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Academic literature on the topic 'ACML'

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Published: 9 March 2023
Last updated: 10 March 2023

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Journal articles on the topic "ACML"

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Piazza, Rocco, Sara Redaelli, Simona Valletta, Alessandra Pirola, Roberta Spinelli, Vera Magistroni, Dong-Wook Kim, Nicholas C. P. Cross, and Carlo Gambacorti-Passerini. "SETBP1 and CSF3R Mutations In Atypical Chronic Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 2598. http://dx.doi.org/10.1182/blood.v122.21.2598.2598.

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Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. In aCML many clinical features suggest the diagnosis of CML, however the lack of the BCR-ABL1 fusion point to a different pathogenetic process. Recently, we identified the presence of clonal somatic mutations occurring in the SETBP1 gene in approximately 25% of aCML samples (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). A subsequent study (Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90) demonstrated the presence of somatic mutations of the CSF3R gene in Chronic Neutrophilic Leukemia (CNL) and, with lower frequency, in aCML. In a recent follow-up of the first study (Gotlib J. et al., Blood. 2013 Jul 29), the presence of both CSF3R and SETBP1 variants was tested in a cohort of 9 CNL and 20 aCML cases, demonstrating the presence of CSF3R somatic mutations in 40% of the aCML patients. Of these mutations, 20% were membrane, 5% truncating and 15% compound variants. Interestingly, 5% of the aCML patients showed coexistence of CSF3R and SETBP1 mutations, suggesting that variants occurring in these genes are not mutually exclusive. To gain further insight into the relationship between CSF3R and SETBP1 in aCML, we extended our initial study by analyzing an expanded cohort of 65 aCML plus a total of 230 AML, ALL, CLL, CML, PV, TE, MMM, CMML and MDS cases for the presence of CSF3R and SETBP1 mutations. In line with previous findings (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24; Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90), we found evidence of SETBP1 and/or CSF3R mutations only in MDS/MPN disorders. In aCML we identified a total of 18 (27.7%) mutations occurring in SETBP1 and 8 (12.3%) in the CSF3R gene. A large fraction (94.4 %) of the SETBP1 mutations was clustered in a 14 amino acid stretch that is also mutated in the Schinzel-Giedion syndrome, as previously reported (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Of the 8 CSF3R mutations 5 were membrane proximal (4 T618I and 1 T615A) and 3 were truncating (2 Q776X and 1 Q781X). In 2 aCML samples we detected the coexistence of CSF3R and SETBP1 mutations. In both cases the CSF3R variant was a membrane proximal mutation; CSF3R and SETBP1 mutations were at comparable levels at the time of detection, therefore no conclusion can be drawn about the timing of the two mutational events. Taken globally these data indicate that somatic mutations occurring in SETBP1 and CSF3R are present in aCML and can coexist. Interestingly, the frequency of the CSF3R mutations in our aCML cohort is largely different from that of Maxson and colleagues (12.3 vs 40%), although the frequency of the combined CSF3R/SETBP1 mutations is similar (3.1 vs 5%): the reasons for this discrepancy are actually unclear. Previously we demonstrated that the presence of SETBP1 mutations in aCML is an independent negative prognostic factor (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Further studies with larger cohorts will be required to assess the prognostic impact of concurrent SETBP1 and CSF3R mutations. Disclosures: Cross: Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Gambacorti-Passerini:Pfizer, BMS: Consultancy, Consultancy Other; Pfizer: Research Funding.
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Huard, Carine, Guy Miranda, Yulia Redko, Fran�oise Wessner, Simon J. Foster, and Marie-Pierre Chapot-Chartier. "Analysis of the Peptidoglycan Hydrolase Complement of Lactococcus lactis: Identification of a Third N-Acetylglucosaminidase, AcmC." Applied and Environmental Microbiology 70, no. 6 (June 2004): 3493–99. http://dx.doi.org/10.1128/aem.70.6.3493-3499.2004.

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ABSTRACT The peptidoglycan hydrolase (PGH) complement of Lactococcus lactis was identified by amino acid sequence similarity searching of the L. lactis IL-1403 complete genome sequence. Five PGHs that are not encoded by prophages were detected, including the previously characterized AcmA and AcmB proteins. Four of these PGHs, AcmA to AcmD, contain a catalytic domain homologous to that of enterococcal muramidase, but they have different domain structures. The fifth one (YjgB) has sequence similarity with the active-site domain of peptidoglycan-specific endopeptidases. The three new PGH-encoding genes identified in this study are all actively transcribed in L. lactis subsp. cremoris MG1363. The relative abundance of their transcripts varied during growth and was maximal during the early exponential growth phase. The three encoded proteins have peptidoglycan-hydrolyzing activities which are detected only at acidic pHs by zymography. Like AcmA and AcmB, AcmC has N-acetylglucosaminidase activity rather than the N-acetylmuramidase activity predicted by sequence similarity.
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3

Crisà, Elena, Maura Nicolosi, Valentina Ferri, Chiara Favini, Gianluca Gaidano, and Andrea Patriarca. "Atypical Chronic Myeloid Leukemia: Where Are We Now?" International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6862. http://dx.doi.org/10.3390/ijms21186862.

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Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.
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Dao, Kim-Hien T., and Jeffrey W. Tyner. "What's different about atypical CML and chronic neutrophilic leukemia?" Hematology 2015, no. 1 (December 5, 2015): 264–71. http://dx.doi.org/10.1182/asheducation-2015.1.264.

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Abstract Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding—our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I–positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
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Gambacorti-Passerini, Carlo, Simona Valletta, Nils Winkelmann, Sara Redaelli, Roberta Spinelli, Alessandra Pirola, Laura Antolini, et al. "Recurrent SETBP1 Mutations in Atypical Chronic Myeloid Leukemia Abrogate an Ubiquitination Site and Dysregulate SETBP1 Protein Levels." Blood 120, no. 21 (November 16, 2012): LBA—2—LBA—2. http://dx.doi.org/10.1182/blood.v120.21.lba-2.lba-2.

