an important role in regulating bone formation in part by modulating expression of Osx and bone formation marker genes. © 2014 American Society for Bone and Mineral Research.

Low Performance on Mathematical Tasks in Preschoolers: The Importance of Domain-General and Domain-Specific Abilities

ERIC Educational Resources Information Center

Costa, H. M.; Nicholson, B.; Donlan, C.; Van Herwegen, J.

2018-01-01

Background: Different domain-specific and domain-general cognitive precursors play a key role in the development of mathematical abilities. The contribution of these domains to mathematical ability changes during development. Primary school-aged children who show mathematical difficulties form a heterogeneous group, but it is not clear whether…

Near-Death Experiences and Posttraumatic Growth.

PubMed

Khanna, Surbhi; Greyson, Bruce

2015-10-01

Posttraumatic growth denotes positive psychological change after a traumatic experience that is an improvement over the state before the trauma. Inasmuch as it involves existential reevaluation, posttraumatic growth overlaps with spiritual change, although it also encompasses other domains of positive outcome. This study investigated posttraumatic growth and presence and depth of near-death experience at the time of the close brush with death among 251 survivors of a close brush with death, using the Posttraumatic Growth Inventory and the Near-Death Experience (NDE) Scale. Near-death experiences were associated with greater posttraumatic growth than were close brushes with death in the absence of such an experience, and scores on the NDE Scale were significantly correlated with scores on the Posttraumatic Growth Inventory. To the extent that NDEs are interpreted as spiritual events, these findings support prior research suggesting that spiritual factors make a significant contribution to posttraumatic growth and are consistent with the model that posits challenges to the assumptive worldview as a major stimulus to posttraumatic growth.

Solution NMR investigation of the CD95/FADD homotypic death domain complex suggests lack of engagement of the CD95 C terminus.

PubMed

Esposito, Diego; Sankar, Andrew; Morgner, Nina; Robinson, Carol V; Rittinger, Katrin; Driscoll, Paul C

2010-10-13

We have addressed complex formation between the death domain (DD) of the death receptor CD95 (Fas/APO-1) with the DD of immediate adaptor protein FADD using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and size-exclusion chromatography with in-line light scattering. We find complexation to be independent of the C-terminal 12 residues of CD95 and insensitive to mutation of residues that engage in the high-order clustering of CD95-DD molecules in a recently reported crystal structure obtained at pH 4. Differential NMR linewidths indicate that the C-terminal region of the CD95 chains remains in a disordered state and (13)C-methyl TROSY data are consistent with a lack of high degree of symmetry for the complex. The overall molecular mass of the complex is inconsistent with that in the crystal structure, and the complex dissociates at pH 4. We discuss these findings using sequence analysis of CD95 orthologs and the effect of FADD mutations on the interaction with CD95. Copyright © 2010 Elsevier Ltd. All rights reserved.

Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43

PubMed Central

Meessen-Pinard, Mathieu; Le Coupanec, Alain

2016-01-01

ABSTRACT Human coronaviruses (HCoV) are respiratory pathogens with neuroinvasive, neurotropic, and neurovirulent properties, highlighting the importance of studying the potential implication of these viruses in neurological diseases. The OC43 strain (HCoV-OC43) was reported to induce neuronal cell death, which may participate in neuropathogenesis. Here, we show that HCoV-OC43 harboring two point mutations in the spike glycoprotein (rOC/Us183–241) was more neurovirulent than the wild-type HCoV-OC43 (rOC/ATCC) in mice and induced more cell death in murine and human neuronal cells. To evaluate the role of regulated cell death (RCD) in HCoV-OC43-mediated neural pathogenesis, we determined if knockdown of Bax, a key regulator of apoptosis, or RIP1, a key regulator of necroptosis, altered the percentage of neuronal cell death following HCoV-OC43 infection. We found that Bax-dependent apoptosis did not play a significant role in RCD following infection, as inhibition of Bax expression mediated by RNA interference did not confer cellular protection against the cell death process. On the other hand, we demonstrated that RIP1 and MLKL were involved in neuronal cell death, as RIP1 knockdown and chemical inhibition of MLKL significantly increased cell survival after infection. Taken together, these results indicate that RIP1 and MLKL contribute to necroptotic cell death after HCoV-OC43 infection to limit viral replication. However, this RCD could lead to neuronal loss in the mouse CNS and accentuate the neuroinflammation process, reflecting the severity of neuropathogenesis. IMPORTANCE Because they are naturally neuroinvasive and neurotropic, human coronaviruses are suspected to participate in the development of neurological diseases. Given that the strain OC43 is neurovirulent in mice and induces neuronal cell death, we explored the neuronal response to infection by characterizing the activation of RCD. Our results revealed that classical apoptosis associated with the Bax

Identification of novel key amino acids at the interface of the transmembrane domains of human BST-2 and HIV-1 Vpu.

PubMed

Pang, Xiaojing; Hu, Siqi; Li, Jian; Xu, Fengwen; Mei, Shan; Zhou, Jinming; Cen, Shan; Jin, Qi; Guo, Fei

2013-08-06

BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu. Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14-16 (AII to VAA) and 26-28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14-16 (AII to VAA) and 26-28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization. Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu.

Identification of novel key amino acids at the interface of the transmembrane domains of human BST-2 and HIV-1 Vpu

PubMed Central

2013-01-01

Background BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu. Results Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14–16 (AII to VAA) and 26–28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14–16 (AII to VAA) and 26–28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization. Conclusions Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu. PMID:23919512

Making death 'good': instructional tales for dying in newspaper accounts of Jade Goody's death.

PubMed

Frith, Hannah; Raisborough, Jayne; Klein, Orly

2013-03-01

Facilitating a 'good' death is a central goal for hospices and palliative care organisations. The key features of such a death include an acceptance of death, an open awareness of and communication about death, the settling of practical and interpersonal business, the reduction of suffering and pain, and the enhancement of autonomy, choice and control. Yet deaths are inherently neither good nor bad; they require cultural labour to be 'made over' as good. Drawing on media accounts of the controversial death of UK reality television star Jade Goody, and building on existing analyses of her death, we examine how cultural discourses actively work to construct deaths as good or bad and to position the dying and those witnessing their death as morally accountable. By constructing Goody as bravely breaking social taboos by openly acknowledging death, by contextualising her dying as occurring at the end of a life well lived and by emphasising biographical continuity and agency, newspaper accounts serve to position themselves as educative rather than exploitative, and readers as information-seekers rather than ghoulishly voyeuristic. We argue that popular culture offers moral instruction in dying well which resonates with the messages from palliative care. © 2012 The Authors. Sociology of Health & Illness © 2012 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.

Cytosolic activation of cell death and stem rust resistance by cereal MLA-family CC-NLR proteins.

PubMed

Cesari, Stella; Moore, John; Chen, Chunhong; Webb, Daryl; Periyannan, Sambasivam; Mago, Rohit; Bernoux, Maud; Lagudah, Evans S; Dodds, Peter N

2016-09-06

Plants possess intracellular immune receptors designated "nucleotide-binding domain and leucine-rich repeat" (NLR) proteins that translate pathogen-specific recognition into disease-resistance signaling. The wheat immune receptors Sr33 and Sr50 belong to the class of coiled-coil (CC) NLRs. They confer resistance against a broad spectrum of field isolates of Puccinia graminis f. sp. tritici, including the Ug99 lineage, and are homologs of the barley powdery mildew-resistance protein MLA10. Here, we show that, similarly to MLA10, the Sr33 and Sr50 CC domains are sufficient to induce cell death in Nicotiana benthamiana Autoactive CC domains and full-length Sr33 and Sr50 proteins self-associate in planta In contrast, truncated CC domains equivalent in size to an MLA10 fragment for which a crystal structure was previously determined fail to induce cell death and do not self-associate. Mutations in the truncated region also abolish self-association and cell-death signaling. Analysis of Sr33 and Sr50 CC domains fused to YFP and either nuclear localization or nuclear export signals in N benthamiana showed that cell-death induction occurs in the cytosol. In stable transgenic wheat plants, full-length Sr33 proteins targeted to the cytosol provided rust resistance, whereas nuclear-targeted Sr33 was not functional. These data are consistent with CC-mediated induction of both cell-death signaling and stem rust resistance in the cytosolic compartment, whereas previous research had suggested that MLA10-mediated cell-death and disease resistance signaling occur independently, in the cytosol and nucleus, respectively.

Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition.

PubMed

Liu, Zhonghua; Wang, Chuanping; Rathkey, Joseph K; Yang, Jie; Dubyak, George R; Abbott, Derek W; Xiao, Tsan Sam

2018-05-01

Pyroptosis is an inflammatory form of programmed cell death that plays important roles in immune protection against infections and in inflammatory disorders. Gasdermin D (GSDMD) is an executor of pyroptosis upon cleavage by caspases-1/4/5/11 following canonical and noncanonical inflammasome activation. GSDMD N-terminal domain assembles membrane pores to induce cytolysis, whereas its C-terminal domain inhibits cell death through intramolecular association with the N domain. The molecular mechanisms of autoinhibition for GSDMD are poorly characterized. Here we report the crystal structures of the human and murine GSDMD C-terminal domains, which differ from those of the full-length murine GSDMA3 and the human GSDMB C-terminal domain. Mutations of GSDMD C-domain residues predicted to locate at its interface with the N-domain enhanced pyroptosis. Our results suggest that GSDMDs may employ a distinct mode of intramolecular domain interaction and autoinhibition, which may be relevant to its unique role in pyroptosis downstream of inflammasome activation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Framing Effects: Dynamics and Task Domains

PubMed

Wang

1996-11-01

The author examines the mechanisms and dynamics of framing effects in risky choices across three distinct task domains (i.e., life-death, public property, and personal money). The choice outcomes of the problems presented in each of the three task domains had a binary structure of a sure thing vs a gamble of equal expected value; the outcomes differed in their framing conditions and the expected values, raging from 6000, 600, 60, to 6, numerically. It was hypothesized that subjects would become more risk seeking, if the sure outcome was below their aspiration level (the minimum requirement). As predicted, more subjects preferred the gamble when facing the life-death choice problems than facing the counterpart problems presented in the other two task domains. Subjects' risk preference varied categorically along the group size dimension in the life-death domain but changed more linearly over the expected value dimension in the monetary domain. Framing effects were observed in 7 of 13 pairs of problems, showing a positive frame-risk aversion and negative frame-risk seeking relationship. In addition, two types of framing effects were theoretically defined and empirically identified. A bidirectional framing effect involves a reversal in risk preference, and occurs when a decision maker's risk preference is ambiguous or weak. Four bidirectional effects were observed; in each case a majority of subjects preferred the sure outcome under a positive frame but the gamble under a negative frame. In contrast, a unidirectional framing effect refers to a preference shift due to the framing of choice outcomes: A majority of subjects preferred one choice outcome (either the sure thing or the gamble) under both framing conditions, with positive frame augmented the preference for the sure thing and negative frame augmented the preference for the gamble. These findings revealed some dynamic regularities of framing effects and posed implications for developing predictive and testable

Plasticity of a critical antigenic determinant in the West Nile virus NY99 envelope protein domain III.

PubMed

Plante, Jessica A; Torres, Maricela; Huang, Claire Y-H; Beasley, David W C

2016-09-01

West Nile virus (WNV) is a mosquito-borne flavivirus that causes febrile illness, encephalitis, and occasionally death in humans. The envelope protein is the main component of the WNV virion surface, and domain III of the envelope protein (EIII) is both a putative receptor binding domain and a target of highly specific, potently neutralizing antibodies. Envelope E-332 (E-332) is known to have naturally occurring variation and to be a key determinant of neutralization for anti-EIII antibodies. A panel of viruses containing all possible amino acid substitutions at E-332 was constructed. E-332 was found to be highly tolerant of mutation, and almost all of these changes had large impacts on antigenicity of EIII but only limited effects on growth or virulence phenotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Deaths: Leading Causes for 2015.

PubMed

Heron, Melonie

2017-11-01

Objectives-This report presents final 2015 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2015," the National Center for Health Statistics' annual report of final mortality statistics. Methods-Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2015. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. Results-In 2015, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Accidents (unintentional injuries); Cerebrovascular diseases; Alzheimer's disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2015 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. All material appearing in this report is in the public domain and may be reproduced or copied without

Deaths: Leading Causes for 2013.

PubMed

Heron, Melonie

2016-02-16

This report presents final 2013 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2013," the National Center for Health Statistics’ annual report of final mortality statistics. Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2013. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD–10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. In 2013, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Accidents (unintentional injuries); Cerebrovascular diseases; Alzheimer’s disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2013 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Newborn affected by maternal complications of pregnancy; Sudden infant death syndrome; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as

Deaths: Leading Causes for 2011.

PubMed

Heron, Melonie

2015-07-27

This report presents final 2011 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements ‘‘Deaths: Final Data for 2011,’’ the National Center for Health Statistics’ annual report of final mortality statistics. Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2011. Causes of death classified by the International Classification of Diseases, 10th Revision (ICD–10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. In 2011, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Cerebrovascular diseases; Accidents (unintentional injuries); Alzheimer’s disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2011 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. All material appearing in this report is in the public domain and may be reproduced or copied without permission

Death Attitudes and Changes in Existential Outlook in Parents of Vulnerable Newborns.

PubMed

Barr, Peter

2015-01-01

This study is an Actor-Partner Interdependence Model analysis of the relation of death attitudes with changes in outlook in 59 parent couples of neonatal intensive care newborns. Death attitudes effects with changes in outlook were mostly intrapersonal and they mainly occurred in fathers, though between gender differences were not usually significant. Death avoidance and neutral death acquiescence were positive predictors of positive changes in outlook, and fear of death and neutral death acquiescence were respective positive and inverse predictors of negative changes. Multidimensional measures of death attitudes and personal change should be used when studying these domains of psychological functioning.

Aberrant expression and function of death receptor-3 and death decoy receptor-3 in human cancer.

PubMed

Ge, Zhicheng; Sanders, Andrew J; Ye, Lin; Jiang, Wen G

2011-03-01

Death receptor-3 (DR3) and death decoy receptor-3 (DcR3) are both members of the tumour necrosis factor receptor (TNFR) superfamily. The TNFR superfamily contains eight death domain-containing receptors, including TNFR1 (also called DR1), Fas (also called DR2), DR3, DR4, DR5, DR6, NGFR and EDAR. Upon the binding of these receptors with their corresponding ligands, the death domain recruits various proteins that mediate both the death and proliferation of cells. Receptor function is negatively regulated by decoy receptors (DcR1, DcR2, DcR3 and OPG). DR3/DcR3 are a pair of positive and negative players with which vascular endothelial growth inhibitor (VEGI) interacts. VEGI has been suggested to be a potential tumour suppressor. The inhibitory effects of VEGI on cancer are manifested in three main areas: a direct effect on cancer cells, an anti-angiogenic effect on endothelial cells, and the stimulation of dendritic cell maturation. A recent study indicated that DR3 may be a new receptor for E-selectin, which has been reported to be associated with cancer metastasis. DcR3 is a soluble receptor, highly expressed in various tumours, which lacks an apparent transmembrane segment, prevents cytokine response through ligand binding and neutralization, and is an inhibitor of apoptosis. DcR3 serves as a decoy receptor for FasL, LIGHT and VEGI. The cytokine LIGHT activates various anti-tumour functions and is expected to be a promising candidate for cancer therapy. Certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing DcR3, which blocks FasL function. DR3/DcR3 play profound roles in regulating cell death and proliferation in cancer. The present review briefly discusses DR3/DcR3 and attempts to elucidate the role of these negative and positive players in cancer.

Programmed Cell Death During Caenorhabditis elegans Development

PubMed Central

Conradt, Barbara; Wu, Yi-Chun; Xue, Ding

2016-01-01

Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. PMID:27516615

Deaths: leading causes for 2010.

PubMed

Heron, Melonie

2013-12-20

This report presents final 2010 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements the Division of Vital Statistics' annual report of final mortality statistics. Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2010. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. In 2010, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Cerebrovascular diseases; Accidents (unintentional injuries); Alzheimer's disease; Diabetes mellitus; Nephritis, nephrotic syndrome and nephrosis; Influenza and pneumonia; and Intentional self-harm (suicide). These 10 causes accounted for 75% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2010 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Necrotizing enterocolitis of newborn. Important variations in the leading causes of infant death are noted for the neonatal and post-neonatal periods. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source

The physical size of transcription factors is key to transcriptional regulation in chromatin domains

NASA Astrophysics Data System (ADS)

Maeshima, Kazuhiro; Kaizu, Kazunari; Tamura, Sachiko; Nozaki, Tadasu; Kokubo, Tetsuro; Takahashi, Koichi

2015-02-01

Genetic information, which is stored in the long strand of genomic DNA as chromatin, must be scanned and read out by various transcription factors. First, gene-specific transcription factors, which are relatively small (˜50 kDa), scan the genome and bind regulatory elements. Such factors then recruit general transcription factors, Mediators, RNA polymerases, nucleosome remodellers, and histone modifiers, most of which are large protein complexes of 1-3 MDa in size. Here, we propose a new model for the functional significance of the size of transcription factors (or complexes) for gene regulation of chromatin domains. Recent findings suggest that chromatin consists of irregularly folded nucleosome fibres (10 nm fibres) and forms numerous condensed domains (e.g., topologically associating domains). Although the flexibility and dynamics of chromatin allow repositioning of genes within the condensed domains, the size exclusion effect of the domain may limit accessibility of DNA sequences by transcription factors. We used Monte Carlo computer simulations to determine the physical size limit of transcription factors that can enter condensed chromatin domains. Small gene-specific transcription factors can penetrate into the chromatin domains and search their target sequences, whereas large transcription complexes cannot enter the domain. Due to this property, once a large complex binds its target site via gene-specific factors it can act as a ‘buoy’ to keep the target region on the surface of the condensed domain and maintain transcriptional competency. This size-dependent specialization of target-scanning and surface-tethering functions could provide novel insight into the mechanisms of various DNA transactions, such as DNA replication and repair/recombination.

Comparison of Types of Cell Death: Apoptosis and Necrosis.

ERIC Educational Resources Information Center

Manning, Francis; Zuzel, Katherine

2003-01-01

Cell death is an essential factor in many biological processes including development. Discusses two types of cell death: (1) necrosis (induced by sodium azide); and (2) apoptosis (induced by sodium chromate). Illustrates key features that differ between these two types of cells death including loss of membrane integrity and internucleosomal DNA…

Hypertrophic Cardiomyopathy: Practical Steps for Preventing Sudden Death.

ERIC Educational Resources Information Center

Maron, Barry J.

2002-01-01

Hypertrophic cardiomyopathy (HCM) is a rare cause of death among athletes, with deaths occurring in young, apparently healthy people. Differentiating HCM from conditioning hypertrophy is challenging. Routine detection involves family history, physical examination, electrocardiography, and echocardiography. Keys to differential diagnosis include…

‘Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death

PubMed Central

Qiu, Shiqiao; Liu, Jing; Xing, Feiyue

2017-01-01

Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases. PMID:28362726

Cytoskeleton-interacting LIM-domain protein CRP1 suppresses cell proliferation and protects from stress-induced cell death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Latonen, Leena; Jaervinen, Paeivi M.; Haartman Institute, University of Helsinki, FIN-00014 Helsinki

2008-02-15

Members of the cysteine-rich protein (CRP) family are actin cytoskeleton-interacting LIM-domain proteins known to act in muscle cell differentiation. We have earlier found that CRP1, a founding member of this family, is transcriptionally induced by UV radiation in human diploid fibroblasts [M. Gentile, L. Latonen, M. Laiho, Cell cycle arrest and apoptosis provoked by UV radiation-induced DNA damage are transcriptionally highly divergent responses, Nucleic Acids Res. 31 (2003) 4779-4790]. Here we show that CRP1 is induced by growth-inhibitory signals, such as increased cellular density, and cytotoxic stress induced by UV radiation or staurosporine. We found that high levels of CRP1more » correlate with differentiation-associated morphology towards the myofibroblast lineage and that expression of ectopic CRP1 suppresses cell proliferation. Following UV- and staurosporine-induced stresses, expression of CRP1 provides a survival advantage evidenced by decreased cellular death and increased cellular metabolic activity and attachment. Our studies identify that CRP1 is a novel stress response factor, and provide evidence for its growth-inhibitory and cytoprotective functions.« less

Hospice-assisted death? A study of Oregon hospices on death with dignity.

PubMed

Campbell, Courtney S; Cox, Jessica C

2012-05-01

Nearly 90% of terminally ill patients who have used Oregon's distinctive death with dignity law to receive a medication to end their lives are enrolled in hospice care programs. In 2009-2010, we conducted a study of the policies developed by Oregon hospices to address patient inquiries and requests for death with dignity. The study examined the stated hospice values and positions and identified the boundaries to participation drawn by the hospice programs to protect personal and programmatic integrity. The boundaries were drawn around 6 key caregiving considerations: (1) language regarding physician-assisted death (PAD); (2) informed decision making by patients; (3) collaboration with physicians; (4) provision of lethal medication; (5) assistance in the patient's act of taking the medication; and (6) staff presence at the time of medication ingestion.

Older adults' perspectives on key domains of childhood social and economic experiences and opportunities: a first step to creating a multidimensional measure

PubMed Central

Yen, Irene H; Stewart, Anita L; Scherzer, Teresa; Pérez-Stable, Eliseo J

2007-01-01

Objectives Although research has found that childhood socioeconomic status (SES) is associated with physical and mental health in mid- and later life, most of these studies used conventional, single dimension SES measures for the childhood period such as household income or educational attainment of parents. Life course and health disparities research would benefit from identification and measurement of a variety of childhood social and economic experiences and opportunities that might affect health in later life. Design This study utilized qualitative research methods to identify key dimensions of childhood experiences related to SES. We conducted in-depth interviews with 25 adults age 55 to 80 years from diverse economic and ethnic backgrounds. Topics included home, neighborhood, school, and work experiences during early childhood and adolescence. Interviews were audio-taped and transcripts were coded to identify thematic domains. Results We identified eight thematic domains, many of which had clear subdomains: home and family circumstances, neighborhood, work and money, potential for advancement through schooling, school quality and content, discrimination, influence and support of adults, and leisure activities. These domains highlight individual characteristics and experiences and also economic and educational opportunities. Conclusion These domains of childhood social and economic circumstances add breadth and depth to conventional conceptualization of childhood SES. When the domains are translated into a measurement tool, it will allow for the possibility of classifying people along multiple dimensions, such as from a low economic circumstance with high levels of adult support. PMID:17986341

Loss of BID Delays FASL-Induced Cell Death of Mouse Neutrophils and Aggravates DSS-Induced Weight Loss.

PubMed

Wicki, Simone; Gurzeler, Ursina; Corazza, Nadia; Genitsch, Vera; Wong, Wendy Wei-Lynn; Kaufmann, Thomas

2018-02-28

Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID.

Loss of BID Delays FASL-Induced Cell Death of Mouse Neutrophils and Aggravates DSS-Induced Weight Loss

PubMed Central

Wicki, Simone; Gurzeler, Ursina; Corazza, Nadia; Genitsch, Vera

2018-01-01

Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID. PMID:29495595

Identification of pneumonia and influenza deaths using the death certificate pipeline

PubMed Central

2012-01-01

alternative that allows for coding free-text death certificates in real time that may increase its utilization not only in the public health domain but also for biomedical researchers and developers. Trial Registration This study did not involved any clinical trials. PMID:22569097

Independent regulation of reovirus membrane penetration and apoptosis by the mu1 phi domain.

PubMed

Danthi, Pranav; Coffey, Caroline M; Parker, John S L; Abel, Ty W; Dermody, Terence S

2008-12-01

Apoptosis plays an important role in the pathogenesis of reovirus encephalitis. Reovirus outer-capsid protein mu1, which functions to penetrate host cell membranes during viral entry, is the primary regulator of apoptosis following reovirus infection. Ectopic expression of full-length and truncated forms of mu1 indicates that the mu1 phi domain is sufficient to elicit a cell death response. To evaluate the contribution of the mu1 phi domain to the induction of apoptosis following reovirus infection, phi mutant viruses were generated by reverse genetics and analyzed for the capacity to penetrate cell membranes and elicit apoptosis. We found that mutations in phi diminish reovirus membrane penetration efficiency by preventing conformational changes that lead to generation of key reovirus entry intermediates. Independent of effects on membrane penetration, amino acid substitutions in phi affect the apoptotic potential of reovirus, suggesting that phi initiates apoptosis subsequent to cytosolic delivery. In comparison to wild-type virus, apoptosis-defective phi mutant viruses display diminished neurovirulence following intracranial inoculation of newborn mice. These results indicate that the phi domain of mu1 plays an important regulatory role in reovirus-induced apoptosis and disease.

Aspartate 102 in the Heme Domain of Soluble Guanylyl Cyclase Has a Key Role in NO Activation

PubMed Central

Baskaran, Padmamalini; Heckler, Erin J.; van den Akker, Focco; Beuve, Annie

2012-01-01

Nitric oxide (NO) is involved in the physiology and pathophysiology of the cardiovascular and neuronal systems via activation of soluble guanylyl cyclase (sGC), a heme-containing heterodimer. Recent structural studies have allowed a better understanding of the residues that dictate the affinity and binding of NO to the heme and the resulting breakage of the bond between the heme iron and histidine 105 (H105) of the β subunit of sGC. Still, it is unknown how the breakage of the iron–His bond translates into NO-dependent increased catalysis. Structural studies on homologous H-NOX domains in various states pointed to a role for movement of the H105 containing αF helix. Our modeling of the heme-binding domain highlighted conserved residues in the vicinity of H105 that could potentially regulate the extent to which the αF helix shifts and/or propagate the activation signal once the covalent bond with H105 has been broken. These include a direct interaction of αF helix residue D102 with the backbone nitrogen of F120. Mutational analysis of this region points to an essential role of the interactions in the vicinity of H105 for heme stability and identifies aspartate 102 (D102) as having a key role in NO activation following breakage of the iron–His bond. PMID:21491881

Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.

PubMed

Chaabane, Wiem; Cieślar-Pobuda, Artur; El-Gazzah, Mohamed; Jain, Mayur V; Rzeszowska-Wolny, Joanna; Rafat, Mehrdad; Stetefeld, Joerg; Ghavami, Saeid; Los, Marek J

2014-09-01

The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Regulatory role of calpain in neuronal death

PubMed Central

Cheng, Si-ying; Wang, Shu-chao; Lei, Ming; Wang, Zhen; Xiong, Kun

2018-01-01

Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases. PMID:29623944

Good and bad death: exploring the perspectives of older Mexican Americans.

PubMed

Ko, Eunjeong; Cho, Sunhee; Perez, Ramona L; Yeo, Younsook; Palomino, Helen

2013-01-01

The purpose of this study was to identify and describe the domains that define a good death from the perspectives of healthy Mexican American older adults. Qualitative data from face-to-face interviews with 18 participants residing in Southern California were analyzed. Five categories regarding the concepts of good and bad death include no suffering, living life with faith, having time for closure with family, dying at home, and a natural death. Understanding the meaning of good and bad death within specific cultural contexts is integral to promoting cultural sensitivity when working with older adults, especially in end-of-life care.

Prominent dominant negative effect of a mutant Fas molecule lacking death domain on cell-mediated induction of apoptosis.

PubMed

Yokota, Aya; Takeuchi, Emiko; Iizuka, Misao; Ikegami, Yuko; Takayama, Hajime; Shinohara, Nobukata

2005-01-01

Using a panel of transfectant B lymphoma cells expressing varying amounts of the mutant Fas together with the endogenous wild type Fas, semi-quantitative studies on the dominant negative effect of a murine mutant Fas molecule lacking death domain were carried out. In anti-Fas antibody-mediated induction of apoptosis, the mutant molecules exerted significant dominant-negative effect only when their expression level was comparable to or higher than that of wild type molecules, or when exposed to low amounts of the antibody. The inhibitory effect was accompanied by the failure in DISC formation in spite of Fas aggregation. When they were subjected to T cell-mediated Fas-based induction of apoptosis, however, the dominant negative effect was prominent such that the expression of even a small amount of the mutant molecules resulted in significant inhibition. Such a strong inhibitory effect explains the dominant phenotype of this type of mutant Fas molecules in ALPS heterozygous patients and also implies that the physiological effectors for Fas in vivo are cells, i.e., FasL-expressing activated T cells.

Birth, growth and death of an antivortex during the propagation of a transverse domain wall in magnetic nanostrips

NASA Astrophysics Data System (ADS)

Yuan, H. Y.; Wang, X. R.

2014-11-01

Antivortex birth, growth and death accompanying the propagation of a transverse domain wall (DW) in magnetic nanostrips are observed and analyzed. Antivortex formation is an intrinsic process of a strawberry-like transverse DW originated from magnetostatic interaction. Under an external magnetic field, the wider width region of a DW tends to move faster than the narrower one. This speed mismatch tilts and elongates DW center line. As a result, an antivortex with a well-defined polarity is periodically born near the tail of the DW center line. The antivortex either moves along the center line and dies on the other side of the nanostrip, or grows to its maximum size, detaches itself from the DW, and vanishes eventually. The former route reverses the polarity of DW while the later keeps the DW polarity unchanged. The evolution of the DW structures is analyzed using winding numbers assigned to each topological defects. The phase diagram in the field-width plane is obtained and the damping constant's influence on the phase diagram is discussed.

K6 linked polyubiquitylation of FADD by CHIP prevents death inducing signaling complex formation suppressing cell death.

PubMed

Seo, Jinho; Lee, Eun-Woo; Shin, Jihye; Seong, Daehyeon; Nam, Young Woo; Jeong, Manhyung; Lee, Seon-Hyeong; Lee, Cheolju; Song, Jaewhan

2018-05-23

Fas-associated death domain (FADD) is an adaptor protein recruiting complexes of caspase 8 to death ligand receptors to induce extrinsic apoptotic cell death in response to a TNF superfamily member. Although, formation of the complex of FADD and caspase 8 upon death stimuli has been studied in detail, posttranslational modifications fine-tuning these processes have yet to be identified. Here we revealed that K6-linked polyubiquitylation of FADD on lysines 149 and 153 mediated by C terminus HSC70-interacting protein (CHIP) plays an important role in preventing formation of the death inducing signaling complex (DISC), thus leading to the suppression of cell death. Cells depleted of CHIP showed higher sensitivity toward death ligands such as FasL and TRAIL, leading to upregulation of DISC formation composed of a death receptor, FADD, and caspase 8. CHIP was able to bind to FADD, induce K6-linked polyubiquitylation of FADD, and suppress DISC formation. By mass spectrometry, lysines 149 and 153 of FADD were found to be responsible for CHIP-mediated FADD ubiquitylation. FADD mutated at these sites was capable of more potent cell death induction as compared with the wild type and was no longer suppressed by CHIP. On the other hand, CHIP deficient in E3 ligase activity was not capable of suppressing FADD function and of FADD ubiquitylation. CHIP depletion in ME-180 cells induced significant sensitization of these cells toward TRAIL in xenograft analyses. These results imply that K6-linked ubiquitylation of FADD by CHIP is a crucial checkpoint in cytokine-dependent extrinsic apoptosis.

Proteomics and Functional Analyses of Pepper Abscisic Acid–Responsive 1 (ABR1), Which Is Involved in Cell Death and Defense Signaling[C][W

PubMed Central

Choi, Du Seok; Hwang, Byung Kook

2011-01-01

Abscisic acid (ABA) is a key regulator of plant growth and development, as well as plant defense responses. A high-throughput in planta proteome screen identified the pepper (Capsicum annuum) GRAM (for glucosyltransferases, Rab-like GTPase activators, and myotubularins) domain-containing ABA-RESPONSIVE1 (ABR1), which is highly induced by infection with avirulent Xanthomonas campestris pv vesicatoria and also by treatment with ABA. The GRAM domain is essential for the cell death response and for the nuclear localization of ABR1. ABR1 is required for priming cell death and reactive oxygen species production, as well as ABA-salicylic acid (SA) antagonism. Silencing of ABR1 significantly compromised the hypersensitive response but enhanced bacterial pathogen growth and ABA levels in pepper. High levels of ABA in ABR1-silenced plants antagonized the SA levels induced by pathogen infection. Heterologous transgenic expression of ABR1 in Arabidopsis thaliana conferred enhanced resistance to Pseudomonas syringae pv tomato and Hyaloperonospora arabidopsidis infection. The susceptibility of the Arabidopsis ABR1 putative ortholog mutant, abr1, to these pathogens also supports the involvement of ABR1 in disease resistance. Together, these results reveal ABR1 as a novel negative regulator of ABA signaling and suggest that the nuclear ABR1 pool is essential for the cell death induction associated with ABA-SA antagonism. PMID:21335377

The relationships of attachment style and social maladjustment to death ideation in depressed women with a history of childhood sexual abuse.

PubMed

Smith, Phillip N; Gamble, Stephanie A; Cort, Natalie A; Ward, Erin A; Conwell, Yeates; Talbot, Nancy L

2012-01-01

The current study examined the interaction of attachment orientation and acute social maladjustment as risk factors for death ideation in a sample of women with Major Depression and histories of childhood sexual abuse. Social maladjustment was associated with greater endorsement of death ideation. Avoidant and anxious attachment orientations moderated the social maladjustment and death ideation associations in some domains. Work-related maladjustment was associated with greater odds of death ideation for those with higher attachment avoidance. Parent-role maladjustment was associated with greater odds of death ideation for those with lower attachment anxiety. Findings demonstrate strong associations between death ideation and social maladjustment, and suggest that death ideation may be specific to certain domains of adjustment for anxious and avoidant attachment styles. © 2011 Wiley Periodicals, Inc.

[Organ donation after death in Moroccan population].

PubMed

Esqalli, Imane; Knidiri, Hafssa; Mahoungou, Gael; Aitlahcen, Zineb; Fadili, Wafaa; Laouad, Inass

2015-07-01

Morocco stays far behind other countries in the domain of organ donation and transplantation. Improving the knowledge of Moroccan students, about organ donation and transplantation, can be a key factor in the development of transplant activity. The aim of this study is to evaluate the knowledge, attitudes and beliefs of students concerning organ donation and transplantation. The opinion survey was conducted in Marrakech city, with four high education structures with a pre-established questionnaire. The survey questions answered four main themes, which are: the evaluation of knowledge, the opinion and attitude of citizen, the explanation of refusal and the propositions to encourage organ donation in Morocco. Hundred percent of surveyed subjects answered the questionnaire. Among them, 40.3% were men. The middle age was 21.5 years. Out of 503 surveyed students, 89.4% were aware of organ transplant in Morocco. A quarter of students believed that removal and transplant acts were realized just in public health establishments, which have the authorization. Two persons out of 3 were able to identify transplantable organs and tissues. More than half accepted to donate their organs after death. The religious reason was in the head list of refusal determinants of organ donation after death, with a prevalence of 39.7%. Young Moroccans have limited knowledge relating to organ donation. The development of this therapy needs to establish an adequate project of information and motivation of general population. Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Further considerations on in vitro skeletal muscle cell death

PubMed Central

Battistelli, Michela; Salucci, Sara; Burattini, Sabrina; Falcieri, Elisabetta

2013-01-01

Summary The present review discusses the apoptotic behavior induced by chemical and physical triggers in C2C12 skeletal muscle cells, comparing myoblast to myotube sensitivity, and investigating it by means of morphological, biochemical and cytofluorimetric analyses. After all treatments, myotubes, differently from myoblasts, showed a poor sensitivity to cell death. Intriguingly, in cells exposed to staurosporine, etoposide and UVB radiation, apoptotic and normal nuclei within the same fibercould be revealed. The presence of nuclear-dependent “territorial” death domains in the syncytium could explain a delayed cell death of myotubes compared to mononucleated cells. Moreover, autophagic granules abundantly appeared in myotubes after each treatment. Autophagy could protect muscle cell integrity against chemical and physical stimuli, making C2C12 myotubes, more resistant to cell death induction. PMID:24596689

Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.

PubMed

Jiang, Ke; Liu, Min; Lin, Guibin; Mao, Beibei; Cheng, Wei; Liu, Han; Gal, Jozsef; Zhu, Haining; Yuan, Zengqiang; Deng, Wuguo; Liu, Quentin; Gong, Peng; Bi, Xiaolin; Meng, Songshu

2016-05-03

The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner.

Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death

PubMed Central

Lin, Guibin; Mao, Beibei; Cheng, Wei; Liu, Han; Gal, Jozsef; Zhu, Haining; Yuan, Zengqiang; Deng, Wuguo; Liu, Quentin; Gong, Peng; Bi, Xiaolin; Meng, Songshu

2016-01-01

The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner. PMID:27028858

Amyloid cores in prion domains: Key regulators for prion conformational conversion.

PubMed

Fernández, María Rosario; Batlle, Cristina; Gil-García, Marcos; Ventura, Salvador

2017-01-02

Despite the significant efforts devoted to decipher the particular protein features that encode for a prion or prion-like behavior, they are still poorly understood. The well-characterized yeast prions constitute an ideal model system to address this question, because, in these proteins, the prion activity can be univocally assigned to a specific region of their sequence, known as the prion forming domain (PFD). These PFDs are intrinsically disordered, relatively long and, in many cases, of low complexity, being enriched in glutamine/asparagine residues. Computational analyses have identified a significant number of proteins having similar domains in the human proteome. The compositional bias of these regions plays an important role in the transition of the prions to the amyloid state. However, it is difficult to explain how composition alone can account for the formation of specific contacts that position correctly PFDs and provide the enthalpic force to compensate for the large entropic cost of immobilizing these domains in the initial assemblies. We have hypothesized that short, sequence-specific, amyloid cores embedded in PFDs can perform these functions and, accordingly, act as preferential nucleation centers in both spontaneous and seeded aggregation. We have shown that the implementation of this concept in a prediction algorithm allows to score the prion propensities of putative PFDs with high accuracy. Recently, we have provided experimental evidence for the existence of such amyloid cores in the PFDs of Sup35, Ure2, Swi1, and Mot3 yeast prions. The fibrils formed by these short stretches may recognize and promote the aggregation of the complete proteins inside cells, being thus a promising tool for targeted protein inactivation.

Cutting Edge: Molecular Structure of the IL-1R-Associated Kinase-4 Death Domain and Its Implications for TLR Signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lasker, Michael V.; Gajjar, Mark M.; Nair, Satish K.

2010-07-19

IL-1R-associated kinase (IRAK) 4 is an essential component of innate immunity. IRAK-4 deficiency in mice and humans results in severe impairment of IL-1 and TLR signaling. We have solved the crystal structure for the death domain of Mus musculus IRAK-4 to 1.7 {angstrom} resolution. This is the first glimpse of the structural details of a mammalian IRAK family member. The crystal structure reveals a six-helical bundle with a prominent loop, which among IRAKs and Pelle, a Drosophila homologue, is unique to IRAK-4. This highly structured loop contained between helices two and three, comprises an 11-aa stretch. Although innate immune domainmore » recognition is thought to be very similar between Drosophila and mammals, this structural component points to a drastic difference. This structure can be used as a framework for future mutation and deletion studies and potential drug design.« less

Functional evidence for the critical amino-terminal conserved domain and key amino acids of Arabidopsis 4-HYDROXY-3-METHYLBUT-2-ENYL DIPHOSPHATE REDUCTASE.

PubMed

Hsieh, Wei-Yu; Sung, Tzu-Ying; Wang, Hsin-Tzu; Hsieh, Ming-Hsiun

2014-09-01

The plant 4-HYDROXY-3-METHYLBUT-2-ENYL DIPHOSPHATE REDUCTASE (HDR) catalyzes the last step of the methylerythritol phosphate pathway to synthesize isopentenyl diphosphate and its allyl isomer dimethylallyl diphosphate, which are common precursors for the synthesis of plastid isoprenoids. The Arabidopsis (Arabidopsis thaliana) genomic HDR transgene-induced gene-silencing lines are albino, variegated, or pale green, confirming that HDR is essential for plants. We used Escherichia coli isoprenoid synthesis H (Protein Data Bank code 3F7T) as a template for homology modeling to identify key amino acids of Arabidopsis HDR. The predicted model reveals that cysteine (Cys)-122, Cys-213, and Cys-350 are involved in iron-sulfur cluster formation and that histidine (His)-152, His-241, glutamate (Glu)-242, Glu-243, threonine (Thr)-244, Thr-312, serine-379, and asparagine-381 are related to substrate binding or catalysis. Glu-242 and Thr-244 are conserved only in cyanobacteria, green algae, and land plants, whereas the other key amino acids are absolutely conserved from bacteria to plants. We used site-directed mutagenesis and complementation assay to confirm that these amino acids, except His-152 and His-241, were critical for Arabidopsis HDR function. Furthermore, the Arabidopsis HDR contains an extra amino-terminal domain following the transit peptide that is highly conserved from cyanobacteria, and green algae to land plants but not existing in the other bacteria. We demonstrated that the amino-terminal conserved domain was essential for Arabidopsis and cyanobacterial HDR function. Further analysis of conserved amino acids in the amino-terminal conserved domain revealed that the tyrosine-72 residue was critical for Arabidopsis HDR. These results suggest that the structure and reaction mechanism of HDR evolution have become specific for oxygen-evolving photosynthesis organisms and that HDR probably evolved independently in cyanobacteria versus other prokaryotes. © 2014

Belief in Afterlife and Death Anxiety: Correlates and Comparisons.

ERIC Educational Resources Information Center

Aday, Ronald H.

1985-01-01

Investigated key variables associated with death anxiety and belief in afterlife among college students (N=181). Results supported the notion that belief in afterlife is primarily a function of religion and not directly a correlate of fear of death. Church attendance was found to be significantly related to both. (JAC)

Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase

PubMed Central

Petrova, Olga A; Mantsyzov, Alexey B; Rodina, Elena V; Efimov, Sergey V; Hackenberg, Claudia; Hakanpää, Johanna; Klochkov, Vladimir V; Lebedev, Andrej A; Chugunova, Anastasia A; Malyavko, Alexander N; Zatsepin, Timofei S; Mishin, Alexey V; Zvereva, Maria I

2018-01-01

Abstract The elongation of single-stranded DNA repeats at the 3′-ends of chromosomes by telomerase is a key process in maintaining genome integrity in eukaryotes. Abnormal activation of telomerase leads to uncontrolled cell division, whereas its down-regulation is attributed to ageing and several pathologies related to early cell death. Telomerase function is based on the dynamic interactions of its catalytic subunit (TERT) with nucleic acids—telomerase RNA, telomeric DNA and the DNA/RNA heteroduplex. Here, we present the crystallographic and NMR structures of the N-terminal (TEN) domain of TERT from the thermotolerant yeast Hansenula polymorpha and demonstrate the structural conservation of the core motif in evolutionarily divergent organisms. We identify the TEN residues that are involved in interactions with the telomerase RNA and in the recognition of the ‘fork’ at the distal end of the DNA product/RNA template heteroduplex. We propose that the TEN domain assists telomerase biological function and is involved in restricting the size of the heteroduplex during telomere repeat synthesis. PMID:29294091

The compression of deaths above the mode.

PubMed

Thatcher, A Roger; Cheung, Siu Lan K; Horiuchi, Shiro; Robine, Jean-Marie

2010-03-26

Kannisto (2001) has shown that as the frequency distribution of ages at death has shifted to the right, the age distribution of deaths above the modal age has become more compressed. In order to further investigate this old-age mortality compression, we adopt the simple logistic model with two parameters, which is known to fit data on old-age mortality well (Thatcher 1999). Based on the model, we show that three key measures of old-age mortality (the modal age of adult deaths, the life expectancy at the modal age, and the standard deviation of ages at death above the mode) can be estimated fairly accurately from death rates at only two suitably chosen high ages (70 and 90 in this study). The distribution of deaths above the modal age becomes compressed when the logits of death rates fall more at the lower age than at the higher age. Our analysis of mortality time series in six countries, using the logistic model, endorsed Kannisto's conclusion. Some possible reasons for the compression are discussed.

