Zeitschriftenartikel: „Activating supports“

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Prades, Floran, Jean-Pierre Broyer, Islem Belaid, Olivier Boyron, Olivier Miserque, Roger Spitz und Christophe Boisson. „Borate and MAO Free Activating Supports for Metallocene Complexes“. ACS Catalysis 3, Nr. 10 (16.09.2013): 2288–93. http://dx.doi.org/10.1021/cs400655y.

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Mantanona, Alex J., Katelyn Wood, Yann Schrodi und Simon J. Garrett. „Activating Ru nanoparticles on oxide supports for ring-opening metathesis polymerization“. Dalton Transactions 47, Nr. 23 (2018): 7754–60. http://dx.doi.org/10.1039/c8dt00354h.

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Muro, Ryunosuke, Takeshi Nitta, Toshiyuki Okada, Hitoshi Ideta, Takeshi Tsubata und Harumi Suzuki. „The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells“. PLOS ONE 10, Nr. 3 (20.03.2015): e0119898. http://dx.doi.org/10.1371/journal.pone.0119898.

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Subrizi, Fabiana, Marcello Crucianelli, Valentina Grossi, Maurizio Passacantando, Lorenzo Pesci und Raffaele Saladino. „Carbon Nanotubes as Activating Tyrosinase Supports for the Selective Synthesis of Catechols“. ACS Catalysis 4, Nr. 3 (05.02.2014): 810–22. http://dx.doi.org/10.1021/cs400856e.

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Skowronek, Patrycja, und Aneta Strachecka. „Cannabidiol (CBD) Supports the Honeybee Worker Organism by Activating the Antioxidant System“. Antioxidants 12, Nr. 2 (27.01.2023): 279. http://dx.doi.org/10.3390/antiox12020279.

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In the experiment, we tested the effect of 30% CBD oil on the activity of the antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, glutathione), the level of total antioxidant capacity, and the concentrations of ions (calcium, magnesium, and phosphorus) in honeybee workers in the hive test. For this purpose, we prepared hives containing all stages of the development of honey bees and started the experiment by adding 200 marked, one-day old bees to each colony (intended for hemolymph collection). In the test, we created three groups (two colonies per group): (1) Experimental with CBD oil mixed with sugar syrup (CSy); (2) experimental with CBD oil on textile strips (CSt); and (3) control with pure sugar syrup only (C). Every week, we collected hemolymph from the marked bees. In the experiment, all antioxidant enzyme activities were higher for the experimental groups CSy and CSt compared to group C. The highest concentrations/levels were obtained for the CSy group. Concentrations of calcium, magnesium, and phosphorus ions were also higher for the experimental groups compared to the C group (the highest concentration for the CSy group). We conclude that CBD oil positively contributes to stimulating the antioxidant system of honeybees.

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Valentin, P., und O. Schmetzer. „402 B cell activating factor, BAFF, supports MC development from CD34+ stem cells“. Journal of Investigative Dermatology 136, Nr. 9 (September 2016): S229. http://dx.doi.org/10.1016/j.jid.2016.06.422.

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Whitmore, Kathryn F., James S. Chisholm und Lauren Fletcher. „Fostering, Activating, and Curating: Approaching Books about Social Injustices with the Arts“. Language Arts 98, Nr. 1 (01.09.2020): 7–18. http://dx.doi.org/10.58680/la202030812.

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Alon, R., P. D. Kassner, M. W. Carr, E. B. Finger, M. E. Hemler und T. A. Springer. „The integrin VLA-4 supports tethering and rolling in flow on VCAM-1.“ Journal of Cell Biology 128, Nr. 6 (15.03.1995): 1243–53. http://dx.doi.org/10.1083/jcb.128.6.1243.

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Selectins have previously been shown to tether a flowing leukocyte to a vessel wall and mediate rolling. Here, we report that an intergrin, VLA-4, can also support tethering and rolling. Blood T lymphocytes and alpha 4 integrin-transfected cells can tether in shear flow, and then roll, through binding of the intergrin VLA-4 to purified VCAM-1 on the wall of a flow chamber. VLA-4 transfectants showed similar tethering and rolling on TNF-stimulated endothelium. Tethering efficiency, rolling velocity, and resistance to detachment are related to VCAM-1 density. Tethering and rolling did not occur on ICAM-1, fibronectin, or fibronectin fragments, and tethering did not require integrin activation or the presence of an alpha 4 cytoplasmic domain. Arrest of rolling cells on VCAM-1 occurred spontaneously, and/or was triggered by integrin activating agents Mn2+, phorbol ester, and mAb TS2/16. These agents, and the alpha 4 cytoplasmic domain, promoted increased resistance to detachment. Together the results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1.

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Metelli, Alessandra, Bill Wu, Brian Riesenberg, Caroline Wallace Fugle, Shaoli Sun, Bei Liu und Zihai Li. „GARP-TGFβ Axis on Activated Platelets Supports Tumor Progression“. Journal of Immunology 198, Nr. 1_Supplement (01.05.2017): 126.17. http://dx.doi.org/10.4049/jimmunol.198.supp.126.17.

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Abstract Platelet-induced cancer progression is a well-known process driven by mitogenic factors released by activated platelets, among them the most pro-oncogenic is Latent Transforming Growth Factor Beta (LTGFβ). Glycoprotein-A Repetitions Predominant Protein (GARP), a receptor for LTGFβ that enhances its bioactivation, is expressed by regulatory T cells, platelets, and several human cancers. Upon activation platelets dramatically upregulate GARP, suggesting that GARP might play a role in activating LTGFβ released upon platelet degranulation and thus in platelet-induced cancer progression. To address this point we employed a novel mouse model based on the platelet-specific knock-out of the GARP gene. We show that in activated platelets GARP is critical for the expression of surface LTGFβ and for its conversion to the bioactive form. Lack of GARP on platelets, indeed, resulted in the complete absence of serum active TGFβ. To investigate whether GARP plays a role in platelet-induced cancer progression we tested multiple tumor models and observed that genetic deletion of GARP enhanced adoptive T cell therapy of B16 melanoma. We also found that in MC38 colon tumor model GARP on platelets contributes to cancer progression by increasing TGFβ bioavailability, promoting regulatory T lymphocytes and myeloid cells, and favoring the immune evasion of cancer cells. These results demonstrate that platelet-specific deletion of GARP blunted TGFβ activity in the tumor microenvironment and boosted protective immunity against pre-established cancers. We conclude that platelets constrain anti-tumor immunity via a GARP-TGFβ axis and we propose the combination of immunotherapy and platelet inhibitors as a novel treatment strategy against cancer.

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Chen, Jasper R., Jincheng Han, Cullen M. Taniguchi und Ronald A. DePinho. „Abstract 4757: Loss of KDM5A supports KRAS-driven pancreatic cancer“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 4757. http://dx.doi.org/10.1158/1538-7445.am2023-4757.

