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Dynamics of Advantageous Mutant Spread in Spatial Death-Birth and Birth-Death Moran Models

Communications on Applied Mathematics and Computation 2024年第1期6卷 576-604页

作者： Jasmine Foo Einar Bjarki Gunnarsson Kevin Leder David Sivakoff School of Mathematics University of MinnesotaTwin CitiesMN55455USA Department of Industrial and Systems Engineering University of MinnesotaTwin CitiesMN55455USA Departments of Statistics and Mathematics The Ohio State UniversityColumbusOH43210USA

The spread of an advantageous mutation through a population is of fundamental interest in population genetics. While the classical Moran model is formulated for a well-mixed population, it has long been recognized that in real-world applications, the population usually has an explicit spatial structure which can significantly influence the dynamics. In the context of cancer initiation in epithelial tissue, several recent works have analyzed the dynamics of advantageous mutant spread on integer lattices, using the biased voter model from particle systems theory. In this spatial version of the Moran model, individuals first reproduce according to their fitness and then replace a neighboring individual. from a biological standpoint, the opposite dynamics, where individuals first die and are then replaced by a neighboring individual according to its fitness, are equally relevant. Here, we investigate this death-birth analogue of the biased voter model. We construct the process mathematically, derive the associated dual process, establish bounds on the survival probability of a single mutant, and prove that the process has an asymptotic shape. We also briefly discuss alternative birth-death and death-birth dynamics, depending on how the mutant fitness advantage affects the dynamics. We show that birth-death and death-birth formulations of the biased voter model are equivalent when fitness affects the former event of each update of the model, whereas the birth-death model is fundamentally different from the death-birth model when fitness affects the latter event.

关键词： Spatial death-birth models Spatial birth-death models Spatial evolutionary models Spatial cancer models Evolutionary graph theory Stochastic processes Biased voter model Dual process Fixation probability Shape theorem

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MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth

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Journal of Molecular Cell Biology 2018年第3期10卷 195-204页

作者： Rachel Xi-Yeen Ho Rosana D. Meyer Kevin B. Chandler Esma Ersoy Michael Park Philip A. Bondzie Nima Rahimi Huihong Xu Catherine E. Costello Nader Rahimi Department of Pathology School of Medicine Boston University Medical Campus Boston MA 02118 USA Department of Biochemistry and Center for Biomedical Mass Spectrometry School of Medicine Boston University Medical Campus Boston MA 02118 USA

Intrinsically disordered proteins （IDPs）/intrinsicaUy unstructured proteins are characterized by the lack of fixed or stable tertiary structure, and are increasingly recognized as an important class of proteins with major roles in signal transduction and transcriptional regulation. In this study, we report the identification and functional characterization of a previously uncharacterized protein （UPFO258/KIAA1024）, major intrinsically disordered Notch2-associated receptor 1 （MINAR1）. While MINAR1 carries a single transmembrane domain and a short cytoplasmic domain, it has a large extraceUular domain that shares no similarity with known protein sequences. Uncharacteristically, MINAR1 is a highly IDP with nearly 70% of its amino acids sequences unstructured. We demonstrate that MINAR1 physically interacts with Notch2 and its binding to Notch2 increases its stability and function. MINAR1 is widely expressed in various tissues including the epithelial cells of the breast and endothelial cells of blood vessels. MINAR1 plays a negative role in angioganesis as it inhibits angioganesis in cell culture and in mouse matrigal plug and zebraflsh anglo- genesis models. Furthermore, while MINAR1 is highly expressed in the normal human breast, its expression is significantly down- regulated in advanced human breast cancer and its re-expression in breast cancer cells inhibited tumor growth. Our study demonstrates that MINAR1 is an IDP that negatively regulates angioganesis and growth of breast cancer cells.

关键词： intrinsically disordered proteins Notch2 angiogenesis breast cancer MINAR1

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Lineage plasticity-mediated therapy resistance in prostate cancer

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Asian Journal of Andrology 2019年第3期21卷 241-248页

作者： Alexandra M Blee Haojie Huang Department of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN 55905 USA Biochemistry and Molecular Biology Graduate Program Mayo Clinic Graduate School of Biomedical Sciences Rochester MN 55905 USA Department of Urology Mayo Clinic College of Medicine Rochester MN 55905 USA Mayo Clinic Cancer Center Mayo Clinic College of Medicine Rochester MN 55905 USA

Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.