Revisiting medicalisation and 'natural' death.

PubMed

Seymour, J E

1999-09-01

The contemporary conceptualisation of natural death in social science and health care literature may be seen as elision of potentially paradoxical ideas in which the process of dying, as opposed to the moment of death, is a key determinant of the manner in which death is regarded. In the predominant rhetoric, medical-technological intervention during dying is emblematic of inhumane and unnatural death. Highly technological clinical settings, where medical intervention in the process of dying is so clearly visible, are held up as extreme examples of the metamorphosis of death from 'natural' into 'unnatural' events. This paper examines the reification of 'natural' death within these writings, focusing on the taken for granted polarisation of technology and 'natural' death with which they are underpinned. The paper then turns to an assessment of the validity of this reification by examining some ethnographic case study data concerning the experiences of the close companions of three people who died, or came near to death, within intensive care: arguably an environment in which death is at its most highly medicalised. The data, which are drawn from a wider ethnography of death and dying in two general adult intensive care units, suggest that it is perceptions of the meaning of technology, rather than its simple minimisation or absence, which determine representations of death within highly technological settings. These perceptions in their turn depend crucially on the circumstances with which dying is attended. In this study the 'natural' process of death was preserved for the companions of dying people when medical technology delivered the outcomes they expected, appeared to be amenable to human manipulation and intention, was accessible to their understanding and seemed to 'fit' with the wider context of the dying person's life. The paper concludes by arguing that it is within the phenomenology of suffering associated with the critical illness or death of a close

A type III effector antagonizes death receptor signalling during bacterial gut infection.

PubMed

Pearson, Jaclyn S; Giogha, Cristina; Ong, Sze Ying; Kennedy, Catherine L; Kelly, Michelle; Robinson, Keith S; Lung, Tania Wong Fok; Mansell, Ashley; Riedmaier, Patrice; Oates, Clare V L; Zaid, Ali; Mühlen, Sabrina; Crepin, Valerie F; Marches, Olivier; Ang, Ching-Seng; Williamson, Nicholas A; O'Reilly, Lorraine A; Bankovacki, Aleksandra; Nachbur, Ueli; Infusini, Giuseppe; Webb, Andrew I; Silke, John; Strasser, Andreas; Frankel, Gad; Hartland, Elizabeth L

2013-09-12

Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively) Escherichia coli use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.

A type III effector antagonises death receptor signalling during bacterial gut infection

PubMed Central

Pearson, Jaclyn S; Giogha, Cristina; Ong, Sze Ying; Kennedy, Catherine L; Kelly, Michelle; Robinson, Keith S; Wong, Tania; Mansell, Ashley; Riedmaier, Patrice; Oates, Clare VL; Zaid, Ali; Mühlen, Sabrina; Crepin, Valerie F; Marches, Olivier; Ang, Ching-Seng; Williamson, Nicholas A; O’Reilly, Lorraine A; Bankovacki, Aleksandra; Nachbur, Ueli; Infusini, Giuseppe; Webb, Andrew I; Silke, John; Strasser, Andreas; Frankel, Gad; Hartland, Elizabeth L

2013-01-01

Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonise the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic E. coli (EPEC and EHEC), utilise a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonisation and interfere with antimicrobial host responses 1-3. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death domain containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death receptor induced apoptosis. This inhibition depended on the N-GlcNAc transferase activity of NleB1, which specifically modified Arg117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing (A/E) pathogens antagonise death receptor induced apoptosis of infected cells, thereby blocking a major antimicrobial host response. PMID:24025841

Susceptibility to Phytophthora ramorum in California bay laurel, a key foliar host of sudden oak death

Treesearch

Brian L. Anacker; Nathan E. Rank; Daniel Hüberli; Matteo Garbelotto; Sarah Gordon; Rich Whitkus; Tami Harnik; Matthew Meshriy; Lori Miles; Ross K. Meentemeyer

2008-01-01

Sudden oak death, caused by the water mold Phytophthora ramorum, is a plant disease responsible for the death of hundreds of thousands of oak and tanoak trees. Some foliar hosts play a major role in the epidemiology of this disease. Upon infection by P. ramorum, these foliar hosts express non-fatal leaf lesions from which large...

The coexistence of natural and supernatural explanations within and across domains and development.

PubMed

Busch, Justin T A; Watson-Jones, Rachel E; Legare, Cristine H

2017-03-01

People across highly diverse cultural contexts use both natural and supernatural explanations to explain questions of fundamental concern such as death, illness, and human origins. The present study examines the development of explanatory coexistence within and across domains of existential concern in individuals in Tanna, Vanuatu. We examined three age groups: 7- to 12-year-old children, 13- to 18-year-old adolescents, and 19- to 70-year-old adults (N = 72). Within the domain of death, biological and spontaneous explanations were most common across all ages. For illness, children showed the highest rates of explanatory coexistence, while adolescents and adults favoured biological explanations. Within the human origins domain, theistic explanations were most common across the age groups. Overall, these data show that coexistence reasoning in these domains is pervasive across cultures, yet at the same time it is deeply contextually specific, reflecting the nuanced differences in local ecologies and cultural beliefs. Statement of contribution What is already known on this subject? Individuals across highly diverse cultural contexts use both natural and supernatural explanations to understand the events that occur in their lives. Context and cultural input play a large role in determining when and how individuals incorporate natural and supernatural explanations. The development of explanatory coexistence has primarily studied explanations for isolated domains. What does this study add? We examined explanatory coexistence in a culture with recent conversion to Christianity and formal education. The current research examines how individuals reason within and across the domains of human origins, illness, and death. Developmental differences associated with explanatory coexistence are examined. © 2016 The British Psychological Society.

Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain.

PubMed

Terracciano, Stefania; Russo, Alessandra; Chini, Maria G; Vaccaro, Maria C; Potenza, Marianna; Vassallo, Antonio; Riccio, Raffaele; Bifulco, Giuseppe; Bruno, Ines

2018-01-26

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone deeply involved in the complex network of cellular signaling governing some key functions, such as cell proliferation and survival, invasion and angiogenesis. Over the past years the N-terminal protein domain has been fully investigated as attractive strategy against cancer, but despite the many efforts lavished in the field, none of the N-terminal binders (termed "classical inhibitors"), currently in clinical trials, have yet successfully reached the market, because of the detrimental heat shock response (HSR) that showed to induce; thus, recently, the selective inhibition of Hsp90 C-terminal domain has powerfully emerged as a more promising alternative strategy for anti-cancer therapy, not eliciting this cell rescue cascade. However, the structural complexity of the target protein and, mostly, the lack of a co-crystal structure of C-terminal domain-ligand, essential to drive the identification of new hits, represent the largest hurdles in the development of new selective C-terminal inhibitors. Continuing our investigations on the identification of new anticancer drug candidates, by using an orthogonal screening approach, here we describe two new potent C-terminal inhibitors able to induce cancer cell death and a considerable down-regulation of Hsp90 client oncoproteins, without triggering the undesired heat shock response.

Early induction of c-Myc is associated with neuronal cell death.

PubMed

Lee, Hyun-Pil; Kudo, Wataru; Zhu, Xiongwei; Smith, Mark A; Lee, Hyoung-gon

2011-11-14

Neuronal cell cycle activation has been implicated in neurodegenerative diseases such as Alzheimer's disease, while the initiating mechanism of cell cycle activation remains to be determined. Interestingly, our previous studies have shown that cell cycle activation by c-Myc (Myc) leads to neuronal cell death which suggests Myc might be a key regulator of cell cycle re-entry mediated neuronal cell death. However, the pattern of Myc expression in the process of neuronal cell death has not been addressed. To this end, we examined Myc induction by the neurotoxic agents camptothecin and amyloid-β peptide in a differentiated SH-SY5Y neuronal cell culture model. Myc expression was found to be significantly increased following either treatment and importantly, the induction of Myc preceded neuronal cell death suggesting it is an early event of neuronal cell death. Since ectopic expression of Myc in neurons causes the cell cycle activation and neurodegeneration in vivo, the current data suggest that induction of Myc by neurotoxic agents or other disease factors might be a key mediator in cell cycle activation and consequent cell death that is a feature of neurodegenerative diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death.

PubMed

Graham, A; Koentges, G; Lumsden, A

1996-01-01

During development of the vertebrate head neural crest cells emigrate from the hindbrain and populate the branchial arches, giving rise to distinct skeletal elements and muscle connective tissues in each arch. The production of neural crest from the hindbrain is discontinuous and crest cells destined for different arches, carrying different positional cues, are separated by regions of apoptosis centered on rhombomeres (r) 3 and r5. This cell death program is under the interactive control of the neighboring hindbrain segments. Both r3 and r5 produce large numbers of crest cells when freed from their flanking rhombomere, but when conjoined with their neighbor the cell death program is restored. Two key components of this program are Bmp 4 and msx-2, both of which are expressed in the apoptotic foci of r3 and r5 and which are also regulated by neighbor interactions. Importantly, the addition of recombinant Bmp 4 to isolated cultures of r3 and r5 induces the expression of Bmp 4 and msx-2 and restores the cell death program. This early neural crest segregation is maintained during development and it has profound effects upon the final craniofacial pattern. Even though crest cells from different axial origins will contribute to compound skeletal elements, these distinct populations do not intermingle. Furthermore head muscle connective tissues are exclusively anchored to skeletal domains arising from neural crest from the same axial level. Thus the discontinuous production of neural crest sculpts the crest into nonmixing streams and consequently ensures the fidelity of patterning.

The key DNA-binding residues in the C-terminal domain of Mycobacterium tuberculosis DNA gyrase A subunit (GyrA)

PubMed Central

Huang, You-Yi; Deng, Jiao-Yu; Gu, Jing; Zhang, Zhi-Ping; Maxwell, Anthony; Bi, Li-Jun; Chen, Yuan-Yuan; Zhou, Ya-Feng; Yu, Zi-Niu; Zhang, Xian-En

2006-01-01

As only the type II topoisomerase is capable of introducing negative supercoiling, DNA gyrase is involved in crucial cellular processes. Although the other domains of DNA gyrase are better understood, the mechanism of DNA binding by the C-terminal domain of the DNA gyrase A subunit (GyrA-CTD) is less clear. Here, we investigated the DNA-binding sites in the GyrA-CTD of Mycobacterium tuberculosis gyrase through site-directed mutagenesis. The results show that Y577, R691 and R745 are among the key DNA-binding residues in M.tuberculosis GyrA-CTD, and that the third blade of the GyrA-CTD is the main DNA-binding region in M.tuberculosis DNA gyrase. The substitutions of Y577A, D669A, R691A, R745A and G729W led to the loss of supercoiling and relaxation activities, although they had a little effect on the drug-dependent DNA cleavage and decatenation activities, and had no effect on the ATPase activity. Taken together, these results showed that the GyrA-CTD is essential to DNA gyrase of M.tuberculosis, and promote the idea that the M.tuberculosis GyrA-CTD is a new potential target for drug design. It is the first time that the DNA-binding sites in GyrA-CTD have been identified. PMID:17038336

Death with dignity from the Confucian perspective.

PubMed

Li, Yaming; Li, Jianhui

2017-02-01

Death with dignity is a significant issue in modern bioethics. In modern healthcare, the wide use of new technologies at the end of life has caused heated debate on how to protect human dignity. The key point of contention lies in the different understandings of human dignity and the dignity of death. Human dignity has never been a clear concept in Western ethical explorations, and the dignity of death has given rise to more confusions. Although there is no such term as "dignity" in Confucian ethics, there are discussions of a number of ideas related to human dignity and the dignity of death. Therefore, Confucian bioethics can offer a new perspective for understanding the theoretical difficulties associated with the dignity of death and new methods for solving them. In this article, we attempt to reconstruct Confucian views on human dignity and the dignity of death and, based on those views, to analyze the following issues: the relationship between the dignity of death and biological life, the relationship between the dignity of death and suffering, the relationship between the dignity of death and the autonomy of human beings, and the relationship between the dignity of death and social justice. This article will also compare the Confucian views on these issues with the views of Western philosophers. Confucian ethics can offer distinct answers to the above issues and help resolve some confusions concerning concepts and theories in Western research on the dignity of death.

Drug-poisoning Deaths Involving Opioid Analgesics: United States, 1999-2011.

PubMed

Chen, Li Hui; Hedegaard, Holly; Warner, Margaret

2014-09-01

Data from the National Vital Statistics System, Mortality File. The age-adjusted rate for opioid-analgesic poisoning deaths nearly quadrupled from 1.4 per 100,000 in 1999 to 5.4 per 100,000 in 2011. Although the opioid-analgesic poisoning death rates increased each year from 1999 through 2011, the rate of increase has slowed since 2006. Natural and semisynthetic opioid analgesics, such as hydrocodone, morphine, and oxycodone, were involved in 11,693 drug-poisoning deaths in 2011, up from 2,749 deaths in 1999. Benzodiazepines were involved in 31% of the opioid-analgesic poisoning deaths in 2011, up from 13% of the opioid-analgesic poisoning deaths in 1999. During the past decade, adults aged 55-64 and non-Hispanic white persons experienced the greatest increase in the rates of opioid-analgesic poisoning deaths. Poisoning is the leading cause of injury death in the United States (1). Drugs-both illicit and pharmaceutical-are the major cause of poisoning deaths, accounting for 90% of poisoning deaths in 2011. Misuse or abuse of prescription drugs, including opioid-analgesic pain relievers, is responsible for much of the recent increase in drug-poisoning deaths (2). This report highlights trends in drug-poisoning deaths involving opioid analgesics (referred to as opioid-analgesic poisoning deaths) and updates previous Data Briefs on this topic. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

A safe way to talk about death.

PubMed

2016-11-09

Could a learning disability-specific death cafe be the key to initiating conversations about death and dying in a safe way? Paula Hopes writes in Learning Disability Practice about a conference on breaking bad news and noted that while some people with learning disabilities were ready to deal with the issues, healthcare professionals were not. Reasons varied from protecting people with learning disabilities to the assumption that they cannot cope with or understand the information. Ms Hopes says nurses should be advocates for people with learning disabilities and provide them with information to engage them in the process of dying. A learning disability-specific death cafe could support nurses to develop confidence in discussing this sensitive issue.

A Unified Approach to Intra-Domain Security

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shue, Craig A; Kalafut, Andrew J.; Gupta, Prof. Minaxi

2009-01-01

While a variety of mechanisms have been developed for securing individual intra-domain protocols, none address the issue in a holistic manner. We develop a unified framework to secure prominent networking protocols within a single domain. We begin with a secure version of the DHCP protocol, which has the additional feature of providing each host with a certificate. We then leverage these certificates to secure ARP, prevent spoofing within the domain, and secure SSH and VPN connections between the domain and hosts which have previously interacted with it locally. In doing so, we also develop an incrementally deployable public key infrastructuremore » which can later be leveraged to support inter-domain authentication.« less

Causes of deaths data, linkages and big data perspectives.

PubMed

Rey, Grégoire; Bounebache, Karim; Rondet, Claire

2018-07-01

The study of cause-specific mortality data is one of the main sources of information for public health monitoring. In most industrialized countries, when a death occurs, it is a legal requirement that a medical certificate based on the international form recommended by World Health Organization's (WHO) is filled in by a physician. The physician reports the causes of death that directly led or contributed to the death on the death certificate. The death certificate is then forwarded to a coding office, where each cause is coded, and one underlying cause is defined, using the rules of the International Classification of Diseases and Related Health Problems, now in its 10th Revision (ICD-10). Recently, a growing number of countries have adopted, or have decided to adopt, the coding software Iris, developed and maintained by an international consortium 1 . This whole standardized production process results in a high and constantly increasing international comparability of cause-specific mortality data. While these data could be used for international comparisons and benchmarking of global burden of diseases, quality of care and prevention policies, there are also many other ways and methods to explore their richness, especially when they are linked with other data sources. Some of these methods are potentially referring to the so-called "big data" field. These methods could be applied both to the production of the data, to the statistical processing of the data, and even more to process these data linked to other databases. In the present note, we depict the main domains in which this new field of methods could be applied. We focus specifically on the context of France, a 65 million inhabitants country with a centralized health data system. Finally we will insist on the importance of data quality, and the specific problematics related to death certification in the forensic medicine domain. Copyright © 2016 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All

Testing domain general learning in an Australian lizard.

PubMed

Qi, Yin; Noble, Daniel W A; Fu, Jinzhong; Whiting, Martin J

2018-06-02

A key question in cognition is whether animals that are proficient in a specific cognitive domain (domain specific hypothesis), such as spatial learning, are also proficient in other domains (domain general hypothesis) or whether there is a trade-off. Studies testing among these hypotheses are biased towards mammals and birds. To understand constraints on the evolution of cognition more generally, we need broader taxonomic and phylogenetic coverage. We used Australian eastern water skinks (Eulamprus quoyii) with known spatial learning ability in three additional tasks: an instrumental and two discrimination tasks. Under domain specific learning we predicted that lizards that were good at spatial learning would perform less well in the discrimination tasks. Conversely, we predicted that lizards that did not meet our criterion for spatial learning would likewise perform better in discrimination tasks. Lizards with domain general learning should perform approximately equally well (or poorly) in these tasks. Lizards classified as spatial learners performed no differently to non-spatial learners in both the instrumental and discrimination learning tasks. Nevertheless, lizards were proficient in all tasks. Our results reveal two patterns: domain general learning in spatial learners and domain specific learning in non-spatial learners. We suggest that delineating learning into domain general and domain specific may be overly simplistic and we need to instead focus on individual variation in learning ability, which ultimately, is likely to play a key role in fitness. These results, in combination with previously published work on this species, suggests that this species has behavioral flexibility because they are competent across multiple cognitive domains and are capable of reversal learning.

A Preliminary Core Domain Set for Clinical Trials of Shoulder Disorders: A Report from the OMERACT 2016 Shoulder Core Outcome Set Special Interest Group.

PubMed

Buchbinder, Rachelle; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Beaton, Dorcas; Kopkow, Christian; Lenza, Mario; Jain, Nitin B; Richards, Bethan; Richards, Pamela; Voshaar, Marieke; van der Windt, Danielle; Gagnier, Joel J

2017-12-01

The Outcome Measures in Rheumatology (OMERACT) Shoulder Core Outcome Set Special Interest Group (SIG) was established to develop a core outcome set (COS) for clinical trials of shoulder disorders. In preparation for OMERACT 2016, we systematically examined all outcome domains and measurement instruments reported in 409 randomized trials of interventions for shoulder disorders published between 1954 and 2015. Informed by these data, we conducted an international Delphi consensus study including shoulder trial experts, clinicians, and patients to identify key domains that should be included in a shoulder disorder COS. Findings were discussed at a stakeholder premeeting of OMERACT. At OMERACT 2016, we sought consensus on a preliminary core domain set and input into next steps. There were 13 and 15 participants at the premeeting and the OMERACT 2016 SIG meeting, respectively (9 attended both meetings). Consensus was reached on a preliminary core domain set consisting of an inner core of 4 domains: pain, physical function/activity, global perceived effect, and adverse events including death. A middle core consisted of 3 domains: emotional well-being, sleep, and participation (recreation and work). An outer core of research required to inform the final COS was also formulated. Our next steps are to (1) analyze whether participation (recreation and work) should be in the inner core, (2) conduct a third Delphi round to finalize definitions and wording of domains and reach final endorsement for the domains, and (3) determine which instruments fulfill the OMERACT criteria for measuring each domain.

Quality of dying and death with cancer in Israel.

PubMed

Braun, Michal; Hasson-Ohayon, Ilanit; Hales, Sarah; Zimmermann, Camilla; Rydall, Anne; Peretz, Tamar; Rodin, Gary

2014-07-01

The quality of dying and death refers to the evaluation of the final days of life and the moment of death with respect to how it is prepared for, faced and experienced by those with a terminal illness. It includes experience in multiple domains: physical, psychological, social, spiritual or existential, the nature of health care, life closure and death preparation, and the circumstances of death. To explore the quality of dying and death in cancer patients in Israel and its relationship to place of death and socio-demographic characteristics of the primary caregivers and the deceased. Retrospective assessment of the quality of dying and death, based on caregiver responses to the Quality of Dying and Death (QODD) questionnaire (overall score ranges from 0 to 100; higher scores reflect better dying and death experiences) 8 to 10 months after the death. Ninety-five caregivers of Jewish cancer patients, most of whom were female spouses or children of the deceased. Mean QODD score was 57.2 (standard deviation [SD]=15), which is in the low-moderate range. Place of death, gender and age of the caregiver, and age of the deceased, were associated with QODD score. This retrospective study in Israel demonstrated that the overall quality of dying and death was regarded as poor by almost half of the caregivers. These findings may reflect the relative lack of specialized palliative care and advance care planning in Israel at the time of this study, which took place between 2006 and 2009. Further research and enhancement of palliative care resources may be needed in Israel and several encouraging recent developments (e.g. staff training and legislation) suggest that such changes are now underway.

Discussion of death and dying in surgical textbooks.

PubMed

Easson, A M; Crosby, J A; Librach, S L

2001-07-01

Quality end-of-life care is an increasing concern for the public and the medical profession. Surgical textbooks could serve as an important educational and reference resource to improve this care. Four general surgical textbooks were scored for helpful information on death and dying for eight surgical diseases. For each disease, nine content domains related to care of the dying patient were evaluated. Three texts included a chapter on cancer that was evaluated separately. Disease epidemiology, prognosis/prevention, progression, and medical interventions were generally well discussed in all textbooks. However, little helpful information was provided with regards to breaking bad news/advanced care planning, mode of death, treatment decision-making, effect on family/surgeon, and symptom management. Cancer chapters also addressed only a few of these concerns. Death and the dying patient are sufficiently frequent in surgical practice that it would be appropriate to increase the amount of information provided.

Formation and stability of synaptic receptor domains.

PubMed

Haselwandter, Christoph A; Calamai, Martino; Kardar, Mehran; Triller, Antoine; da Silveira, Rava Azeredo

2011-06-10

Neurotransmitter receptor molecules, concentrated in postsynaptic domains along with scaffold and a number of other molecules, are key regulators of signal transmission across synapses. Combining experiment and theory, we develop a quantitative description of synaptic receptor domains in terms of a reaction-diffusion model. We show that interactions between only receptors and scaffolds, together with the rapid diffusion of receptors on the cell membrane, are sufficient for the formation and stable characteristic size of synaptic receptor domains. Our work reconciles long-term stability of synaptic receptor domains with rapid turnover and diffusion of individual receptors, and suggests novel mechanisms for a form of short-term, postsynaptic plasticity.

Death-domain associated protein-6 (DAXX) mediated apoptosis in hantavirus infection is counter-balanced by activation of interferon-stimulated nuclear transcription factors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khaiboullina, Svetlana F., E-mail: sv.khaiboullina@gmail.com; Morzunov, Sergey P.; Boichuk, Sergei V.

2013-09-01

Hantaviruses are negative strand RNA species that replicate predominantly in the cytoplasm. They also activate numerous cellular responses, but their involvement in nuclear processes is yet to be established. Using human umbilical vein endothelial cells (HUVECs), this study investigates the molecular finger-print of nuclear transcription factors during hantavirus infection. The viral-replication-dependent activation of pro-myelocytic leukemia protein (PML) was followed by subsequent localization in nuclear bodies (NBs). PML was also found in close proximity to activated Sp100 nuclear antigen and interferon-stimulated gene 20 kDa protein (ISG-20), but co-localization with death-domain associated protein-6 (DAXX) was not observed. These data demonstrate that hantavirusmore » triggers PML activation and localization in NBs in the absence of DAXX-PLM-NB co-localization. The results suggest that viral infection interferes with DAXX-mediated apoptosis, and expression of interferon-activated Sp100 and ISG-20 proteins may indicate intracellular intrinsic antiviral attempts.« less

The Phe105 loop of Alix Bro1 domain plays a key role in HIV-1 release

PubMed Central

Sette, Paola; Mu, Ruiling; Dussupt, Vincent; Jiang, Jiansheng; Snyder, Greg; Smith, Patrick; Xiao, Tsan. Sam; Bouamr, Fadila

2011-01-01

Summary Alix and cellular paralogs HD-PTP and Brox contain N-terminal Bro1 domains that bind ESCRT-III CHMP4. In contrast to HD-PTP and Brox, expression of the Bro1 domain of Alix alleviates HIV-1 release defects due to interrupted access to ESCRT. In an attempt to elucidate this functional discrepancy, we solved the crystal structures of the Bro1 domains of HD-PTP and Brox. They revealed typical “boomerang” folds they share with the Bro1 Alix domain. However, they each contain unique structural features that may be relevant to their specific function(s). In particular, phenylalanine residue in position 105 (Phe105) of Alix belongs to a long loop that is unique to its Bro1 domain. Concurrently mutation of Phe105 and surrounding residues at the tip of the loop compromises the function of Alix in HIV-1 budding without affecting its interactions with Gag or CHMP4. These studies identify a new functional determinant in the Bro1 domain of Alix. PMID:21889351

Coroners' recommendations for prevention of resident deaths in aged care: The role of primary care providers

PubMed

Aitken, Georgia; Demosthenous, Athena; Bugeja, Lyndal; Willoughby, Melissa; Young, Carmel; E Ibrahim, Joseph

2018-05-01

Currently, very little is known about how coroners consider a role for general practitioners (GPs) and registered nurses (RNs) in recommendations for the prevention of premature death. Involving these professions in recommendations generally directed towards government organisations or residential aged care providers and management may contribute to more successful broader policy changes. The aim of this article was to examine whether coroners' recommendations describe a specific role for GPs and RNs in the prevention of premature death in residential aged care settings and, if so, what domains of practice were considered. This study was part of a larger retrospective cohort study. The National Coronial Information System (NCIS) was used to extract coroners' reports that included recommendations directed towards GPs and RNs. The following information was extracted: mechanism of death, incident location, text of coroners' recommendations. Of 162 unique recommendations, 14 (8.6%) were relevant to GPs and 10 (6.2%) were relevant to RNs. Most recommendations were made in the domains of 'applied professional knowledge and skills', 'organisations and legal dimensions' and 'provision and coordination of care'. Recommendations were primarily made in response to natural cause deaths and complications of clinical care. Coroners' recommendations have a limited focus directed towards GPs and RNs, and recommendations focus on their roles in application of skills and knowledge, legal domains, and provision and coordination of care. Recommendations were mainly made in response to deaths due to suboptimal care or from 'complications of clinical care'. Formulating recommendations for these health professions may increase accountability and the likelihood of a recommendation being effectively implemented.

Mitochondrial fission proteins regulate programmed cell death in yeast.

PubMed

Fannjiang, Yihru; Cheng, Wen-Chih; Lee, Sarah J; Qi, Bing; Pevsner, Jonathan; McCaffery, J Michael; Hill, R Blake; Basañez, Gorka; Hardwick, J Marie

2004-11-15

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.

Domain-specific rationality in human choices: violations of utility axioms and social contexts.

PubMed

Wang, X T

1996-07-01

This study presents a domain-specific view of human decision rationality. It explores social and ecological domain-specific psychological mechanisms underlying choice biases and violations of utility axioms. Results from both the USA and China revealed a social group domain-specific choice pattern. The irrational preference reversal in a hypothetical life-death decision problem (a classical example of framing effects) was eliminated by providing a small group or family context in which most subjects favored a risky choice option regardless of the positive/negative framing of choice outcomes. The risk preference data also indicate that the subjective scope of small group domain is larger for Chinese subjects, suggesting that human choice mechanisms are sensitive to culturally specific features of group living. A further experiment provided evidence that perceived fairness might be one major factor regulating the choice preferences found in small group (kith-and-kin) contexts. Finally, the violation of the stochastic dominance axiom of the rational theory of choice was predicted and tested. The violations were found only when the "life-death" problem was presented in small group contexts; the strongest violation was found in a family context. These results suggest that human decisions and choices are regulated by domain-specific choice mechanisms designed to solve evolutionary recurrent and adaptively important problems.

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex.

PubMed

Bright, Fiona M; Vink, Robert; Byard, Roger W; Duncan, Jhodie R; Krous, Henry F; Paterson, David S

2017-01-01

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

PubMed Central

Vink, Robert; Byard, Roger W.; Duncan, Jhodie R.; Krous, Henry F.; Paterson, David S.

2017-01-01

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and

Supplementary motor area as key structure for domain-general sequence processing: A unified account.

PubMed

Cona, Giorgia; Semenza, Carlo

2017-01-01

The Supplementary Motor Area (SMA) is considered as an anatomically and functionally heterogeneous region and is implicated in several functions. We propose that SMA plays a crucial role in domain-general sequence processes, contributing to the integration of sequential elements into higher-order representations regardless of the nature of such elements (e.g., motor, temporal, spatial, numerical, linguistic, etc.). This review emphasizes the domain-general involvement of the SMA, as this region has been found to support sequence operations in a variety of cognitive domains that, albeit different, share an inherent sequence processing. These include action, time and spatial processing, numerical cognition, music and language processing, and working memory. In this light, we reviewed and synthesized recent neuroimaging, stimulation and electrophysiological studies in order to compare and reconcile the distinct sources of data by proposing a unifying account for the role of the SMA. We also discussed the differential contribution of the pre-SMA and SMA-proper in sequence operations, and possible neural mechanisms by which such operations are executed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ferroptosis and Cell Death Analysis by Flow Cytometry.

PubMed

Chen, Daishi; Eyupoglu, Ilker Y; Savaskan, Nicolai

2017-01-01

Cell death and its recently discovered regulated form ferroptosis are characterized by distinct morphological, electrophysiological, and pharmacological features. In particular ferroptosis can be induced by experimental compounds and clinical drugs (i.e., erastin, sulfasalazine, sorafenib, and artesunate) in various cell types and cancer cells. Pharmacologically, this cell death process can be inhibited by iron chelators and lipid peroxidation inhibitors. Relevance of this specific cell death form has been found in different pathological conditions such as cancer, neurotoxicity, neurodegeneration, and ischemia. Distinguishing cell viability and cell death is essential for experimental and clinical applications and a key component in flow cytometry experiments. Dead cells can compromise the integrity of the data by nonspecific binding of antibodies and dyes. Therefore it is essential that dead cells are robustly and reproducibly identified and characterized by means of cytometry application. Here we describe a procedure to detect and quantify cell death and its specific form ferroptosis based on standard flow cytometry techniques.

Drug Overdose Deaths Among Adolescents Aged 15-19 in the United States: 1999-2015.

PubMed

Curtin, Sally C; Tejada-Vera, Betzaida; Warmer, Margaret

2017-08-01

Drug overdose deaths in the United States are a pressing public health challenge (1–3). In particular, drug overdoses involving opioids have increased since 1999 (1). This report focuses specifically on drug overdose deaths for older adolescents aged 15–19. In 2015, 772 drug overdose deaths occurred in this age group. Rates for 1999–2015 are presented and trends compared for both females and males. Percent distributions of drug overdose deaths for 2015 by intent (e.g., unintentional, suicide, homicide) are presented. Trends in drug overdose death rates by type of drug involved are also presented. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

On an aggregation in birth-and-death stochastic dynamics

NASA Astrophysics Data System (ADS)

Finkelshtein, Dmitri; Kondratiev, Yuri; Kutoviy, Oleksandr; Zhizhina, Elena

2014-06-01

We consider birth-and-death stochastic dynamics of particle systems with attractive interaction. The heuristic generator of the dynamics has a constant birth rate and density-dependent decreasing death rate. The corresponding statistical dynamics is constructed. Using the Vlasov-type scaling we derive the limiting mesoscopic evolution and prove that this evolution propagates chaos. We study a nonlinear non-local kinetic equation for the first correlation function (density of population). The existence of uniformly bounded solutions as well as solutions growing inside of a bounded domain and expanding in the space are shown. These solutions describe two regimes in the mesoscopic system: regulation and aggregation.

Low performance on mathematical tasks in preschoolers: the importance of domain-general and domain-specific abilities.

PubMed

Costa, H M; Nicholson, B; Donlan, C; Van Herwegen, J

2018-04-01

Different domain-specific and domain-general cognitive precursors play a key role in the development of mathematical abilities. The contribution of these domains to mathematical ability changes during development. Primary school-aged children who show mathematical difficulties form a heterogeneous group, but it is not clear whether this also holds for preschool low achievers (LAs) and how domain-specific and domain-general abilities contribute to mathematical difficulties at a young age. The aim of this study was to explore the cognitive characteristics of a sample of preschool LAs and identify sub-types of LAs. 81 children were identified as LAs from 283 preschoolers aged 3 to 5 years old and were assessed on a number of domain-general and domain-specific tasks. Cluster analysis revealed four subgroups of LAs in mathematics: (1) a weak processing sub-type; (2) a general mathematical LAs sub-type; (3) a mixed abilities sub-type; and (4) a visuo-spatial deficit sub-type. Whilst two of the groups showed specific domain-general difficulties, none showed only domain-specific difficulties. Current findings suggest that preschool LAs constitute a heterogeneous group and stress the importance of domain-general factors for the development of mathematical abilities during the preschool years. © 2018 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Mitochondrial protection impairs BET bromodomain inhibitor-mediated cell death and provides rationale for combination therapeutic strategies.

PubMed

Lasorsa, E; Smonksey, M; Kirk, J S; Rosario, S; Hernandez-Ilizaliturri, F J; Ellis, L

2015-12-10

Inhibitors of the bromodomain and extraterminal domain family (BETI) have recently entered phase I clinical trials. In patients with advanced leukemia's, potent antileukemia activity was displayed with minimum dose-limiting toxicity. In preclinical models of hematological malignancies, including aggressive B-cell lymphomas, BETI induced cell-cycle arrest and apoptosis. However, the underlying cell death mechanisms are still not well understood. Dissecting the mechanisms required by BETI to mediate cell death would provide strong direction on how to best utilize BETI to treat patients with aggressive hematological malignancies. Herein, we provide understanding of the molecular mechanisms underlying BETI-mediated cell death using I-BET762. Induction of cell death occurred in primary murine and human B-cell lymphomas through apoptosis. Genetic dissection using Eμ-myc B-cell lymphoma compound mutants demonstrated that I-BET762-induced apoptosis does not require the p53 pathway. Furthermore, deletion of Apaf1, and thus the absence of a functional apoptosome, is associated with a delayed drug response but do not provide long-term resistance. Prolonged treatment of this model in fact fails to suppress the therapeutic efficacy of the drug and is associated with biochemical features of autophagy. However, lack of mitochondrial permeability completely inhibited I-BET762-mediated tumor cell death, indicating mitochondrial damage as key events for its activity. Combination of I-BET762 with BH3-only mimetics ABT-263 or obatoclax, restored sensitivity to I-BET762 lymphoma killing; however, success was determined by expression of Bcl-2 family antiapoptotic proteins. Our study provides critical insight for clinical decisions regarding the appropriate strategy for using BETI as a single agent or in combination to treat patients with aggressive B-cell lymphomas.

The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability

PubMed Central

Kurabe, Nobuya; Mori, Mayumi; Kurokawa, Jun; Taniguchi, Kaori; Aoyama, Hisatoshi; Atsuda, Kazuhiro; Nishijima, Akemi; Odawara, Nariaki; Harada, Saori; Nakashima, Katsuhiko; Arai, Satoko; Miyazaki, Toru

2010-01-01

Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase 1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD−/− mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD−/− cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus. PMID:20043882

Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways.

PubMed

Larrous, Florence; Gholami, Alireza; Mouhamad, Shahul; Estaquier, Jérôme; Bourhy, Hervé

2010-10-01

The lyssavirus matrix (M) protein induces apoptosis. The regions of the M protein that are essential for triggering cell death pathways are not yet clearly defined. We therefore compared the M proteins from two viruses that have contrasting characteristics in terms of cellular apoptosis: a genotype 3 lyssavirus, Mokola virus (MOK), and a genotype 1 rabies virus isolated from a dog from Thailand (THA). We identified a 20-amino-acid fragment (corresponding to positions 67 to 86) that retained the cell death activities of the full-length M protein from MOK via both the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and inhibition of cytochrome c oxidase (CcO) activity. We found that the amino acids at positions 77 and 81 have an essential role in triggering these two cell death pathways. Directed mutagenesis demonstrated that the amino acid at position 77 affects CcO activity, whereas the amino acid at position 81 affects TRAIL-dependent apoptosis. Mutations in the full-length M protein that compromised induction of either of these two pathways resulted in delayed apoptosis compared with the time to apoptosis for the nonmutated control.

Understanding death attitudes: the integration of movies, positive psychology, and meaning management.

PubMed

Niemiec, Ryan M; Schulenberg, Stefan E

2011-01-01

The portrayal of death is one of the most common themes in movies and is often unrealistic, promoting misconceptions to the public. However, there are also many films that portray death acceptance in an instructive way. Such films depict the development of character strengths useful in embracing life and lessening death anxiety, namely zest, curiosity, self-regulation, and humor. Moreover, the role of meaning in films is pivotal for understanding death attitudes. The authors discussed key elements in a number of popular, independent, and international films and emphasized the use of films as an important adjunct for both teachers and clinicians addressing death attitudes with students and clients. A program of death education using movies is briefly discussed.

Causes of death and associated conditions (Codac): a utilitarian approach to the classification of perinatal deaths.

PubMed

Frøen, J Frederik; Pinar, Halit; Flenady, Vicki; Bahrin, Safiah; Charles, Adrian; Chauke, Lawrence; Day, Katie; Duke, Charles W; Facchinetti, Fabio; Fretts, Ruth C; Gardener, Glenn; Gilshenan, Kristen; Gordijn, Sanne J; Gordon, Adrienne; Guyon, Grace; Harrison, Catherine; Koshy, Rachel; Pattinson, Robert C; Petersson, Karin; Russell, Laurie; Saastad, Eli; Smith, Gordon C S; Torabi, Rozbeh

2009-06-10

A carefully classified dataset of perinatal mortality will retain the most significant information on the causes of death. Such information is needed for health care policy development, surveillance and international comparisons, clinical services and research. For comparability purposes, we propose a classification system that could serve all these needs, and be applicable in both developing and developed countries. It is developed to adhere to basic concepts of underlying cause in the International Classification of Diseases (ICD), although gaps in ICD prevent classification of perinatal deaths solely on existing ICD codes.We tested the Causes of Death and Associated Conditions (Codac) classification for perinatal deaths in seven populations, including two developing country settings. We identified areas of potential improvements in the ability to retain existing information, ease of use and inter-rater agreement. After revisions to address these issues we propose Version II of Codac with detailed coding instructions.The ten main categories of Codac consist of three key contributors to global perinatal mortality (intrapartum events, infections and congenital anomalies), two crucial aspects of perinatal mortality (unknown causes of death and termination of pregnancy), a clear distinction of conditions relevant only to the neonatal period and the remaining conditions are arranged in the four anatomical compartments (fetal, cord, placental and maternal).For more detail there are 94 subcategories, further specified in 577 categories in the full version. Codac is designed to accommodate both the main cause of death as well as two associated conditions. We suggest reporting not only the main cause of death, but also the associated relevant conditions so that scenarios of combined conditions and events are captured.The appropriately applied Codac system promises to better manage information on causes of perinatal deaths, the conditions associated with them, and the most

Why different countries manage death differently: a comparative analysis of modern urban societies.

PubMed

Walter, Tony

2012-03-01

The sociology of death, dying and bereavement tends to take as its implicit frame either the nation state or a homogenous modernity. Between-nation differences in the management of death and dying are either ignored or untheorized. This article seeks to identify the factors that can explain both similarities and differences in the management of death between different modern western nations. Structural factors which affect all modern nations include urbanization and the division of labour leading to the dominance of professionals, migration, rationality and bureaucracy, information technology and the risk society. How these sociologically familiar structural features are responded to, however, depends on national histories, institutions and cultures. Historically, key transitional periods to modernity, different in different nations, necessitated particular institutional responses in the management of dying and dead bodies. Culturally, key factors include individualism versus collectivism, religion, secularization, boundary regulation, and expressivism. Global flows of death practices depend significantly on subjugated nations' perceptions of colonialism, neo-colonialism and modernity, which can lead to a dominant power's death practices being either imitated or rejected. © London School of Economics and Political Science 2012.

Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.

PubMed

Corradi, Hazel R; Schwager, Sylva L U; Nchinda, Aloysius T; Sturrock, Edward D; Acharya, K Ravi

2006-03-31

Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.

Brain death: the challenges of translating medical science into Islamic bioethical discourse.

PubMed

Padela, Aasim I; Basser, Taha A

2012-09-01

Islamic ethico-legal assessments of brain death are varied and controversial. Some Islamic ethico-legal bodies have concluded that brain death is equivalent to cardiopulmonary death; others regard it as an intermediate state between life and death, and a few opine that it does not meet the standards for legal death according to Islamic law. Yet this translation of the concept of brain death into the Islamic ethico-legal domain has generated multiple ethical complexities that receive insufficient attention within the extant medical and fiqh literature. How do Islamic legists understand brain death as a clinical phenomenon? How does the Islamic ethico-legal system treat medical uncertainty? What Islamic ethico-legal principles should apply to bioethical questions about life and death? In this paper, we analyze the arguments for, and against, the acceptance of brain death within the context of the deliberation of a representative juridical council. In our discussion we focus on areas in which the legists' ethico-legal reasoning hinges upon clinical conceptions of the state of the individual when diagnosed as brain dead. As Islamic ethics continues to engage scientific and technological advancements in these areas, such exploration of internal workings is necessary if we wish to better understand how Islamic ethical principles can contribute to bioethical deliberation.

Exploring metazoan evolution through dynamic and holistic changes in protein families and domains

PubMed Central

2012-01-01

Background Proteins convey the majority of biochemical and cellular activities in organisms. Over the course of evolution, proteins undergo normal sequence mutations as well as large scale mutations involving domain duplication and/or domain shuffling. These events result in the generation of new proteins and protein families. Processes that affect proteome evolution drive species diversity and adaptation. Herein, change over the course of metazoan evolution, as defined by birth/death and duplication/deletion events within protein families and domains, was examined using the proteomes of 9 metazoan and two outgroup species. Results In studying members of the three major metazoan groups, the vertebrates, arthropods, and nematodes, we found that the number of protein families increased at the majority of lineages over the course of metazoan evolution where the magnitude of these increases was greatest at the lineages leading to mammals. In contrast, the number of protein domains decreased at most lineages and at all terminal lineages. This resulted in a weak correlation between protein family birth and domain birth; however, the correlation between domain birth and domain member duplication was quite strong. These data suggest that domain birth and protein family birth occur via different mechanisms, and that domain shuffling plays a role in the formation of protein families. The ratio of protein family birth to protein domain birth (domain shuffling index) suggests that shuffling had a more demonstrable effect on protein families in nematodes and arthropods than in vertebrates. Through the contrast of high and low domain shuffling indices at the lineages of Trichinella spiralis and Gallus gallus, we propose a link between protein redundancy and evolutionary changes controlled by domain shuffling; however, the speed of adaptation among the different lineages was relatively invariant. Evaluating the functions of protein families that appeared or disappeared at the

Sports and Marfan Syndrome: Awareness and Early Diagnosis Can Prevent Sudden Death.

ERIC Educational Resources Information Center

Salim, Mubadda A.; Alpert, Bruce S.

