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1
Espinosa-Chaurand, Luis Daniel, Antonio Silva-Loera, Zaúl García-Esquivel, and Lus Mercedes López-Acuña. "Using shrimp head meal as protein replacement of fish meal in diets for juvenile of Totoaba macdonaldi (Gilbert, 1890)." Latin American Journal of Aquatic Research 43, no. 3 (February 23, 2017): 457–65. http://dx.doi.org/10.3856/vol43-issue3-fulltext-7.
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In diets for Totoaba macdonaldi juveniles (26.3 ± 4.7g y 13.6 ± 1cm) the partial replacement of fishmeal protein (HP) with shrimp head meal (HCC) was evaluated, over their growth, survival, fed conversion (FCA) and chemical composition of tissues and the apparent digestibility coefficient of dry matter (CDA), protein (CDAP) and lipids (CDAL) of these diets. The HCC used were from the whole shrimp head sun dried (F) and smashed shrimp head dehydrated in a hot air drier. Diets were isoproteic (55.5% crude protein), isolipídic (15% lipids) and isocaloric (4.6 kcal g-1) replacing 0% (control diet; DC), 15% (F15 and M15) and 30% (F30 and M30) of the HP protein by the HCC. At 57th day, survival with HCC (99.44 ± 1.92%) was higher than DC (88.89 ± 3.85 %). The gain weight, weight specific growth (TCE) and total intake were not statistically different (P > 0.05) between organisms feed with HCC, however with the M30 diet the TCE had higher average (0.99 ± 0.06) and growth (19.82 ± 1.64 g/fish). With diet M30 the FCA was the best significantly (1.61 ± 0.13) and the higher CDA (66.18 ± 1.28), CDAP (86.51 ± 0.53) and CDAL (72.29 ± 1.10). It concluded that replaced protein of HP by HCC in diet for juvenile totoaba improved the growth and CDAs, yielding better results with the inclusion of macerated HCC with a replacement level of 30%.
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Agrigento, Veronica, Sclafani Serena, Paolo Rigano, Rita Barone, Giuseppina Calvaruso, Rosario Di Maggio, Massimiliano Sacco, et al. "Congenital Dyserythropoietic Anemias: Molecular Diagnosis and Diagnostic Approach in a Cohort of Italian Patients." Blood 126, no. 23 (December 3, 2015): 2142. http://dx.doi.org/10.1182/blood.v126.23.2142.2142.
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Abstract Introduction. Congenital dyserythropoietic anemias (CDAs) are hereditary rare erythropoietic disorder characterized by distinct morphological abnormalities of the bone marrow cells, ineffective erythropoiesis and systemic iron overload. This conditions is characterized by a maturation arrest during erythropoiesis with a reduced reticulocyte production in contrast with erythroid hyperplasia in bone marrow. Three types of CDA are known: types 1, 2 and 3.The identification of their causative genes provided evidence that these conditions have different molecular mechanisms that induce abnormal cell maturation and division. We describe the clinical and laboratory manifestations, the diagnosis procedure, the therapeutic approaches and the clinical phenotype in some cases of congenital dyserythropoietic anemia (CDAs) in Italian patients. The molecular analysis allow us to identify several genetic variants some of which have never been described previously. This report highlights the importance of recognizing CDAI even in countries where thalassemia is common. Among the different tools genetic study of CDA-related genes remains the main approach for pursuing the right diagnosis. Methods. Peripheral blood samples from 100 normal adults and 20 patients with different types of anemia were collected. Blood samples were analyzed by EMA binding test and by polyacrylamide gel electrophoresis in presence of sodium dodecyl sulphate ( SDS-PAGE). SDS PAGE was carried out in a 3.5-17% exponential gradient gel in Fairbanks buffer Genomic DNA was extracted from mononuclear cells of peripheral blood samples, by using a phenol-chloroform method. Polymerase chain reaction (PCR) products were sequenced directly using Big-Dye terminator 3.1 cycle sequencing kit and run on ABI PRISM 3130 DNA analyzer. The bone marrow of all patients was analysed with light or electron microscopy. The diagnosis of CDAs was based on the presence of mild to moderate anemia ineffective erythropoiesis and bone marrow erythroblasts morphological abnormalities. SEC23B, CDAN1, KLF1, BCL11A gene sequencing analysis was performed to highlight the presence of nucleotide variations and their relationship with the clinical presentation. Results and Discussion. We collected blood samples from 20 Italian patients with suspect of CDAs and 100 samples belonging to the healthy control subjects.None mutation in the genes analyzed was found in the samples controls.We identified SEC 23 B mutations in 4 out of 20 patients analysed. In two patients with suspect of CDAII we found two nucleotide variations; SDS PAGE in these patients identified the presence of abnormal band 3 and the EMA binding test resulted pathologic. Bone marrow (BM) light microscopy revealed more than 10% mature binucleated erythroblasts. In the patients suspected of CDA1, several gene variants were found in the CDAN1 gene, some described in the literature as mutations or polymorphisms, others of uncertain significance. In a patient diagnosed with CDA1 two novel mutations was found. EMA binding test resulted normal in all patients with CDA1. Light microscopy of the BM of CDA1 patients showed erythroid hyperplasia, presence of internuclear bridges between intermediate erythroblasts and characteristic pattern of spongy "swiss cheese" hetrochromatin in electron microscopy. None KLF1 and BCL11A mutations correlated with atypical CDAs was identified. In this last patients the EMA binding test resulted normal. CDAs are rare clinical hereditary disorders whose correct diagnosis is often delayed to adolescence or adulthood, when significant iron overload and end organ damage may have been occurred. Patients are often misdiagnosed with other congenital haemolytic anaemias. Inaccurate diagnosis can lead to inappropriate therapies, such as iron supplements, aggressive transfusion or splenectomy. However even if the gold standard for the CDAs diagnosis is the electronic microscopy, the identification of the mutated genes involved in the majority of CDAs patients made in recent years has improved the possibility of detecting these diseases. Disclosures No relevant conflicts of interest to declare.
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Rismondo, Jeanine, Johannes Gibhardt, Jonathan Rosenberg, Volkhard Kaever, Sven Halbedel, and Fabian M. Commichau. "Phenotypes Associated with the Essential Diadenylate Cyclase CdaA and Its Potential Regulator CdaR in the Human Pathogen Listeria monocytogenes." Journal of Bacteriology 198, no. 3 (November 2, 2015): 416–26. http://dx.doi.org/10.1128/jb.00845-15.
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ABSTRACTCyclic diadenylate monophosphate (c-di-AMP) is a second messenger utilized by diverse bacteria. In many species, including the Gram-positive human pathogenListeria monocytogenes, c-di-AMP is essential for growth. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with its potential regulatory protein, CdaR, via the transmembrane protein domain. The presence of the CdaR protein is not required for the membrane localization and abundance of CdaA. We have also found that CdaR negatively influences CdaA activity inL. monocytogenesand that the role of CdaR is most evident at a high growth temperature. Interestingly, acdaRmutant strain is less susceptible to lysozyme. Moreover, CdaA contributes to cell division, and cells depleted of CdaA are prone to lysis. The observation that the growth defect of a CdaA depletion strain can be partially restored by increasing the osmolarity of the growth medium suggests that c-di-AMP is important for maintaining the integrity of the protective cell envelope. Overall, this work provides new insights into the relationship between CdaA and CdaR.IMPORTANCECyclic diadenylate monophosphate (c-di-AMP) is a recently identified second messenger that is utilized by the Gram-positive human pathogenListeria monocytogenes. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with CdaR, its potential regulatory protein. We show that CdaR is not required for membrane localization or abundance of the diadenylate cyclase, but modulates its activity. Moreover, CdaA seems to contribute to cell division. Overall, this work provides new insights into the relationship between CdaA and CdaR and their involvement in cell growth.
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Holland, Stephen J., Lesley M. Berghuis, Justin J. King, Lakshminarayan M. Iyer, Katarzyna Sikora, Heather Fifield, Sarah Peter, et al. "Expansions, diversification, and interindividual copy number variations of AID/APOBEC family cytidine deaminase genes in lampreys." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): E3211—E3220. http://dx.doi.org/10.1073/pnas.1720871115.
