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Journal articles on the topic "SAMD14"
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Hewitt, Kyle J., Suhita Ray, Srinivas Chava, and Linda Chee. "The Samd14 Sterile Alpha Motif Domain Promotes Stress-Induced Cellular Signaling and Survival." Blood 134, Supplement_1 (November 13, 2019): 1184. http://dx.doi.org/10.1182/blood-2019-131228.
Full textAbstract:
More than 200 mammalian proteins contain Sterile Alpha Motif (SAM) domains. While some of these domains are reported to mediate protein, lipid or RNA binding, the majority have not been analyzed. Our prior work discovered that Samd14, a SAM-domain containing protein, was transcriptionally activated by the GATA2 and Scl/TAL1-occupied Samd14 enhancer (Samd14-Enh). Deletion of Samd14-Enh lowers Samd14 expression in mouse bone marrow and spleen and causes lethality in a mouse model of severe hemolytic anemia. In anemia, stress erythroid progenitors respond to a multitude of paracrine signals, including erythropoietin (Epo) and stem cell factor (SCF), to induce rapid expansion and differentiation until homeostasis is re-established. Mechanistic analyses revealed that Samd14 regulates SCF/c-Kit signaling, erythroid progenitor function and promotes erythrocyte regeneration in anemia. Ex vivo, Samd14-Enh-/- erythroid progenitors (CD71+Ter119-Kit+) exhibited 2.1-fold and 1.6-fold lower phospho (Serine 473) AKT (pAKT) vs. WT in response to 5 min and 10 min SCF stimulation, respectively. To rigorously establish whether the Samd14-Enh deletion reduces anemia-dependent c-Kit signaling by lowering Samd14 levels in erythroid progenitors, we restored Samd14 expression in Samd14-Enh-/- primary erythroid precursor cells. Defective SCF/c-Kit signaling in Samd14-Enh-/- spleen progenitors could be rescued by reestablishing expression of Samd14. To test the role of the SAM domain in Samd14-mediated promotion of stress-induced erythroid progenitor function, we generated a SAM-domain deleted construct of Samd14 (Samd14 Δ SAM) to replace endogenous expression in cells from Samd14-Enh-deleted bone marrow and spleen ex vivo. In colony assays, full-length Samd14 increased GFP+ colony formation 2.7-fold, whereas there was no significant increase in colonies when expressing Samd14 Δ SAM vs. EV. Compared to expression of full-length Samd14, Samd14 Δ SAM exhibited 1.9-fold fewer (p=0.0006) BFU-E colonies (Figure 4B). Together, these results indicated that the Samd14 SAM domain is required for maximal promotion of colony forming ability, cell signaling and survival of erythroid progenitors. As the Samd14 SAM domain mediates SCF/c-Kit signaling, and cells lacking Samd14-Enh have impaired c-Kit signaling following anemia, this protein motif controls anemia-dependent erythroid progenitor cell genesis and/or function. Ongoing analyses to fuse the SAM structural domains of related proteins Neurabin-1 and SHIP-2 will test the sequence requirements of the Samd14 SAM domain on c-Kit signaling and stress erythroid progenitor function. These findings reveal a vital SAM domain-dependent molecular mechanism in stress erythroid progenitors whereby a GATA2 and anemia-activated protein facilitates SCF/c-Kit signaling during regenerative erythropoiesis. Given the importance of GATA2 and GATA2-dependent mechanisms in hematopoiesis, determining the role of the GATA2-Samd14-c-Kit axis in hematologic diseases may reveal unique functions. Disclosures No relevant conflicts of interest to declare.
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Ray, Suhita, Linda Chee, Daniel R. Matson, Nick Y. Palermo, Emery H. Bresnick, and Kyle J. Hewitt. "Sterile α-motif domain requirement for cellular signaling and survival." Journal of Biological Chemistry 295, no. 20 (April 2, 2020): 7113–25. http://dx.doi.org/10.1074/jbc.ra119.011895.
Full textAbstract:
Hundreds of sterile α-motif (SAM) domains have predicted structural similarities and are reported to bind proteins, lipids, or RNAs. However, the majority of these domains have not been analyzed functionally. Previously, we demonstrated that a SAM domain-containing protein, SAMD14, promotes SCF/proto-oncogene c-Kit (c-Kit) signaling, erythroid progenitor function, and erythrocyte regeneration. Deletion of a Samd14 enhancer (Samd14–Enh), occupied by GATA2 and SCL/TAL1 transcription factors, reduces SAMD14 expression in bone marrow and spleen and is lethal in a hemolytic anemia mouse model. To rigorously establish whether Samd14–Enh deletion reduces anemia-dependent c-Kit signaling by lowering SAMD14 levels, we developed a genetic rescue assay in murine Samd14–Enh−/− primary erythroid precursor cells. SAMD14 expression at endogenous levels rescued c-Kit signaling. The conserved SAM domain was required for SAMD14 to increase colony-forming activity, c-Kit signaling, and progenitor survival. To elucidate the molecular determinants of SAM domain function in SAMD14, we substituted its SAM domain with distinct SAM domains predicted to be structurally similar. The chimeras were less effective than SAMD14 itself in rescuing signaling, survival, and colony-forming activities. Thus, the SAMD14 SAM domain has attributes that are distinct from other SAM domains and underlie SAMD14 function as a regulator of cellular signaling and erythrocyte regeneration.
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Ray, Suhita, Linda Chee, Nicholas T. Woods, and Kyle J. Hewitt. "Functional Requirements of a Samd14-Capping Protein Interaction in Stress Erythropoiesis." Blood 138, Supplement 1 (November 5, 2021): 288. http://dx.doi.org/10.1182/blood-2021-152898.
Full textAbstract:
Abstract Stress erythropoiesis describes the process of accelerating red blood cell (RBC) production in anemia. Among a number of important mediators of stress erythropoiesis, paracrine signals - involving cooperation between SCF/c-Kit signaling and other signaling inputs - are required for the activation/function of stress erythroid progenitors. Whereas many critical factors required to drive erythropoiesis in normal physiological conditions have been described, whether distinct mechanisms control developmental, steady-state, and stress erythropoiesis in anemia is poorly understood. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated in a model of acute hemolytic anemia induced by the RBC-lysing chemical phenylhydrazine. Samd14 is regulated by GATA binding transcription factors via an intronic enhancer (Samd14-Enh). In a mouse knockout of Samd14-Enh (Samd14-Enh -/-), we established that the Samd14-Enh is dispensable for steady-state erythropoiesis but is required for recovery from severe hemolytic anemia. Samd14 promotes c-Kit signaling in vivo and ex vivo, and the SAM domain of Samd14 facilitates c-Kit-mediated cellular signaling and stress progenitor activity. In addition, the Samd14 SAM domain is functionally distinct from closely related SAM domains, which demonstrates a unique role for this SAM domain in stress signaling and cell survival. In our working model, Samd14-Enh is part of an ensemble of anemia-responsive enhancers which promote stress erythroid progenitor activity. However, the mechanism underlying Samd14's role in stress erythropoiesis is unknown. To identify potential Samd14-interacting proteins that mediate its function, we performed immunoprecipitation-mass spectrometry on the Samd14 protein. We found that Samd14 interacted with α- and β heterodimers of the F-actin capping protein (CP) complex independent of the SAM domain. CP binds to actin during filament assembly/disassembly and plays a role in cell morphology, migration, and signaling. Deleting a 17 amino acid sequence near the N-terminus of Samd14 disrupted the Samd14-CP interaction. However, mutating the canonical RxR of the CP interaction (CPI) motif, which is required for CP-binding in other proteins, does not abrogate the Samd14-CP interaction. Moreover, replacing this sequence with the canonical CPI domain of CKIP-1 completely disrupts the interaction, indicating that other sequence features are required to maintain the Samd14-CP complex. Ex vivo knockdown of the β-subunit of CP (CPβ), which disrupts the integrity of the CP complex, decreased the percentage of early erythroid precursors (p<0.0001) and decreased (3-fold) progenitor activity as measured by colony formation assays (similar to knockdown of Samd14). Taken together, these data indicate that Samd14 interacts with CP via a unique CP binding (CPB) domain, and that the CP complex coordinates erythroid differentiation in stress erythroid progenitors. To test the function of the Samd14-CP complex, we designed an ex vivo genetic complementation assay to express Samd14 lacking the CPB-domain (Samd14∆CPB) in stress erythroid progenitors isolated from anemic Samd14-Enh -/- mice. Phospho-AKT (Ser473) and phospho-ERK (Thr202/Tyr204) levels in Samd14∆CPB were, respectively, 2.2 fold (p=0.007) and ~7 fold (n=3) lower than wild type Samd14 expressing cells, 5 min post SCF stimulation. Relative to Samd14, Samd14∆CPB expression reduced burst forming unit-erythroid (BFU-E) (2.0 fold) and colony forming unit-erythroid (CFU-E) (1.5 fold). These results revealed that the Samd14-CP interaction is a determinant of BFU-E and CFU-E progenitor cell levels and function. Remarkably, as the requirement of the CPB domain in BFU-E and CFU-E progenitors is distinct from the Samd14-SAM domain (which promotes BFU-E but not CFU-E), the function of Samd14 in these two cell types may differ. Ongoing studies will examine whether the function of Samd14 extends beyond SCF/c-Kit signaling and establish cell type-dependent functions of Samd14 and Samd14-interacting proteins. Given the critical importance of c-Kit signaling in hematopoiesis, the role of Samd14 in mediating pathway activation, and our discovery implicating the capping protein complex in erythropoiesis, it is worth considering the pathological implications of this mechanism in acute/chronic anemia and leukemia. Disclosures No relevant conflicts of interest to declare.