2001-01-01

Physicians who work with athletes play an important role in preventing sudden death related to physical activity in people who have Marfan syndrome. Flagging those who have the physical stigmata and listening for certain cardiac auscultation sounds are early diagnostic keys that can help prevent deaths. People with Marfan syndrome should be…

Impairment of Fas-ligand-caveolin-1 interaction inhibits Fas-ligand translocation to rafts and Fas-ligand-induced cell death.

PubMed

Glukhova, Xenia A; Trizna, Julia A; Proussakova, Olga V; Gogvadze, Vladimir; Beletsky, Igor P

2018-01-22

Fas-ligand/CD178 belongs to the TNF family proteins and can induce apoptosis through death receptor Fas/CD95. The important requirement for Fas-ligand-dependent cell death induction is its localization to rafts, cholesterol- and sphingolipid-enriched micro-domains of membrane, involved in regulation of different signaling complexes. Here, we demonstrate that Fas-ligand physically associates with caveolin-1, the main protein component of rafts. Experiments with cells overexpressing Fas-ligand revealed a FasL N-terminal pre-prolin-rich region, which is essential for the association with caveolin-1. We found that the N-terminal domain of Fas-ligand bears two caveolin-binding sites. The first caveolin-binding site binds the N-terminal domain of caveolin-1, whereas the second one appears to interact with the C-terminal domain of caveolin-1. The deletion of both caveolin-binding sites in Fas-ligand impairs its distribution between cellular membranes, and attenuates a Fas-ligand-induced cytotoxicity. These results demonstrate that the interaction of Fas-ligand and caveolin-1 represents a molecular basis for Fas-ligand translocation to rafts, and the subsequent induction of Fas-ligand-dependent cell death. A possibility of a similar association between other TNF family members and caveolin-1 is discussed.

Variability in hospital-based brain death guidelines in Canada.

PubMed

Hornby, Karen; Shemie, Sam D; Teitelbaum, Jeanni; Doig, Christopher

2006-06-01

Variability has been reported in the practices to determine death by neurological criteria for adults and children. The objective of this study was to determine if this variability exists in the Canadian context. A cross-sectional survey of the Canadian intensive care units (ICUs) involved in the care of potential organ donors, and Canadian organ procurement organizations (OPOs) was undertaken. We contacted the medical directors of these units and asked them to provide their guidelines for the neurological determination of death (NDD). A framework, which identifies key diagnostic criteria for NDD, was used to assess the content of all study documents. With a response rate of 68%, we found that key diagnostic criteria for NDD were incorporated inconsistently in the guidelines from Canadian ICUs and OPOs. Areas of concern include omissions in: the testing of brainstem reflexes; components of the apnea test; indications for the use of supplementary testing; wait intervals prior to performing the first NDD examination; the definition of NDD; and potential confounding factors. In addition, inconsistencies were found pertaining to wait intervals required between examinations and the legal timing of death. These findings reinforce the need to standardize the practice of the neurological determination of death in Canadian centres, which has the potential to reduce practice variation. Clear medical standards for NDD augment the quality, rigour and credibility of this determination.

The Digital Thread as the Key Enabler

DTIC Science & Technology

2016-11-01

17 Defense AT&L: November-December 2016 The Digital Thread as the Key Enabler Col. Keith Bearden, USAF Bearden is the deputy director of...enabling you to do your job better, faster and cheaper. There is one initiative, the key enabler, to accomplish this goal—the digital thread . But let’s... process that would allow for rapid cross- domain analysis and technology transition prior to bending metal. • Re-establish a culture of “hands-on

Domain Specific Language Support for Exascale

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mellor-Crummey, John

A multi-institutional project known as D-TEC (short for “Domain- specific Technology for Exascale Computing”) set out to explore technologies to support the construction of Domain Specific Languages (DSLs) to map application programs to exascale architectures. DSLs employ automated code transformation to shift the burden of delivering portable performance from application programmers to compilers. Two chief properties contribute: DSLs permit expression at a high level of abstraction so that a programmer’s intent is clear to a compiler and DSL implementations encapsulate human domain-specific optimization knowledge so that a compiler can be smart enough to achieve good results on specific hardware. Domainmore » specificity is what makes these properties possible in a programming language. If leveraging domain specificity is the key to keep exascale software tractable, a corollary is that many different DSLs will be needed to encompass the full range of exascale computing applications; moreover, a single application may well need to use several different DSLs in conjunction. As a result, developing a general toolkit for building domain-specific languages was a key goal for the D-TEC project. Different aspects of the D-TEC research portfolio were the focus of work at each of the partner institutions in the multi-institutional project. D-TEC research and development work at Rice University focused on on three principal topics: understanding how to automate the tuning of code for complex architectures, research and development of the Rosebud DSL engine, and compiler technology to support complex execution platforms. This report provides a summary of the research and development work on the D-TEC project at Rice University.« less

N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting.

PubMed

Lin, Pei-Hsuan; Lin, Hsien-Yi; Kuo, Cheng-Chin; Yang, Liang-Tung

2015-06-24

The epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3's action remain unanswered. We demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants. Our results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on

Causes of death and associated conditions (Codac) – a utilitarian approach to the classification of perinatal deaths

PubMed Central

Frøen, J Frederik; Pinar, Halit; Flenady, Vicki; Bahrin, Safiah; Charles, Adrian; Chauke, Lawrence; Day, Katie; Duke, Charles W; Facchinetti, Fabio; Fretts, Ruth C; Gardener, Glenn; Gilshenan, Kristen; Gordijn, Sanne J; Gordon, Adrienne; Guyon, Grace; Harrison, Catherine; Koshy, Rachel; Pattinson, Robert C; Petersson, Karin; Russell, Laurie; Saastad, Eli; Smith, Gordon CS; Torabi, Rozbeh

2009-01-01

A carefully classified dataset of perinatal mortality will retain the most significant information on the causes of death. Such information is needed for health care policy development, surveillance and international comparisons, clinical services and research. For comparability purposes, we propose a classification system that could serve all these needs, and be applicable in both developing and developed countries. It is developed to adhere to basic concepts of underlying cause in the International Classification of Diseases (ICD), although gaps in ICD prevent classification of perinatal deaths solely on existing ICD codes. We tested the Causes of Death and Associated Conditions (Codac) classification for perinatal deaths in seven populations, including two developing country settings. We identified areas of potential improvements in the ability to retain existing information, ease of use and inter-rater agreement. After revisions to address these issues we propose Version II of Codac with detailed coding instructions. The ten main categories of Codac consist of three key contributors to global perinatal mortality (intrapartum events, infections and congenital anomalies), two crucial aspects of perinatal mortality (unknown causes of death and termination of pregnancy), a clear distinction of conditions relevant only to the neonatal period and the remaining conditions are arranged in the four anatomical compartments (fetal, cord, placental and maternal). For more detail there are 94 subcategories, further specified in 577 categories in the full version. Codac is designed to accommodate both the main cause of death as well as two associated conditions. We suggest reporting not only the main cause of death, but also the associated relevant conditions so that scenarios of combined conditions and events are captured. The appropriately applied Codac system promises to better manage information on causes of perinatal deaths, the conditions associated with them, and the

UXDs-Driven Transferring Method from TRIZ Solution to Domain Solution

NASA Astrophysics Data System (ADS)

Ma, Lihui; Cao, Guozhong; Chang, Yunxia; Wei, Zihui; Ma, Kai

The translation process from TRIZ solutions to domain solutions is an analogy-based process. TRIZ solutions, such as 40 inventive principles and the related cases, are medium-solutions for domain problems. Unexpected discoveries (UXDs) are the key factors to trigger designers to generate new ideas for domain solutions. The Algorithm of UXD resolving based on Means-Ends Analysis(MEA) is studied and an UXDs-driven transferring method from TRIZ solution to domain solution is formed. A case study shows the application of the process.

ATPase domain and interdomain linker play a key role in aggregation of mitochondrial Hsp70 chaperone Ssc1.

PubMed

Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai

2010-02-12

The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Delta hep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer.

ATPase Domain and Interdomain Linker Play a Key Role in Aggregation of Mitochondrial Hsp70 Chaperone Ssc1*

PubMed Central

Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai

2010-01-01

The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Δhep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer. PMID:20007714

Causes of Death of Adults and Elderly and Healthcare-seeking before Death in Rural Bangladesh

PubMed Central

Chowdhury, Hafizur Rahman; Bhuiyan, Monirul Alam; Streatfield, Peter Kim

2010-01-01

The health system of a country needs to be adjusted to patterns of morbidity and mortality to mitigate the income-erosion consequences of prolonged ill-health and premature death of adults. Population-based data on mortality by cause are a key to modifying the health system. However, these data are scarce, particularly for rural populations in developing countries. The objectives of this study were to determine the burdens of health due to major causes of death obtained from verbal autopsy of adults and the elderly and their healthcare-seeking patterns before death in a well-defined rural population. There were 2,397 deaths—613 were among adults aged 15-59 years and 1,784 among the elderly aged 60+ years—during 2003-2004 in the health and demographic surveillance area in Matlab, a rural area of Bangladesh. Trained interviewers interviewed close relatives of the deceased using a structured verbal-autopsy questionnaire to record signs and symptoms of diseases/conditions that led to death and medical consultations before death. Two physicians independently assigned the underlying causes of deaths with disagreements resolved by a third physician. The physicians were able to assign a specific cause in 91% of the cases. Rates and proportions were used for estimating the burden of diseases by cause. Of all deaths of adults and the elderly, communicable diseases accounted for 18% and non-communicable diseases for 66%, with the proportion of non-communicable diseases increasing with age. Leading non-communicable diseases were diseases of the circulatory system (35%), neoplasms (11%), diseases of the respiratory system (10%), diseases of the digestive system (6%), and endocrine and metabolic disorders (6%), all of which accounted for 68% of deaths. Injury and other external causes accounted for another 5% of the deaths. During terminal illness, 31% of the adults and 25% of the elderly sought treatment from medical doctors, and 14% of the adults and 4% of the elderly died

Core outcome domains for clinical trials in non-specific low back pain.

PubMed

Chiarotto, Alessandro; Deyo, Richard A; Terwee, Caroline B; Boers, Maarten; Buchbinder, Rachelle; Corbin, Terry P; Costa, Leonardo O P; Foster, Nadine E; Grotle, Margreth; Koes, Bart W; Kovacs, Francisco M; Lin, Chung-Wei Christine; Maher, Chris G; Pearson, Adam M; Peul, Wilco C; Schoene, Mark L; Turk, Dennis C; van Tulder, Maurits W; Ostelo, Raymond W

2015-06-01

the domain 'number of deaths'. The following outcome domains were included in this updated COS: 'physical functioning', 'pain intensity', 'health-related quality of life' and 'number of deaths'. The next step for the development of this COS will be to determine which measurement instruments best measure these domains.

Nonlinear (time domain) and linearized (time and frequency domain) solutions to the compressible Euler equations in conservation law form

NASA Technical Reports Server (NTRS)

Sreenivas, Kidambi; Whitfield, David L.

1995-01-01

Two linearized solvers (time and frequency domain) based on a high resolution numerical scheme are presented. The basic approach is to linearize the flux vector by expressing it as a sum of a mean and a perturbation. This allows the governing equations to be maintained in conservation law form. A key difference between the time and frequency domain computations is that the frequency domain computations require only one grid block irrespective of the interblade phase angle for which the flow is being computed. As a result of this and due to the fact that the governing equations for this case are steady, frequency domain computations are substantially faster than the corresponding time domain computations. The linearized equations are used to compute flows in turbomachinery blade rows (cascades) arising due to blade vibrations. Numerical solutions are compared to linear theory (where available) and to numerical solutions of the nonlinear Euler equations.

Of Blue Badges and Purple Cloth, the Impact of Battle Death in a Cohesive Unit

DTIC Science & Technology

1988-12-18

the small-unit level. History shows that the key to understanding the problem of death in a cohesive unit is that the danger of being killed or...cohesion and motivation are rooted in intensely personal attachments at the small-unit level. History shows that the key to understanding the problem of...without fear of mortal peril." (8) In this one sentence he shows his awareness of the necessity for leadership and cohesiveness in the face of death

Are the Keys loved to death? A study of diver specialization levels and preferences in the Florida Keys

Treesearch

Shona Paterson; David K. Loomis

2010-01-01

This paper presents research conducted for the Florida Reef Resilience Program on nonresident recreational SCUBA divers in three zones of the Florida Keys. When divers were segmented into specialization subgroups for analysis, divers in different subgroups tended to use different geographic locations. These results suggest differences in user preferences; yet when...

Necroptosis: an alternative cell death program defending against cancer

PubMed Central

Chen, Dongshi; Yu, Jian; Zhang, Lin

2016-01-01

One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID:26968619

Necroptosis: an alternative cell death program defending against cancer.

PubMed

Chen, Dongshi; Yu, Jian; Zhang, Lin

2016-04-01

One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL) protein. Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. Copyright © 2016 Elsevier B.V. All rights reserved.

Assisted or Hastened Death: The Healthcare Practitioner’s Dilemma

PubMed Central

MacLeod, Rod D; Wilson, Donna M; Malpas, Phillipa

2012-01-01

Assisting or hastening death is a dilemma with many ethical as well as practical issues facing healthcare practitioners in most countries worldwide now. Various arguments for and against assisted dying have been made over time but the call from the public for the legalisation of euthanasia and assisted suicide has never been stronger. While some studies have documented the reluctance of medical and other healthcare professionals to be involved in the practice of assisted dying or euthanasia, there is still much open debate in the public domain. Those who have the most experience of palliative care are strongest in their opposition to hastening death. This paper explores salient practical and ethical considerations for healthcare practitioners associated with assisting death, including a focus on examining the concepts of autonomy for patients and healthcare practitioners. The role of the healthcare practitioner has clearly and undoubtedly changed over time with advances in healthcare practices but the duty of care has not changed. The dilemmas for healthcare practitioners thus who have competent patients requesting hastened death extends far beyond acting within a country’s laws as they go to the very heart of the relationship between the practitioner and patient. PMID:23121745

Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial) Endosymbiont

PubMed Central

Zheng, Weiwen; Rasmussen, Ulla; Zheng, Siping; Bao, Xiaodong; Chen, Bin; Gao, Yuan; Guan, Xiong; Larsson, John; Bergman, Birgitta

2013-01-01

Programmed cell death (PCD) is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20%) of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays), together with visualization of cytoskeleton alterations (FITC-phalloidin staining), showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20) further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom. PMID:23822984

Uncovering the 2010 Haiti earthquake death toll

NASA Astrophysics Data System (ADS)

Daniell, J. E.; Khazai, B.; Wenzel, F.

2013-05-01

Casualties are estimated for the 12 January 2010 earthquake in Haiti using various reports calibrated by observed building damage states from satellite imagery and reconnaissance reports on the ground. By investigating various damage reports, casualty estimates and burial figures, for a one year period from 12 January 2010 until 12 January 2011, there is also strong evidence that the official government figures of 316 000 total dead and missing, reported to have been caused by the earthquake, are significantly overestimated. The authors have examined damage and casualties report to arrive at their estimation that the median death toll is less than half of this value (±137 000). The authors show through a study of historical earthquake death tolls, that overestimates of earthquake death tolls occur in many cases, and is not unique to Haiti. As death toll is one of the key elements for determining the amount of aid and reconstruction funds that will be mobilized, scientific means to estimate death tolls should be applied. Studies of international aid in recent natural disasters reveal that large distributions of aid which do not match the respective needs may cause oversupply of help, aggravate corruption and social disruption rather than reduce them, and lead to distrust within the donor community.

δ-COP contains a helix C-terminal to its longin domain key to COPI dynamics and function

PubMed Central

Arakel, Eric C.; Richter, Kora P.; Clancy, Anne; Schwappach, Blanche

2016-01-01

Membrane recruitment of coatomer and formation of coat protein I (COPI)-coated vesicles is crucial to homeostasis in the early secretory pathway. The conformational dynamics of COPI during cargo capture and vesicle formation is incompletely understood. By scanning the length of δ-COP via functional complementation in yeast, we dissect the domains of the δ-COP subunit. We show that the μ-homology domain is dispensable for COPI function in the early secretory pathway, whereas the N-terminal longin domain is essential. We map a previously uncharacterized helix, C-terminal to the longin domain, that is specifically required for the retrieval of HDEL-bearing endoplasmic reticulum-luminal residents. It is positionally analogous to an unstructured linker that becomes helical and membrane-facing in the open form of the AP2 clathrin adaptor complex. Based on the amphipathic nature of the critical helix it may probe the membrane for lipid packing defects or mediate interaction with cargo and thus contribute to stabilizing membrane-associated coatomer. PMID:27298352

Two Overlapping Domains of a Lyssavirus Matrix Protein That Acts on Different Cell Death Pathways ▿

PubMed Central

Larrous, Florence; Gholami, Alireza; Mouhamad, Shahul; Estaquier, Jérôme; Bourhy, Hervé

2010-01-01

The lyssavirus matrix (M) protein induces apoptosis. The regions of the M protein that are essential for triggering cell death pathways are not yet clearly defined. We therefore compared the M proteins from two viruses that have contrasting characteristics in terms of cellular apoptosis: a genotype 3 lyssavirus, Mokola virus (MOK), and a genotype 1 rabies virus isolated from a dog from Thailand (THA). We identified a 20-amino-acid fragment (corresponding to positions 67 to 86) that retained the cell death activities of the full-length M protein from MOK via both the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and inhibition of cytochrome c oxidase (CcO) activity. We found that the amino acids at positions 77 and 81 have an essential role in triggering these two cell death pathways. Directed mutagenesis demonstrated that the amino acid at position 77 affects CcO activity, whereas the amino acid at position 81 affects TRAIL-dependent apoptosis. Mutations in the full-length M protein that compromised induction of either of these two pathways resulted in delayed apoptosis compared with the time to apoptosis for the nonmutated control. PMID:20631119

Mutations in the FMN domain modulate MCD spectra of the heme site in the oxygenase domain of inducible nitric oxide synthase.

PubMed

Sempombe, Joseph; Elmore, Bradley O; Sun, Xi; Dupont, Andrea; Ghosh, Dipak K; Guillemette, J Guy; Kirk, Martin L; Feng, Changjian

2009-05-27

The nitric oxide synthase (NOS) output state for NO production is a complex of the flavin mononucleotide (FMN)-binding domain and the heme domain, and thereby it facilitates the interdomain electron transfer from the FMN to the catalytic heme site. Emerging evidence suggests that interdomain FMN-heme interactions are important in the formation of the output state because they guide the docking of the FMN domain to the heme domain. In this study, notable effects of mutations in the adjacent FMN domain on the heme structure in a human iNOS bidomain oxygenase/FMN construct have been observed by using low-temperature magnetic circular dichroism (MCD) spectroscopy. The comparative MCD study of wild-type and mutant proteins clearly indicates that a properly docked FMN domain contributes to the observed L-Arg perturbation of the heme MCD spectrum in the wild-type protein and that the conserved surface residues in the FMN domain (E546 and E603) play key roles in facilitating a productive alignment of the FMN and heme domains in iNOS.

Remote-sensing image encryption in hybrid domains

NASA Astrophysics Data System (ADS)

Zhang, Xiaoqiang; Zhu, Guiliang; Ma, Shilong

2012-04-01

Remote-sensing technology plays an important role in military and industrial fields. Remote-sensing image is the main means of acquiring information from satellites, which always contain some confidential information. To securely transmit and store remote-sensing images, we propose a new image encryption algorithm in hybrid domains. This algorithm makes full use of the advantages of image encryption in both spatial domain and transform domain. First, the low-pass subband coefficients of image DWT (discrete wavelet transform) decomposition are sorted by a PWLCM system in transform domain. Second, the image after IDWT (inverse discrete wavelet transform) reconstruction is diffused with 2D (two-dimensional) Logistic map and XOR operation in spatial domain. The experiment results and algorithm analyses show that the new algorithm possesses a large key space and can resist brute-force, statistical and differential attacks. Meanwhile, the proposed algorithm has the desirable encryption efficiency to satisfy requirements in practice.

Optical-domain subsampling for data efficient depth ranging in Fourier-domain optical coherence tomography

PubMed Central

Siddiqui, Meena; Vakoc, Benjamin J.

2012-01-01

Recent advances in optical coherence tomography (OCT) have led to higher-speed sources that support imaging over longer depth ranges. Limitations in the bandwidth of state-of-the-art acquisition electronics, however, prevent adoption of these advances into the clinical applications. Here, we introduce optical-domain subsampling as a method for imaging at high-speeds and over extended depth ranges but with a lower acquisition bandwidth than that required using conventional approaches. Optically subsampled laser sources utilize a discrete set of wavelengths to alias fringe signals along an extended depth range into a bandwidth limited frequency window. By detecting the complex fringe signals and under the assumption of a depth-constrained signal, optical-domain subsampling enables recovery of the depth-resolved scattering signal without overlapping artifacts from this bandwidth-limited window. We highlight key principles behind optical-domain subsampled imaging, and demonstrate this principle experimentally using a polygon-filter based swept-source laser that includes an intra-cavity Fabry-Perot (FP) etalon. PMID:23038343

A SURVEY OF DEATH ADJUSTMENT IN THE INDIAN SUBCONTINENT.

PubMed

Hossain, Mohammad Samir; Irfan, Muhammad; Balhara, Yatan Pal Singh; Giasuddin, Noor Ahmed; Sultana, Syeda Naheed

2015-01-01

The Death Adjustment Hypothesis (DAH) postulates two key themes. Its first part postulates that death should not be considered the end of existence and the second part emphasizes that the belief in immortal pattern of human existence can only be adopted in a morally rich life with the attitude towards morality and materialism balanced mutually. We wanted to explore Death Adjustment in the Indian subcontinent and the differences among, Indians, Pakistanis and Bangladeshis. We also wanted to find the relationship between death adjustment (i.e., adaptation to death), materialistic thoughts and death adjustment thoughts. This was a cross-sectional study, conducted from May 2010 to June 2013. Using a purposive sampling strategy, a sample of 296 participants from the Indian subcontinent [Pakistan (n=100), Bangladesh (n=98) and India (n=98)] was selected. Multidimensional Fear of Death Scale (MFODS) was used to measure death adjustment. The rest of the variables were measured using lists of respective thoughts, described in elaborated DAH. Analyses were carried out using SPSSv13. The mean death adjustment score for Pakistani, Indian and Bangaldeshi population were 115.26 +/- 26.4, 125.87 +/- 24.3 and 114.91 +/- 21.2, respectively. Death adjustment was better with older age (r=0.20) and with lower scores on materialistic thoughts (r = -0.26). However, this was a weak relation. The three nationalities were compared with each other by using Analysis of variance. Death adjustment thoughts and death adjustment were significantly different when Indians were compared with Bangladeshis (p=0.00) and Pakistanis (p=0.006) but comparison between Bangladeshis and Pakistanis showed no significant difference. Subjects with lesser materialistic thoughts showed better death adjustment. There are differences between Muslims and non-Muslims in adjusting to death.

Dowry deaths: a neglected public health issue in India.

PubMed

Babu, Gopalan Retheesh; Babu, Bontha Veerraju

2011-03-01

This paper appraises the public health burden of mortality in India caused by the practice of dowry and examines the association of some demographic and socio-economic factors with dowry deaths and dowry-related suicides. The paper is based on the data available on the public domains of the National Crime Records Bureau (NCRB), third National Family Health and Survey-2005-06, Planning Commission of India and Census of India 2001. In 2007, the total number of dowry deaths and dowry-related suicides reported in India were 8093 and 3148, respectively. There was a 74% increase in dowry-related deaths from1995 to 2007, while there was a 31% increase in the reporting of dowry-related suicides. Occurrence of dowry deaths has significant association with some demographic and socio-economic variables. The data reveal that the status of women is undesirable, and the burden of mortality and related morbidity is enormous. There should be a national injury surveillance system and reliable estimates of dowry-related homicides. However, available information can be used to design and implement some counter-measures to prevent dowry-related violence and deaths. The study warrants the undertaking of research to give insights into circumstances and triggers of such violence, the healthcare seeking of these victims, bottlenecks in seeking health care and reporting to the police.

The Relationships of Attachment Style and Social Maladjustment to Death Ideation in Depressed Women with a History of Childhood Sexual Abuse

PubMed Central

Smith, Phillip N.; Gamble, Stephanie A.; Cort, Natalie A.; Ward, Erin A.; Conwell, Yeates; Talbot, Nancy L.

2012-01-01

Objective Women who experience both depression and a history of childhood sexual abuse are at substantially greater risk for suicide compared to those who experience depression alone. Though psychiatric diagnoses, such as Major Depression and Borderline Personality Disorder, are often considered in the assessment and management of suicide risk, understanding how enduring characteristics interact with contextual factors to result in suicide-related thoughts and behaviors may be more useful for identifying specific targets for intervention. Design The current study used cross-sectional survey methodology to examine the interaction of attachment orientation and acute social maladjustment as risk factors for death ideation in a sample of women with Major Depression and histories of childhood sexual abuse. Results Social maladjustment was associated with greater likelihood of endorsing death ideation. Avoidant and anxious attachment orientations moderated the social maladjustment and death ideation associations in some domains. Specifically, work-related social maladjustment was associated with greater odds of death ideation for those with higher levels of attachment avoidance. Parent-role related maladjustment was associated with greater odds of death ideation for those with lower levels of attachment anxiety. Conclusions Findings demonstrate strong associations between death ideation and acute social maladjustment, and suggest that death ideation may be specific to certain domains of adjustment for anxious and avoidant attachment styles. Implications for the conceptualization and treatment of patients who report death ideation are discussed. PMID:22125120

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

PubMed

Ganjam, Goutham K; Terpolilli, Nicole Angela; Diemert, Sebastian; Eisenbach, Ina; Hoffmann, Lena; Reuther, Christina; Herden, Christiane; Roth, Joachim; Plesnila, Nikolaus; Culmsee, Carsten

2018-01-19

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

SH2 Domain Histochemistry.

PubMed

Buhs, Sophia; Nollau, Peter

2017-01-01

Among posttranslational modifications, the phosphorylation of tyrosine residues is a key modification in cell signaling. Because of its biological importance, characterization of the cellular state of tyrosine phosphorylation is of great interest. Based on the unique properties of endogenously expressed SH2 domains recognizing tyrosine phosphorylated signaling proteins with high specificity we have developed an alternative approach, coined SH2 profiling, enabling us to decipher complex patterns of tyrosine phosphorylation in various normal and cancerous tissues. So far, SH2 profiling has largely been applied for the analysis of protein extracts with the limitation that information on spatial distribution and intensity of tyrosine phosphorylation within a tissue is lost. Here, we describe a novel SH2 domain based strategy for differential characterization of the state of tyrosine phosphorylation in formaldehyde-fixed and paraffin-embedded tissues. This approach demonstrates that SH2 domains may serve as very valuable tools for the analysis of the differential state of tyrosine phosphorylation in primary tissues fixed and processed under conditions frequently applied by routine pathology laboratories.

Key factors affecting dying children and their families.

PubMed

Hinds, Pamela S; Schum, Lisa; Baker, Justin N; Wolfe, Joanne

2005-01-01

The death of a child alters the life and health of others immediately and for the rest of their lives. How a child dies influences parents' abilities to continue their role functions as well as siblings' abilities to make and maintain friendships, and may be the basis for health care providers' decisions to exit direct care roles. Thus, facilitating a "good death"-an obvious care priority for all involved with the dying child-ought also to be a priority for the health of bereaved families and affected health care providers. Making this a care priority is complicated by a serious lack of data, as details of the last hours or weeks of a dying child or adolescent's life are largely unknown. The purpose of this paper is to identify key factors that affect the course of dying children and adolescents and that of their bereaved survivors, and to link those key factors to needed research that could produce clinically relevant findings to improve the care of these patients. Key factors described here include suffering (physical, psychological, and spiritual), communication, decision making, prognostic ambiguities, ability of the seriously ill child to give assent to research participation, and educational preparation of health care providers to give competent end-of-life care.

Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

PubMed

Liu, Qiang; Li, Chun-Sheng

2017-04-20

Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

Current at domain walls, roughly speaking: nanoscales studies of disorder roughening and conduction

NASA Astrophysics Data System (ADS)

Paruch, Patrycja

2013-03-01

Domain walls in (multi)ferroic materials are the thin elastic interfaces separating regions with different orientations of magnetisation, electric polarisation, or spontaneous strain. Understanding their behaviour, and controlling domain size and stability, is key for their integration into applications, while fundamentally, domain walls provide an excellent model system in which the rich physics of disordered elastic interfaces can be accesses. In addition, domain walls can present novel properties, quite different from those of their parent materials, making them potentially useful as active components in future nano-devices. Here, we present our atomic force microscopy studies of ferroelectric domain walls in epitaxial Pb(Zr0.2Ti0.8)O3 and BiFeO3 thin films, in which we use piezorespose force microscopy to show unusual domain wall roughening behaviour, with very localised disorder regions in the sample leading to a complex, multi-affine scaling of the domain wall shape. We also show the effects of temperature, environmental conditions, and defects on switching dynamics and domain wall roughness. We combine these observations with parallel conductive-tip atomic force microscopy current measurements, which also show highly localised variations in conduction, and highlight the key role played by oxygen vacancies in the observed domain wall conduction.

Where Health and Death Intersect: Insights from a Terror Management Health Model.

PubMed

Arndt, Jamie; Goldenberg, Jamie L

2017-01-01

This paper offers an integrative understanding of the intersection between "health" and "death" from the perspective of the terror management health model. After highlighting the potential for health-related situations to elicit concerns about mortality, we turn to the question, how do thoughts of death influence health decision-making? Across varied health domains, the answer depends on whether these cognitions are in conscious awareness or not. When mortality concerns are conscious, people engage in healthy intentions and behavior if efficacy and coping resources are present. In contrast, when contending with accessible but non-conscious thoughts of death, health relevant decisions are guided more by esteem implications of the behavior. Lastly, we present research suggesting how these processes can be leveraged to facilitate health promotion and reduce health risk.

Contribution of TMEM16F to pyroptotic cell death.

PubMed

Ousingsawat, Jiraporn; Wanitchakool, Podchanart; Schreiber, Rainer; Kunzelmann, Karl

2018-02-20

Pyroptosis is a highly inflammatory form of programmed cell death that is caused by infection with intracellular pathogens and activation of canonical or noncanonical inflammasomes. The purinergic receptor P2X 7 is activated by the noncanonical inflammasome and contributes essentially to pyroptotic cell death. The Ca 2+ activated phospholipid scramblase and ion channel TMEM16F has been shown earlier to control cellular effects downstream of purinergic P2X 7 receptors that ultimately lead to cell death. As pyroptotic cell death is accompanied by an increases in intracellular Ca 2+ , we asked whether TMEM16F is activated during pyroptosis. The N-terminal cleavage product of gasdermin D (GD-N) is an executioner of pyroptosis by forming large plasma membrane pores. Expression of GD-N enhanced basal Ca 2+ levels and induced cell death. We observed that GD-N induced cell death in HEK293 and HAP1 cells, which was depending on expression of endogenous TMEM16F. GD-N activated large whole cell currents that were suppressed by knockdown or inhibition of TMEM16F. The results suggest that whole cell currents induced by the pore forming domain of gasdermin-D, are at least in part due to activation of TMEM16F. Knockdown of other TMEM16 paralogues expressed in HAP1 cells suggest TMEM16F as a crucial element during pyroptosis and excluded a role of other TMEM16 proteins. Thus TMEM16F supports pyroptosis and other forms of inflammatory cell death such as ferroptosis. Its potent inhibition by tannic acid may be part of the anti-inflammatory effects of flavonoids.

Surveillance for violent deaths--National Violent Death Reporting System, 16 states, 2005.

PubMed

Karch, Debra L; Lubell, Keri M; Friday, Jennifer; Patel, Nimesh; Williams, Dionne D

2008-04-11

firearms in the home. Suicides were precipitated primarily by mental illness, intimate partner or physical health problems, or a crisis during the previous 2 weeks. Homicides occurred at higher rates among males and young adult blacks and most often involved the use of firearms in the home or on a street/highway. Homicides were precipitated primarily by an argument over something other than money or property or in conjunction with another crime. Similar variation was reported among the other manners of death and special situations or populations highlighted in this report. This report provides the first detailed summary of data concerning violent deaths collected by NVDRS. The results indicate that deaths resulting from self-inflicted or interpersonal violence occur to a varying extent among males and females of every age group and racial/ethnic population. Key factors affecting rates of violent fatal injuries include sex, age group, method of injury, location of injury, and precipitating circumstances (e.g., mental health and substance abuse). Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. Accurate, timely, and comprehensive surveillance data are necessary for the occurrence of violent deaths in the United States to be understood better and ultimately prevented. NVDRS data can be used to track the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths and injuries at the national, state, and local levels. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal costs of violence. Further efforts are needed to increase the number of states using NVDRS, with an ultimate goal of full national representation.

The ethics of hastening death during terminal weaning.

PubMed

Walton, Laura; Bell, Dominic

2013-12-01

Withdrawal of life-sustaining medical treatment (LSMT) is under scrutiny as next-of-kin challenge medical decision-making in the courts and established end-of-life pathways are withdrawn in the face of public criticism. With persistent lobbying for medically assisted dying as the other side of the coin, and professional advice that doctors distance themselves from this activity, the fine line between defensible palliative care and hastening a death needs to be unambiguously defined, particularly with additional confounders such as transplantation initiatives. The medical literature in this domain is dominated by ethical debate on euthanasia and medically assisted dying rather than defensibility within intensive care at the point of withdrawal of LSMT. The process and, therefore, the timing of dying is open to manipulation by intensivists, families, other hospital physicians, courts of law and extraneous influences such as organ donation. Intensivists faced with these challenging processes need to consider some key principles to help them navigate the management of dying. They need to demonstrate transparency in order to engender trust, be responsive to the dynamically evolving needs of patient and family, avoid ambiguity, show consistency and predictability and, finally, they need to conform with society's expectations and professional standards to achieve defensibility for their actions. Adherence to these principles is likely to minimize conflict, maximize patient benefit, maintain public confidence and avoid professional jeopardy.

Exploring metazoan evolution through dynamic and holistic changes in protein families and domains

USDA-ARS?s Scientific Manuscript database

Understanding proteome evolution is important for deciphering processes that drive species diversity and adaptation. Herein, the dynamics of change in protein families and protein domains over the course of metazoan evolution was explored. Change, as defined by birth/death and duplication/deletion ...

Neonatal Death

MedlinePlus

... Home > Complications & Loss > Loss & grief > Neonatal death Neonatal death E-mail to a friend Please fill in ... cope with your baby’s death. What is neonatal death? Neonatal death is when a baby dies in ...

Regulated Forms of Cell Death in Fungi

PubMed Central

Gonçalves, A. Pedro; Heller, Jens; Daskalov, Asen; Videira, Arnaldo; Glass, N. Louise

2017-01-01

Cell death occurs in all domains of life. While some cells die in an uncontrolled way due to exposure to external cues, other cells die in a regulated manner as part of a genetically encoded developmental program. Like other eukaryotic species, fungi undergo programmed cell death (PCD) in response to various triggers. For example, exposure to external stress conditions can activate PCD pathways in fungi. Calcium redistribution between the extracellular space, the cytoplasm and intracellular storage organelles appears to be pivotal for this kind of cell death. PCD is also part of the fungal life cycle, in which it occurs during sexual and asexual reproduction, aging, and as part of development associated with infection in phytopathogenic fungi. Additionally, a fungal non-self-recognition mechanism termed heterokaryon incompatibility (HI) also involves PCD. Some of the molecular players mediating PCD during HI show remarkable similarities to major constituents involved in innate immunity in metazoans and plants. In this review we discuss recent research on fungal PCD mechanisms in comparison to more characterized mechanisms in metazoans. We highlight the role of PCD in fungi in response to exogenic compounds, fungal development and non-self-recognition processes and discuss identified intracellular signaling pathways and molecules that regulate fungal PCD. PMID:28983298

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer's Disease.

PubMed

Cheng, Bo; Liu, Mingxia; Shen, Dinggang; Li, Zuoyong; Zhang, Daoqiang

2017-04-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer's Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multi-domain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods.

Death Cafe.

PubMed

Miles, Lizzy; Corr, Charles A

2017-06-01

This article explains the meaning of the phrase Death Cafe and describes what typically occurs at a Death Cafe gathering. The article traces the history of the Death Cafe movement, explores some reasons why people take part in a Death Cafe gathering, and gives examples of what individuals think they might derive from their participation. In addition, this article notes similarities between the Death Cafe movement and three other developments in the field of death, dying, and bereavement. Finally, this article identifies two provisional lessons that can be drawn from Death Cafe gatherings and the Death Cafe movement itself.

Compensation for Combat Deaths: Policy Considerations

DTIC Science & Technology

2012-01-01

through the courts for deaths resulting from other parties’ negligence or criminal behavior; a key difference between the tort system and many other...funding facilities that function outside of the tort system— for example, workers’ compensation programs for workplace fatalities and the Victims...receive $100,000 if the 10-percent risk of a loss of $100,000 actually came to pass. Tort law generally uses an ex post approach to compensation and

Site-specific chemical conjugation of human Fas ligand extracellular domain using trans-cyclooctene - methyltetrazine reactions.

PubMed

Muraki, Michiro; Hirota, Kiyonori

2017-07-03

Fas ligand plays a key role in the human immune system as a major cell death inducing protein. The extracellular domain of human Fas ligand (hFasLECD) triggers apoptosis of malignant cells, and therefore is expected to have substantial potentials in medical biotechnology. However, the current application of this protein to clinical medicine is hampered by a shortage of the benefits relative to the drawbacks including the side-effects in systemic administration. Effective procedures for the engineering of the protein by attaching useful additional functions are required to overcome the problem. A procedure for the site-specific chemical conjugation of hFasLECD with a fluorochrome and functional proteins was devised using an inverse-electron-demand Diels-Alder reaction between trans-cyclooctene group and methyltetrazine group. The conjugations in the present study were attained by using much less molar excess amounts of the compounds to be attached as compared with the conventional chemical modification reactions using maleimide derivatives in the previous study. The isolated conjugates of hFasLECD with sulfo-Cy3, avidin and rabbit IgG Fab' domain presented the functional and the structural integrities of the attached molecules without impairing the specific binding activity toward human Fas receptor extracellular domain. The present study provided a new fundamental strategy for the production of the engineered hFasLECDs with additional beneficial functions, which will lead to the developments of the improved diagnostic systems and the effective treatment methods of serious diseases by using this protein as a component of novel molecular tools.

Portrayal of Brain Death in Film and Television.

PubMed

Lewis, A; Weaver, J; Caplan, A

2017-03-01

We sought to evaluate whether television and cinematic coverage of brain death is educational or misleading. We identified 24 accessible productions that addressed brain death using the archives of the Paley Center for Media (160 000 titles) and the Internet Movie Database (3.7 million titles). Productions were reviewed by two board-certified neurologists. Although 19 characters were pronounced brain dead, no productions demonstrated a complete examination to assess for brain death (6 included an assessment for coma, 9 included an evaluation of at least 1 brainstem reflex, but none included an assessment of every brainstem reflex, and 2 included an apnea test). Subjectively, both authors believed only a small fraction of productions (13% A.L., 13% J.W.) provided the public a complete and accurate understanding of brain death. Organ donation was addressed in 17 productions (71%), but both reviewers felt that the discussions about organ donation were professional in a paucity of productions (9% for A.L., 27% for J.W.). Because television and movies serve as a key source for public education, the quality of productions that feature brain death must be improved. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells.

PubMed

Ziauddin, S M; Yoshimura, A; Montenegro Raudales, J L; Ozaki, Y; Higuchi, K; Ukai, T; Kaneko, T; Miyazaki, T; Latz, E; Hara, Y

2018-06-01

Dental calculus is a mineralized deposit attached to the tooth surface. We have shown that cellular uptake of dental calculus triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, leading to the processing of the interleukin-1β precursor into its mature form in mouse and human phagocytes. The activation of the NLRP3 inflammasome also induced a lytic form of programmed cell death, pyroptosis, in these cells. However, the effects of dental calculus on other cell types in periodontal tissue have not been investigated. The aim of this study was to determine whether dental calculus can induce cell death in oral epithelial cells. HSC-2 human oral squamous carcinoma cells, HOMK107 human primary oral epithelial cells and immortalized mouse macrophages were exposed to dental calculus or 1 of its components, hydroxyapatite crystals. For inhibition assays, the cells were exposed to dental calculus in the presence or absence of cytochalasin D (endocytosis inhibitor), z-YVAD-fmk (caspase-1 inhibitor) or glyburide (NLRP3 inflammasome inhibitor). Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release and staining with propidium iodide. Tumor necrosis factor-α production was quantified by enzyme-linked immunosorbent assay. Oral epithelial barrier function was examined by permeability assay. Dental calculus induced cell death in HSC-2 cells, as judged by LDH release and propidium iodide staining. Dental calculus also induced LDH release from HOMK107 cells. Following heat treatment, dental calculus lost its capacity to induce tumor necrosis factor-α in mouse macrophages, but could induce LDH release in HSC-2 cells, indicating a major role of inorganic components in cell death. Hydroxyapatite crystals also induced cell death in both HSC-2 and HOMK107 cells, as judged by LDH release, indicating the capacity of crystal particles to induce cell death. Cell death induced by dental

Sensitization of vascular smooth muscle cell to TNF-{alpha}-mediated death in the presence of palmitate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rho, Mun-Chual; Ah Lee, Kyeong; Mi Kim, Sun

2007-05-01

Saturated free fatty acids (FFAs), including palmitate, can activate the intrinsic death pathway in cells. However, the relationship between FFAs and receptor-mediated death pathway is still unknown. In this study, we have investigated whether FFAs are able to trigger receptor-mediated death. In addition, to clarify the mechanisms responsible for the activation, we examined the biochemical changes in dying vascular smooth muscle cell (VSMC) and the effects of various molecules to the receptor-mediated VSMC death. Tumor necrosis factor (TNF)-{alpha}-mediated VSMC death occurred in the presence of sub-cytotoxic concentration of palmitate as determined by assessing viability and DNA degradation, while the cytokinemore » did not influence VSMC viability in the presence of oleate. The VSMC death was inhibited by the gene transfer of a dominant-negative Fas-associated death domain-containing protein and the baculovirus p35, but not by the bcl-xL or the c-Jun N-terminal kinase (JNK) binding domain of JNK-interacting protein-1, in tests utilizing recombinant adenoviruses. The VSMC death was also inhibited by a neutralizing anti-TNF receptor 1 antibody, the caspase inhibitor z-VAD, and the cathepsin B inhibitor CA074, a finding indicative of the role of both caspases and cathepsin B in this process. Consistent with this finding, caspase-3 activation and an increase in cytosolic cathepsin B activity were detected in the dying VSMC. Palmitate inhibited an increase of TNF-{alpha}-mediated nuclear factor kappa B (NF-{kappa}B) activity, the survival pathway activated by the cytokine, by hindering the translocation of the NF-{kappa}B subunit of p65 from the cytosol into the nucleus. The gene transfer of inhibitor of NF-{kappa}B predisposed VSMC to palmitate-induced cell death. To the best of our knowledge, this study is the first report to demonstrate the activation of TNF-{alpha}-mediated cell death in the presence of palmitate. The current study proposes that FFAs would take

Tunable inertia of chiral magnetic domain walls

PubMed Central

Torrejon, Jacob; Martinez, Eduardo; Hayashi, Masamitsu

2016-01-01

The time it takes to accelerate an object from zero to a given velocity depends on the applied force and the environment. If the force ceases, it takes exactly the same time to completely decelerate. A magnetic domain wall is a topological object that has been observed to follow this behaviour. Here we show that acceleration and deceleration times of chiral Neel walls driven by current are different in a system with low damping and moderate Dzyaloshinskii–Moriya exchange constant. The time needed to accelerate a domain wall with current via the spin Hall torque is much faster than the time it needs to decelerate once the current is turned off. The deceleration time is defined by the Dzyaloshinskii–Moriya exchange constant whereas the acceleration time depends on the spin Hall torque, enabling tunable inertia of chiral domain walls. Such unique feature of chiral domain walls can be utilized to move and position domain walls with lower current, key to the development of storage class memory devices. PMID:27882932

Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.