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Cytidine deaminases of the AID/APOBEC family catalyze C-to-U nucleotide transitions in mRNA or DNA. Members of the APOBEC3 branch are involved in antiviral defense, whereas AID contributes to diversification of antibody repertoires in jawed vertebrates via somatic hypermutation, gene conversion, and class switch recombination. In the extant jawless vertebrate, the lamprey, two members of the AID/APOBEC family are implicated in the generation of somatic diversity of the variable lymphocyte receptors (VLRs). Expression studies linked CDA1 and CDA2 genes to the assembly of VLRA/C genes in T-like cells and the VLRB genes in B-like cells, respectively. Here, we identify and characterize several CDA1-like genes in the larvae of different lamprey species and demonstrate that these encode active cytidine deaminases. Structural comparisons of the CDA1 variants highlighted substantial differences in surface charge; this observation is supported by our finding that the enzymes require different conditions and substrates for optimal activity in vitro. Strikingly, we also found that the number of CDA-like genes present in individuals of the same species is variable. Nevertheless, irrespective of the number of different CDA1-like genes present, all lamprey larvae have at least one functional CDA1-related gene encoding an enzyme with predicted structural and chemical features generally comparable to jawed vertebrate AID. Our findings suggest that, similar to APOBEC3 branch expansion in jawed vertebrates, the AID/APOBEC family has undergone substantial diversification in lamprey, possibly indicative of multiple distinct biological roles.
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Sherraden, Michael, Margaret Clancy, Yunju Nam, Jin Huang, Youngmi Kim, Sondra Beverly, Lisa Reyes Mason, et al. "Universal and Progressive Child Development Accounts: A Policy Innovation to Reduce Educational Disparity." Urban Education 53, no. 6 (December 22, 2016): 806–33. http://dx.doi.org/10.1177/0042085916682573.
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Child Development Accounts (CDAs) aim to increase college completion rates among disadvantaged youth by helping youth see themselves as “college bound.” This article summarizes findings about the implementation and impacts of universal, progressive CDAs, with emphasis on outcomes for disadvantaged children. Data come from a large randomized experiment. CDAs positively affect ownership of college savings accounts and assets, educational expectations, and other indicators of well-being. Disadvantaged children especially benefit from having a CDA. If CDAs prove to have long-term effects on educational expectations, college preparation, and educational achievement, then a national universal, progressive CDA could reduce educational disparities.
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Fereli, Fernanda, Antonio Ferriani Branco, Clóves Cabreira Jobim, Sabrina Marcantonio Coneglian, Fernanda Granzotto, and Julio Cezar Barreto. "Monensina sódica e Saccharomyces cerevisiae em dietas para bovinos: fermentação ruminal, digestibilidade dos nutrientes e eficiência de síntese microbiana." Revista Brasileira de Zootecnia 39, no. 1 (January 2010): 183–90. http://dx.doi.org/10.1590/s1516-35982010000100024.
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Avaliaram-se os efeitos do uso de monensina sódica, Saccharomyces cerevisiae e da mistura de ambos na dieta de bovinos sobre o pH e a concentração de amônia no rúmen, a digestibilidade aparente parcial e total dos nutrientes e a síntese de proteína microbiana no rúmen. Foram utilizados quatro bovinos da raça Holandesa Preto e Branco, castrados, com 320 kg de peso vivo, e canulados no rúmen. O delineamento experimental utilizado foi o quadrado latino 4 × 4, e os tratamentos consistiram de doses diárias de: 200 mg de monensina sódica (100I); 100 mg monensina sódica + 2,5 g Saccharomyces cerevisiae (50IP); 200 mg de monensina sódica + 5 g Saccharomyces cerevisiae (100IP); e 5 g Saccharomyces cerevisiae (100P), fornecidos diariamente pela cânula ruminal. A dieta contendo 100I promoveu menor digestão intestinal e total da matéria seca (MS), maior digestão intestinal da fibra em detergente neutro (FDN) e do extrato etéreo (EE), maior digestão total da proteína bruta (PB) e do EE e maior coeficiente de digestibilidade aparente ruminal (CDAR) e total (CDAT) da PB. A dieta contendo 100P resultou em menor digestão ruminal da PB, maior digestão ruminal da FDN, maior digestão intestinal da matéria orgânica (MO), da PB e dos carboidratos não-fibrosos (CNF), maior digestão total da matéria orgânica e do extrato etéreo, maior CDAR da FDN, maior coeficiente de digestibilidade intestinal (CDAI) da MO e dos CNF e maior CDAT da MO. A dieta 100P promoveu maior fluxo omasal de nitrogênio bacteriano e maior eficiência microbiana aparente e verdadeira. A dieta com 5 g/dia de Saccharomyces cerevisiae apresentou valor de NDT superior ao das outras dietas. As dietas não diferem quanto ao pH e à concentração de amônia no rúmen.
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Weng, Peter J., Yang Gao, Mark T. Gregory, Pengcheng Wang, Yinsheng Wang, and Wei Yang. "Bypassing a 8,5′-cyclo-2′-deoxyadenosine lesion by human DNA polymerase η at atomic resolution." Proceedings of the National Academy of Sciences 115, no. 42 (October 1, 2018): 10660–65. http://dx.doi.org/10.1073/pnas.1812856115.
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Oxidatively induced DNA lesions 8,5′-cyclopurine-2′-deoxynucleosides (cdPus) are prevalent and cytotoxic by impeding DNA replication and transcription. Both the 5′R- and 5′S-diastereomers of cdPu can be removed by nucleotide excision repair; however, the 5′S-cdPu is more resistant to repair than the 5′R counterpart. Here, we report the crystal structures of human polymerase (Pol) η bypassing 5′S-8,5′-cyclo-2′-deoxyadenosine (cdA) in insertion and the following two extension steps. The cdA-containing DNA structures vary in response to the protein environment. Supported by the “molecular splint” of Pol η, the structure of 5′S-cdA at 1.75-Å resolution reveals that the backbone is pinched toward the minor groove and the adenine base is tilted. In the templating position, the cdA takes up the extra space usually reserved for the thymine dimer, and dTTP is efficiently incorporated by Pol η in the presence of Mn2+. Rigid distortions of the DNA duplex by cdA, however, prevent normal base pairing and hinder immediate primer extension by Pol η. Our results provide structural insights into the strong replication blockage effect and the mutagenic property of the cdPu lesions in cells.
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Niss, Omar, Robert B. Lorsbach, David K. Buchbinder, Satheesh Chonat, Morgan L. McLemore, Timothy McCavit, Jeffrey H. Schwartz, et al. "Congenital Dyserythropoietic Anemia Type I Due to Biallelic CDAN1 mutations: Report from the Congenital Dyserythropoietic Anemia Registry (CDAR)." Blood 134, Supplement_1 (November 13, 2019): 3521. http://dx.doi.org/10.1182/blood-2019-128975.