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Abstract Objective: Mutant KRAS is a primary driver of pancreatic ductal adenocarcinoma (PDAC), which exhibits marked hypoxia. Despite the strong association of hypoxia and PDAC, the relationship between KRAS and hypoxia is still poorly understood. The oxygen-sensitive histone lysine demethylase, KDM5A, was recently reported to mediate epigenetic responses to hypoxia independent of the hypoxia-inducible factors. KDM5A epigenetically represses transcription via two mechanisms: by its demethylase activity on activating H3K4me3 marks, and through its interaction with deacetylase complexes containing HDAC1/2, which deacetylates activating H3K9ac and H4K16ac histone marks. Under hypoxic conditions, KDM5A loses its activity, leading to restoration of these H3K4me3 marks, thereby activating KDM5A target genes. The purpose of this study is to understand how KDM5A loss of function contributes to pathogenesis of mutant KRAS-driven pancreatic cancer. Methods: Cell lines derived from mice with pancreas-specific p53 deletion and doxycycline-inducible expression of KrasG12D (iKPC). Protein lysates were prepared using RIPA buffer. Histones were purified by acid extraction. Immunoblotting was used to probe for protein levels of Kdm5a, H3K4me3, H3K9ac, and H4K16ac. Genetic ablation of KrasG12D was performed by culturing iKPCs in tetracycline-free medium. Kras was induced by adding doxycycline to the culture medium. Pharmaceutical inhibition of MEK, proteasome, and Kdm5a were performed by treating iKPCs with mirdametinib, MG-132, and CPI-455, respectively. Knockdown of β-TrCP and FBXW7 were performed by stable expression of shRNA in iKPCs. Protein motif scanning was performed using the Eukaryotic Linear Motif (ELM) Prediction online software. Results: We discovered that Kdm5a protein levels were abrogated by induction of KrasG12D and stabilized by genetic ablation of Kras. Pharmaceutical inhibition of MEK or proteasome function stabilized Kdm5a, indicating that Kras induces Kdm5a proteasomal degradation through the MEK/ERK pathway. H3K4me3, H3K9ac, and H4K16ac histone marks were increased in Kras-on iKPC compared to Kras-off iKPC, consistent the expected effect of Kras-induced Kdm5a degradation. Pharmaceutical inhibition Kdm5a in the Kras-off setting restored H3K4me3, suggesting that Kdm5a contributes to demethylation of H3K4me3 in iKPC. We identified two phosphodegron sites corresponding to β-TrCP and FBXW7 of the ubiquitin ligase complex within the Kdm5a protein sequence. Knockdown of either β-TrCP or FBXW7 in iKPC both stabilized Kdm5a despite induction of Kras. Conclusion: We conclude that Kdm5a plays a tumor suppressor role in pancreatic cancer by epigenetically repressing transcriptional programs necessary for KRAS-driven oncogenesis. Citation Format: Jasper R. Chen, Jincheng Han, Cullen M. Taniguchi, Ronald A. DePinho. Loss of KDM5A supports KRAS-driven pancreatic 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 4757.

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Hashemi, Elaheh, und Subramaniam Malarkannan. „Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance“. Cancers 12, Nr. 6 (12.06.2020): 1553. http://dx.doi.org/10.3390/cancers12061553.

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Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells.

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Lee, Jounghyun Helen, Joanne Haeun Lee, David Rothstein und Lance C. Kam. „CD45 ligation reduces Tregs’ motility and enhances recognition of activating signals in vitro“. Journal of Immunology 200, Nr. 1_Supplement (01.05.2018): 55.45. http://dx.doi.org/10.4049/jimmunol.200.supp.55.45.

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Abstract Regulatory T cells (Tregs) play a pivotal role in modulating immune response hence supporting immune tolerance. Recently, CD45 ligation with anti-CD45RB mAb MB23G2 (anti-CD45RB) was reported to enhance graft-survival; evidence shows it was by homeostatic Treg proliferation in vivo. While many in vivo data support the notion that anti-CD45RB supports Tregs expansion, it is still unclear if the ligation ex vivo is sufficient to enhance Tregs’ avidity for activation and further promote their expansion and function. Here, we were to see if anti-CD45RB ligation can enhance Treg’s sensitivity to perceive activating signals in varying strength in vitro. To test this hypothesis, mouse CD4+ T cells (Foxp3-GFP linked B6 mouse, both Foxp3+ and Foxp3−, or Tregs and Tconvs, respectively) were seeded onto surfaces micropatterned with an antibody targeting the CD3 on T cell (anti-CD3) with and without the presence of anti-CD45RB. These surfaces were created by first microcontact printing of 2-μm diameter features of anti-CD3 at various concentrations (i.e., 1, 5, and 20 μg/mL) on glass coverslips and back-filled with ICAM-1. The effect of anti-CD45RB on Treg and Tconv activation was compared by the ratios of phosphorylation of Lck at Tyr 394 to 505 sites, cell registration on anti-CD3 dot array, and motility of each cell type on varying concentration of activation signals. Overall results show that anti-CD45RB specifically slow-down Treg motility and, therefore, enhance the probability to contact to activating signals (cell registration) and improve T cell activation indicated by ratios of phospho-Lck at active over inactive sites. This study assures the importance of further investigation on the role of anti-CD45RB in Treg activation mechanism.

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Bian, Jin-Song, Anna Kagan und Thomas V. McDonald. „Molecular analysis of PIP2 regulation of HERG and IKr“. American Journal of Physiology-Heart and Circulatory Physiology 287, Nr. 5 (November 2004): H2154—H2163. http://dx.doi.org/10.1152/ajpheart.00120.2004.

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We previously reported that cloned human ether-à-go-go-related gene (HERG) K+ channels are regulated by changes in phosphatidylinositol 4,5-bisphosphate (PIP2) concentration. Here we investigated the molecular determinants of PIP2 interactions with HERG channel protein. To establish the molecular nature of the PIP2-HERG interaction, we examined a segment of the HERG COOH terminus with a high concentration of positively charged amino acids (nos. 883–894) as a possible site of interaction with negatively charged PIP2. When we excised deletion-HERG (D-HERG) or mutated methionine-substituted-HERG (M-HERG) this segment of HERG to neutralize the amino acid charge, the mutant channels produced current that was indistinguishable from wild-type HERG. Elevating internal PIP2, however, no longer accelerated the activation kinetics of the mutant HERG. Moreover, PIP2-dependent hyperpolarizing shifts in the voltage dependence of activation were abolished with both mutants. PIP2 effects on channel-inactivation kinetics remained intact, which suggests an uncoupling of inactivation and activation regulation by PIP2. The specific binding of radiolabeled PIP2 to both mutant channel proteins was nearly abolished. Stimulation of α1A-adrenergic receptors produced a reduction in current amplitude of the rapidly activating delayed rectifier K+ current (the current carried by ERG protein) from rabbit ventricular myocytes. The α-adrenergic-induced current reduction was accentuated by PKC blockers and also unmasked a depolarizing shift in the voltage dependence of activation, which supports the conclusion that receptor activation of PLC results in PIP2 consumption that alters channel activity. These results support a physiological role for PIP2 regulation of the rapidly activating delayed rectifier K+ current during autonomic stimulation and localize a site of interaction to the COOH-terminal tail of the HERG K+ channel.

