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Czuba, Beata. "Social support for veterans." Scientific Journal of the Military University of Land Forces 199, no. 1 (March 18, 2021): 5–20. http://dx.doi.org/10.5604/01.3001.0014.8106.
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The article aims to outline how mission-traumatized veterans perceive social support. Social support is an essential resource for an individual in coping with the difficulties in everyday life. The subject of the examination is quantitative research with veterans’ participation and own qualitative research – free interviews analyzed using the IPA (Individual Phenomenological Analysis) method. The obtained results indicate that social support can be considered in terms of a meta-resource that activates other vital resources of humans, thereby strengthening them in difficult situations. The expected support criteria are met by friendly self-help groups that can operate in military units and complement the help provided by professionals.
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Solmonson, Ashley, Brandon Faubert, Wen Gu, Aparna Rao, Mitzy A. Cowdin, Ivan Menendez-Montes, Sherwin Kelekar, et al. "Compartmentalized metabolism supports midgestation mammalian development." Nature 604, no. 7905 (April 6, 2022): 349–53. http://dx.doi.org/10.1038/s41586-022-04557-9.
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AbstractMammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.
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Myers, Elizabeth A., and Linda Rinaman. "Trimethylthiazoline supports conditioned flavor avoidance and activates viscerosensory, hypothalamic, and limbic circuits in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 6 (June 2005): R1716—R1726. http://dx.doi.org/10.1152/ajpregu.00479.2004.
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Interoceptive stimuli modulate stress responses and emotional state, in part, via ascending viscerosensory inputs to the hypothalamus and limbic forebrain. It is unclear whether similar viscerosensory pathways are recruited by emotionally salient exteroceptive stimuli, such as odors. To address this question, we investigated conditioned avoidance and central c-Fos activation patterns in rats exposed to synthetic trimethylthiazoline (TMT), an odiferous natural component of fox feces. Experiment 1 demonstrated that rats avoid consuming novel flavors that previously were paired with TMT exposure, evidence that TMT supports conditioned flavor avoidance. Experiment 2 examined central neural systems activated by TMT. Odor-naive rats were acutely exposed to low or high levels of TMT or a novel nonaversive control odor and were perfused with fixative 60–90 min later. A subset of rats received retrograde neural tracer injections into the central nucleus of the amygdala (CeA) 7–10 days before odor exposure and perfusion. Brain sections were processed for dual-immunocytochemical detection of c-Fos and other markers to identify noradrenergic (NA) neurons, corticotropin-releasing hormone (CRH) neurons, and retrogradely labeled neurons projecting to the CeA. Significantly greater proportions of medullary and pontine NA neurons, hypothalamic CRH neurons, and CeA-projecting neurons were activated in rats exposed to TMT compared with activation in rats exposed to the nonaversive control odor. Thus the ability of TMT to support conditioned avoidance behavior is correlated with significant odor-induced recruitment of hypothalamic CRH neurons and brain stem viscerosensory inputs to the CeA.
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Pollak, Shaul, Shira Omer-Bendori, Eran Even-Tov, Valeria Lipsman, Tasneem Bareia, Ishay Ben-Zion, and Avigdor Eldar. "Facultative cheating supports the coexistence of diverse quorum-sensing alleles." Proceedings of the National Academy of Sciences 113, no. 8 (January 19, 2016): 2152–57. http://dx.doi.org/10.1073/pnas.1520615113.
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Bacterial quorum sensing enables bacteria to cooperate in a density-dependent manner via the group-wide secretion and detection of specific autoinducer molecules. Many bacterial species show high intraspecific diversity of autoinducer–receptor alleles, called pherotypes. The autoinducer produced by one pherotype activates its coencoded receptor, but not the receptor of another pherotype. It is unclear what selection forces drive the maintenance of pherotype diversity. Here, we use the ComQXPA system of Bacillus subtilis as a model system, to show that pherotype diversity can be maintained by facultative cheating—a minority pherotype exploits the majority, but resumes cooperation when its frequency increases. We find that the maintenance of multiple pherotypes by facultative cheating can persist under kin-selection conditions that select against “obligate cheaters” quorum-sensing response null mutants. Our results therefore support a role for facultative cheating and kin selection in the evolution of quorum-sensing diversity.
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Fraser, Lynn R. "Strontium supports capacitation and the acrosome reaction in mouse sperm and rapidly activates mouse eggs." Gamete Research 18, no. 4 (December 1987): 363–74. http://dx.doi.org/10.1002/mrd.1120180410.
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Grisan, Francesca, Martina Spacci, Carlotta Paoli, Andrea Costamagna, Marco Fantuz, Miriam Martini, Konstantinos Lefkimmiatis, and Alessandro Carrer. "Cholesterol Activates Cyclic AMP Signaling in Metaplastic Acinar Cells." Metabolites 11, no. 3 (February 26, 2021): 141. http://dx.doi.org/10.3390/metabo11030141.
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Cholesterol is a non-essential metabolite that exerts both structural and signaling functions. However, cholesterol biosynthesis is elevated, and actively supports, pancreatic carcinogenesis. Our previous work showed that statins block the reprogramming of mutant KRAS-expressing acinar cells, that spontaneously undergo a metaplastic event termed acinar-to-ductal metaplasia (ADM) to initiate carcinogenesis. Here we tested the impact of cholesterol supplementation on isolated primary wild-type acinar cells and observed enhanced ductal transdifferentiation, associated with generation of the second messenger cyclic adenosine monophosphate (cAMP) and the induction of downstream protein kinase A (PKA). Inhibition of PKA suppresses cholesterol-induced ADM ex vivo. Live imaging using fluorescent biosensors dissected the temporal and spatial dynamics of PKA activation upon cholesterol addition and showed uneven activation both in the cytosol and on the outer mitochondrial membrane of primary pancreatic acinar cells. The ability of cholesterol to activate cAMP signaling is lost in tumor cells. Qualitative examination of multiple normal and transformed cell lines supports the notion that the cAMP/PKA axis plays different roles during multi-step pancreatic carcinogenesis. Collectively, our findings describe the impact of cholesterol availability on the cyclic AMP/PKA axis and plasticity of pancreatic acinar cells.
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Wu, Sheng-Shiung, Sing-Jie Jong, Kai Hu, and Jiann-Ming Wu. "Learning Neural Representations and Local Embedding for Nonlinear Dimensionality Reduction Mapping." Mathematics 9, no. 9 (April 30, 2021): 1017. http://dx.doi.org/10.3390/math9091017.
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This work explores neural approximation for nonlinear dimensionality reduction mapping based on internal representations of graph-organized regular data supports. Given training observations are assumed as a sample from a high-dimensional space with an embedding low-dimensional manifold. An approximating function consisting of adaptable built-in parameters is optimized subject to given training observations by the proposed learning process, and verified for transformation of novel testing observations to images in the low-dimensional output space. Optimized internal representations sketch graph-organized supports of distributed data clusters and their representative images in the output space. On the basis, the approximating function is able to operate for testing without reserving original massive training observations. The neural approximating model contains multiple modules. Each activates a non-zero output for mapping in response to an input inside its correspondent local support. Graph-organized data supports have lateral interconnections for representing neighboring relations, inferring the minimal path between centroids of any two data supports, and proposing distance constraints for mapping all centroids to images in the output space. Following the distance-preserving principle, this work proposes Levenberg-Marquardt learning for optimizing images of centroids in the output space subject to given distance constraints, and further develops local embedding constraints for mapping during execution phase. Numerical simulations show the proposed neural approximation effective and reliable for nonlinear dimensionality reduction mapping.
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Kolańczyk, Alina. "When Affect Supports Cognitive Control – A Working Memory Perspective." Polish Psychological Bulletin 47, no. 1 (April 1, 2016): 29–42. http://dx.doi.org/10.1515/ppb-2016-0004.