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Congenital dyserythropoietic anemias (CDA) are rare hereditary diseases of abnormal erythropoiesis. The CDA Registry of North America (CDAR) (NCT02964494) was opened in 2016 to investigate the natural history and molecular biology of CDA. CDA type I (CDA-I) is a recessive form of CDA characterized by macrocytic anemia, hemolysis with inadequate reticulocytosis, and iron overload. The bone marrow shows binucleated erythroblasts with chromatin bridges by light microscopy and spongy heterochromatin in erythroblasts by electron microscopy. The phenotypic heterogeneity in presentation and course of CDA-I is remarkable. Most CDA-I cases are caused by biallelic mutations in CDAN1or C15orf41, and 10-20% do not have an identifiable mutation. Non-hematological features, especially skeletal features, were historically reported in 10-20% of patients (Wickramasinghe, 1998). Due to the rarity of CDA-I and its clinical overlap with several disorders, the diagnosis is often missed or delayed by up to 17 yrs (median) (Roy, 2019). We describe in this study the characteristics and clinical course of CDA-I patients due to CDAN1 mutations enrolled in CDAR. Patients with a phenotypic diagnosis of CDA and their family members were enrolled in CDAR. Clinical and demographic data were gathered from participants at study entry and updated periodically thereafter. Participants elect to give blood, bone marrow, and DNA samples to the biorepository associated with CDAR. Participants with a phenotypic diagnosis of CDA-I and confirmed mutations in CDAN1 were included in this study. Six participants had a diagnosis of CDA-I due to biallelic CDAN1 mutations, comprising 18% (6/33) of affected CDAR participants. CDAN1 mutations were found in 75% of cases diagnosed phenotypically as CDA-I. All six participants presented early in life with a variable degree of non-immune hemolysis, and the diagnosis was confirmed within a median of 2 years from presentation. The characteristics of participants are summarized in table 1. Two had family history of stillbirth or fetal demise in older siblings due to hydrops fetalis. One participant presented prenatally with fetal anemia and started intrauterine transfusions at 24 weeks of gestation; 2 presented with severe anemia and signs of hydrops, pulmonary hypertension, transaminitis, severe hyperbilirubinemia, and thrombocytopenia at birth; and 3 presented with neonatal jaundice and moderate anemia. All participants required blood transfusions in the neonatal period. Three had spontaneous improvement and did not require transfusions after the first year of life. One remained transfusion-dependent at last follow up at the age of 4 yrs. One became transfusion-independent after starting interferon-alpha at 1 yr of age and did not need further transfusions even after discontinuation at 3 yrs of age. One had splenectomy at 11 y.o because he was misdiagnosed to have a membrane disorder but presented in adulthood with hemolytic anemia and pulmonary hypertension and was diagnosed at that time with CDA-I by genetic sequencing. All participants had one or more non-hematological manifestations, including hypertrophic skin folds, onychocryptosis, curved toenails, syndactyly, café-au-lait spots, macrocephaly, spinal fusion, scoliosis, and short stature. One participant suffered a thalamic stroke in the postnatal period, 2 had transient neonatal pulmonary hypertension in the setting of severe anemia, and one had pulmonary hypertension post-splenectomy in adulthood. Ferritin was high in all participants at last follow up, and 4 received chelation therapy. In summary, mutations in CDAN1 are the most common identified mutations in CDAR. CDA-I causes early-onset macrocytic anemia, which may present prenatally, with variable severity of hemolysis ranging from hydrops to mild neonatal jaundice and anemia. Non-hematological manifestations, mainly skeletal, nail and skin abnormalities are more common in CDA-I than previously reported, and their presence in infants with unexplained anemia should raise suspicion for the diagnosis. The availability of molecular testing has significantly accelerated the diagnosis. Management of patients with CDA-I requires multidisciplinary approach from an early age to improve outcome. Collaboration between clinicians, scientists, patients, and families is needed to advance the understanding and treatment of this rare disease. Disclosures Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kalfa:Agios: Other: local PI of clinical research trial; FORMA: Other: sponsored research agreement.
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Emberesh, Myesa, Katie Giger Seu, Sana Emberesh, Lisa Trump, Mary Risinger, Wenying Zhang, Ammar Husami, et al. "Peroxiredoxin II (PRDX2) Is a Novel Candidate Gene for Congenital Dyserythropoietic Anemia." Blood 132, Supplement 1 (November 29, 2018): 3605. http://dx.doi.org/10.1182/blood-2018-99-120056.
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Abstract CDAR (ClinicalTrials.gov Identifier: NCT02964494), a registry for patients with Congenital Dyserythropoietic Anemia (CDA) in North America, has been created with the goal to provide a longitudinal database and associated biorepository to facilitate natural history studies and research on the molecular pathways involved in the pathogenesis of CDAs. A 1 y.o. female patient with non-immune hemolytic anemia with suboptimal reticulocytosis, requiring frequent transfusions, and with the pathologic diagnosis of CDA was enrolled in CDAR. Her father had a similar phenotypical presentation in early childhood and underwent splenectomy at 3 years of age. Since then, he has rarely required transfusions but he continues to have a mild anemia at baseline with characteristics of hemolysis and with suboptimal reticulocytosis; at the time of enrollment, he had hemoglobin of 9.3 g/dL with absolute reticulocyte count of 115 x 106 cells/µl. Next Generation sequencing and deletion/duplication assay for the known CDA-associated genes (CDAN1, C15ORF41, SEC23B, KIF23, GATA1) identified no mutations. Whole-exome sequencing for the patient and her parents (family-trio design) revealed a novel PRDX2 missense variant (c.154C>T; p.Pro52Ser) present in heterozygous state in both proband and her father; no mutation in this gene was present in the asymptomatic mother. In silico prediction programs suggest that this variant is probably damaging and deleterious, causing a non-conservative substitution of a phylogenetically highly-conserved amino acid (down to Baker's yeast), and located in an enzymatically active protein domain, adjacent to the active Cys51, with the potential to change its conformation. Peroxiredoxin II is highly expressed during terminal erythropoiesis and is one of the most abundant proteins after hemoglobin in erythroblasts and mature erythrocytes. It is an antioxidant enzyme that reduces the reactive oxygen species (ROS), like hydrogen peroxide and alkyl hydroperoxides readily produced within the erythroid cells due to the presence of heme iron and oxygen. In addition, PRDX2 has been implicated in intracellular signaling, cellular proliferation and differentiation, and as a regulator of iron homeostasis. PRDX2-/- mice were found to have hemolytic anemia with evidence of oxidative damage of the erythrocyte proteins resulting to decreased red blood cell (RBC) survival. The aim of this work is to validate the pathogenetic role of the PRDX2 variant found in this family as the molecular cause of this dominantly-inherited CDA and further investigate the role of PRDX2 in human terminal erythropoiesis. Central review of the patient's bone marrow aspirate and biopsy slides, according to the CDAR protocol, revealed erythroid hyperplasia with dyserythropoiesis, including megaloblastoid changes, nuclear lobation and fragmentation, and binucleated erythroblasts (less than 10%), compatible with atypical CDA. There were rare erythroids with cytoplasmic bridging but no nuclear bridges. Review of the peripheral blood smear showed significant poikilocytosis, mild polychromasia, and the presence of blister and ghost cells reminiscent of G6PD deficiency, pointing to RBC damage by oxidative stress. Induced pluripotent stem cells (iPSCs) and EBV-immortalized lymphocytes were generated from the patients' peripheral blood mononuclear cells after informed consent per CDAR protocol, to allow further in vitro studies of the peroxiredoxin II-deficiency. Flow cytometry confirmed significantly increased ROS in the patients' derived versus control EBV-immortalized lymphocytes as well as in the reticulocytes and mature erythrocytes of the proband and her father, indicating that their PRDX2 variant is causing loss-of-function of the enzyme and increased oxidative stress. Further work is ongoing to explore the mechanisms of pathogenicity of peroxiredoxin II deficiency towards human dyserythropoiesis and decreased erythrocyte lifespan. To our knowledge, this is the first case of anemia described in humans associated with PRDX2 mutation implicating this gene as a novel candidate gene for atypical, dominantly-inherited CDA. Disclosures No relevant conflicts of interest to declare.
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Micklefield, Jason. "Biosynthesis and biosynthetic engineering of calcium-dependent lipopeptide antibiotics." Pure and Applied Chemistry 81, no. 6 (May 5, 2009): 1065–74. http://dx.doi.org/10.1351/pac-con-08-08-29.
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Biosynthetic engineering involves the reprogramming of genes that are involved in the biosynthesis of natural products to generate new "non-natural" products, which might otherwise not exist in nature. Potentially this approach can be used to provide large numbers of secondary metabolites variants, with altered biological activities, many of which are too complex for effective total synthesis. Recently we have been investigating the biosynthesis of the calcium-dependent antibiotics (CDAs) which are members of the therapeutically relevant class of acidic lipopeptide antibiotics. CDAs are assembled by nonribosomal peptide synthetase (NRPS) enzymes. These large modular assembly-line enzymes process intermediates that are covalently tethered to peptidyl carrier protein (PCP) domain bonds bonds, which makes them particularly amenable to reprogramming. The CDA producer, Streptomyces coelicolor, is also a genetically tractable model organism which makes CDA an ideal template for biosynthetic engineering. To this end we have elucidated many of the key steps in CDA biosynthesis and utilized this information to develop methods that have enabled the engineered biosynthesis of wide range of CDA-type lipopeptides.
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Giger, Katie, Georgios E. Christakopoulos, Lisa Trump, Clarissa E. Johnson, Haripriya Sakthivel, Mary Risinger, Omar Niss, et al. "VPS4A : A Novel Candidate Gene for Congenital Dyserythropoietic Anemia." Blood 130, Suppl_1 (December 7, 2017): 923. http://dx.doi.org/10.1182/blood.v130.suppl_1.923.923.