关键词： lineage plasticity neuroendocrine prostate cancer therapy resistance transdifferentiation

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Dynamic Behavior and Function of Foxp3^+ Regulatory T Cells in Tumor Bearing Host

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Cellular & Molecular Immunology 2009年第1期6卷 3-13页

作者： F. Xiao-Feng Qin Department of Immunology The University of TexasMD Anderson Cancer Center The University of Texas Graduate School of Biomedical Sciences at Houston

Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.

关键词： Treg APC tumor microenvironment immune suppression anti-tumor immunity

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Roles of the main olfactory and vomeronasal systems in the detection of androstenone in inbred strains of mice

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Current Zoology 2010年第6期56卷 813-818页

作者： Vera V. VOZNESSENSKAYA Maria A. KLYUCHNIKOVA Charles J. WYSOCKI A.N. Severtzov Institute of Ecology & Evolution RAS Monell Chemical Senses Center

We investigated the role of the main olfactory and accessory olfactory systems （MOS and AOS respectively） in the detection of androstenone. We used the following experimental approaches： behavioral, surgical removal of the vomeronasal organ （VNX） followed by histochemical verification and Fos immunohistochemistry. Using a Y-maze paradigm we estimated sensitivity of NZB/B1NJ and CBA/J mice to androstenone. CBA mice were 2,000-fold more sensitive to androstenone than NZB mice. VNX caused a 4-tol6-fold decrease in sensitivity to androstenone in highly-sensitive CBA mice, but did not affect thresholds in NZB mice. Results indicate the involvement of the MOS and AOS in the detection of androstenone. We observed a specific pattern of Fos-positive cells in the main olfactory bulb of CBA mice but not in NZB mice subsequent to exposure of mice to androstenone; the compound activated cells in the accessory olfactory bulb in both strains of mice, indicating the involvement of the vomeronasal organ. Patterns of Fos-positive cells in the vomeronasal organ were recorded subsequent to exposure to androstenone. Fos-positive receptor cells in the vomeronasal organ of CBA and NZB mice were different, in CBA mice Fos-positive cells were noted in both the basal and apical zones, however, in NZB mice activation was observed only in the apical zone [Current Zoology 56 （6）： 813-818, 2010].

关键词： Olfaction Vomeronasal organ Chemosensory receptors Olfactory behavior Immunohistochemistry

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Curcumin induces differentiation of embryonic stem cells through possible modulation of nitric oxide-cyclic GMP pathway

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Protein & Cell 2012年第7期3卷 535-544页

作者： Kalpana Mujoo Lubov ENikonoff Vladislav G Sharin Nathan SBryan Alexander YKots Ferid Murad Texas Therapeutics Institute Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science Center at Houston1825 Pressler StreetHoustonTX 77030USA Departments of Immunology and Pathology One Baylor PlazaBaylor College of MedicineHoustonTX 77030USA Departments of Biochemistry and Molecular Biology George Washington University2300 Eye St.NW Suite 530WashingtonDC 20037USA

Curcumin,an active ingredient of dietary spice used in curry,has been shown to exhibit anti-oxidant,anti-inflammatory and anti-proliferative *** EB directed differentiation protocol of H-9 human em-bryonic stem(ES)cells;we evaluated the effect of cur-cumin(0-20μmol/L)in enhancing such *** results using real time PCR,western blotting and immunostaining demonstrated that curcumin signifi-cantly increased the gene expression and protein levels of cardiac specific transcription factor NKx2.5,cardiac troponin I,myosin heavy chain,and endothelial nitric oxide synthase during ES cell ***-more,an NO donor enhanced the curcumin-mediated induction of NKx2.5 and other cardiac specific *** of cells with curcumin led to a dose depend-ent increase in intracellular nitrite to the same extent as giving an authentic NO *** assay for second messenger(s)cyclic AMP(cAMP)and cyclic GMP(cGMP)revealed that continuous presence of cur-cumin in differentiated cells induced a decrease in the baseline levels of cAMP but it significantly elevated baseline contents of *** addition to a cell free assay significantly suppressed cAMP and cGMP degradation in the extracts while long term treatment of intact cells with curcumin increased the rates of cAMP and cGMP degradation suggesting that this might be due to direct suppression of some cyclic nucleo-tide-degrading enzyme(phosphodiesterase)by *** studies demonstrate that polyphenol curcu-min may be involved in differentiation of ES cells partly due to manipulation of nitric oxide signaling.

