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11.
ALS/FTD‐associated FUS activates GSK‐3β to disrupt the VAPB–PTPIP51 interaction and ER–mitochondria associations
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Patricia Gomez‐Suaga Jacqueline C Mitchell Dawn HW Lau Emma H Gray Rosa M Sancho Gema Vizcay‐Barrena Kurt J De Vos Christopher E Shaw Diane P Hanger Wendy Noble Christopher CJ Miller 《EMBO reports》2016,17(9):1326-1342
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD. 相似文献
12.
Herbert W. Hethcote 《Bulletin of mathematical biology》1973,35(5-6):607-614
The effects of a periodic contact rate and of carriers are considered for a generalization of Bailey's simple epidemic model.
In this model it is assumed that individuals become susceptible again as soon as they recover from the infection so that a
fixed population can be divided into a class of infectives and a class of susceptibles which vary with time. If the contact
rate is periodic, then the number of infectives as time approaches infinity either tends to zero or is asymptotically periodic
depending on whether the total population size is less than or greater than a threshold value. The behavior for large time
of the number of infectives is determined for three modifications of the model which involve carriers. 相似文献
13.
14.
Hethcote HW 《Mathematical biosciences》1999,158(1):47-73
An expanded pertussis (whooping cough) vaccination program which includes adult boosters every 10 yr is studied using computer simulations of two models. These age-structured pertussis transmission models include waning of both infection-acquired and vaccine-induced immunity, and vaccination of children corresponding to the vaccination coverage since 1940. Adult vaccinations cause a larger boost in the immunity level in the second model than in the first model. In the simulations the addition of adult pertussis booster vaccinations every 10 yr is beneficial in reducing adult incidence, but causes only modest reductions in the incidence in infants and young children. These simulations suggest that a careful cost effectiveness analysis is needed before implementation of an adult pertussis vaccination program. 相似文献
15.
A population dynamics model for a heterogeneous population is used to compare the effectiveness of six prevention methods for gonorrhea involving population screening and contact tracing of selected groups. The population is subdivided according to sex, sexual activity, and symptomatic or asymptomatic infection. For this model contact tracing of certain groups is more effective than general population screening. 相似文献
16.
Supramolecular structures of peptide assemblies in membranes by neutron off-plane scattering: method of analysis 总被引:2,自引:1,他引:1
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In a previous paper (Yang et al., Biophys. J. 75:641-645, 1998), we showed a simple, efficient method of recording the diffraction patterns of supramolecular peptide assemblies in membranes where the samples were prepared in the form of oriented multilayers. Here we develop a method of analysis based on the diffraction theory of two-dimensional liquids. Gramicidin was used as a prototype model because its pore structure in membrane in known. At full hydration, the diffraction patterns of alamethicin and magainin are similar to gramicidin except in the scale of q (the momentum transfer of scattering), clearly indicating that both alamethicin and magainin form pores in membranes but of different sizes. When the hydration of the multilayer samples was decreased while the bilayers were still fluid, the in-plane positions of the membrane pores became correlated from one bilayer to the next. We believe that this is a new manifestation of the hydration force. The effect is most prominent in magainin patterns, which are used to demonstrate the method of analysis. When magainin samples were further dehydrated or cooled, the liquid-like diffraction turned into crystal-like patterns. This discovery points to the possibility of investigating the supramolecular structures with high-order diffraction. 相似文献
17.
In 1997–99 the occurrence ofFusarium spp. on winter wheat and the contamination with mycotoxins was investigated at three locations in the Rhineland, Germany. All cultivation methods investigated had an effect on the level ofFusarium infection, however, rainfall during flowering was the most important factor. The choice of cultivar and soil cultivation proved to be the most promising tools to reduce head scab severity and mycotoxin contamination. 相似文献
18.
Christina Brunke Stefan Lohse Stefanie Derer Matthias Peipp Peter Boross Christian Kellner Thomas Beyer Michael Dechant Louise Royle Li Phing Liew Jeanette HW Leusen Thomas Valerius 《MABS-AUSTIN》2013,5(6):936-945
Antibodies of human IgA isotype are critical components of the mucosal immune system, but little is known about their immunotherapeutic potential. Compared with IgG antibodies, IgA molecules carry a C-terminal tail piece extension of 18 amino acids with a free cysteine at position 471. This cysteine is required for the formation of dimeric IgA antibodies, but may impair molecular characteristics of monomeric IgA antibodies as therapeutic reagents. Thus, we generated and characterized a d471-mutated antibody against the epidermal growth factor receptor (EGFR) and compared it to its respective IgA2 m(1) wild type antibody. Both wild type and mutated IgA antibodies demonstrated similar EGFR binding and were similarly efficient in inhibiting EGF binding and in blocking EGF-mediated cell proliferation. Recruitment of Fc-mediated effector functions like antibody-dependent cell-mediated cytotoxicity by monocytes, macrophages or PMN was similar, but the d471-mutated IgA exhibited different biochemical properties compared with wild type antibody. As expected, mutated IgA did not form stable dimers in the presence of human joining (J)-chain, but we also observed reduced levels of dimeric aggregates in the absence of J-chain. Furthermore, glycoprofiling revealed different glycosylation patterns for both antibodies, including considerably less mannosylation of d471-mutated antibodies. Overall, our results demonstrate that the deletion of the C-terminal cysteine of IgA2 did not affect the investigated effector functions compared with wild type antibody, but it improved biochemical properties of an IgA2 m(1) antibody against EGFR, and may thereby assist in exploring the immunotherapeutic potential of recombinant IgA antibodies. 相似文献
19.
Magdalena Winiarska Kamil Bojarczuk Beata Pyrzynska Jacek Bil Marta Siernicka Michal Dwojak Malgorzata Bobrowicz Nina Miazek Piotr Zapala Agnieszka Zagozdzon Magdalena Krol Aleksandra Syta Paulina Podszywalow-Bartnicka Zofia Pilch Anna Dabrowska-Iwanicka Przemyslaw Juszczynski Dimitar G Efremov Mikolaj Slabicki Thorsten Zenz Aude Le Roy Daniel Olive Tomasz P Rygiel Jeanette HW Leusen Jakub Golab 《MABS-AUSTIN》2014,6(5):1300-1313
20.
María Teruel Carmen P Simeon Jasper Broen Madelon C Vonk Patricia Carreira Maria Teresa Camps Rosa García-Portales Esmeralda Delgado-Frías Maria Gallego Gerard Espinosa the Spanish Scleroderma Group Lorenzo Beretta Paolo Airó Claudio Lunardi Gabriela Riemekasten Torsten Witte Thomas Krieg Alexander Kreuter J?rg HW Distler Nicolas Hunzelmann Bobby P Koeleman Alexandre E Voskuyl Annemie J Schuerwegh Miguel ángel González-Gay Timothy RDJ Radstake Javier Martin 《Arthritis research & therapy》2012,14(3):R154-6