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Abstract CDAR (ClinicalTrials.gov Identifier: NCT02964494), a registry for patients with Congenital Dyserythropoietic Anemia (CDA) in North America, was recently created with the goal to provide a longitudinal database and associated biorepository to facilitate natural history studies and research on the molecular pathways involved in the pathogenesis of CDAs. A 2 y.o. female patient with transfusion dependent anemia, pathologic diagnosis of Congenital Dyserythropoietic Anemia type I (CDA-I), and neurodevelopmental delay was enrolled in CDAR. Next Generation sequencing and deletion/duplication assay identified no mutations in the known CDA-associated genes, including CDAN1 and C15orf41, which are causative for CDA-I. Whole-exome sequencing for the patient and her parents (family-trio design) revealed a novel, de novo VPS4A missense variant located in the last codon of exon 8, potentially affecting splicing. VPS4A is an ATPase which, in association with the endosomal sorting complex required for transport (ESCRT), has been shown to play a critical role in cell division of HeLa cells in vitro, concentrating at the spindle poles during mitosis and at the midbody during cytokinesis. The aim of this work is to validate the pathogenetic role of the VPS4A variant for CDA and further investigate the role of VPS4A in erythroblast mitosis and cytokinesis. Central review of the patient's bone marrow aspirate smears revealed bi-nucleated erythroblasts in the range of 3-7%, a criterion compatible with CDA-I. However, cytoplasmic bridges were noted (arrows in Figure 1A) rather than the nuclear bridges typical of CDA-I. Immunofluorescence staining performed on erythroblasts generated ex vivo from normal CD34+ cells verified that VPS4A localizes to the spindle poles during mitosis and the midbody during cytokinesis in dividing human erythroid cells analyzed by Imaging Flow Cytometry (Figure 1B). The level of VPS4A mRNA expression in the patient's reticulocytes was evaluated by qPCR using three different sets of primers and found to be decreased by 55-70% compared to control reticulocytes and knock-down of VPS4A in normal CD34+ cells resulted in erythroid cultures enriched in binucleated cells. Induced pluripotent stem cells (iPSCs) were generated from the patient's peripheral blood mononuclear cells after the family's consent. Erythroblasts produced from these iPSCs exhibited decreased VPS4A localization at the spindle poles and midbody and fail to divide properly, frequently maintaining cytoplasmic bridges as seen in the patient's bone marrow. Additionally, flow cytometry analysis of the patient's peripheral blood cells stained with anti-CD71 for the transferrin receptor and Thiazol Orange (TO) for RNA revealed a unique cell population which is TO negative, yet CD71 positive implying that VPS4A is also involved in reticulocyte maturation, likely participating in vesicle formation and the normal exocytosis of the transferrin receptor. VPS4A appears to play a critical role in erythroblast mitosis and cytokinesis, as well as erythrocyte maturation, and is a novel candidate gene for congenital dyserythropoietic anemia. Figure 1. A) Binucleated erythroblasts and cytoplasmic bridges (arrows) were noted on the patient's bone marrow aspirate smears. B) VPS4A localizes at the spindle poles (upper image) and midbody (lower image) in normal human erythroblasts. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Iolascon, Achille, Hermann Heimpel, Anders Wahlin, and Hannah Tamary. "Congenital dyserythropoietic anemias: molecular insights and diagnostic approach." Blood 122, no. 13 (September 26, 2013): 2162–66. http://dx.doi.org/10.1182/blood-2013-05-468223.
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Abstract The congenital dyserythropoietic anemias (CDAs) are hereditary disorders characterized by distinct morphologic abnormalities of marrow erythroblasts. The unveiling of the genes mutated in the major CDA subgroups (I-CDAN1 and II-SEC23B) has now been completed with the recent identification of the CDA III gene (KIF23). KIF23 encodes mitotic kinesin-like protein 1, which plays a critical role in cytokinesis, whereas the cellular role of the proteins encoded by CDAN1 and SEC23B is still unknown. CDA variants with mutations in erythroid transcription factor genes (KLF1 and GATA-1) have been recently identified. Molecular diagnosis of CDA is now possible in most patients.
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Klann, Jeffrey G., Michael Mendis, Lori C. Phillips, Alyssa P. Goodson, Beatriz H. Rocha, Howard S. Goldberg, Nich Wattanasin, and Shawn N. Murphy. "Taking advantage of continuity of care documents to populate a research repository." Journal of the American Medical Informatics Association 22, no. 2 (October 15, 2014): 370–79. http://dx.doi.org/10.1136/amiajnl-2014-003040.
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Abstract Objective Clinical data warehouses have accelerated clinical research, but even with available open source tools, there is a high barrier to entry due to the complexity of normalizing and importing data. The Office of the National Coordinator for Health Information Technology's Meaningful Use Incentive Program now requires that electronic health record systems produce standardized consolidated clinical document architecture (C-CDA) documents. Here, we leverage this data source to create a low volume standards based import pipeline for the Informatics for Integrating Biology and the Bedside (i2b2) clinical research platform. We validate this approach by creating a small repository at Partners Healthcare automatically from C-CDA documents. Materials and methods We designed an i2b2 extension to import C-CDAs into i2b2. It is extensible to other sites with variances in C-CDA format without requiring custom code. We also designed new ontology structures for querying the imported data. Results We implemented our methodology at Partners Healthcare, where we developed an adapter to retrieve C-CDAs from Enterprise Services. Our current implementation supports demographics, encounters, problems, and medications. We imported approximately 17 000 clinical observations on 145 patients into i2b2 in about 24 min. We were able to perform i2b2 cohort finding queries and view patient information through SMART apps on the imported data. Discussion This low volume import approach can serve small practices with local access to C-CDAs and will allow patient registries to import patient supplied C-CDAs. These components will soon be available open source on the i2b2 wiki. Conclusions Our approach will lower barriers to entry in implementing i2b2 where informatics expertise or data access are limited.
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Das, Reena, Manu Jamwal, Anu Aggarwal, Prashant Sharma, Man Updesh Singh Sachdeva, Deepak Bansal, Sreejesh Sreedharanunni, et al. "Spectrum of Genetic Defects and Phenotype-Genotype Correlation in Dyserythropoietic Anemias: Bench to Bedside Approach in the Indian Scenario." Blood 134, Supplement_1 (November 13, 2019): 950. http://dx.doi.org/10.1182/blood-2019-126453.
