المؤلفون: Hyung Chul Lee, Nidia M. M. Oliveira, Cato Hastings, Peter Baillie-Benson, Adam A. Moverley, Hui-Chun Lu, Yi Zheng, Elise L. Wilby, Timothy T. Weil, Karen M. Page, Jianping Fu, Naomi Moris, Claudio D. Stern

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-13 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract Many amniote vertebrate species including humans can form identical twins from a single embryo, but this only occurs rarely. It has been suggested that the primitive-streak-forming embryonic region emits signals that inhibit streak formation elsewhere but the signals involved, how they are transmitted and how they act has not been elucidated. Here we show that short tracks of calcium firing activity propagate through extraembryonic tissue via gap junctions and prevent ectopic primitive streak formation in chick embryos. Cross-regulation of calcium activity and an inhibitor of primitive streak formation (Bone Morphogenetic Protein, BMP) via NF-κB and NFAT establishes a long-range BMP gradient spanning the embryo. This mechanism explains how embryos of widely different sizes can maintain positional information that determines embryo polarity. We provide evidence for similar mechanisms in two different human embryo models and in Drosophila, suggesting an ancient evolutionary origin.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/9c08b08f731a4b5bbf4643f49d1dc0e7

المؤلفون: Karen M. Page, Jessica J. McCormack, Mafalda Lopes-da-Silva, Francesca Patella, Kimberly Harrison-Lavoie, Jemima J. Burden, Ying-Yi Bernadette Quah, Dominic Scaglioni, Francesco Ferraro, Daniel F. Cutler

المصدر: BMC Biology, Vol 20, Iss 1, Pp 1-16 (2022)

مصطلحات موضوعية: Golgi apparatus, Golgi ribbon, Organelle structure, Weibel-Palade body, Mathematical modeling, Biology (General), QH301-705.5

الوصف: Abstract Background In vertebrate cells, the Golgi functional subunits, mini-stacks, are linked into a tri-dimensional network. How this “ribbon” architecture relates to Golgi functions remains unclear. Are all connections between mini-stacks equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, without a quantifiable readout of the output of ribbon-embedded mini-stacks. Endothelial cells produce secretory granules, the Weibel-Palade bodies (WPB), whose von Willebrand Factor (VWF) cargo is central to hemostasis. The Golgi apparatus controls WPB size at both mini-stack and ribbon levels. Mini-stack dimensions delimit the size of VWF "boluses” whilst the ribbon architecture allows their linear co-packaging, thereby generating WPBs of different lengths. This Golgi/WPB size relationship suits mathematical analysis. Results WPB lengths were quantized as multiples of the bolus size and mathematical modeling simulated the effects of different Golgi ribbon organizations on WPB size, to be compared with the ground truth of experimental data. An initial simple model, with the Golgi as a single long ribbon composed of linearly interlinked mini-stacks, was refined to a collection of mini-ribbons and then to a mixture of mini-stack dimers plus long ribbon segments. Complementing these models with cell culture experiments led to novel findings. Firstly, one-bolus sized WPBs are secreted faster than larger secretory granules. Secondly, microtubule depolymerization unlinks the Golgi into equal proportions of mini-stack monomers and dimers. Kinetics of binding/unbinding of mini-stack monomers underpinning the presence of stable dimers was then simulated. Assuming that stable mini-stack dimers and monomers persist within the ribbon resulted in a final model that predicts a “breathing” arrangement of the Golgi, where monomer and dimer mini-stacks within longer structures undergo continuous linking/unlinking, consistent with experimentally observed WPB size distributions. Conclusions Hypothetical Golgi organizations were validated against a quantifiable secretory output. The best-fitting Golgi model, accounting for stable mini-stack dimers, is consistent with a highly dynamic ribbon structure, capable of rapid rearrangement. Our modeling exercise therefore predicts that at the fine-grained level the Golgi ribbon is more complex than generally thought. Future experiments will confirm whether such a ribbon organization is endothelial-specific or a general feature of vertebrate cells.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1741-7007

URL الوصول: https://doaj.org/article/ea370c24b3234d728be9cf0d1e4f597f

المؤلفون: James O. Meyer, Shehrazade Dahimene, Karen M. Page, Laurent Ferron, Ivan Kadurin, Joseph I.J. Ellaway, Pengxiang Zhao, Tarun Patel, Simon W. Rothwell, Peipeng Lin, Wendy S. Pratt, Annette C. Dolphin