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Hewitt, Kyle J. "The Samd14-Capping Protein Complex Controls Cell Signaling in the Erythropoietic Stress Response." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-143020.
Full textAbstract:
In anemia, restoring homeostatic levels of erythrocytes requires an erythropoietic regenerative response to accelerate red blood cell (RBC) production. Elucidating mechanisms that drive the process of erythropoiesis in the context of regeneration or "stress erythropoiesis" can reveal new strategies for targeting ineffective erythropoiesis. An important component of stress erythropoiesis involves stress-dependent activation of genes/proteins through transcriptional enhancers. We discovered an enhancer in intron 1 of the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene elevates Samd14 expression, facilitates SCF/c-Kit signaling, and is needed for survival in a hemolytic anemia model. However, it is dispensable for erythropoietic development. Our prior work demonstrated that the SAM domain of Samd14 promotes c-Kit-mediated cellular signaling to regulate progenitor function, and this SAM domain has functional attributes unique from those of structurally related SAM domains. Using immunoprecipitation-mass spectrometry, we determined that Samd14 interacts with the Capzβ protein. Capzβ is a component of the actin capping protein (CP) complex, which interact as α- and β heterodimers during actin filament assembly/disassembly. CP exerts diverse functions in cell motility, vesicular transport, cell signaling and cytokinesis. Using a series of Samd14 deletion constructs, we tested whether the Samd14-Capzβ interaction is important for Samd14 promotion of c-Kit signaling in stress erythroid progenitors. Our findings determined that the region of Samd14 required for binding to Capzβ (amino acids 38-54) were required to restore c-Kit signaling. Our ongoing studies are examining whether Samd14-Capzβ is similarly required for colony formation and cell survival of stress erythroid progenitors, and whether additional SAM domain-containing proteins have a similar role in regulating stress erythropoiesis. Understanding the fundamental drivers of regenerative erythropoiesis can lead to new therapeutic strategies and prognostic/diagnostic markers. Disclosures No relevant conflicts of interest to declare.
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Thurner, Lorenz, Klaus-Dieter Preuss, Moritz Bewarder, Maria Kemele, Natalie Fadle, Evi Regitz, Sarah Altmeyer, et al. "Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma." Blood 132, no. 26 (December 27, 2018): 2744–53. http://dx.doi.org/10.1182/blood-2018-03-836932.
Full textAbstract:
Abstract To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
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Hewitt, Kyle, Kirby D. Johnson, Duk-Hyoung Kim, Prithvia Devadas, Rajalekshmi Prathibha, Chandler Zuo, Colin Dewey, et al. "Cistrome Control of Hematopoieitic Stem/Progenitor Cell Function." Blood 126, no. 23 (December 3, 2015): 43. http://dx.doi.org/10.1182/blood.v126.23.43.43.
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Abstract Cis-regulatory mechanisms control chromatin structure and cellular identity. At the GATA2 locus, two cis-elements are linked to human pathologies, including a primary immunodeficiency (MonoMAC syndrome) associated with multiple complex phenotypes, myelodysplastic syndrome, and acute myeloid leukemia (AML). Mutations that disrupt the function of an intronic GATA2 +9.5 element cause MonoMAC syndrome, while an inversion that relocates the distal GATA2 -77 element to the EVI1 locus induces AML. The +9.5 and -77 cis-elements are GATA-2-occupied and confer context-dependent enhancer activities in select hematopoietic cell types in vivo. In knockout mouse models, the Gata2 +9.5 cis-element is required for hematopoietic stem cell (HSC) genesis, whereas the Gata2 -77 cis-element governs a unique sector of the myeloid progenitor cell transcriptome without impacting HSC genesis. Three other GATA-2-occupied cis-elements (-1.8, -2.8 and -3.9) were not individually required for hematopoietic development, and had relatively mild effects on Gata2 expression; the -1.8 site was required to maintain Gata2 repression in late-stage erythroblasts, the -2.8 conferred maximal Gata2 expression, and the -3.9 had no effect on Gata2 expression. We predict that additional cis-elements exist in the genome with functions resembling the +9.5 and -77, and their analysis will provide important mechanistic and biological insights. We utilized the known properties of Gata2 cis-elements as learning tools to identify prospective constituents of a hematopoietic stem/progenitor cell (HSPC) regulatory cistrome genome-wide. Using sequence attributes shared with the critically-important +9.5 element, namely a CATCTG-8bp spacer-AGATAA, we generated a list of 797 candidate cis-elements ("+9.5-like" elements). This list was prioritized using chromatin occupancy by GATA-2 and Scl/TAL-1, among others, chromatin accessibility, evolutionary conservation, and histone modifications in a multitude of biologically-relevant cell types. Gene editing was used to delete three high-ranked elements (Samd14 +2.5, Bcl2l1 +12.2, and Dapp1 +23.5), revealing their importance for transcriptional activation, GATA-2 occupancy and chromatin accessibility, while deletion of two low-ranked elements (Mrps9 +17.6 and Mgmt +182) had no effect on gene transcription. One such cis-element (Samd14 +2.5) resided in Samd14, a gene with undescribed biological function. Samd14 has a conserved sterile α-motif and coiled-coil domain, and is highly expressed in hematopoietic progenitors and differentiated progeny. Mouse knockout of the Samd14 +2.5 element dramatically lowered expression of Samd14 in hematopoietic progenitors. We conducted loss-of-function analysis to elucidate Samd14 function in lineage-depleted (Lin-) E14.5 fetal liver cells infected with control or Samd14 shRNA-expressing retrovirus. In a CFU assay, Samd14 knockdown reduced BFU-E and CFU-GM colonies 3.4-fold. Early erythroid precursor R1 (CD71low, Ter119-) and R2 (CD71high, Ter119-) cell populations decreased ~2-fold, concomitant with increases in more mature R3 and R4/5 populations (Ter119+). In R1/R2 cells, Samd14 knockdown reduced surface c-Kit expression by 1.6-fold and prevented Stem Cell Factor/c-Kit activation of AKT. Cellular deficits resulting from Samd14 knockdown could be rescued by c-Kit. In -77-/- common myeloid progenitors, Samd14 was ~20-fold downregulated. Thus, the importance of Samd14 and the Samd14 +2.5 element on progenitor function and SCF/c-Kit signaling validates our strategy for identifying cis-elements relevant for hematopoiesis. Our findings demonstrate that +9.5-like elements control cell signaling (Samd14 +2.5) and apoptosis (Bcl2l1 +12.2), and we predict that additional cistrome constituents will control these and other important HSPC processes. I will discuss the mechanistic and biological properties of additional cis-elements analyzed from a cohort of 68 GATA-2-occupied elements and general principles arising from the HSPC cistrome analysis, which provide unique insights into the control of hematopoiesis and GATA-2-linked pathologies. Disclosures No relevant conflicts of interest to declare.