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Introduction Congenital dyserythropoietic anemias (CDA) are rare inherited red cell disorders characterized by ineffective erythropoiesis and inappropriate reticulocytopenia. CDAs are usually difficult to diagnose due to variable phenotypes and overlapping bone marrow (BM) morphology with other disorders. Numerous implicated causal genes make Sanger sequencing a less likely approach and hence, the use of targeted resequencing can expedite molecular diagnosis. This study aimed at determining the genetic spectrum of CDAs and translating the results into patient care. Methods Twenty nine patients with clinical and laboratory evidence suggestive of CDA and 1 patient suggestive of CDA with thrombocytopenia by BM morphology were studied. Various biochemical and molecular tests were done to exclude common hemolytic anemias. Common SEC23B: p.Tyr462Cys variant in our patients with CDA was screened by Sanger sequencing. DNA libraries were prepared using TruSight One Sequencing Panel and TruSeq Custom Amplicon Panel and sequenced on Illumina platform. After data analysis variants were classified and the most likely disease-causing variants were validated by Sanger sequencing followed by pedigree analysis. Results Out of 27 patients of suspected CDA, SEC23B: p.Tyr462Cys variant was found in 10 patients. Rest of the remaining 17 patients were subjected to targeted resequencing. Data analysis revealed novel potentially pathogenic variants in compound heterozygosity in SEC23B in 4 patients and 1 patient had a heterozygous variant in SEC23B. There could be the possibility of intronic or large indel in her. The variants were distributed throughout the SEC23B gene. Notably, in 7 patients with suspected CDA, the final molecular diagnosis were hemolytic anemias. Of them, 4 showed likely pathogenic variants in PKLR gene and 1 each had probably causal variant in MTRR, SPTB and PIEZO1 genes. In the patient's with pyruvate kinase deficiency, screening by enzyme assays were normal. Except for the patient with MTRR gene defect all 6 had transfusion dependent anemia and BM showed dyserythropoiesis. One patient each of GATA1 gene variant (novel) and a known pathogenic variant p.Glu325Lys in KLF1 gene (CDA type IV) was detected. Of 17 cases subjected to targeted resequencing the diagnosis was achieved in ~76% (13/17) of cases. The phenotypes correlated with the genetic defects found in the SEC23B gene. The homozygous and compound heterozygous defects in this gene cause CDA type II. As anticipated GATA1 gene defect (p.Val205Leu) was found in a patient of X-linked thrombocytopenia with dyserythropoietic anemia. Patient with KLF1 had high levels of fetal hemoglobin along with features of dyserythropoiesis in BM compatible with the phenotype of variant p.Glu325Lys causing CDA type IV. Phenotype-genotype correlation was discrepant in 7 cases of CDA. In 4 cases pyruvate kinase deficiency (PKLR) was found and each case of hereditary xerocytosis (PIEZO1), membrane defect (SPTB) and MTRR defect was found. Conclusion(s) CDA showed a highly varied etiology. Our experience demonstrates a high diagnostic yield (~76%) of targeted resequencing for molecular diagnosis of suspected CDAs. Discrepancy was noted in 41% (7/17) cases with suspected CDA which were diagnosed as hemolytic anemia after molecular analysis. Establishing the correct diagnosis of pyruvate kinase deficiency led to an evidence-based decision of splenectomy that eliminated transfusion dependence. In the patient with MTRR defect change in therapy was suggested. Prenatal diagnosis was done for 2 families, where in 1 of the family both the SEC23B variants were novel and in compound heterozygosity. This study highlights the importance of genetic testing in patients under frequent blood transfusions and suspected CDAs, to provide accurate diagnosis and therapeutic interventions. Disclosures No relevant conflicts of interest to declare.
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Oganesian, Aram, Sanjeev Redkar, Pietro Taverna, Rajashree Joshi-Hangal, and Mohammad Azab. "Preclinical Data In Cynomolgus (cyn) Monkeys Of ASTX727, a Novel Oral Hypomethylating Agent (HMA) Composed Of Low-Dose Oral Decitabine Combined With a Novel Cytidine Deaminase Inhibitor (CDAi) E7727." Blood 122, no. 21 (November 15, 2013): 2526. http://dx.doi.org/10.1182/blood.v122.21.2526.2526.
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Abstract Background Hypomethylating agents (HMAs) such as decitabine and azacitidine have been successfully used in the clinic to treat hematological malignancies by parenteral administration (IV or SC). Due to low oral bioavailability of these agents, relatively high doses are required to achieve therapeutic systemic exposures by the oral route. Higher oral doses can be associated with significant GI toxicities due to intestinal enterocytes being exposed to high concentrations of these agents in the lumen. One of the main factors contributing to low oral bioavailability of HMAs is the high first-pass effect due to cytidine deaminase in GI and liver. Methods In this study, E7727, a novel CDA inhibitor (CDAi) was combined with decitabine (3 mg/kg) for oral administration in cynomolgus (cyn) monkeys at E7727 doses of 0.1-10 mg/kg. Results Systemic AUC exposures for decitabine increased from 21.7 ng*hr/mL (without E7727) to as high as 1,494 ng*hr/mL at 10mg/kg E7727. At a dose combination of 1 mg/kg CDAi and 3 mg/kg decitabine (corresponding to a human equivalent dose of 36 mg/m2), AUC exposures were 301±94 ng*hr/mL, which are slightly higher than the published clinical therapeutic range after decitabine IV infusion of 20 mg/m2 (115-220 ng*hr/mL), suggesting that a combination approach for oral CDAi+decitabine is feasible to achieve required clinical exposures at a range of relatively low-dose(s). In addition, the concentration-time profile of decitabine when combined with CDAi resembled that achieved with IV decitabine over 1 hour infusion. The effect of drug-drug interaction between CDAi and decitabine was modeled based on a relationship between CDAi Ki (∼ 0.14 µM based on IC50) and Cmaxlevels and appeared to predict the observed fold-increases in decitabine AUC with high concordance. In addition, low dose oral decitabine+CDAi achieved decitabine exposures that produce potent hypomethylation as observed by LINE-1 assay. Conclusion Pronounced increase in oral decitabine exposures was achieved when combined with the novel CDA inhibitor E7727. Cyn monkeys appear to be a relevant model for human PK based on similar background of circulating serum cytidine levels reflective of similar CDA status between humans and cyn monkeys. These data support the initiation of clinical First in Human (FIH) study of ASTX727, a novel oral HMA combining oral decitabine with the CDAi E7727. Disclosures: Oganesian: Astex Pharmaceuticals: Employment. Redkar:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Joshi-Hangal:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment.
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Miller, Sherry, Teresa D. Shippy, Blessy Tamayo, Prashant S. Hosmani, Mirella Flores-Gonzalez, Lukas A. Mueller, Wayne B. Hunter, Susan J. Brown, Tom D’Elia, and Surya Saha. "In silico characterization of chitin deacetylase genes in the Diaphorina citri genome." Gigabyte 2021 (June 11, 2021): 1–11. http://dx.doi.org/10.46471/gigabyte.25.
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Chitin deacetylases (CDAs) are one of the least understood components of insect chitin metabolism. The partial deacetylation of chitin polymers appears to be important for the proper formation of higher order chitin structures, such as long fibers and bundles, which contribute to the integrity of the insect exoskeleton and other structures. Some CDAs may also be involved in bacterial defense. Here, we report the manual annotation of four CDA genes from the Asian citrus psyllid, Diaphorina citri, laying the groundwork for future study of these genes.
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Harmsen, Rianne A. G., Tina R. Tuveng, Simen G. Antonsen, Vincent G. H. Eijsink, and Morten Sørlie. "Can we make Chitosan by Enzymatic Deacetylation of Chitin?" Molecules 24, no. 21 (October 26, 2019): 3862. http://dx.doi.org/10.3390/molecules24213862.
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Chitin, an insoluble linear polymer of β-1,4-N-acetyl-d-glucosamine (GlcNAc; A), can be converted to chitosan, a soluble heteropolymer of GlcNAc and d-glucosamine (GlcN; D) residues, by partial deacetylation. In nature, deacetylation of chitin is catalyzed by enzymes called chitin deacetylases (CDA) and it has been proposed that CDAs could be used to produce chitosan. In this work, we show that CDAs can remove up to approximately 10% of N-acetyl groups from two different (α and β) chitin nanofibers, but cannot produce chitosan.
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Santana, Priscila Monise Santos, Anailton Carlos Alves Almeida, Ubatã Correa Pereira, Brenda Vieira Santos, Jodnes Sobreira Vieira, and Carolina Nunes Costa Bomfim. "Digestibilidade aparente da quirera e farelo de arroz para o tambaqui (Colossoma macropomum, Cuvier, 1818)." Medicina Veterinária (UFRPE) 13, no. 3 (April 23, 2019): 438. http://dx.doi.org/10.26605/medvet-v13n3-3307.
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Os coeficientes de digestibilidade aparente (CDA) de subprodutos do beneficiamento do arroz (farelo e quirera de arroz) foram estimados para o tambaqui (Colossoma macropomum). Juvenis com peso médio de 63,5 g (± 2,7g) foram distribuídos em tanques de fundo cônico com capacidade de 100 L. Uma dieta referência foi formulada de acordo com as exigências nutricionais do tambaqui, enquanto duas dietas-teste foram constituídas de 70% da dieta referência e 30% de farelo ou quirera de arroz, sendo incorporado 0,5% de óxido de cromo como marcador externo. A determinação do CDA foi realizada pelo método de Guelph modificado com a coleta das excretas por sedimentação e quantificação do óxido de cromo. Os CDAs da matéria seca (MS), proteína bruta (PB), extrato etéreo (EE), fibra bruta (FB) e energia bruta (EB) da dieta referência foram 71,7; 88,9; 86,1; 42,6 e 91,6%, respectivamente. Os CDAs da dieta com o farelo de arroz foram semelhantes à da dieta referência (MS, 72,6%; PB, 90,2%; EE, 86,0%; FB, 48,8% e EB, 86,1%). A dieta com quirera apresentou CDAs de 74,3% para MS, 88,2% para PB; 82,8% para EE, 55,7% para FB e 84,1% para EB. O farelo e a quirera de arroz foram altamente digeridos pelo tambaqui, podendo ser utilizados como ingredientes em dietas para essa espécie.