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Abstract Abstract LBA-2 The SETBP1 gene codes for a predominantly nuclear protein with a predicted MW of 170 kD. Germline mutations of SETBP1 were described in patients affected by the Schinzel-Giedion syndrome (SGS), a rare disease characterized by bone, muscle and cardiac abnormalities, and presenting neuroepithelial neoplasms. In an effort to investigate the molecular pathogenesis of myeloid malignancies we applied a HTS strategy, including both exome sequencing and RNA-SEQ, to atypical Chronic Myeloid Leukemia (aCML), as defined by WHO criteria, with the aim of identifying novel recurrent driver mutations. aCML shares clinical and laboratory features with CML, but it lacks the pathognomonic BCR-ABL1fusion. Since no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, the molecular pathogenesis of this disease has remained elusive and the outcome dismal (median survival 37 months) with no improvement over the last 20 years. This sharply contrasts with the outcome for CML, for which the prognosis was dramatically improved by the development of imatinib as a specific inhibitor of the BCR/ABL protein. Whole-exome sequencing of 9 aCML patients revealed the presence of 62 unique mutations (range 5–14 per patient), including a recurrent alteration of SETBP1 (G870S and D868N) in three cases. Targeted resequencing performed in 70 aCMLs, 574 patients with different hematological malignancies and 344 cell lines, identified SETBP1 mutations in 17 of 70 aCML patients (24.3%; 95% CI: 16–35%), 4 of 30 (13%) MDS/MPN-u and 3 of 82 (3.6%) CMML patients. Patients with mutations had higher white blood cell counts (p=0.008) and worse prognosis (p=0.01) when tested in multivariate analysis. TF1 cells transfected with SETBP1G870S showed increased SET levels, decreased PP2A activity and increased proliferation rates. The vast majority of mutations (85%) was located between residues 858 and 871, in the SKI homologous region of SETBP1, and were identical to germline changes seen in patients with SGS. This region may be critical for ubiquitin binding and for subsequent protein degradation, since the Eukaryotic Linear Motif (ELM) identified with high probability score a putative functional site (aa. 868–873) for beta-TrCP, the substrate recognition subunit of the E3 ubiquitin ligase. This prediction was experimentally validated using biotinylated, phosphorylated peptides encompassing this region (aa 859–879): while the wild type peptide could efficiently bind beta-TrCP as predicted, a peptide presenting the G870S mutation was incapable of binding this E3 ligase subunit, indicating a possible alteration in SETBP1 protein stability caused by this mutation. In agreement with these findings, cells transfected with SETBP1G870Sshowed increased levels of SETBP1 protein when compared to cells with similar expression levels of the wild type gene. Finally, RNA-SEQ yielded gene expression profiles with overrepresentation of genes under the control of Transforming Growth Factor Beta 1 (TGFβ1) among genes differentially expressed between SETBP1-mutated and unmutated aCML patients. Mutated SETBP1 represents a novel type of oncogene which is specifically present in aCML and closely related diseases. These data allow for a better understanding of the molecular pathogenesis of this disease; they provide evidence that SETBP1 mutations might be a new biomarker for future diagnosis and classification of aCML and related diseases, and indicate a potential strategy to develop new treatment modalities for malignancies caused by mutated SETBP1. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
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Raizada, N., T. Sagar, and S. Ramanan. "Comparative study of safety and efficacy of imatinib mesylate therapy in pediatric and adult chronic myeloid leukemia." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 20016. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.20016.

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20016 Background: Chronic Myeloid Leukemia (CML) is one of the rare pediatric cancers. Imatinib is now the standard of care in adult CML (ACML) with newer compounds being investigated to overcome the burden of Imatinib resistance. Pediatric CML (PCML) has been an area little explored and effective strategies are not yet defined. Although, allogenic hematopoietic stem cell transplantation (HSCT) still remains the gold-standard treatment, the choice of drug in the subset in which HSCT is not a suitable option remains to be determined. Methods: This was a single-institution prospective study conducted from April 2004-March 2006, analyzing and comparing 293 Philadelphia chromosome (PH) positive CML patients in pediatric and adolescent subsets (i.e. age =18 years) not eligible for allogenic HSCT with ACML. After obtaining a written informed consent, a starting dose of 400 mg/m2/d Imatinib mesylate was administered in adults, whereas in pediatric and adolescents it was 400 mg/m2/d if the body surface area (BSA) was <1 m2, or 400 mg/d if BSA was >1m2. Results: 27 patients were in the age group =18 years; male to female ratio was 1.07:1. Gender ratio in 266 ACML patients showed a male preponderance (2.5:1). The mean age in ACML was 37.4 years. In pediatric subsets, a trend toward CML in adolescents was observed with mean age 14.85 years. Majority of the patients were in chronic phase (81.5% PCML and 85.7% ACML) with overall 93% patients receiving prior hydroxyurea as a cytoreductive agent. An unusual finding was higher incidence of Hypodiploidy (significance undetermined) and 5 patients had double PH. 80.1% ACML patients achieved complete hematological response, but it was significantly lower (59.3%) in PCML. 39.5% ACML achieved major cytogenetic response which was less than most published western data. Hematologic and non-hematologic toxicities (GI, dermatological etc) were found to be higher in ACML. Low toxicities in PCML were attributed to good tolerance to Imatinib therapy; however a higher dropout rate in pediatric subsets was possibly due to poor social and parental support. Conclusion: We conclude that imatinib mesylate is both safe and efficacious drug for ACML, however further research is warranted in pediatric and adolescent population to establish its efficacy. No significant financial relationships to disclose.
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Kahleifeh, Zachary, and Himanshu Thapliyal. "EE-ACML: Energy-Efficient Adiabatic CMOS/MTJ Logic for CPA-Resistant IoT Devices." Sensors 21, no. 22 (November 18, 2021): 7651. http://dx.doi.org/10.3390/s21227651.

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Internet of Things (IoT) devices have strict energy constraints as they often operate on a battery supply. The cryptographic operations within IoT devices consume substantial energy and are vulnerable to a class of hardware attacks known as side-channel attacks. To reduce the energy consumption and defend against side-channel attacks, we propose combining adiabatic logic and Magnetic Tunnel Junctions to form our novel Energy Efficient-Adiabatic CMOS/MTJ Logic (EE-ACML). EE-ACML is shown to be both low energy and secure when compared to existing CMOS/MTJ architectures. EE-ACML reduces dynamic energy consumption with adiabatic logic, while MTJs reduce the leakage power of a circuit. To show practical functionality and energy savings, we designed one round of PRESENT-80 with the proposed EE-ACML integrated with an adiabatic clock generator. The proposed EE-ACML-based PRESENT-80 showed energy savings of 67.24% at 25 MHz and 86.5% at 100 MHz when compared with a previously proposed CMOS/MTJ circuit. Furthermore, we performed a CPA attack on our proposed design, and the key was kept secret.
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Redaelli, Sara, Rocco Piazza, Alessandra Pirola, Vera Magistroni, Susanne Schnittger, Manja Meggendorfer, Nicholas C. P. Cross, Delphine Rea, and Carlo Gambacorti-Passerini. "Recurrent KIT D816V Mutation in Atypical Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 3576. http://dx.doi.org/10.1182/blood.v124.21.3576.3576.