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Thurner, Lorenz, Maria Kemele, Natalie Fadle, Evi Regitz, Patrick Roth, Michael Weller, Monika Szczepanowski, et al. "Postranslationally Modified Proteins in the Central Nervous System (CNS) Are the Dominant Antigenic Target/Stimulus of the B-Cell Receptor (BCR) in Primary CNS Lymphomas (PCNSL) Providing Strong Evidence for the Role of Chronic Autoantigenic Stimulation As an Early Step in the Pathogenesis of Aggressive B-Cell Lymphomas." Blood 124, no. 21 (December 6, 2014): 142. http://dx.doi.org/10.1182/blood.v124.21.142.142.
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Abstract Background: Sequence analyses of variable immunoglobulin gene fragments of PCNSL from immunocompetent patients have shown a VH4-34 restriction raising speculations on a selection/stimulation of a functional BCR by an autoantigen in the central nervous system. The present study focused on the search for these hypothetic autoantigens presumably driving the malignant transformation of B-cells into PCNSL cells by chronic BCR stimulation in immunocompetent patients. Methods: BCRs were expressed as recombinant Fabs based on corresponding pairs of functional variable region heavy and light chain genes, which had been amplified from isolated genomic DNA of snap-frozen lymphoma specimens and checked for binding to proteins expressed on macroarrays of human cDNA expression libraries. Results: Recombinant BCR expression was attempted in 21 and successful in twelve PCNSL cases. The VH4-34 family was overrepresented, but was found in less than a quarter of the PCNSL patients (4/21). Screening of the recombinant BCRs on protein arrays revealed that 8 of 12 recombinant PCNSL-BCRs reacted with SAMD14 and the SAM domain of neurabin-1, two proteins with high homology and preferential expression in the CNS. Subsequent proteomic analysis of cryoconserved lymphoma specimens showed that SAMD14 and the SAM domain of neurabin-1 were alternatively N-glycosylated in patients with a PCNSL-BCR specific for SAMD14 and neurabin-1, but not in the remaining PCNSL patients with BCR specificities other than for SAMD14/neurabin-1. Compared to SAMD14 and neurabin-1 from healthy controls, Asn 339 of SAMD14 and Asn 1277 of neurabin-1 were shown to carry additionally glycosylated Asn residues. Of interest, both additional glycosylation sites belonged to atypical, non-canonical Asn-Leu-Glu-Gln (N-L-E-Q) sites instead of the Asn-X-Ser/Thre consensus sequence (N-X-S/T; where X can be any amino acid except proline), which is reported to constitute 97% of N-glycosylation sites under physiologic circumstances. These atypical N-hyperglycosylations were shown for every case with sufficient biopsy material for this proteomic analysis and a PCNSL-BCR specific for SAMD14 and neurabin-1 in their PCNSL and CNS, and to a lesser degree in their peripheral blood mononuclear cells and patient-derived EBV-transformed lymphoblastoid cell lines (LCLs). Of the recombinant BCRs of all cases with sufficient material to test for hyperglycosylation, only the BCRs of the 6 cases with hyperglycosylated SAMD14/neurabin-1 reacted against SAMD14/neurabin-1. Of note, glycosylation status of 2/8 cases with recombinant SAMD14/neurabin-1 reactive BCRs could not be analyzed due to insufficient cryomaterial left after variable region gene PCRs. No hyperglycosylation of SAMD14 and neurabin-1 was found in the peripheral blood of 400 healthy controls, 100 newborns and 50 nursery residents. Moreover, antibodies against SAMD14 and neurabin-1 were detected in the sera and cerebrospinal fluids of an independent second cohort of patients with PCNSL (8/22), but not in sera of patients with secondary CNS manifestations of systemic DLBCL (0/17) or of healthy controls (0/92). Conclusion: Our results strongly suggest that the atypical (NLEQ) glycosylation of the highly homologous SAMD14 and the SAM domain of neurabin-1 maintains a chronic autoimmunogenic stimulation in the CNS, ultimately leading to the malignant transformation of B-cells with a BCR specific for these atypically N-hyperglycosylated proteins into an aggressive B-cell lymphoma in the CNS in a majority of patients with PCNSL. The fact that the VH4-34 family represents only a minority of VH families recognizing SAMD14/neurabin-1 underlines the extraordinary autoimmunogenicity of these posttranslationally modified proteins in a broad range of individuals. Our results provide the first and strongest experimental evidence for the role of chronic autoantigenic stimulation as a first step in the pathogenesis of aggressive B-cell lymphomas. Supported by Deutsche Forschungsgemeinschaft DFG, Deutsche José Carreras Leukämie Stiftung, Wilhelm-Sander-Stiftung, Deutsche Krebshilfe e.V. Disclosures No relevant conflicts of interest to declare.
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Teng, Linda K. H., Brooke A. Pereira, Shivakumar Keerthikumar, Cheng Huang, Birunthi Niranjan, Sophie N. Lee, Michelle Richards, et al. "Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment." Cancers 13, no. 6 (March 11, 2021): 1237. http://dx.doi.org/10.3390/cancers13061237.
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Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.
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Hewitt, Kyle, Prithvia Devadas, Lily Zemelko, Sunduz Keles, and Emery Bresnick. "SAMD14 enhancer-mediated hematopoietic stress signaling." Experimental Hematology 44, no. 9 (September 2016): S79. http://dx.doi.org/10.1016/j.exphem.2016.06.156.
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Thurner, L., M. Bewarder, N. Fadle, E. Regitz, V. Poeschel, M. Ziepert, R. Schuck, et al. "SAMD14/NEURABIN-I AS BCR-ANTIGENS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA." Hematological Oncology 37 (June 2019): 195–96. http://dx.doi.org/10.1002/hon.9_2630.
Full textDissertations / Theses on the topic "SAMD14"
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Sébert, Marie. "Génétique et évolution clonale des syndromes d’insuffisance médullaire." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC271.