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Abstract The paper delineates a study of executive functions (EFs), construed as procedural working memory (WM), from a motivational perspective. Since WM theories and motivation theories are both concerned with purposive activity, the role of implicit evaluations (affects) observed in goal pursuit can be anticipated to arise also in the context of cognitive control, e.g., during the performance of the Stroop task. The role of positive and negative affect in goal pursuit consists in controlling attention resources according to the goal and situational requirements. Positive affect serves to maintain goals and means in the scope of attention (EF1), whereas negative affect activates the inhibition of non-functional contents, e.g., distractors and irrelevant objects (resulting in attention disengagement; EF2). Adaptation to conflict proceeds via sequential triggering of negative and positive affect (EF3). Moreover, it was demonstrated that the focus on action or reflection changes the scope of contents subjected to implicit (affective) control. Therefore, I suggest that the motivational system, to a large extent, plays the role of the Central Executive. The paper opens a discussion and proposes studies on affective mechanisms of cognitive control.
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Rafei, Moutih, Alexandre Rouette, Sylvie Brochu, Juan Ruiz Vanegas, and Claude Perreault. "Differential effects of γc cytokines on postselection differentiation of CD8 thymocytes." Blood 121, no. 1 (January 3, 2013): 107–17. http://dx.doi.org/10.1182/blood-2012-05-433508.
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Abstract The primary consequence of positive selection is to render thymocytes responsive to cytokines and chemokines expressed in the thymic medulla. In the present study, our main objective was to discover which cytokines could support the differentiation of positively selected thymocytes. To this end, we have developed an in vitro model suitable for high-throughput analyses of positive selection and CD8 T-cell differentiation. The model involves coculture of TCRhiCD5intCD69− double-positive (DP) thymocytes with peptide-pulsed OP9 cells and γc-cytokines. We report that IL-4, IL-7, and IL-21 have nonredundant effects on positively selected DP thymocytes. IL-7 signaling phosphorylates STAT5 and ERK; induces Foxo1, Klf2, and S1pr1; and supports the differentiation of classic CD8 T cells. IL-4 activates STAT6 and ERK and supports the differentiation of CD8intPD-L1hiCD44hiEOMES+ innate CD8 T cells. IL-21 is produced by thymic epithelial cells and the IL-21 receptor-α is strongly induced on DP thymocytes undergoing positive selection. IL-21 signaling phosphorylates STAT3 and STAT5, but not ERK, and does not support CD8 T-cell differentiation. However, IL-21 has a unique ability to up-regulate BCL-6, expand DP thymocytes undergoing positive selection, and increase the production of mature T cells. Our data suggest that injection of recombinant IL-21 might enhance thymic output in subjects with age- or disease-related thymic atrophy.
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Shih, Han-Yu, William Olcott, and Michael Krangel. "Chromatin conformations and contacts that support Tcra/d locus rearrangement (62.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 62.2. http://dx.doi.org/10.4049/jimmunol.186.supp.62.2.
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Abstract The Tcra/d locus rearranges in DN thymocytes to assemble Tcrd genes and in DP thymocytes to assemble Tcra genes. We used 3D-FISH to show that the 3’ portion of the locus is contracted in both DN and DP thymocytes, whereas the 5’ portion is contracted in DN but decontracts in DP thymocytes. We proposed that the fully contracted conformation in DN thymocytes allows dispersed Vαs to be used in a single round of Vδ-Dδ-Jδ rearrangement, whereas the 3’-contracted, 5’-decontracted conformation in DP thymocytes allows for multiple rounds of Vα-to-Jα rearrangement initiating with 3' Vαs. For high resolution analysis, we used the 3C method to detect molecular interactions between different sites in the locus. The Tcra enhancer (Eα) activates the T early α promoter (TEA) to target 5’Jαs for initial rearrangement. Eα also activates proximal Vαs over 500 kb. We detected molecular interactions between Eα and TEA, between Eα and proximal Vαs, and between different proximal Vαs, in DP but not DN thymocytes. All pairwise interactions depended on Eα. With TEA deleted, Eα also interacted with downstream Jαs. We propose that Eα nucleates a chromatin hub that supports transcription and ordered Vα-to-Jα recombination. However, deletion of Eα does not impact Tcra/d locus 3’end contraction as measured by 3D-FISH. Thus, overall locus conformation is independent of Eα, but this conformation may facilitate Eα interactions with distant sites.
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Xiong, Ying, Liqing Fan, Yan Hao, Yalin Cheng, Yongbin Chang, Jing Wang, Haiyan Lin, Gang Song, Yanhua Qu, and Fumin Lei. "Physiological and genetic convergence supports hypoxia resistance in high-altitude songbirds." PLOS Genetics 16, no. 12 (December 28, 2020): e1009270. http://dx.doi.org/10.1371/journal.pgen.1009270.
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Skeletal muscle plays a central role in regulating glucose uptake and body metabolism; however, highland hypoxia is a severe challenge to aerobic metabolism in small endotherms. Therefore, understanding the physiological and genetic convergence of muscle hypoxia tolerance has a potential broad range of medical implications. Here we report and experimentally validate a common physiological mechanism across multiple high-altitude songbirds that improvement in insulin sensitivity contributes to glucose homeostasis, low oxygen consumption, and relative activity, and thus increases body weight. By contrast, low-altitude songbirds exhibit muscle loss, glucose intolerance, and increase energy expenditures under hypoxia. This adaptive mechanism is attributable to convergent missense mutations in the BNIP3L gene, and METTL8 gene that activates MEF2C expression in highlanders, which in turn increases hypoxia tolerance. Together, our findings from wild high-altitude songbirds suggest convergent physiological and genetic mechanisms of skeletal muscle in hypoxia resistance, which highlights the potentially medical implications of hypoxia-related metabolic diseases.
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Celenza, James. "Protecting Disaster Site, Support, and Recovery Workers." NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy 18, no. 3 (September 30, 2008): 329–32. http://dx.doi.org/10.2190/ns.18.3.f.
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When a disaster strikes, FEMA activates the worker safety and health provisions (annex document) of the National Response Plan (NRP). The annex describes actions needed to ensure that threats to safety and health are recognized, evaluated, and controlled consistently so that responders are properly protected during incident management operations. The activation of the Worker Safety and Health Annex gives the Occupational Safety and Health Administration (OSHA) the responsibility to coordinate a comprehensive response involving federal, state, and local agencies and private-sector organizations to ensure the safety and health needs of responders are met. There is confusion, however, as to whether OSHA is acting as an advisory “coordinator” or as an enforcement agency. OSHA personnel at the WTC and the Gulf region reported they were not clear what role they must perform (and the language in the National Response Plan is not explicit). Thus, the need for a clear and comprehensive mandatory program.
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Stone, S., M. Sacher, Y. Mao, C. Carr, P. Lyons, A. M. Quinn, and S. Ferro-Novick. "Bet1p activates the v-SNARE Bos1p." Molecular Biology of the Cell 8, no. 7 (July 1997): 1175–81. http://dx.doi.org/10.1091/mbc.8.7.1175.
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Bet1p is a type II membrane protein that is required for vesicular transport between the endoplasmic reticulum and Golgi complex in the yeast Saccharomyces cerevisiae. A domain of Bet1p, that shows potential to be involved in a coiled-coil interaction, is homologous to a region of the neuronal protein SNAP-25. Here, we used in vitro binding studies to demonstrate that Bet1p plays a role in potentiating soluble NSF attachment protein receptor (SNARE) interactions. Mutational analysis points to the coiled-coil region as necessary for Bet1p function, and circular dichroism experiments support this theory. In vitro binding studies were also used to demonstrate that a direct interaction between Bet1p and Bos1p is required for the efficient interaction of the vesicle SNARE with its SNARE target. Genetic studies suggest that the interactions of Bet1p with Bos1p are regulated by the small GTP-binding protein Ypt1p.
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Tukachinsky, Hanna, Lyle V. Lopez, and Adrian Salic. "A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes." Journal of Cell Biology 191, no. 2 (October 18, 2010): 415–28. http://dx.doi.org/10.1083/jcb.201004108.