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Abstract INTRODUCTION: Atypical Chronic Myeloid Leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative syndromes, characterized by a poor prognosis with a median survival time of 37 months. In 2013, by applying Next Generation Sequencing (NGS) technologies on 8 aCML cases, we demonstrated the presence of a recurrent somatic mutations in the SETBP1 gene (Piazza et al, Nat Gen 2013). SETBP1 mutations were identified in approximately 30% of aCML cases. AIM: To further characterize the molecular pathogenesis of aCML and to possibly identify other recurrent lesions responsible for SETBP1 unmutated cases, we extended our initial NGS effort: we applied whole-exome and transcriptome sequencing to a total of 16 matched samples taken at onset of the disease. MATERIAL and METHODS: Whole-exome and transcriptome sequencing data were generated using an Illumina Genome Analyzer IIx following standard library-preparation protocols. Alignment to the reference GRCh37/hg19 genome was performed using BWA. Alignment data were processed using Samtools. Single nucleotide and small indel detection was performed using in-house software. Copy number analyses from whole-exome data were generated using CEQer (Piazza et al, PLoS One 2013) and gene fusions transcriptome data were screened using FusionAnalyser (Piazza et al, Nucleic Acids Res. 2012). RESULTS: The application of NGS techniques to the cohort of aCML cases led to the identification of a somatic, non-synonymous single-nucleotide mutation (chr4:g.55599321A>T) in the KIT gene in 1/16 (6%) cases. At protein level this mutation translated into the D816V variant that has been already described in several clonal disorders, such as systemic mastocytosis, gastrointestinal stromal tumors and acute myeloid leukemia. To assess whether the mutation identified by NGS was recurrent, we extended our analysis by targeted resequencing on a larger cohort of 68 aCML cases. This analysis revealed the presence of KIT mutations in 3 additional patients, thus confirming the recurrence of KIT variants in aCML. All the KIT mutations identified correspond to the D816V that is responsible for the constitutive activation of the tyrosine kinase. This finding suggests that the activation of the KIT tyrosine kinase signaling may play an important role in this subset of aCML patients. It is known from the literature that KIT D816V is highly sensitive to the tyrosine kinase inhibitor dasatinib (Schittenhelm MM, Cancer Res 2006). To test whether dasatinib is able to affect the growth of the leukemic clone in KIT mutated aCML cases, we performed ex vivo tritiated thymidine proliferation assays on bone marrow (BM) cells from one of the KIT D816V positive aCML patients in presence of either dasatinib, imatinib or vehicle alone: the proliferation assay showed that dasatinib was able to inhibit the proliferation of the leukemic clone with an IC50 of 1nM, while, as expected, neither imatinib nor vehicle alone were able to significantly impair cell growth. In line with these data, western blot with an anti- Phospho-KIT antibody on KIT+ lysates after treatment with increasing concentration of dasatinib showed that the drug was highly effective in inhibiting KIT autophosphorylation. To further confirm the inhibitory activity of dasatinib, we performed a colony assay on peripheral blood cells from a KIT D816V positive aCML patient grown in presence of increasing concentrations of the drug: treatment with 100nM dasatinib was able to completely inhibit cell growth, leading to a virtually complete absence of colonies in the D816V-positive plates. CONCLUSION: These data indicate that KIT D816V is a pro-oncogenic lesion recurrently present in aCML, albeit with low frequency (5/84, 6%) and that aCML cells bearing this mutation are highly sensitive to dasatinib, at least ex vivo. Given the very poor prognosis of this disorder, these findings suggest a new, highly efficient targeted treatment for a subset of aCML patients. Disclosures Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment.
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Nam, Myung-Hyun, Ju-Yeon Kim, Soo-Young Yoon, Chae Seung Lim, Chang Kyu Lee, Yunjung Cho, Young-Kee Kim, and Kap No Lee. "JAK2 V617F Mutation In Atypical Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 5069. http://dx.doi.org/10.1182/blood.v116.21.5069.5069.

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Abstract Abstract 5069 Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder which shows myelodysplastic and myeloproliferative features simultaneously. Some cases of JAK2 V617F mutation in aCML were reported before WHO criteria introduced (Jelinek J et al. Blood 2005; Jones AV et al. Blood 2005; Levine RL et al. Blood 2005). However, Fend F et al observed no JAK2 V617F mutation in aCML as defined by WHO classification (Fend F et al. Leuk Res 2008), which result was refuted by a case report (Campiotti L et al. Leuk Res 2009). Here we analyzed JAK2 V617F mutation with amplification refractory mutation system (ARMS) and direct sequencing in three cases of aCML and found a case with JAK2 V617F mutation. All three cases were diagnosed as aCML according to WHO classification and showed significant myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. Absence of BCR/ABL1 gene rearrangement was confirmed by FISH analysis, and conventional cytogenetic analysis revealed trisomy 8 in a case with no JAK2 V617F mutation. The patient with JAK2 V617F mutation poorly responds with hydroxyurea therapy and is showing prolonged leukocytosis. Disclosures: No relevant conflicts of interest to declare.
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Schauwecker, Florian, Frank Pfennig, Werner Schröder, and Ullrich Keller. "Molecular Cloning of the Actinomycin Synthetase Gene Cluster from Streptomyces chrysomallus and Functional Heterologous Expression of the Gene Encoding Actinomycin Synthetase II." Journal of Bacteriology 180, no. 9 (May 1, 1998): 2468–74. http://dx.doi.org/10.1128/jb.180.9.2468-2474.1998.

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ABSTRACT The actinomycin synthetases ACMS I, II, and III catalyze the assembly of the acyl peptide lactone precursor of actinomycin by a nonribosomal mechanism. We have cloned the genes of ACMS I (acmA) and ACMS II (acmB) by hybridization screening of a cosmid library of Streptomyces chrysomallusDNA with synthetic oligonucleotides derived from peptide sequences of the two enzymes. Their genes were found to be closely linked and are arranged in opposite orientations. Hybridization mapping and partial sequence analyses indicate that the gene of an additional peptide synthetase, most likely the gene of ACMS III (acmC), is located immediately downstream of acmB in the same orientation. The protein sequence of ACMS II, deduced fromacmB, shows that the enzyme contains two amino acid activation domains, which are characteristic of peptide synthetases, and an additional epimerization domain. Heterologous expression ofacmB from the mel promoter of plasmid PIJ702 inStreptomyces lividans yielded a functional 280-kDa peptide synthetase which activates threonine and valine as enzyme-bound thioesters. It also catalyzes the dipeptide formation of threonyl–l-valine, which is epimerized to threonyl–d-valine. Both of these dipeptides are enzyme bound as thioesters. This catalytic activity is identical to the in vitro activity of ACMS II from S. chrysomallus.
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Dissertations / Theses on the topic "ACML"

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FONTANA, DILETTA. "Characterization of the role of mutated ETNK1 in the onset of atypical Chronic Myeloid Leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241117.

