60 research outputs found
Frizzled 7 and PIPâ binding by syntenin PDZâ domain supports Frizzled 7 trafficking and signalling
PDZ domain-containing proteins work as intracellular scaffolds to control spatio-temporal aspects of cell signalling. This function is supported by the ability of their PDZ domains to bind other proteins such as receptors, but also phosphoinositide lipids important for membrane trafficking. Here we report a crystal structure of the syntenin PDZ tandem in complex with the carboxy-terminal fragment of Frizzled 7 and phosphatidylinositol 4,5-bisphosphate (PIPâ). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish co-operative binding of the tripartite complex and identify residues crucial for membrane PIPâ-specific recognition. Experiments with cells support the importance of the synteninâPIPâ interaction for plasma membrane targeting of Frizzled 7 and c-jun phosphorylation. This study contributes to our understanding of the biology of PDZ proteins as key players in membrane compartmentalization and dynamics
Relative contribution of various chronic diseases and multi-morbidity to potential disability among Dutch elderly
BACKGROUND: The amount of time spent living with disease greatly influences elderly peopleâs wellbeing, disability
and healthcare costs, but differs by disease, age and sex.
METHODS: We assessed how various single and combined diseases differentially affect life years spent living with
disease in Dutch elderly men and women (65+) over their remaining life course. Multistate life table calculations
were applied to age and sex-specific disease prevalence, incidence and death rates for the Netherlands in 2007. We
distinguished congestive heart failure, coronary heart disease (CHD), breast and prostate cancer, colon cancer, lung
cancer, diabetes, COPD, stroke, dementia and osteoarthritis.
RESULTS: Across ages 65, 70, 75, 80 and 85, CHD caused the most time spent living with disease for Dutch men
(from 7.6 years at age 65 to 3.7 years at age 85) and osteoarthritis for Dutch women (from 11.7 years at age 65 to 4.
8 years at age 85). Of the various co-occurrences of disease, the combination of diabetes and osteoarthritis led to
the most time spent living with disease, for both men (from 11.2 years at age 65 to 4.9 -years at age 85) and
women (from 14.2 years at age 65 to 6.0 years at age 85).
CONCLUSIONS: Specific single and multi-morbid diseases affect men and women differently at different phases in the
life course in terms of the time spent living with disease, and consequently, their potential disability. Timely sex and
age-specific interventions targeting prevention of the single and combined diseases identified could reduce
healthcare costs and increase wellbeing in elderly people
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as âaccidental cell deathâ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. âRegulated cell deathâ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death
Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview
Public Health and primary carePrevention and community carePrevention, Population and Disease management (PrePoD
The unfolded protein response in immunity and inflammation.
The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6
PDZ domains and their binding partners: structure, specificity, and modification
PDZ domains are abundant protein interaction modules that often recognize short amino acid motifs at the C-termini of target proteins. They regulate multiple biological processes such as transport, ion channel signaling, and other signal transduction systems. This review discusses the structural characterization of PDZ domains and the use of recently emerging technologies such as proteomic arrays and peptide libraries to study the binding properties of PDZ-mediated interactions. Regulatory mechanisms responsible for PDZ-mediated interactions, such as phosphorylation in the PDZ ligands or PDZ domains, are also discussed. A better understanding of PDZ protein-protein interaction networks and regulatory mechanisms will improve our knowledge of many cellular and biological processes
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
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
[18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches
New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling
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