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Vivanco, Igor, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras und Nikolaos Palaskas. „Abstract 632: AKT supports cancer cell survival through modulation of cholesterol homeostasis“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 632. http://dx.doi.org/10.1158/1538-7445.am2024-632.

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Abstract AKT is a critical effector kinase downstream of PI3K activation. It has been shown to regulate a variety of cellular processes important for homeostasis, many of which are altered during oncogenesis. Not surprisingly, AKT is constitutively activated in a large number of human cancers, and has consequently been pursued as a therapeutic target for many years. Some of these functions are directly involved in establishing one or more hallmarks of cancer including sustained proliferative signaling, resisting cell death, and reprogrammed cellular metabolism. Although AKT inhibitors have demonstrated clinical benefit (most recently in a phase III trial) in combination with other therapies, single agent activity has been limited to a few cases with relatively infrequent activating AKT1 mutations. We have previously proposed that the clear disconnect between the high frequency of AKT activation in cancer and the lack of broad clinical activity of AKT inhibitors is due, at least in part, to the inability of existing compounds to block non-catalytic functions. We have found that while allosteric AKT inhibitors are partial suppressors of these functions, ATP-competitive inhibitors fail to suppress these functions to any significant extent. We now provide evidence that one important non-catalytic function of AKT that impinges on its oncogenic function is the regulation of cholesterol metabolism. We show that AKT represses the activation of LXRβ, thereby maintaining a level of intracellular cholesterol that is compatible with cancer cell viability, and that this repression does not require catalytic activity. Consistently, we find that allosteric AKT inhibitors induce LXRβ activation, and that genetic or pharmacological suppression of LXRβ function limit the growth inhibiting effects of these drugs. Our findings suggest that through a kinase-independent activity, AKT may play a significant role in the regulation of cholesterol homeostasis, and that the therapeutic potential of AKT inhibitors could be broaden by optimizing their ability to interfere with these functions. Citation Format: Igor Vivanco, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras, Nikolaos Palaskas. AKT supports cancer cell survival through modulation of cholesterol homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 632.

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Kilpatrick, Alexander F. R., Nicholas H. Rees, Zoë R. Turner, Jean-Charles Buffet und Dermot O’Hare. „Physicochemical surface-structure studies of highly active zirconocene polymerisation catalysts on solid polymethylaluminoxane activating supports“. Materials Chemistry Frontiers 4, Nr. 11 (2020): 3226–33. http://dx.doi.org/10.1039/d0qm00482k.

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Static ⁹¹Zr ssNMR, SEM-EDX, and DRIFT spectroscopy indicate that a common zirconium species, [Cp^R₂ZrMe]⁺, is present in all sMAO supported catalyst systems.

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Lenz, B. Keith, Gordon R. Alley und Jean B. Schumaker. „Activating the Inactive Learner: Advance Organizers in the Secondary Content Classroom“. Learning Disability Quarterly 10, Nr. 1 (Februar 1987): 53–67. http://dx.doi.org/10.2307/1510755.

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The success of current mainstreaming efforts for LD adolescents is dependent, in part, on the environmental supports available in regular secondary classrooms. The present study investigated the effects of the regular teacher's delivery of an advance organizer prior to each lesson on LD students' retention and expression of information from a given lesson. The results indicated that teaching techniques used by regular secondary teachers can benefit handicapped students in their classrooms, but, in the case of advance organizers, only when students are taught to make use of such techniques.

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Guidetti, Gianni, Alessandra Bertoni, Manuela Viola, Enrica Tira, Cesare Balduini und Mauro Torti. „The small proteoglycan decorin supports adhesion and activation of human platelets“. Blood 100, Nr. 5 (01.09.2002): 1707–14. http://dx.doi.org/10.1182/blood.v100.5.1707.h81702001707_1707_1714.

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Decorin is a small leucine-rich proteoglycan able to interact with several molecules of the subendothelial matrix, such as collagen and fibronectin. In this work, we investigated the ability of purified decorin to support adhesion of human platelets. We found that gel-filtered platelets were actually able to interact with immobilized decorin. Platelet adhesion to decorin was time dependent, required the presence of Mg2+ ions, and was totally mediated by the protein core of the proteoglycan. Platelet stimulation with either adenosine diphosphate (ADP) or a thrombin receptor–activating peptide significantly increased interaction of these cells with the proteoglycan. Upon adhesion to immobilized decorin a number of platelet proteins were found to become tyrosine-phosphorylated. By immunoprecipitation experiments with specific antibodies, the tyrosine phosphorylation of the tyrosine kinase Syk and the phospholipase Cγ2 (PLCγ2) isozyme was demonstrated in decorin-adherent platelets. Interaction of platelets with decorin was selectively prevented by 2 different antibodies against membrane integrin α2β1, but not by a number of antibodies against other membrane receptors. In addition, integrin α2β1, purified from platelet membranes, was able to specifically interact with immobilized decorin. Finally, purified decorin bound to Sepharose beads could precipitate integrin α2β1 from a platelet membrane glycoprotein preparation. Therefore, these results demonstrate that human platelets can bind to immobilized decorin through integrin α2β1, and that this interaction results in the tyrosine phosphorylation of intracellular proteins.

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Eikmeier, Ginger M. „D’oh! Using The Simpsons to Improve Student Response to Literature“. English Journal 97, Nr. 4 (01.03.2008): 1–4. http://dx.doi.org/10.58680/ej20086299.

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Students in Ginger M. Eikmeier’s high school classes link themes and terms from their readings to episodes of The Simpsons. Because students are already familiar with The Simpsons, Eikmeier believes that using the show supports students’ comprehension and retention by activating prior knowledge. Additionally, it shows students that she cares about their interests when designing the curriculum.

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Arden, Jessica D., Kari I. Lavik, Kaitlin A. Rubinic, Nicolas Chiaia, Sadik A. Khuder, Marthe J. Howard, Andrea L. Nestor-Kalinoski, Arthur S. Alberts und Kathryn M. Eisenmann. „Small-molecule agonists of mammalian Diaphanous–related (mDia) formins reveal an effective glioblastoma anti-invasion strategy“. Molecular Biology of the Cell 26, Nr. 21 (November 2015): 3704–18. http://dx.doi.org/10.1091/mbc.e14-11-1502.