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La leucemia mieloide cronica atipica (aCML) è un disordine clonale appartenente al gruppo delle sindromi mielodisplastiche/mieloproliferative (MDS/MPN). Circa il 13% dei casi di aCML è caratterizzato dalla presenza di mutazioni somatiche a carico del gene ETNK1, codificanti per le sostituzioni amminoacidiche H243Y, N244S e G245V. Precedentemente, abbiamo dimostrato che sia in campioni primari di aCML ETNK1-positiva sia nella linea cellulare TF1 trasdotta con ETNK1 mutato, le mutazioni causano una diminuzione dell’attività enzimatica di ETNK1, causando una riduzione nei livelli intracellulari di fosfoetanolamina (P-Et). Per caratterizzare il ruolo funzionale delle mutazioni di ETNK1, ho creato un nuovo modello cellulare isogenico CRISPR/Cas9 nel quale la mutazione N244S è presente come variante in eterozigosi, e ho studiato l’effetto funzionale della modulazione di P-Et applicando diverse strategie, tra cui approcci di metabolimica, lipidomica, analisi di espressione genica, ed esperimenti di respirazione mitocondriale, dimostrando che la mutazione di ETNK1 (i) causa un aumento del potenziale di membrana mitocondriale, (ii) un cambiamento della morfologia mitocondriale, (iii) un aumento della produzione di ROS, (iv) e aumenta il tasso di mutazioni al DNA genomico. Inoltre, ho dimostrato che l’aumentata attività mitocondriale causata dalla mutazione di ETNK1 è dovuta a una diretta competizione tra P-Et e succinato per l’enzima succinato deidrogenasi (complesso II). Infine, esperimenti di ricostruzione della gerarchia clonale delle mutazioni somatiche nei pazienti affetti da aCML indicano che le mutazioni di ETNK1 sono eventi precoci nel processo evolutivo della patologia, suggerendo per ETNK1 un ruolo di induttore di un fenotipo mutante, il quale a sua volta contribuisce all’accumulo di ulteriori mutazioni oncogeniche.
Atypical chronic myeloid leukemia (aCML) is a clonal disorder belonging to the MDS/MPN syndromes. About 13% of aCML cases carry somatic mutations in ETNK1 gene, encoding for H243Y, N244S and G245V substitutions. We previously showed that, in both ETNK1-positive aCML primary samples and TF1 cells transduced with mutated ETNK1, the mutations lead to an impairment of ETNK1 enzymatic activity, responsible for a decrease in the intracellular level of phosphoethanolamine (P-Et). To dissect the functional role of ETNK1 mutations I created a new isogenic CRISPR/Cas9 cellular model in which ETNK1 N244S mutation was present as heterozygous variant, and I investigated the functional effect of P-Et modulation by a combined approach involving metabolomics, lipidomics, whole-transcriptome sequencing, ChIP and mitochondria respiration analyses, showing that it causes (i) increased mitochondria potential, (ii) change in mitochondria morphology, (iii) increased ROS production, (iv) increased gDNA mutation rate. I also showed that the increased mitochondrial activity in presence of ETNK1 mutations is caused by a direct competition between P-Et and succinate for complex II succinate dehydrogenase enzyme. Finally, experiments focused on the reconstruction of the hierarchy of somatic mutations in aCML patients showed that ETNK1 somatic mutations are early events in the subclonal history of aCML, which fits with a role of ETNK1 as an inducer of a mutant phenotype, which in turn would accelerate the accumulation of further oncogenic mutations.
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KHANDELWAL, PRAVEEN. "Elucidating the oncogenic role of genetic events in BCR-ABL1 positive chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/99449.

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In hematological myeloid malignancies the accumulation of oncogenic events plays a significant role in disease progression. Therefore, in this work, we studied (i) the mutational landscape in typical chronic myeloid leukemia (CML) patients and (ii) the neoplastic role of Setbp1 mutation in atypical chronic myeloid leukemia (aCML). 1) We evaluated somatic variants in CML patients by Next Generation Sequencing, to study the molecular pathogenesis of cancer. We conducted a mutational analysis on 23 chronic phase BCR-ABL1+ CML patients through exome and RNA sequencing performed on diagnosis samples. A total of 107 non-synonymous variants (range 0-11 per patient) were identified by setting a threshold of mutation frequency >25%, which corresponds to the presence of a heterozygous mutation in >50% of cells, assuming a pure tumoral sample. A positive correlation was observed between number of mutations and patient age, indicating that several events were passenger mutations, being immortalized by the neoplastic transformation. However, when using a newly in-house developed tool (Oncoscore) to weigh the oncogenic potential of each mutation, a significant correlation was observed between the Sokal score and Oncoscore by using linear model statistical analysis. In long term follow-up (>2 years), 21 CML patients achieved complete cytogenetic responses (CCyR) and 2 failed to achieve any cytogenetic response with tyrosine kinase inhibitors. These two patients showed an Oncoscore value of (165.4 ±27.2) which was significantly higher than the one (80.6 ±12.7) in the 21 responding patients. No fusions (other than BCR/ABL1) were identified by RNA Seq, and no chromosomal alterations were observed by using the CEQer software. In conclusion, CML patients at diagnosis carry genetic alterations additional to the BCR/ABL1 fusion, which could be relevant for response to treatment and progression of the disease. 2) We aimed to gain insights into the biological role of Setbp1 mutations found in aCML patients, by invivo genetic manipulation techniques. Recently, by NGS approach, we identified a recurrent SETBP1 missense mutation in aCML patients, associated with poor overall survival. The most frequent SETBP1 mutations identified in various MDS/MPN neoplasms were positioned at D868N, S869G, G870S and I871T. The same mutations identified in myeloid malignancies had previously been observed as de novo recurrent germline mutations responsible for Schinzel-Giedion syndrome. Unfortunately, the biological role of Setbp1 and its activity in leukemic transformation is not exactly known. Therefore, an improved understanding of the molecular mechanism is imperative. So, we applied genetic engineering to construct a conditional knock-in model for dissecting the role of leukemia transforming factors in heterozygous Setbp1G870S mice. For construction, 3 genomic fragments of Setbp1 intron 3 and exons 4 through 6 were subcloned into the conditional replacement vector pDELBOY-3X. The linearised vector was then transfected into murine ES cells. We are currently screening ES cells to identify a correctly targeted clone for blastocyst injection and transplantion into pseudo-pregnant mice. The 1st generation Setbp1WT/floxed mice will express wild type Setbp1 under the control of its endogenous promoter. Thereafter, the expression of Setbp1G870S would be induced in a conditional manner with Cre-mediated recombination. Depending on the type of promoter driving Cre recombinase expression, the mutant allele will be expressed either constitutively (germline) or somatically, and it will be possible to study the oncogenic effects of Setbp1G870S in specific tissues, or in all tissue/cells. Additionally, the molecular interactions and physiological pathways accountable for tumorigenesis and the clonal evolution pattern will be examined by implementing the molecular and functional genomic techniques, which help in better understanding of developing targeted therapies.
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PERONACI, MARCO. "Characterization of new oncogenes identified through NGS-based analysis of leukemias: SETBP1 and ETS2-ERG." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/144663.