PubMed

Huculeci, Radu; Cilia, Elisa; Lyczek, Agatha; Buts, Lieven; Houben, Klaartje; Seeliger, Markus A; van Nuland, Nico; Lenaerts, Tom

2016-11-01

Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information. We reveal that binding the phosphorylated tail of Fyn perturbs a residue cluster near the linker connecting the SH2 and SH3 domains of Fyn, which is known to be relevant in the regulation of the activity of Fyn. Biochemical perturbation experiments validate that those residues are essential for inhibition of Fyn, leading to a gain of function upon mutation. These findings reveal how side-chain dynamics may facilitate the allosteric regulation of the different members of the Src kinase family. Copyright © 2016 Elsevier Ltd. All rights reserved.

Community Advisory Boards Guiding Engaged Research Efforts within a Clinical Translational Sciences Award: Key Contextual Factors Explored.

PubMed

Halladay, Jacqueline R; Donahue, Katrina E; Sleath, Betsy; Reuland, Dan; Black, Adina; Mitchell, C Madeline; Breland, Carol E; Coyne-Beasley, Tamera; Mottus, Kathleen; Watson, Sable Noelle; Lewis, Virginia; Wynn, Mysha; Corbie-Smith, Giselle

2017-01-01

Engaging stakeholders in research carries the promise of enhancing the research relevance, transparency, and speed of getting findings into practice. By describing the context and functional aspects of stakeholder groups, like those working as community advisory boards (CABs), others can learn from these experiences and operationalize their own CABs. Our objective is to describe our experiences with diverse CABs affiliated with our community engagement group within our institution's Clinical Translational Sciences Award (CTSA). We identify key contextual elements that are important to administering CABs. A group of investigators, staff, and community members engaged in a 6-month collaboration to describe their experiences of working with six research CABs. We identified the key contextual domains that illustrate how CABS are developed and sustained. Two lead authors, with experience with CABs and identifying contextual domains in other work, led a team of 13 through the process. Additionally, we devised a list of key tips to consider when devising CABs. The final domains include (1) aligned missions among stakeholders (2) resources/support, (3) defined operational processes/shared power, (4) well-described member roles, and (5) understanding and mitigating challenges. The tips are a set of actions that support the domains. Identifying key contextual domains was relatively easy, despite differences in the respective CAB's condition of focus, overall mission, or patient demographics represented. By contextualizing these five domains, other research and community partners can take an informed approach to move forward with CAB planning and engaged research.

Structural analysis of key gap junction domains--Lessons from genome data and disease-linked mutants.

PubMed

Bai, Donglin

2016-02-01

A gap junction (GJ) channel is formed by docking of two GJ hemichannels and each of these hemichannels is a hexamer of connexins. All connexin genes have been identified in human, mouse, and rat genomes and their homologous genes in many other vertebrates are available in public databases. The protein sequences of these connexins align well with high sequence identity in the same connexin across different species. Domains in closely related connexins and several residues in all known connexins are also well-conserved. These conserved residues form signatures (also known as sequence logos) in these domains and are likely to play important biological functions. In this review, the sequence logos of individual connexins, groups of connexins with common ancestors, and all connexins are analyzed to visualize natural evolutionary variations and the hot spots for human disease-linked mutations. Several gap junction domains are homologous, likely forming similar structures essential for their function. The availability of a high resolution Cx26 GJ structure and the subsequently-derived homology structure models for other connexin GJ channels elevated our understanding of sequence logos at the three-dimensional GJ structure level, thus facilitating the understanding of how disease-linked connexin mutants might impair GJ structure and function. This knowledge will enable the design of complementary variants to rescue disease-linked mutants. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effective suppression of dengue virus using a novel group-I intron that induces apoptotic cell death upon infection through conditional expression of the Bax C-terminal domain.

PubMed

Carter, James R; Keith, James H; Fraser, Tresa S; Dawson, James L; Kucharski, Cheryl A; Horne, Kate M; Higgs, Stephen; Fraser, Malcolm J

2014-06-13

Approximately 100 million confirmed infections and 20,000 deaths are caused by Dengue virus (DENV) outbreaks annually. Global warming and rapid dispersal have resulted in DENV epidemics in formally non-endemic regions. Currently no consistently effective preventive measures for DENV exist, prompting development of transgenic and paratransgenic vector control approaches. Production of transgenic mosquitoes refractory for virus infection and/or transmission is contingent upon defining antiviral genes that have low probability for allowing escape mutations, and are equally effective against multiple serotypes. Previously we demonstrated the effectiveness of an anti-viral group I intron targeting U143 of the DENV genome in mediating trans-splicing and expression of a marker gene with the capsid coding domain. In this report we examine the effectiveness of coupling expression of ΔN Bax to trans-splicing U143 intron activity as a means of suppressing DENV infection of mosquito cells. Targeting the conserved DENV circularization sequence (CS) by U143 intron trans-splicing activity appends a 3' exon RNA encoding ΔN Bax to the capsid coding region of the genomic RNA, resulting in a chimeric protein that induces premature cell death upon infection. TCID50-IFA analyses demonstrate an enhancement of DENV suppression for all DENV serotypes tested over the identical group I intron coupled with the non-apoptotic inducing firefly luciferase as the 3' exon. These cumulative results confirm the increased effectiveness of this αDENV-U143-ΔN Bax group I intron as a sequence specific antiviral that should be useful for suppression of DENV in transgenic mosquitoes. Annexin V staining, caspase 3 assays, and DNA ladder observations confirm DCA-ΔN Bax fusion protein expression induces apoptotic cell death. This report confirms the relative effectiveness of an anti-DENV group I intron coupled to an apoptosis-inducing ΔN Bax 3' exon that trans-splices conserved sequences of the 5' CS

Exploiting domain information for Word Sense Disambiguation of medical documents.

PubMed

Stevenson, Mark; Agirre, Eneko; Soroa, Aitor

2012-01-01

Current techniques for knowledge-based Word Sense Disambiguation (WSD) of ambiguous biomedical terms rely on relations in the Unified Medical Language System Metathesaurus but do not take into account the domain of the target documents. The authors' goal is to improve these methods by using information about the topic of the document in which the ambiguous term appears. The authors proposed and implemented several methods to extract lists of key terms associated with Medical Subject Heading terms. These key terms are used to represent the document topic in a knowledge-based WSD system. They are applied both alone and in combination with local context. A standard measure of accuracy was calculated over the set of target words in the widely used National Library of Medicine WSD dataset. The authors report a significant improvement when combining those key terms with local context, showing that domain information improves the results of a WSD system based on the Unified Medical Language System Metathesaurus alone. The best results were obtained using key terms obtained by relevance feedback and weighted by inverse document frequency.

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

PubMed Central

Mahul-Mellier, A-L; Vercruysse, F; Maco, B; Ait-Bouziad, N; De Roo, M; Muller, D; Lashuel, H A

2015-01-01

The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable

Brain death and marginal grafts in liver transplantation.

PubMed

Jiménez-Castro, M B; Gracia-Sancho, J; Peralta, C

2015-06-04

It is well known that most organs for transplantation are currently procured from brain-dead donors; however, the presence of brain death is an important risk factor in liver transplantation. In addition, one of the mechanisms to avoid the shortage of liver grafts for transplant is the use of marginal livers, which may show higher risk of primary non-function or initial poor function. To our knowledge, very few reviews have focused in the field of liver transplantation using brain-dead donors; moreover, reviews that focused on both brain death and marginal grafts in liver transplantation, both being key risk factors in clinical practice, have not been published elsewhere. The present review aims to describe the recent findings and the state-of-the-art knowledge regarding the pathophysiological changes occurring during brain death, their effects on marginal liver grafts and summarize the more controversial topics of this pathology. We also review the therapeutic strategies designed to date to reduce the detrimental effects of brain death in both marginal and optimal livers, attempting to explain why such strategies have not solved the clinical problem of liver transplantation.

Organ donation after assisted death: Is it more or less ethically-problematic than donation after circulatory death?

PubMed

Kirby, Jeffrey

2016-12-01

A provocative question has emerged since the Supreme Court of Canada's decision on assisted dying: Should Canadians who request, and are granted, an assisted death be considered a legitimate source of transplantable organs? A related question is addressed in this paper: is controlled organ donation after assisted death (cDAD) more or less ethically-problematic than standard, controlled organ donation after circulatory determination of death (cDCDD)? Controversial, ethics-related dimensions of cDCD that are of relevance to this research question are explored, and morally-relevant distinctions between cDAD and cDCD are identified. In addition, a set of morally-relevant advantages of one practice over the other is uncovered, and a few potential, theoretical issues specifically related to cDAD practice are articulated. Despite these concerns, the analysis suggests a counterintuitive conclusion: cDAD is, overall, less ethically-problematic than cDCDD. The former practice better respects the autonomy interests of the potential donor, and a claim regarding irreversibility of cessation of the donor's circulatory function in the cDAD context can be supported. Further, with cDAD, there is no possibility that the donor will have negative sensory experiences during organ procurement surgery. Although the development of appropriate policy-decision and regulatory approaches in this domain will be complex and challenging, the comparative ethical analysis of these two organ donation practices has the potential to constructively inform the deliberations of relevant stakeholders, resource persons and decision makers.

The death spiral: predicting death in Drosophila cohorts.

PubMed

Mueller, Laurence D; Shahrestani, Parvin; Rauser, Casandra L; Rose, Michael R

2016-11-01

Drosophila research has identified a new feature of aging that has been called the death spiral. The death spiral is a period prior to death during which there is a decline in life-history characters, such as fecundity, as well as physiological characters. First, we review the data from the Drosophila and medfly literature that suggest the existence of death spirals. Second, we re-analyze five cases with such data from four laboratories using a generalized statistical framework, a re-analysis that strengthens the case for the salience of the death spiral phenomenon. Third, we raise the issue whether death spirals need to be taken into account in the analysis of functional characters over age, in aging research with model species as well as human data.

The Cyber War: Maintaining and Controlling the Key Cyber Terrain of the Cyberspace Domain

DTIC Science & Technology

2016-06-26

solution strategy to assess options that will enable the commander to realize the Air Force’s cyber mission. Recommendations will be made that will...will present a solution to assist the JFC in achieving cyberspace dominance. Background In the modern world of advanced technology, control of...the solutions are: 1) timely identification of key cyber terrain, 2) accurate mapping of the cyber terrain, 3) defense of key cyber terrain, and 4

Deliberating death.

PubMed

Landes, Scott D

2010-01-01

Utilizing a particular case study of a woman attempting to come to terms with her death, this article explores the difficult metaphors of death present within the Christian tradition. Tracing a Christian understanding of death back to the work of Augustine, the case study is utilized to highlight the difficulties presented by past and present theology embracing ideas of punishment within death. Following the trajectory of the case study, alternative understandings of death present in recent Christian theology and within Native American spirituality are presented in an attempt to find room for a fuller meaning of death post-reconciliation, but premortem.

Key papers in prostate cancer.

PubMed

Rodney, Simon; Shah, Taimur Tariq; Patel, Hitendra R H; Arya, Manit

2014-11-01

Prostate cancer is the most common cancer and second leading cause of death in men. The evidence base for the diagnosis and treatment of prostate cancer is continually changing. We aim to review and discuss past and contemporary papers on these topics to provoke debate and highlight key dilemmas faced by the urological community. We review key papers on prostate-specific antigen screening, radical prostatectomy versus surveillance strategies, targeted therapies, timing of radiotherapy and alternative anti-androgen therapeutics. Previously, the majority of patients, irrespective of risk, underwent radical open surgical procedures associated with considerable morbidity and mortality. Evidence is emerging that not all prostate cancers are alike and that low-grade disease can be safely managed by surveillance strategies and localized treatment to the prostate. The question remains as to how to accurately stage the disease and ultimately choose which treatment pathway to follow.

Domains in Ferroelectric Nanostructures

NASA Astrophysics Data System (ADS)

Gregg, Marty

2010-03-01

Ferroelectric materials have great potential in influencing the future of small scale electronics. At a basic level, this is because ferroelectric surfaces are charged, and so interact strongly with charge-carrying metals and semiconductors - the building blocks for all electronic systems. Since the electrical polarity of the ferroelectric can be reversed, surfaces can both attract and repel charges in nearby materials, and can thereby exert complete control over both charge distribution and movement. It should be no surprise, therefore, that microelectronics industries have already looked very seriously at harnessing ferroelectric materials in a variety of applications, from solid state memory chips (FeRAMs) to field effect transistors (FeFETs). In all such applications, switching the direction of the polarity of the ferroelectric is a key aspect of functional behavior. The mechanism for switching involves the field-induced nucleation and growth of domains. Domain coarsening, through domain wall propagation, eventually causes the entire ferroelectric to switch its polar direction. It is thus the existence and behavior of domains that determine the switching response, and ultimately the performance of the ferroelectric device. A major issue, associated with the integration of ferroelectrics into microelectronic devices, has been that the fundamental properties associated with ferroelectrics, when in bulk form, appear to change quite dramatically and unpredictably when at the nanoscale: new modes of behaviour, and different functional characteristics from those seen in bulk appear. For domains, in particular, the proximity of surfaces and boundaries have a dramatic effect: surface tension and depolarizing fields both serve to increase the equilibrium density of domains, such that minor changes in scale or morphology can have major ramifications for domain redistribution. Given the importance of domains in dictating the overall switching characteristics of a device

Geometrical Dependence of Domain-Wall Propagation and Nucleation Fields in Magnetic-Domain-Wall Sensors

NASA Astrophysics Data System (ADS)

Borie, B.; Kehlberger, A.; Wahrhusen, J.; Grimm, H.; Kläui, M.

2017-08-01

We study the key domain-wall properties in segmented nanowire loop-based structures used in domain-wall-based sensors. The two reasons for device failure, namely, distribution of the domain-wall propagation field (depinning) and the nucleation field are determined with magneto-optical Kerr effect and giant-magnetoresistance (GMR) measurements for thousands of elements to obtain significant statistics. Single layers of Ni81 Fe19 , a complete GMR stack with Co90 Fe10 /Ni81Fe19 as a free layer, and a single layer of Co90 Fe10 are deposited and industrially patterned to determine the influence of the shape anisotropy, the magnetocrystalline anisotropy, and the fabrication processes. We show that the propagation field is influenced only slightly by the geometry but significantly by material parameters. Simulations for a realistic wire shape yield a curling-mode type of magnetization configuration close to the nucleation field. Nonetheless, we find that the domain-wall nucleation fields can be described by a typical Stoner-Wohlfarth model related to the measured geometrical parameters of the wires and fitted by considering the process parameters. The GMR effect is subsequently measured in a substantial number of devices (3000) in order to accurately gauge the variation between devices. This measurement scheme reveals a corrected upper limit to the nucleation fields of the sensors that can be exploited for fast characterization of the working elements.

Structural Landscape of the Proline-Rich Domain of Sos1 Nucleotide Exchange Factor

PubMed Central

McDonald, Caleb B.; Bhat, Vikas; Kurouski, Dmitry; Mikles, David C.; Deegan, Brian J.; Seldeen, Kenneth L.; Lednev, Igor K.; Farooq, Amjad

2013-01-01

Despite its key role in mediating a plethora of cellular signaling cascades pertinent to health and disease, little is known about the structural landscape of the proline-rich (PR) domain of Sos1 guanine nucleotide exchange factor. Herein, using a battery of biophysical tools, we provide evidence that the PR domain of Sos1 is structurally disordered and adopts an extended random coil-like conformation in solution. Of particular interest is the observation that while chemical denaturation of PR domain results in the formation of a significant amount of polyproline II (PPII) helices, it has little or negligible effect on its overall size as measured by its hydrodynamic radius. Our data also show that the PR domain displays a highly dynamic conformational basin in agreement with the knowledge that the intrinsically unstructured proteins rapidly interconvert between an ensemble of conformations. Collectively, our study provides new insights into the conformational equilibrium of a key signaling molecule with important consequences on its physiological function. PMID:23528987

The nanoscale organization of signaling domains at the plasma membrane.

PubMed

Griffié, Juliette; Burn, Garth; Owen, Dylan M

2015-01-01

In this chapter, we present an overview of the role of the nanoscale organization of signaling domains in regulating key cellular processes. In particular, we illustrate the importance of protein and lipid nanodomains as triggers and mediators of cell signaling. As particular examples, we summarize the state of the art of understanding the role of nanodomains in the mounting of an immune response, cellular adhesion, intercellular communication, and cell proliferation. Thus, this chapter underlines the essential role the nanoscale organization of key signaling proteins and lipid domains. We will also see how nanodomains play an important role in the lifecycle of many pathogens relevant to human disease and therefore illustrate how these structures may become future therapeutic targets. Copyright © 2015 Elsevier Inc. All rights reserved.

OST-HTH: a novel predicted RNA-binding domain

PubMed Central

2010-01-01

Background The mechanism by which the arthropod Oskar and vertebrate TDRD5/TDRD7 proteins nucleate or organize structurally related ribonucleoprotein (RNP) complexes, the polar granule and nuage, is poorly understood. Using sequence profile searches we identify a novel domain in these proteins that is widely conserved across eukaryotes and bacteria. Results Using contextual information from domain architectures, sequence-structure superpositions and available functional information we predict that this domain is likely to adopt the winged helix-turn-helix fold and bind RNA with a potential specificity for dsRNA. We show that in eukaryotes this domain is often combined in the same polypeptide with protein-protein- or lipid- interaction domains that might play a role in anchoring these proteins to specific cytoskeletal structures. Conclusions Thus, proteins with this domain might have a key role in the recognition and localization of dsRNA, including miRNAs, rasiRNAs and piRNAs hybridized to their targets. In other cases, this domain is fused to ubiquitin-binding, E3 ligase and ubiquitin-like domains indicating a previously under-appreciated role for ubiquitination in regulating the assembly and stability of nuage-like RNP complexes. Both bacteria and eukaryotes encode a conserved family of proteins that combines this predicted RNA-binding domain with a previously uncharacterized domain (DUF88). We present evidence that it is an RNAse belonging to the superfamily that includes the 5'->3' nucleases, PIN and NYN domains and might be recruited to degrade certain RNAs. Reviewers This article was reviewed by Sandor Pongor and Arcady Mushegian. PMID:20302647

Fourier domain asymmetric cryptosystem for privacy protected multimodal biometric security

NASA Astrophysics Data System (ADS)

Choudhury, Debesh

2016-04-01

We propose a Fourier domain asymmetric cryptosystem for multimodal biometric security. One modality of biometrics (such as face) is used as the plaintext, which is encrypted by another modality of biometrics (such as fingerprint). A private key is synthesized from the encrypted biometric signature by complex spatial Fourier processing. The encrypted biometric signature is further encrypted by other biometric modalities, and the corresponding private keys are synthesized. The resulting biometric signature is privacy protected since the encryption keys are provided by the human, and hence those are private keys. Moreover, the decryption keys are synthesized using those private encryption keys. The encrypted signatures are decrypted using the synthesized private keys and inverse complex spatial Fourier processing. Computer simulations demonstrate the feasibility of the technique proposed.

Effect of cocaine on Fas-associated protein with death domain in the rat brain: individual differences in a model of differential vulnerability to drug abuse.

PubMed

García-Fuster, María-Julia; Clinton, Sarah M; Watson, Stanley J; Akil, Huda

2009-04-01

This study was designed to (1) assess the effects of cocaine on Fas-associated protein with death domain (FADD) system and its role in the activation of apoptotic vs nonapoptotic events and (2) ascertain whether animals selectively bred for their differential propensity to drug-seeking show differences in FADD levels or response to cocaine. Acute cocaine, through D(2) dopamine receptors, induced a dose-response increase in FADD protein in the cortex, with opposite effects over pFADD (Ser191/194), and no induction of apoptotic cell death (poly-(ADP-ribose) polymerase cleavage). FADD was increased by cocaine in cytosol (approximately 142%), membranes (approximately 23%) and nucleus (approximately 54%). The modulation of the FADD system showed tolerance of the acute effect over time, as well as a compensatory response on withdrawal that mirrored the acute effect--ie a transient FADD decrease on day 3 of withdrawal, both at mRNA and protein levels. In a second experiment, possible FADD differences were investigated in rats selectively bred for differential responsiveness to novelty, propensity for drug-seeking and cocaine sensitization. High-responders (HR), who were more prone to drug abuse, exhibited higher FADD and lower pFADD levels than low-responder (LR) rats. However, HR and LR rats showed similar rates of cocaine-induced apoptosis, and exhibited a parallel impact of cocaine over FADD within each phenotype. Thus, FADD is a signaling protein modulated by cocaine, regulating apoptosis/proliferative mechanisms in relation to its FADD/pFADD content. Interestingly, animals selectively bred for differential propensity to substance abuse show basal differences in the expression of this protein, suggesting FADD may also be a molecular correlate for the HR/LR phenotype.

Effective Moment Feature Vectors for Protein Domain Structures

PubMed Central

Shi, Jian-Yu; Yiu, Siu-Ming; Zhang, Yan-Ning; Chin, Francis Yuk-Lun

2013-01-01

Imaging processing techniques have been shown to be useful in studying protein domain structures. The idea is to represent the pairwise distances of any two residues of the structure in a 2D distance matrix (DM). Features and/or submatrices are extracted from this DM to represent a domain. Existing approaches, however, may involve a large number of features (100–400) or complicated mathematical operations. Finding fewer but more effective features is always desirable. In this paper, based on some key observations on DMs, we are able to decompose a DM image into four basic binary images, each representing the structural characteristics of a fundamental secondary structure element (SSE) or a motif in the domain. Using the concept of moments in image processing, we further derive 45 structural features based on the four binary images. Together with 4 features extracted from the basic images, we represent the structure of a domain using 49 features. We show that our feature vectors can represent domain structures effectively in terms of the following. (1) We show a higher accuracy for domain classification. (2) We show a clear and consistent distribution of domains using our proposed structural vector space. (3) We are able to cluster the domains according to our moment features and demonstrate a relationship between structural variation and functional diversity. PMID:24391828

Non-apoptotic cell death in animal development.

PubMed

Kutscher, Lena M; Shaham, Shai

2017-08-01

Programmed cell death (PCD) is an important process in the development of multicellular organisms. Apoptosis, a form of PCD characterized morphologically by chromatin condensation, membrane blebbing, and cytoplasm compaction, and molecularly by the activation of caspase proteases, has been extensively investigated. Studies in Caenorhabditis elegans, Drosophila, mice, and the developing chick have revealed, however, that developmental PCD also occurs through other mechanisms, morphologically and molecularly distinct from apoptosis. Some non-apoptotic PCD pathways, including those regulating germ cell death in Drosophila, still appear to employ caspases. However, another prominent cell death program, linker cell-type death (LCD), is morphologically conserved, and independent of the key genes that drive apoptosis, functioning, at least in part, through the ubiquitin proteasome system. These non-apoptotic processes may serve as backup programs when caspases are inactivated or unavailable, or, more likely, as freestanding cell culling programs. Non-apoptotic PCD has been documented extensively in the developing nervous system, and during the formation of germline and somatic gonadal structures, suggesting that preservation of these mechanisms is likely under strong selective pressure. Here, we discuss our current understanding of non-apoptotic PCD in animal development, and explore possible roles for LCD and other non-apoptotic developmental pathways in vertebrates. We raise the possibility that during vertebrate development, apoptosis may not be the major PCD mechanism.

Exploiting domain information for Word Sense Disambiguation of medical documents

PubMed Central

Agirre, Eneko; Soroa, Aitor

2011-01-01

Objective Current techniques for knowledge-based Word Sense Disambiguation (WSD) of ambiguous biomedical terms rely on relations in the Unified Medical Language System Metathesaurus but do not take into account the domain of the target documents. The authors' goal is to improve these methods by using information about the topic of the document in which the ambiguous term appears. Design The authors proposed and implemented several methods to extract lists of key terms associated with Medical Subject Heading terms. These key terms are used to represent the document topic in a knowledge-based WSD system. They are applied both alone and in combination with local context. Measurements A standard measure of accuracy was calculated over the set of target words in the widely used National Library of Medicine WSD dataset. Results and discussion The authors report a significant improvement when combining those key terms with local context, showing that domain information improves the results of a WSD system based on the Unified Medical Language System Metathesaurus alone. The best results were obtained using key terms obtained by relevance feedback and weighted by inverse document frequency. PMID:21900701

Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains

PubMed Central

Ulianov, Sergey V.; Khrameeva, Ekaterina E.; Gavrilov, Alexey A.; Flyamer, Ilya M.; Kos, Pavel; Mikhaleva, Elena A.; Penin, Aleksey A.; Logacheva, Maria D.; Imakaev, Maxim V.; Chertovich, Alexander; Gelfand, Mikhail S.; Shevelyov, Yuri Y.; Razin, Sergey V.

2016-01-01

Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)+ RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin. PMID:26518482

Stochastic lattice model of synaptic membrane protein domains.

PubMed

Li, Yiwei; Kahraman, Osman; Haselwandter, Christoph A

2017-05-01

Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction-diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components.

Life Experience with Death: Relation to Death Attitudes and to the Use of Death-Related Memories

ERIC Educational Resources Information Center

Bluck, Susan; Dirk, Judith; Mackay, Michael M.; Hux, Ashley

2008-01-01

The study examines the relation of death experience to death attitudes and to autobiographical memory use. Participants (N = 52) completed standard death attitude measures and wrote narratives about a death-related autobiographical memory and (for comparison) a memory of a low point. Self-ratings of the memory narratives were used to assess their…

Photobiomodulation reduces photoreceptor death and regulates cytoprotection in early states of P23H retinal dystrophy

NASA Astrophysics Data System (ADS)

Kirk, Diana K.; Gopalakrishnan, Sandeep; Schmitt, Heather; Abroe, Betsy; Stoehr, Michele; Dubis, Adam; Carroll, Joseph; Stone, Jonathan; Valter, Krisztina; Eells, Janis

2013-03-01

Irradiation by light in the far-red to near-infrared (NIR) region of the spectrum (photobiomodulation, PBM) has been demonstrated to attenuate the severity of neurodegenerative disease in experimental and clinical studies. The purpose of this study was to test the hypothesis that 670 nm PBM would protect against the loss of retinal function and improve photoreceptor survival in a rodent model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated once per day with a 670 nm LED array (180 sec treatments at 50 mW/cm2; fluence 9 joules/cm2) (Quantum Devices Inc., Barneveld WI) from postnatal day (p) 16-20 or from p10-20. Sham-treated rats were restrained, but not exposed to NIR light. The status of the retina was determined at p22 by assessment of mitochondrial function, oxidative stress and cell death. In a second series of studies, retinal status was assessed at p30 by measuring photoreceptor function by ERG and retinal morphology by Spectral Domain Optical Coherence Tomography (SD-OCT). 670 nm PBM increased retinal mitochondrial cytochrome oxidase activity and upregulated the retina's production of the key mitochondrial antioxidant enzyme, MnSOD. PBM also attenuated photoreceptor cell loss and improved photoreceptor function. PBM protects photoreceptors in the developing P23H retina, by augmenting mitochondrial function and stimulating antioxidant protective pathways. Photobiomodulation may have therapeutic potential, where mitochondrial damage is a step in the death of photoreceptors.

Separating the Wheat from the Chaff: Identifying Key Elements in the NLA .AU Domain Harvest

ERIC Educational Resources Information Center

Fellows, Geoff; Harvey, Ross; Lloyd, Annemaree; Pymm, Bob; Wallis, Jake

2008-01-01

In 2005 and 2006 the National Library of Australia (NLA) carried out two whole-domain web harvests which complement the selective web archiving approach taken by PANDORA. Web harvests of this size pose significant challenges to their use. Despite these challenges, such harvests present fascinating research opportunities. The NLA has provided…

Simple stochastic birth and death models of genome evolution: was there enough time for us to evolve?

PubMed

Karev, Georgy P; Wolf, Yuri I; Koonin, Eugene V

2003-10-12

The distributions of many genome-associated quantities, including the membership of paralogous gene families can be approximated with power laws. We are interested in developing mathematical models of genome evolution that adequately account for the shape of these distributions and describe the evolutionary dynamics of their formation. We show that simple stochastic models of genome evolution lead to power-law asymptotics of protein domain family size distribution. These models, called Birth, Death and Innovation Models (BDIM), represent a special class of balanced birth-and-death processes, in which domain duplication and deletion rates are asymptotically equal up to the second order. The simplest, linear BDIM shows an excellent fit to the observed distributions of domain family size in diverse prokaryotic and eukaryotic genomes. However, the stochastic version of the linear BDIM explored here predicts that the actual size of large paralogous families is reached on an unrealistically long timescale. We show that introduction of non-linearity, which might be interpreted as interaction of a particular order between individual family members, allows the model to achieve genome evolution rates that are much better compatible with the current estimates of the rates of individual duplication/loss events.

Characterizing Functional Domains for TIM-Mediated Enveloped Virus Entry

PubMed Central

Moller-Tank, Sven; Albritton, Lorraine M.; Rennert, Paul D.

2014-01-01

ABSTRACT T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members were recently identified as phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance entry of Ebola virus (EBOV) and other viruses by binding PtdSer on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. The PtdSer-binding activity of the immunoglobulin-like variable (IgV) domain is essential for both virus binding and internalization by TIM-1. However, TIM-3, whose IgV domain also binds PtdSer, does not effectively enhance virus entry, indicating that other domains of TIM proteins are functionally important. Here, we investigate the domains supporting enhancement of enveloped virus entry, thereby defining the features necessary for a functional PVEER. Using a variety of chimeras and deletion mutants, we found that in addition to a functional PtdSer-binding domain PVEERs require a stalk domain of sufficient length, containing sequences that promote an extended structure. Neither the cytoplasmic nor the transmembrane domain of TIM-1 is essential for enhancing virus entry, provided the protein is still plasma membrane bound. Based on these defined characteristics, we generated a mimic lacking TIM sequences and composed of annexin V, the mucin-like domain of α-dystroglycan, and a glycophosphatidylinositol anchor that functioned as a PVEER to enhance transduction of virions displaying Ebola, Chikungunya, Ross River, or Sindbis virus glycoproteins. This identification of the key features necessary for PtdSer-mediated enhancement of virus entry provides a basis for more effective recognition of unknown PVEERs. IMPORTANCE T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members are recently identified phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance virus entry by binding the phospholipid, PtdSer, present on the viral

Modern Radiobiology: Contention Of Concepts: Advanced Technology And Development Of Effective Prophylaxis, Prevention And Treatment Of Biological Consequences After Irradiation.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey

"Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis macht, daß ein Ding kein Gift ist." Paracelsus Philippus Aureolus Theophrastus Bombastus von Hohenheim. Key worlds: Apoptosis, Necrosis, Domains associated with Cell Death, Caspase (catalytic) Domains, Death Domains (DDs), Death Effector Domains (DEDs), Caspase-Associated Recruitment Domains (CARDs, BIR Domains (IAPs), Bcl-2 Homology (BH) Domains, death ligands - TRAIL (TNF-Related Apoptosis-Inducing Ligand), FasL (Fas Ligand), TNFalpha (Tumor Necrosis Factor alpha), Toll-like receptors (TLR), Systemic inflammatory response syndrome (SIRS), Toxic Multiple Organ Injury (TMOI), Toxic Multiple Organ Dysfunction Syndromes (TMODS), Toxic Multiple Organ Failure (TMOF), Anaphylatoxins, or complement peptides; membrane attack complex (MAC), ROS - Reactive Oxygen Species; ASMase, acid sphingomyelinase; Neurotoxins, Cytotoxins, Haemotoxins. Introduction: Radiation affects many cell structures, organelles and metabolic pathways. Different doses and types of radiation ( gamma-radiation, neutron, heavy ion radiation) progress to reversible and irreversible forms of cell injury. Consideration: Apoptosis and Necrosis, major forms of post-radiation cell death, can be initiated and modulated by programmed control and proceed by similar or different pathways.[Akadi et al.,1993, Dunlacht J., et al. 1999] Radiation induced cell death by triggering apoptosis pathways was described in many articles and supported by many scientists. [Rio et al. 2002, Rakesh et al. 1997.] However some authors present results that two distinct pathways can initiate or apoptotic or necrotic responses: the death receptors and mitochondrial pathways.

Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein- and Receptor-Interacting Protein Kinase 1-Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis.

PubMed

Boyd-Tressler, Andrea M; Lane, Graham S; Dubyak, George R

2017-07-01

Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins. Tumor necrosis factor- α induced extrinsic apoptosis in control Jurkat cells and necroptosis in FADD-deficient cells; treatment of both lines with chemotherapeutic drugs elicited similar intrinsic apoptosis. Robust extracellular ATP/AMP accumulation was observed in the FADD-deficient cells during necroptosis, but not during apoptotic activation of Panx1 channels. Accumulation of extracellular ATP/AMP was similarly absent in RIP1-deficient Jurkat cells during apoptotic responses to chemotherapeutic agents. Apoptotic activation triggered equivalent proteolytic gating of Panx1 channels in all three Jurkat cell lines. The differences in extracellular ATP/AMP accumulation correlated with cell-line-specific expression of ectonucleotidases that metabolized the released ATP/AMP. CD73 mRNA, and α β -methylene-ADP-inhibitable ecto-AMPase activity were elevated in the FADD-deficient cells. In contrast, the RIP1-deficient cells were defined by increased expression of tartrate-sensitive prostatic acid phosphatase as a broadly acting ectonucleotidase. Thus, extracellular nucleotide accumulation during regulated tumor cell death involves interplay between ATP/AMP efflux pathways and different cell-autonomous ectonucleotidases. Differential expression of particular ectonucleotidases in tumor cell variants will determine whether chemotherapy-induced activation of Panx1 channels

Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial?

PubMed

Marcus, Pamela M; Doria-Rose, Vincent Paul; Gareen, Ilana F; Brewer, Brenda; Clingan, Kathy; Keating, Kristen; Rosenbaum, Jennifer; Rozjabek, Heather M; Rathmell, Joshua; Sicks, JoRean; Miller, Anthony B

2016-08-01

Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55-74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2-25.0), as

Regional Variations in Suicide and Undetermined Death Rates among Adolescents across Canada.

PubMed

Renaud, Johanne; Lesage, Alain; Gagné, Mathieu; MacNeil, Sasha; Légaré, Gilles; Geoffroy, Marie-Claude; Skinner, Robin; McFaull, Steven

2018-04-01

Trends in rates of adolescent suicide and undetermined deaths in Canada from 1981 to 2012 were examined, focusing specifically on variations between Canadian regions. Exploratory hypotheses were formulated for regional variability in adolescent suicide rates over time in Canada. A descriptive time trend analysis using public domain vital statistics data was performed. All deaths from 1981 to 2012 among 15 to 19 year olds coded as suicides or undetermined intent according to the International Classification of Diseases, 9 th and 10 th Revisions were included. While there was an overall stability in adolescent suicide and undetermined death rates across Canada, regional analyses showed that Quebec experienced a 7.6% annual reduction between 2001 and 2012 while the Prairies and Atlantic provinces experienced significant annual increases since 2001. Ontario and British Columbia have had non-significant fluctuations since 2001. The trends remained similar overall when excluding undetermined deaths from the analyses. Variations in adolescent suicide trends across provinces were found. Factors such as provincial suicide action and prevention legislation contributing to these variations remain to be studied, but these regional differences point towards the need for better consistency of suicide prevention strategies across the country.

Lessons from 150 years of UK maternal hemorrhage deaths.

PubMed

Kerr, Robert Stuart; Weeks, Andrew David

2015-06-01

We have reviewed maternal hemorrhage death rates in the UK over the past 150 years in order to draw lessons from this material for current attempts to reduce global maternal mortality. Mortality rates from data in the UK Annual Reports from the Registrar General were entered into a database. Charts were created to display trends in hemorrhage mortality, allowing comparison with historical medical advances. Hemorrhage death rates fell steadily before the 1930s; between 1874 and 1926 they fell by 56%. In contrast, there was no consistent reduction in overall maternal mortality rates until the 1930s; from 1932 to 1952 they fell by 85%, primarily due to a reduction in sepsis deaths. In conclusion the majority of maternal hemorrhage mortality reductions in the UK occurred prior to the availability of effective oxytocics, antibiotics, and blood transfusion. Improving access to and standards of maternal care is key to addressing global maternal mortality today. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Cryptographic Key Management and Critical Risk Assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abercrombie, Robert K

The Department of Energy Office of Electricity Delivery and Energy Reliability (DOE-OE) CyberSecurity for Energy Delivery Systems (CSEDS) industry led program (DE-FOA-0000359) entitled "Innovation for Increasing CyberSecurity for Energy Delivery Systems (12CSEDS)," awarded a contract to Sypris Electronics LLC to develop a Cryptographic Key Management System for the smart grid (Scalable Key Management Solutions for Critical Infrastructure Protection). Oak Ridge National Laboratory (ORNL) and Sypris Electronics, LLC as a result of that award entered into a CRADA (NFE-11-03562) between ORNL and Sypris Electronics, LLC. ORNL provided its Cyber Security Econometrics System (CSES) as a tool to be modified and usedmore » as a metric to address risks and vulnerabilities in the management of cryptographic keys within the Advanced Metering Infrastructure (AMI) domain of the electric sector. ORNL concentrated our analysis on the AMI domain of which the National Electric Sector Cyber security Organization Resource (NESCOR) Working Group 1 (WG1) has documented 29 failure scenarios. The computational infrastructure of this metric involves system stakeholders, security requirements, system components and security threats. To compute this metric, we estimated the stakes that each stakeholder associates with each security requirement, as well as stochastic matrices that represent the probability of a threat to cause a component failure and the probability of a component failure to cause a security requirement violation. We applied this model to estimate the security of the AMI, by leveraging the recently established National Institute of Standards and Technology Interagency Report (NISTIR) 7628 guidelines for smart grid security and the International Electrotechnical Commission (IEC) 63351, Part 9 to identify the life cycle for cryptographic key management, resulting in a vector that assigned to each stakeholder an estimate of their average loss in terms of dollars per day of

Changes in Parents After the Death of a Child from Cancer

PubMed Central

Gilmer, Mary Jo; Foster, Terrah L.; Vannatta, Kathryn; Barrera, Maru; Davies, Betty; Dietrich, Mary S.; Fairclough, Diane L.; Grollman, Jamie; Gerhardt, Cynthia A.

2012-01-01

Context Few studies have compared multiple perspectives of changes experienced by parents after a child’s death. Objectives This study used interviews with bereaved parents and siblings to examine changes in parents during the first year after the death of a child from cancer. Methods Mothers (n = 36), fathers (n = 24), and siblings (n = 39) from 40 families were recruited from three hospitals in the U.S. and Canada 3-12 months post-death (M = 10.7, SD = 3.5). Semi-structured interviews with open-ended questions were conducted in the home with each participating parent and sibling separately. Content analysis identified emerging themes, and frequencies were compared between each paired set of reports (mother versus sibling, father versus sibling, mother versus father). Results Parents and siblings identified two major categories of change experienced by bereaved parents. These changes occurred in their personal lives (e.g., emotions, perspectives and priorities, physical state, work habits, coping/behaviors, spiritual beliefs, and feeling something is missing) and relationships (e.g., family, others). Ninety-four percent of mothers, 87% of fathers, and 69% of siblings reported parental changes in at least one of these categories. Parents were more likely to report changes in priorities, whereas siblings reported more sadness in parents after the death. Conclusion Positive and negative changes in parents after the death of a child from cancer occur in both personal and relational domains. Additional research is needed to determine the impact of a child’s death on bereaved parents over time and to develop strategies to promote healthy adjustment. PMID:22784555

Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

NASA Astrophysics Data System (ADS)

Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

2016-02-01

High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis.

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer’s Disease

PubMed Central

Cheng, Bo; Liu, Mingxia; Li, Zuoyong

2017-01-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer’s Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multidomain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods. PMID:27928657

A FYVE zinc finger domain protein specifically links mRNA transport to endosome trafficking.

PubMed

Pohlmann, Thomas; Baumann, Sebastian; Haag, Carl; Albrecht, Mario; Feldbrügge, Michael

2015-05-18

An emerging theme in cellular logistics is the close connection between mRNA and membrane trafficking. A prominent example is the microtubule-dependent transport of mRNAs and associated ribosomes on endosomes. This coordinated process is crucial for correct septin filamentation and efficient growth of polarised cells, such as fungal hyphae. Despite detailed knowledge on the key RNA-binding protein and the molecular motors involved, it is unclear how mRNAs are connected to membranes during transport. Here, we identify a novel factor containing a FYVE zinc finger domain for interaction with endosomal lipids and a new PAM2-like domain required for interaction with the MLLE domain of the key RNA-binding protein. Consistently, loss of this FYVE domain protein leads to specific defects in mRNA, ribosome, and septin transport without affecting general functions of endosomes or their movement. Hence, this is the first endosomal component specific for mRNP trafficking uncovering a new mechanism to couple mRNPs to endosomes.

In vivo contributions of BH3-only proteins to neuronal death following seizures, ischemia, and traumatic brain injury

PubMed Central

Engel, Tobias; Plesnila, Nikolaus; Prehn, Jochen H M; Henshall, David C

2011-01-01

The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins. PMID:21364604

The serine protease inhibitor TLCK attenuates intrinsic death pathways in neurons upstream of mitochondrial demise.

PubMed

Reuther, C; Ganjam, G K; Dolga, A M; Culmsee, C

2014-11-01

It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces oxytosis, a form of caspase-independent cell death that involves activation of the pro-apoptotic protein BH3 interacting-domain death agonist (Bid), leading to mitochondrial demise and ensuing cell death. In this model system, the trypsin-like serine protease inhibitor Nα-tosyl-l-lysine chloromethyl ketone hydrochloride (TLCK) inhibited mitochondrial damage and cell death. Mitochondrial morphology alterations, the impairment of the mitochondrial membrane potential and ATP depletion were prevented and, moreover, lipid peroxidation induced by glutamate was completely abolished. Strikingly, truncated Bid-induced cell death was not affected by TLCK, suggesting a detrimental activity of serine proteases upstream of Bid activation and mitochondrial demise. In summary, this study demonstrates the protective effect of serine protease inhibition by TLCK against oxytosis-induced mitochondrial damage and cell death. These findings indicate that TLCK-sensitive serine proteases play a crucial role in cell death mechanisms upstream of mitochondrial demise and thus, may serve as therapeutic targets in diseases, where oxidative stress and intrinsic pathways of PCD mediate neuronal cell death.

Is death our business? Philosophical conflicts over the end-of-life in old age psychiatry.