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Les syndromes d’insuffisance médullaire sont liés à des mutations constitutionnelles à l’origine d’une hématopoïèse déficiente chez les patients atteints. Ils représentent un groupe hétérogène de maladies syndromiques, et impliquent plusieurs familles de gènes avec des mécanismes biologiques différents conduisant à l’insuffisance médullaire. Ces maladies prédisposent à une évolution clonale somatique, avec un risque accru de développer un syndrome myélodysplasique (SMD) ou une leucémie aigüe myéloïde (LAM) au cours du temps. Nous avons séquencé et analysé l’exome d’ADN fibroblastique d’une cohorte de 179 patients ayant des insuffisances médullaires, des SMD ou des LAM, supposés d’origine constitutionnelle mais sans diagnostic établi. Ce travail a permis de porter un diagnostic moléculaire chez 86 (48%) patients, et de participer à la description de nouveaux syndromes impliquant les gènes SAMD9/SAMD9L (N=16/86, 18,6%), MECOM/EVI1 (N=6, 7%) et ERCC6L2 (N=7, 8,1%). Le suivi longitudinal des patients nous a permis de décrire un modèle d’évolution clonale particulier chez les patients ayant des mutations SAMD9/SAMD9L. Le syndrome d’insuffisance médullaire le plus fréquent est la maladie de Fanconi (AF ou FA), causée par une mutation germinale dans un des gènes de la voie de réparation FA/BRCA. Les cellules des patients FA ont une instabilité chromosomique liée à un défaut de réparation, avec une pression de sélection conduisant à une évolution clonale prototypique. Nous avons étudié une cohorte de 335 patients FA et confirmé de façon statistiquement significative l’ordre d’apparition des évènements cytogénétiques de ces patients au cours de l’évolution clonale et de la leucémogenèse : 1q+, 3q+, -7/del7q, délétion ou mutation RUNX1. L’étude moléculaire longitudinale des patients (NGS panel, WES, WGS) a confirmé un mécanisme oncogénique en rapport avec une instabilité chromosomique plus que génomique. En nous intéressant à l’anomalie cytogénétique la plus fréquente et la plus précoce : le 1q+, nous avons observé que le point de cassure péricentromérique sur ce chromosome correspondait à un site fragile, réparé ensuite par une voie de réparation alt NHEJ. La zone minimale dupliquée contenait le gène MDM4, un inhibiteur des fonctions transactivatrices de p53, qui constituait ainsi un bon candidat pour conférer aux cellules un avantage clonal et initier la leucémogenèse. Nous avons d’abord confirmé que les cellules des patients 1q+ avaient une surexpression de MDM4 et une inactivation de la voie p53 en aval (RNAseq). Puis, nous avons montré que cette surexpression permettait de restaurer les capacités fonctionnelles des progéniteurs hématopoïétiques humains FA, de façon réversible avec l’inhibition de MDM4, constituant ainsi une éventuelle cible thérapeutique. Les syndromes d’insuffisance médullaire sont des maladies rares, et nos travaux, en parallèle de ceux d’autres équipes, ont participé à la description de nouveaux gènes impliqués. L’étude de l’évolution clonale de ces syndromes représente une évolution dans la compréhension de la physiopathologie des SMD/LAM, et peut conduire à l’identification de cibles thérapeutiques chez ces patientsInherited bone marrow failure (IBMF) syndromes are heterogeneous diseases related to germ line mutations causing deficient hematopoiesis in mutated patients. Mutations involve several families of genes with different biological pathways driving the bone marrow failure. Most germ line genetic BMF disorders are characterized by a high propensity to clonal evolution and to develop MDS or AML. We used a whole-exome sequencing (WES) comprehensive analysis on fibroblast DNA samples from 179 patients with BMF/MDS of unresolved inherited origin. We provided a molecular diagnosis for 86/179 BMF patients (48%) including several seldom-reported IBMF/MDS entities like SAMD9/SAMD9L, MECOM/EVI1, and ERCC6L2. In particular, we described a specific clonal evolution in patients having mutations in SAMD9 and SAMD9L.Fanconi anemia (FA) is the most common IBMF syndrome, caused by a germ line mutation in one gene of the FA pathway. DNA repair deficiency in patient’s FA cells leads to chromosomal instability, which sets the stage for clonal evolution with a specific pattern of chromosomal abnormalities. We used integrated clinical, next-generation genomic and functional studies on primary cells from a National cohort of 335 FA patients, including 98 with clonal evolution, to decipher the mechanisms of BM progression. While relatively few somatic point mutations were found, unbalanced translocations leading to gross chromosomal copy-number abnormalities were most prominent. Whole genome sequencing revealed an FA-specific signature in which microhomology-mediated end joining (MMEJ) or non homologous end joining (NHEJ) repair had mediated genome rearrangements, consistent with the constitutive homologous repair defect. Longitudinal studies confirmed the order of chromosomal events during FA patients oncogenesis: 1q+, 3q+, -7/del7q, del or RUNX1 mutations. A major initial step was duplication of chromosome 1q, resulting in strong expression of MDM4, a negative regulator of p53, which can be targeted by MDM4-inhibitors.IBMF are rare diseases and our study participated to describe new genetic and clinical entities. Studying the clonal evolution of IBMF syndromes can help to understand MDS and AML pathophysiology and lead to therapeutic target identification
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Hani, Lylia. "Caractérisation et rôle des lymphocytes T CD4+ mémoires SAMHD1low au cours de l'infection par le VIH-1." Thesis, Paris Est, 2018. http://www.theses.fr/2018PESC0087/document.
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La mise en évidence du rôle de la molécule SAMHD1 dans l’infection par le VIH-1 en tant que facteur de restriction a ouvert de nouvelles perspectives dans la compréhension de la pathogénicité du virus.En effet, il a été clairement démontré que dans les cellules myéloïdes comme les monocytes/macrophages et les cellules dendritiques ainsi que les lymphocytes T CD4+ quiescents, SAMHD1 jouait un rôle important dans la protection de ces cellules de l’infection. En revanche, le rôle de cette molécule dans l’infection des lymphocytes activés, qui sont souvent la cible préférentielle du virus, n’est pas élucidé.Nos résultats ont révélé l'existence d'une sous-population de lymphocytes T CD4+ mémoires exprimant de faibles niveaux de SAMHD1 (CD4+ CD45RO+ SAMHD1low), tandis que la grande majorité des lymphocytes expriment cette molécule à des niveaux plus élevés (94±0.7%). Nous montrons également que ces cellules sont hautement différenciées, qu’elles expriment en larges proportions le marqueur de cycle cellulaire Ki67 et qu’elles sont enrichies en cellules « T helper 17 » (Th17) dans le sang périphérique.De plus, la fréquence de la population CD4+ CD45RO+ SAMHD1low, est diminuée de manière significative chez les patients infectés par le VIH-1 par rapport aux sujets sains. De manière intéressante, nous montrons que dans les ganglions, les cellules T follicular helper (Tfh) expriment faiblement SAMHD1 et sont plus susceptibles à l’infection par le VIH-1 in vitro.L’ensemble de ces résultats suggère que les cellules SAMHD1 low représentent une cible préférentielle pour le virus et pourraient contribuer au réservoir viral.Les objectifs de ce projet sont:1. Déterminer si les cellules SAMHD1low contiennent plus de virus par comparaison aux cellules mémoires SAMHD1high et comparer les séquences virales isolées des cellules mémoires SAMHD1low et SAMHD1high.2. Caractérisation des cellules SAMHD1low au niveau moléculaire par une analyse transcriptomique qui permettra la mise en évidence de marqueurs membranairesWe have previously reported the presence of memory CD4+ T cells that display low levels of SAMHD1 (SAMHD1low ) enriched in Th17 and Tfh cells. Here we investigated gene expression profile and the size and composition of HIV DNA population in SAMHD1 low cells.A total of 36 individuals on c-ART (median: 7y) with median CD4+ counts and nadir of 549 cells/ul and 210 cells/ul respectively, including 6 elite controllers (EC, CD4+: 900 cells/ul) and 8 healthy donors were studied. Blood memory CD4+ CD45RO+ SAMHD1low, CD45RO+ SAMHD1high and naive CD45RO- SAMHD1high cells were sorted. Cell associated HIV-1 DNA levels were quantified (HIV DNA Cell, Biocentric) and ultra-deep-sequencing (UDS, 454/Roche) of partial env (C2/V3) HIV-1 DNA was performed. Gene expression profile on sorted cells was deternined with RNA-Sequencing (Illumina RNASeq technology). Levels of HIV-1 DNA were significantly higher in memory SAMHD1low cells compared to SAMHD1high cells (4.5 [3.1-6.2] vs 3.8 [2.9-5.7] log/10 6 cells, respectively, p=0.02) among c-ART individuals, while naïve CD45RO- SAMHD1high showed lower levels (3.1 [1.6-4.4]). EC exhibited low HIV-1 DNA level in both SAMHD1low and SAMHD1high (1.6 and 2.3 log/10 6 cells respectively p>0.05). Naïve CD45RO - SAMHD1 high cells from EC showed lower DNA compared to naïve cells from c-ART pts (1.6 and 3.1 log/10 6 cells, respectively, p=0.01). Phylogenetic analyses revealed well-segregated HIV-DNA populations between subsets with significant compartmentalization between SAMHD1low and SAMHD1high cells in all but 2 participants (p<0.001) and limited viral exchange. Moreover SAMHD1low cells exhibited a distinct gene profile as compared to SAMHD1high allowing thus further characterisation of these cells.This pilot study revealed distinct HIV DNA populations in size and composition associated with unique genes profile in memory SAMHD1low cells. We show that memory SAMHD1low cells exhibit distinct genes profile which segregates them from the SAMHD1 high counterpart, and contain the highest level of HIV-1 DNA. We reveal distinct/well-segregated HIV-1 DNA populations in both subsets, suggesting minimal viral exchange
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Argüelles, Camilla. "Étude du rôle de la protéine de liaison aux ARN messagers Smaug dans la voie Hedgehog chez la drosophile." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC053.