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In the past years, the improvements in sequencing technology led to the development of “Next Generation Sequencing” (NGS) technologies. Several NGS approaches exist. Whole genome sequencing (WGS) and whole exome sequencing (WES) allow the identification of genomic alterations such as small insertions/deletions, point mutations and structural variants. Whole transcriptome sequencing (RNA-Seq) permits to quantify gene expression profiles and to detect alternative splicing and fusion transcripts. Recently, by using WES on atypical chronic myeloid leukemia (aCML) samples, our group identified recurrent mutations in SETBP1 gene; also, by using RNA-Seq on acute myeloid leukemia (AML), we identified a new fusion gene: ETS2-ERG. In aCML, SETBP1 mutations disrupt a degron binding site, leading to a decreased protein degradation. This leads to an increased amount of SETBP1 protein interacting with its natural ligand SET, which in turn acts inhibiting the protein phosphatase 2A (PP2A) oncosuppressor. Interestingly, the SETBP1 mutational cluster affected in aCML is highly conserved and the same mutations were also observed in the Schinzel-Giedion syndrome (SGS). However, the inhibition of the PP2A by SET, the only known interactor of SETBP1, does not explain the phenotype of SGS. To further characterize the role of SETBP1 protein, 293 Flp-In isogenic cellular models expressing the empty vector or the wild type (WT) or mutated (G870S) form of SETBP1 were established. In these models SETBP1 was fused with a V5 tag. Chromatin Immunoprecipitation sequencing experiments (Chip-Seq) performed against V5 confirmed the binding of SETBP1 to DNA, both for the WT and G870S forms. In addition, RNA-Seq experiments were performed. The comparison between Chip-Seq and RNA-Seq data has allowed us to identify 130 genes presenting both the binding of SETBP1 to their promoter region and transcriptional upregulation. Together these data suggest a role for SETBP1 as a transcriptional activator. Co-immunoprecipitation (Co-IP) experiments in transiently transfected HEK293T cells coupled with mass spectrometry (MS) analysis were performed to identify potential interactors of SETBP1. MS analysis led to the identification of the host cell factor 1 (HCF1), a component of the SET1/KMT2A COMPASS-like complex. Independent validation by western blot and fluorescence resonance energy transfer (FRET) confirmed the direct binding of HCF1 to SETBP1. Further independent experiments confirmed the Co-Ip of SET1/KMT2A and PHF8 with SETBP1. SET1/KMT2A is a core component of COMPASS-like complex and possesses H3K4 methyltransferase activity, whereas PHF8 possesses H4K20 demethylase activity. Both marks are associated with actively transcribed genes. Taken together, we have shown that SETBP1 protein is able to act as a transcriptional activator recruiting the HCF1/KMT2A/PHF8 complex. In a previous study, comparing cytogenetic analysis and RNA-Seq to detect chromosomal abnormalities on AML patient samples, a new fusion between the ETS2 and ERG genes was reported. The patient carrying this fusion was affected by acute promyelocytic leukemia (APL) and did not respond to therapy with retinoic acid. The role of the ETS2-ERG fusion is not known. To gain insight about the functional role of ETS2-ERG fusion in APL two cellular models were established. HL-60 and NB-4 cells were stable transfected with retroviral empty vector or with a vector carrying the fusion gene. This vector also carries the GFP as a positive selection marker. HL-60 cells carrying the ETS2-ERG fusion treated with retinoic acid showed a decrease in the expression at membrane level of the differentiation marker CD11b. This suggests that the ETS2-ERG fusion is able to impair the differentiation of APL cells upon retinoic acid treatment. Further experiments are ongoing to confirm the data in the NB4 cellular model.
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VALLETTA, SIMONA. "Recurrent SETBP1 mutations in atypical chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50227.

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Atypical chronic myeloid leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. aCML shares clinical and laboratory features with Chronic Myeloid Leukemia (CML), but it lacks the Philadelphia chromosome and the resulting BCR-ABL fusion gene. This crucial difference with CML points to a different pathogenetic process. Because no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, and the molecular pathogenesis of this disease has remained elusive with a dismal outcome, we performed exome-sequencing of eight aCML patients, in order to identify new possible recurrent mutations. The presence of an identical mutation not previously involved in cancer in two different aCML cases altering SETBP1 gene, prompted us to resequence this particular gene in samples from additional subjects with aCML or other hematological malignancies and in cell lines representative of the most common human solid cancers. SETBP1 mutations were identified only in aCML and in the closely related disorders and represents the first gene shown to be enriched and recurrently mutated in aCML. Most SETBP1 mutations were located between codons 858 and 871 causing abrogation of a degron binding site for E3-ubiquitin β-TrCP1 and protection from proteasomal degradation. This causes accumulation of SETBP1 and SET protein, decreased PP2A phosphatase activity and higher proliferation rates. Individuals with SETBP1 mutations had higher white blood cell counts and worse prognosis, indicating SETBP1 as a possible valuable diagnostic tool in the differential diagnosis of MDS/MPN syndromes and their prognosis. This study increases the knowledge of the mechanisms by which malignancy arises and will have important consequences for the diagnosis, prognosis and treatment of aCML and diseases associated with SETBP1 alterations.
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Souza, Clarice de Azevedo. "The Acyl-CoA ligase-like (ACLL) gene family in Arabidopsis and poplar." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31283.

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Many genes of unknown function have been annotated in plant genome projects, and many of these may encode undiscovered enzymes. For example, completion of the Arabidopsis thaliana genome sequence revealed large families of phenylpropanoid-like enzymes of unknown functions. Using an in silico similarity search based on the amino-acid sequences of known Arabidopsis genes encoding 4-coumarate:CoA ligase (4CL), I identified nine putative genes as members of the Arabidopsis acyl-CoA ligase-like (ACLL) gene superfamily which encode a plant-specific clade of enzymes closely related to true 4CLs. I also identified all ACLLs in the fully sequenced poplar and rice genomes. Phylogenetic analysis of amino-acid sequences revealed five ACLL clades, each containing at least one ACLL member from each species, suggesting conserved biochemical functions for ACLL enzymes. In four of five clades, most of the ACLL representatives have the PTS1 peroxisomal target sequence, indicating a likely function in that organelle. I established tissue expression profiles and the wound and herbivory responsiveness of Arabidopsis and poplar ACLL genes, and this revealed similar expression patterns for potentially orthologous genes. Finally, I mined publicly available microarray databases for co-expressed Arabidopsis genes, and this data provides clues for potential ACLL biochemical functions. The only non-peroxisomal clade is the one most closely related to true 4CLs and contains a single copy gene in Arabidopsis (ACLL5) and poplar (ACLL13). These genes are flower and anther-preferred in expression, and because of the apparent conservation in sequence and in expression, were chosen for functional analysis. ACLL5 is transiently expressed in tapetum cells just prior to release of microspores from tetrads, suggesting a role in pollen wall and/or sporopollenenin formation. In support of this, an acll5 transposon insertion mutant is male sterile and fails to produce pollen grains. These data suggest that ACLL5 and similar enzymes from other species, produce CoA ester intermediates used in an unknown pathway required for pollen wall formation. In silico co-expression analysis in Arabidopsis has revealed potential other members of this pathway, also conserved across angiosperms. This work highlights the utility of the Arabidopsis model system in the discovery of genes in other plant species with genome sequence information.
Science, Faculty of
Botany, Department of
Graduate
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Pomini, Armando Mateus. "Acil-homosserina lactonas produzidas pelas bacterias fitopatogenicas Pantoea ananatis e Methylobacterium mesophilicum e defesa quimica no opilião Hoplobunus mexicanus." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249296.