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Renella, Raffaele, Nigel Roberts, Jill M. Brown, Marco De Gobbi, Louise Bird, Tasneem Hassanali, Jacqueline Sloane-Stanley, et al. "Codanin-1 Mutations In Congenital Dyserythropoietic Anemia Type 1 Affect HP1α Localization In Erythroblasts." Blood 116, no. 21 (November 19, 2010): 1003. http://dx.doi.org/10.1182/blood.v116.21.1003.1003.
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Abstract Abstract 1003 Introduction: The Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of rare inborn disorders mainly affecting erythropoiesis. Distinct from other inherited bone marrow failure syndromes, they are marked by morphological abnormalities of the erythroblasts leading to ineffective erythropoiesis/dyserythropoiesis, while the other hematopoietic lineages appear to be unaffected. Based largely on the dysplastic changes observed in erythroblasts by light and electron microscopy, the CDAs have been divided into 3 major types (CDA-1, 2 and 3). Causative genes have been identified for CDA-1 (CDAN1/15q15) and CDA-2 (CDAN2/20p11), while the chromosomal locus is known for CDA-3 (15q22). The majority of CDA-1 cases are associated with CDAN1 missense mutations, leading to single amino-acid substitutions in the 134 kDa Codanin-1 protein. Electron microscopy of CDA-1 erythroblasts reveals a characteristic pattern of spongy (“Swiss cheese”) heterochromatin. We investigated the chromatin in CDA-1 patients, the localization, distribution and interactions of Codanin-1 and generated a murine knock-out model for CDAN1. Results: Given the grossly abnormal chromatin ultrastructure in CDA-1 erythroblasts, we examined its overall content. No gross differences between normal and patient samples were seen, both in the amounts of histone proteins or various epigenetic marks of histone tails, suggesting that histone signatures, involved in maintenance of chromatin structure and epigenetic regulation, are globally maintained CDA-1. We confirmed the latter by ChIP-on-chip analysis where immunoprecipitated H4 acetylated, H3K4 dimethylated, H3K9 trimethylated and H3K27 trimethylated chromatin from CDA-1 erythroblasts and normal controls was hybridized to ENCODE genome-wide microrrays. Using a hybridoma technique, we produced 3 novel monoclonal antibodies to Codanin-1. These consistently demonstrate its distribution in both nucleus and cytoplasm of cells by immunofluorescence and Western Blotting. While Codanin-1 is found in the nucleus, it is more abundant in the cytoplasm in primary human erythroblasts. This localization pattern was unchanged in CDA-1 erythroblasts. Within the nucleus, Codanin-1 is localized in foci, while in the cytoplasm it shows an aggregated distribution, with the endoplasmic reticulum and Golgi apparatus being the most likely locations. No differences were found in the distribution patterns of RNA-polymerase-II, PML, nucleophosmin, HP1β and HP1γ between patients' and control erythroblasts. However, the localization of HP1α, a key component of heterochromatin, was found to be markedly perturbed. HP1α accumulates in the Golgi apparatus of CDA-1 but not normal erythroblasts. This was not seen in lymphoblasts derived from CDA-1 patients, nor in erythroblasts from a patient with CDA-2. We confirmed that the abnormal localization of HP1α in CDA-1 patients is confined to the intermediate erythroblast maturation stage, where the characteristic ultrastructural chromatin pattern of CDA-1 is observed. Immunoprecipitation of erythroblast protein extracts with anti- HP1α antibodies co-precipitated Codanin-1, suggesting that an abnormality in Codanin-1 could be responsible for the aberrant localization of HP1α. By confocal immunofluorescence, we also found Codanin-1 to co-localize partially with SEC23B, the protein mutated in CDA-2, suggesting a molecular link between the two major types of CDA. We generated the first murine Cdan1 gene-trap model demonstrating its widespread expression during embryonic development. Cdan1gt/gt homozygotes die in-utero before the onset of primitive erythropoiesis, suggesting that Cdan1 has other critical roles during embryogenesis. Adult heterozygous Cdan1wt/gt mice had normal hematopoietic function and morphology, normal life expectancy and fertility. No extra-hematopoietic macroscopic phenotype could be identified. Conclusions: Our results show that the absence of the highly conserved and ubiquitously expressed Codanin-1 is embryonic lethal, and suggest that missense CDAN1 mutations are responsible for the erythroid specific phenotype of CDA-1 via the abnormal cellular trafficking of the heterochromatin protein HP1α. Moreover, our findings suggest that common molecular pathways underlie the CDAs. Disclosures: No relevant conflicts of interest to declare.
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Iolascon, Achille, Immacolata Andolfo, and Roberta Russo. "Congenital dyserythropoietic anemias." Blood 136, no. 11 (September 10, 2020): 1274–83. http://dx.doi.org/10.1182/blood.2019000948.
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Abstract Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation–proliferation pathways of the erythroid lineage. They belong to the wide group of ineffective erythropoiesis conditions that mainly result in monolinear cytopenia. CDAs are classified into the 3 major types (I, II, III), plus the transcription factor-related CDAs, and the CDA variants, on the basis of the distinctive morphological, clinical, and genetic features. Next-generation sequencing has revolutionized the field of diagnosis of and research into CDAs, with reduced time to diagnosis, and ameliorated differential diagnosis in terms of identification of new causative/modifier genes and polygenic conditions. The main improvements regarding CDAs have been in the study of iron metabolism in CDAII. The erythroblast-derived hormone erythroferrone specifically inhibits hepcidin production, and its role in the mediation of hepatic iron overload has been dissected out. We discuss here the most recent advances in this field regarding the molecular genetics and pathogenic mechanisms of CDAs, through an analysis of the clinical and molecular classifications, and the complications and clinical management of patients. We summarize also the main cellular and animal models developed to date and the possible future therapies.
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Babcock, Gregory J., Teresa J. Broering, Hector J. Hernandez, Robert B. Mandell, Katherine Donahue, Naomi Boatright, Anne M. Stack, et al. "Human Monoclonal Antibodies Directed against Toxins A and B Prevent Clostridium difficile-Induced Mortality in Hamsters." Infection and Immunity 74, no. 11 (September 11, 2006): 6339–47. http://dx.doi.org/10.1128/iai.00982-06.
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ABSTRACT Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P < 0.0001) in the primary disease hamster model and from 78% to 32% (P < 0.0001) in the less stringent relapse model.
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Baker, Lorina G., Charles A. Specht, Maureen J. Donlin, and Jennifer K. Lodge. "Chitosan, the Deacetylated Form of Chitin, Is Necessary for Cell Wall Integrity in Cryptococcus neoformans." Eukaryotic Cell 6, no. 5 (March 30, 2007): 855–67. http://dx.doi.org/10.1128/ec.00399-06.
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ABSTRACT Cryptococcus neoformans is an opportunistic fungal pathogen that causes cryptococcal meningoencephalitis, particularly in immunocompromised patients. The fungal cell wall is an excellent target for antifungal therapies as it is an essential organelle that provides cell structure and integrity, it is needed for the localization or attachment of known virulence factors, including the polysaccharide capsule, melanin, and phospholipase, and it is critical for host-pathogen interactions. In C. neoformans, chitosan produced by the enzymatic removal of acetyl groups from nascent chitin polymers has been implicated as an important component of the vegetative cell wall. In this study, we identify four putative chitin/polysaccharide deacetylases in C. neoformans. We have demonstrated that three of these deacetylases, Cda1, Cda2, and Cda3, can account for all of the chitosan produced during vegetative growth in culture, but the function for one, Fpd1, remains undetermined. The data suggest a model for chitosan production in vegetatively growing C. neoformans where the three chitin deacetylases convert chitin generated by the chitin synthase Chs3 into chitosan. Utilizing a collection of chitin/polysaccharide deacetylase deletion strains, we determined that during vegetative growth, chitosan helps to maintain cell integrity and aids in bud separation. Additionally, chitosan is necessary for maintaining normal capsule width and the lack of chitosan results in a “leaky melanin” phenotype. Our analysis indicates that chitin deacetylases and the chitosan made by them may prove to be excellent antifungal targets.