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Les protéines signal Hedgehog (HH) sont des acteurs majeurs du développement animal et de la carcinogenèse. Leur transduction requiert la protéine à 7 domaines transmembranaires Smoothened (SMO) dont l’activité est régulée par Patched (PTC), un récepteur et antagoniste d’HH. PTC et HH régulent le trafic, la phosphorylation et l’accumulation de SMO mais de nombreux aspects de sa régulation restent incompris. Au cours de ma thèse, j’ai travaillé sur Smaug, un nouveau partenaire de SMO chez la drosophile identifié au laboratoire dans un crible double-hybride. Smaug est connue pour lier et réprimer de nombreux ARNm au cours de l’embryogenèse chez la mouche. Durant ma thèse j’ai étudié comment Smaug agit sur SMO et la voie HH et aussi comment elle est régulée par HH. J’ai montré que Smaug était un régulateur positif de la voie HH et ce très probablement via sa capacité à fixer des ARNm. J’ai également montré que SMO et Smaug colocalisaient dans des foci cytoplasmiques en absence de signal et que Smaug était relocalisée à la membrane plasmique avec SMO en réponse à HH. Enfin j’ai mis en évidence un effet de SMO et d’HH sur la phosphorylation de Smaug suggérant une potentielle régulation en retour sur l’activité de Smaug. Ce travail m’a permis de proposer à la fois un nouveau rôle de la protéine de liaison aux ARN Smaug dans un processus de signalisation cellulaire ainsi que l’implication jusqu’ici insoupçonnée, d’une possible régulation post-transcriptionnelle d’ARNm dans la voie HHHedgehog Proteins (HH) are major players of animal development and carcinogenesis. Their transduction requires the 7 transmembrane protein Smoothened (SMO) whose activity is regulated by Patched (PTC), the HH receptor and antagonist. PTC and HH regulates SMO trafficking, phosphorylation and accumulation but numerous aspects of these regulations remain poorly understood. During my thesis, I focused on Smaug, a new partner of SMO in drosophila which was identified in the laboratory in a yeast two-hybrid screen. Smaug is known to bind and repress numerous mRNA during embryonic development in fly. I analyzed how it acts on SMO and HH signaling and also how is it regulated by HH. I have shown that Smaug is a positive regulator of the HH pathway and that it probably acts via its capacity to bind mRNA. I have also demonstrated that SMO and Smaug colocalise in cytoplasmic foci in absence of signal and that SMO is sufficient to localized Smaug to the plasma membrane in response to HH. Finally, I highlighted an effect of SMO and HH on the phosphorylation of Smaug suggesting the existence of a regulatory loop
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Valverde, Estrella Lorena. "TREX1 and SAMHD1, and Aicardi-Goutières Syndrome." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/291940.
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Aicardi-Goutières Syndrome (AGS) is a rare encephalopathy which mimics a viral intrauterine infection and is characterized by calcifications of the basal ganglia, cerebral atrophy and IFN-a in the cerebrospinal fluid. AGS is a heterogenic disease associated with mutations in the gene of the exonuclease TREX1, in any of the genes codifying for the ribonuclease H2, in the phosphohydrolase SAMHD1, in the deaminase ADAR1 or in the cytoplasmic sensor MDA5. The knowledge of these functions is basic for the comprehension of the beginning of the pathogenesis of AGS. In this thesis we focused in the mechanism of Samhd1 transcription. We have seen that Samhd1 is induced by pro-inflammatory stimuli but neither by anti-inflammatory stimuli nor TNF-a, and that the induction of Samhd1 is through STAT1 pathway. We wanted to know a bit more about Samhd1 induction so we focused on the study of its promoter. We did a construct in a luciferase-reporter vector with 1500bp of Samhd1 promoter, and we saw that this region of the promoter is enough to induce luciferase expression. From this construct, we did new plasmids and when deleting a specific region, the luciferase expression was abolished, indicating that in Samhd1 promoter, 161bp are critical for Samhd1 induction. EMSA assays showed that Samhd1 expression is repressed in basal conditions by an unknown protein, and ChIP assays also showed that IRF1 is involved in Samhd1 induction by IFN-.. We hypothesized that the regulation mechanism is depending in an STAT1-depending pathway, through IRF1, and also in an STAT1-independing pathway, through an unknown mechanism up to date. We checked with proteomics analysis the protein which might be involved in Samhd1 repression but the results were not significant. We also constructed a conditional KO mouse for TREX1, and now we are crossing it with different CRESocs2 expressing strands. Homozygous KO expressing CRElitter, show a similar phenotype to TREX1 total KO. We are in the process to obtain homozygous KO expressing CRELysM, but due to problems with the penetrance of this CRE allele we have some difficulties. All together, the results of this thesis will shed light in the inner operation of AGS.La síndrome d'Aicardi-Goutières (AGS), és una malaltia autoimmunitària recessiva que mimetitza una infecció vírica intrauterina, i la qual és caracteritzada per calcificacions intracranials, atròfia cerebral i augment d'IFN-alfa al líquid cefaloraquidi. L'AGS és una malaltia genètica heterogènia associada amb mutacions al gen que codifica per a l'exonucleasa TREX1, a qualsevol dels gens codificants per a les components de la ribonucleasa RNASE H2, a la fosfohidrolasa SAMHD1, a la deaminasa ADAR1 o al sensor citoplasmàtic MDA5. El coneixement d'aquestes funcions és fonamental per tal d'entendre la patogènesi de l'AGS. En aquesta tesi s'ha aprofundit en el coneixement del mecanisme regulador de la transcripció de Samhd1. Hem vist que Samhd1 es troba expressat en diferents òrgans sense necessitat de cap estímul previ, com el pàncrees, l’intestí prim i els macròfags derivats de moll d’os, i en diferents quantitats en altres òrgans de ratolí. Donada la important afectació que té l’AGS al cervell, també es va analitzar la seva expressió en neurones i cèl·lules de la micròglia. També hem vist que Samhd1 es troba induït en presència de citocines proinflamatòries, però no es troba afectada la seva expressió en presència de citocines antiinflamatòries així com tampoc en presència de TNF-gamma. Utilitzant macròfags derivats de ratolins deficients en STAT1, hem pogut demostrar que l’expressió de Samhd1 per IFN-alfa és a través d’STAT1, ja que la seva expressió es troba completament reprimida en aquestes cèl·lules. Ens vam centrar en la inducció de Samhd1 i per la seva comprensió vam focalitzar en l’estudi del seu promotor. Es van clonar 1500 parells de bases del promotor de Samhd1 en un plasmidi reporter de luciferasa, i es va veure que aquest fragment era suficient per induir l’expressió de luciferasa. A partir d’aquest constructe, es van realitzar llavors noves construccions delecionant cada vegada una regió del promotor. Es va veure que en delecionar una regió específica de 161pb, l’expressió de luciferasa es trobava completament reprimida, indicant que aquesta regió del promotor és crítica per a la inducció de Samhd1. Experiments de retard en gel (EMSA) van mostrar que Samhd1 es troba reprimit en condicions basals per una proteïna que no hem arribat a caracteritzar, i experiments de precipitació de cromatina (ChIP) van mostrar que IRF1 es troba involucrada en la inducció de Samhd1 per IFN-alfa. La nostra hipòtesi doncs, és que l’expressió de Samhd1 té un mecanisme de regulació doble: en condicions basals es troba reprimit i en presència d’IFN-alfa s’indueix una via de senyalització independent d’STAT1 que fa saltar el complex repressor del promotor, i també s’indueix una via de senyalització dependent d’STAT1, que indueix l’expressió d’IRF1 i que activa la transducció de Samhd1. Fins ara no hem caracteritzat la proteïna o complex de proteïnes que reprimeix l’expressió de Samhd1 en condicions basals, però s’està investigant mitjançant anàlisis proteòmics. En aquesta tesi també s’ha fet la construcció d’un ratolí KO condicional per a TREX1. Una vegada aconseguit aquest animal condicional, el qual conté el gen de Trex1 flanquejat per dues dianes LoxP, aquest s’està encreuant amb diferents soques que expressen CRE sota regulació de diferents Socs2 promotors. Els ratolins homozigots KO i que expressen CRE, tenen un fenotip similar al fenotip que mostren els ratolins KO totals de TREX1. Estem en el procés d’obtenció de ratolins homozigots KO i que expressen CRELysM però, donat a problemes amb la penetrància d’aquest al·lel, hem tingut algunes dificultats. Els resultats d’aquesta tesi en conjunt poden ajudar a entendre una mica més el funcionament de l'AGS.
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Antonucci, Jenna Marie. "Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524006072232491.