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Orientador: Anita Jocelyne Marsaioli
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
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As bactérias Gram-positivas e Gram-negativas possuem um mecanismo de comunicação química intra-específico conhecido como ¿quorum-sensing¿, regulando a expressão de uma vasta gama de atividades biológicas. As bactérias Gram-negativas utilizam acil-homosserina lactonas (acil-HSLs) como principais substâncias sinalizadoras. Na presente tese, relatamos a determinação da configuração absoluta do raro metabólito (S)-(-)-N-heptanoil-HSL produzida pela bactéria fitopatogênica Pantoea ananatis. A configuração absoluta desta substância foi determinada através da técnica de cromatografia gasosa com detecção por ionização em chama com coluna quiral, através de comparações de tempo de retenção e co-injeção com padrões sintetizados. Avaliou-se também a importância da configuração absoluta para a atividade antimicrobiana de acil-HSLs contra bactérias Gram-positivas (Bacillus subtilis, Bacillus cereus e Staphylococcus aureus). Curiosamente, o enantiômero não natural (R)-N-3-oxo-octanoil-HSL foi tão ativo quanto o produto natural (S). Estudou-se também as interações da (S)-N-3-oxo-octanoil-HSL com células de Agrobacterium tumefaciens NTL4(pZLR4) através da técnica de ressonância magnética nuclear de hidrogênio por diferença de transferência de saturação (STD-RMN), revelando que o primeiro evento de interação da substância com a célula ocorre com a região lipídica da membrana celular externa. Finalmente, realizou-se o estudo químico das substâncias sinalizadoras produzidas pela bactéria Methylobacterium mesophilicum, que ocorre simbioticamente com a bactéria Xylella fastidiosa nos vasos condutores de laranjeiras atacadas pela clorose variegada dos citros. Entre os vários resultados inéditos, reportamos a caracterização e síntese do produto natural inédito (S)-N-(2E)-dodecenoil-HSL e a primeira síntese do metabólito (S)-N-(2E, 7Z)-tetradecadienil-HSL. Outrossim, reportamos a primeira caracterização da configuração absoluta de cinco acil-HSLs naturais de cadeia longa. Realizou-se também estudos relacionados aos efeitos das acil-HSLs sintéticas contra bactérias Gram-positivas endofíticas da laranjeira. Adicionalmente, caracterizou-se a secreção de defesa do opilião Hoplobunus mexicanus. O repertório de defesa deste animal é composto por dois componentes voláteis de alta irritabilidade (2,5-dimetil-fenol e 2-metil-5-etil-fenol), além da tanatose e emissão de sons, uma característica inédita em opiliões
Gram-positive and Gram-negative bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities. In general, Gram-negative bacteria use acylated homoserine lactones (acyl-HSLs) as autoinducers, and Gram-positive bacteria use processed oligo-peptides. In the present work, we relate the absolute configuration determination of the rare metabolite (S)-(-)-N-heptanoyl-HSL produced by the phytopathogen Pantoea ananatis. The absolute configuration was determined by gas chromatography coupled to flame ionization detection with chiral column, through retention time comparison and co-injections with synthetic products. The importance of the absolute configuration for the antimicrobial activity of acyl-HSL against Gram-positive bacteria (Bacillus subtilis, Bacillus cereus and Staphylococcus aureus) was assessed. Curiously, non-natural (R)-N-3-oxo-octanoyl-HSL was as active as the natural product with (S) absolute configuration. The interaction of (S)-N-3-oxo-octanoil-HSL with Agrobacterium tumefaciens NTL4(pZLR4) cells was further studied using hydrogen nuclear magnetic resonance experiments with saturation transfer difference (STD-NMR) revealing that the first binding event is the diffusion through the lipidic part of the outer membrane. Finally, we have investigated the chemical study of the signaling substances produced by Methylobacterium mesophilicum, which co-occurs with Xylella fastidiosa in orange trees affected by the citrus variegated chlorosis disease. Among several results, we report herein the characterization and synthesis of a new natural product [(S)-N-(2E)-dodecenoyl-HSL], the first synthetic procedure for the rare (S)-N-(2E,7Z)-tetradecadienyl-HSL and the occurrence of a rare long, odd chain representative (N-tridecanoyl-HSL) in trace amounts. We report the first absolute configuration determination for five natural acyl-HSLs. We have also studied the effects of synthetic acyl-HSLs on Gram positive bacteria isolated from orange tissues. Additionally, the defensive secretion produced by the harvestman Hoplobunus mexicanus was characterized. The defensive repertory of this arachnid includes two irritating and volatile components (2,5-dimethyl-phenol and 2-methyl-5-ethyl-phenol), besides thanatosis and sound emission, a new behavioral artifice in opilionids
Doutorado
Quimica Organica
Doutor em Ciências
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Costa, Bruna Vieira de Lima. "Consumo de carnes e derivados e fatores associados ao estado nutricional de idosos em instiruição de longa permanência de Belo Horizonte - MG." Universidade Federal de Minas Gerais, 2009. http://hdl.handle.net/1843/ACSL-7YAQLW.

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Sectional study, to identify the consumption of meat and meat products of elderly residents in geriatric institution of Belo Horizonte. Random sample (n = 52). Nutritional assessment was made by anthropometry, dietary and MAN. The process of acquisition, receipt, storage, handling of meat and meat products was observed. Was also carried out a cohort study to determine the anthropometric development. The results showed the need to reassess the process of buying, receiving and preparation of foodstuffs since there was a delivery of meat inappropriate amount and form of receipt, which contributed to a correction factor and per capita inadequate. The sample studied, 82.7% were women. The prevalence of overweight (BMI) was 46.1% and 23.1% underweight. According to MAN the prevalence of risk for malnutrition was 67.3%. According to the dietary analysis, the consumption of fat, polyunsaturated fatty acid and potassium had been insufficient in 100% of the elderly. The intake of B12 and zinc was inadequate in 44.2% and 82.7%, respectively, suggesting a low consumption of meat products. There was a prevalence of overweight and older people at high risk of diseases associated with obesity. However, from the MAN, there was a high rate of elderly people at risk for malnutrition
Estudo seccional, objetivo de identificar o consumo de carnes e derivados de idosos residentes em Instituição Geriátrica de Belo Horizonte. Amostra aleatória simples (n=52). A avaliação nutricional foi composta pela antropometria, MAN e dietética. O processo de aquisição, recepção, armazenamento, manipulação da carne e derivados foi observado. Realizou-se também estudo de coorte para verificar a evolução antropométrica. Os resultados mostraram a necessidade de reavaliar o processo de compra, recebimento e preparo dos gêneros alimentícios já que se observou uma entrega inapropriada das carnes em quantidade e forma de recebimento, o que contribuía para um fator de correção e per capita inadequados. Da amostra estudada, 82,7% eram mulheres. A prevalência de sobrepeso (IMC) foi de 46,1% e de baixo peso 23,1%. Segundo a MAN a prevalência de risco para desnutrição foi 67,3%. Segundo a análise dietética, o consumo de lipídeo, ácido graxo poliinsaturado e potássio apresentaram-se insuficiente em 100% dos idosos. A ingestão de B12 e zinco foi insuficiente em 44,2% e 82,7%, respectivamente, o que sugere um baixo consumo de produtos cárneos. Observou-se uma prevalência de idosos com sobrepeso e com risco elevado de doenças associadas à obesidade. Em contrapartida, a partir da MAN, observou-se um alto índice de idosos com risco para desnutrição
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Teodoro, Bruno Gonzaga. "Função da Acil-CoA Sintetase 6 no metabolismo de músculo esquelético de ratos e humanos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-29082016-100827/.