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In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu–Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu–Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu–Gli complexes, a process inhibited by PKA.
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Gil-Henn, Hava, and Ari Elson. "Tyrosine Phosphatase-ε Activates Src and Supports the Transformed Phenotype of Neu-induced Mammary Tumor Cells." Journal of Biological Chemistry 278, no. 18 (February 21, 2003): 15579–86. http://dx.doi.org/10.1074/jbc.m210273200.
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Baek, Jung-Hwan, Seok-Jun Kim, Hyeok Gu Kang, Hyun-Woo Lee, Jung-Hoon Kim, Kyung-A. Hwang, Jaewhan Song, and Kyung-Hee Chun. "Galectin-3 Activates PPARγ and Supports White Adipose Tissue Formation and High-Fat Diet-Induced Obesity." Endocrinology 156, no. 1 (January 2015): 147–56. http://dx.doi.org/10.1210/en.2014-1374.
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Rio, Danila Del, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, and Laura Rosanò. "Abstract 6137: Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6137. http://dx.doi.org/10.1158/1538-7445.am2022-6137.
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Abstract The recruitment of fibroblasts to tumor and their activation to cancer-associated fibroblast (CAF) is an exploited strategy used by tumor to guide matrix remodeling, supporting cancer invasion and metastatic disease. CAFs are the major effectors of extracellular matrix (ECM) remodelling through secretion of collagens, cross-linking enzymes and proteases, and in turn engagement of integrins. Although several tumor cell-secreted factors have been identified in generating tumor-promoting stroma, there has been a great interest to define factors and associated molecular mechanisms involved in promoting CAF premetastatic function. Tumor-related endothelin-1 (ET-1) has an important role in the crosstalk between cancer and stromal cells supporting serous ovarian cancer (SOC) progression. By binding its receptors (ETAR and ETBR), ET-1 favours the recruitment of the protein β-arrestin-1 and the generation of signaling complexes regulating also cytoskeleton reorganization, thereby fine-tuning SOC cell invasion and metastasis. However, how the integration of ET-1 receptors might “educate” stroma to become permissive for invasion, supplying an altered ECM governing metastasis needs to be investigated. In this study, we identified endothelin-1 as a key factor in priming CAF conversion in SOC. We demonstrate that primary ovarian fibroblasts express ETA and ETB, along with β-arrestin1, and secrete ET-1; b) the autocrine and cancer-secreted ET-1 promotes fibroblast proliferation, and an increase in the expression of CAF markers (αSMA, vimentin and FAP), secretion of proinflammatory cytokines, collagen contraction ability and cell motility. Moreover, ET-1 induces activation of b1 integrin and downstream signaling. Mechanistically, ET1R/intb1 signaling allows ECM remodeling, either by promoting and invasive protrusion formation, invadosome, and collagen secretion. Importantly, therapeutical inhibition of ET-1 receptors with Ambrisentan and intβ1 with ATN-116 markedly reduced the ability of SOC cells to adhere in the intraperitoneal organs and to metastasize. Our findings support a model in which ET-1 educates the stromal fibroblasts to become permissive for tumor invasion and demonstrate for the time the significance of an ET-1-dependent integrin signaling in this process. Citation Format: Danila Del Rio, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, Laura Rosanò. Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6137.
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Mayer, Sabrina Jasmin, and Christoph Giang Nguyen. "Angry Reactionary Narcissists? Anger Activates the Link Between Narcissism and Right-Populist Party Support." Politics and Governance 9, no. 3 (August 27, 2021): 248–59. http://dx.doi.org/10.17645/pag.v9i3.4000.
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Even though previous research connected personality traits and support for radical-right populist parties (RRP), the question of which mechanisms connect these concepts is still underexplored. In particular, we focus on narcissistic rivalry, a maladaptive path of grandiose narcissism. Drawing on the affective intelligence framework and the narcissistic admiration and rivalry concept, we propose that the effect of rival narcissism on vote choice for the German Alternative für Deutschland is mediated by reactionary political orientations and activated by anger. Drawing on 2017 data from the mixed-mode representative GESIS panel (N = 2,552 & 1,901), we employ moderated mediation analyses. We show that reactionary political orientations mediate the relationship between narcissistic rivalry and RRP support. However, high levels of generalised anger are needed to activate the relationship between personality, reactionary values, and RRP support, whereas the mediating role of anti-immigrant sentiment is not affected by anger. Our study emphasises the role of anger in RRP support, thus showing that anger might explain why only some people with a specific predisposition support RRPs. The study also stresses the complexity of the relationship between personality, value orientations, and political behaviour.
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Ang, M. L., J. T. Miller, Y. Cui, L. Mo, and S. Kawi. "Bimetallic Ni–Cu alloy nanoparticles supported on silica for the water-gas shift reaction: activating surface hydroxyls via enhanced CO adsorption." Catalysis Science & Technology 6, no. 10 (2016): 3394–409. http://dx.doi.org/10.1039/c5cy01885d.
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Shalgimbekova, Kenzhegul, Tatyana Smagliy, Bibigul Utegenova, and Shnar Demisenova. "ORGANIZATION OF SOCIAL AND PEDAGOGICAL SUPPORT FOR ORPHANS IN FOSTER CARE FAMILIES." 3i intellect idea innovation - интеллект идея инновация 2 (2023): 241–48. http://dx.doi.org/10.52269/22266070_2023_2_241.
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This article reveals the study relevance of the socio-pedagogical support for orphans in foster care families’ problem, reveals the essence of a comprehensive axiological approach as a theoretical and methodological strategy for research, describes the leading concepts: "foster care," "socio-pedagogical support." The technique that activates social and pedagogical support for orphans in foster care families has become the goal of experimental work, which has a theoretical justification. During the experiment, such tasks were solved: checking the effectiveness of socio-pedagogical support for orphans in foster care families by experimental means; processing, analysis and interpretation of the obtained experimental results; shows the statistical fidelity of the hypothesis put forward. Experimental work consisted of the stating, forming, control stages of the experiment, each of which solved certain tasks to confirm the purpose of the study. Two groups were formed: one experimental and one control groups. (EG – 1, EG – 2, CG). Diagnosis was carried out before placement in the family, in the first days and six months later. In EG-1, the methodology was partially tested, in EG-2 the methodology that activates social and pedagogical support for orphans in the foster care family was fully implemented, in the CG – social and pedagogical support was carried out standard according to basic requirements. Comparison of the results obtained at the CG and EG concluded that the organization of socio-pedagogical support gave a number of positive results in foster care families orphans in terms of the main indicators of adaptation.
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Hughes, Craig E., Alice Y. Pollitt, Jun Mori, Johannes A. Eble, Michael G. Tomlinson, John H. Hartwig, Christopher A. O'Callaghan, Klaus Fütterer, and Steve P. Watson. "CLEC-2 activates Syk through dimerization." Blood 115, no. 14 (April 8, 2010): 2947–55. http://dx.doi.org/10.1182/blood-2009-08-237834.
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Abstract The C-type lectin receptor CLEC-2 activates platelets through Src and Syk tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including phospholipase-C γ2. Signaling is initiated through phosphorylation of a single conserved tyrosine located in a YxxL sequence in the CLEC-2 cytosolic tail. The signaling pathway used by CLEC-2 shares many similarities with that used by receptors that have 1 or more copies of an immunoreceptor tyrosine-based activation motif, defined by the sequence Yxx(L/I)x6-12Yxx(L/I), in their cytosolic tails or associated receptor chains. Phosphorylation of the conserved immunoreceptor tyrosine-based activation motif tyrosines promotes Syk binding and activation through binding of the Syk tandem SH2 domains. In this report, we present evidence using peptide pull-down studies, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence measurements, and competition experiments that Syk activation by CLEC-2 is mediated by the cross-linking through the tandem SH2 domains with a stoichiometry of 2:1. In support of this model, cross-linking and electron microscopy demonstrate that CLEC-2 is present as a dimer in resting platelets and converted to larger complexes on activation. This is a unique mode of activation of Syk by a single YxxL-containing receptor.