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Louis, Tania. "Étude des fonctions cellulaires de SAMHD1, facteur de restriction du VIH-1." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTS050/document.
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L'étude des interactions entre un pathogène et son hôte, bien qu'ayant généralement pour objectif de contrôler l'infection par le pathogène, permet parfois de découvrir des éléments fondamentaux sur le fonctionnement de l'hôte. J'ai choisi d'étudier les fonctions cellulaires d'une protéine initialement identifiée comme un facteur de restriction du VIH-1. SAMHD1 (SAM domain and HD domain-containing protein 1) est une protéine exprimée dans la plupart des tissus humains. Elle est capable d'hydrolyser les déoxyribonucléotides triphosphates (dNTP) cellulaires et possède une activité nucléase ciblant différents acides nucléiques dont les ARN simple brin in vitro. Des mutations dans le gène SAMHD1 entraînent le développement d'une maladie auto-immune pouvant conduire à la mort précoce des nourrissons, ce qui suggère un rôle de la protéine correspondante dans la régulation de la réponse immunitaire. Il a été montré que SAMHD1 est un facteur de restriction capable d'empêcher l'infection de cellules ne se divisant pas par le VIH-1. La protéine virale Vpx, exprimée par le VIH-2, est capable d'induire la dégradation de SAMHD1 par le protéasome et permet de rendre permissives les cellules initialement résistantes à l'infection par le VIH. SAMHD1 est en réalité capable de restreindre l'infection par des virus aussi différents que les rétrovirus et le virus de l'herpès simplex 1. Néanmoins, le mécanisme permettant à SAMHD1 de contrecarrer différents virus reste aujourd'hui sujet à controverse. Initialement considéré comme agissant en dégradant les dNTP cellulaires, SAMHD1 semble également capable de dégrader l'ARN génomique du VIH-1. Si de nombreux travaux portent sur l'activité antivirale de SAMHD1, peu de données sont disponibles concernant la fonction cellulaire de cette protéine. Or SAMHD1 est capable de réguler la quantité de dNTP cellulaires et d'interagir avec certains acides nucléiques. Ces données font de SAMHD1 un acteur potentiel de différents processus cellulaires fondamentaux sensibles à la quantité intracellulaire de dNTP, notamment la réplication du génome ou la réparation des dommages à l'ADN. J'ai montré au cours de mon doctorat que SAMHD1 module le cycle cellulaire et notamment que la surexpression de cette protéine ralentit la prolifération cellulaire. J'ai également observé que la surexpression de SAMHD1 augmente la sensibilité des cellules aux agents induisant des ruptures double brin de l'ADN. De plus, j'ai découvert qu'en cas de ruptures double brin de l'ADN cellulaire, SAMHD1 est régulé de façon spécifique par phosphorylation sur sa thréonine 592 et est recruté aux sites de cassures. D'autres travaux ont confirmé l'importance de la régulation de SAMHD1 au cours du cycle cellulaire, sa surexpression et sa réduction induisant toutes deux un ralentissement de la prolifération cellulaire. En complément de mes résultats, quelques études suggèrent que SAMHD1 joue un rôle dans le maintien de l'intégrité du génome, qui pourrait être dû à son effet sur la réponse aux dommages à l'ADN. Dans l'ensemble, ces résultats font de SAMHD1 un garant de l'homéostasie cellulaire. J'ai de plus montré que l'expression de SAMHD1 est réduite chez environ 80% des patients souffrant de leucémie lymphoïde chronique. La perte de cette protéine est donc corrélée à l'apparition d'une maladie découlant de la perturbation du fonctionnement cellulaire. L'étude d'échantillons d'autres types de tumeurs montre que, dans de moindres proportions, l'altération de l'expression de SAMHD1 est une caractéristique générale des cancers. Mes travaux de doctorat soulignent ainsi le rôle fondamental de SAMHD1 dans le maintien de l'intégrité cellulaireUnderstanding host pathogen interactions reveals not only important information regarding the replication cycle of the pathogen but it often leads to the discovery and better understanding of key biological processes of the host. The aim of my PhD was to decipher the cellular functions of the HIV-1 restriction factor SAMHD1. SAMHD1 (SAM domain and HD domain-containing protein 1) is expressed in most human tissues. This protein is able to hydrolyze cellular deoxyribonucleotides triphosphate (dNTP) and possesses a nuclease activity primarily against single stranded RNA. Mutations in SAMHD1 have been described in patients suffering from an auto-immune disease causing premature death of newborns. This phenotype suggests a role of SAMHD1 in the control of immune response. Moreover, SAMHD1 restricts HIV-1 in non-cycling cells. The HIV-2 accessory protein Vpx induces SAMHD1 degradation by the proteasome, conferring cell permissiveness to HIV. In fact, the antiviral activity of SAMHD1 has been extended to other viruses including Herpes Simplex Virus 1 and Hepatitis B virus. Nevertheless, the mechanism by which SAMHD1 restrict HIV replication is debated. It was initially thought to act by depleting the dNTP pool but recent studies highlighted a potential role of SAMHD1 nuclease function in degrading HIV-1 genomic RNA. Many studies aiming at understanding the antiviral activity of SAMHD1 are being pursued, whereas little is known about the cellular function of this protein. The fact that SAMHD1 is able to regulate the cellular dNTP pool and to interact with nucleic acids suggests a key role of this protein in cellular processes, such as DNA replication and repair. During my PhD, I showed that SAMHD1 modulates the cell cycle, as the overexpression of this protein slows down cell proliferation. I also observed that SAMHD1 overexpression increases cellular sensitivity to double strand DNA breaks-inducing agents. Moreover I discovered that, after double strand breaks induction, SAMHD1 is specifically regulated by phosphorylation on its threonine 592 and recruited at the damaged sites. Other studies confirmed the importance of SAMHD1 regulation along the cell cycle as its overexpression and depletion both decrease cell proliferation. In addition to my observations, some studies suggested that SAMHD1 is important to maintain genomic integrity, presumably through its implication in DNA repair. Altogether, these results promote SAMHD1 as a key player in cellular homeostasis. I additionally showed that SAMHD1 expression is reduced in 80% of patients suffering from chronic lymphocytic leukemia (CLL). SAMHD1 loss is therefore correlated to the development of a disease due to disturbances of cellular integrity. Looking at samples from different types of tumors, I showed that SAMHD1 loss is shared between all tested cancers, although at lesser extent than in CLL. My PhD work underlines the central role of SAMHD1 to maintain cellular integrity
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Jaffer, Ali Mohammed Hakim. "Multifaceted roles of the transmembrane nuclear envelope protein, Samp1." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-141816.
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The eukaryotic nuclear envelope (NE), separates the nucleoplasm from cytoplasm and is made up of two concentric lipid membranes, the outer and the inner nuclear membranes (ONM and INM), the nuclear pore complexes (NPCs) and an underlying filamentous nuclear lamina. The INM contains hundreds of unique transmembrane proteins of which only a handful have been characterized. In this thesis, I aimed to understand the functional organization of proteins in the nuclear envelope and I focused on investigating the functions of a recently identified INM transmembrane protein, Samp1. We have developed a novel and robust approach, MCLIP, to identify specific protein-protein interactions taking place in live cells. Using MCLIP, we have shown that Samp1 interacts with proteins of the LINC complex, the nuclear lamina and components of the mitotic spindle. Samp1's specific interactions with a variety of binding partners, suggest that Samp1 plays important roles both in interphase and in mitosis. We have also shown that Samp1 can provide a binding site at the INM for the GTPase Ran, a master regulator of protein interactions in interphase and in mitosis. Furthermore, we have also investigated the role of Samp1 in cell differentiation using two independent model systems. In human iPSCs, ectopic expression of Samp1 promoted differentiation despite pluripotent culture conditions. In C2C12 myoblast, depletion of Samp1 completely blocked differentiation into myotubes. The two studies complement each other and suggest that Samp1 has a strong differentiation promoting activity. Taken together, the findings in this thesis, give insights on the unexpected and unforeseen roles played by a transmembrane protein in different fundamental cellular process.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.
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Silva, Maria-João. "Role of CTF18 and SAMHD1 in human DNA replication and genome integrity maintenance." Thesis, Montpellier 2, 2014. http://www.theses.fr/2014MON20236.