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Melo, Karen Daianny Macedo, Giovanni Resende de Oliveira, Túlio Soares de Brito, Déborah Rodrigues Pedrosa Soares, Antonio Jessey de Abreu Tessitore, Érika Ramos de Alvarenga, Eduardo Maldonado Turra, Francisco Carlos de Oliveira Silva, and Edgar de Alencar Teixeira. "Digestibilidade de ingredientes em dietas para juvenis de pacamã (Lophiosilurus alexandri)." Pesquisa Agropecuária Brasileira 51, no. 6 (June 2016): 785–88. http://dx.doi.org/10.1590/s0100-204x2016000600012.
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Resumo: O objetivo deste trabalho foi determinar o coeficiente de digestibilidade aparente (CDA) de seis ingredientes, em dietas-referência prática e purificada, e determinar a influência das dietas-referência sobre a digestibilidade dos ingredientes em juvenis de pacamã. Avaliaram-se os seguintes ingredientes: farinha de peixe, farinha de carne e ossos, farelo de soja, soja integral tostada, farelo de trigo e protenose de milho. Houve interação entre a dieta-referência e os ingredientes estudados. A dieta purificada proporcionou maior CDA quanto à proteína bruta e energia bruta. O pacamã apresentou CDAs elevados quanto aos ingredientes proteicos de origem vegetal, nas duas dietas-referência.
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Seligmann, Hervé, and Jacques Demongeot. "Codon Directional Asymmetry Suggests Swapped Prebiotic 1st and 2nd Codon Positions." International Journal of Molecular Sciences 21, no. 1 (January 5, 2020): 347. http://dx.doi.org/10.3390/ijms21010347.
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Background: Codon directional asymmetry (CDA) classifies the 64 codons into palindromes (XYX, CDA = 0), and 5′- and 3′-dominant (YXX and XXY, CDA < 0 and CDA > 0, respectively). Previously, CDA was defined by the purine/pyrimidine divide (A,G/C,T), where X is either a purine or a pyrimidine. For the remaining codons with undefined CDA, CDA was defined by the 5′ or 3′ nucleotide complementary to Y. This CDA correlates with cognate amino acid tRNA synthetase classes, antiparallel beta sheet conformation index and the evolutionary order defined by the self-referential genetic code evolution model (CDA < 0: class I, high beta sheet index, late genetic code inclusion). Methods: We explore associations of CDAs defined by nucleotide classifications according to complementarity strengths (A:T, weak; C:G, strong) and keto-enol/amino-imino groupings (G,T/A,C), also after swapping 1st and 2nd codon positions with amino acid physicochemical and structural properties. Results: Here, analyses show that for the eight codons whose purine/pyrimidine-based CDA requires using the rule of complementarity with the midposition, using weak interactions to define CDA instead of complementarity increases associations with tRNA synthetase classes, antiparallel beta sheet index and genetic code evolutionary order. CDA defined by keto-enol/amino-imino groups, 1st and 2nd codon positions swapped, correlates with amino acid parallel beta sheet formation indices and Doolittle’s hydropathicities. Conclusions: Results suggest (a) prebiotic swaps from N2N1N3 to N1N2N3 codon structures, (b) that tRNA-mediated translation replaced direct codon-amino acid interactions, and (c) links between codon structures and cognate amino acid properties.
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Spadão, Fernanda, Juliana Gerhardt, Thais Guimarães, Frederico Dulley, João Nóbrega de Almeida Junior, Marjorie Vieira Batista, Maria Aparecida Shikanai-Yasuda, Anna Sara Levin, and Silvia Figueiredo Costa. "INCIDENCE OF DIARRHEA BY Clostridium difficile IN HEMATOLOGIC PATIENTS AND HEMATOPOIETIC STEM CELL TRANSPLANTATION PATIENTS: RISK FACTORS FOR SEVERE FORMS AND DEATH." Revista do Instituto de Medicina Tropical de São Paulo 56, no. 4 (July 2014): 325–31. http://dx.doi.org/10.1590/s0036-46652014000400010.
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We describe the rate of incidence of Clostridium difficile-associated diarrhea (CDAD) in hematologic and patients undergone stem cell transplant (HSCT) at HC-FMUSP, from January 2007 to June 2011, using two denominators 1,000 patient and 1,000 days of neutropenia and the risk factors associated with the severe form of the disease and death. The ELISA method (Ridascreen-Biopharm, Germany) for the detections of toxins A/B was used to identify C. difficile. A multivariate analysis was performed to evaluate potential factors associated with severe CDAD and death within 14 days after the diagnosis of CDAD, using multiple logistic regression. Sixty-six episodes were identified in 64 patients among 439 patients with diarrhea during the study period. CDA rate of incidence varied from 0.78 to 5.45 per 1,000 days of neutropenia and from 0.65 to 5.45 per 1,000 patient-days. The most common underlying disease was acute myeloid leukemia 30/64 (44%), 32/64 (46%) patients were neutropenic, 31/64 (45%) undergone allogeneic HSCT, 61/64 (88%) had previously used antibiotics and 9/64 (13%) have severe CDAD. Most of the patients (89%) received treatment with oral metronidazole and 19/64 (26%) died. The independent risk factors associated with death were the severe form of CDAD, and use of linezolid.
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Gundlach, Jan, Felix M. P. Mehne, Christina Herzberg, Jan Kampf, Oliver Valerius, Volkhard Kaever, and Jörg Stülke. "An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis." Journal of Bacteriology 197, no. 20 (August 3, 2015): 3265–74. http://dx.doi.org/10.1128/jb.00564-15.
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ABSTRACTGram-positive bacteria synthesize the second messenger cyclic di-AMP (c-di-AMP) to control cell wall and potassium homeostasis and to secure the integrity of their DNA. In the firmicutes, c-di-AMP is essential for growth. The model organismBacillus subtilisencodes three diadenylate cyclases and two potential phosphodiesterases to produce and degrade c-di-AMP, respectively. Among the three cyclases, CdaA is conserved in nearly all firmicutes, and this enzyme seems to be responsible for the c-di-AMP that is required for cell wall homeostasis. Here, we demonstrate that CdaA localizes to the membrane and forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. Interestingly,cdaA,cdaR, andglmMform a gene cluster that is conserved throughout the firmicutes. This conserved arrangement and the observed interaction between the three proteins suggest a functional relationship. Our data suggest that GlmM and GlmS are involved in the control of c-di-AMP synthesis. These enzymes convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. c-di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate compared to that in glutamine-grown cells. Thus, the quality of the nitrogen source is an important signal for c-di-AMP production. In the analysis of c-di-AMP-degrading phosphodiesterases, we observed that both phosphodiesterases, GdpP and PgpH (previously known as YqfF), contribute to the degradation of the second messenger. Accumulation of c-di-AMP in agdpP pgpHdouble mutant is toxic for the cells, and the cells respond to this accumulation by inactivation of the diadenylate cyclase CdaA.IMPORTANCEBacteria use second messengers for signal transduction. Cyclic di-AMP (c-di-AMP) is the only second messenger known so far that is essential for a large group of bacteria. We have studied the regulation of c-di-AMP synthesis and the role of the phosphodiesterases that degrade this second messenger. c-di-AMP synthesis strongly depends on the nitrogen source: glutamate-grown cells produce more c-di-AMP than glutamine-grown cells. The accumulation of c-di-AMP in a strain lacking both phosphodiesterases is toxic and results in inactivation of the diadenylate cyclase CdaA. Our results suggest that CdaA is the critical diadenylate cyclase that produces the c-di-AMP that is both essential and toxic upon accumulation.
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Joaquim, Andrei F., and K. Daniel Riew. "Multilevel cervical arthroplasty: current evidence. A systematic review." Neurosurgical Focus 42, no. 2 (February 2017): E4. http://dx.doi.org/10.3171/2016.10.focus16354.