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Obsilova, Veronika, Karolina Honzejkova, and Tomas Obsil. "Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions." International Journal of Molecular Sciences 22, no. 24 (December 13, 2021): 13395. http://dx.doi.org/10.3390/ijms222413395.
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Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer’s, Parkinson’s and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.
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Johnston, Benjamin P., Eric S. Pringle, and Craig McCormick. "KSHV Activates Unfolded Protein Response Sensors but Suppresses Downstream Transcriptional Responses to Support Lytic Replication." Proceedings 50, no. 1 (July 3, 2020): 116. http://dx.doi.org/10.3390/proceedings2020050116.
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Herpesviruses usurp host cell protein synthesis machinery to convert viral mRNAs into proteins, and the endoplasmic reticulum (ER) to ensure the proper folding, post-translational modification and trafficking of secreted and transmembrane viral proteins. Overloading the ER folding capacity activates the unfolded protein response (UPR), whereby sensor proteins, ATF6, PERK and IRE1, initiate a stress-mitigating transcription program that accelerates the catabolism of misfolded proteins, while increasing the ER folding capacity. Kaposi’s sarcoma-associated herpesvirus (KSHV) can be reactivated from latency through the chemical induction of ER stress, which causes an accumulation of the XBP1s transcription factor that transactivates the viral RTA lytic switch gene. The presence of XBP1s-responsive elements in the RTA promoter suggests that KSHV evolved a mechanism to respond to ER stress. Here, we report that ATF6, PERK and IRE1 were activated upon reactivation from latency and were required for efficient KSHV lytic replication. The genetic or pharmacologic inhibitions of each UPR sensor reduced virion production. Despite UPR sensor activation during KSHV lytic replication, downstream UPR transcriptional responses were restricted: (1) ATF6 was cleaved to activate the ATF6(N) transcription factor but ATF6(N)-responsive genes were not transcribed; (2) PERK phosphorylated eIF2, but ATF4 did not accumulate; (3) IRE1 caused XBP1–mRNA splicing, but the XBP1s protein did not accumulate and the XBP1s-responsive genes were not transcribed. The complementation of XBP1s deficiency during KSHV lytic replication inhibited virion production in a dose-dependent manner in epithelial cells. Taken together, these findings indicate that, while XBP1s plays an important role in reactivation from latency, it can inhibit virus replication at a later step, which the virus overcomes by preventing its synthesis. These findings suggest that KSHV hijacks UPR sensors to promote efficient viral replication while sustaining ER stress.
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Johnston, Benjamin P., Eric S. Pringle, and Craig McCormick. "KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication." PLOS Pathogens 15, no. 12 (December 2, 2019): e1008185. http://dx.doi.org/10.1371/journal.ppat.1008185.
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Figl, Marianne, Clémence Jacquemin, Laure Perrin-Cocon, Patrice Andre, Vincent Lotteau, and Olivier Diaz. "SAT-390-Dengue virus protein NS3 activates hexokinase activity in hepatocytes to support virus replication." Journal of Hepatology 70, no. 1 (April 2019): e805. http://dx.doi.org/10.1016/s0618-8278(19)31609-3.
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Cheon, Bobby, and Gianluca Esposito. "Brief Exposure to Infants Activates Social and Intergroup Vigilance." Behavioral Sciences 10, no. 4 (April 3, 2020): 72. http://dx.doi.org/10.3390/bs10040072.
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Among humans, simply looking at infants can activate affiliative and nurturant behaviors. However, it remains unknown whether mere exposure to infants also activates other aspects of the caregiving motivational system, such as generalized defensiveness in the absence of immediate threats. Here, we demonstrate that simply viewing faces of infants (especially from the ingroup) may heighten vigilance against social threats and support for institutions that purportedly maintain security. Across two studies, participants viewed and rated one among several image types (between-subjects design): Infants, adult males, adult females, and puppies in Study 1, and infants of varying racial/ethnic groups (including one’s ingroup) and puppies in Study 2. Following exposure to one of these image types, participants completed measures of intergroup bias from a range of outgroups that differed in perceived threat, belief in a dangerous world, right-wing authoritarianism and social-political conservatism (relative to liberalism). In Study 1 (United States), stronger affiliative reactions to images of infants (but not adults or puppies) predicted stronger perceptions of a dangerous world, endorsement of right-wing authoritarianism, and support for social-political conservatism (relative to liberalism). Study 2 (Italy) revealed that exposure to images of ingroup infants (compared to outgroup infants) increased intergroup bias against outgroups that are characterized as threatening (immigrants and Arabs) and increased conservatism. These findings suggest a predisposed preparedness for social vigilance in the mere suggested presence of infants (e.g., viewing images) even in the absence of salient external threats.
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Armendariz Miranda, Paula, and Matthew Cawvey. "Introverted and Closed-Minded: The Psychological Roots of Support for Autocracy in Latin America." Journal of Politics in Latin America 13, no. 1 (March 3, 2021): 40–66. http://dx.doi.org/10.1177/1866802x21991261.
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What activates individuals’ support for autocratic governments? Some suggest that the answer is perceptions of increased corruption and/or poor economic performance. We do not dispute this explanation but instead contend that it depends on individual differences in personality. We hypothesise that introverted and closed-minded citizens are generally resistant to democracy. When democracies appear unable to address problems, introverted and closed-minded citizens defer to authoritarian leaders for efficient solutions. We test our hypotheses with cross-national survey data from Latin America. Our findings have important implications for how we understand the roots of autocratic attitudes.
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Jun, Jesse E., Kayla R. Kulhanek, Hang Chen, Arup Chakraborty, and Jeroen P. Roose. "Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation." Science Signaling 12, no. 591 (July 23, 2019): eaao0736. http://dx.doi.org/10.1126/scisignal.aao0736.
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T cell receptor (TCR) stimulation activates diverse kinase pathways, which include the mitogen-activated protein kinases (MAPKs) ERK and p38, the phosphoinositide 3-kinases (PI3Ks), and the kinase mTOR. Although TCR stimulation activates the p38 pathway through a “classical” MAPK cascade that is mediated by the adaptor protein LAT, it also stimulates an “alternative” pathway in which p38 is activated by the kinase ZAP70. Here, we used dual-parameter, phosphoflow cytometry and in silico computation to investigate how both classical and alternative p38 pathways contribute to T cell activation. We found that basal ZAP70 activation in resting T cell lines reduced the threshold (“primed”) TCR-stimulated activation of the classical p38 pathway. Classical p38 signals were reduced after T cell–specific deletion of the guanine nucleotide exchange factors Sos1 and Sos2, which are essential LAT signalosome components. As a consequence of Sos1/2 deficiency, production of the cytokine IL-2 was impaired, differentiation into regulatory T cells was reduced, and the autoimmune disease EAE was exacerbated in mice. These data suggest that the classical and alternative p38 activation pathways exist to generate immune balance.
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Moldakarimov, Samat, Maxim Bazhenov, Daniel E. Feldman, and Terrence J. Sejnowski. "Structured networks support sparse traveling waves in rodent somatosensory cortex." Proceedings of the National Academy of Sciences 115, no. 20 (April 30, 2018): 5277–82. http://dx.doi.org/10.1073/pnas.1710202115.
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Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons.
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Sharma, Balkrishan, Duaa Mureb, Sumit Murab, Leah A. Rosenfeldt, Brenton J. Francisco, Alexander A. Boucher, Rachel Cantrell, et al. "Fibrinogen Activates FAK to Promote the Colorectal Adenocarcinoma Growth." Blood 134, Supplement_1 (November 13, 2019): 1111. http://dx.doi.org/10.1182/blood-2019-130497.