المصدر: Cell Reports, Vol 29, Iss 1, Pp 22-33.e5 (2019)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Summary: Voltage-gated calcium channels are exquisitely Ca2+ selective, conferred primarily by four conserved pore-loop glutamate residues contributing to the selectivity filter. There has been little previous work directly measuring whether the trafficking of calcium channels requires their ability to bind Ca2+ in the selectivity filter or to conduct Ca2+. Here, we examine trafficking of neuronal CaV2.1 and 2.2 channels with mutations in their selectivity filter and find reduced trafficking to the cell surface in cell lines. Furthermore, in hippocampal neurons, there is reduced trafficking to the somatic plasma membrane, into neurites, and to presynaptic terminals. However, the CaV2.2 selectivity filter mutants are still influenced by auxiliary α2δ subunits and, albeit to a reduced extent, by β subunits, indicating the channels are not grossly misfolded. Our results indicate that Ca2+ binding in the pore of CaV2 channels may promote their correct trafficking, in combination with auxiliary subunits. Furthermore, physiological studies utilizing selectivity filter mutant CaV channels should be interpreted with caution. : Meyer et al. examine whether selectivity filtering mutations in CaV2 channels, preventing inward Ba2+ currents, would reduce trafficking. Pore-mutant channels show strongly reduced cell-surface expression in cell lines and neurons, but still require β and α2δ subunits and thus are not grossly misfolded. Keywords: N-type, P/Q-type, calcium channel, selectivity filter, α2δ subunit, β subunit, divalent cation, permeation, trafficking, calcium currents

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2211124719311349; https://doaj.org/toc/2211-1247

URL الوصول: https://doaj.org/article/b96fac46c3774fd5a3d05be757aa82e6

المؤلفون: Shehrazade Dahimene, Karen M. Page, Manuela Nieto-Rostro, Wendy S. Pratt, Marianna D'Arco, Annette C. Dolphin

المصدر: Neurobiology of Disease, Vol 93, Iss , Pp 243-256 (2016)

مصطلحات موضوعية: Episodic ataxia-2, P/Q-type calcium channel, Dominant negative suppression, N-terminus, Misfolded protein, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S0969996116301231; https://doaj.org/toc/1095-953X

URL الوصول: https://doaj.org/article/7f9c96e2028b44edbadf8d67e0de0f2f

المؤلفون: Shehrazade Dahimene, Karen M. Page, Ivan Kadurin, Laurent Ferron, Dominique Y. Ho, Gareth T. Powell, Wendy S. Pratt, Stephen W. Wilson, Annette C. Dolphin

المصدر: Cell Reports, Vol 25, Iss 6, Pp 1610-1621.e5 (2018)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Summary: Voltage-gated calcium channel auxiliary α2δ subunits are important for channel trafficking and function. Here, we compare the effects of α2δ-1 and an α2δ-like protein called Cachd1 on neuronal N-type (CaV2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in CaV1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif and additional Cache domain interactions. Cachd1 has a disrupted MIDAS motif. However, Cachd1 increases CaV2.2 currents substantially (although less than α2δ-1) and increases CaV2.2 cell surface expression by reducing endocytosis. Although the effects of α2δ-1 are abolished by mutation of Asp122 in CaV2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with CaV2.2 and inhibits co-immunoprecipitation of α2δ-1 by CaV2.2. Cachd1 also competes with α2δ-1 for effects on trafficking. Thus, Cachd1 influences both CaV2.2 trafficking and function and can inhibit responses to α2δ-1. : Dahimene et al. examine the role of Cachd1, a protein with similarity to the auxiliary α2δ subunits of voltage-gated calcium channels. They find that Cachd1 increases N-type calcium currents substantially despite having a disrupted VWA interaction domain. Cachd1 also enhances channel trafficking and inhibits responses to α2δ-1. Keywords: voltage-gated calcium channel, Cachd1, cell surface expression, interaction site, cache domain

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2211124718316097; https://doaj.org/toc/2211-1247

URL الوصول: https://doaj.org/article/18afc7732ea249b79a59826d0608911d

المؤلفون: Mika M. Tabata, Luqman Mushila Hodgkinson, Tiffany T. Wu, Shufeng Li, Christine Huard, Shanrong Zhao, Donald Bennett, Jillian Johnson, Cassandra Tierney, Wen He, Janet E. Buhlmann, Karen M. Page, Kristen Johnson, Livia Casciola‐Rosen, Lorinda Chung, Kavita Y. Sarin, David Fiorentino

المصدر: Arthritis & Rheumatology.

