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121.
The classical Hodgkin-Huxley (HH) model neglects the time-dependence of ion concentrations in spiking dynamics. The dynamics is therefore limited to a time scale of milliseconds, which is determined by the membrane capacitance multiplied by the resistance of the ion channels, and by the gating time constants. We study slow dynamics in an extended HH framework that includes time-dependent ion concentrations, pumps, and buffers. Fluxes across the neuronal membrane change intra- and extracellular ion concentrations, whereby the latter can also change through contact to reservoirs in the surroundings. Ion gain and loss of the system is identified as a bifurcation parameter whose essential importance was not realized in earlier studies. Our systematic study of the bifurcation structure and thus the phase space structure helps to understand activation and inhibition of a new excitability in ion homeostasis which emerges in such extended models. Also modulatory mechanisms that regulate the spiking rate can be explained by bifurcations. The dynamics on three distinct slow times scales is determined by the cell volume-to-surface-area ratio and the membrane permeability (seconds), the buffer time constants (tens of seconds), and the slower backward buffering (minutes to hours). The modulatory dynamics and the newly emerging excitable dynamics corresponds to pathological conditions observed in epileptiform burst activity, and spreading depression in migraine aura and stroke, respectively. 相似文献
122.
Nora Wallot-Hieke Neha Verma David Schlütermann Niklas Berleth Jana Deitersen Philip Böhler 《Autophagy》2018,14(5):743-763
Macroautophagy/autophagy is an evolutionarily conserved cellular process whose induction is regulated by the ULK1 protein kinase complex. The subunit ATG13 functions as an adaptor protein by recruiting ULK1, RB1CC1 and ATG101 to a core ULK1 complex. Furthermore, ATG13 directly binds both phospholipids and members of the Atg8 family. The central involvement of ATG13 in complex formation makes it an attractive target for autophagy regulation. Here, we analyzed known interactions of ATG13 with proteins and lipids for their potential modulation of ULK1 complex formation and autophagy induction. Targeting the ATG101-ATG13 interaction showed the strongest autophagy-inhibitory effect, whereas the inhibition of binding to ULK1 or RB1CC1 had only minor effects, emphasizing that mutations interfering with ULK1 complex assembly do not necessarily result in a blockade of autophagy. Furthermore, inhibition of ATG13 binding to phospholipids or Atg8 proteins had only mild effects on autophagy. Generally, the observed phenotypes were more severe when autophagy was induced by MTORC1/2 inhibition compared to amino acid starvation. Collectively, these data establish the interaction between ATG13 and ATG101 as a promising target in disease-settings where the inhibition of autophagy is desired. 相似文献
123.
O. F. Niklas 《BioControl》1956,1(1):100-101
Ohne Zusammenfassung 相似文献
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126.
The LKB1 tumor suppressor kinase in human disease 总被引:1,自引:0,他引:1
Katajisto P Vallenius T Vaahtomeri K Ekman N Udd L Tiainen M Mäkelä TP 《Biochimica et biophysica acta》2007,1775(1):63-75
Inactivating germline mutations in the LKB1 gene underlie Peutz-Jeghers syndrome characterized by hamartomatous polyps and an elevated risk for cancer. Recent studies suggest the involvement of LKB1 also in more common human disorders including diabetes and in a significant fraction of lung adenocarcinomas. These observations have increased the interest towards signaling pathways of this tumor suppressor kinase. The recent breakthroughs in understanding the molecular functions of the LKB1 indicate its contribution as a regulator of cell polarity, energy metabolism and cell proliferation. Here we review how the substrates and cellular functions of LKB1 may be linked to Peutz-Jeghers syndrome and other diseases, and discuss how some of the molecular changes associated with altered LKB1 signaling might be used in therapeutic approaches. 相似文献
127.
E. Iwarsson Monalill Lundqvist José Inzunza Lars Ährlund-Richter Peter Sjöblom Örjan Lundkvist Niklas Simberg Magnus Nordenskjöld Elisabeth Blennow 《Human genetics》1999,104(5):376-382
We have studied the chromosomal content in 68 normally fertilised freeze-thawed human embryos of good morphology from 34
patients with an average maternal age of 32,6 years. Forty embryos showed post-thaw cellular division and twenty-eight post-thaw
cleavage arrest. After spreading of the embryos on microscope slides, analysis of chromosomes X, Y, 15, 16, 17 and 18 was
performed using two rounds of fluorescent in situ hybridisation (FISH). According to the results, the embryos were divided into four groups: (I) normal, all nuclei uniformly
diploid, (II) diploid mosaics, normal diploid blastomeres in combination with abnormal blastomeres, (III) abnormal, all nuclei
abnormal, (IV) chaotic, the chromosome constitution varies randomly from cell to cell. Approximately 25% of the embryos had
normal number of the chromosomes tested, while the majority of the embryos were abnormal. Most of the abnormal embryos were
diploid mosaics (57%). This was true for the embryos showing cleavage division as well as the embryos showing cleavage arrest.
Our data show a slightly higher incidence of abnormal embryos compared to those obtained with FISH in non-cryopreserved embryos
and confirm that the majority of preimplantation embryos fertilised in vitro contain abnormal blastomeres. The results, mechanisms, significance and implications are discussed.
Received: 19 November 1998 / Accepted: 4 March 1999 相似文献
128.
Yadong Sun Niklas Berleth Wenxian Wu David Schlütermann Jana Deitersen Fabian Stuhldreier Lena Berning Annabelle Friedrich Seda Akgün María Jos Mendiburo Sebastian Wesselborg Marcus Conrad Carsten Berndt Bjrn Stork 《Cell death & disease》2021,12(11)
Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.Subject terms: Macroautophagy, Macroautophagy 相似文献
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130.
Seventy-five years ago, the geneticist Richard Goldschmidt hypothesized that single mutations affecting development could
result in major phenotypic changes in a single generation to produce unique organisms within animal populations that he called
“hopeful monsters”. Three decades ago, Sarah P. Gibbs proposed that photosynthetic unicellular micro-organisms like euglenoids
and dinoflagellates are the products of a process now called “secondary endosymbiosis” (i.e., the evolution of a chloroplast
surrounded by three or four membranes resulting from the incorporation of a eukaryotic alga by a eukaryotic heterotrophic
host cell). In this article, we explore the evidence for Goldschmidt’s “hopeful monster” concept and expand the scope of this
theory to include the macroevolutionary emergence of organisms like Euglena and Chlorarachnion from secondary endosymbiotic events. We argue that a Neo-Goldschmidtian perspective leads to the conclusion that cell chimeras
such as euglenids and dinoflagellates, which are important groups of phytoplankton in freshwater and marine ecosystems, should
be interpreted as “successful monsters”. In addition, we argue that Charles Darwin had euglenoids (infusoria) in mind when
he speculated on the “primordial intermediate form”, although his Proto-Euglena-hypothesis for the origin of the last common
ancestor of all forms of life is no longer acceptable. 相似文献