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La phase S est une période critique du cycle cellulaire au cours de laquelle le génome est particulièrement vulnérable. La duplication efficace des génomes eucaryotes dépend de la progression de milliers de fourches de réplication. Les premières étapes de la tumorigenèse sont associées au stress de réplication spontané, caractérisé par un blocage de la fourche. Comprendre comment le stress de réplication survient dans les cellules normales et contribue à la tumorigenèse est un grand défi dans la recherche sur le cancer. Mon travail de thèse vise à comprendre la régulation de la progression de la fourche de réplication par deux protéines différentes,SAMHD1 et CTF18, qui participent à divers aspects du métabolisme de l'ADN.La duplication du génome dépend d'un approvisionnement équilibré de désoxyribonucléosides triphosphates (dNTP).Des pools de dNTP déséquilibrées augmentent les taux de mutation. SAMHD1 a été identifié comme une triphosphohydrolase de dNTPs. Cette enzyme est impliquée dans le syndrome d'Aicardi-Goutières. Récemment, il a été montré que SAMHD1 est impliquée dans la régulation des pools de dNTPs dans des cellules humaines. Cette protéine est exprimée au maximum pendant la quiescence et peu en phase S. Cependant, l'impact de SAMHD1 sur la réplication de l'ADN n'a pas encore été abordée. En utilisant la technique DNA fiber spreading, nous avons constaté que SAMHD1 module la vitesse de progression de la fourche. En plus de son activité de dNTPase, SAMHD1 contient un domaine putatif 3'-5 'exonucléase qui clive à la fois l'ADN et l'ARN in vitro. Un nombre croissant de preuves indique que les exonucléases 3'-5 'sont essentielles pour assurer la progression de la fourche et la fidélité de la réplication de l'ADN. Nous avons constaté que l'activité d'exonucléase de SAMHD1 favorise le backtracking des fourches arrêtées et qu'elle est requise pour la progression normale des fourches de réplication. Nous proposons que cette activité de backtracking est importante pour enlever désoxynucléotides ou ribonucléotides mal incorporés. Au-delà du cancer, notre découverte pourrait avoir des implications pour la compréhension du lien entre SAMHD1 et le syndrome d'Aicardi-Goutières. CTF18 fait partie d'un complexe de type RFC impliqué dans la cohésion des chromatides sœurs (CCS). Dans les cellules humaines, il a été suggéré que CTF18 contrôle la progression des fourches de réplication, en favorisant l'acétylation de la cohésine SMC3 à la fourche de réplication. Cependant, plusieurs résultats indiquent que la fonction de CTF18 n'est pas limitée à la mise en place de la CCS.En effet, notre groupe a montré que Ctf18 chez la levure est essentielle pour l'activation du checkpoint de la réplication, indépendamment de son rôle dans la CCS.Chez l'homme, CTF18 participe également au recrutement de PCNA, le facteur de processivité des ADN polymérases δ et ε. CTF18 interagit également avec la polymérase translésionnelle ƞ. Le but de mon travail était de caractériser le rôle de CTF18 lors de la réplication de l'ADN. En utilisant le peignage moléculaire, nous avons remarqué que la vitesse de la fourche de réplication est plus lente dans les cellules dépletés en CTF18 dans une phase S normale.Curieusement, l'augmentation de la vitesse de la fourche a été observée dans les cellules dépletés en CTF18 traités avec l'hydroxyurée (HU), qui ressemble au phénotype des cellules dépletés pour SAMHD1. Avec l'utilisation de la technique iPOND, nous avons observé une accumulation de PCNA aux fourches de réplication dans les cellules CTF18 traités avec HU. Nous avons également constaté que la déplétion de CTF18 induit une accumulation de yH2AX, ce qui suggère que CTF18 est nécessaire pour la stabilité du génome. Enfin, nous avons observé que la résection dépendante de SAMHD1 ne se produit pas en l'absence de CTF18. Collectivement, ces données indiquent que CTF18 agit en amont de SAMHD1 aux fourches arrêtées, probablement par le déchargement de PCNAS phase is a critical period of the cell cycle during which the genome is particularly vulnerable. The efficient duplication of eukaryotic genomes depends on the unperturbed progression of thousands of replication forks.The early stages of tumorigenesis are associated with spontaneous replication stress, characterized with a blockage of fork progression. Understanding how replication stress arises in normal cells and contributes to tumorigenesis is a major challenge in cancer research.My thesis work aims at understanding the regulation of replication fork progression by two different proteins, SAMHD1 and CTF18, which have important roles in various aspects of DNA metabolism.Faithful duplication of the genome depends on a balanced supply of deoxyribonucleoside triphosphates (dNTPs). Imbalanced dNTP pools decrease the fidelity of DNA polymerases and increase mutation rates. SAMHD1 was originally identified as a dNTP triphosphohydrolase. This enzyme is implicated in Aicardi-Goutières syndrome. It has also been identified as a component of the human innate immune system that restricts HIV-1 infection. Recently, SAMHD1 was shown to be involved in the regulation of dNTP pools in cultured human cells. This protein is maximally expressed during quiescence and minimally during S phase. However, the impact of SAMHD1 upon DNA replication has not been addressed. Using DNA fiber spreading, we found that SAMHD1 modulates the speed of fork progression. In addition to its dNTPase activity, SAMHD1 contains a putative 3'-5' exonuclease domain that cleaves both DNA and RNA in vitro. A growing body of evidence indicates that 3'-5' exonucleases are critical to ensure fork progression and the fidelity of DNA replication. Remarkably, we found that the exonuclease activity of SAMHD1 promotes backtracking at paused forks and is important for replication fork progression. We propose that this backtracking activity is important to remove miss-incorporated deoxynucleotides or ribonucleotides. Our finding may have implications for our understanding of the link between SAMHD1 and the Aicardi-Goutières syndrome.CTF18 is part of a RFC-like complex involved in sister chromatid cohesion (SCC). In human cells it has been suggested that CTF18 controls the progression of replication forks, presumably by promoting acetylation of the SMC3 cohesin at replication forks. However, several results indicate that the function of CTF18 is not restricted to the establishment of SCC. Indeed, our group has shown that the yeast Ctf18 is essential for activation of the replication checkpoint, independently of its role in SCC. In human, CTF18 also participates in the recruitment of PCNA, the processivity factor of DNA polymerases δ and ε. CTF18 also interacts with the translesion polymerase . The aim of my work was to characterize the role of CTF18 during DNA replication. Using DNA combing, we first noticed that replication fork speed is slower in CTF18-depleted cells under unperturbed conditions. Intriguingly, increased fork speed was observed in CTF18-depleted cells challenged with hydroxyurea (HU), which is reminiscent of the phenotype of SAMHD1-depleted cells. Using iPOND, we observed an accumulation of PCNA at replication forks in HU-treated CTF18-depleted cells. We also found that CTF18 depletion induces an accumulation of yH2AX, suggesting that CTF18 is required for genome stability. Finally, we observed that the resection mediated by SAMHD1 at paused forks does not occur in the absence of CTF18. Together, these data indicate that CTF18 acts upstream of SAMHD1 at stalled forks, presumably through the unloading of PCNA
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Qin, Zhihua. "SAMHD1 Negatively Regulates the Innate Immune Responses to Inflammatory Stimuli and Viral Infection." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587587968104986.
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Cenker, Jennifer Jean. "DIFFERENTIAL HIV-1 SUSCEPTIBILITY OF PRIMARY MACROPHAGE POPULATIONS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491656059069304.
Full textBooks on the topic "SAMD14"
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Yŏm, Sang-sŏp. Samdae. Sŏul Tʻŭkpyŏlsi: Yangudang, 1986.
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1948-, Kwŏn Yŏng-min, ed. Samdae. Sŏul: Minŭmsa, 1987.
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Samdae. Sŏul-si: Chisŏng ŭi saem, 1991.
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Yŏm, Sang-sŏp. Samdae [oe]. Sŏul: Hagwŏn Chʻulpʻan Kongsa, 1987.
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Chʻoe, Chin-u. Pak Ssi samdae. Sŏul: Sosŏl Munhaksa, 1985.