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The extensive invasive capacity of glioblastoma (GBM) makes it resistant to surgery, radiotherapy, and chemotherapy and thus makes it lethal. In vivo, GBM invasion is mediated by Rho GTPases through unidentified downstream effectors. Mammalian Diaphanous (mDia) family formins are Rho-directed effectors that regulate the F-actin cytoskeleton to support tumor cell motility. Historically, anti-invasion strategies focused upon mDia inhibition, whereas activation remained unexplored. The recent development of small molecules directly inhibiting or activating mDia-driven F-actin assembly that supports motility allows for exploration of their role in GBM. We used the formin inhibitor SMIFH2 and mDia agonists IMM-01/-02 and mDia2-DAD peptides, which disrupt autoinhibition, to examine the roles of mDia inactivation versus activation in GBM cell migration and invasion in vitro and in an ex vivo brain slice invasion model. Inhibiting mDia suppressed directional migration and spheroid invasion while preserving intrinsic random migration. mDia agonism abrogated both random intrinsic and directional migration and halted U87 spheroid invasion in ex vivo brain slices. Thus mDia agonism is a superior GBM anti-invasion strategy. We conclude that formin agonism impedes the most dangerous GBM component—tumor spread into surrounding healthy tissue. Formin activation impairs novel aspects of transformed cells and informs the development of anti-GBM invasion strategies.

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Vincent-Ruz, Paulette, und Nathan R. B. Boase. „Activating discipline specific thinking with adaptive learning: A digital tool to enhance learning in chemistry“. PLOS ONE 17, Nr. 11 (15.11.2022): e0276086. http://dx.doi.org/10.1371/journal.pone.0276086.

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In tertiary science education, students are encouraged to engage in discipline specific thinking, to learn their chosen subject. The challenge for educators is engaging all students equitably, despite their educational backgrounds and depth of discipline specific knowledge. Personalising learning in the context of large-scale tertiary courses can only be achieved by using digital technologies. In the context of chemistry education, this project has investigated how an adaptive learning technology can effectively and consistently engage students in discipline specific thinking, by personalising their learning pathway. Adaptive learning has been integrated into a foundational chemistry subject and through quantitative analysis there is empirical evidence to support the benefit adaptive learning has on outcomes, in both the short and long term. This study shows adaptive learning can equitably meet the needs for all students and can lead to improvements in educational behaviour beyond grades. The evidence supports adaptive learning as one critical tool for chemistry educators, and educators in other disciplines of science, to include in their suite of pedagogical strategies to meet the needs of all their students.

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Shekar, Meghan, Gabriela Llaurador Caraballo, Jyotinder N. Punia, Choladda Curry, Kevin E. Fisher und Michele S. Redell. „ALK Fusion in an Adolescent with Acute Myeloid Leukemia: A Case Report and Review of the Literature“. Biomedicines 11, Nr. 7 (27.06.2023): 1842. http://dx.doi.org/10.3390/biomedicines11071842.

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Activating mutations and fusions of the ALK oncogene have been identified as drivers in a number of malignancies. Crizotinib and subsequent ALK tyrosine kinase inhibitors have improved treatment outcomes for these patients. In this paper, we discuss the case of an adolescent patient with acute myeloid leukemia, who was identified to have an activating ALK fusion, which is a rare finding and has never been reported in cases of AML without monosomy 7. Crizotinib was added to this patient’s frontline therapy and was well tolerated. In cases of more common gene alterations, existing data supports the use of targeted agents as post-HSCT maintenance therapy; however, crizotinib was not able to be used post-HSCT for this patient due to the inability to obtain insurance coverage.

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Burge, D. J., J. Eisenman, K. Byrnes-Blake, P. Smolak, K. Lau, S. B. Cohen, A. J. Kivitz et al. „Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study“. Lupus 26, Nr. 8 (16.11.2016): 825–34. http://dx.doi.org/10.1177/0961203316678675.

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Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

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von Roemeling, Christina A., Derek C. Radisky, Laura A. Marlow, Simon J. Cooper, Stefan K. Grebe, Panagiotis Z. Anastasiadis, Han W. Tun und John A. Copland. „Neuronal Pentraxin 2 Supports Clear Cell Renal Cell Carcinoma by Activating the AMPA-Selective Glutamate Receptor-4“. Cancer Research 74, Nr. 17 (24.06.2014): 4796–810. http://dx.doi.org/10.1158/0008-5472.can-14-0210.

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Gorgojo, P., M. F. Jimenez-Solomon und A. G. Livingston. „Polyamide thin film composite membranes on cross-linked polyimide supports: Improvement of RO performance via activating solvent“. Desalination 344 (Juli 2014): 181–88. http://dx.doi.org/10.1016/j.desal.2014.02.009.

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Stutchfield, J., und S. Cockcroft. „Guanine nucleotides stimulate polyphosphoinositide phosphodiesterase and exocytotic secretion from HL60 cells permeabilized with streptolysin O“. Biochemical Journal 250, Nr. 2 (01.03.1988): 375–82. http://dx.doi.org/10.1042/bj2500375.

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The non-differentiated HL60 cell can be stimulated to secrete when Ca2+ and guanosine 5′-[gamma-thio]-triphosphate (GTP gamma S) are introduced into streptolysin-O-permeabilized cells. Secretion is accompanied by activation of polyphosphoinositide phosphodiesterase (PPI-pde). Both responses show a concentration-dependence on Ca2+ between pCa 8 and pCa 5. The half-maximal requirements for Ca2+ for PPI-pde activation and secretion are pCa 6.4 +/- 0.1 and pCa 6.2 +/- 0.2 respectively. The rank order of potency of the GTP analogues to stimulate PPI-pde activation and secretion is similar; GTP gamma S greater than guanosine 5′-[beta gamma-imido]-triphosphate greater than guanosine 5′-[beta gamma-methylene]triphosphate greater than XTP approximately equal to ITP, but the maximal response achieved by each compound compared with GTP gamma S is much greater for secretion than for PPI-pde activation. A dissociation of the two responses is obtained with 10 mM-XTP and -ITP; secretion is always observed but not inositol trisphosphate formation at this concentration. GTP, dGTP, UTP and CTP are inactive for both secretion and PPI-pde activation. Both GDP and dGDP are competitive inhibitors of both GTP gamma S-induced secretion and PPI-pde activation. Phorbol 12-myristate 13-acetate could not fully substitute for GTP gamma S in stimulating secretion, suggesting that the effect of GTP gamma S cannot result simply from the generation of diacylglycerol. In the absence of MgATP, secretion and PPI-pde activation is still evident, albeit at a reduced level. This also supports the hypothesis that protein kinase C-dependent phosphorylation is not essential for secretion. The effect of MgATP is to enhance secretion, and to reduce both the Ca2+ and GTP gamma S requirement for secretion. In conclusion, two roles for guanine nucleotides can be identified; one for activating PPI-pde (GP) and the other for activating exocytosis (GE), acting in series.

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Wang, Han, Jianxun Qi, Shuijun Zhang, Yan Li, Shuguang Tan und George F. Gao. „Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5“. Proceedings of the National Academy of Sciences 116, Nr. 3 (27.12.2018): 988–96. http://dx.doi.org/10.1073/pnas.1815716116.