PubMed

McKellar, Duncan; Ng, Felicity; Chur-Hansen, Anna

2016-01-01

Old age psychiatrists work with end-of-life (EOL) issues and encounter patient deaths, but death and dying have received limited focus in old age psychiatry training and research. This qualitative study explores old age psychiatrists' experience of and approach to working with patients at the EOL. Australian old age psychiatrists were purposively sampled and interviewed in-depth. Data saturation was achieved after nine participant interviews. Verbatim transcripts were analysed for themes, which were independently verified. Two dichotomous overarching themes were identified. Death is not our business reflected participants' experience of working in a mental health framework and incorporated four themes: death should not occur in psychiatry; working in a psychiatric treatment model; keeping a distance from death and unexpected death is a negative experience. Death is our business reflected participants' experience of working in an aged care context and incorporated four themes: death is part of life; encountering the EOL through dementia care; doing EOL work and expected death is a positive experience. Participants reported conflict because of the contradictory domains in which they work. They were comfortable working with patients at the EOL when death was expected, particularly in dementia. By contrast, they struggled with death as an adverse outcome in circumstances influenced by mental health culture, which was characterised by risk management, suicide prevention and a focus on recovery. This study has implications for models of care underpinning old age psychiatry. An integrated person-centred model of care may provide a contextually appropriate approach for practice.

Abandoning the dead donor rule? A national survey of public views on death and organ donation

PubMed Central

Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

2015-01-01

Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the ‘dead donor rule’, which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma. PMID:25260779

Trauma deaths outside the hospital: uncovering the typology in Kenyan capital.

PubMed

Saidi, Hassan; Oduor, Johannes

2013-08-01

Immediate trauma fatality is not amenable to trauma care and primary prevention is the key. The published profiles of deaths due to trauma differ in different regions. Injury mortality rates are higher in developing countries where injury data capture systems are unreliable for prevention purposes. To describe the pattern of pre-hospital injury (immediate) deaths at the Nairobi city mortuary and compare these with hospital (late) trauma deaths. Consecutive trauma autopsies performed over one year (November 2009 to December 2010) at the main mortuary of the Nairobi city council were analyzed for demographic (age, sex, occupation) characteristics, circumstances of the trauma and injury patterns. The patterns of injuries were compared to those of victims who survived and later died at the Kenyatta National Hospital over the same period. Two hundred and thirty seven trauma autopsies were analyzed. The average age of the victims was 29.8 years (range 1-67 years). Christians (93.7%) and males (89.5%) predominated. The place of injury was the road in 32.9% and home/neighborhood in 57.5% of cases. The main mechanisms of fatal injury were traffic (35.4%), gunshot wounds (25.7%) and assault (19.8%). Burns and suicides accounted for 5.9% and 6.3% of fatalities. Most fatalities were intentional (59.4%) Of vehicular injuries, pedestrians predominated (65.5%). For assault, blunt and penetrating injuries accounted for 68.7% and 31.11% of fatalities. Law enforcement officers were responsible for majority of gunshot deaths. Fatal injuries were sustained in single, two and multiple regions in 56.2%, 25.7% and 14.2% of cases. The body region most involved was the head/neck (40.5%). Twelve children under 15 years died. Compared to in-hospital deaths, pre-hospital deaths were associated with intentional injuries, night-time occurrence and preponderance of gun involvement. Injury was a significant cause of mortality among adults of working age in this urban African setting. Intentional

Children's and adults' understanding of death: Cognitive, parental, and experiential influences.

PubMed

Panagiotaki, Georgia; Hopkins, Michelle; Nobes, Gavin; Ward, Emma; Griffiths, Debra

2018-02-01

This study explored the development of understanding of death in a sample of 4- to 11-year-old British children and adults (N=136). It also investigated four sets of possible influences on this development: parents' religion and spiritual beliefs, cognitive ability, socioeconomic status, and experience of illness and death. Participants were interviewed using the "death concept" interview that explores understanding of the subcomponents of inevitability, universality, irreversibility, cessation, and causality of death. Children understood key aspects of death from as early as 4 or 5years, and with age their explanations of inevitability, universality, and causality became increasingly biological. Understanding of irreversibility and the cessation of mental and physical processes also emerged during early childhood, but by 10years many children's explanations reflected not an improved biological understanding but rather the coexistence of apparently contradictory biological and supernatural ideas-religious, spiritual, or metaphysical. Evidence for these coexistent beliefs was more prevalent in older children than in younger children and was associated with their parents' religious and spiritual beliefs. Socioeconomic status was partly related to children's biological ideas, whereas cognitive ability and experience of illness and death played less important roles. There was no evidence for coexistent thinking among adults, only a clear distinction between biological explanations about death and supernatural explanations about the afterlife. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Quality insights of university teachers on dying, death, and death education.

PubMed

Mak, Mui-Hing June

One of the main responsibilities of teachers is to help individual students cope with life difficulties such as grief following a death. However, very little research explores teachers' views on death, dying, and how they handle grief and loss in schools. This study aims to explore university teachers' knowledge and attitudes on dying, death, and death education. Fifteen university teachers were recruited using a qualitative method. This study reveals that most teachers' views on death and related issues are largely affected by their death experiences, religious beliefs, professional background, and the mass media. Although they have a general negative response toward death and dying, some teachers begin to affirm their meanings of life and death. Most teachers agree that they do not feel adequate about managing and teaching on life and death issues, so they strongly support including death education in the formal programs in Hong Kong.

The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis.

PubMed

Kögel, Donat; Concannon, Caoimhín G; Müller, Thorsten; König, Hildegard; Bonner, Caroline; Poeschel, Simone; Chang, Steffi; Egensperger, Rupert; Prehn, Jochen H M

2012-09-01

Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Structural landscape of the proline-rich domain of Sos1 nucleotide exchange factor.

PubMed

McDonald, Caleb B; Bhat, Vikas; Kurouski, Dmitry; Mikles, David C; Deegan, Brian J; Seldeen, Kenneth L; Lednev, Igor K; Farooq, Amjad

2013-01-01

Despite its key role in mediating a plethora of cellular signaling cascades pertinent to health and disease, little is known about the structural landscape of the proline-rich (PR) domain of Sos1 guanine nucleotide exchange factor. Herein, using a battery of biophysical tools, we provide evidence that the PR domain of Sos1 is structurally disordered and adopts an extended random coil-like conformation in solution. Of particular interest is the observation that while chemical denaturation of PR domain results in the formation of a significant amount of polyproline II (PPII) helices, it has little or negligible effect on its overall size as measured by its hydrodynamic radius. Our data also show that the PR domain displays a highly dynamic conformational basin in agreement with the knowledge that the intrinsically unstructured proteins rapidly interconvert between an ensemble of conformations. Collectively, our study provides new insights into the conformational equilibrium of a key signaling molecule with important consequences on its physiological function. Copyright © 2013 Elsevier B.V. All rights reserved.

Fork head controls the timing and tissue selectivity of steroid-induced developmental cell death

PubMed Central

Cao, Chike; Liu, Yanling; Lehmann, Michael

2007-01-01

Cell death during Drosophila melanogaster metamorphosis is controlled by the steroid hormone 20-hydroxyecdysone (20E). Elements of the signaling pathway that triggers death are known, but it is not known why some tissues, and not others, die in response to a particular hormone pulse. We found that loss of the tissue-specific transcription factor Fork head (Fkh) is both required and sufficient to specify a death response to 20E in the larval salivary glands. Loss of fkh itself is a steroid-controlled event that is mediated by the 20E-induced BR-C gene, and that renders the key death regulators hid and reaper hormone responsive. These results implicate the D. melanogaster FOXA orthologue Fkh with a novel function as a competence factor for steroid-controlled cell death. They explain how a specific tissue is singled out for death, and why this tissue survives earlier hormone pulses. More generally, they suggest that cell identity factors like Fkh play a pivotal role in the normal control of developmental cell death. PMID:17339378

Death revisited: rethinking death and the dead donor rule.

PubMed

Iltis, Ana Smith; Cherry, Mark J

2010-06-01

Traditionally, people were recognized as being dead using cardio-respiratory criteria: individuals who had permanently stopped breathing and whose heart had permanently stopped beating were dead. Technological developments in the middle of the twentieth century and the advent of the intensive care unit made it possible to sustain cardio-respiratory and other functions in patients with severe brain injury who previously would have lost such functions permanently shortly after sustaining a brain injury. What could and should physicians caring for such patients do? Significant advances in human organ transplantation also played direct and indirect roles in discussions regarding the care of such patients. Because successful transplantation requires that organs be removed from cadavers shortly after death to avoid organ damage due to loss of oxygen, there has been keen interest in knowing precisely when people are dead so that organs could be removed. Criteria for declaring death using neurological criteria developed, and today a whole brain definition of death is widely used and recognized by all 50 states in the United States as an acceptable way to determine death. We explore the ongoing debate over definitions of death, particularly over brain death or death determined using neurological criteria, and the relationship between definitions of death and organ transplantation.

Magnetic domain wall engineering in a nanoscale permalloy junction

NASA Astrophysics Data System (ADS)

Wang, Junlin; Zhang, Xichao; Lu, Xianyang; Zhang, Jason; Yan, Yu; Ling, Hua; Wu, Jing; Zhou, Yan; Xu, Yongbing

2017-08-01

Nanoscale magnetic junctions provide a useful approach to act as building blocks for magnetoresistive random access memories (MRAM), where one of the key issues is to control the magnetic domain configuration. Here, we study the domain structure and the magnetic switching in the Permalloy (Fe20Ni80) nanoscale magnetic junctions with different thicknesses by using micromagnetic simulations. It is found that both the 90-° and 45-° domain walls can be formed between the junctions and the wire arms depending on the thickness of the device. The magnetic switching fields show distinct thickness dependencies with a broad peak varying from 7 nm to 22 nm depending on the junction sizes, and the large magnetic switching fields favor the stability of the MRAM operation.

PsANT, the adenine nucleotide translocase of Puccinia striiformis, promotes cell death and fungal growth

PubMed Central

Tang, Chunlei; Wei, Jinping; Han, Qingmei; Liu, Rui; Duan, Xiaoyuan; Fu, Yanping; Huang, Xueling; Wang, Xiaojie; Kang, Zhensheng

2015-01-01

Adenine nucleotide translocase (ANT) is a constitutive mitochondrial component that is involved in ADP/ATP exchange and mitochondrion-mediated apoptosis in yeast and mammals. However, little is known about the function of ANT in pathogenic fungi. In this study, we identified an ANT gene of Puccinia striiformis f. sp. tritici (Pst), designated PsANT. The PsANT protein contains three typical conserved mitochondrion-carrier-protein (mito-carr) domains and shares more than 70% identity with its orthologs from other fungi, suggesting that ANT is conserved in fungi. Immuno-cytochemical localization confirmed the mitochondrial localization of PsANT in normal Pst hyphal cells or collapsed cells. Over-expression of PsANT indicated that PsANT promotes cell death in tobacco, wheat and fission yeast cells. Further study showed that the three mito-carr domains are all needed to induce cell death. qRT-PCR analyses revealed an in-planta induced expression of PsANT during infection. Knockdown of PsANT using a host-induced gene silencing system (HIGS) attenuated the growth and development of virulent Pst at the early infection stage but not enough to alter its pathogenicity. These results provide new insight into the function of PsANT in fungal cell death and growth and might be useful in the search for and design of novel disease control strategies. PMID:26058921

Is It Time for a Sudden Infant Death Syndrome (SIDS) Awareness Campaign? Community Stakeholders' Perceptions of SIDS

ERIC Educational Resources Information Center

Gollenberg, Audra; Fendley, Kim

2018-01-01

Sudden infant death syndrome (SIDS) remains a leading cause of infant death in the United States, and in Virginia. We sought to gauge the perceptions among community-identified stakeholders regarding community resource needs to reduce SIDS. Snowball sampling identified important community stakeholders to be interviewed as key informants. A…

Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke

PubMed Central

Ramsey, Lenny E.; Metcalf, Nicholas V.; Chacko, Ravi V.; Weinberger, Kilian; Baldassarre, Antonello; Hacker, Carl D.; Shulman, Gordon L.; Corbetta, Maurizio

2016-01-01

Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography. Attention and language deficits were well predicted by both. Next, we identified a general pattern of physiological network dysfunction consisting of decrease of interhemispheric integration and intrahemispheric segregation, which strongly related to behavioral impairment in multiple domains. Network-specific patterns of dysfunction predicted specific behavioral deficits, and loss of interhemispheric communication across a set of regions was associated with impairment across multiple behavioral domains. These results link key organizational features of brain networks to brain–behavior relationships in stroke. PMID:27402738

Deaths of Detainees in the Custody of US Forces in Iraq and Afghanistan From 2002 to 2005

PubMed Central

Allen, Scott A.; Rich, Josiah D.; Bux, Robert C.; Farbenblum, Bassina; Berns, Matthew; Rubenstein, Leonard

2006-01-01

In light of the large number of detainees who continue to be taken and held in US custody in settings with limited judicial or public oversight, deaths of detainees warrant scrutiny. We have undertaken the task of reviewing all known detainee deaths between 2002 and early 2005 based on reports available in the public domain. Using documents obtained from the Department of Defense through a Freedom of Information Act request, combined with a review of anecdotal published press accounts, 112 cases of death of detainees in United States custody (105 in Iraq, 7 in Afghanistan) during the period from 2002 to early 2005 were identified. Homicide accounted for the largest number of deaths (43) followed by enemy mortar attacks against the detention facility (36). Deaths attributed to natural causes numbered 20. Nine were listed as unknown cause of death, and 4 were reported as accidental or natural. A clustering of 8 deaths ascribed to natural causes in Iraq in August 2003 raises questions about the adequacy and availability of medical care, as well as other conditions of confinement that may have had an impact on the mortality rate. PMID:17415327

America's Children: Key National Indicators of Well-Being. 2009

ERIC Educational Resources Information Center

Blachman, Dara; Laughlin, Lynda; Lukacs, Susan; Pastor, Patricia; Howie, LaJeana; Sonnenberg, William; Axelrad, Daniel; Steffen, Barry; Baum, Katrina; Lopez, Marsha; Jekielek, Susan; Nord, Mark; Morisi, Teri; Avenevoli, Shelli; Singleton, James; Colpe, Lisa; Fungwe, Thomas; Ghandour, Reem

2009-01-01

"America's Children: Key National Indicators of Well-Being" provides annual updates on the well-being of children and families in the United States across a range of domains. A more detailed report alternates every other year with a condensed version that highlights selected indicators. This year, the Forum is publishing the full report…

7-Ketocholesterol Incorporation into Sphingolipid/Cholesterol-enriched (Lipid Raft) Domains Is Impaired by Vitamin E

PubMed Central

Royer, Marie-Charlotte; Lemaire-Ewing, Stéphanie; Desrumaux, Catherine; Monier, Serge; Pais de Barros, Jean-Paul; Athias, Anne; Néel, Dominique; Lagrost, Laurent

2009-01-01

Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike γ-tocopherol, the α-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, α-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre- and co-treatment of the cells with α-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of α-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by α-tocopherol, but not γ-tocopherol pretreatment. PMID:19351882

BARI+: a biometric based distributed key management approach for wireless body area networks.

PubMed

Muhammad, Khaliq-ur-Rahman Raazi Syed; Lee, Heejo; Lee, Sungyoung; Lee, Young-Koo

2010-01-01

Wireless body area networks (WBAN) consist of resource constrained sensing devices just like other wireless sensor networks (WSN). However, they differ from WSN in topology, scale and security requirements. Due to these differences, key management schemes designed for WSN are inefficient and unnecessarily complex when applied to WBAN. Considering the key management issue, WBAN are also different from WPAN because WBAN can use random biometric measurements as keys. We highlight the differences between WSN and WBAN and propose an efficient key management scheme, which makes use of biometrics and is specifically designed for WBAN domain.

Time-domain damping models in structural acoustics using digital filtering

NASA Astrophysics Data System (ADS)

Parret-Fréaud, Augustin; Cotté, Benjamin; Chaigne, Antoine

2016-02-01

This paper describes a new approach in order to formulate well-posed time-domain damping models able to represent various frequency domain profiles of damping properties. The novelty of this approach is to represent the behavior law of a given material directly in a discrete-time framework as a digital filter, which is synthesized for each material from a discrete set of frequency-domain data such as complex modulus through an optimization process. A key point is the addition of specific constraints to this process in order to guarantee stability, causality and verification of thermodynamics second law when transposing the resulting discrete-time behavior law into the time domain. Thus, this method offers a framework which is particularly suitable for time-domain simulations in structural dynamics and acoustics for a wide range of materials (polymers, wood, foam, etc.), allowing to control and even reduce the distortion effects induced by time-discretization schemes on the frequency response of continuous-time behavior laws.

Structural Characterization of Monomeric/Dimeric State of p59fyn SH2 Domain.

PubMed

Huculeci, Radu; Kieken, Fabien; Garcia-Pino, Abel; Buts, Lieven; van Nuland, Nico; Lenaerts, Tom

2017-01-01

Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59 fyn SH2 domain.

[Cause of death: from primary disease to direct cause of death].

PubMed

Oppewal, F; Smedts, F M M; Meyboom-de Jong, B

2005-07-23

Following the death of a patient, the treating physician in the Netherlands is required to fill out two forms. Form A, which is the certificate of death and Form B, which is used by the Statistics Netherlands to compile data on causes ofdeath. The latter form often poses difficulty for the physician with respect to the primary cause of death. This applies particularly to cases of sudden death, which account for one third of all deaths in the Netherlands. As a result, the statistical analyses appear to lead to an incorrect representation of the distribution of causes of death. A more thorough investigation into the primary cause of death is desirable, if necessary, supported by a request for an autopsy. The primary cause of death is to be regarded as the basic disease from which the cascade of changes ultimately leading to death originated.

The death of an animal should be acknowledged.

PubMed

2016-06-22

How should nurses help clients deal with grief following the loss of an animal? Grief following the death of a pet can be significant, but such reactions can be viewed as abnormal by family, friends and professionals. Mental health training team leader Bronwen Williams and veterinary surgeon Rebecca Green, writing in Mental Health Practice, say that a lack of understanding can compound grief. Simply acknowledging the significance of the loss is key.

Properties of branching exponential flights in bounded domains

NASA Astrophysics Data System (ADS)

Zoia, A.; Dumonteil, E.; Mazzolo, A.

2012-11-01

In a series of recent works, important results have been reported concerning the statistical properties of exponential flights evolving in bounded domains, a widely adopted model for finite-speed transport phenomena (Blanco S. and Fournier R., Europhys. Lett., 61 (2003) 168; Mazzolo A., Europhys. Lett., 68 (2004) 350; Bénichou O. et al., Europhys. Lett., 70 (2005) 42). Motivated by physical and biological systems where random spatial displacements are coupled with Galton-Watson birth-death mechanisms, such as neutron multiplication, diffusion of reproducing bacteria or spread of epidemics, in this letter we extend those results in two directions, via a Feynman-Kac formalism. First, we characterize the occupation statistics of exponential flights in the presence of absorption and branching, and give explicit moment formulas for the total length travelled by the walker and the number of performed collisions in a given domain. Then, we show that the survival and escape probability can be derived as well by resorting to a similar approach.

Exploring children's understanding of death: through drawings and the Death Concept Questionnaire.

PubMed

Bonoti, Fotini; Leondari, Angeliki; Mastora, Adelais

2013-01-01

To investigate whether children's understanding of the concept of death varies as a function of death experience and age, 52 children aged 7, 9, and 11 years (26 had a personal death experience), drew a picture reflecting the meaning of the word death and completed the Death Concept Questionnaire for examination of Human and Animal Death. The results showed that the 2 methodological tools used offered complementary information and that children's understanding of death is related both to age and past experience. Children with death experience seem to have a more realistic understanding of death than their inexperienced age-mates. As regards to the effect of age, our findings support the assumption that the different components of death develop through different processes.

From surveillance to action: early gains from the National Violent Death Reporting System.

PubMed

Campbell, R; Weis, M A; Millet, L; Powell, V; Hull-Jilly, D; Hackman, H

2006-12-01

Drawing from the experiences of individual state programs that currently participate in the National Violent Death Reporting System (NVDRS), this article reviews some of the practical benefits that may accrue from the introduction of violent death surveillance systems. As a state-based surveillance system that uses multiple data sources and relies upon multiple stakeholders, the NVDRS program has fostered an array of initiatives within and among individual state programs. State-based initiatives highlighted in this article were selected on the basis of a purposive sampling strategy intended to illustrate key aspects of program development. The NVDRS state programs are in Alaska, California, Colorado, Georgia, Kentucky, Maryland, Massachusetts, New Jersey, New Mexico, North Carolina, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, and Wisconsin. The NVDRS has helped to build alliances and collaborative efforts between key stakeholders, facilitated the recognition of violent death as a public health problem through outreach and media attention, acted as a catalyst for new projects, enhanced surveillance of special populations and utility for evaluation, and identified key circumstances that will target interventions in state prevention planning. The NVDRS has implemented data collection efforts and is beginning to produce and analyze findings. In the process of implementing the data collection system and publicizing findings, state NVDRS programs are realizing other gains that strengthen their surveillance efforts. The use of data for prevention purposes will be the ultimate indicator of program success.

The Domain-Specificity of Creativity: Insights from New Phenomenology

ERIC Educational Resources Information Center

Julmi, Christian; Scherm, Ewald

2015-01-01

The question of the domain-specificity of creativity represents one of the key questions in creativity research. This article contributes to the discussion by applying insights from "new phenomenology," which is a phenomenological movement from Germany initiated by philosopher Hermann Schmitz. The findings of new phenomenology suggest…

Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells.

PubMed

Gröbner, Sabine; Adkins, Irena; Schulz, Sebastian; Richter, Kathleen; Borgmann, Stefan; Wesselborg, Sebastian; Ruckdeschel, Klaus; Micheau, Olivier; Autenrieth, Ingo B

2007-10-01

Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.

S-SAD phasing study of death receptor 6 and its solution conformation revealed by SAXS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ru, Heng; Graduate University of Chinese Academy of Sciences, Beijing 100 049; Zhao, Lixia

A comparative analysis of sulfur phasing of death receptor 6 (DR6) using data collected at wavelengths of 2.0 and 2.7 Å is presented. SAXS analysis of unliganded DR6 defines a dimer as the minimum physical unit in solution. A subset of tumour necrosis factor receptor (TNFR) superfamily members contain death domains in their cytoplasmic tails. Death receptor 6 (DR6) is one such member and can trigger apoptosis upon the binding of a ligand by its cysteine-rich domains (CRDs). The crystal structure of the ectodomain (amino acids 1–348) of human death receptor 6 (DR6) encompassing the CRD region was phased usingmore » the anomalous signal from S atoms. In order to explore the feasibility of S-SAD phasing at longer wavelengths (beyond 2.5 Å), a comparative study was performed on data collected at wavelengths of 2.0 and 2.7 Å. In spite of sub-optimal experimental conditions, the 2.7 Å wavelength used for data collection showed potential for S-SAD phasing. The results showed that the R{sub ano}/R{sub p.i.m.} ratio is a good indicator for monitoring the anomalous data quality when the anomalous signal is relatively strong, while d′′/sig(d′′) calculated by SHELXC is a more sensitive and stable indicator applicable for grading a wider range of anomalous data qualities. The use of the ‘parameter-space screening method’ for S-SAD phasing resulted in solutions for data sets that failed during manual attempts. SAXS measurements on the ectodomain suggested that a dimer defines the minimal physical unit of an unliganded DR6 molecule in solution.« less

Domain Evolution and Functional Diversification of Sulfite Reductases

NASA Astrophysics Data System (ADS)

Dhillon, Ashita; Goswami, Sulip; Riley, Monica; Teske, Andreas; Sogin, Mitchell

2005-02-01

Sulfite reductases are key enzymes of assimilatory and dissimilatory sulfur metabolism, which occur in diverse bacterial and archaeal lineages. They share a highly conserved domain "C-X5-C-n-C-X3-C" for binding siroheme and iron-sulfur clusters that facilitate electron transfer to the substrate. For each sulfite reductase cluster, the siroheme-binding domain is positioned slightly differently at the N-terminus of dsrA and dsrB, while in the assimilatory proteins the siroheme domain is located at the C-terminus. Our sequence and phylogenetic analysis of the siroheme-binding domain shows that sulfite reductase sequences diverged from a common ancestor into four separate clusters (aSir, alSir, dsr, and asrC) that are biochemically distinct; each serves a different assimilatory or dissimilatory role in sulfur metabolism. The phylogenetic distribution and functional grouping in sulfite reductase clusters (dsrA and dsrB vs. aSiR, asrC, and alSir) suggest that their functional diversification during evolution may have preceded the bacterial/archaeal divergence.

Can Statewide Emergency Department, Hospital Discharge, and Violent Death Reporting System Data Be Used to Monitor Burden of Firearm-Related Injury and Death in Rhode Island?

PubMed

Jiang, Yongwen; Ranney, Megan L; Sullivan, Brian; Hilliard, Dennis; Viner-Brown, Samara; Alexander-Scott, Nicole

2018-03-07

National data on the epidemiology of firearm injuries and circumstances of firearm deaths are difficult to obtain and often are nonreliable. Since firearm injury and death rates and causes can vary substantially between states, it is critical to consider state-specific data sources. In this study, we illustrate how states can systematically examine demographic characteristics, firearm information, type of wound, toxicology tests, precipitating circumstances, and costs to provide a comprehensive picture of firearm injuries and deaths using data sets from a single state with relatively low rates of firearm injury and death. Cross-sectional study. Firearm-related injury data for the period 2005-2014 were obtained from the Rhode Island emergency department and hospital discharge data sets; death data for the same period were obtained from the Rhode Island Violent Death Reporting System. Descriptive statistics were used. Healthcare Cost and Utilization Project cost-to-charge ratios were used to convert total hospital charges to costs. Most firearm-related emergency department visits (55.8%) and hospital discharges (79.2%) in Rhode Island were from assaults; however, most firearm-related deaths were suicides (60.1%). The annual cost of firearm-related hospitalizations was more than $830 000. Most decedents who died because of firearms tested positive for illicit substances. Nearly a quarter (23.5%) of firearm-related homicides were due to a conflict between the decedent and suspect. More than half (59%) of firearm suicide decedents were reported to have had current mental or physical problems prior to death. Understanding the state-specific magnitude and patterns (who, where, factors, etc) of firearm injury and death may help inform local injury prevention efforts. States with similar data sets may want to adopt our analyses. Surveillance of firearm-related injury and death is essential. Dissemination of surveillance findings to key stakeholders is critical in improving

Supra-domains: evolutionary units larger than single protein domains.

PubMed

Vogel, Christine; Berzuini, Carlo; Bashton, Matthew; Gough, Julian; Teichmann, Sarah A

2004-02-20

Domains are the evolutionary units that comprise proteins, and most proteins are built from more than one domain. Domains can be shuffled by recombination to create proteins with new arrangements of domains. Using structural domain assignments, we examined the combinations of domains in the proteins of 131 completely sequenced organisms. We found two-domain and three-domain combinations that recur in different protein contexts with different partner domains. The domains within these combinations have a particular functional and spatial relationship. These units are larger than individual domains and we term them "supra-domains". Amongst the supra-domains, we identified some 1400 (1203 two-domain and 166 three-domain) combinations that are statistically significantly over-represented relative to the occurrence and versatility of the individual component domains. Over one-third of all structurally assigned multi-domain proteins contain these over-represented supra-domains. This means that investigation of the structural and functional relationships of the domains forming these popular combinations would be particularly useful for an understanding of multi-domain protein function and evolution as well as for genome annotation. These and other supra-domains were analysed for their versatility, duplication, their distribution across the three kingdoms of life and their functional classes. By examining the three-dimensional structures of several examples of supra-domains in different biological processes, we identify two basic types of spatial relationships between the component domains: the combined function of the two domains is such that either the geometry of the two domains is crucial and there is a tight constraint on the interface, or the precise orientation of the domains is less important and they are spatially separate. Frequently, the role of the supra-domain becomes clear only once the three-dimensional structure is known. Since this is the case for only a

Changes in parents after the death of a child from cancer.

PubMed

Gilmer, Mary Jo; Foster, Terrah L; Vannatta, Kathryn; Barrera, Maru; Davies, Betty; Dietrich, Mary S; Fairclough, Diane L; Grollman, Jamie; Gerhardt, Cynthia A

2012-10-01

Few studies have compared multiple perspectives of changes experienced by parents after a child's death. This study used interviews with bereaved parents and siblings to examine changes in parents during the first year after the death of a child from cancer. Mothers (n=36), fathers (n=24), and siblings (n=39) from 40 families were recruited from three hospitals in the U.S. and Canada three to 12 months after the death (M=10.7, SD=3.5). Semistructured interviews with open-ended questions were conducted in the home with each participating parent and sibling separately. Content analysis identified emerging themes, and frequencies were compared between each paired set of reports (mother vs. sibling, father vs. sibling, and mother vs. father). Parents and siblings identified two major categories of change experienced by bereaved parents. These changes occurred in their personal lives (e.g., emotions, perspectives and priorities, physical state, work habits, coping/behaviors, spiritual beliefs, and feeling something is missing) and relationships (e.g., family, others). Ninety-four percent of the mothers, 87% of the fathers, and 69% of the siblings reported parental changes in at least one of these categories. Parents were more likely to report changes in priorities, whereas siblings reported more sadness in parents after the death. Positive and negative changes in parents after the death of a child from cancer occur in both personal and relational domains. Additional research is needed to determine the impact of a child's death on bereaved parents over time and to develop strategies to promote healthy adjustment. Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Caspase-9 Mediates Photoreceptor Death After Blunt Ocular Trauma

PubMed Central

Blanch, Richard J.; Ahmed, Zubair; Thompson, Adam R.; Akpan, Nsikan; Snead, David R. J.; Berry, Martin; Troy, Carol M.; Scott, Robert A. H.; Logan, Ann

2014-01-01

Purpose. Ocular trauma is common in civilian and military populations. Commotio retinae involves acute disruption of photoreceptor outer segments after blunt ocular trauma, with subsequent photoreceptor apoptosis causing permanent visual impairment. The mechanisms of photoreceptor death in commotio retinae have not previously been described, although caspase-dependent death is important in other nontraumatic retinal degenerations. We assessed the role of caspase-9 as a mediator of photoreceptor death in a rat model of ballistic ocular trauma causing commotio retinae. Methods. Bilateral commotio retinae was induced in rats by ballistic ocular trauma. Caspase-9 activity was assessed by immunohistochemistry, Western blotting, and bVAD-fmk active caspase capture. Caspase-9 was inhibited by unilateral intravitreal injection of highly specific X-linked inhibitor of apoptosis (IAP) baculoviral IAP repeat 3 (XBIR3) domain linked to the cell transduction peptide penetratin 1 (Pen-1) after ballistic injury, and the affected eyes were compared with control eyes treated with Pen-1 injection alone, and retinal function was assessed by electroretinogram a-wave amplitude and photoreceptor survival by outer nuclear layer thickness. Results. Increased levels of cleaved caspase-9 were shown in photoreceptors 5 hours after injury, and catalytically active full-length caspase-9 was isolated from retinas. Photoreceptor death after commotio retinae was reduced by caspase-9 inhibition by using Pen-1–XBIR3, and electroretinographic measurements of photoreceptor function was preserved, providing structural and functional neuroprotection. Conclusions. The time course of caspase-9 activation and the neuroprotective effects of inhibition suggest that caspase-9 initiates cell death in a proportion of photoreceptors after blunt ocular trauma and that an intravitreally delivered biologic inhibitor may be an effective translational treatment strategy. PMID:25190658

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death

PubMed Central

Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J.; Cheng, Qiang (Shawn); D’Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M.; Gonzalez Guzman, Michael J.; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K.; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G.; Ryan, Elizabeth P.; Colacci, Anna Maria; Hamid, Roslida A.; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K.; Woodrick, Jordan; Scovassi, A.Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H.; Lowe, Leroy; Park, Hyun Ho

2015-01-01

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID:26106145

Exploring Children's Understanding of Death: Through Drawings and the Death Concept Questionnaire

ERIC Educational Resources Information Center

Bonoti, Fotini; Leondari, Angeliki; Mastora, Adelais

2013-01-01

To investigate whether children's understanding of the concept of death varies as a function of death experience and age, 52 children aged 7, 9, and 11 years (26 had a personal death experience), drew a picture reflecting the meaning of the word death and completed the Death Concept Questionnaire for examination of Human and Animal Death. The…

Key factors influencing allied health research capacity in a large Australian metropolitan health district

PubMed Central

Alison, Jennifer A; Zafiropoulos, Bill; Heard, Robert

2017-01-01

Objective The aim of this study was to identify key factors affecting research capacity and engagement of allied health professionals working in a large metropolitan health service. Identifying such factors will assist in determining strategies for building research capacity in allied health. Materials and methods A total of 276 allied health professionals working within the Sydney Local Health District (SLHD) completed the Research Capacity in Context Tool (RCCT) that measures research capacity and culture across three domains: organization, team, and individual. An exploratory factor analysis was undertaken to identify common themes within each of these domains. Correlations were performed between demographic variables and the identified factors to determine possible relationships. Results Research capacity and culture success/skill levels were reported to be higher within the organization and team domains compared to the individual domain (median [interquartile range, IQR] 6 [5–8], 6 [5–8], 5 [3–7], respectively; Friedman χ2(2)=42.04, p<0.001). Exploratory factor analyses were performed to identify factors that were perceived by allied health respondents to affect research capacity. Factors identified within the organization domain were infrastructure for research (eg, funds and equipment) and research culture (eg, senior manager’s support for research); within the team domain the factors were research orientation (eg, dissemination of results at research seminars) and research support (eg, providing staff research training). Within the individual domain, only one factor was identified which was the research skill of the individual (eg, literature evaluation, submitting ethics applications and data analysis, and writing for publication). Conclusion The reported skill/success levels in research were lower for the individual domain compared to the organization or team domains. Key factors were identified in each domain that impacted on allied health

Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling.

PubMed

Menendez, Javier A; Schroeder, Barbara; Peirce, Susan K; Vellon, Luciano; Papadimitropoulou, Adriana; Espinoza, Ingrid; Lupu, Ruth

2015-06-01

Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2's extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective. To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student's t test were used to analyze differences. All statistical tests were two-sided. The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451-466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451-466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested. These findings reveal that an essential "activating" sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas. © The Author 2015. Published by Oxford University Press. All

Where Health and Death Intersect: Insights from a Terror Management Health Model

PubMed Central

Arndt, Jamie; Goldenberg, Jamie L.

2017-01-01

This paper offers an integrative understanding of the intersection between “health” and “death” from the perspective of the terror management health model. After highlighting the potential for health-related situations to elicit concerns about mortality, we turn to the question, how do thoughts of death influence health decision-making? Across varied health domains, the answer depends on whether these cognitions are in conscious awareness or not. When mortality concerns are conscious, people engage in healthy intentions and behavior if efficacy and coping resources are present. In contrast, when contending with accessible but non-conscious thoughts of death, health relevant decisions are guided more by esteem implications of the behavior. Lastly, we present research suggesting how these processes can be leveraged to facilitate health promotion and reduce health risk PMID:28924332

Mastoparan-induced programmed cell death in the unicellular alga Chlamydomonas reinhardtii

PubMed Central

Yordanova, Zhenya P.; Woltering, Ernst J.; Kapchina-Toteva, Veneta M.; Iakimova, Elena T.

2013-01-01

Background and Aims Under stress-promoting conditions unicellular algae can undergo programmed cell death (PCD) but the mechanisms of algal cellular suicide are still poorly understood. In this work, the involvement of caspase-like proteases, DNA cleavage and the morphological occurrence of cell death in wasp venom mastoparan (MP)-treated Chlamydomonas reinhardtii were studied. Methods Algal cells were exposed to MP and cell death was analysed over time. Specific caspase inhibitors were employed to elucidate the possible role of caspase-like proteases. YVADase activity (presumably a vacuolar processing enzyme) was assayed by using a fluorogenic caspase-1 substrate. DNA breakdown was evaluated by DNA laddering and Comet analysis. Cellular morphology was examined by confocal laser scanning microscopy. Key Results MP-treated C. reinhardtii cells expressed several features of necrosis (protoplast shrinkage) and vacuolar cell death (lytic vesicles, vacuolization, empty cell-walled corpse-containing remains of digested protoplast) sometimes within one single cell and in different individual cells. Nucleus compaction and DNA fragmentation were detected. YVADase activity was rapidly stimulated in response to MP but the early cell death was not inhibited by caspase inhibitors. At later time points, however, the caspase inhibitors were effective in cell-death suppression. Conditioned medium from MP-treated cells offered protection against MP-induced cell death. Conclusions In C. reinhardtii MP triggered PCD of atypical phenotype comprising features of vacuolar and necrotic cell deaths, reminiscent of the modality of hypersensitive response. It was assumed that depending on the physiological state and sensitivity of the cells to MP, the early cell-death phase might be not mediated by caspase-like enzymes, whereas later cell death may involve caspase-like-dependent proteolysis. The findings substantiate the hypothesis that, depending on the mode of induction and sensitivity of

The antibiotic cyclomarin blocks arginine-phosphate-induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis.

PubMed

Weinhäupl, Katharina; Brennich, Martha; Kazmaier, Uli; Lelievre, Joel; Ballell, Lluis; Goldberg, Alfred; Schanda, Paul; Fraga, Hugo

2018-06-01

Mycobacterium tuberculosis can remain dormant in the host, an ability that explains the failure of many current tuberculosis treatments. Recently, the natural products cyclomarin, ecumicin, and lassomycin have been shown to efficiently kill Mycobacterium tuberculosis persisters. Their target is the N-terminal domain of the hexameric AAA+ ATPase ClpC1, which recognizes, unfolds, and translocates protein substrates, such as proteins containing phosphorylated arginine residues, to the ClpP1P2 protease for degradation. Surprisingly, these antibiotics do not inhibit ClpC1 ATPase activity, and how they cause cell death is still unclear. Here, using NMR and small-angle X-ray scattering, we demonstrate that arginine-phosphate binding to the ClpC1 N-terminal domain induces millisecond dynamics. We show that these dynamics are caused by conformational changes and do not result from unfolding or oligomerization of this domain. Cyclomarin binding to this domain specifically blocked these N-terminal dynamics. On the basis of these results, we propose a mechanism of action involving cyclomarin-induced restriction of ClpC1 dynamics, which modulates the chaperone enzymatic activity leading eventually to cell death. © 2018 Weinhäupl et al.

B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins.

PubMed

Renault, Thibaud T; Elkholi, Rana; Bharti, Archana; Chipuk, Jerry E

2014-09-19

The B cell lymphoma-2 (BCL-2) family is the key mediator of cellular sensitivity to apoptosis during pharmacological interventions for numerous human pathologies, including cancer. There is tremendous interest to understand how the proapoptotic BCL-2 effector members (e.g. BCL-2-associated X protein, BAX) cooperate with the BCL-2 homology domain only (BH3-only) subclass (e.g. BCL-2 interacting mediator of death, BIM; BCL-2 interacting-domain death agonist, BID) to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis and whether these mechanisms may be pharmacologically exploited to enhance the killing of cancer cells. Indeed, small molecule inhibitors of the anti-apoptotic BCL-2 family members have been designed rationally. However, the success of these "BH3 mimetics" in the clinic has been limited, likely due to an incomplete understanding of how these drugs function in the presence of multiple BCL-2 family members. To increase our mechanistic understanding of how BH3 mimetics cooperate with multiple BCL-2 family members in vitro, we directly compared the activity of several BH3-mimetic compounds (i.e. ABT-263, ABT-737, GX15-070, HA14.1, TW-37) in biochemically defined large unilamellar vesicle model systems that faithfully recapitulate BAX-dependent mitochondrial outer membrane permeabilization. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to derepress proapoptotic molecules from anti-apoptotic proteins. Using mitochondria loaded with fluorescent BH3 peptides and cells treated with inducers of cell death, these differences were supported. Together, these data suggest that although the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by proapoptotic BCL-2 proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Regional Variations in Suicide and Undetermined Death Rates among Adolescents across Canada

PubMed Central

Lesage, Alain; Gagné, Mathieu; MacNeil, Sasha; Légaré, Gilles; Geoffroy, Marie-Claude; Skinner, Robin; McFaull, Steven

2018-01-01

Objective Trends in rates of adolescent suicide and undetermined deaths in Canada from 1981 to 2012 were examined, focusing specifically on variations between Canadian regions. Exploratory hypotheses were formulated for regional variability in adolescent suicide rates over time in Canada. Methods A descriptive time trend analysis using public domain vital statistics data was performed. All deaths from 1981 to 2012 among 15 to 19 year olds coded as suicides or undetermined intent according to the International Classification of Diseases, 9th and 10th Revisions were included. Results While there was an overall stability in adolescent suicide and undetermined death rates across Canada, regional analyses showed that Quebec experienced a 7.6% annual reduction between 2001 and 2012 while the Prairies and Atlantic provinces experienced significant annual increases since 2001. Ontario and British Columbia have had non-significant fluctuations since 2001. The trends remained similar overall when excluding undetermined deaths from the analyses. Conclusions Variations in adolescent suicide trends across provinces were found. Factors such as provincial suicide action and prevention legislation contributing to these variations remain to be studied, but these regional differences point towards the need for better consistency of suicide prevention strategies across the country. PMID:29662522

Therapeutic approaches to preventing cell death in Huntington disease.

PubMed

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Therapeutic approaches to preventing cell death in Huntington disease

PubMed Central

Kaplan, Anna; Stockwell, Brent R.

2012-01-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

Quality of Care: A Review of Maternal Deaths in a Regional Hospital in Ghana.

PubMed

Adusi-Poku, Yaw; Antwil, Edward; Osei-Kwakye, Kingsley; Tetteh, Chris; Detoh, Eric Kwame; Antwi, Phyllis

2015-09-01

The government of Ghana and key stakeholders have put into place several interventions aimed at reducing maternal deaths. At the institutional level, the conduct of maternal deaths audit has been instituted. This also contributes to reducing maternal deaths as shortcomings that may have contributed to such deaths could be identified to inform best practice and forestall such occurrences in the future. The objective of this study was to review the quality of maternal care in a regional hospital. A review of maternal deaths using Quality of Care Evaluation Form adapted from the Komfo Anokye Teaching Hospital (KATH) Maternal Death Audit Evaluation Committee was used. About fifty-five percent, 18 (55%) of cases were deemed to have received adequate documentation, senior clinicians were involved in 26(85%) of cases. Poor documentation, non-involvement of senior clinicians in the management of cases, laboratory related issues particularly in relation to blood and blood products as well as promptness of care and adequacy of intensive care facilities and specialists in the hospital were contributory factors to maternal deaths . These are common themes contributing to maternal deaths in developing countries which need to be urgently tackled. Maternal death review with emphasis on quality of care, coupled with facility gap assessment, is a useful tool to address the adequacy of emergency obstetric care services to prevent further maternal deaths.

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons.

PubMed

Tenn, Catherine C; Wang, Yushan

2007-05-01

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.

Prioritisation of associations between protein domains and complex diseases using domain-domain interaction networks.

PubMed

Wang, W; Zhang, W; Jiang, R; Luan, Y

2010-05-01

It is of vital importance to find genetic variants that underlie human complex diseases and locate genes that are responsible for these diseases. Since proteins are typically composed of several structural domains, it is reasonable to assume that harmful genetic variants may alter structures of protein domains, affect functions of proteins and eventually cause disorders. With this understanding, the authors explore the possibility of recovering associations between protein domains and complex diseases. The authors define associations between protein domains and disease families on the basis of associations between non-synonymous single nucleotide polymorphisms (nsSNPs) and complex diseases, similarities between diseases, and relations between proteins and domains. Based on a domain-domain interaction network, the authors propose a 'guilt-by-proximity' principle to rank candidate domains according to their average distance to a set of seed domains in the domain-domain interaction network. The authors validate the method through large-scale cross-validation experiments on simulated linkage intervals, random controls and the whole genome. Results show that areas under receiver operating characteristic curves (AUC scores) can be as high as 77.90%, and the mean rank ratios can be as low as 21.82%. The authors further offer a freely accessible web interface for a genome-wide landscape of associations between domains and disease families.