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Cambodian Buddhist Temple (Washington, D.C.), ed. Braḥrājajīvapravatti nai Samdec Braḥsaṅgharāj Samdec Braḥsaṅghanāyak niṅ braḥmahāthera: Caek knuṅ okās buny Divā Samdec Juan Nāt. Kruṅ Vāsiṅtan, Dī. Sī: Vatt Buddhikārām, 1987.
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Luvsanzunduĭ, S. Túúkhénd mónkhórsón Samdan avarga. Ulaanbaatar: Zhikom press, 2006.
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Samdae: Yi Wŏn-ho changp'yŏn sosŏl. Sŏul T'ŭkpyŏlsi: P'aendŏm, 2010.
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Yŏm, Sang-sŏp. Samdae ; Manse chŏn ; Pʻyobonsil ŭi chʻŏng kaeguri [oe]. Sŏul: Tongsŏ Munhwasa, 1987.
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Yŏm Sang-sŏp "Samdae" ŭi inmul sŭt'orit'elling chŏllyak. Sŏul T'ŭkpyŏlsi: Munhyŏn, 2015.
Find full textBook chapters on the topic "SAMD14"
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Kania, Stefan. "Samba4 als Printserver." In Samba 4, 379–96. München: Carl Hanser Verlag GmbH & Co. KG, 2019. http://dx.doi.org/10.3139/9783446457355.019.
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Kania, Stefan. "WINS und Samba4." In Samba 4, 397–403. München: Carl Hanser Verlag GmbH & Co. KG, 2019. http://dx.doi.org/10.3139/9783446457355.020.
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de Silva, Suresh, Corine St. Gelais, Nagaraja Tirumuru, and Li Wu. "Counteraction of SAMHD1 by Vpx." In Encyclopedia of AIDS, 1–11. New York, NY: Springer New York, 2015. http://dx.doi.org/10.1007/978-1-4614-9610-6_375-1.
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de Silva, Suresh, Corine St. Gelais, Nagaraja Tirumuru, and Li Wu. "Counteraction of SAMHD1 by Vpx." In Encyclopedia of AIDS, 385–94. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-7101-5_375.
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Kania, Stefan. "Samba4 über die Kommandozeile verwalten." In Samba 4, 335–62. München: Carl Hanser Verlag GmbH & Co. KG, 2019. http://dx.doi.org/10.3139/9783446457355.017.
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Chabah, Myriam, Nicolas Burlet, Jean-Philippe Malkasse, Guy Le Bihan, and Bruno Quellec. "SAMDIS: A New SAS Imaging System for AUV." In Quantitative Monitoring of the Underwater Environment, 107–18. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-32107-3_10.
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Khaslan, Zaki, Noor Hidayah Mohd Yunus, Mohd Shahrul Mohd Nadzir, Jahariah Sampe, Noorazlina Mohamad Salih, and Kemal Maulana Alhasa. "IoT-Based Indoor Air Quality Monitoring System Using SAMD21 ARM Cortex Processor." In Advanced Structured Materials, 245–53. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-92964-0_24.
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Maehigashi, Tatsuya, Dong-Hyun Kim, Raymond F. Schinazi, and Baek Kim. "SAMHD1-Mediated Negative Regulation of Cellular dNTP Levels: HIV-1, Innate Immunity, and Cancers." In Enzymatic and Chemical Synthesis of Nucleic Acid Derivatives, 313–25. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2018. http://dx.doi.org/10.1002/9783527812103.ch12.
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Holder, Andrew J., and Earl M. Evleth. "SAM1: General Description and Performance Evaluation for Hydrogen Bonds." In ACS Symposium Series, 113–24. Washington, DC: American Chemical Society, 1994. http://dx.doi.org/10.1021/bk-1994-0569.ch007.
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Dong, Guozhong, Bo Wang, Wu Yang, Wei Wang, and Rui Sun. "SAMD: A System for Abnormal Messages Detection Oriented Microblog Message Stream." In Communications in Computer and Information Science, 113–24. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-662-49014-3_11.
Full textConference papers on the topic "SAMD14"
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Bryant, Victoria, Jasmine Wong, Jason Schwartz, Tamara Lamprecht, Jing Ma, Charles Mullighan, Mignon Loh, Kevin Shannon, and Jeffery Klco. "Abstract 2063:SAMD9/SAMD9Lmutations in familial monosomy 7." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-2063.
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Margeli, Mireia, Eudald Felip, Lucia Gutierrez Chamorro, Eva Riveira, Laura Layos, Teresa Moran, Margarita Romeo, Anna Matinez-Cardús, and Ester Ballana. "Abstract LB112: SAMHD1: A new Prognostic Marker in Breast Cancer (BC)." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-lb112.
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Sendon, C., Y. A. Collado, and A. E. Esquibies. "De Novo Variant of the SAMD9 Gene: Mirage Syndrome." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5025.
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Sakai, Michiya, Kenji Kanazawa, and Yasuki Ohtori. "Development of High Acceleration Shaking Table System Using Resonance Vibration." In ASME 2016 Pressure Vessels and Piping Conference. American Society of Mechanical Engineers, 2016. http://dx.doi.org/10.1115/pvp2016-63752.
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High acceleration shaking table system to be called “Strong Shake Generator” (SSG) using resonance vibration has been developed. New concept of setting the resonance table on outside shaking table is devised. Maximum acceleration of 200 m/s2 with 5 ton specimen weight is achieved. At the trial operation of SSG, the environmental influence exceeding the regulation value of vibration level has been occurred at the site boundary of CRIEPI. In order to suppress vibration of SSG, the semi-active mass damper (SAMD) has been additionally installed on base of shaking table. Vibration of SSG was reduced by counterforce of the SAMD. For the confirmation of the earthquake-proof safety for various nuclear facilities, strong shake generator will be utilized.
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Faraj, R., G. T. Kelly, A. Feng, and T. Wang. "A Novel Role of SAMD4A in Endothelial Cell Barrier Regulation in Response to Simvastatin." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5391.
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Margeli, Mireia, Eudald Felip, Maica Gomez, Pedro Fernandez, Laia Pérez-Roca, Eva Riveira-Muñoz, Anna Martinez-Cardús, et al. "Abstract P3-08-32: Predictive value of SAMHD1 expression in early relapse breast cancer." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p3-08-32.
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Lee, Jaehun, Hochul Lee, Byoungjun Seo, Min Kyung Chae, Young Choon Lee, Hyuck Han, and Sooyong Kang. "SAMD Apps: Install Once, Run Anywhere Instantly." In 2018 IEEE International Conference on Pervasive Computing and Communications Workshops (PerCom Workshops). IEEE, 2018. http://dx.doi.org/10.1109/percomw.2018.8480287.
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Felip, Eudald, Roger Badia, Mireia Margelí, Marc Castellví, Vanesa Quiroga, Iris Teruel, Beatriz Cirauqui, et al. "Abstract P5-05-14: Cyclin-dependent kinases inhibitors improve antimetabolite drug potency depending on SAMHD1 expression." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p5-05-14.
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Lee, Jaehun, Hochul Lee, Byoungjun Seo, Young Choon Lee, Hyuck Han, and Sooyong Kang. "SAMD: Fine-Grained Application Sharing for Mobile Collaboration." In 2018 IEEE International Conference on Pervasive Computing and Communications (PerCom). IEEE, 2018. http://dx.doi.org/10.1109/percom.2018.8444574.
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Schwartz, Jason R., Jon P. Connelly, Shondra M. Pruett-Miller, and Jeffery M. Klco. "Abstract B49: Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells." In Abstracts: AACR Special Conference on the Advances in Pediatric Cancer Research; September 17-20, 2019; Montreal, QC, Canada. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.pedca19-b49.
Full textReports on the topic "SAMD14"
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Holder, Andrew J. SAM1-A New Semiempirical Method Including D-Orbitals. Fort Belvoir, VA: Defense Technical Information Center, January 1995. http://dx.doi.org/10.21236/ada290903.
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Manni, Andrea. Relative Contribution of Ornithine Decarboxylase (ODC) Versus S-adenosylmethionine Decarboxylase (SAMDC) to Human Breast Cancer Progression and Development. Fort Belvoir, VA: Defense Technical Information Center, July 2002. http://dx.doi.org/10.21236/ada408110.
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