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Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.

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Mao, Po-Hsin, Eilhann Kwon, Hou-Chien Chang, Ha Manh Bui, Songkeart Phattarapattamawong, Yu-Chih Tsai, Kun-Yi Andrew Lin, Afshin Ebrahimi, Yeoh Fei Yee und Min-Hao Yuan. „Modulating Direct Growth of Copper Cobaltite Nanostructure on Copper Mesh as a Hierarchical Catalyst of Oxone Activation for Efficient Elimination of Azo Toxicant“. Nanomaterials 12, Nr. 24 (09.12.2022): 4396. http://dx.doi.org/10.3390/nano12244396.

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As cobalt (Co) has been the most useful element for activating Oxone to generate SO4•−, this study aims to develop a hierarchical catalyst with nanoscale functionality and macroscale convenience by decorating nanoscale Co-based oxides on macroscale supports. Specifically, a facile protocol is proposed by utilizing Cu mesh itself as a Cu source for fabricating CuCo2O4 on Cu mesh. By changing the dosages of the Co precursor and carbamide, various nanostructures of CuCo2O4 grown on a Cu mesh can be afforded, including nanoscale needles, flowers, and sheets. Even though the Cu mesh itself can be also transformed to a Cu-Oxide mesh, the growth of CuCo2O4 on the Cu mesh significantly improves its physical, chemical, and electrochemical properties, making these CuCo2O4@Cu meshes much more superior catalysts for activating Oxone to degrade the Azo toxicant, Acid Red 27. More interestingly, the flower-like CuCo2O4@Cu mesh exhibits a higher specific surface area and more superior electrochemical performance, enabling the flower-like CuCo2O4@Cu mesh to show the highest catalytic activity for Oxone activation to degrade Acid Red 27. The flower-like CuCo2O4@Cu mesh also exhibits a much lower Ea of Acid Red 27 degradation than the reported catalysts. These results demonstrate that CuCo2O4@Cu meshes are advantageous heterogeneous catalysts for Oxone activation, and especially, the flower-like CuCo2O4@Cu mesh appears as the most effective CuCo2O4@Cu mesh to eliminate the toxic Acid Red 27.

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Zou, Xuan, Mengqi Zeng, Yuan Zheng, Adi Zheng, Li Cui, Wenli Cao, Xueqiang Wang, Jiankang Liu, Jie Xu und Zhihui Feng. „Comparative Study of Hydroxytyrosol Acetate and Hydroxytyrosol in Activating Phase II Enzymes“. Antioxidants 12, Nr. 10 (07.10.2023): 1834. http://dx.doi.org/10.3390/antiox12101834.

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Nuclear factor E2-related factor 2 (Nrf2) is fundamental to the maintenance of redox homeostasis within cells via the regulation of a series of phase II antioxidant enzymes. The unique olive-derived phenolic compound hydroxytyrosol (HT) is recognized as an Nrf2 activator, but knowledge of the HT derivative hydroxytyrosol acetate (HTac) on Nrf2 activation remains limited. In this study, we observed that an HT pretreatment could protect the cell viability, mitochondrial membrane potential, and redox homeostasis of ARPE-19 cells against a t-butyl hydroperoxide challenge at 50 μM. HTac exhibited similar benefits at 10 μM, indicating a more effective antioxidative capacity compared with HT. HTac consistently and more efficiently activated the expression of Nrf2-regulated phase II enzymes than HT. PI3K/Akt was the key pathway accounting for the beneficial effects of HTac in ARPE-19 cells. A further RNA-Seq analysis revealed that in addition to the consistent upregulation of phase II enzymes, the cells presented distinct expression profiles after HTac and HT treatments. This indicated that HTac could trigger a diverse cellular response despite its similar molecular structure to HT. The evidence in this study suggests that Nrf2 activation is the major cellular activity shared by HTac and HT, and HTac is more efficient at activating the Nrf2 system. This supports its potential future employment in various disease management strategies.

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Kalra, Rashi, Ching Hui Chen, Junkai Wang, Ahmad Bin Salam, Lacey E. Dobrolecki, Alaina Lewis, Christina Sallas et al. „Poziotinib Inhibits HER2-Mutant–Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer“. Cancer Research 82, Nr. 16 (23.06.2022): 2928–39. http://dx.doi.org/10.1158/0008-5472.can-21-3106.

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Abstract The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2-mutant metastatic breast cancer. Significance: Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.

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Varga, Krisztina. „Social Innovation for the Welfare of the Community“. International Journal of Engineering and Management Sciences 5, Nr. 1 (14.04.2020): 480–94. http://dx.doi.org/10.21791/ijems.2020.1.39.

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The aim of the study is to highlight the focal points that are potentially activating factors in social innovation efforts in the most disadvantaged areas. The study examines certain social initiatives in the Nyírbátor district, with particular emphasis on the efforts promoting community welfare. The study primarily presents the results of qualitative interviews as part of a doctoral research. The examined cases play an important role in the management of the unfavourable processes in the region, and their adaptation as good practice can support the catching-up process. The study identifies the main groups of aspects that, in addition to structuring the case descriptions, also facilitate comparability of good practice. Documentation based on defined criteria supports the adaptation process, which is critical to the successful implementation of social innovation efforts.

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Haketa, Tomoki, Toshiaki Nozawa, Jun Nakazawa, Masaya Okamura und Shiro Hikichi. „Oxidation Catalysis of Au Nano-Particles Immobilized on Titanium(IV)- and Alkylthiol-Functionalized SBA-15 Type Mesoporous Silicate Supports“. Catalysts 13, Nr. 1 (24.12.2022): 35. http://dx.doi.org/10.3390/catal13010035.

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Novel Au nano-particle catalysts immobilized on both titanium(IV)- and alkylthiol-functionalized SBA-15 type ordered mesoporous silicate supports were developed. The bi-functionalized SBA-15 type support could be synthesized by a one-pot method. To the synthesized supports, Au was immobilized by the reaction of the alkylthiol groups on the supports with AuCl4−, following reduction with NaBH4. The immobilized amount and the formed structures and the electronic property of the Au species depended on the loading of alkylthiol. The moderate size (2–3 nm) nano particulate Au sites formed on Ti(0.5)-SBASH(0.5) were negatively charged. The aerobic alcohol oxidation activity of the catalysts depended on the loading of alkylthiol and the structure of the Au nano-particles. The non-thiol-functionalized catalyst (Au/Ti(0.5)-SBASH(0)) composed of the large (5–30 nm) and the higher thiol-loaded catalyst (Au/Ti(0.5)-SBASH(8)) composed of the small cationic Au species were almost inactive. The most active catalyst was Au/Ti(0.5)-SBASH(0.5) composed of the electron-rich Au nano-particles formed by the electron donation from the highly dispersed thiol groups. Styrene oxidation activity in the presence of 1-phenylethanol with O2 depended on the loadings of titanium(IV) on the Au/Ti(x)-SBASH(0.5). The titanium(IV) sites trapped the H2O2 generated through the alcohol oxidation reaction, and also contributed to the alkene oxidation by activating the trapped H2O2.