A FYVE zinc finger domain protein specifically links mRNA transport to endosome trafficking

PubMed Central

Pohlmann, Thomas; Baumann, Sebastian; Haag, Carl; Albrecht, Mario; Feldbrügge, Michael

2015-01-01

An emerging theme in cellular logistics is the close connection between mRNA and membrane trafficking. A prominent example is the microtubule-dependent transport of mRNAs and associated ribosomes on endosomes. This coordinated process is crucial for correct septin filamentation and efficient growth of polarised cells, such as fungal hyphae. Despite detailed knowledge on the key RNA-binding protein and the molecular motors involved, it is unclear how mRNAs are connected to membranes during transport. Here, we identify a novel factor containing a FYVE zinc finger domain for interaction with endosomal lipids and a new PAM2-like domain required for interaction with the MLLE domain of the key RNA-binding protein. Consistently, loss of this FYVE domain protein leads to specific defects in mRNA, ribosome, and septin transport without affecting general functions of endosomes or their movement. Hence, this is the first endosomal component specific for mRNP trafficking uncovering a new mechanism to couple mRNPs to endosomes. DOI: http://dx.doi.org/10.7554/eLife.06041.001 PMID:25985087

Mechanical Unfolding Studies on Single-Domain SUMO and Multi-Domain Periplasmic Binding Proteins

NASA Astrophysics Data System (ADS)

Kotamarthi, Hema Chandra; Ainavarapu, Sri Rama Koti

Protein mechanics is a key component of many cellular and sub-cellular processes. The current review focuses on recent studies from our laboratory that probe the effect of sequence on the mechanical stability of structurally similar proteins and the unfolding mechanisms of multi-domain periplasmic binding proteins. Ubiquitin and small ubiquitin-related modifiers (SUMOs) are structurally similar and possess different mechanical stabilities, ubiquitin being stronger than SUMOs as revealed from their unfolding forces. These differences are plausibly due to the variation in number of inter-residue contacts. The unfolding potential widths determined from the pulling speed-dependent studies revealed that SUMOs are mechanically more flexible than ubiquitin. This flexibility of SUMOs plays a role in ligand binding and our single-molecule studies on SUMO interaction with SUMO binding motifs (SBMs) have shown that ligand binding decreases the SUMO flexibility and increases its mechanical stability. Studies on multi-domain periplasmic binding proteins have revealed that the unfolding energy landscape of these proteins is complex and they follow kinetic partitioning between two-state and multiple three-state pathways.

Drama as a pedagogical tool for practicing death notification-experiences from Swedish medical students.

PubMed

Nordström, Anna; Fjellman-Wiklund, Anncristine; Grysell, Tomas

2011-09-28

One of the toughest tasks in any profession is the deliverance of death notification. Marathon Death is an exercise conducted during the fourth year of medical school in northern Sweden to prepare students for this responsibility. The exercise is designed to enable students to gain insight into the emotional and formal procedure of delivering death notifications. The exercise is inspired by Augusto Boal's work around Forum Theatre and is analyzed using video playback. The aim of the study was to explore reflections, attitudes and ideas toward training in delivering death notifications among medical students who participate in the Marathon Death exercise based on forum play. After participation in the Marathon Death exercise, students completed semi-structured interviews. The transcribed interviews were analyzed using the principles of qualitative content analysis including a deductive content analysis approach with a structured matrix based on Bloom's taxonomy domains. The Marathon Death exercise was perceived as emotionally loaded, realistic and valuable for the future professional role as a physician. The deliverance of a death notification to the next of kin that a loved one has died was perceived as difficult. The exercise conjured emotions such as positive expectations and sheer anxiety. Students perceived participation in the exercise as an important learning experience, discovering that they had the capacity to manage such a difficult situation. The feedback from the video playback of the exercise and the feedback from fellow students and teachers enhanced the learning experience. The exercise, Marathon Death, based on forum play with video playback is a useful pedagogical tool that enables students to practice delivering death notification. The ability to practice under realistic conditions contributes to reinforce students in preparation for their future professional role.

Sudden death after pediatric heart transplantation: analysis of data from the Pediatric Heart Transplant Study Group.

PubMed

Daly, Kevin P; Chakravarti, Sujata B; Tresler, Margaret; Naftel, David C; Blume, Elizabeth D; Dipchand, Anne I; Almond, Christopher S

2011-12-01

Sudden death is a well-recognized complication of heart transplantation. Little is known about the incidence and risk factors for sudden death after transplant in children. The purpose of this study was to determine the incidence of and risk factors for sudden death. This retrospective multicenter cohort study used the Pediatric Heart Transplant Study Group (PHTS) database, an event-driven registry of children aged <18 at listing undergoing heart transplantation between 1993 and 2007. Standard Kaplan-Meier and parametric analyses were used for survival analysis. Multivariate analysis in the hazard-function domain was used to identify risk factors for sudden death after transplant. Of 604 deaths in 2,491 children who underwent heart transplantation, 94 (16%) were classified as sudden. Freedom from sudden death was 97% at 5 years, and the hazard for sudden death remained constant over time at 0.01 deaths/year. Multivariate risk factors associated with sudden death included black race (hazard ratio [HR], 2.6; p < 0.0001), United Network of Organ Sharing (UNOS) status 2 at transplant (HR, 1.8; p = 0.008), older age (HR, 1.4/10 years of age; p = 0.03), and an increased number of rejection episodes in the first post-transplant year (HR, 1.6/episode; p = 0.03). Sudden death accounts for 1 in 6 deaths after heart transplant in children. Older recipient age, recurrent rejection within the first year, black race, and UNOS status 2 at listing were associated with sudden death. Patients with 1 or more of these risk factors may benefit from primary prevention efforts. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

DEATH, DYING AND NEAR DEATH EXPERIENCE

PubMed Central

Singh, Ajai R.; Bagadia, V.N.; Pradhan, P.V.; Acharya, V.N.

1988-01-01

SUMMARY Psychology of deaths due to acute medical emergencies is under-researched. Most studies till now have concentrated on extended-death situations like malignancy. This open pilot study of twenty five patients examines the psychological state of patients during a life threatening acute medical illness (Group A, ten patients) and of those who survive such an experience (Group B, fifteen patients). The study finds psychological exploration both possible and necessary if carried out in a discreet manner. Salient features of the interview technique are discussed. The study finds out whether patients are aware of the possibility of terminality. The psychological disturbances manifest and nature of care expected are also discussed. Near Death Experiences of those who acknowledge their occurence are reported. Some nuances of thanatological research are high-lighted: What are the abilities needed in an interviewer? Can such exploration increase psychological distress in a patient already prone to it because of serious medical sickness? What impact such research can have on the interviewer himself? The paper answers some of these common questions while developing the method of thanatological study in acute medical death-situations. PMID:21927325

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis.

PubMed

Mistry, Pragnesh; Kaplan, Mariana J

2017-12-01

Nephritis is one of the most severe complications of systemic lupus erythematosus (SLE). One key characteristic of lupus nephritis (LN) is the deposition of immune complexes containing nucleic acids and/or proteins binding to nucleic acids and autoantibodies recognizing these molecules. A variety of cell death processes are implicated in the generation and externalization of modified nuclear autoantigens and in the development of LN. Among these processes, apoptosis, primary and secondary necrosis, NETosis, necroptosis, pyroptosis, and autophagy have been proposed to play roles in tissue damage and immune dysregulation. Cell death occurs in healthy individuals during conditions of homeostasis yet autoimmunity does not develop, at least in part, because of rapid clearance of dying cells. In SLE, accelerated cell death combined with a clearance deficiency may lead to the accumulation and externalization of nuclear autoantigens and to autoantibody production. In addition, specific types of cell death may modify autoantigens and alter their immunogenicity. These modified molecules may then become novel targets of the immune system and promote autoimmune responses in predisposed hosts. In this review, we examine various cell death pathways and discuss how enhanced cell death, impaired clearance, and post-translational modifications of proteins could contribute to the development of lupus nephritis. Published by Elsevier Inc.

BARI+: A Biometric Based Distributed Key Management Approach for Wireless Body Area Networks

PubMed Central

Muhammad, Khaliq-ur-Rahman Raazi Syed; Lee, Heejo; Lee, Sungyoung; Lee, Young-Koo

2010-01-01

Wireless body area networks (WBAN) consist of resource constrained sensing devices just like other wireless sensor networks (WSN). However, they differ from WSN in topology, scale and security requirements. Due to these differences, key management schemes designed for WSN are inefficient and unnecessarily complex when applied to WBAN. Considering the key management issue, WBAN are also different from WPAN because WBAN can use random biometric measurements as keys. We highlight the differences between WSN and WBAN and propose an efficient key management scheme, which makes use of biometrics and is specifically designed for WBAN domain. PMID:22319333

Children and Death.

ERIC Educational Resources Information Center

Brennan, Andrew J. J.

Health professionals and educators should develop their abilities to educate about death and to comfort the bereaved. Due to lower death rates, the lack of philosophical religious views, and distorted perceptions of death contributed by television, death has become a mystery instead of a segment of the common experience. Particularly when a child…

Understanding suicide risk within the Research Domain Criteria (RDoC) framework: A meta-analytic review.

PubMed

Glenn, Catherine R; Kleiman, Evan M; Cha, Christine B; Deming, Charlene A; Franklin, Joseph C; Nock, Matthew K

2018-01-01

The field is in need of novel and transdiagnostic risk factors for suicide. The National Institute of Mental Health's Research Domain Criteria (RDoC) provides a framework that may help advance research on suicidal behavior. We conducted a meta-analytic review of existing prospective risk and protective factors for suicidal thoughts and behaviors (ideation, attempts, and deaths) that fall within one of the five RDoC domains or relate to a prominent suicide theory. Predictors were selected from a database of 4,082 prospective risk and protective factors for suicide outcomes. A total of 460 predictors met inclusion criteria for this meta-analytic review and most examined risk (vs. protective) factors for suicidal thoughts and behaviors. The overall effect of risk factors was statistically significant, but relatively small, in predicting suicide ideation (weighted mean odds ratio: wOR = 1.72; 95% CI: 1.59-1.87), suicide attempt (wOR = 1.66 [1.57-1.76), and suicide death (wOR = 1.41 [1.24-1.60]). Across all suicide outcomes, most risk factors related to the Negative Valence Systems domain, although effect sizes were of similar magnitude across RDoC domains. This study demonstrated that the RDoC framework provides a novel and promising approach to suicide research; however, relatively few studies of suicidal behavior fit within this framework. Future studies must go beyond the "usual suspects" of suicide risk factors (e.g., mental disorders, sociodemographics) to understand the processes that combine to lead to this deadly outcome. © 2017 Wiley Periodicals, Inc.

Frontal gamma noise power and cognitive domains in schizophrenia.

PubMed

Díez, Alvaro; Suazo, Vanessa; Casado, Pilar; Martín-Loeches, Manuel; Perea, María Victoria; Molina, Vicente

2014-01-30

The cognitive deficit profile is different among individuals with schizophrenia. We quantified the amount of electroencephalographic activity unlocked to stimuli onset (noise power) over frontal regions regarding deficit in cognitive domains. Forty-six patients with schizophrenia and 27 healthy controls underwent clinical, cognitive and electrophysiological assessments. Noise power studies may be considered complementary but not equivalent to induced power studies. We compared gamma and theta noise power magnitude during a P300 paradigm between subsets of patients divided according to cognitive deficit in key domains and controls. Patients displayed higher gamma noise power activity at Fz site and significantly lower performance in all cognitive domains when compared to controls. The subset of patients with cognitive deficit for working memory and problem solving/executive functions domains displayed significantly higher frontal-lateral noise power values in comparison to the subset of patients without cognitive deficit and controls. Patients with significant cognitive deficits in domains with greater frontal contribution are also characterized by an abnormally higher gamma band noise power over the frontal region. Our data may endorse various biological subsets within schizophrenia, characterized by the presence or absence of a significant cognitive deficit in frontal domains. © 2013 Published by Elsevier Ireland Ltd.

Religiosity and the Construction of Death in Turkish Death Announcements, 1970-2009

ERIC Educational Resources Information Center

Ergin, Murat

2012-01-01

Death and rituals performed after death reflect and reproduce social distinctions despite death's popular reputation as a great leveler. This study examines expressions of religiosity and constructions of death in Turkish death announcements, paying particular attention to gendered, ethnic, and temporal variations as well as markers of status and…

PA6 Death chat: engaging with dying and death.

PubMed

Goodhead, Andrew; Hartley, Nigel

2015-04-01

Talking about death continues to be a social taboo. St Christopher's has a large, welcoming social space, (The Anniversary Centre) and is committed to opening up its buildings in a number of ways. The St Christopher's social programme, of which Death Chat is part, aims to break down social taboos. Hospices have a responsibility to engage creatively with patients, family members, carers and the wider community. Death Chat, held in the hospice buildings, enables honest discussion about dying and death and topics surrounding these themes. Death Chat meets weekly and is an open meeting that takes a different subject each week as the starting point for conversation. Cheese and wine are shared and participants quickly find a place in the group. Death Chat has attracted patients, family members, bereaved relatives and the community since September 2013. Attendees have reflected that coming has broken taboos. Peter said, 'it's nowhere near as depressing as it sounds; it's a nice, friendly atmosphere - a convivial place.' Molly found Death Chat to be a welcoming, open and challenging space, 'I have learnt that death is more about my attitude to life than anything else. It has been by far the most important lesson I have learnt since dealing with bereavement.' Death Chat provides a forum in which discussion of dying and death for recognises that these are social events and reclaims them from being taboo, to being a normal part of life's experience. © 2015, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A conserved glutamine plays a central role in LOV domain signal transmission and duration

PubMed Central

Nash, Abigail I.; Ko, Wen-Huang; Harper, Shannon M.; Gardner, Kevin H.

2009-01-01

Light is a key stimulus for plant biological functions, several of which are controlled by light-activated kinases known as phototropins, a group of kinases that contain two light-sensing domains (LOV, Light-Oxygen-Voltage domains) and a C-terminal serine/threonine kinase domain. The second sensory domain, LOV2, plays a key role in regulating kinase enzymatic activity via the photochemical formation of a covalent adduct between a LOV2 cysteine residue and an internally-bound flavin mononucleotide (FMN) chromophore. Subsequent conformational changes in LOV2 lead to the unfolding of a peripheral Jα helix, and ultimately, phototropin kinase activation. To date, the mechanism coupling bond formation and helix dissociation has remained unclear. Previous studies found that a conserved glutamine residue (Q513 in the Avena sativa phototropin 1 LOV2 (AsLOV2) domain) switches its hydrogen-bonding pattern with FMN upon light stimulation. Located in the immediate vicinity of the FMN binding site, this Gln residue is provided by the Iβ strand that interacts with the Jα helix, suggesting a route for signal propagation from the core of the LOV domain to its peripheral Jα helix. To test whether Q513 plays a key role in tuning the photochemical and transduction properties of AsLOV2, we designed two point mutations, Q513L and Q513N, and monitored the effects on the chromophore and protein using a combination of UV-visible absorbance and circular dichroism spectroscopy, limited proteolysis, and solution NMR. The results show that these mutations significantly dampen the changes between the dark and lit state AsLOV2 structures, leaving the protein in a pseudo-dark state (Q513L) or a pseudo-lit state (Q513N) conformation. Further, both mutations changed the photochemical properties of this receptor, particularly the lifetime of the photoexcited signaling states. Together, these data establish that this residue plays a central role in both spectral tuning and signal propagation from

Towards communication-efficient quantum oblivious key distribution

NASA Astrophysics Data System (ADS)

Panduranga Rao, M. V.; Jakobi, M.

2013-01-01

Symmetrically private information retrieval, a fundamental problem in the field of secure multiparty computation, is defined as follows: A database D of N bits held by Bob is queried by a user Alice who is interested in the bit Db in such a way that (1) Alice learns Db and only Db and (2) Bob does not learn anything about Alice's choice b. While solutions to this problem in the classical domain rely largely on unproven computational complexity theoretic assumptions, it is also known that perfect solutions that guarantee both database and user privacy are impossible in the quantum domain. Jakobi [Phys. Rev. APLRAAN1050-294710.1103/PhysRevA.83.022301 83, 022301 (2011)] proposed a protocol for oblivious transfer using well-known quantum key device (QKD) techniques to establish an oblivious key to solve this problem. Their solution provided a good degree of database and user privacy (using physical principles like the impossibility of perfectly distinguishing nonorthogonal quantum states and the impossibility of superluminal communication) while being loss-resistant and implementable with commercial QKD devices (due to the use of the Scarani-Acin-Ribordy-Gisin 2004 protocol). However, their quantum oblivious key distribution (QOKD) protocol requires a communication complexity of O(NlogN). Since modern databases can be extremely large, it is important to reduce this communication as much as possible. In this paper, we first suggest a modification of their protocol wherein the number of qubits that need to be exchanged is reduced to O(N). A subsequent generalization reduces the quantum communication complexity even further in such a way that only a few hundred qubits are needed to be transferred even for very large databases.

Leading School-Wide Improvement in Low-Performing Schools Facing Conditions of Accountability: Key Actions and Considerations

ERIC Educational Resources Information Center

Cosner, Shelby; Jones, Mary F.

2016-01-01

Purpose: The purpose of this paper is to advance a framework that identifies three key domains of work and a set of more nuanced considerations and actions within each domain for school leaders seeking to improve school-wide student learning in low-performing schools facing conditions of accountability. Design/methodology/approach: Review of…

Crystal structure of a shark single-domain antibody V region in complex with lysozyme.

PubMed

Stanfield, Robyn L; Dooley, Helen; Flajnik, Martin F; Wilson, Ian A

2004-09-17

Cartilaginous fish are the phylogenetically oldest living organisms known to possess components of the vertebrate adaptive immune system. Key to their immune response are heavy-chain, homodimeric immunoglobulins called new antigen receptors (IgNARs), in which the variable (V) domains recognize antigens with only a single immunoglobulin domain, akin to camelid heavy-chain V domains. The 1.45 angstrom resolution crystal structure of the type I IgNAR V domain in complex with hen egg-white lysozyme (HEL) reveals a minimal antigen-binding domain that contains only two of the three conventional complementarity-determining regions but still binds HEL with nanomolar affinity by means of a binding interface comparable in size to conventional antibodies.

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

PubMed Central

Suh, Sang Won; Gum, Elizabeth T.; Hamby, Aaron M.; Chan, Pak H.; Swanson, Raymond A.

2007-01-01

Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase. PMID:17404617

Differences Between Rural and Urban Areas in Mortality Rates for the Leading Causes of Infant Death: United States, 2013-2015.

PubMed

Ely, Danielle M; Hoyert, Donna L

2018-02-01

The leading causes of infant death vary by age at death but were consistent from 2005 to 2015 (1-6). Previous research shows higher infant mortality rates in rural counties compared with urban counties and differences in cause of death for individuals aged 1 year and over by urbanization level (4,5,7,8). No research, however, has examined if mortality rates from the leading causes of infant death differ by urbanization level. This report describes the mortality rates for the five leading causes of infant, neonatal, and postneonatal death in the United States across rural, small and medium urban, and large urban counties defined by maternal residence, as reported on the birth certificate for combined years 2013-2015. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

From Domain Specific Languages to DEVS Components: Application to Cognitive M&S

DTIC Science & Technology

2011-04-01

AND SUBTITLE From Domain Specific Languages to DEVS Components: Application to Cognitive M&S 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ...that is devoid of any DEVS and programming language constructs (Figure 4). The key idea being domain specialists need not delve in the DEVS world to...DSL. DSLs can be created using many available tools and technologies such as: Generic Modeling Environment (GME) [23], Xtext, Ruby, Scala and many

Cell death versus cell survival instructed by supramolecular cohesion of nanostructures

NASA Astrophysics Data System (ADS)

Newcomb, Christina J.; Sur, Shantanu; Ortony, Julia H.; Lee, One-Sun; Matson, John B.; Boekhoven, Job; Yu, Jeong Min; Schatz, George C.; Stupp, Samuel I.

2014-02-01

Many naturally occurring peptides containing cationic and hydrophobic domains have evolved to interact with mammalian cell membranes and have been incorporated into materials for non-viral gene delivery, cancer therapy or treatment of microbial infections. Their electrostatic attraction to the negatively charged cell surface and hydrophobic interactions with the membrane lipids enable intracellular delivery or cell lysis. Although the effects of hydrophobicity and cationic charge of soluble molecules on the cell membrane are well known, the interactions between materials with these molecular features and cells remain poorly understood. Here we report that varying the cohesive forces within nanofibres of supramolecular materials with nearly identical cationic and hydrophobic structure instruct cell death or cell survival. Weak intermolecular bonds promote cell death through disruption of lipid membranes, while materials reinforced by hydrogen bonds support cell viability. These findings provide new strategies to design biomaterials that interact with the cell membrane.

Abandoning the dead donor rule? A national survey of public views on death and organ donation.

PubMed

Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

2015-04-01

Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the 'dead donor rule', which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The Dynamics and Evolutionary Potential of Domain Loss and Emergence

PubMed Central

Moore, Andrew D.; Bornberg-Bauer, Erich

2012-01-01

The wealth of available genomic data presents an unrivaled opportunity to study the molecular basis of evolution. Studies on gene family expansions and site-dependent analyses have already helped establish important insights into how proteins facilitate adaptation. However, efforts to conduct full-scale cross-genomic comparisons between species are challenged by both growing amounts of data and the inherent difficulty in accurately inferring homology between deeply rooted species. Proteins, in comparison, evolve by means of domain rearrangements, a process more amenable to study given the strength of profile-based homology inference and the lower rates with which rearrangements occur. However, adapting to a constantly changing environment can require molecular modulations beyond reach of rearrangement alone. Here, we explore rates and functional implications of novel domain emergence in contrast to domain gain and loss in 20 arthropod species of the pancrustacean clade. Emerging domains are more likely disordered in structure and spread more rapidly within their genomes than established domains. Furthermore, although domain turnover occurs at lower rates than gene family turnover, we find strong evidence that the emergence of novel domains is foremost associated with environmental adaptation such as abiotic stress response. The results presented here illustrate the simplicity with which domain-based analyses can unravel key players of nature's adaptational machinery, complementing the classical site-based analyses of adaptation. PMID:22016574

Akt1 binds focal adhesion kinase via the Akt1 kinase domain independently of the pleckstrin homology domain.

PubMed

Basson, M D; Zeng, B; Wang, S

2015-10-01

Akt1 and focal adhesion kinase (FAK) are protein kinases that play key roles in normal cell signaling. Individually, aberrant expression of these kinases has been linked to a variety of cancers. Together, Akt1/FAK interactions facilitate cancer metastasis by increasing cell adhesion under conditions of increased extracellular pressure. Pathological and iatrogenic sources of pressure arise from tumor growth against constraining stroma or direct perioperative manipulation. We previously reported that 15 mmHg increased extracellular pressure causes Akt1 to both directly interact with FAK and to phosphorylate and activate it. We investigated the nature of the Akt1/FAK binding by creating truncations of recombinant FAK, conjugated to glutathione S-transferase (GST), to pull down full-length Akt1. Western blots probing for Akt1 showed that FAK/Akt1 binding persisted in FAK truncations consisting of only amino acids 1-126, FAK(NT1), which contains the F1 subdomain of its band 4.1, ezrin, radixin, and moesin (FERM) domain. Using FAK(NT1) as bait, we then pulled down truncated versions of recombinant Akt1 conjugated to HA (human influenza hemagglutinin). Probes for GST-FAK(NT1) showed Akt1-FAK binding to occur in the absence of the both the Akt1 (N)-terminal pleckstrin homology (PH) domain and its adjacent hinge region. The Akt1 (C)-terminal regulatory domain was equally unnecessary for Akt1/FAK co-immunoprecipitation. Truncations involving the Akt1 catalytic domain showed that the domain by itself was enough to pull down FAK. Additionally, a fragment spanning from the PH domain to half way through the catalytic domain demonstrated increased FAK binding compared to full length Akt1. These results begin to delineate the Akt1/FAK interaction and can be used to manipulate their force-activated signal interactions. Furthermore, the finding that the N-terminal half of the Akt1 catalytic domain binds so strongly to FAK when cleaved from the rest of the protein may suggest a means

Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2010-2014.

PubMed

Warner, Margaret; Trinidad, James P; Bastian, Brigham A; Minino, Arialdi M; Hedegaard, Holly

2016-12-01

methamphetamine. During this 5-year period, the age-adjusted rate of drug overdose deaths involving heroin more than tripled, and the rate of drug overdose deaths involving methamphetamine more than doubled. The rate of drug overdose deaths involving fentanyl more than doubled in a single year (from 2013 to 2014). In 2014, of the 36,667 drug overdose deaths involving at least one specific drug, 52% of these deaths specified one drug, 38% specified two or three drugs, and 11% specified four or more drugs. Conclusions-Analysis of the literal text from death certificates can be used to identify patterns in the specific drugs most frequently involved in drug overdose deaths. From 2010 through 2014, the top 10 drugs involved were the same, but the relative ranking and age-adjusted rates for deaths involving these drugs changed. Literal text analysis also revealed that many drug overdose deaths involved multiple drugs. Findings should be interpreted in light of the improvement in the quality of the data that resulted from better reporting of specific drugs on death certificates from 2010 through 2014. Relative increases in the death rates involving specific drugs and the rankings of these drugs may be affected by improvements in reporting, real increases in the numbers of death, or both. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Injury Deaths Among U.S. Females: CDC Resources and Programs

PubMed Central

Mack, Karin A.; Peterson, Cora; Zhou, Chao; MacConvery, Elliane; Wilkins, Natalie

2017-01-01

Injury death rates are lower for women than for men at all ages, but we have a long way to go in understanding the circumstances of injury fatalities among females. This article presents resources that can be used to examine the most recent data on injury fatalities among females and highlights activities of CDC’s Injury Center. The National Center for Injury Prevention and Control’s (NCIPC’s) Web-based Injury Statistics Query and Reporting System, an online surveillance database, can be used to examine injury deaths. We present examples that show the 2015 number of female fatal injuries by age group and injury cause and method, as well as a 2008–2014 county-level map of female fatal injury rates. In 2015, there were 68,572 injury fatalities of females of age ≥1 year, equivalent to 1 death every 7 minutes. Injuries were the leading cause of death for females of ages 1–41 years and the sixth-ranked cause of female death overall. Falls were the leading cause of injury death overall (and for women ≥70 years), unintentional poisonings were second, and motor vehicle traffic injuries were third. NCIPC funds national organizations, state health agencies, and other groups to develop, implement, and promote effective injury and violence prevention and control practices. Five key programs are discussed. Presenting data on injury fatalities is an essential element in identifying meaningful prevention efforts. Further investigation of the causes and impact of female injury fatalities can refine the public health approach to reduce this injury burden. PMID:28294691

The Life and Death of a Plant Cell.

PubMed

Kabbage, Mehdi; Kessens, Ryan; Bartholomay, Lyric C; Williams, Brett

2017-04-28

Like all eukaryotic organisms, plants possess an innate program for controlled cellular demise termed programmed cell death (PCD). Despite the functional conservation of PCD across broad evolutionary distances, an understanding of the molecular machinery underpinning this fundamental program in plants remains largely elusive. As in mammalian PCD, the regulation of plant PCD is critical to development, homeostasis, and proper responses to stress. Evidence is emerging that autophagy is key to the regulation of PCD in plants and that it can dictate the outcomes of PCD execution under various scenarios. Here, we provide a broad and comparative overview of PCD processes in plants, with an emphasis on stress-induced PCD. We also discuss the implications of the paradox that is functional conservation of apoptotic hallmarks in plants in the absence of core mammalian apoptosis regulators, what that means, and whether an equivalent form of death occurs in plants.

From Death to Death Certificate: What do the Dead say?

PubMed

Gill, James R

2017-03-01

This is an overview of medicolegal death investigation and death certification. Postmortem toxicological analysis, particularly for ethanol and drugs of abuse, plays a large role in the forensic investigation of natural and unnatural deaths. Postmortem drug concentrations must be interpreted in light of the autopsy findings and circumstances. Interpretations of drug and ethanol concentrations are important for death certification, but they also may be important for other stakeholders such as police, attorneys, public health practitioners, and the next-of-kin.

Measuring chronic liver disease mortality using an expanded cause of death definition and medical records in Connecticut, 2004.

PubMed

Ly, Kathleen N; Speers, Suzanne; Klevens, R Monina; Barry, Vaughn; Vogt, Tara M

2014-10-16

Chronic liver disease (CLD) is a leading cause of death and is defined based on a specific set of underlying cause-of-death codes on death certificates. This conventional approach to measuring CLD mortality underestimates the true mortality burden because it does not consider certain CLD conditions like viral hepatitis and hepatocellular carcinoma. We measured how much the conventional CLD mortality case definition will underestimate CLD mortality and described the distribution of CLD etiologies in Connecticut. We used 2004 Connecticut death certificates to estimate CLD mortality two ways. One way used the conventional definition and the other used an expanded definition that included more conditions suggestive of CLD. We compared the number of deaths identified using this expanded definition with the number identified using the conventional definition. Medical records were reviewed to confirm CLD deaths. Connecticut had 29 314 registered deaths in 2004. Of these, 282 (1.0%) were CLD deaths identified by the conventional CLD definition while 616 (2.1%) were CLD deaths defined by the expanded definition. Medical record review confirmed that most deaths identified by the expanded definition were CLD-related (550/616); this suggested a 15.8 deaths/100 000 population mortality rate. Among deaths for which hepatitis B, hepatitis C and alcoholic liver disease were identified during medical record review, only 8.6%, 45.4% and 36.5%, respectively, had that specific cause-of-death code cited on the death certificate. An expanded CLD mortality case definition that incorporates multiple causes of death and additional CLD-related conditions will better estimate CLD mortality. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Research on Agriculture Domain Meta-Search Engine System

NASA Astrophysics Data System (ADS)

Xie, Nengfu; Wang, Wensheng

The rapid growth of agriculture web information brings a fact that search engine can not return a satisfied result for users’ queries. In this paper, we propose an agriculture domain search engine system, called ADSE, that can obtains results by an advance interface to several searches and aggregates them. We also discuss two key technologies: agriculture information determination and engine.

KeyWare: an open wireless distributed computing environment

NASA Astrophysics Data System (ADS)

Shpantzer, Isaac; Schoenfeld, Larry; Grindahl, Merv; Kelman, Vladimir

1995-12-01

Deployment of distributed applications in the wireless domain lack equivalent tools, methodologies, architectures, and network management that exist in LAN based applications. A wireless distributed computing environment (KeyWareTM) based on intelligent agents within a multiple client multiple server scheme was developed to resolve this problem. KeyWare renders concurrent application services to wireline and wireless client nodes encapsulated in multiple paradigms such as message delivery, database access, e-mail, and file transfer. These services and paradigms are optimized to cope with temporal and spatial radio coverage, high latency, limited throughput and transmission costs. A unified network management paradigm for both wireless and wireline facilitates seamless extensions of LAN- based management tools to include wireless nodes. A set of object oriented tools and methodologies enables direct asynchronous invocation of agent-based services supplemented by tool-sets matched to supported KeyWare paradigms. The open architecture embodiment of KeyWare enables a wide selection of client node computing platforms, operating systems, transport protocols, radio modems and infrastructures while maintaining application portability.

Size and mobility of lipid domains tuned by geometrical constraints.

PubMed

Schütte, Ole M; Mey, Ingo; Enderlein, Jörg; Savić, Filip; Geil, Burkhard; Janshoff, Andreas; Steinem, Claudia

2017-07-25

In the plasma membrane of eukaryotic cells, proteins and lipids are organized in clusters, the latter ones often called lipid domains or "lipid rafts." Recent findings highlight the dynamic nature of such domains and the key role of membrane geometry and spatial boundaries. In this study, we used porous substrates with different pore radii to address precisely the extent of the geometric constraint, permitting us to modulate and investigate the size and mobility of lipid domains in phase-separated continuous pore-spanning membranes (PSMs). Fluorescence video microscopy revealed two types of liquid-ordered ( l o ) domains in the freestanding parts of the PSMs: ( i ) immobile domains that were attached to the pore rims and ( ii ) mobile, round-shaped l o domains within the center of the PSMs. Analysis of the diffusion of the mobile l o domains by video microscopy and particle tracking showed that the domains' mobility is slowed down by orders of magnitude compared with the unrestricted case. We attribute the reduced mobility to the geometric confinement of the PSM, because the drag force is increased substantially due to hydrodynamic effects generated by the presence of these boundaries. Our system can serve as an experimental test bed for diffusion of 2D objects in confined geometry. The impact of hydrodynamics on the mobility of enclosed lipid domains can have great implications for the formation and lateral transport of signaling platforms.

Changes in the Leading Cause of Death: Recent Patterns in Heart Disease and Cancer Mortality.

PubMed

Heron, Melonie; Anderson, Robert N

2016-08-01

Data from the National Vital Statistics System •Heart disease has consistently been the leading cause of death in the United States and remained so in 2014. •The gap between the number of heart disease and cancer deaths generally widened from 1950 through 1968, narrowed from 1968 through 2012, and then slightly widened again from 2012 through 2014. •The mortality burden of cancer has surpassed that of heart disease in several states. In 2000, there were only 2 states where cancer was the leading cause of death; in 2014, there were 22. •Heart disease remained the leading cause of death for the non-Hispanic white and non-Hispanic black populations in 2014. •Cancer is now the leading cause of death for the non-Hispanic Asian or Pacific Islander and Hispanic populations. The timing of the leading-cause crossover varied by group. For the total U.S. population, heart disease has been the leading cause of death for decades, with cancer the second leading cause (1). However, the ranking of these causes has varied across demographic group and geographic unit over time. Rankings are based on the number of deaths and reflect mortality burden rather than risk of death (2). This report highlights changes in the mortality burden of heart disease and cancer and presents findings by state, race, and Hispanic origin. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site.

PubMed

Claveria-Gimeno, Rafael; Lanuza, Pilar M; Morales-Chueca, Ignacio; Jorge-Torres, Olga C; Vega, Sonia; Abian, Olga; Esteller, Manel; Velazquez-Campoy, Adrian

2017-01-31

Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction. The flanking disordered intervening domain (ID) increased the structural stability of MBD, modified its dsDNA binding profile from an entropically-driven moderate-affinity binding to an overwhelmingly enthalpically-driven high-affinity binding. Additionally, ID provided an additional site for simultaneously and autonomously binding an independent dsDNA molecule, which is a key feature linked to the chromatin remodelling and looping activity of MeCP2, as well as its ability to interact with nucleosomes replacing histone H1. The dsDNA interaction is characterized by an unusually large heat capacity linked to a cluster of water molecules trapped within the binding interface. The dynamics of disordered regions together with extrinsic factors are key determinants of MeCP2 global structural properties and functional capabilities.

The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site

PubMed Central

Claveria-Gimeno, Rafael; Lanuza, Pilar M.; Morales-Chueca, Ignacio; Jorge-Torres, Olga C.; Vega, Sonia; Abian, Olga; Esteller, Manel; Velazquez-Campoy, Adrian

2017-01-01

Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction. The flanking disordered intervening domain (ID) increased the structural stability of MBD, modified its dsDNA binding profile from an entropically-driven moderate-affinity binding to an overwhelmingly enthalpically-driven high-affinity binding. Additionally, ID provided an additional site for simultaneously and autonomously binding an independent dsDNA molecule, which is a key feature linked to the chromatin remodelling and looping activity of MeCP2, as well as its ability to interact with nucleosomes replacing histone H1. The dsDNA interaction is characterized by an unusually large heat capacity linked to a cluster of water molecules trapped within the binding interface. The dynamics of disordered regions together with extrinsic factors are key determinants of MeCP2 global structural properties and functional capabilities. PMID:28139759

Aging and Death Education.

ERIC Educational Resources Information Center

Pinder, Margaret M.; Hayslip, Bert, Jr.

1980-01-01

The elderly death rate is somewhat higher than the death rate in general. Numbers of schools with gerontological curricula and frequency of death education courses are positively related to elderly death rates. The contention that elderly deaths have less social impact is not supported. (JAC)

Mechanistic insights into phosphoprotein-binding FHA domains.

PubMed

Liang, Xiangyang; Van Doren, Steven R

2008-08-01

[Structure: see text]. FHA domains are protein modules that switch signals in diverse biological pathways by monitoring the phosphorylation of threonine residues of target proteins. As part of the effort to gain insight into cellular avoidance of cancer, FHA domains involved in the cellular response to DNA damage have been especially well-characterized. The complete protein where the FHA domain resides and the interaction partners determine the nature of the signaling. Thus, a key biochemical question is how do FHA domains pick out their partners from among thousands of alternatives in the cell? This Account discusses the structure, affinity, and specificity of FHA domains and the formation of their functional structure. Although FHA domains share sequence identity at only five loop residues, they all fold into a beta-sandwich of two beta-sheets. The conserved arginine and serine of the recognition loops recognize the phosphorylation of the threonine targeted. Side chains emanating from loops that join beta-strand 4 with 5, 6 with 7, or 10 with 11 make specific contacts with amino acids of the ligand that tailor sequence preferences. Many FHA domains choose a partner in extended conformation, somewhat according to the residue three after the phosphothreonine in sequence (pT + 3 position). One group of FHA domains chooses a short carboxylate-containing side chain at pT + 3. Another group chooses a long, branched aliphatic side chain. A third group prefers other hydrophobic or uncharged polar side chains at pT + 3. However, another FHA domain instead chooses on the basis of pT - 2, pT - 3, and pT + 1 positions. An FHA domain from a marker of human cancer instead chooses a much longer protein fragment that adds a beta-strand to its beta-sheet and that presents hydrophobic residues from a novel helix to the usual recognition surface. This novel recognition site and more remote sites for the binding of other types of protein partners were predicted for the entire family

Cross-Domain Semi-Supervised Learning Using Feature Formulation.

PubMed

Xingquan Zhu

2011-12-01

Semi-Supervised Learning (SSL) traditionally makes use of unlabeled samples by including them into the training set through an automated labeling process. Such a primitive Semi-Supervised Learning (pSSL) approach suffers from a number of disadvantages including false labeling and incapable of utilizing out-of-domain samples. In this paper, we propose a formative Semi-Supervised Learning (fSSL) framework which explores hidden features between labeled and unlabeled samples to achieve semi-supervised learning. fSSL regards that both labeled and unlabeled samples are generated from some hidden concepts with labeling information partially observable for some samples. The key of the fSSL is to recover the hidden concepts, and take them as new features to link labeled and unlabeled samples for semi-supervised learning. Because unlabeled samples are only used to generate new features, but not to be explicitly included in the training set like pSSL does, fSSL overcomes the inherent disadvantages of the traditional pSSL methods, especially for samples not within the same domain as the labeled instances. Experimental results and comparisons demonstrate that fSSL significantly outperforms pSSL-based methods for both within-domain and cross-domain semi-supervised learning.

Declines in Cancer Death Rates Among Children and Adolescents in the United States, 1999-2014.

PubMed

Curtin, Sally C; Minino, Arialdi M; Anderson, Robert N

2016-09-01

Data from the National Vital Statistics System •During 1999-2014, the cancer death rate for children and adolescents aged 1-19 years in the United States declined 20%, from 2.85 to 2.28 per 100,000 population. •The cancer death rate for males aged 1-19 years in 2014 was 30% higher than for females. •Declines in cancer death rates during 1999-2014 were experienced among both white and black persons aged 1-19 years and for all 5-year age groups. •During 1999-2014, brain cancer replaced leukemia as the most common cancer causing death among children and adolescents aged 1-19 years, accounting for 3 out of 10 cancer deaths in 2014. Since the mid-1970s, cancer death rates among children and adolescents in the United States showed marked declines despite a slow increase in incidence for some of the major types (1-3). These trends have previously been shown through 2012. This data brief extends previous research by showing trends in cancer death rates through 2014 among children and adolescents aged 1-19 years in the United States. Cancer death rates for 1999-2014 are presented and trends are compared for both females and males, by 5-year age group, and for white and black children and adolescents. Percent distributions of cancer deaths among children and adolescents aged 1-19 years are shown by anatomical site for 1999 and 2014. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Optical image encryption using QR code and multilevel fingerprints in gyrator transform domains

NASA Astrophysics Data System (ADS)

Wei, Yang; Yan, Aimin; Dong, Jiabin; Hu, Zhijuan; Zhang, Jingtao

2017-11-01

A new concept of GT encryption scheme is proposed in this paper. We present a novel optical image encryption method by using quick response (QR) code and multilevel fingerprint keys in gyrator transform (GT) domains. In this method, an original image is firstly transformed into a QR code, which is placed in the input plane of cascaded GTs. Subsequently, the QR code is encrypted into the cipher-text by using multilevel fingerprint keys. The original image can be obtained easily by reading the high-quality retrieved QR code with hand-held devices. The main parameters used as private keys are GTs' rotation angles and multilevel fingerprints. Biometrics and cryptography are integrated with each other to improve data security. Numerical simulations are performed to demonstrate the validity and feasibility of the proposed encryption scheme. In the future, the method of applying QR codes and fingerprints in GT domains possesses much potential for information security.

Fas Apoptosis Inhibitory Molecule (FAIM) Contains a Novel Beta Sandwich in Contact with a Partially Ordered Domain

PubMed Central

Hemond, Michael; Rothstein, Thomas L.; Wagner, Gerhard

2009-01-01

Summary Fas apoptosis inhibitory molecule (FAIM) is a soluble cytosolic protein inhibitor of programmed cell death and is found in organisms throughout the animal kingdom. A short isoform (FAIM-S) is expressed in all tissue types, while an alternatively spliced long isoform (FAIM-L) is specifically expressed in the brain. Here FAIM-S is shown to consist of two independently folding domains in contact with one another. The NMR solution structure of the C-terminal domain of murine FAIM is solved in isolation and revealed to be a novel protein fold, a noninterleaved seven-stranded beta sandwich. The structure and sequence reveal several residues that are likely to be involved in functionally significant interactions with the N-terminal domain or other binding partners. Chemical shift perturbation is used to elucidate contacts made between the N- and C-terminal domains. PMID:19168072

A 'beautiful death': mortality, death, and holidays in a Mexican municipality.

PubMed

Wilches-Gutiérrez, José L; Arenas-Monreal, Luz; Paulo-Maya, Alfredo; Peláez-Ballestas, Ingris; Idrovo, Alvaro J

2012-03-01

Several studies have reported increased mortality during holidays. Using a cultural epidemiological, sequential mixed-methods approach, this study explored holiday-related trends using mortality data from Yautepec (Morelos, Mexico) collected between 1986 and 2008 (N=5027 deaths). This analysis found that mortality increased on Christmas Day and All Saints' Day. Mortality increased on Candlemas Day among women, and increased on New Year's Day among men. More deaths caused by cardiovascular disease among women and traumatic injuries among men occurred during holidays than in non-holiday periods. To ascertain the elements comprising the health/illness/death process in the context of a holiday in this municipality, we conducted semi-structured interviews in March and April 2009 with relatives of seven individuals who had died during holidays in the previous 4 years (N=11); data from these interviews were analyzed from a grounded theory perspective to ascertain common conceptual themes. The "beautiful death" emerged as the main concept in the interpretation of death; this concept was related to the expectation of a good death and the particularly special nature of death during a holiday because of the involvement of religious entities, such as God, the Virgin Mary, and/or a saint, at the moment of death. Quantitative and qualitative results provided information about the important effects of holidays, culture, and religious belief on mortality patterns within a Mexican context, and contributed to a better understanding of the relationships among mortality, the nature of death, and holidays. Our results suggest that, in the studied region, death can be interpreted as a "beautiful process". More research is needed to explore this process in other similar contexts and to address topics related to the care and attention given the dying person and the expectation of a good death. Copyright © 2012 Elsevier Ltd. All rights reserved.