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Along with other proteins in the coagulation cascade, including tissue factor and thrombin, fibrinogen has been shown to promote tumor metastasis across numerous cancer types. However, the role of fibrin(ogen) in primary tumor growth is context dependent and not universally important. One cancer strongly dependent on fibrin(ogen) for primary tumor growth is colorectal cancer (CRC), but the mechanisms by which fibrinogen supports colon cancer growth are not well understood. To delineate the mechanism of fibrin(ogen)-supported tumor growth, we implanted C57BL/6-derived murine colon cancer cells (MC38) into the dorsal subcutis of syngeneic mice with specific deletions/alteration in fibrinogen or FXIII-deficiency. Complete fibrinogen deficiency significantly limited the growth of colon cancer cells. However, the imposition of FXIII-deficiency or specific mutations in fibrinogen that 1) prevent the formation of fibrin polymer (FibAEK), limit fibrin(ogen) binding to the integrin αMβ2 (Fibɣ390-396A), or remove the ɣ chain binding motif for the platelet integrin αIIbβ3 (FibɣΔ5) had no impact on colon cancer growth. To explore the mechanisms coupling fibrin(ogen) to colon cancer growth using a nonbiased approach, we performed RNA-Seq analyses of murine CRC tumors harvested from Fib+ and Fib- mice. We detected significant differences in the expression of 214 genes (128 downregulated and 86 upregulated) involved in cellular proliferation, survival, migration and metabolism. Notably, Stratifin (SFN), which encodes 14-3-3-σ, was one of the genes found to be highly upregulated in tumors from Fib- mice relative to Fib+ mice. 14-3-3-σ is a potent cell cycle regulator and it is also known to stabilize p53, which ultimately inhibits tumor growth. In a separate validation cohort, we observed significantly increased protein expression of 14-3-3-σ and its upstream and downstream targets (i.e., p53, p21 and p27) in tumors harvested from Fib- mice relative to controls. We also compared FAK activation, a key negative regulator of p53, in tumors from Fib+ and Fib- mice. FAK was inactive in tumors from Fib- mice, as indicated by lack of phosphorylation at tyrosine 397 (p-FAK Tyr397). Also, MDM2 was less phosphorylated at Ser166 in Fib- tumors, suggesting that p53 is not degraded by MDM2 in the absence of fibrinogen. Taken together, these data suggest that fibrin(ogen)-mediated downregulation of p53 and other targets via FAK activation and downregulation of 14-3-3-σ results in senescence of CRC cells. Consistent with this view, Ki67 positive nuclei were significantly less in tumor from Fib- mice relative to controls We also observed senescence-associated-β-galactosidase (SA-β-gal) activity in the tumors from Fib- mice, but not those from Fib+ animals. Furthermore, NMR-based metabolomics analyses demonstrated significantly less NAD+ and lactate levels in tumors from Fib- mice, which further confirms that fibrinogen deficiency hampers proliferation by inhibiting major metabolic pathways. In order to determine if fibrinogen-mediated support of CRC growth is tumor cell intrinsic, we compared MC38 growth in the 3D bioprinted matrices consisting of fibrin or albumin. MC38 cells showed a higher proliferation rate in the fibrinogen printed 3D environment compared to the albumin environment. These findings suggest that fibrin(ogen)-mediated engements of tumor cells activates FAK which inhibits p53 and its downstream targets including 14-3-3-σ and p21 which promote cellular proliferation and prevent senescence. Overall, these studies suggest that fibrin(ogen) is the important component of the CRC microenvironment and could be exploited for targeting and treating the CRC. Disclosures Whitlock: POSNA: Other: Research Committee; MTF Biologics Grant Program: Other: site co-investigator. Palumbo:Ionis Pharmaceuticals: Research Funding.
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Fehrmann, Frauke, David J. Klumpp, and Laimonis A. Laimins. "Human Papillomavirus Type 31 E5 Protein Supports Cell Cycle Progression and Activates Late Viral Functions upon Epithelial Differentiation." Journal of Virology 77, no. 5 (March 1, 2003): 2819–31. http://dx.doi.org/10.1128/jvi.77.5.2819-2831.2003.
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ABSTRACT The function of the E5 protein of human papillomaviruses (HPV) is not well characterized, and controversies exist about its role in the viral life cycle. To determine the function of E5 within the life cycle of HPV type 31 (HPV31) we first constructed HPV31 mutant genomes that contained an altered AUG initiation codon or stop codons in E5. Cell lines were established which harbored transfected wild-type or E5 mutant HPV31 genomes. These cell lines all maintained episomal copies of HPV31 and revealed similar phenotypes with respect to growth rate, early gene expression, and viral copy number in undifferentiated monolayer cultures. Following epithelial differentiation, genome amplification and differentiation-dependent late gene expression were observed in mutant cell lines, but at a rate significantly reduced from that observed in cells containing the wild-type genomes. Organotypic raft cultures indicated that E5 does not effect the expression of differentiation markers but does reduce expression of late viral proteins. Western analysis and immunofluorescence staining for cyclins during epithelial differentiation revealed a decreased expression of cyclin A and B in E5 mutant cells compared to HPV wild-type cells. Using a replating assay, a significant reduction in colony-forming ability was detected in the absence of E5 expression when cells containing wild-type or E5 mutant HPV genomes were allowed to proliferate following 24 h in suspension-induced differentiation. This suggests that HPV E5 modifies the differentiation-induced cell cycle exit and supports the ability of HPV31-positive keratinocytes to retain proliferative competence. In these studies, E5 was found to have little effect on the levels of the epidermal growth factor receptor (EGFR) or on its phosphorylation status. This indicates that EGFR is not a target of E5 action. Our results propose a role for high risk HPV E5 in modulation of late viral functions through activation of proliferative capacity in differentiated cells. We suspect that the primary target of E5 is a membrane protein or receptor that then acts to alter the levels or activities of cell cycle regulators.
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Fong, David, Martine Bisson, Gino Laberge, Stephen McManus, Guillaume Grenier, Nathalie Faucheux, and Sophie Roux. "Bone morphogenetic protein-9 activates Smad and ERK pathways and supports human osteoclast function and survival in vitro." Cellular Signalling 25, no. 4 (April 2013): 717–28. http://dx.doi.org/10.1016/j.cellsig.2012.12.003.
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Ordentlich, Peter, Arthur Lin, Chun-Pyn Shen, Chris Blaumueller, Kenji Matsuno, Spyros Artavanis-Tsakonas, and Tom Kadesch. "Notch Inhibition of E47 Supports the Existence of a Novel Signaling Pathway." Molecular and Cellular Biology 18, no. 4 (April 1, 1998): 2230–39. http://dx.doi.org/10.1128/mcb.18.4.2230.
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ABSTRACT E47 is a widely expressed transcription factor that activates B-cell-specific immunoglobulin gene transcription and is required for early B-cell development. In an effort to identify processes that regulate E47, and potentially B-cell development, we found that activated Notch1 and Notch2 effectively inhibit E47 activity. Only the intact E47 protein was inhibited by Notch—fusion proteins containing isolated DNA binding and activation domains were unaffected—suggesting that Notch targets an atypical E47 cofactor. Although overexpression of the coactivator p300 partially reversed E47 inhibition, results of several assays indicated that p300/CBP is not a general target of Notch. Notch inhibition of E47 did not correlate with its ability to activate CBF1/RBP-Jκ, the mammalian homolog of Suppressor of Hairless, a protein that associates physically with Notch and defines the only known Notch signaling pathway in drosophila. Importantly, E47 was inhibited independently of CBF1/RPB-Jκ by Deltex, a second Notch-interacting protein. We provide evidence that Notch and Deltex may act on E47 by inhibiting signaling through Ras because (i) full E47 activity was found to be dependent on Ras and (ii) both Notch and Deltex inhibited GAL4-Jun, a hybrid transcription factor whose activity is dependent on signaling from Ras to SAPK/JNK.
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Chen, Kai, Yuhan Zheng, Ji-an Wei, Huan Ouyang, Xiaodan Huang, Feilong Zhang, Cora Sau Wan Lai, Chaoran Ren, Kwok-Fai So, and Li Zhang. "Exercise training improves motor skill learning via selective activation of mTOR." Science Advances 5, no. 7 (July 2019): eaaw1888. http://dx.doi.org/10.1126/sciadv.aaw1888.