关键词： curcumin nitric oxide cyclic GMP embryonic stem cells

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Crawling of effector T cells on extracellular matrix： role of integrins in interstitial migration in inflamed tissues

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Cellular & Molecular Immunology 2014年第1期11卷 1-4页

作者： Chang H Kim Laboratory of Immunology and Hematopoiesis Department of Comparative Pathobiology Weldon School of Biomedical Engineering Purdue Center for Cancer Research PurdueUniversity West Lafayette IN 47907 USA

Tcells are one of the most migratory cells in the body. The development and function of T cells depend on their interaction with other cells, which is, in turn, dependent on optimal cell migra- tion. T cells migrate largely in three dif- ferent ways： rapid distribution via blood vessels through hemodynamic move- ment, transendothelial migration and interstitial movement. Transendothelial migration involves sequential activation of selectins, chemokine receptors and integrin molecules expressed by migrat- ing T cells, leading to extravasation from blood vessel into local tissue environ- ments.

关键词：受体趋化因子细胞外基质细胞黏附分子选择素类移民(移出和移入) 胰岛素运动(Movement) 整合素类

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A Dominant Allele of Arabidopsis Pectin-Binding Wall-Associated Kinase Induces a Stress Response Suppressed by MPK6 but Not MPK3 Mutations

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Molecular Plant 2012年第4期5卷 841-851页

作者： Bruce D. Kohorn Susan L. Kohorn Tanya Todorova Gillian Baptiste Kevin Stansky Meghan McCullough Department of Biology Bowdoin College ME 04011 USA

The plant cell wall is composed of a matrix of cellulose fibers, flexible pectin polymers, and an array of as- sorted carbohydrates and proteins. The receptor-like Wall-Associated Kinases （WAKs） of Arabidopsis bind pectin in the wall, and are necessary both for cell expansion during development and for a response to pathogens and wounding. Mitogen Activated Protein Kinases （MPKs） form a major signaling link between cell surface receptors and both transcrip- tional and enzyme regulation in eukaryotes, and Arabidopsis MPK6 and MPK3 indeed have important roles in develop- ment and the response to stress and pathogens. A dominant allele of WAK2 requires kinase activity and activates a stress response that includes an increased ROS accumulation and the up-regulation of numerous genes involved in pathogen resistance, wounding, and cell wall biogenesis. This dominant allele requires a functional pectin binding and kinase domain, indicating that it is engaged in a WAK signaling pathway. A null mutant of the major plasma membrane ROS-producing enzyme complex, rbohd/f does not suppress the WAK2cTAP-induced phenotype. A mpk6, but not a mpk3, null allele is able to suppress the effects of this dominant WAK2 mutation, thus distinguishing MPK3 and MPK6, whose activity previously was thought to be redundant. Pectin activation of gene expression is abated in a wak2-null, but is tempered by the WAK-dominant allele that induces elevated basal stress-related transcript levels. The results suggest a mechanism in which changes to the cell wall can lead to a large change in cellular responses and help to explain how pathogens and wounding can have general effects on growth.

关键词： Wall Associated Kinases MPK3 MPK6 pectin oligogalacturonides.

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The unfolded protein response signaling and retinal Müller cell metabolism

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Neural Regeneration Research 2018年第11期13卷 1861-1870页

作者： Kristen Kelly Joshua J.Wang Sarah X.Zhang Department of Ophthalmology and Neuroscience Program Ross Eye InstituteUniversity at BuffaloState University of New York SUNY Eye Institute State University of New YorkBuffaloNYUSA

The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate（ATP） to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response（UPR）, and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.

关键词： unfolded protein response retina Müller glia metabolism neurodegeneration X-box binding protein 1 glycolysis glucose transporter

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Current development of the second generation of mTOR inhibitors as anticancer agents

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Chinese Journal of Cancer 2012年第1期31卷 8-18页

作者： Hong-Yu Zhou Shi-Le Huang Department of Biochemistry and Molecular Biology Feist-Weiller Cancer Center Louisiana State University Health Sciences Center 1501 Kings Highway Shreveport LA 71130-3932 USA.

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a "master switch" for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.

关键词： mTOR 抗癌药物抑制剂第二代丝氨酸/苏氨酸蛋白激酶蛋白质相互作用雷帕霉素细胞生长

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