Attenuation of cadmium-induced necrotic cell death by necrostatin-1: Potential necrostatin-1 acting sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, T.-S.; Yang, P.-M.; Tsai, J.-S.

2009-03-01

Cadmium (Cd) induces necrotic death in Chinese hamster ovary (CHO) K1 cells and we have established the responsible signaling pathway. Reportedly, necrostatin-1 (Nec-1) rescues cells from necrotic death by mediating through the death domain receptor (DR) signaling pathway. We show here that Nec-1 also effectively attenuates necrotic death triggered by Cd. Two other treatments that cause necrotic cell death, one can (z-VAD-fmk/TNF-{alpha} on U937 cells) and the other cannot (etherynic acid (EA) on DLD-1 cells) be rescued by Nec-1, were also studied in parallel for comparison. Results show that Nec-1 is ineffectual in modulating intracellular calcium contents, calpain activity (amore » downstream protease), or reactive oxygen species production. It can counteract the reduction in mitochondrial membrane potential (MMP) caused by treating CHO K1 or U937 cells with necrosis-inducing agent. However, this effect was not found in EA-treated DLD-1 cells. Notably, Nec-1 elevates NF-{kappa}B activity in the presence or absence of necrosis-inducing agents. Our study shows that, in addition to DR-mediated necrosis, Nec-1 is effective in attenuating Cd-induced necrosis. It rescues cells with reduced MMP implying that mitochondrion is its major acting site.« less

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

PubMed

Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J; Cheng, Qiang Shawn; D'Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M; Gonzalez Guzman, Michael J; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Ryan, Elizabeth P; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H; Lowe, Leroy; Park, Hyun Ho

2015-06-01

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3.

PubMed

Koehler, Heather; Cotsmire, Samantha; Langland, Jeffrey; Kibler, Karen V; Kalman, Daniel; Upton, Jason W; Mocarski, Edward S; Jacobs, Bertram L

2017-10-24

Vaccinia virus (VACV) encodes an innate immune evasion protein, E3, which contains an N-terminal Z-nucleic acid binding (Zα) domain that is critical for pathogenicity in mice. Here we demonstrate that the N terminus of E3 is necessary to inhibit an IFN-primed virus-induced necroptosis. VACV deleted of the Zα domain of E3 (VACV-E3LΔ83N) induced rapid RIPK3-dependent cell death in IFN-treated L929 cells. Cell death was inhibited by the RIPK3 inhibitor, GSK872, and infection with this mutant virus led to phosphorylation and aggregation of MLKL, the executioner of necroptosis. In 293T cells, induction of necroptosis depended on expression of RIPK3 as well as the host-encoded Zα domain-containing DNA sensor, DAI. VACV-E3LΔ83N is attenuated in vivo, and pathogenicity was restored in either RIPK3- or DAI-deficient mice. These data demonstrate that the N terminus of the VACV E3 protein prevents DAI-mediated induction of necroptosis.

Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death.

PubMed

Kim, Jin Hee; Kang, Tae Heung; Noh, Kyung Hee; Bae, Hyun Cheol; Kim, Seok-Ho; Yoo, Young Do; Seong, Seung-Yong; Kim, Tae Woo

2009-01-29

Dendritic cells (DCs) have become an important measure for the treatment of malignancies. Current DC preparations, however, generate short-lived DCs because they are subject to cell death from various apoptotic pressures. Antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) is one of the main obstacles to limit the DC-mediated immune priming since CTLs can recognize the target antigen expressing DCs as target cells and kill the DCs. CTLs secret perforin and serine protease granzymes during CTL killing. Perforin and serine protease granzymes induce the release of a number of mitochondrial pro-apoptotic factors, which are controlled by members of the BCL-2 family, such as BAK, BAX and BIM. FasL linking to Fas on DCs triggers the activation of caspase-8, which eventually leads to mitochondria-mediated apoptosis via truncation of BID. In this study, we tried to enhance the DC priming capacity by prolonging DC survival using anti-apoptotic siRNA targeting these key pro-apoptotic molecules in CTL killing. Human papillomavirus (HPV)-16 E7 antigen presenting DCs that were transfected with these anti-apoptotic siRNAs showed increased resistance to T cell-mediated death, leading to enhanced E7-specific CD8(+) T cell activation in vitro and in vivo. Among them, siRNA targeting BIM (siBIM) generated strongest E7-specific E7-specific CD8(+) T cell immunity. More importantly, vaccination with E7 presenting DCs transfected with siBIM was capable of generating a marked therapeutic effect in vaccinated mice. Our data indicate that ex vivo manipulation of DCs with siBIM may represent a plausible strategy for enhancing dendritic cell-based vaccine potency.

Fibromyalgia syndrome module at OMERACT 9: domain construct.

PubMed

Mease, Philip; Arnold, Lesley M; Choy, Ernest H; Clauw, Daniel J; Crofford, Leslie J; Glass, Jennifer M; Martin, Susan A; Morea, Jessica; Simon, Lee; Strand, C Vibeke; Williams, David A

2009-10-01

The objective of the module was to (1) establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measure performance characteristics, (3) discuss development of a responder index for assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, and (6) establish a research agenda for outcomes research. Presentations at the module included: (1) Results of univariate and multivariate analysis of 10 FM clinical trials of 4 drugs, mapping key domains identified in previous patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, and breakout discussions to vote on possible essential domains and reliable measures; (2) Updates regarding outcome measure status; (3) Update on objective markers to measure FM disease state; and (4) Review of the issue of cognitive dysfunction (dyscognition) in FM. Consensus was reached as follows: (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials; dyscognition and depression should be measured in some trials; and stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers were identified as domains of research interest. (2) FM domain outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing numbers of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. In conclusion, a multidimensional symptom core set is proposed for evaluation of FM in clinical trials. Research on improved measures of single domains and composite measures is ongoing.

Domainal cleavage as an Anisotropic Reaction-diffusion Process

NASA Astrophysics Data System (ADS)

Mulchrone, Kieran; Meere, Patrick

2017-04-01

Domainal cleavage comprises zones dominated by quartz and feldspar (QF-domains) and zones dominated by Mica (M-domains) which form at low metamorphic grades. The protolith is typically fairly homogeneous mudstone, siltstone, sandstone or limestone. Wet diffusion or pressure solution along grain boundaries is a key mechanism in the development of domanial cleavage. However, this does not explain why M-domains become sub-regularly spaced, visually evident in coarser-grained rocks, and take on an anastomising morphology. The ratio of M to QF-domains by volume can range from 1 to 0.1 and lower i.e. in extreme cases M-domains are intermittent but regularly spaced. It is suggested here that an anisotropic reaction-diffusion process model can explain these features. The imposed stress field instantaneously leads to anisotropy of diffusion by narrowing intergranular channels perpendicular to the principal stress. This leads to a preferred diffusion of chemicals parallel to the principal stress direction and lower diffusion rates in the normal direction. Combining this with the chemical reaction of pressure solution produces an anisotropic reaction-diffusion system. Both isotropic and anistropic reaction diffusion systems lead to pattern formation as discovered by Alan Turing on the 1950's as an explanation for patterns found in animal skins such as spots and stripes. Thus domanial cleavage is a striped pattern induced by diffusion anisotropy combined with a chemical reaction. Furthermore, rates of chemical reaction in intergranular fluids is likely to be many orders of magnitude greater that rates of deformation. Therefore we expect domanial cleavage to form relatively rapidly. As deformation progresses the M-domains behave less competently and may be the site of enhanced shearing. An example from Co. Cork, Ireland demonstrates shear folding in low-grade metasedimentary rocks with reverse shear along M-domains at a high angle to the maximum compressive stress.

How does metabolism affect cell death in cancer?

PubMed

Villa, Elodie; Ricci, Jean-Ehrland

2016-07-01

In cancer research, identifying a specificity of tumor cells compared with 'normal' proliferating cells for targeted therapy is often considered the Holy Grail for researchers and clinicians. Although diverse in origin, most cancer cells share characteristics including the ability to escape cell death mechanisms and the utilization of different methods of energy production. In the current paradigm, aerobic glycolysis is considered the central metabolic characteristic of cancer cells (Warburg effect). However, recent data indicate that cancer cells also show significant changes in other metabolic pathways. Indeed, it was recently suggested that Kreb's cycle, pentose phosphate pathway intermediates, and essential and nonessential amino acids have key roles. Renewed interest in the fact that cancer cells have to reprogram their metabolism in order to proliferate or resist treatment must take into consideration the ability of tumor cells to adapt their metabolism to the local microenvironment (low oxygen, low nutrients). This variety of metabolic sources might be either a strength, resulting in infinite possibilities for adaptation and increased ability to resist chemotherapy-induced death, or a weakness that could be targeted to kill cancer cells. Here, we discuss recent insights showing how energetic metabolism may regulate cell death and how this might be relevant for cancer treatment. © 2015 FEBS.

Uncoupling phototoxicity-elicited neural dysmorphology and death by insidious function and selective impairment of Ran-binding protein 2 (Ranbp2).

PubMed

Cho, Kyoung-in; Haney, Victoria; Yoon, Dosuk; Hao, Yin; Ferreira, Paulo A

2015-12-21

Morphological disintegration of neurons is coupled invariably to neural death. In particular, disruption of outer segments of photoreceptor neurons triggers photoreceptor death regardless of the pathological stressors. We show that Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) mice with mutations in SUMO-binding motif (SBM) of cyclophilin-like domain (CLD) of Ran-binding protein 2 (Ranbp2) expressed in a null Ranbp2 background lack untoward effects in photoreceptors in the absence of light-stress. However, compared to wild type photoreceptors, light-stress elicits profound disintegration of outer segments of Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) with paradoxical age-dependent resistance of photoreceptors to death and genotype-independent activation of caspases. Ranbp2(-/-)::Tg-Ranbp2(CLDm-HA) exhibit photoreceptor death-independent changes in ubiquitin-proteasome system (UPS), but death-dependent increase of ubiquitin carrier protein 9(ubc9) levels. Hence, insidious functional impairment of SBM of Ranbp2's CLD promotes neuroprotection and uncoupling of photoreceptor degeneration and death against phototoxicity. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Death and Grief

MedlinePlus

... Staying Safe Videos for Educators Search English Español Death and Grief KidsHealth / For Teens / Death and Grief What's in this article? What Is ... the reaction we have in response to a death or loss. Grief can affect our body, mind, ...

Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs).

PubMed

Danese, Alberto; Patergnani, Simone; Bonora, Massimo; Wieckowski, Mariusz R; Previati, Maurizio; Giorgi, Carlotta; Pinton, Paolo

2017-08-01

Until 1972, the term 'apoptosis' was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca 2+ ) release from the ER allows selective Ca 2+ uptake by the mitochondria. The perturbation of Ca 2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca 2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. Copyright © 2017 Elsevier B.V. All rights reserved.

Top 10 Research Questions Related to Preventing Sudden Death in Sport and Physical Activity.

PubMed

Katch, Rachel K; Scarneo, Samantha E; Adams, William M; Armstrong, Lawrence E; Belval, Luke N; Stamm, Julie M; Casa, Douglas J

2017-09-01

Participation in organized sport and recreational activities presents an innate risk for serious morbidity and mortality. Although death during sport or physical activity has many causes, advancements in sports medicine and evidence-based standards of care have allowed clinicians to prevent, recognize, and treat potentially fatal injuries more effectively. With the continual progress of research and technology, current standards of care are evolving to enhance patient outcomes. In this article, we provided 10 key questions related to the leading causes and treatment of sudden death in sport and physical activity, where future research will support safer participation for athletes and recreational enthusiasts. The current evidence indicates that most deaths can be avoided when proper strategies are in place to prevent occurrence or provide optimal care.

A Death in the Family: Death as a Zen Concept

ERIC Educational Resources Information Center

Black, Helen K.; Rubinstein, Robert L.

2013-01-01

This study is based on original research that explored family reaction to the death of an elderly husband and father. We interviewed 34 families (a family included a widow and two adult biological children) approximately 6 to 10 months after the death. In one-on-one interviews, we discussed family members' initial reaction to the death, how the…

Moral individualism and elective death.

PubMed

Prado, C G

2013-01-01

Moral individualism (Brooks, 2011; Smith, 2011) is a contemporary interpretation of morality as entirely a matter of personal choice. It is a popular rather than theory-based interpretation and has a number of social generative sources related to present-day preoccupation with individuality and personal distinctiveness. A key generative source is popularization of postmodernism, which prioritizes self-reinvention and provides moral individualism with the appearance of intellectual legitimacy. Moral individualism is a deeply flawed misconception of morality because it abolishes moral communality. My concern in this paper is that in doing so, it seriously jeopardizes productive discussion of the moral permissibility of elective death or choosing to die in despairingly and dire circumstances. Copyright © 2013 Elsevier Ltd. All rights reserved.

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

PubMed Central

Bailey, Liane Jennifer; Alahari, Sruthi; Tagliaferro, Andrea; Post, Martin; Caniggia, Isabella

2017-01-01

Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia. PMID:28151467

Size and mobility of lipid domains tuned by geometrical constraints

PubMed Central

Schütte, Ole M.; Mey, Ingo; Savić, Filip; Geil, Burkhard; Janshoff, Andreas

2017-01-01

In the plasma membrane of eukaryotic cells, proteins and lipids are organized in clusters, the latter ones often called lipid domains or “lipid rafts.” Recent findings highlight the dynamic nature of such domains and the key role of membrane geometry and spatial boundaries. In this study, we used porous substrates with different pore radii to address precisely the extent of the geometric constraint, permitting us to modulate and investigate the size and mobility of lipid domains in phase-separated continuous pore-spanning membranes (PSMs). Fluorescence video microscopy revealed two types of liquid-ordered (lo) domains in the freestanding parts of the PSMs: (i) immobile domains that were attached to the pore rims and (ii) mobile, round-shaped lo domains within the center of the PSMs. Analysis of the diffusion of the mobile lo domains by video microscopy and particle tracking showed that the domains’ mobility is slowed down by orders of magnitude compared with the unrestricted case. We attribute the reduced mobility to the geometric confinement of the PSM, because the drag force is increased substantially due to hydrodynamic effects generated by the presence of these boundaries. Our system can serve as an experimental test bed for diffusion of 2D objects in confined geometry. The impact of hydrodynamics on the mobility of enclosed lipid domains can have great implications for the formation and lateral transport of signaling platforms. PMID:28696315

The multiple decrement life table: a unifying framework for cause-of-death analysis in ecology.

PubMed

Carey, James R

1989-01-01

The multiple decrement life table is used widely in the human actuarial literature and provides statistical expressions for mortality in three different forms: i) the life table from all causes-of-death combined; ii) the life table disaggregated into selected cause-of-death categories; and iii) the life table with particular causes and combinations of causes eliminated. The purpose of this paper is to introduce the multiple decrement life table to the ecological literature by applying the methods to published death-by-cause information on Rhagoletis pomonella. Interrelations between the current approach and conventional tools used in basic and applied ecology are discussed including the conventional life table, Key Factor Analysis and Abbott's Correction used in toxicological bioassay.

Validation of Toolkit After-Death Bereaved Family Member Interview.

PubMed

Teno, J M; Clarridge, B; Casey, V; Edgman-Levitan, S; Fowler, J

2001-09-01

The purpose of this study was to examine the reliability and validity of the Toolkit After-Death Bereaved Family Member Interview to measure quality of care at the end of life from the unique perspective of family members. The survey included proposed problem scores (a count of the opportunity to improve the quality of care) and scales. Data were collected through a retrospective telephone survey with a family member who was interviewed between 3 and 6 months after the death of the patient. The setting was an outpatient hospice service, a consortium of nursing homes, and a hospital in New England. One hundred fifty-six family members from across these settings participated. The 8 proposed domains of care, as represented by problem scores or scales, were based on a conceptual model of patient-focused, family-centered medical care. The survey design emphasized face validity in order to provide actionable information to health care providers. A correlational and factor analysis was undertaken of the 8 proposed problem scores or scales. Cronbach's alpha scores varied from 0.58 to 0.87, with two problem scores (each of which had only 3 survey items) having a low alpha of 0.58. The mean item-to-total correlations for the other problem scores varied from 0.36 to 0.69, and the mean item-to-item correlations were between 0.32 and 0.70. The proposed problem scores or scales, with the exception of closure and advance care planning, demonstrated a moderate correlation (i.e., from 0.44 to 0.52) with the overall rating of satisfaction (as measured by a five-point, "excellent" to "poor" scale). Family members of persons who died with hospice service reported fewer problems in each of the six domains of medical care, gave a higher rating of the quality of care, and reported higher self-efficacy in caring for their loved ones. These results indicate that 7 of the 8 proposed problem scores or scales demonstrated psychometric properties that warrant further testing. The domain of

Psychological Defenses against Death Anxiety: Integrating Terror Management Theory and Firestone's Separation Theory

ERIC Educational Resources Information Center

Bassett, Jonathan F.

2007-01-01

The author attempts to integrate Terror Management Theory (TMT) and R. W. Firestone's Separation Theory (1984, 1994). Both theories emphasize defense against death anxiety as a key human motive. Whereas TMT focuses extensively on self-esteem and cultural worldview, Firestone posited additional defenses such as gene survival, self-nourishing…

Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.

PubMed

Bottomley, Matthew J; Lo Surdo, Paola; Di Giovine, Paolo; Cirillo, Agostino; Scarpelli, Rita; Ferrigno, Federica; Jones, Philip; Neddermann, Petra; De Francesco, Raffaele; Steinkühler, Christian; Gallinari, Paola; Carfí, Andrea

2008-09-26

Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.

Cot Deaths.

ERIC Educational Resources Information Center

Tyrrell, Shelagh

1985-01-01

Addresses the tragedy of crib deaths, giving particular attention to causes, prevention, and medical research on Sudden Infant Death Syndrome (SIDS). Gives anecdotal accounts of coping strategies used by parents and families of SIDS infants. (DT)

Infrared Space Observatory (ISO) Key Project: the Birth and Death of Planets

NASA Technical Reports Server (NTRS)

Stencel, Robert E.; Creech-Eakman, Michelle; Fajardo-Acosta, Sergio; Backman, Dana

1999-01-01

This program was designed to continue to analyze observations of stars thought to be forming protoplanets, using the European Space Agency's Infrared Space Observatory, ISO, as one of NASA Key Projects with ISO. A particular class of Infrared Astronomy Satellite (IRAS) discovered stars, known after the prototype, Vega, are principal targets for these observations aimed at examining the evidence for processes involved in forming, or failing to form, planetary systems around other stars. In addition, this program continued to provide partial support for related science in the WIRE, SOFIA and Space Infrared Telescope Facility (SIRTF) projects, plus approved ISO supplementary time observations under programs MCREE1 29 and VEGADMAP. Their goals include time dependent changes in SWS spectra of Long Period Variable stars and PHOT P32 mapping experiments of recognized protoplanetary disk candidate stars.

Breast milk donation after neonatal death in Australia: a report.

PubMed

Carroll, Katherine E; Lenne, Brydan S; McEgan, Kerri; Opie, Gillian; Amir, Lisa H; Bredemeyer, Sandra; Hartmann, Ben; Jones, Rachel; Koorts, Pieter; McConachy, Helen; Mumford, Patricia; Polverino, Jan

2014-01-01

Lactation and breast milk can hold great value and meaning for grieving mothers who have experienced a recent death of an infant. Donation to a human milk bank (HMB) as an alternative to discarding breast milk is one means of respecting the value of breast milk. There is little research, national policy discussion, or organizational representation in Australia on the subject of breast milk donation after infant death. On 29 November 2013 the Mercy Hospital for Women in Melbourne, Australia hosted Australia's first National Stakeholder Meeting (NSM) on the topic of milk donation after neonatal death. The NSM drew together representatives from Australian HMBs, neonatal intensive care units (NICUs) currently using donor human milk, and Australia's chief NICU parent support organization. The NSM was video-recorded and transcribed, and analyzed thematically by researchers. This article reports the seven dominant themes discussed by stakeholders during the NSM: the spectrum of women's lactation and donation experiences after infant death; the roles of the HMB and NICU in meeting the needs of the bereaved donor; how bereaved mothers' lactation autonomy may interface with a HMB's donation guidelines; how milk donation may be discussed with bereaved mothers; the variation between four categories of milk donation after neonatal death; the impact of limited resources and few HMBs on providing donation programs for bereaved mothers in Australia. This article provides evidence from researchers and practitioners that can assist HMB staff in refining their bank's policy on milk donation after infant death, and provides national policy makers with key considerations to support lactation, human milk banking, and bereavement services nation-wide.

Imaging workflow and calibration for CT-guided time-domain fluorescence tomography

PubMed Central

Tichauer, Kenneth M.; Holt, Robert W.; El-Ghussein, Fadi; Zhu, Qun; Dehghani, Hamid; Leblond, Frederic; Pogue, Brian W.

2011-01-01

In this study, several key optimization steps are outlined for a non-contact, time-correlated single photon counting small animal optical tomography system, using simultaneous collection of both fluorescence and transmittance data. The system is presented for time-domain image reconstruction in vivo, illustrating the sensitivity from single photon counting and the calibration steps needed to accurately process the data. In particular, laser time- and amplitude-referencing, detector and filter calibrations, and collection of a suitable instrument response function are all presented in the context of time-domain fluorescence tomography and a fully automated workflow is described. Preliminary phantom time-domain reconstructed images demonstrate the fidelity of the workflow for fluorescence tomography based on signal from multiple time gates. PMID:22076264

Domain atrophy creates rare cases of functional partial protein domains.

PubMed

Prakash, Ananth; Bateman, Alex

2015-04-30

Protein domains display a range of structural diversity, with numerous additions and deletions of secondary structural elements between related domains. We have observed a small number of cases of surprising large-scale deletions of core elements of structural domains. We propose a new concept called domain atrophy, where protein domains lose a significant number of core structural elements. Here, we implement a new pipeline to systematically identify new cases of domain atrophy across all known protein sequences. The output of this pipeline was carefully checked by hand, which filtered out partial domain instances that were unlikely to represent true domain atrophy due to misannotations or un-annotated sequence fragments. We identify 75 cases of domain atrophy, of which eight cases are found in a three-dimensional protein structure and 67 cases have been inferred based on mapping to a known homologous structure. Domains with structural variations include ancient folds such as the TIM-barrel and Rossmann folds. Most of these domains are observed to show structural loss that does not affect their functional sites. Our analysis has significantly increased the known cases of domain atrophy. We discuss specific instances of domain atrophy and see that there has often been a compensatory mechanism that helps to maintain the stability of the partial domain. Our study indicates that although domain atrophy is an extremely rare phenomenon, protein domains under certain circumstances can tolerate extreme mutations giving rise to partial, but functional, domains.

Tunable short-wavelength spin wave excitation from pinned magnetic domain walls

PubMed Central

Van de Wiele, Ben; Hämäläinen, Sampo J.; Baláž, Pavel; Montoncello, Federico; van Dijken, Sebastiaan

2016-01-01

Miniaturization of magnonic devices for wave-like computing requires emission of short-wavelength spin waves, a key feature that cannot be achieved with microwave antennas. In this paper, we propose a tunable source of short-wavelength spin waves based on highly localized and strongly pinned magnetic domain walls in ferroelectric-ferromagnetic bilayers. When driven into oscillation by a microwave spin-polarized current, the magnetic domain walls emit spin waves with the same frequency as the excitation current. The amplitude of the emitted spin waves and the range of attainable excitation frequencies depend on the availability of domain wall resonance modes. In this respect, pinned domain walls in magnetic nanowires are particularly attractive. In this geometry, spin wave confinement perpendicular to the nanowire axis produces a multitude of domain wall resonances enabling efficient spin wave emission at frequencies up to 100 GHz and wavelengths down to 20 nm. At high frequency, the emission of spin waves in magnetic nanowires becomes monochromatic. Moreover, pinning of magnetic domain wall oscillators onto the same ferroelectric domain boundary in parallel nanowires guarantees good coherency between spin wave sources, which opens perspectives towards the realization of Mach-Zehnder type logic devices and sensors. PMID:26883893

Impact of protein domains on PE_PGRS30 polar localization in Mycobacteria.

PubMed

De Maio, Flavio; Maulucci, Giuseppe; Minerva, Mariachiara; Anoosheh, Saber; Palucci, Ivana; Iantomasi, Raffaella; Palmieri, Valentina; Camassa, Serena; Sali, Michela; Sanguinetti, Maurizio; Bitter, Wilbert; Manganelli, Riccardo; De Spirito, Marco; Delogu, Giovanni

2014-01-01

PE_PGRS proteins are unique to the Mycobacterium tuberculosis complex and a number of other pathogenic mycobacteria. PE_PGRS30, which is required for the full virulence of M. tuberculosis (Mtb), has three main domains, i.e. an N-terminal PE domain, repetitive PGRS domain and the unique C-terminal domain. To investigate the role of these domains, we expressed a GFP-tagged PE_PGRS30 protein and a series of its functional deletion mutants in different mycobacterial species (Mtb, Mycobacterium bovis BCG and Mycobacterium smegmatis) and analysed protein localization by confocal microscopy. We show that PE_PGRS30 localizes at the mycobacterial cell poles in Mtb and M. bovis BCG but not in M. smegmatis and that the PGRS domain of the protein strongly contributes to protein cellular localization in Mtb. Immunofluorescence studies further showed that the unique C-terminal domain of PE_PGRS30 is not available on the surface, except when the PGRS domain is missing. Immunoblot demonstrated that the PGRS domain is required to maintain the protein strongly associated with the non-soluble cellular fraction. These results suggest that the repetitive GGA-GGN repeats of the PGRS domain contain specific sequences that contribute to protein cellular localization and that polar localization might be a key step in the PE_PGRS30-dependent virulence mechanism.

A residue-specific shift in stability and amyloidogenicity of antibody variable domains.

PubMed

Nokwe, Cardine N; Zacharias, Martin; Yagi, Hisashi; Hora, Manuel; Reif, Bernd; Goto, Yuji; Buchner, Johannes

2014-09-26

Variable (V) domains of antibodies are essential for antigen recognition by our adaptive immune system. However, some variants of the light chain V domains (VL) form pathogenic amyloid fibrils in patients. It is so far unclear which residues play a key role in governing these processes. Here, we show that the conserved residue 2 of VL domains is crucial for controlling its thermodynamic stability and fibril formation. Hydrophobic side chains at position 2 stabilize the domain, whereas charged residues destabilize and lead to amyloid fibril formation. NMR experiments identified several segments within the core of the VL domain to be affected by changes in residue 2. Furthermore, molecular dynamic simulations showed that hydrophobic side chains at position 2 remain buried in a hydrophobic pocket, and charged side chains show a high flexibility. This results in a predicted difference in the dissociation free energy of ∼10 kJ mol(-1), which is in excellent agreement with our experimental values. Interestingly, this switch point is found only in VL domains of the κ family and not in VLλ or in VH domains, despite a highly similar domain architecture. Our results reveal novel insight into the architecture of variable domains and the prerequisites for formation of amyloid fibrils. This might also contribute to the rational design of stable variable antibody domains. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Induction of cell death by tospoviral protein NSs and the motif critical for cell death does not control RNA silencing suppression activity.

PubMed

Singh, Ajeet; Permar, Vipin; Jain, R K; Goswami, Suneha; Kumar, Ranjeet Ranjan; Canto, Tomas; Palukaitis, Peter; Praveen, Shelly

2017-08-01

Groundnut bud necrosis virus induces necrotic symptoms in different hosts. Previous studies showed reactive oxygen species-mediated programmed cell death (PCD) resulted in necrotic symptoms. Transgenic expression of viral protein NSs mimics viral symptoms. Here, we showed a role for NSs in influencing oxidative burst in the cell, by analyzing H 2 O 2 accumulation, activities of antioxidant enzymes and expression levels of vacuolar processing enzymes, H 2 O 2 -responsive microRNA 319a.2 plus its possible target metacaspase-8. The role of NSs in PCD, was shown using two NSs mutants: one in the Trp/GH3 motif (a homologue of pro-apototic domain) (NSs S189R ) and the other in a non-Trp/GH3 motif (NSs L172R ). Tobacco rattle virus (TRV) expressing NSs S189R enhanced the PCD response, but not TRV-NSs L172R , while RNA silencing suppression activity was lost in TRV-NSs L172R , but not in TRV-NSs S189R . Therefore, we propose dual roles of NSs in RNA silencing suppression and induction of cell death, controlled by different motifs. Copyright © 2017 Elsevier Inc. All rights reserved.

Dreams of Death.

ERIC Educational Resources Information Center

Barrett, Deirdre

1989-01-01

Examined frequency and characteristics of overt dreams of dying among healthy young adults. Dreams of dying were found to be rare but distinctive content category, representing overwhelmingly pleasant dreams. Over one-half of death dreams involved lengthy afterlife sequence, remainder focused on process of death. Death dreams of these healthy…

An antifungal protein from Ginkgo biloba binds actin and can trigger cell death.

PubMed

Gao, Ningning; Wadhwani, Parvesh; Mühlhäuser, Philipp; Liu, Qiong; Riemann, Michael; Ulrich, Anne S; Nick, Peter

2016-07-01

Ginkbilobin is a short antifungal protein that had been purified and cloned from the seeds of the living fossil Ginkgo biloba. Homologues of this protein can be detected in all seed plants and the heterosporic fern Selaginella and are conserved with respect to domain structures, peptide motifs, and specific cysteine signatures. To get insight into the cellular functions of these conserved motifs, we expressed green fluorescent protein fusions of full-length and truncated ginkbilobin in tobacco BY-2 cells. We show that the signal peptide confers efficient secretion of ginkbilobin. When this signal peptide is either cleaved or masked, ginkbilobin binds and visualizes the actin cytoskeleton. This actin-binding activity of ginkbilobin is mediated by a specific subdomain just downstream of the signal peptide, and this subdomain can also coassemble with actin in vitro. Upon stable overexpression of this domain, we observe a specific delay in premitotic nuclear positioning indicative of a reduced dynamicity of actin. To elucidate the cellular response to the binding of this subdomain to actin, we use chemical engineering based on synthetic peptides comprising different parts of the actin-binding subdomain conjugated with the cell-penetrating peptide BP100 and with rhodamine B as a fluorescent reporter. Binding of this synthetic construct to actin efficiently induces programmed cell death. We discuss these findings in terms of a working model, where ginkbilobin can activate actin-dependent cell death.

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

PubMed Central

Pamenter, Matthew E.; Powell, Frank L.

2016-01-01

Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields. PMID:27347896

Fire-related deaths among Aboriginal people in British Columbia, 1991-2001.

PubMed

Gilbert, Mark; Dawar, Meenakshi; Armour, Rosemary

2006-01-01

Fire-related mortality rates are known to be higher in Aboriginal people in BC. The purpose of this study was to describe the epidemiology and context of fire-related deaths in this population. All death registrations attributable to fires in the province were identified by the B.C. Vital Statistics Agency (1991-2001). Age-specific death rates (ASDR) and age-standardized mortality rates (ASMR) were calculated for Status Indians and other residents. Data from Coroner's reports from the B.C. Coroners' Service (1997-2001) were used to describe the context of Aboriginal fire-related deaths. The overall fire-related ASMR for Status Indians and other residents were 0.66 deaths and 0.07 deaths/10,000 population respectively. Annual ASMR for both populations were constant over the study period. ASDR were higher in every age category for Status Indians; children and seniors had higher rates in both populations. Twenty-seven Aboriginal fatalities (20 fires) were identified for the contextual analysis. Key findings were: 48% of the total sample had elevated blood alcohol levels; 30% of the fires were caused by lit cigarettes (majority of decedents were intoxicated); 15% of the fires were caused by electric heating sources; at least 34% of fires occurred in homes with absent or non-functional smoke alarms. Fire-related mortality among Aboriginal people in BC is a preventable public health concern. In this population, fire safety and prevention programs should consider improving the prevalence of functioning smoke alarms, promoting the safe use of heat sources, and decreasing smoking behaviours and the use of alcohol.

Comparison of cause of death between anzdata and the australian national death index.

PubMed

Sypek, Matthew P; Dansie, Kathryn B; Clayton, Phil; Webster, Angela C; McDonald, Stephen

2018-03-01

To understand the differences in how cause of death for patients receiving renal replacement therapy in Australia is recorded in The Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) compared to the National Death Index (NDI). Data linkage was performed between ANZDATA and NDI for all deaths in the period 1980-2013. Cause of death was classified according to ICD-10 chapter. Overall and chapter specific agreement were assessed using the Kappa statistic. Descriptive analysis was used to explore differences where there was disagreement on primary cause of death. The analysis cohort included 28,675 patients. Ninety five percent of ANZDATA reported deaths fell within +/- 3 days of the date recorded by NDI. Circulatory death was the most common cause of death in both databases (ANZDATA 48%, NDI 32%). Overall agreement at ICD chapter level of primary cause was poor (36%, kappa 0.22). Agreement was best for malignancy (kappa 0.71). When there was disagreement on primary cause of death these were most commonly coded as genitourinary (35%) and endocrine (25.0%) in NDI, and circulatory (39%) and withdrawal (24%) in ANZDATA. Sixty-nine percent of patients had a renal related cause documented as either primary or a contributing cause of death in the NDI. There is poor agreement in primary cause of death between ANZDATA and NDI which is in part explained by the absence of diabetes and renal failure as causes of death in ANZDATA and the absence of 'withdrawal' in NDI. These differences should be appreciated when interpreting epidemiological data on cause of death in the Australian end stage kidney disease population. This article is protected by copyright. All rights reserved.

The Molecular Ecophysiology of Programmed Cell Death in Marine Phytoplankton

NASA Astrophysics Data System (ADS)

Bidle, Kay D.

2015-01-01

Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

Deaths from international terrorism compared with road crash deaths in OECD countries.

PubMed

Wilson, N; Thomson, G

2005-12-01

To estimate the relative number of deaths in member countries of the Organisation for Economic Co-operation and Development (OECD) from international terrorism and road crashes. Data on deaths from international terrorism (US State Department database) were collated (1994-2003) and compared to the road injury deaths (year 2000 and 2001 data) from the OECD International Road Transport Accident Database. In the 29 OECD countries for which comparable data were available, the annual average death rate from road injury was approximately 390 times that from international terrorism. The ratio of annual road to international terrorism deaths (averaged over 10 years) was lowest for the United States at 142 times. In 2001, road crash deaths in the US were equal to those from a September 11 attack every 26 days. There is a large difference in the magnitude of these two causes of deaths from injury. Policy makers need to be aware of this when allocating resources to preventing these two avoidable causes of mortality.

Sibling death and death fear in relation to depressive symptomatology in older adults.

PubMed

Cicirelli, Victor G

2009-01-01

Previously overlooked factors in elders' depressive symptomatology were examined, including death fear, sibling death, and sibling closeness. Participants were 150 elders (61 men, 89 women) aged 65-97 years with at least one sibling. Measures were proportion of deceased siblings, sibling closeness, the Death Fear Subscale of the Death Attitude Profile-Revised, and the Center for Epidemiological Studies-Depression scale (20-item adult form). Age and education were exogenous variables in a structural equation model. Death fear, sibling closeness, and proportion of dead siblings were directly related to depression, with path coefficients of .42, -.24, and .13, respectively. Proportion of dead siblings had indirect effects on depression, as did age and education. Depressive symptomatology in old age is influenced by death fear related to sibling death as well as by poor relationships with them; it must be understood within a situational context including death fear and sibling relationships.

Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains.

PubMed

Hong, Liang; Pathak, Medha M; Kim, Iris H; Ta, Dennis; Tombola, Francesco

2013-01-23

Voltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open channel blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates. Copyright © 2013 Elsevier Inc. All rights reserved.

A Service evaluation of a hospital child death review process to elucidate understanding of contributory factors to child mortality and inform practice in the English National Health Service.

PubMed

Magnus, Daniel S; Schindler, Margrid B; Marlow, Robin D; Fraser, James I

2018-03-16

To describe a novel approach to hospital mortality meetings to elucidate understanding of contributory factors to child death and inform practice in the National Health Service. All child deaths were separately reviewed at a meeting attended by professionals across the healthcare pathway, and an assessment was made of contributory factors to death across domains intrinsic to the child, family and environment, parenting capacity and service delivery. Data were analysed from a centrally held database of records. All child deaths in a tertiary children's hospital between 1 April 2010 and 1 April 2013. Descriptive data summarising contributory factors to child deaths. 95 deaths were reviewed. In 85% cases, factors intrinsic to the child provided complete explanation for death. In 11% cases, factors in the family and environment and, in 5% cases, factors in parenting capacity, contributed to patient vulnerability. In 33% cases, factors in service provision contributed to patient vulnerability and in two patients provided complete explanation for death. 26% deaths were classified as potentially preventable and in those cases factors in service provision were more commonly identified than factors across other domains (OR: 4.89; 95% CI 1.26 to 18.9). Hospital child death review meetings attended by professionals involved in patient management across the healthcare pathway inform understanding of events leading to a child's death. Using a bioecological approach to scrutinise contributory factors the multidisciplinary team concluded most deaths occurred as a consequence of underlying illness. Although factors relating to service provision were commonly identified, they rarely provided a complete explanation for death. Efforts to reduce child mortality should be driven by an understanding of modifiable risk factors. Systematic data collection arising from a standardised approach to hospital reviews should be the basis for national mortality review processes and database

Testing key predictions of the associative account of mirror neurons in humans using multivariate pattern analysis.

PubMed

Oosterhof, Nikolaas N; Wiggett, Alison J; Cross, Emily S

2014-04-01

Cook et al. overstate the evidence supporting their associative account of mirror neurons in humans: most studies do not address a key property, action-specificity that generalizes across the visual and motor domains. Multivariate pattern analysis (MVPA) of neuroimaging data can address this concern, and we illustrate how MVPA can be used to test key predictions of their account.

Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain

PubMed Central

Steel, John; Lowen, Anice C.; Wang, Taia T.; Yondola, Mark; Gao, Qinshan; Haye, Kester; García-Sastre, Adolfo; Palese, Peter

2010-01-01

ABSTRACT Although highly effective in the general population when well matched to circulating influenza virus strains, current influenza vaccines are limited in their utility due to the narrow breadth of protection they provide. The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA). Herein, we describe the construction of a novel immunogen comprising the conserved influenza HA stalk domain and lacking the globular head. Vaccination of mice with this headless HA construct elicited immune sera with broader reactivity than those obtained from mice immunized with a full-length HA. Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge. Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine. PMID:20689752

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

PubMed

Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A; Abrams, John M; Adam, Dieter; Agostinis, Patrizia; Alnemri, Emad S; Altucci, Lucia; Amelio, Ivano; Andrews, David W; Annicchiarico-Petruzzelli, Margherita; Antonov, Alexey V; Arama, Eli; Baehrecke, Eric H; Barlev, Nickolai A; Bazan, Nicolas G; Bernassola, Francesca; Bertrand, Mathieu J M; Bianchi, Katiuscia; Blagosklonny, Mikhail V; Blomgren, Klas; Borner, Christoph; Boya, Patricia; Brenner, Catherine; Campanella, Michelangelo; Candi, Eleonora; Carmona-Gutierrez, Didac; Cecconi, Francesco; Chan, Francis K-M; Chandel, Navdeep S; Cheng, Emily H; Chipuk, Jerry E; Cidlowski, John A; Ciechanover, Aaron; Cohen, Gerald M; Conrad, Marcus; Cubillos-Ruiz, Juan R; Czabotar, Peter E; D'Angiolella, Vincenzo; Dawson, Ted M; Dawson, Valina L; De Laurenzi, Vincenzo; De Maria, Ruggero; Debatin, Klaus-Michael; DeBerardinis, Ralph J; Deshmukh, Mohanish; Di Daniele, Nicola; Di Virgilio, Francesco; Dixit, Vishva M; Dixon, Scott J; Duckett, Colin S; Dynlacht, Brian D; El-Deiry, Wafik S; Elrod, John W; Fimia, Gian Maria; Fulda, Simone; García-Sáez, Ana J; Garg, Abhishek D; Garrido, Carmen; Gavathiotis, Evripidis; Golstein, Pierre; Gottlieb, Eyal; Green, Douglas R; Greene, Lloyd A; Gronemeyer, Hinrich; Gross, Atan; Hajnoczky, Gyorgy; Hardwick, J Marie; Harris, Isaac S; Hengartner, Michael O; Hetz, Claudio; Ichijo, Hidenori; Jäättelä, Marja; Joseph, Bertrand; Jost, Philipp J; Juin, Philippe P; Kaiser, William J; Karin, Michael; Kaufmann, Thomas; Kepp, Oliver; Kimchi, Adi; Kitsis, Richard N; Klionsky, Daniel J; Knight, Richard A; Kumar, Sharad; Lee, Sam W; Lemasters, John J; Levine, Beth; Linkermann, Andreas; Lipton, Stuart A; Lockshin, Richard A; López-Otín, Carlos; Lowe, Scott W; Luedde, Tom; Lugli, Enrico; MacFarlane, Marion; Madeo, Frank; Malewicz, Michal; Malorni, Walter; Manic, Gwenola; Marine, Jean-Christophe; Martin, Seamus J; Martinou, Jean-Claude; Medema, Jan Paul; Mehlen, Patrick; Meier, Pascal; Melino, Sonia; Miao, Edward A; Molkentin, Jeffery D; Moll, Ute M; Muñoz-Pinedo, Cristina; Nagata, Shigekazu; Nuñez, Gabriel; Oberst, Andrew; Oren, Moshe; Overholtzer, Michael; Pagano, Michele; Panaretakis, Theocharis; Pasparakis, Manolis; Penninger, Josef M; Pereira, David M; Pervaiz, Shazib; Peter, Marcus E; Piacentini, Mauro; Pinton, Paolo; Prehn, Jochen H M; Puthalakath, Hamsa; Rabinovich, Gabriel A; Rehm, Markus; Rizzuto, Rosario; Rodrigues, Cecilia M P; Rubinsztein, David C; Rudel, Thomas; Ryan, Kevin M; Sayan, Emre; Scorrano, Luca; Shao, Feng; Shi, Yufang; Silke, John; Simon, Hans-Uwe; Sistigu, Antonella; Stockwell, Brent R; Strasser, Andreas; Szabadkai, Gyorgy; Tait, Stephen W G; Tang, Daolin; Tavernarakis, Nektarios; Thorburn, Andrew; Tsujimoto, Yoshihide; Turk, Boris; Vanden Berghe, Tom; Vandenabeele, Peter; Vander Heiden, Matthew G; Villunger, Andreas; Virgin, Herbert W; Vousden, Karen H; Vucic, Domagoj; Wagner, Erwin F; Walczak, Henning; Wallach, David; Wang, Ying; Wells, James A; Wood, Will; Yuan, Junying; Zakeri, Zahra; Zhivotovsky, Boris; Zitvogel, Laurence; Melino, Gerry; Kroemer, Guido

2018-03-01

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Scattering Theory for the Acoustic Wave Equation in an Arbitrary Exterior Domain

DTIC Science & Technology

1976-08-30

65) will be further studied in the follow-up article. REFERENCES 1. C.H. Wilcox, Scattering Theory for the d - Alembert Equation in Exterior Domains...Exterior Domain Naval Research Lab Washington D C 30 Aug 76 254060 NRL Report 8030 Scattering Theory for the Acoustic Wave SEquation in an Arbitrary...STATEMENT (of the .b.Ia te ntere., d in loc k 10. If diferegn from R pr)A. 16 SUPPLEMENTARY NOTES IS KEY WORDS (Co.n.v onl r*eers Od*e ifftoneemy and

Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments

PubMed Central

Miller, Ona K; Potter, Jane A; Vijayakrishnan, Swetha; Bhella, David; Naismith, James H; Elliott, Richard M

2017-01-01

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83–248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence. PMID:28915104

Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments.