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Cinco membros da família das Acil-CoA sintetases de cadeia longa (ACSL) são responsáveis por ativar ácidos graxos, produzindo acil-CoA, e distribuí-los entre diversas vias metabólicas no interior da célula, tais como a síntese de triacilglicerol (TAG) e ?- oxidação mitocondrial. Apesar das disfunções nas ACSLs contribuirem para muitas doenças metabólicasa função de algumas isoformas de ACSL em tecidos específicos permanece ainda sem descrição na literatura. Aqui mostramos pela primeira vez a presença de mRNA da ACSL6 no músculo esquelético de seres humanos. Além disso, indivíduos obesos apresentaram menores níveis de mRNA de ACSL6 quando comparados à indivíduos magros. Após refeição hiperlipídica aguda (high fat meal, HFM, 90% de gordura) a expressão ACSL6 aumentou 2,5 vezes em relação aos níveis de jejum. Nós também verificamos as condições metabólicas que controlam a expressão ACSL6 em ratos: o jejum de 48h modulou negativamente a expressão gênica de ACSL6 e de outros genes de síntese de lipídeos tais como SREBP-1c e DGAT1, enquanto que a ingestão aguda de HFM (80% de gordura saturada , 10 mL/kg) teve o efeito oposto; Após o treinamento aeróbio (6 semanas, 5 dias /semana, uma vez por dia, 60 min a 70% da capacidade aeróbica máxima) o mRNA da ACSL6 foi reduzido em 35%. Em células primárias de músculo esquelético de ratos, a transfecção com siRNA de ACSL6 diminuiu a expressão de ACSL6, DGAT1 e SREBP-1c e o acúmulo de TAGs e gotas lipídicas. O silenciamento gênico da ACSL6 também aumentou o conteúdo dos ácidos graxos C16:0 e C18:0, AMPK-fosforilada, capacidade respiratória mitocondrial, a oxidação de palmitato e mRNA de PGC-1?, UCP2 e UCP3, mas diminuiu a produção de espécies 11 reativas de oxigênio. Em células primárias de músculo esquelético de seres humanos, a superexpressão da ACSL6 não alterou o conteúdo de TAG e da proteína DGAT1, mas aumentou as espécies lipídicas esfingomielina e fosfatidilcolinas, e reduziu a oxidação de 1-14C-palmitato e a expressão do PGC1?. Em conclusão, ACSL6 está envolvida na síntese e distribuição de acil-CoA para a síntese de lipídeos. A inibição gênica da ACSL6 melhora a capacidade de respiração mitocondrial e oxidação lipídica, através da ativação da via AMPK/PGC1?.
Five members of long-chain acyl-CoA synthetase (ACSL) family activate fatty acids providing acyl-CoA for several metabolic pathways within the cell, such as synthesis of triacylglycerol (TAG) and mitochondrial ?-oxidation, and their dysfunctions contribute to many metabolic diseases. Despite this, the existence and function of some ACSL isoforms in specific tissues remains unclear. Here we show for the first time the presence of ACSL6 mRNA and protein in skeletal muscle (SM) of humans. Obese subjects had lower levels of ACSL6 mRNA when compared to leans, and acute high fat meal (HFM, 90% fat) increased ACSL6 expression 2.5 times over fasted levels in both. We also verify the metabolic conditions that control ACSL6 expression in rats: fasting (48h) negatively modulated the ACSL6 mRNA and the expression of other genes of lipid synthesis SREBP-1c and DGAT1 in rat SM, while acute ingestion of HFM (80% saturated fat, 10 mL/Kg) had the opposite effect; After aerobic training (6 weeks, 5 days/week, once a day, 60 min at 70% of maximal aerobic capacity) ACSL6 mRNA was reduced 35%. In primary skeletal muscle cells (PSMC) of rats, ACSL6-specific siRNA oligo transfection (20 nM) decreased ACSL6, DGAT1 and SREBP-1c mRNA and the accumulation of TAGs and lipid droplets (LD). The knockdown also increased the content of C16:0 and C18:0 fatty acids, AMPK-Phosphorylated, mitochondrial content and respiratory rates, palmitate oxidation and PGC-1?, UCP2 and UCP3 mRNA, but decreased reactive oxygen species production. In PSMC of humans, ACSL6 overexpression did not change the contents of TAG or DGAT1 mRNA, but increased sphingomyelin and phosphatidylcholines and reduced 14C-palmitate oxidation and PGC1? mRNA expression. In conclusion, ACSL6 drives acyl-CoA toward lipid synthesis and its 13 downregulation improves mitochondrial capacity of respiration, lipid oxidation and biogenesis, which involves the activation of AMPK/PGC1-? pathway.
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Al-Faiyz, Yasair S. S. "The chemistry of O-acyl derivatives of N-acyl hydroxamic acid." Thesis, University of Warwick, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252534.

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Chalfoun, David Joseph. "Acyl transfer to lysine : an investigation acyl transfer across large rings." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/38769.

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Books on the topic "ACML"

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Takashi, Washio, and SpringerLink (Online service), eds. Advances in Machine Learning: First Asian Conference on Machine Learning, ACML 2009, Nanjing, China, November 2-4, 2009. Proceedings. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg, 2009.

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(Firm), Over TheNet, ed. ACME. Camarillo, CA: Over TheNet, 2003.

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Tim, Bourke, ed. Tournament Acol. London: Gollancz, 1995.

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Acme rubbers. Jackson Heights, NY: Insurance Editions, 2018.

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(London), Acme Gallery, Acme Housing Association, and Chisenhale Gallery, eds. Art from Acme houses 1987: Leyton Acme artists. (London: Leyton Acme Artists, 1987.

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Frazier, Ian. Coyote v. Acme. New York: Picador USA, 2002.

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Breitenecker, Felix, Horst Ecker, and Ingrid Bausch-Gall. Simulation mit ACSL. Wiesbaden: Vieweg+Teubner Verlag, 1993. http://dx.doi.org/10.1007/978-3-322-96175-4.

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Frazier, Ian. Coyote v. Acme. New York: Noonday Press, 1997.

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Frazier, Ian. Coyote v. Acme. New York: Farrar, Straus and Giroux, 1996.

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Frazier, Ian. Coyote v. Acme. New York: Noonday Press, 1997.

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Book chapters on the topic "ACML"

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Gooch, Jan W. "Acyl, Acyl Groups." In Encyclopedic Dictionary of Polymers, 17. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-6247-8_232.

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Gooch, Jan W. "Acme." In Encyclopedic Dictionary of Polymers, 871. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-6247-8_13040.

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Schomburg, Dietmar, and Dörte Stephan. "Acyl-[acyl-carrier-protein] desaturase." In Enzyme Handbook, 765–68. Berlin, Heidelberg: Springer Berlin Heidelberg, 1994. http://dx.doi.org/10.1007/978-3-642-57942-4_158.