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SANTORO, ANDREA, und FRANCESCO QUAGLIA. „SOFTWARE SUPPORTS FOR EVENT PREEMPTIVE ROLLBACK IN OPTIMISTIC PARALLEL SIMULATION ON MYRINET CLUSTERS“. Journal of Interconnection Networks 06, Nr. 04 (Dezember 2005): 435–57. http://dx.doi.org/10.1142/s0219265905001514.

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Optimistic synchronization protocols for parallel discrete event simulation employ rollback techniques to ensure causally consistent execution of simulation events. Although event preemptive rollback (i.e. rollback based on timely event execution interruption upon the arrival of a message revealing a causality inconsistency) is recognized as an approach for increasing the performance and tackling run-time anomalies of this type of synchronization, the lack of adequate functionalities at the level of general purpose communication layers typically prevents any effective implementation of event preemptive rollback operations. In this paper we present the design and implementation of a communication layer for Myrinet based clusters, which efficiently supports event preemptive rollback operations. Beyond standard low latency message delivery funcbionalities, this layer also embeds functionalities for allowing the overlying simulation application to efficiently track whether a message will actually produce causality inconsistency of the currently executed simulation event upon its receipt at the application level. Exploiting these functionalities, awareness of the inconsistency precedes the message receipt at the application level, thus allowing timely event execution interruption for activating rollback procedures. We also report experimental results demonstrating the effectiveness of our solution for a Personal Communication System (PCS) simulation application.

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Rodríguez-Lara, Simón Quetzalcóatl, Leonel García-Benavides und Alejandra Guillermina Miranda-Díaz. „The Renin-Angiotensin-Aldosterone System as a Therapeutic Target in Late Injury Caused by Ischemia-Reperfusion“. International Journal of Endocrinology 2018 (04.04.2018): 1–18. http://dx.doi.org/10.1155/2018/3614303.

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Ischemia-reperfusion (I/R) injury is a well-known phenomenon that involves different pathophysiological processes. Connection in diverse systems of survival brings about cellular dysfunction or even apoptosis. One of the survival systems of the cells, to the assault caused by ischemia, is the activation of the renin-angiotensin-aldosterone system (also known as an axis), which is focused on activating diverse signaling pathways to favor adaptation to the decrease in metabolic supports caused by the hypoxia. In trying to adapt to the I/R event, great changes occur that unchain cellular dysfunction with the capacity to lead to cell death, which translates into a poor prognosis due to the progression of dysfunction of the cellular activity. The search for the understanding of the diverse therapeutic alternatives in molecular coupling could favor the prognosis and evolution of patients who are subject to the I/R process.

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Ramos, Delma. „Mexican origin First-generation College Students Activating Funds of Knowledge to Navigate Basic Needs Insecurity“. JCSCORE 8, Nr. 2 (25.10.2022): 115–42. http://dx.doi.org/10.15763/issn.2642-2387.2022.8.2.115-142.

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The present study examines the presence of Basic Needs Insecurity (BNI) among Mexican origin first-generation college students. Specifically, this transformative mixed methods study explores BNI in access to healthcare, housing, employment, and transportation among study participants. Most importantly, this research illuminates students’ Funds of Knowledge (FK) as assets and strategies that Mexican origin first-generation college students activate to navigate BNI. Findings reveal higher levels of BNI present among first-generation compared to continuing-generation college students and highlight familial, community, and institutional supports as sources of FK for Mexican origin first-generation college students to address BNI. Implications for research and practice are provided.

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Hassan, Mohammad Q., Rahul Tare, Suk Hee Lee, Matthew Mandeville, Brian Weiner, Martin Montecino, Andre J. van Wijnen, Janet L. Stein, Gary S. Stein und Jane B. Lian. „HOXA10 Controls Osteoblastogenesis by Directly Activating Bone Regulatory and Phenotypic Genes“. Molecular and Cellular Biology 27, Nr. 9 (26.02.2007): 3337–52. http://dx.doi.org/10.1128/mcb.01544-06.

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ABSTRACT HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes.

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Liu, Zhihong, Vincent S. Stoll, Peter J. DeVries, Clarissa G. Jakob, Nancy Xie, Robert L. Simmer, Susan E. Lacy et al. „A potent erythropoietin-mimicking human antibody interacts through a novel binding site“. Blood 110, Nr. 7 (01.10.2007): 2408–13. http://dx.doi.org/10.1182/blood-2007-04-083998.

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Recombinant human erythropoietin (rHu-EPO) is used to treat anemia by activating the erythropoietin receptor (EPOR) in erythroid progenitor cells, leading to proliferation and differentiation into mature red blood cells. To allow less frequent dosing, a hyperglycosylated version of EPO has been developed with a longer half-life. In principle, an agonistic antibody targeting EPOR would offer an even longer half-life, support robust monthly dosing, and, unlike EPO products, reduce the risk of pure red cell aplasia. The efficiency of signaling and corresponding potency of previously reported antibody mimics are generally suboptimal compared with EPO and not suitable for clinical use. Here we describe a potent, fully human, agonistic antibody (ABT007) targeting EPOR that supports potent, more sustained, and less pulsatile elevation of hematocrit in a human EPOR–expressing transgenic mouse model compared with standard doses of rHu-EPO while requiring less frequent dosing. Resolution of the crystal structure of the EPOR extracellular domain (ECD) complexed to the ABT007 Fab fragment, determined at 0.32 nm, identifies a binding site that is consistent with a novel mechanism of receptor activation based on a unique antibody-imposed conformational change. These results demonstrate that a symmetric molecule can serve as a potent activator of the EPOR.

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Pitsilos, Stephanie, Jennifer Hunt, Emile Mohler, Anand Prabhakar, Mortimer Poncz, Jennine Dawicki, Tigran Khalapyan et al. „Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters“. Thrombosis and Haemostasis 90, Nr. 12 (2003): 1112–20. http://dx.doi.org/10.1160/th03-02-0069.

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SummaryEmerging evidence supports a role for platelets in the progression of atherosclerosis in addition to an involvement in thrombotic vascular occlusion. Platelet Factor 4 (PF4), a chemokine released by activated platelets, stimulates several pro-atherogenic processes. Therefore, we examined the localization of PF4 and the homologous protein, Neutrophil Activating Protein-2 (NAP-2) in lesions representing the evolution of human atherosclerotic plaques. Carotid plaques from 132 patients with critical carotid stenosis and 6 autopsy specimens were studied. Clinical, histologic and immunohistochemical data were analyzed using a χ2-test. PF4 was detected in the cytoplasm of luminal and neovascular endothelium, in macrophages and in regions of plaque calcification. The presence of PF4 in macrophages and neovascular endothelium correlated with lesion grade (p = 0.004; p = 0.044). Staining of macrophages for PF4 correlated with the presence of symptomatic atherosclerotic disease (p = 0.028). In early lesions, PF4 was commonly found in macrophages of early lesions (Grade I/II), whereas NAP-2 was rarely present.In conclusion, correlation between PF4 deposition, lesion severity and symptomatic atherosclerosis suggests that persistent platelet activation may contribute to the evolution of athero-sclerotic vascular lesions. These studies support the rationale for the chronic use of anti-platelet therapy in patients at risk for developing symptomatic atherosclerosis.