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Physical exercise improves learning and memory, but little in vivo evidence has been provided to illustrate the molecular mechanisms. Here, we show that chronic treadmill exercise activates the mechanistic target of rapamycin (mTOR) pathway in mouse motor cortex. Both ex vivo and in vivo recordings suggest that mTOR activation leads to potentiated postsynaptic excitation and enhanced neuronal activity of layer 5 pyramidal neurons after exercise, in association with increased oligodendrogenesis and axonal myelination. Exercise training also increases dendritic spine formation and motor learning. Together, exercise activates mTOR pathway, which is necessary for spinogenesis, neuronal activation, and axonal myelination leading to improved motor learning. This model provides new insights for neural network adaptations through exercises and supports the intervention of cognitive deficits using exercise training.
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Li, Lingchang, Haiyan Wang, Jun Qian, Guoli Wei, Rong Ding, Canhong Hu, Dong Fang, et al. "FuFangChangTai Decoction Activates Macrophages via Inducing Autophagy." Evidence-Based Complementary and Alternative Medicine 2019 (June 12, 2019): 1–10. http://dx.doi.org/10.1155/2019/5657035.
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The traditional Chinese medicine decoction FuFangChangTai (FFCT) has been used in the therapy of colon cancer clinically, yielding alleviated toxicity and enhanced immunity. In our previous study, FFCT exerted its antitumor activity not only by inducing apoptosis but also by activating autophagy to eliminate tumor cells. However, its mechanism is not well understood. The purpose of this study was to investigate the relationship between macrophages activation and FFCT-induced autophagy. Results showed that FFCT could induce autophagy in colon cancer, as demonstrated by increased level of intracellular autophagy marker LC3 II in CT26.WT cells by fluorescence microscope and western blot assay. FFCT also facilitated numbers of vesicular bodies with bilayer membrane in CT26.WT cells, which were indicative of autophagosomes formation. Autophagosomes secreted by FFCT-treated CT26.WT cells can activate M1 type macrophages, accompanied with increased expression of costimulatory molecules CD86 and CD40 on the surface of RAW264.7 cells, and more inflammatory cytokines secretion, such as TNF-α, IL-6, MCP-1, and IL-1β. mRNA expressions of M2 macrophages markers, such as IL-10, CD206, Arg-1, and FIZZ-1, were downregulated. And this process helps regulate the polarization of macrophages and promote the immune response. These findings support a mechanism of FFCT-induced autophagy and provide novel evidence demonstrating that macrophages are involved in FFCT-induced autophagy progression.
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Hasani, Sumati, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, and Tianyan Gao. "Abstract 4837: Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4837. http://dx.doi.org/10.1158/1538-7445.am2023-4837.
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Abstract Metabolic reprogramming has been increasingly recognized as one of the major mechanisms that fuels tumorigenesis and disease progression. Our previous studies have shown that in response to fatty acid uptake, colon cancer cells activate mitochondrial fission to support fatty acid oxidation and downstream Wnt signaling. Given the potential benefit of inhibiting mitochondrial fission, Dynamin-Related Protein 1 (Drp1), a pro-fission factor, has become an attractive target for developing anticancer agents. Here we investigated the role of Drp1 in promoting metabolic adaptation in colon cancer. We found that knockdown of Drp1 decreased mitochondrial respiration which resulted in increased glucose uptake and lactate production. In addition, downregulation of Drp1 increased AMP-activated protein kinase (AMPK) activity which coincided with glycogen accumulation. Consistently, results from GC/MS analysis of cellular metabolites revealed that the levels of glucose-6-phosphate, a precursor for glycogenesis, were significantly elevated in Drp1 knockdown cells whereas pyruvate and other TCA cycle metabolites remained unchanged. Mechanistically, AMPK transcriptionally activates the expression of glycogen synthase 1 (GYS1) and hexokinase 2 (HK2) genes and silencing GYS1 abolished the glycogen accumulation phenotype in Drp1 knockdown cells. Using APC-derived 3D organoids, we demonstrated that the glycogen levels were elevated in Apcf/f Drp1f/f tumor organoids upon deletion of Drp1. Similarly, increased GYS1 expression and glycogen levels were detected in xenograft tumors derived from Drp1 knockdown colon cancer cells compared to control. Functionally, increased glycogen storage allowed Drp1 knockdown cells to survive glucose starvation conditions suggesting an enhanced survival capacity compared to control cells. Taken together, our findings indicate that Drp1 inhibition by itself is unlikely to be sufficient to eradicate cancer cells as adaptive metabolic mechanisms are activated to promote cell survival. However, combining Drp1 inhibition may enhance the efficacy of chemotherapeutic agents for colon cancer treatment. Citation Format: Sumati Hasani, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, Tianyan Gao. Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4837.
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Al Kafri, Nour, and Sassan Hafizi. "Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis." Cancers 11, no. 12 (November 22, 2019): 1843. http://dx.doi.org/10.3390/cancers11121843.
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The TAM subfamily (Tyro3, Axl, MerTK) of receptor tyrosine kinases are implicated in several cancers, where they have been shown to support primary tumorigenesis as well as secondary resistance to cancer therapies. Relatively little is known about the oncogenic role of Tyro3, including its ligand selectivity and signalling in cancer cells. Tyro3 showed widespread protein and mRNA expression in a variety of human cancer cell lines. In SCC-25 head and neck cancer cells expressing both Tyro3 and Axl, Western blotting showed that both natural TAM ligands ProS1 and Gas6 rapidly stimulated Tyro3 and Erk kinase phosphorylation, with ProS1 eliciting a greater effect. In contrast, Gas6 was the sole stimulator of Axl and Akt kinase phosphorylation. In MGH-U3 bladder cancer cells, which express Tyro3 alone, ProS1 was again the stronger stimulator of Tyro3 and Erk stimulation but additionally stimulated Akt phosphorylation. Conditioned medium from ProS1-secreting 786-0 kidney cancer cells replicated the kinase activation effects of recombinant ProS1 in SCC-25 cells, with specificity confirmed by ProS1 ligand traps and warfarin. In addition, ProS1 protected cancer cells from acute apoptosis induced by staurosporine, as well as additionally, long-term serum starvation-induced apoptosis in MGH-U3 cells (Tyro3 only), which reflects its additional coupling to Akt signalling in these cells. In conclusion, we have shown that ProS1 is a tumour-derived functional ligand for Tyro3 that supports cancer cell survival. Furthermore, the ProS1-Tyro3 interaction is primarily coupled to Erk signalling although it displays signalling diversity dependent upon its representative expression as a TAM receptor in tumour cells.
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Speer, Nicole K., Jeremy R. Reynolds, Khena M. Swallow, and Jeffrey M. Zacks. "Reading Stories Activates Neural Representations of Visual and Motor Experiences." Psychological Science 20, no. 8 (August 2009): 989–99. http://dx.doi.org/10.1111/j.1467-9280.2009.02397.x.
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To understand and remember stories, readers integrate their knowledge of the world with information in the text. Here we present functional neuroimaging evidence that neural systems track changes in the situation described by a story. Different brain regions track different aspects of a story, such as a character's physical location or current goals. Some of these regions mirror those involved when people perform, imagine, or observe similar real-world activities. These results support the view that readers understand a story by simulating the events in the story world and updating their simulation when features of that world change.
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Lulli, Matteo, Lorenzo Cavallini, Laura Gragnani, Caecilia Sukowati, Tommaso Mello, Andrea Galli, Veronica Ghini, Krista Rombouts, and Vinicio Carloni. "THU-447-DNA damage response CHK2 activates senescence cellular program and supports oxidative metabolism to drive hepatocellular carcinoma development." Journal of Hepatology 70, no. 1 (April 2019): e355. http://dx.doi.org/10.1016/s0618-8278(19)30694-2.