PubMed

Barski, Michal; Brennan, Benjamin; Miller, Ona K; Potter, Jane A; Vijayakrishnan, Swetha; Bhella, David; Naismith, James H; Elliott, Richard M; Schwarz-Linek, Ulrich

2017-09-15

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.

Effects of opiate drugs on Fas-associated protein with death domain (FADD) and effector caspases in the rat brain: regulation by the ERK1/2 MAP kinase pathway.

PubMed

García-Fuster, María-Julia; Miralles, Antonio; García-Sevilla, Jesús A

2007-02-01

This study was designed to assess the effects of opiate treatment on the expression of Fas-associated protein with death domain (FADD) in the rat brain. FADD is involved in the transmission of Fas-death signals that have been suggested to contribute to the development of opiate tolerance and addiction. Acute treatments with high doses of sufentanil and morphine (mu-agonists), SNC-80 (delta-agonist), and U50488H (kappa-agonist) induced significant decreases (30-60%) in FADD immunodensity in the cerebral cortex, through specific opioid receptor mechanisms (effects antagonized by naloxone, naltrindole, or nor-binaltorphimine). The cannabinoid CB1 receptor agonist WIN 55,212-2 did not alter FADD content in the brain. Chronic (5 days) morphine (10-100 mg/kg), SNC-80 (10 mg/kg), or U50488H (10 mg/kg) was associated with the induction of tachyphylaxis to the acute effects. In morphine- and SNC-80-tolerant rats, antagonist-precipitated (2 h) or spontaneous withdrawal (24-48 h) induced a new and sustained inhibition of FADD (13-50%). None of these treatments altered the densities of caspases 8/3 (including the active cleaved forms) in the brain. Pretreatment of rats with SL 327 (a selective MEK1/2 inhibitor that blocks ERK activation) fully prevented the reduction of FADD content induced by SNC-80 in the cerebral cortex (43%) and corpus striatum (29%), demonstrating the direct involvement of ERK1/2 signaling in the regulation of FADD by the opiate agonist. The results indicate that mu- and delta-opioid receptors have a prominent role in the modulation of FADD (opposite to that of Fas) shortly after initiating treatment. Opiate drugs (and specifically the delta-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway.

Cell death proteomics database: consolidating proteomics data on cell death.

PubMed

Arntzen, Magnus Ø; Bull, Vibeke H; Thiede, Bernd

2013-05-03

Programmed cell death is a ubiquitous process of utmost importance for the development and maintenance of multicellular organisms. More than 10 different types of programmed cell death forms have been discovered. Several proteomics analyses have been performed to gain insight in proteins involved in the different forms of programmed cell death. To consolidate these studies, we have developed the cell death proteomics (CDP) database, which comprehends data from apoptosis, autophagy, cytotoxic granule-mediated cell death, excitotoxicity, mitotic catastrophe, paraptosis, pyroptosis, and Wallerian degeneration. The CDP database is available as a web-based database to compare protein identifications and quantitative information across different experimental setups. The proteomics data of 73 publications were integrated and unified with protein annotations from UniProt-KB and gene ontology (GO). Currently, more than 6,500 records of more than 3,700 proteins are included in the CDP. Comparing apoptosis and autophagy using overrepresentation analysis of GO terms, the majority of enriched processes were found in both, but also some clear differences were perceived. Furthermore, the analysis revealed differences and similarities of the proteome between autophagosomal and overall autophagy. The CDP database represents a useful tool to consolidate data from proteome analyses of programmed cell death and is available at http://celldeathproteomics.uio.no.

Potentially preventable deaths from the five leading causes of death--United States, 2008-2010.

PubMed

Yoon, Paula W; Bastian, Brigham; Anderson, Robert N; Collins, Janet L; Jaffe, Harold W

2014-05-02

In 2010, the top five causes of death in the United States were 1) diseases of the heart, 2) cancer, 3) chronic lower respiratory diseases, 4) cerebrovascular diseases (stroke), and 5) unintentional injuries. The rates of death from each cause vary greatly across the 50 states and the District of Columbia (2). An understanding of state differences in death rates for the leading causes might help state health officials establish disease prevention goals, priorities, and strategies. States with lower death rates can be used as benchmarks for setting achievable goals and calculating the number of deaths that might be prevented in states with higher rates. To determine the number of premature annual deaths for the five leading causes of death that potentially could be prevented ("potentially preventable deaths"), CDC analyzed National Vital Statistics System mortality data from 2008-2010. The number of annual potentially preventable deaths per state before age 80 years was determined by comparing the number of expected deaths (based on average death rates for the three states with the lowest rates for each cause) with the number of observed deaths. The results of this analysis indicate that, when considered separately, 91,757 deaths from diseases of the heart, 84,443 from cancer, 28,831 from chronic lower respiratory diseases, 16,973 from cerebrovascular diseases (stroke), and 36,836 from unintentional injuries potentially could be prevented each year. In addition, states in the Southeast had the highest number of potentially preventable deaths for each of the five leading causes. The findings provide disease-specific targets that states can use to measure their progress in preventing the leading causes of deaths in their populations.

mlCAF: Multi-Level Cross-Domain Semantic Context Fusioning for Behavior Identification.

PubMed

Razzaq, Muhammad Asif; Villalonga, Claudia; Lee, Sungyoung; Akhtar, Usman; Ali, Maqbool; Kim, Eun-Soo; Khattak, Asad Masood; Seung, Hyonwoo; Hur, Taeho; Bang, Jaehun; Kim, Dohyeong; Ali Khan, Wajahat

2017-10-24

The emerging research on automatic identification of user's contexts from the cross-domain environment in ubiquitous and pervasive computing systems has proved to be successful. Monitoring the diversified user's contexts and behaviors can help in controlling lifestyle associated to chronic diseases using context-aware applications. However, availability of cross-domain heterogeneous contexts provides a challenging opportunity for their fusion to obtain abstract information for further analysis. This work demonstrates extension of our previous work from a single domain (i.e., physical activity) to multiple domains (physical activity, nutrition and clinical) for context-awareness. We propose multi-level Context-aware Framework (mlCAF), which fuses the multi-level cross-domain contexts in order to arbitrate richer behavioral contexts. This work explicitly focuses on key challenges linked to multi-level context modeling, reasoning and fusioning based on the mlCAF open-source ontology. More specifically, it addresses the interpretation of contexts from three different domains, their fusioning conforming to richer contextual information. This paper contributes in terms of ontology evolution with additional domains, context definitions, rules and inclusion of semantic queries. For the framework evaluation, multi-level cross-domain contexts collected from 20 users were used to ascertain abstract contexts, which served as basis for behavior modeling and lifestyle identification. The experimental results indicate a context recognition average accuracy of around 92.65% for the collected cross-domain contexts.

mlCAF: Multi-Level Cross-Domain Semantic Context Fusioning for Behavior Identification

PubMed Central

Villalonga, Claudia; Lee, Sungyoung; Akhtar, Usman; Ali, Maqbool; Kim, Eun-Soo; Khattak, Asad Masood; Seung, Hyonwoo; Hur, Taeho; Kim, Dohyeong; Ali Khan, Wajahat

2017-01-01

The emerging research on automatic identification of user’s contexts from the cross-domain environment in ubiquitous and pervasive computing systems has proved to be successful. Monitoring the diversified user’s contexts and behaviors can help in controlling lifestyle associated to chronic diseases using context-aware applications. However, availability of cross-domain heterogeneous contexts provides a challenging opportunity for their fusion to obtain abstract information for further analysis. This work demonstrates extension of our previous work from a single domain (i.e., physical activity) to multiple domains (physical activity, nutrition and clinical) for context-awareness. We propose multi-level Context-aware Framework (mlCAF), which fuses the multi-level cross-domain contexts in order to arbitrate richer behavioral contexts. This work explicitly focuses on key challenges linked to multi-level context modeling, reasoning and fusioning based on the mlCAF open-source ontology. More specifically, it addresses the interpretation of contexts from three different domains, their fusioning conforming to richer contextual information. This paper contributes in terms of ontology evolution with additional domains, context definitions, rules and inclusion of semantic queries. For the framework evaluation, multi-level cross-domain contexts collected from 20 users were used to ascertain abstract contexts, which served as basis for behavior modeling and lifestyle identification. The experimental results indicate a context recognition average accuracy of around 92.65% for the collected cross-domain contexts. PMID:29064459

Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy

PubMed Central

Guerrero-Beltrán, Carlos Enrique; Mukhopadhyay, Partha; Horváth, Béla; Rajesh, Mohanraj; Tapia, Edilia; García-Torres, Itzhel; Pedraza-Chaverri, José; Pacher, Pál

2011-01-01

Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of the dose-dependent nephrotoxicity. Cell death and inflammation play key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of pro-survival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways (p53, Jun N-terminal kinase (JNK), and p38-α MAPK) and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, TUNEL), associated with attenuation of various pro-survival signaling pathways (e.g. extracellular signal-regulated kinase (ERK) and p38-β MAPK). Cisplatin also markedly enhanced inflammation in the kidneys (promoted NF-κB activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-alpha (TNF-α) levels, and inflammatory cell infiltration). These effects were significantly attenuated by pre-treatment of rodents with SFN. Cisplatin-induced nephropathy is associated with activation of various cell death and pro-inflammatory pathways (p53, JNK, p38-α, TNF-α, and NF-κB) and impairments of key pro-survival signaling mechanisms (ERK and p38-β). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of the chemotherapy. PMID:21684138

Conservation of the Human Integrin-Type Beta-Propeller Domain in Bacteria

PubMed Central

Chouhan, Bhanupratap; Denesyuk, Alexander; Heino, Jyrki; Johnson, Mark S.; Denessiouk, Konstantin

2011-01-01

Integrins are heterodimeric cell-surface receptors with key functions in cell-cell and cell-matrix adhesion. Integrin α and β subunits are present throughout the metazoans, but it is unclear whether the subunits predate the origin of multicellular organisms. Several component domains have been detected in bacteria, one of which, a specific 7-bladed β-propeller domain, is a unique feature of the integrin α subunits. Here, we describe a structure-derived motif, which incorporates key features of each blade from the X-ray structures of human αIIbβ3 and αVβ3, includes elements of the FG-GAP/Cage and Ca2+-binding motifs, and is specific only for the metazoan integrin domains. Separately, we searched for the metazoan integrin type β-propeller domains among all available sequences from bacteria and unicellular eukaryotic organisms, which must incorporate seven repeats, corresponding to the seven blades of the β-propeller domain, and so that the newly found structure-derived motif would exist in every repeat. As the result, among 47 available genomes of unicellular eukaryotes we could not find a single instance of seven repeats with the motif. Several sequences contained three repeats, a predicted transmembrane segment, and a short cytoplasmic motif associated with some integrins, but otherwise differ from the metazoan integrin α subunits. Among the available bacterial sequences, we found five examples containing seven sequential metazoan integrin-specific motifs within the seven repeats. The motifs differ in having one Ca2+-binding site per repeat, whereas metazoan integrins have three or four sites. The bacterial sequences are more conserved in terms of motif conservation and loop length, suggesting that the structure is more regular and compact than those example structures from human integrins. Although the bacterial examples are not full-length integrins, the full-length metazoan-type 7-bladed β-propeller domains are present, and sometimes two tandem

Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain*S⃞

PubMed Central

Bottomley, Matthew J.; Lo Surdo, Paola; Di Giovine, Paolo; Cirillo, Agostino; Scarpelli, Rita; Ferrigno, Federica; Jones, Philip; Neddermann, Petra; De Francesco, Raffaele; Steinkühler, Christian; Gallinari, Paola; Carfí, Andrea

2008-01-01

Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR·HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions. PMID:18614528

The Celebration of Death: Two Folk Tales about DEath. Mini-Module.

ERIC Educational Resources Information Center

African-American Inst., New York, NY. School Services Div.

This module contains two African folk tales about death, two descriptions of African funerals, a lesson plan with 11 questions exploring the finality of and customs surrounding death, and a bibliography of five books which deal with African religious beliefs. The folk tales present concepts of death and immortality of the soul. The descriptions of…

NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR.

PubMed

Mukai, J; Hachiya, T; Shoji-Hoshino, S; Kimura, M T; Nadano, D; Suvanto, P; Hanaoka, T; Li, Y; Irie, S; Greene, L A; Sato, T A

2000-06-09

The low affinity neurotrophin receptor p75NTR can mediate cell survival as well as cell death of neural cells by NGF and other neurotrophins. To elucidate p75NTR-mediated signal transduction, we screened p75NTR-associated proteins by a yeast two-hybrid system. We identified one positive clone and named NADE (p75NTR-associated cell death executor). Mouse NADE has marked homology to the human HGR74 protein. NADE specifically binds to the cell-death domain of p75NTR. Co-expression of NADE and p75NTR induced caspase-2 and caspase-3 activities and the fragmentation of nuclear DNA in 293T cells. However, in the absence of p75NTR, NADE failed to induce apoptosis, suggesting that NADE expression is necessary but insufficient for p75NTR-mediated apoptosis. Furthermore, p75NTR/NADE-induced cell death was dependent on NGF but not BDNF, NT-3, or NT-4/5, and the recruitment of NADE to p75NTR (intracellular domain) was dose-dependent. We obtained similar results from PC12 cells, nnr5 cells, and oligodendrocytes. Taken together, NADE is the first signaling adaptor molecule identified in the involvement of p75NTR-mediated apoptosis induced by NGF, and it may play an important role in the pathogenesis of neurogenetic diseases.

Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor

PubMed Central

2015-01-01

Recent work on WW domain-containing oxidoreductase (WWOX) tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1–WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1–WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology. PMID:25662954

Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor.

PubMed

Farooq, Amjad

2015-03-01

Recent work on WW domain-containing oxidoreductase (WWOX) tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1-WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1-WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology. © 2015 by the Society for Experimental Biology and Medicine.

'Natural' and 'Unnatural' medical deaths and coronial law: A UK and international review of the medical literature on natural and unnatural death and how it applies to medical death certification and reporting deaths to coroners: Natural/Unnatural death: A Scientific Review.

PubMed

Harris, Andrew

2017-07-01

In the United Kingdom, when people die, either a doctor writes an acceptable natural cause of death medical certificate, or a coroner (fiscal in Scotland) investigates the case, usually with an autopsy. An inquest may or may not follow. The concept of 'natural or unnatural cause' death is not internationally standardized. This article reviews scientific evidence as to what is a natural death or unnatural death and how that relates to the international classification of deaths. Whilst there is some consensus on the definition, its application in considering whether to report to the coroner is more difficult. Depictions of deaths in terminal care, medical emergencies and post-operative care highlight these difficulties. It secondly reviews to what extent natural and unnatural are criteria for notification of deaths in England and Wales and internationally. It concludes with consideration of how medical concepts of unnatural death relate in England and Wales to coroners' legal concepts of what is unnatural. Deaths that appear natural to clinicians and pathologists may be legally unnatural and vice versa. It is argued that the natural/unnatural dichotomy is not a good criterion for reporting deaths under medical care to coroners, but the notification of a medical cause of death, using the International Classification of Disease Codes and the medical professional view as to whether it is scientifically natural, is of great value to the coroner in deciding whether it is legally unnatural.

Bubbling cell death: A hot air balloon released from the nucleus in the cold

PubMed Central

2016-01-01

Cell death emanating from the nucleus is largely unknown. In our recent study, we determined that when temperature is lowered in the surrounding environment, apoptosis stops and bubbling cell death (BCD) occurs. The study concerns the severity of frostbite. When exposed to severe cold and strong ultraviolet (UV) irradiation, people may suffer serious damages to the skin and internal organs. This ultimately leads to limb amputations, organ failure, and death. BCD is defined as “formation of a single bubble from the nucleus per cell and release of this swelling bubble from the cell surface to extracellular space that causes cell death.” When cells are subjected to UV irradiation and/or brief cold shock (4℃ for 5 min) and then incubated at room temperature or 4℃ for time-lapse microscopy, each cell releases an enlarging nuclear gas bubble containing nitric oxide. Certain cells may simultaneously eject hundreds or thousands of exosome-like particles. Unlike apoptosis, no phosphatidylserine flip-over, mitochondrial apoptosis, damage to Golgi complex, and chromosomal DNA fragmentation are shown in BCD. When the temperature is increased back at 37℃, bubble formation stops and apoptosis restarts. Mechanistically, proapoptotic WW domain-containing oxidoreductase and p53 block the protective TNF receptor adaptor factor 2 that allows nitric oxide synthase 2 to synthesize nitric oxide and bubble formation. In this mini-review, updated knowledge in cell death and the proposed molecular mechanism for BCD are provided. PMID:27075929

An EarthCube Roadmap for Cross-Domain Interoperability in the Geosciences: Governance Aspects

NASA Astrophysics Data System (ADS)

Zaslavsky, I.; Couch, A.; Richard, S. M.; Valentine, D. W.; Stocks, K.; Murphy, P.; Lehnert, K. A.

2012-12-01

The goal of cross-domain interoperability is to enable reuse of data and models outside the original context in which these data and models are collected and used and to facilitate analysis and modeling of physical processes that are not confined to disciplinary or jurisdictional boundaries. A new research initiative of the U.S. National Science Foundation, called EarthCube, is developing a roadmap to address challenges of interoperability in the earth sciences and create a blueprint for community-guided cyberinfrastructure accessible to a broad range of geoscience researchers and students. Infrastructure readiness for cross-domain interoperability encompasses the capabilities that need to be in place for such secondary or derivative-use of information to be both scientifically sound and technically feasible. In this initial assessment we consider the following four basic infrastructure components that need to be present to enable cross-domain interoperability in the geosciences: metadata catalogs (at the appropriate community defined granularity) that provide standard discovery services over datasets, data access services, models and other resources of the domain; vocabularies that support unambiguous interpretation of domain resources and metadata; services used to access data repositories and other resources including models, visualizations and workflows; and formal information models that define structure and semantics of the information returned on service requests. General standards for these components have been proposed; they form the backbone of large scale integration activities in the geosciences. By utilizing these standards, EarthCube research designs can take advantage of data discovery across disciplines using the commonality in key data characteristics related to shared models of spatial features, time measurements, and observations. Data can be discovered via federated catalogs and linked nomenclatures from neighboring domains, while standard data

Surveillance for Violent Deaths - National Violent Death Reporting System, 17 States, 2013.

PubMed

Lyons, Bridget H; Fowler, Katherine A; Jack, Shane P D; Betz, Carter J; Blair, Janet M

2016-08-19

In 2013, more than 57,000 persons died in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 17 U.S. states for 2013. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2013. NVDRS collects data from participating states regarding violent deaths obtained from death certificates, coroner/medical examiner reports, law enforcement reports, and secondary sources (e.g., child fatality review team data, supplemental homicide reports, hospital data, and crime laboratory data). This report includes data from 17 states that collected statewide data for 2013 (Alaska, Colorado, Georgia, Kentucky, Maryland, Massachusetts, North Carolina, New Jersey, New Mexico, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, and Wisconsin). NVDRS collates documents for each death and links deaths that are related (e.g., multiple homicides, a homicide followed by a suicide, or multiple suicides) from a single incident. For 2013, a total of 18,765 fatal incidents involving 19,251 deaths were captured by NVDRS in the 17 states included in this report. The majority (66.2%) of deaths were suicides, followed by homicides (23.2%), deaths of undetermined intent (8.8%), deaths involving legal intervention (1.2%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force, excluding legal executions), and unintentional firearm deaths (<1%). (The term legal intervention is a classification incorporated into the International Classification of Diseases, Tenth Revision [ICD-10] and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.) Suicides occurred at higher rates among males, non-Hispanic whites, American Indian/Alaska Natives, persons aged 45

Between life and death: women's experiences of coming close to death, and surviving a severe postpartum haemorrhage and emergency hysterectomy.

PubMed

Elmir, Rakime; Schmied, Virginia; Jackson, Debra; Wilkes, Lesley

2012-04-01

to describe women's experiences of having an emergency hysterectomy following a severe postpartum haemorrhage. a qualitative research approach was used to guide this study. Data were collected through semi-structured, tape recorded face to face, email internet and telephone interviews. three States in Australia: New South Wales, Victoria and Western Australia. twenty-one Australian women who experienced a severe post partum followed by an emergency hysterectomy participated in the study. The median age of participants at time of interview was 42 years and the median time since having the hysterectomy was four years. a process of inductive analysis revealed the major theme, 'between life and death' and three sub-themes, 'being close to death: bleeding and fear', 'having a hysterectomy: devastation and realisation' and 'reliving the trauma: flashbacks and memories'. formulating a plan of care for women identifiably at risk of PPH and ensuring appropriate follow-up counselling is made, is key to help reduce the emotional and psychological symptoms experienced by these women in the aftermath of severe postpartum haemorrhage and hysterectomy. Copyright © 2011 Elsevier Ltd. All rights reserved.

Death and consciousness--an overview of the mental and cognitive experience of death.

PubMed

Parnia, Sam

2014-11-01

Advances in resuscitation science have indicated that, contrary to perception, death by cardiorespiratory criteria can no longer be considered a specific moment but rather a potentially reversible process that occurs after any severe illness or accident causes the heart, lungs, and brain to stop functioning. The resultant loss of vital signs of life (and life processes) is used to declare a specific time of death by physicians globally. When medical attempts are made to reverse this process, it is commonly referred to as cardiac arrest; however, when these attempts do not succeed or when attempts are not made, it is called death by cardiorespiratory criteria. Thus, biologically speaking, cardiac arrest and death by cardiorespiratory criteria are synonymous. While resuscitation science has provided novel opportunities to reverse death by cardiorespiratory criteria and treat the potentially devastating consequences of the resultant postresuscitation syndrome, it has also inadvertently provided intriguing insights into the likely mental and cognitive experience of death. Recollections reported by millions of people in relation to death, so-called out-of-body experiences (OBEs) or near-death experiences (NDEs), are often-discussed phenomena that are frequently considered hallucinatory or illusory in nature; however, objective studies on these experiences are limited. To date, many consistent themes corresponding to the likely experience of death have emerged, and studies have indicated that the scientifically imprecise terms of NDE and OBE may not be sufficient to describe the actual experience of death. While much remains to be discovered, the recalled experience surrounding death merits a genuine scientific investigation without prejudice. © 2014 New York Academy of Sciences.

The AvrM Effector from Flax Rust Has a Structured C-Terminal Domain and Interacts Directly with the M Resistance Protein

PubMed Central

Catanzariti, Ann-Maree; Dodds, Peter N.; Ve, Thomas; Kobe, Bostjan; Ellis, Jeffrey G.; Staskawicz, Brian J.

2011-01-01

In plant immunity, recognition of pathogen effectors by plant resistance proteins leads to the activation of plant defenses and a localized cell death response. The AvrM effector from flax rust is a small secreted protein that is recognized by the M resistance protein in flax. Here, we investigate the mechanism of M–AvrM recognition and show that these two proteins directly interact in a yeast two-hybrid assay, and that this interaction correlates with the recognition specificity observed for each of the different AvrM variants. We further characterize this interaction by demonstrating that the C-terminal domain of AvrM is required for M-dependent cell death, and show that this domain also interacts with the M protein in yeast. We investigate the role of C-terminal differences among the different AvrM proteins for their involvement in this interaction and establish that M recognition is hindered by an additional 34 amino acids present at the C terminus of several AvrM variants. Structural characterization of recombinant AvrM-A protein revealed a globular C-terminal domain that dimerizes. PMID:19958138

[From dualism to multiplicity: seeing BCL-2 family proteins and cell death with new eyes].

PubMed

Aouacheria, Abdel

2015-01-01

The concept of cell death has many links to the concept of death itself, defined as the opposite of life. Achievements obtained through research on apoptosis have apparently allowed us to transcend this Manichean view. Death is no longer outside, but rather inside living systems, as a constitutive force at work within the living matter. Whereas the death of cells can be positive and breed "creation" (e.g. during morphogenesis), its dysregulation can also cause or contribute to fatal diseases including cancer. It is tempting to apply this biological discourse to illuminate the relations between life and death, taken in general terms, but does this generalization actually hold? Is this discourse not essentially a metaphor? If cell death is considered as a vital aspect of various biological processes, then are we not faced with some vitalistic conception of death? Are there one or more meanings to the word "death"? Does the power to self-destruct act in opposition to other key features of living entities, or rather in juxtaposition to them? In this article, we first describe how the field of cell death has been developed on the basis of perceived and built dichotomies, mirroring the original opposition between life and death. We detail the limitations of the current paradigm of apoptosis regulation by BCL-2 family proteins, which nicely illustrate the problem of binary thinking in biology. Last, we try to show a way out of this dualistic matrix, by drawing on the notions of multiplicity, complexity, diversity, evolution and contingency. © Société de Biologie, 2016.

Five keys to real transformation in health care.

PubMed

Senzon, Simon A

2011-11-01

Transformation in health care requires a deeply holistic approach. Natural leaders of such a transformation are the complementary and alternative medicine practitioners who already share a vision of wellness, prevention, and optimal human function. Central to this shared vision is lifestyle change for patients and practitioners. Yet, to change a lifestyle is to change a self. Assisting individuals to transform their very sense of self in order to live healthier, more fulfilling lives centered on flourishing requires several important keys. Visionary and unified leaders are the first key. Structural support through coordination of health clinics locally and nationally is the second key. This can be optimized by utilizing initiatives of the new Affordable Health Care Act, because it provides a potential impetus for deep structural changes. An expanded evidence base for multifactorial approaches to wellness lifestyles is the third key. A reorganizational orientation with an emphasis on the right timing of transformation is the fourth key. The fifth key is an Integral map, which brings together the personal, behavioral, cultural, and social domains. By utilizing such a map, one ensures that no aspect of the transformative revolution at hand slips away due to any misplaced focus, such as emphasizing only on the things we can see with our eyes. By embracing the essence of transformation in terms of a wholeness to all reality, an evolutionary unifying field with interior depth and exterior expression, health care is redefined more authentically. © Mary Ann Liebert, Inc.

Children's Experience with Death.

ERIC Educational Resources Information Center

Zeligs, Rose

Children's concepts of death grow with their age and development The three-year-old begins to notice that living things move and make sounds. The five-year-old thinks that life and death are reversable, but the six-year-old knows that death is final and brings sorrow. Children from eight through ten are interested in the causes of death and what…

AIDA: ab initio domain assembly for automated multi-domain protein structure prediction and domain–domain interaction prediction

PubMed Central

Xu, Dong; Jaroszewski, Lukasz; Li, Zhanwen; Godzik, Adam

2015-01-01

Motivation: Most proteins consist of multiple domains, independent structural and evolutionary units that are often reshuffled in genomic rearrangements to form new protein architectures. Template-based modeling methods can often detect homologous templates for individual domains, but templates that could be used to model the entire query protein are often not available. Results: We have developed a fast docking algorithm ab initio domain assembly (AIDA) for assembling multi-domain protein structures, guided by the ab initio folding potential. This approach can be extended to discontinuous domains (i.e. domains with ‘inserted’ domains). When tested on experimentally solved structures of multi-domain proteins, the relative domain positions were accurately found among top 5000 models in 86% of cases. AIDA server can use domain assignments provided by the user or predict them from the provided sequence. The latter approach is particularly useful for automated protein structure prediction servers. The blind test consisting of 95 CASP10 targets shows that domain boundaries could be successfully determined for 97% of targets. Availability and implementation: The AIDA package as well as the benchmark sets used here are available for download at http://ffas.burnham.org/AIDA/. Contact: adam@sanfordburnham.org Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25701568

Deaths from international terrorism compared with road crash deaths in OECD countries

PubMed Central

Wilson, N; Thomson, G

2005-01-01

Methods: Data on deaths from international terrorism (US State Department database) were collated (1994–2003) and compared to the road injury deaths (year 2000 and 2001 data) from the OECD International Road Transport Accident Database. Results: In the 29 OECD countries for which comparable data were available, the annual average death rate from road injury was approximately 390 times that from international terrorism. The ratio of annual road to international terrorism deaths (averaged over 10 years) was lowest for the United States at 142 times. In 2001, road crash deaths in the US were equal to those from a September 11 attack every 26 days. Conclusions: There is a large difference in the magnitude of these two causes of deaths from injury. Policy makers need to be aware of this when allocating resources to preventing these two avoidable causes of mortality. PMID:16326764

Chronic disease management in children based on the five domains of health.

PubMed

So, Wing Lung Alvin

2013-01-01

Through a case study of a child with cystic fibrosis, the interactions among various domains of health have been discussed-namely, biomedical, physical, psychological/behavioural, and social. In pediatrics, development is another key domain relevant to the management of a chronic disease. An individualised management plan for this case has been outlined, and consideration of this framework may be worthwhile when managing other paediatric patients with chronic disease. Patient empowerment and parental education, as well as good co-ordination of health service delivery, are imperative to holistic patient care.

Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands

PubMed Central

Das, Payel; King, Jonathan A.; Zhou, Ruhong

2011-01-01

The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain–domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135–164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases. PMID:21670251

Sudden unexpected death in infancy: place and time of death.

PubMed

Glasgow, J F T; Thompson, A J; Ingram, P J

2006-01-01

In recent years, many babies who die of Sudden Unexpected Death in Infancy (SUDI) in Northern Ireland are found dead in bed--i.e. co-sleeping--with an adult. In order to assess its frequency autopsy reports between April 1996 and August 2001 were reviewed and linked to temporal factors. The day and month of death, and the place where the baby was found were compared to a reference population of infant deaths between one week of age and the second birthday. Although the rate of SUDI was lower than the UK average, 43 cases of SUDI were identified, and two additional deaths with virtually identical autopsy findings that were attributed to asphyxia caused by suffocation due to overlaying. Thirty-two of the 45 (71%) were less than four months of age. In 30 of the 45 cases (67%) the history stated that the baby was bed sharing with others; 19 died sleeping in an adult bed, and 11 on a sofa or armchair. In 16 of the 30 (53%) there were at least two other people sharing the sleeping surface, and in one case, three. SUDI was twice as frequent at weekends (found dead Saturday-Monday mornings) compared to weekdays (p<0.02), and significantly more common compared to reference deaths (p<0.002). Co-sleeping deaths were also more frequent at weekends. Almost half of all SUDI (49%) occurred in the summer months--more than twice the frequency of reference deaths. While sharing a place of sleep per se may not increase the risk of death, our findings may be linked to factors such as habitual smoking, consumption of alcohol or illicit drugs as reported in case-control studies. In advising parents on safer childcare practices, health professionals must be knowledgeable of current research and when, for example, giving advice on co-sleeping this needs to be person-specific cognisant of the risks within a household. New and better means of targeting such information needs to be researched if those with higher risk life-styles are to be positively influenced.

Inferring Domain-Domain Interactions from Protein-Protein Interactions with Formal Concept Analysis

PubMed Central

Khor, Susan

2014-01-01

Identifying reliable domain-domain interactions will increase our ability to predict novel protein-protein interactions, to unravel interactions in protein complexes, and thus gain more information about the function and behavior of genes. One of the challenges of identifying reliable domain-domain interactions is domain promiscuity. Promiscuous domains are domains that can occur in many domain architectures and are therefore found in many proteins. This becomes a problem for a method where the score of a domain-pair is the ratio between observed and expected frequencies because the protein-protein interaction network is sparse. As such, many protein-pairs will be non-interacting and domain-pairs with promiscuous domains will be penalized. This domain promiscuity challenge to the problem of inferring reliable domain-domain interactions from protein-protein interactions has been recognized, and a number of work-arounds have been proposed. This paper reports on an application of Formal Concept Analysis to this problem. It is found that the relationship between formal concepts provides a natural way for rare domains to elevate the rank of promiscuous domain-pairs and enrich highly ranked domain-pairs with reliable domain-domain interactions. This piggybacking of promiscuous domain-pairs onto less promiscuous domain-pairs is possible only with concept lattices whose attribute-labels are not reduced and is enhanced by the presence of proteins that comprise both promiscuous and rare domains. PMID:24586450

Brain Death and Islam

PubMed Central

Ziad-Miller, Amna; Elamin, Elamin M.

2014-01-01

How one defines death may vary. It is important for clinicians to recognize those aspects of a patient’s religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only. PMID:25287999

Crystal Structure of the Neuropilin-1 MAM Domain: Completing the Neuropilin-1 Ectodomain Picture.

PubMed

Yelland, Tamas; Djordjevic, Snezana

2016-11-01

Neuropilins (NRPs) are single-pass transmembrane receptors involved in several signaling pathways that regulate key physiological processes such as vascular morphogenesis and axon guidance. The MAM domain of NRP, which has previously been implicated in receptor multimerization, was the only portion of the ectopic domain of the NRPs for which the structure, until now, has been elusive. Using site-directed mutagenesis in the linker region preceding the MAM domain we generated a protein construct amenable to crystallization. Here we present the crystal structure of the MAM domain of human NRP1 at 2.24 Å resolution. The protein exhibits a jellyroll topology, with Ca 2+ ions bound at the inter-strand space enhancing the thermostability of the domain. We show that the MAM domain of NRP1 is monomeric in solution and insufficient to drive receptor dimerization, which leads us to propose a different role for this domain in the context of NRP membrane assembly and signaling. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A single WAP domain (SWD)-containing protein with antiviral activity from Pacific white shrimp Litopenaeus vannamei.

PubMed

Yang, Linwei; Niu, Shengwen; Gao, Jiefeng; Zuo, Hongliang; Yuan, Jia; Weng, Shaoping; He, Jianguo; Xu, Xiaopeng

2018-02-01

The single whey acidic protein (WAP) domain (SWD)-containing proteins, also called type III crustins, are a group of antimicrobial peptides (AMPs) in crustaceans. At present, a number of SWDs have been identified in shrimp, which showed essential antibacterial activities. However, the roles of SWDs in antiviral immune responses have not been reported up to now. In this study, a novel SWD (LvSWD3) was identified from Pacific white shrimp, Litopenaeus vannamei, which contained a typical single WAP domain homologous to those of other crustacean SWDs. Although lacking the pro and arg-rich region between the signal peptide and the WAP domain, LvSWD3 was closely clustered with other shrimp SWDs in the phylogenetic tree. Similar to many shrimp SWDs, the highest expression of LvSWD3 was detected in hemocytes. The LvSWD3 expression exhibited only limited changes after challenges with Vibrio parahaemolyticus, Poly (I:C) and lipopolysaccharide, but was significantly up-regulated after white spot syndrome virus (WSSV) infection. Silencing of LvSWDs significantly accelerated the death of the WSSV-infected but not the V. parahaemolyticus-infected shrimp. The recombinant LvSWD3 protein did not show proteinase inhibitory and antibacterial activities but could significantly postpone the death of WSSV-infected shrimp and reduce the viral load in tissues. These suggested that LvSWD3 was a novel SWD with antiviral activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Unintentional asphyxia, SIDS, and medically explained deaths: a descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy.

PubMed

Garstang, Joanna; Ellis, Catherine; Griffiths, Frances; Sidebotham, Peter

2016-12-01

A comprehensive child death review (CDR) program was introduced in England and Wales in 2008, but as yet data have only been analyzed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for sudden unexpected death in infancy (SUDI) as determined by the new CDR program. This was a descriptive outcome study using data from child death overview panel Form C for SUDI cases dying during 2010-2012 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. Data were obtained for 65/70 (93 %) SUDI cases. 20/65 (31 %) deaths were initially categorized as due to medical causes; 21/65 (32 %) as SIDS; and 24/65 (37 %) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as "undetermined" had significantly higher total family and environmental risk factor scores (mean 2.6, 95 % CI 2.0-3.3) compared to those classified as SIDS (mean 1.6, 95 % CI 1.2-1.9), or medical causes for death (mean 1.1, 95 % CI 0.8-1.3). 9/20 (47 %) of medical deaths, 19/21 (90 %) SIDS, and 23/24 (96 %) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25 %) of medically explained deaths. The CDR program results in detailed information about risk factors for SUDI cases but failed to recognize deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as "undetermined deaths" is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in

Achieving accountability through maternal death reviews in Nigeria: a process analysis.

PubMed

de Kok, Bregje; Imamura, M; Kanguru, L; Owolabi, O; Okonofua, F; Hussein, J

2017-10-01

Maternal death reviews (MDRs) are part of the drive to increase accountability for maternal deaths and reduce their occurrence by identifying barriers to effective, quality care. However, conducting MDRs well is difficult; staff commitment and establishing a blame free environment are key challenges. By examining the communication strategies used in MDRs this study sought to understand how MDR members implement policy imperatives (e.g. 'no blame, no name') and manage the inevitable sensitivities of discussing a client's death in a multidisciplinary team. We observed and recorded four MDRs in Nigerian teaching hospitals and used conversation and discourse analysis to identify patterns in verbal and non-verbal interactions. MDRs were conducted in a structured way and had multidisciplinary representation. We grouped discursive strategies observed into three overlapping clusters: 'doing' no-name no-blame; fostering participation; and managing personal accountability. Within these clusters, explicit reminders, gentle enquiries and instilling a sense of togetherness were used in doing no-name, no-blame. Strategies such as questioning and invoking protocol were only partially successful in fostering participation. Regarding managing accountability, forms of communication which limit personal responsibility ('pass the buck') and resist passing the buck were observed. Detailed, lengthy eye witness accounts of dramatic events appeared to reduce staff's personal accountability. We conclude that interactional processes affect the meaningfulness of MDRs. In-depth, critical analysis depends on resisting 'passing the buck' by practitioners and chairs especially, who are also key to fostering participation and extracting value from multidisciplinary representation. Our innovative methods provide detailed insights into MDRs as an interactional process, which can inform design of training aimed at enhancing MDR members' skills. However, given the multitude of systemic challenges we

Procedures in child deaths in The Netherlands: a comparison with child death review.

PubMed

Gijzen, Sandra; Petter, Jessica; L'Hoir, Monique P; Boere-Boonekamp, Magda M; Need, Ariana

2017-01-01

Child Death Review (CDR) is a method in which every child death is systematically and multidisciplinary examined to (1) improve death statistics, (2) identify factors that give direction for prevention, (3) translate the results into possible interventions, and (4) support families. The aim of this study was to determine to what extent procedures of organizations involved in the (health) care for children in The Netherlands cover these four objectives of CDR. Organizations in the Eastern part of The Netherlands and Dutch umbrella organizations involved in child (health) care were asked to provide their protocols, guidelines or other working agreements that describe their activities and responsibilities in case of a child's death. Eighteen documents and nine interview reports were made available. For the analyses we used scorecards for each CDR objective. The procedures of Perined, the National Cot Death Study Group, Dutch Cot Death Foundation and Child Protection Service cover the largest part of the objectives of CDR. Organizations pay most attention to the translation of results into possible interventions. Family support gets the least attention in protocols, guidelines and other working agreements. Dutch organizations separately cover parts of CDR. When the procedures of organizations are combined, all CDR objectives are covered in the response to only specific groups of child deaths, i.e., perinatal deaths, Sudden Unexpected Deaths in Infants and fatal child abuse cases. Further research into the conditions that are needed for an optimal implementation of CDR in The Netherlands is necessary. This research should also evaluate the recently implemented NODOK procedure (Further Examination of the Causes of death in Children), directed to investigate unexplained deaths in minors 0-18 years old.

Structure of Radical-Induced Cell Death1 Hub Domain Reveals a Common αα-Scaffold for Disorder in Transcriptional Networks.

PubMed

Bugge, Katrine; Staby, Lasse; Kemplen, Katherine R; O'Shea, Charlotte; Bendsen, Sidsel K; Jensen, Mikael K; Olsen, Johan G; Skriver, Karen; Kragelund, Birthe B

2018-05-01

Communication within cells relies on a few protein nodes called hubs, which organize vast interactomes with many partners. Frequently, hub proteins are intrinsically disordered conferring multi-specificity and dynamic communication. Conversely, folded hub proteins may organize networks using disordered partners. In this work, the structure of the RST domain, a unique folded hub, is solved by nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, and its complex with a region of the transcription factor DREB2A is provided through data-driven HADDOCK modeling and mutagenesis analysis. The RST fold is unique, but similar structures are identified in the PAH (paired amphipathic helix), TAFH (TATA-box-associated factor homology), and NCBD (nuclear coactivator binding domain) domains. We designate them as a group the αα hubs, as they share an αα-hairpin super-secondary motif, which serves as an organizing platform for malleable helices of varying topology. This allows for partner adaptation, exclusion, and selection. Our findings provide valuable insights into structural features enabling signaling fidelity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Death with dignity

PubMed Central

Allmark, P.

2002-01-01

The purpose of this article is to develop a conception of death with dignity and to examine whether it is vulnerable to the sort of criticisms that have been made of other conceptions. In this conception "death" is taken to apply to the process of dying; "dignity" is taken to be something that attaches to people because of their personal qualities. In particular, someone lives with dignity if they live well (in accordance with reason, as Aristotle would see it). It follows that health care professionals cannot confer on patients either dignity or death with dignity. They can, however, attempt to ensure that the patient dies without indignity. Indignities are affronts to human dignity, and include such things as serious pain and the exclusion of patients from involvement in decisions about their lives and deaths. This fairly modest conception of death with dignity avoids the traps of being overly subjective or of viewing the sick and helpless as "undignified". PMID:12161582

Potentially Preventable Deaths Among the Five Leading Causes of Death - United States, 2010 and 2014.

PubMed

García, Macarena C; Bastian, Brigham; Rossen, Lauren M; Anderson, Robert; Miniño, Arialdi; Yoon, Paula W; Faul, Mark; Massetti, Greta; Thomas, Cheryll C; Hong, Yuling; Iademarco, Michael F

2016-11-18

Death rates by specific causes vary across the 50 states and the District of Columbia.* Information on differences in rates for the leading causes of death among states might help state health officials determine prevention goals, priorities, and strategies. CDC analyzed National Vital Statistics System data to provide national and state-specific estimates of potentially preventable deaths among the five leading causes of death in 2014 and compared these estimates with estimates previously published for 2010. Compared with 2010, the estimated number of potentially preventable deaths changed (supplemental material at https://stacks.cdc.gov/view/cdc/42472); cancer deaths decreased 25% (from 84,443 to 63,209), stroke deaths decreased 11% (from 16,973 to 15,175), heart disease deaths decreased 4% (from 91,757 to 87,950), chronic lower respiratory disease (CLRD) (e.g., asthma, bronchitis, and emphysema) deaths increased 1% (from 28,831 to 29,232), and deaths from unintentional injuries increased 23% (from 36,836 to 45,331). A better understanding of progress made in reducing potentially preventable deaths in the United States might inform state and regional efforts targeting the prevention of premature deaths from the five leading causes in the United States.

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

NASA Astrophysics Data System (ADS)

Zhang, Xianjun; Zhao, Fei; Wu, Yiran; Yang, Jun; Han, Gye Won; Zhao, Suwen; Ishchenko, Andrii; Ye, Lintao; Lin, Xi; Ding, Kang; Dharmarajan, Venkatasubramanian; Griffin, Patrick R.; Gati, Cornelius; Nelson, Garrett; Hunter, Mark S.; Hanson, Michael A.; Cherezov, Vadim; Stevens, Raymond C.; Tan, Wenfu; Tao, Houchao; Xu, Fei

2017-05-01

The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.