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Liu, Hongxia, Ningning Liu, Yali Zhao, Xiaoshan Zhu, Changsong Wang, Qinqin Liu, Chunfang Gao, Xusheng Zhao und Juntang Li. „Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling“. Aging 11, Nr. 21 (04.11.2019): 9643–60. http://dx.doi.org/10.18632/aging.102410.

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Diamond, Eli L., Elena Pentsova, Laetitia Borsu, April E. Chiu, David Michael Hyman und Marc Rosenblum. „Detection of the NRAS Q61R mutation in Erdheim-Chester disease.“ Journal of Clinical Oncology 31, Nr. 15_suppl (20.05.2013): 7120. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7120.

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7120 Background: There is a high frequency of activating mutations in proteins of the Ras/Raf/MEK/ERK pathway in melanoma and other solid tumors. The BRAF V600E mutation has been found recently to be highly prevalent in ECD, a rare non-Langerhans cell histiocytosis with poor prognosis, as well as Langerhans cell histiocytosis (LCH). Treatment of patients with ECD and the BRAF V600E mutation with vemurafenib has been associated with unprecedented and dramatic response in a few cases. Methods: We present a 66 year-old man evaluated for several months of cognitive and motor decline. He was found to have multifocal enhancing lesions in the cerebral meninges, multiple masses in the abdomen and sacrum, and abnormal nuclear uptake in the long bones of the legs. Results: Biopsy of a renal mass demonstrated a foamy CD68+/CD1a- histiocytic infiltrate, consistent with ECD. Interrogation of tumor tissue with the Sequenom MassArray system demonstrated absence of the BRAF V600E mutation but presence of the NRAS Q61R mutation. Conclusions: This is, to our knowledge, the first report of an activating NRAS mutation in ECD. The finding of an oncogenic NRAS mutation in ECD further supports the hypothesis that this disease is driven by activation of the Ras/Raf/MEK/ERK pathway. Further investigation into the role of this pathway in ECD and LCH is warranted and may open new opportunities for targeted therapies for these disorders.

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Robinson, Nathaniel J., Masaru Miyagi, Jessica A. Scarborough, Jacob G. Scott, Derek J. Taylor und William P. Schiemann. „SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling“. Science Signaling 14, Nr. 689 (29.06.2021): eabe9613. http://dx.doi.org/10.1126/scisignal.abe9613.

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The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

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Belete, Belen, Haiping Lu und Daniel J. Wozniak. „Pseudomonas aeruginosa AlgR Regulates Type IV Pilus Biosynthesis by Activating Transcription of the fimU-pilVWXY1Y2E Operon“. Journal of Bacteriology 190, Nr. 6 (04.01.2008): 2023–30. http://dx.doi.org/10.1128/jb.01623-07.

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ABSTRACT The response regulator AlgR is required for Pseudomonas aeruginosa type IV pilus-dependent twitching motility, a flagellum-independent mode of solid surface translocation. Prior work showed that AlgR is phosphorylated at aspartate 54, and cells expressing an AlgR variant that cannot undergo phosphorylation (AlgRD54N) lack twitching motility. However, the mechanism by which AlgR controls twitching motility is not completely understood. We hypothesized that AlgR functioned by activating genes within the prepilin fimU-pilVWXY1Y2E cluster that are necessary for type IV pilin biogenesis. Reverse transcriptase PCR analysis showed that the fimU-pilVWXY1Y2E genes are cotranscribed in an operon, which is under the control of AlgR. This supports prior transcriptional profiling studies of wild-type strains and algR mutants. Moreover, expression of the fimU-pilVWXY1Y2E operon was reduced in strains expressing AlgRD54N. DNase footprinting and electrophoretic mobility shift assays demonstrate that AlgR but not AlgRD54N bound with high affinity to two sites upstream of the fimU-pilVWXY1Y2E operon. Altogether, our findings indicate that AlgR is essential for proper pilin localization and that phosphorylation of AlgR results in direct activation of the fimU-pilVWXY1Y2E operon, which is required for the assembly and export of a functional type IV pilus.

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Chen, Xizi, Yilun Qi, Zihan Wu, Xinxin Wang, Jiabei Li, Dan Zhao, Haifeng Hou et al. „Structural insights into preinitiation complex assembly on core promoters“. Science 372, Nr. 6541 (01.04.2021): eaba8490. http://dx.doi.org/10.1126/science.aba8490.

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Transcription factor IID (TFIID) recognizes core promoters and supports preinitiation complex (PIC) assembly for RNA polymerase II (Pol II)–mediated eukaryotic transcription. We determined the structures of human TFIID–based PIC in three stepwise assembly states and revealed two-track PIC assembly: stepwise promoter deposition to Pol II and extensive modular reorganization on track I (on TATA–TFIID-binding element promoters) versus direct promoter deposition on track II (on TATA-only and TATA-less promoters). The two tracks converge at an ~50-subunit holo PIC in identical conformation, whereby TFIID stabilizes PIC organization and supports loading of cyclin-dependent kinase (CDK)–activating kinase (CAK) onto Pol II and CAK-mediated phosphorylation of the Pol II carboxyl-terminal domain. Unexpectedly, TBP of TFIID similarly bends TATA box and TATA-less promoters in PIC. Our study provides structural visualization of stepwise PIC assembly on highly diversified promoters.

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Bosch, Naomi C., Lena-Marie Martin, Caroline J. Voskens, Carola Berking, Barbara Seliger, Gerold Schuler, Niels Schaft und Jan Dörrie. „A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells“. International Journal of Molecular Sciences 22, Nr. 19 (23.09.2021): 10227. http://dx.doi.org/10.3390/ijms221910227.

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Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.

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Hull, KL, und S. Harvey. „GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state“. Journal of Endocrinology 172, Nr. 1 (01.01.2002): 1–19. http://dx.doi.org/10.1677/joe.0.1720001.