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Huang, R. P., J. X. Wu, Y. Fan, and E. D. Adamson. "UV activates growth factor receptors via reactive oxygen intermediates." Journal of Cell Biology 133, no. 1 (April 1, 1996): 211–20. http://dx.doi.org/10.1083/jcb.133.1.211.
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Exposure of mammalian cells to UV irradiation induces rapid and transient expression of early growth response-1 gene (Egr-1) encoding a transcription factor that plays a role in cell survival. These signals from the irradiated cell surface are likely to involve more than one pathway, and we show here that an essential pathway involves activation of several growth factor receptors by reactive oxygen intermediates (ROI). UVC irradiation causes the tyrosine phosphorylation of EGF receptor (EGFR) in mouse NIH 3T3 fibroblasts and HC11 mouse mammary cells. EGFR activation by irradiation of cells is abrogated by suramin, by antioxidants, and by the presence of a dominant negative EGFR. UV induces the formation of complexes between activated EGFR and SOS, Grb2, PLC gamma, and SHC that can be precipitated with antibodies to EGFR. The activation of EGFR by UV is mimicked by H2O2, suggesting that ROI may function upstream of EGFR activation. Our observations support the hypothesis that ROI and growth factor receptors operate in the early steps of the UV signal that lead to the enhanced expression and activity of Egr-1.
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Grishko, Valentina, Viktor Pastukh, Viktoriya Solodushko, Mark Gillespie, Junichi Azuma, and Stephen Schaffer. "Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 6 (December 2003): H2364—H2372. http://dx.doi.org/10.1152/ajpheart.00408.2003.
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Angiotensin II contributes to ventricular remodeling by promoting both cardiac hypertrophy and apoptosis; however, the mechanism underlying the latter phenomenon is poorly understood. One possibility that has been advanced is that angiotensin II activates NADPH oxidase, generating free radicals that trigger apoptosis. In apparent support of this notion, it was found that angiotensin II-mediated apoptosis in the cardiomyocyte is blocked by the NADPH oxidase inhibitor diphenylene iodonium. However, three lines of evidence suggest that peroxynitrite, rather than superoxide, is responsible for angiotensin II-mediated DNA damage and apoptosis. First, the inducible nitric oxide inhibitor aminoguanidine prevents angiotensin II-induced DNA damage and apoptosis. Second, based on ligation-mediated PCR, the pattern of angiotensin II-induced DNA damage resembles peroxynitritemediated damage rather than damage caused by either superoxide or nitric oxide. Third, angiotensin II activates p53 through the phosphorylation of Ser15 and Ser20, residues that are commonly phosphorylated in response to DNA damage. It is proposed that angiotensin II promotes the oxidation of DNA, which in turn activates p53 to mediate apoptosis.
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Mao, Kairui, Antonio Baptista, Nicolas Bouladoux, Andrew J. Martins, Samira Tamoutounour, Jacquice Davis, Yuefeng Huang, Michael Y. Gerner, Yasmine Belkaid, and Ronald N. Germain. "Sequential activity of innate and adaptive lymphocytes supports non-inflammatory gut microbial commensalism." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 200.14. http://dx.doi.org/10.4049/jimmunol.198.supp.200.14.
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Abstract The mammalian gut is colonized by trillions of microorganisms termed the “microbiota”, which have a mutually beneficial relationship with their host. In normal individuals, the gut microbiota matures after birth to a state of balanced commensalism that is marked by the absence of adverse inflammation. Both innate lymphoid cells (ILCs) and antigen-specific conventional T cells contribute to containment and clearance of microbial pathogens. But how these two major lymphoid cell populations help shape the mature commensal (non-pathogenic) microbiome and maintain tissue homeostasis has not been determined. Using advanced multiplex quantitative imaging methods, here we show that in the absence of adaptive lymphocytes, IL-23 induced by specific commensal bacteria such as Segmented Filamentous Bacteria (SFB) persistently activates RORgt+ group 3 innate lymphoid cells (ILC3s) in the ileum to produce IL-22, which induces STAT3 activation in virtually all epithelial cells, contributing to production of molecules such as anti-microbial peptides that protect the tissue from microbial damage. The distinct roles of ILCs in handling gut microbes play out in normal mice during development. The pSTAT3 signature is absent after birth, which is followed by microbial colonization and strong ILC3 activation and an extensive epithelial pSTAT3 signature upon weaning. This innate immune activity is subsequently extinguished as adaptive CD4+ T cell immunity develops in response to the expanding commensal burden. Our findings provide new insights into how innate and adaptive lymphocytes sequentially operate during normal development to establish steady state commensalism.
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Ozkul, Burcu, Cemre Candemir, Kaya Oguz, Seda Eroglu-Koc, Gozde Kizilates-Evin, Onur Ugurlu, Yigit Erdogan, et al. "Gradual Loss of Social Group Support during Competition Activates Anterior TPJ and Insula but Deactivates Default Mode Network." Brain Sciences 13, no. 11 (October 25, 2023): 1509. http://dx.doi.org/10.3390/brainsci13111509.
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Group forming behaviors are common in many species to overcome environmental challenges. In humans, bonding, trust, group norms, and a shared past increase consolidation of social groups. Being a part of a social group increases resilience to mental stress; conversely, its loss increases vulnerability to depression. However, our knowledge on how social group support affects brain functions is limited. This study observed that default mode network (DMN) activity reduced with the loss of social group support from real-life friends in a challenging social competition. The loss of support induced anterior temporoparietal activity followed by anterior insula and the dorsal attentional network activity. Being a part of a social group and having support provides an environment for high cognitive functioning of the DMN, while the loss of group support acts as a threat signal and activates the anterior temporoparietal junction (TPJ) and insula regions of salience and attentional networks for individual survival.
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Luo, Min, Elle C. Flood, Dena Almeida, LunBiao Yan, David A. Berlin, Paul M. Heerdt, and Katherine A. Hajjar. "Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases." Journal of Experimental Medicine 214, no. 9 (July 10, 2017): 2535–45. http://dx.doi.org/10.1084/jem.20160652.
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Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia. We demonstrate that microvascular endothelial cells (ECs) from Anxa2−/− mice display reduced barrier function and excessive Src-related tyrosine phosphorylation of the adherens junction protein vascular endothelial cadherin (VEC). Moreover, unlike Anxa2+/+ controls, Anxa2−/− mice develop pulmonary edema and neutrophil infiltration in the lung parenchyma in response to subacute alveolar hypoxia. Mice deficient in the ANXA2-binding partner, S100A10, failed to demonstrate hypoxia-induced pulmonary edema under the same conditions. Further analyses reveal that ANXA2 forms a complex with VEC and its phosphatases, EC-specific protein tyrosine phosphatase (VE-PTP) and Src homology phosphatase 2 (SHP2), both of which are implicated in vascular integrity. In the absence of ANXA2, VEC is hyperphosphorylated at tyrosine 731 in response to vascular endothelial growth factor, which likely contributes to hypoxia-induced extravasation of fluid and leukocytes. We conclude that ANXA2 contributes to pulmonary microvascular integrity by enabling VEC-related phosphatase activity, thereby preventing vascular leak during alveolar hypoxia.
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Carpino, Nick, William E. Thierfelder, Ming-shi Chang, Chris Saris, Steven J. Turner, Steven F. Ziegler, and James N. Ihle. "Absence of an Essential Role for Thymic Stromal Lymphopoietin Receptor in Murine B-Cell Development." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2584–92. http://dx.doi.org/10.1128/mcb.24.6.2584-2592.2004.