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Blaisdell, Eben, Max Kanovich, Stepan L. Kuznetsov, Elaine Pimentel, and Andre Scedrov. "Non-associative, Non-commutative Multi-modal Linear Logic." In Automated Reasoning, 449–67. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-10769-6_27.

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AbstractAdding multi-modalities (called subexponentials) to linear logic enhances its power as a logical framework, which has been extensively used in the specification of e.g. proof systems, programming languages and bigraphs. Initially, subexponentials allowed for classical, linear, affine or relevant behaviors. Recently, this framework was enhanced so to allow for commutativity as well. In this work, we close the cycle by considering associativity. We show that the resulting system ($$\mathsf {acLL}_\varSigma $$ acLL Σ ) admits the (multi)cut rule, and we prove two undecidability results for fragments/variations of $$\mathsf {acLL}_\varSigma $$ acLL Σ .
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Spahn-Langguth, Hildegard, Monika Dahms, and Andreas Hermening. "Acyl Glucuronides." In Advances in Experimental Medicine and Biology, 313–28. Boston, MA: Springer US, 1996. http://dx.doi.org/10.1007/978-1-4757-9480-9_39.

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Gooch, Jan W. "ACM." In Encyclopedic Dictionary of Polymers, 13. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-6247-8_165.

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Schomburg, Dietmar, and Dörte Stephan. "Acyl-[acyl-carrier-protein]-phospholipid O-acyltransferase." In Enzyme Handbook 11, 801–3. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-61030-1_172.

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Schomburg, Dietmar, and Ida Schomburg. "long-chain acyl-[acyl-carrier-protein] reductase 1.2.1.80." In Class 1 Oxidoreductases, 227–28. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-36265-1_37.

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Havranek, William A. "Update on ACSL." In Informatik-Fachberichte, 191–95. Berlin, Heidelberg: Springer Berlin Heidelberg, 1985. http://dx.doi.org/10.1007/978-3-642-70640-0_22.

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Schomburg, Dietmar, Margit Salzmann, and Dörte Stephan. "Acyl-CoA oxidase." In Enzyme Handbook, 603–8. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-58051-2_128.

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Conference papers on the topic "ACML"

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Pandey, Navneet Kumar, S. K. Gupta, Shaveta Leekha, and Jingmin Zhou. "ACML: Capability Based Attack Modeling Language." In 2008 Fourth International Conference on Information Assurance and Security (IAS). IEEE, 2008. http://dx.doi.org/10.1109/ias.2008.26.

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Atef, Fady, Marina Hamdy Zaky, Nada Khaled Ahmed, Mario Adel Messiha, Omar Tarek Abdelwahab, Abanoub Atef Farid, Omar Mohamed Selim, and Hassan Mostafa. "Automated Current Mirror Layout (ACML) Tool." In 2019 31st International Conference on Microelectronics (ICM). IEEE, 2019. http://dx.doi.org/10.1109/icm48031.2019.9021930.

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Ke-Xin Jia and Zi-Shu He. "Detection performance analysis of the digital channelized receiver-based ACML detector." In 2009 International Conference on Apperceiving Computing and Intelligence Analysis (ICACIA 2009). IEEE, 2009. http://dx.doi.org/10.1109/icacia.2009.5361109.

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Zhang, Haijiao, Beth Wilmot, Daniel Bottomly, Libbey White, Erik Segerdell, Shannon K. McWeeney, Vishesh Khanna, et al. "Abstract 2452: Detailed genomic characterization of CNL/aCML/MPN-U/CMML reveals disease subgroups that may benefit from rationally-designed combination therapies." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2452.

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Naushin, Hasan Muhammad, and Ziad Kobti. "ACDL." In the 2009 C3S2E conference. New York, New York, USA: ACM Press, 2009. http://dx.doi.org/10.1145/1557626.1557644.

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Garlan, David, Robert Monroe, and David Wile. "Acme." In CASCON First Decade High Impact Papers. New York, New York, USA: ACM Press, 2010. http://dx.doi.org/10.1145/1925805.1925814.

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Swami, Shivam, and Kartik Mohanram. "ACME." In DAC '18: The 55th Annual Design Automation Conference 2018. New York, NY, USA: ACM, 2018. http://dx.doi.org/10.1145/3195970.3195983.

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Cooper, Keith D., Alexander Grosul, Timothy J. Harvey, Steven Reeves, Devika Subramanian, Linda Torczon, and Todd Waterman. "ACME." In the 2005 ACM SIGPLAN/SIGBED conference. New York, New York, USA: ACM Press, 2005. http://dx.doi.org/10.1145/1065910.1065921.

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Banerjee, Subho S., Zbigniew T. Kalbarczyk, and Ravishankar K. Iyer. "AcMC 2." In ASPLOS '19: Architectural Support for Programming Languages and Operating Systems. New York, NY, USA: ACM, 2019. http://dx.doi.org/10.1145/3297858.3304019.

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Wu, Songyuan, Liyao Jiao, and QingQiang Wu. "ACOL-GAN." In ICCAI '20: 2020 6th International Conference on Computing and Artificial Intelligence. New York, NY, USA: ACM, 2020. http://dx.doi.org/10.1145/3404555.3404581.

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Reports on the topic "ACML"

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Biraud, S. C. ACME-III and ACME-IV Final Campaign Reports. Office of Scientific and Technical Information (OSTI), January 2016. http://dx.doi.org/10.2172/1236473.

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Barbacci, Mario R., and Charles B. Weinstock. Mapping MetaH into ACME. Fort Belvoir, VA: Defense Technical Information Center, July 1998. http://dx.doi.org/10.21236/ada350855.

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Biraud, S. C., M. S. Tom, and C. Sweeney. ARM Airborne Carbon Measurements (ARM-ACME) and ARM-ACME 2.5 Final Campaign Reports. Office of Scientific and Technical Information (OSTI), January 2016. http://dx.doi.org/10.2172/1236602.

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Barnes, R., J. Hoffman-Andrews, D. McCarney, and J. Kasten. Automatic Certificate Management Environment (ACME). RFC Editor, March 2019. http://dx.doi.org/10.17487/rfc8555.

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Myers, J. IMAP4 ACL extension. RFC Editor, January 1997. http://dx.doi.org/10.17487/rfc2086.

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Collins, Thomas R. ACSL as a Parallel Simulation Language. Fort Belvoir, VA: Defense Technical Information Center, January 1990. http://dx.doi.org/10.21236/ada395503.

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Saunders, A. The Preparation of ACEL Thin Films. Fort Belvoir, VA: Defense Technical Information Center, January 1988. http://dx.doi.org/10.21236/ada201813.

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Saunders, A. The Preparation of ACEL Thin Films. Fort Belvoir, VA: Defense Technical Information Center, November 1987. http://dx.doi.org/10.21236/ada196174.

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Saunders, A. The Preparation of ACEL Thin Films. Fort Belvoir, VA: Defense Technical Information Center, January 1988. http://dx.doi.org/10.21236/ada196175.

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Saunders, A. The Preparation of ACEL Thin Films. Fort Belvoir, VA: Defense Technical Information Center, March 1988. http://dx.doi.org/10.21236/ada196176.

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