مصطلحات موضوعية: Rheumatology, Immunology, Immunology and Allergy

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::faed84299c450afa655a30cde9c0bca2
https://doi.org/10.1002/art.42526

المؤلفون: Karen M. Page, Trevor A. Graham, Ian P.M. Tomlinson, Nick A. Wright, J. Louise Jones, George Elia, Tomas Alarcón, Lisa Willis

الوصف: Late relapse of breast cancer can occur more than 25 years after primary diagnosis. During the intervening years between initial treatment and relapse, occult cancers are maintained in an apparent state of dormancy that is poorly understood. In this study, we applied a probabilistic mathematical model to long-term follow-up studies of postresection patients to investigate the factors involved in mediating breast cancer dormancy. Our results suggest that long-term dormancy is maintained most often by just one growth-restricted dangerous micrometastasis. Analysis of the empirical data by Approximate Bayesian Computation indicated that patients in dormancy have between 1 and 5 micrometastases at 10 years postresection, when they escape growth restriction with a half-life of 0.4 mm in diameter. Before resection, primary tumors seed at most an average of 6 dangerous micrometastases that escape from growth restriction with a half-life of at least 12 years. Our findings suggest that effective preventive treatments will need to eliminate these small numbers of micrometastases, which may be preangiogenic and nonvascularized until they switch to growth due to one oncogenic mutation or tumor suppressor gene inactivation. In summary, breast cancer dormancy seems to be maintained by small numbers of sizeable micrometastases that escape from growth restriction with a half-life exceeding 12 years. Cancer Res; 70(11); 4310–7. ©2010 AACR.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::aa1eaa2bb0c05032da100d3878102f04
https://doi.org/10.1158/0008-5472.c.6500331

المؤلفون: Karen M. Page, Trevor A. Graham, Ian P.M. Tomlinson, Nick A. Wright, J. Louise Jones, George Elia, Tomas Alarcón, Lisa Willis

الوصف: Supplementary Methods, Figures 1-4 from Breast Cancer Dormancy Can Be Maintained by Small Numbers of Micrometastases

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::203fe9dd9ff9025b5f242bef6dd15e13
https://doi.org/10.1158/0008-5472.22382847.v1

المؤلفون: Karen M Page, Vadim M Gumerov, Shehrazade Dahimene, Igor B Zhulin, Annette C Dolphin

المصدر: Channels. 17

مصطلحات موضوعية: Biophysics, Biochemistry

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::2d90eb78cd672309b165b5f4ac95cced
https://doi.org/10.1080/19336950.2023.2167563

المؤلفون: Paul Ibbotson, Cristian Jimenez-Romero, Karen M Page

المصدر: International Society for Behavioral Ecology, Behavioral Ecology. 33(1):190-201

الوصف: It has been proposed that environmental stress acted as a selection pressure on the evolution of human cooperation. Through agent-based evolutionary modelling, mathematical analysis, and human experimental data we illuminate the mechanisms by which the environment influences cooperative success and decision making in a Stag Hunt game. The modelling and mathematical results show that only cooperative foraging phenotypes survive the harshest of environments but pay a penalty for miscoordination in favourable environments. When agents are allowed to coordinate their hunting intentions by communicating, cooperative phenotypes outcompete those who pursue individual strategies in almost all environmental and payoff scenarios examined. Data from human participants show flexible decision-making in face of cooperative uncertainty, favouring high-risk, high-reward strategy when environments are harsher and starvation is imminent. Converging lines of evidence from the three approaches indicate a significant role for environmental variability in human cooperative dynamics and the species-unique cognition designed to support it.

الإتاحة: https://ideas.repec.org/a/oup/beheco/v33y2022i1p190-201..html