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ABSTRACT The murine cytokine thymic stromal lymphopoietin (TSLP) supports the development of B220+ IgM+ immature B cells and induces thymocyte proliferation in vitro. Human TSLP, by contrast, activates CD11c+ dendritic cells, but not B or T cells. Recent studies have demonstrated that the receptor for TSLP consists of a heterodimer of the interleukin 7 (IL-7) α chain and a novel protein that resembles the hematopoietic cytokine receptor common γ chain. We examined signal transduction by the γ-like chains using chimeric receptor proteins. The cytoplasmic domain of the human, but not of the murine, γ-like chain, activates Jak2 and Stat5 and supports the proliferation of hematopoietic cell lines. In order to assess the role of the murine γ-like chain in vivo, we generated γ-like chain-deficient mice. Receptor-deficient mice are unresponsive to TSLP but exhibit no obvious phenotypic defects. In particular, hematopoietic cell development appeared normal. B-cell development, including the IgM+ compartment, was unaffected by loss of the TSLP pathway, as were T lymphopoiesis and lymphocyte proliferation in vitro. Cytokine receptors that utilize the common γ chain signal through the lymphocyte-specific kinase Jak3. Mice deficient in Jak3 exhibit a SCID phenotype but harbor a residual B220+ splenic lymphocyte population. We demonstrate here that this residual lymphocyte population is lost in mice lacking both the γ-like chain and Jak3.
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Bhatt, Jay M., William Hancock, Justyna M. Meissner, Aneta Kaczmarczyk, Eunjoo Lee, Ekaterina Viktorova, Sasanka Ramanadham, George A. Belov, and Elizabeth Sztul. "Promiscuity of the catalytic Sec7 domain within the guanine nucleotide exchange factor GBF1 in ARF activation, Golgi homeostasis, and effector recruitment." Molecular Biology of the Cell 30, no. 12 (June 2019): 1523–35. http://dx.doi.org/10.1091/mbc.e18-11-0711.
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The integrity of the Golgi and trans-Golgi network (TGN) is disrupted by brefeldin A (BFA), which inhibits the Golgi-localized BFA-sensitive factor (GBF1) and brefeldin A–inhibited guanine nucleotide-exchange factors (BIG1 and BIG2). Using a cellular replacement assay to assess GBF1 functionality without interference from the BIGs, we show that GBF1 alone maintains Golgi architecture; facilitates secretion; activates ADP-ribosylation factor (ARF)1, 3, 4, and 5; and recruits ARF effectors to Golgi membranes. Unexpectedly, GBF1 also supports TGN integrity and recruits numerous TGN-localized ARF effectors. The impact of the catalytic Sec7 domain (Sec7d) on GBF1 functionality was assessed by swapping it with the Sec7d from ARF nucleotide-binding site opener (ARNO)/cytohesin-2, a plasma membrane GEF reported to activate all ARFs. The resulting chimera (GBF1-ARNO-GBF1 [GARG]) targets like GBF1, supports Golgi/TGN architecture, and facilitates secretion. However, unlike GBF1, GARG activates all ARFs (including ARF6) at the Golgi/TGN and recruits additional ARF effectors to the Golgi/TGN. Our results have general implications: 1) GEF’s targeting is independent of Sec7d, but Sec7d influence the GEF substrate specificity and downstream effector events; 2) all ARFs have access to all membranes, but are restricted in their distribution by the localization of their activating GEFs; and 3) effector association with membranes requires the coincidental presence of activated ARFs and specific membrane identifiers.
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Zhang, Peng, Chun Yang, and Rona J. Delay. "Urine Stimulation Activates BK Channels in Mouse Vomeronasal Neurons." Journal of Neurophysiology 100, no. 4 (October 2008): 1824–34. http://dx.doi.org/10.1152/jn.90555.2008.
Full textAbstract:
Most odor responses in mouse vomeronasal neurons are mediated by the phospholipase C (PLC) pathway, activation of which elevates diacylglycerol (DAG). Lucas et al. showed that DAG activates transient receptor potential channels, subfamily C, member 2 (TRPC2), resulting in a depolarizing Ca2+ influx. DAG can be subsequently converted to arachidonic acid (AA) by a DAG lipase, the role of which remains largely unknown. In this study, we found that urine stimulation of vomeronasal neurons activated large-conductance Ca2+-activated K+ (BK) channels via AA production. Using isolated neurons, we demonstrated that repetitive applications of AA potentiated a K+ current that required a Ca2+ influx and was sensitive to specific BK blockers. Using immunocytochemistry, we found that BK channels are present in vomeronasal neurons with labeling on the soma and heavy labeling on the dendrite with a BK channel antibody. We examined the role of these BK channels in regulating neuronal firing when the neuron was activated by membrane depolarization or urine. Contrary to a recent report, our data suggest that BK channels contribute to adaptation of urine/odor responses because the inhibition of BK channels during urine stimulation promoted repetitive firing. These data strongly support the hypothesis that AA mediates an inhibitory pathway through BK channels, a possible mechanism for odor adaptation in vomeronasal neurons.
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Dabiri, Minoo, Hassan Fazli, Neda Salarinejad, and Siyavash Kazemi Movahed. "Pd nanoparticles supported on cubic shaped ZIF-based materials and their catalytic activates in organic reactions." Materials Research Bulletin 133 (January 2021): 111015. http://dx.doi.org/10.1016/j.materresbull.2020.111015.
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Kamal, Ahmad M., Richard P. G. Hayhoe, Anbalakan Paramasivam, Dianne Cooper, Roderick J. Flower, Egle Solito, and Mauro Perretti. "Antiflammin-2 Activates the Human Formyl-Peptide Receptor Like 1." Scientific World JOURNAL 6 (2006): 1375–84. http://dx.doi.org/10.1100/tsw.2006.247.
Full textAbstract:
The anti-inflammatory actions of the nonapeptide antiflammin-2, identified by homology with uteroglobin and annexin-A1 sequences, have been described in some detail, yet its mechanisms of action remain elusive. Since recent data indicate an involvement of the formyl peptide receptor (FPR)-like 1 (or FPRL-1) in the effects of annexin-A1, we have tested here the effect of antiflammin-2 with respect to this receptor family. Using HEK-293 cells expressing either human FPR and FPRL-1, and an annexin-A1 peptide as tracer ([125I-Tyr]-Ac2-26), we found that antiflammin-2 competed for binding only at FPRL-1, and not FPR, with an approximate EC50of 1 μM. In line with data produced for the full-length protein, genuine receptor activation by antiflammin-2 was confirmed by rapid phosphorylation of extracellular-regulated kinase 1 and 2. Finally, study of the neutrophil interaction with activated endothelium under flow demonstrated an inhibitory effect of antiflammin-2, thus providing functional support to a role for the antiflammin-2/FPRL-1 anti-inflammatory axis.
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Li, Weiyan, Christopher Thaler, and Paul Brehm. "Calcium Channels in Xenopus Spinal Neurons Differ in Somas and Presynaptic Terminals." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 269–79. http://dx.doi.org/10.1152/jn.2001.86.1.269.
Full textAbstract:
Calcium channels play dual roles in cell signaling by promoting membrane depolarization and allowing entry of calcium ions. Patch-clamp recordings of calcium and calcium-dependent currents from the soma of Xenopus spinal neurons indicate key functional differences from those of presynaptic terminals. Both terminals and somas exhibit prominent high-voltage-activated (HVA) calcium current, but only the soma expresses additional low-voltage-activated (LVA) T-type current. Further differences are reflected in the HVA current; N- and R-type channels are predominant in the soma while the terminal calcium current is composed principally of N type with smaller contribution by L- and R-type channels. Potential physiological significance for these different distributions of channel types may lie in the differential channel kinetics. Activation of somatic HVA calcium current occurs more slowly than HVA currents in terminals. Additionally, somatic LVA calcium current activates and deactivates much more slowly than any HVA calcium current. Fast-activating and -deactivating calcium current may be critical to processing the rapid exocytotic response in terminals, whereas slow LVA and HVA calcium currents may play a central role in shaping the somatic firing pattern. In support of different kinetic behavior between these two compartments, we find that somatic calcium current activates a prominent slow chloride current not observed in terminal recordings. This current activates in response to calcium entering through either LVA or HVA channels and likely functions as a modulator of excitability or synaptic input. The restriction of this channel type to the soma lends further support to the idea that differential expression of fast and slow channel types in these neurons is dictated by differences in signaling requirements for somatic and terminal compartments.