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It is now well established that exogenous GH promotes sexual maturation and reproductive function. The possibility that this may reflect physiological actions of endogenous GH has, however, rarely been considered. Correlative changes in GH secretion and reproductive state (puberty, pregnancy, lactation, menopause and ovarian cycles) are thus the primary focus of this review. GH secretion is, for instance, elevated during major transitions in reproductive status such as puberty and pregnancy. In some cases, augmented circulating GH levels are paired with hepatic GH resistance. This interaction may permit selective activation of gonadal responses to GH without activating IGF-I-mediated systemic responses. This selective activation may also be mediated by autocrine, paracrine or intracrine GH actions, since GH is also synthesized in reproductive tissues. Correlative changes in GH secretion and reproductive state may be mediated by events at the hypothalamic, pituitary and gonadal level. In addition to direct effects on gonadal function, GH may influence reproductive activity by increasing gonadotropin secretion at the hypothalamic and pituitary level and by enhancing gonadotropin responsiveness at the gonadal level. The close association between reproductive status and the somatotrophic axis supports the physiological importance of GH in reproductive function.

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Bridgewater, Hannah E., Kathryn L. Date, John D. O’Neil, Chunfang Hu, John R. Arrand, Christopher W. Dawson und Lawrence S. Young. „The Epstein-Barr Virus-Encoded EBNA1 Protein Activates the Bone Morphogenic Protein (BMP) Signalling Pathway to Promote Carcinoma Cell Migration“. Pathogens 9, Nr. 7 (21.07.2020): 594. http://dx.doi.org/10.3390/pathogens9070594.

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The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) protein is expressed in all virus-associated malignancies, where it performs an essential role in the maintenance, replication and transcription of the EBV genome. In recent years, it has become apparent that EBNA1 can also influence cellular gene transcription. Here, we demonstrate that EBNA1 is able to stimulate the expression of the Transforming growth factor-beta (TGFβ) superfamily member, bone morphogenic protein 2 (BMP2), with consequential activation of the BMP signalling pathway in carcinoma cell lines. We show that BMP pathway activation is associated with an increase in the migratory capacity of carcinoma cells, an effect that can be ablated by the BMP antagonist, Noggin. Gene expression profiling of authentic EBV-positive nasopharyngeal carcinoma (NPC) tumours revealed the consistent presence of BMP ligands, established BMP pathway effectors and putative target genes, constituting a prominent BMP “signature” in this virus-associated cancer. Our findings show that EBNA1 is the major viral-encoded protein responsible for activating the BMP signalling pathway in carcinoma cells and supports a role for this pathway in promoting cell migration and possibly, metastatic spread.

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Chowdhury, Parimal, Stewart MacLeod, Kodetthor B. Udupa und Phillip L. Rayford. „Pathophysiological Effects of Nicotine on the Pancreas: An Update“. Experimental Biology and Medicine 227, Nr. 7 (Juli 2002): 445–54. http://dx.doi.org/10.1177/153537020222700708.

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Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic diseases. It is well recognized that nicotine, a major component in cigarette smoke, is an addictive agent and, therefore, reinforces smoking behavior. The current review update focuses on the genetics of nicotine dependence and its role on the development of pancreatic diseases. The role of smoking and nicotine in pancreatitis and pancreatic cancer development is also discussed. Exposure of laboratory animals to nicotine clearly supports the notion that nicotine can induce pancreatic injury. The mechanism by which nicotine induces such effects is perhaps mediated via signal transduction pathways in the pancreatic acinar cell, leading to enhanced levels of intracellular calcium release, resulting in cytotoxicity and eventual cell death. The induction of pancreatic injury by nicotine may also involve activation and expression of protooncogene, H-ras, which can increase cytosolic calcium via second messenger pathways. Development of pancreatic carcinoma in cigarette smokers as observed in human populations may be the result of activation and mutation of the H-ras gene. A possible pathogenetic mechanism of nicotine in the pancreas activating multiple signal transduction pathways is schematically summarized in Figure 1.

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Zhang, Shuaishuai, Yingzhe Qiu, Yuan Feng, Yi Zhang, Yanan Li, Boxin Wang, Heliang Wei et al. „Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO3 Stimulation“. Oxidative Medicine and Cellular Longevity 2023 (17.01.2023): 1–18. http://dx.doi.org/10.1155/2023/3310621.

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Although accumulated evidence supports the notion that calpain contributes to eye disease, the mechanisms by which calpain promotes RPE injury are not defined. The present study is aimed at investigating whether the effect of NaIO3-exos (exosomes derived from RPE cells under NaIO3 stimulation) on the dysfunction of the autophagy-lysosomal pathway (ALP) and apoptosis is based on its regulation of calpain activation in ARPE-19 cells and rats. The results showed that calpain-2 activation, ALP dysfunction, and apoptosis were induced by NaIO3-exos in ARPE-19 cells. NaIO3-exo significantly increased autophagic substrates by activating lysosomal dysfunction. ALP dysfunction and apoptosis in vitro could be eliminated by knocking down calpain-2 (si-C2) or the inhibitor calpain-2-IN-1. Further studies indicated that NaIO3-exo enhanced calpain-2 expression, ALP dysfunction, apoptosis, and retinal damage in rats. In summary, these results demonstrate for the first time that calpain-2 is one of the key players in the NaIO3-exo-mediated ALP dysfunction, apoptosis, and retinal damage and identify calpain-2 as a promising target for therapies aimed at age-related macular degeneration (AMD).

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Wang, Dong, Tiemei Zheng, Xiangyu Ge, Jiacheng Xu, Lingling Feng, Chenxiao Jiang, Jincheng Tao et al. „Unfolded protein response-induced expression of long noncoding RNA Ngrl1 supports peripheral axon regeneration by activating the PI3K-Akt pathway“. Experimental Neurology 352 (Juni 2022): 114025. http://dx.doi.org/10.1016/j.expneurol.2022.114025.

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Nifant’ev, Ilya E., Pavel D. Komarov, Oksana D. Kostomarova, Nikolay A. Kolosov und Pavel V. Ivchenko. „MAO- and Borate-Free Activating Supports for Group 4 Metallocene and Post-Metallocene Catalysts of α-Olefin Polymerization and Oligomerization“. Polymers 15, Nr. 14 (19.07.2023): 3095. http://dx.doi.org/10.3390/polym15143095.

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Modern industry of advanced polyolefins extensively uses Group 4 metallocene and post-metallocene catalysts. High-throughput polyolefin technologies demand the use of heterogeneous catalysts with a given particle size and morphology, high thermal stability, and controlled productivity. Conventional Group 4 metal single-site heterogeneous catalysts require the use of high-cost methylalumoxane (MAO) or perfluoroaryl borate activators. However, a number of inorganic phases, containing highly acidic Lewis and Brønsted sites, are able to activate Group 4 metal pre-catalysts using low-cost and affordable alkylaluminums. In the present review, we gathered comprehensive information on MAO- and borate-free activating supports of different types and discussed the surface nature and chemistry of these phases, examples of their use in the polymerization of ethylene and α-olefins, and prospects of the further development for applications in the polyolefin industry.

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Doheny, Daniel, Sara G. Manore, Grace L. Wong und Hui-Wen Lo. „Hedgehog Signaling and Truncated GLI1 in Cancer“. Cells 9, Nr. 9 (17.09.2020): 2114. http://dx.doi.org/10.3390/cells9092114.

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The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

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