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OBJECTIVE Cervical disc arthroplasty (CDA) has been demonstrated to be an effective treatment modality for single-level cervical radiculopathy or myelopathy. Its advantages over an anterior cervical discectomy and fusion (ACDF) include motion preservation and decreased reoperations at the index and adjacent segments up to 7 years postoperatively. Considering the fact that many patients have multilevel cervical disc degeneration (CDD), the authors performed a systematic review of the clinical studies evaluating patients who underwent multilevel CDA (2 or more levels). METHODS A systematic review in the MEDLINE database was performed. Clinical studies including patients who had multilevel CDA were selected and included. Case reports and literature reviews were excluded. Articles were then grouped according to their main study objective: 1) studies comparing multilevel CDA versus ACDF; 2) studies comparing single-level CDA versus multilevel CDA; and 3) multilevel CDA after a previous cervical spine surgery. RESULTS Fourteen articles met all inclusion criteria. The general conclusions were that multilevel CDA was at least as safe and effective as ACDF, with preservation of cervical motion when compared with ACDF and potentially with fewer reoperations expected in most of the studies. Multilevel CDAs are clinically effective as single-level surgeries, with good clinical and radiological outcomes. Some studies reported a higher incidence of heterotopic ossification in multilevel CDA when compared with single-level procedures, but without clinical relevance during the follow-up period. A CDA may be indicated even after a previous cervical surgery in selected cases. CONCLUSIONS The current literature supports the use of multilevel CDA. Caution is necessary regarding the more restrictive indications for CDA when compared with ACDF. Further prospective, controlled, multicenter, and randomized studies not sponsored by the device manufactures are desirable to prove the superiority of CDA surgery over ACDF as the treatment of choice for CDD in selected cases.
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Wang, Yanxin, Xin Niu, Xiaoli Guo, Han Yu, Zhonghua Liu, Zhenqing Zhang, and Sheng Yuan. "Heterologous expression, characterization and possible functions of the chitin deacetylases, Cda1 and Cda2, from mushroom Coprinopsis cinerea." Glycobiology 28, no. 5 (January 23, 2018): 318–32. http://dx.doi.org/10.1093/glycob/cwy007.
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Renella, Raffaele, Nigel A. Roberts, Jill M. Brown, Marco De Gobbi, Louise E. Bird, Tasneem Hassanali, Jacqueline A. Sharpe, et al. "Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1α localization in erythroblasts." Blood 117, no. 25 (June 23, 2011): 6928–38. http://dx.doi.org/10.1182/blood-2010-09-308478.
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Abstract Congenital dyserythropoietic anemia type 1 (CDA-1), a rare inborn anemia characterized by abnormal chromatin ultrastructure in erythroblasts, is caused by abnormalities in codanin-1, a highly conserved protein of unknown function. We have produced 3 monoclonal antibodies to codanin-1 that demonstrate its distribution in both nucleus and cytoplasm by immunofluorescence and allow quantitative measurements of patient and normal material by Western blot. A detailed analysis of chromatin structure in CDA-1 erythroblasts shows no abnormalities in overall histone composition, and the genome-wide epigenetic landscape of several histone modifications is maintained. However, immunofluorescence analysis of intermediate erythroblasts from patients with CDA-1 reveals abnormal accumulation of HP1α in the Golgi apparatus. A link between mutant codanin-1 and the aberrant localization of HP1α is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1α antibodies. Furthermore, we show colocalization of codanin-1 with Sec23B, the protein defective in CDA-2 suggesting that the CDAs might be linked at the molecular level. Mice containing a gene-trapped Cdan1 locus demonstrate its widespread expression during development. Cdan1gt/gt homozygotes die in utero before the onset of primitive erythropoiesis, suggesting that Cdan1 has other critical roles during embryogenesis.
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Liu, Xuan, Meiyu Lu, Beng Chin Ooi, Yanyan Shen, Sai Wu, and Meihui Zhang. "CDAS." Proceedings of the VLDB Endowment 5, no. 10 (June 2012): 1040–51. http://dx.doi.org/10.14778/2336664.2336676.
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Cummins, Mollie R., Guilherme Del Fiol, Barbara I. Crouch, Pallavi Ranade-Kharkar, Aly Khalifa, Andrew Iskander, Darren Mann, et al. "Enabling health information exchange at a US Poison Control Center." Journal of the American Medical Informatics Association 27, no. 7 (June 1, 2020): 1000–1006. http://dx.doi.org/10.1093/jamia/ocaa055.
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Abstract Objective The objective of this project was to enable poison control center (PCC) participation in standards-based health information exchange (HIE). Previously, PCC participation was not possible due to software noncompliance with HIE standards, lack of informatics infrastructure, and the need to integrate HIE processes into workflow. Materials and Methods We adapted the Health Level Seven Consolidated Clinical Document Architecture (C-CDA) consultation note for the PCC use case. We used rapid prototyping to determine requirements for an HIE dashboard for use by PCCs and developed software called SNOWHITE that enables poison center HIE in tandem with a poisoning information system. Results We successfully implemented the process and software at the PCC and began sending outbound C-CDAs from the Utah PCC on February 15, 2017; we began receiving inbound C-CDAs on October 30, 2018. Discussion With the creation of SNOWHITE and initiation of an HIE process for sending outgoing C-CDA consultation notes from the Utah Poison Control Center, we accomplished the first participation of PCCs in standards-based HIE in the US. We faced several challenges that are also likely to be present at PCCs in other states, including the lack of a robust set of patient identifiers to support automated patient identity matching, challenges in emergency department computerized workflow integration, and the need to build HIE software for PCCs. Conclusion As a multi-disciplinary, multi-organizational team, we successfully developed both a process and the informatics tools necessary to enable PCC participation in standards-based HIE and implemented the process at the Utah PCC.
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Signor, Arcangelo Augusto, Wilson Rogério Boscolo, Aldi Feiden, Altevir Signor, and Adilson Reidel. "Triguilho na alimentação da tilápia do nilo (Oreochromis niloticus L.): digestibilidade e desempenho." Ciência Rural 37, no. 4 (August 2007): 1116–21. http://dx.doi.org/10.1590/s0103-84782007000400032.
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No presente experimento objetivou-se determinar os coeficientes de digestibilidade aparente (CDa) da proteína bruta (PB) e da energia bruta (EB) do triguilho para a tilápia do Nilo (Oreochromis niloticus) e avaliar a inclusão do triguilho sobre o desempenho de alevinos de tilápia do Nilo. Para a determinação dos CDa, foram utilizadas 40 tilápias com peso e comprimento médios de 80,00g e 15,9cm, respectivamente, submetidas à coleta das fezes por sedimentação. Para a avaliação do desempenho, foram utilizados 125 alevinos de tilápia do Nilo, com peso inicial médio de 0,80g, distribuídos em 25 aquários com capacidade de 30L, em um delineamento inteiramente casualizado, com cinco tratamentos e cinco repetições. As rações experimentais continham níveis de inclusão de 0,00; 7,97; 14,94; 23,91 e 31,88% de triguilho substituindo até 100% do milho. Os CDas da PB e EB do triguilho foram de 91,03 e 78,72%, respectivamente, apresentando 11,92% de proteína digestível e 3134Kcal kg-1 de energia digestível. Não foi observada diferença (P>0,05) no desempenho dos peixes alimentados com as rações contendo os diferentes níveis de inclusão do triguilho. O triguilho é um alimento com bons CDa da PB e EB e pode ser incluído em até 31,88% em rações para alevinos de tilápia do Nilo sem causar prejuízo no desempenho.
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Silva, R. S., R. V. E. Santo, A. V. C. Barbosa, M. A. S. Santos, R. O. Corrêa, H. Martins Júnior, and J. B. Lourenço Júnior. "Digestibilidade aparente do farelo de palmiste em tambaqui (Colossoma macropomum)." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 71, no. 5 (October 2019): 1595–600. http://dx.doi.org/10.1590/1678-4162-10968.
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RESUMO O objetivo deste trabalho foi determinar a digestibilidade do farelo de palmiste (Elaeis guineensis) para o tambaqui (Colossoma macropomum), em duas classes de peso: 1 (210 alevinos de 4,45±1,18g) e 2 (54 juvenis de 115,91±4,01g). Os coeficientes de digestibilidade aparente (CDA) da matéria seca, proteína bruta e energia bruta do farelo de palmiste foram avaliados pela metodologia de substituição da dieta referência, utilizando-se 0,1% de óxido crômico como indicador externo. Os dados foram analisados pelo teste t de Student, a 5% de probabilidade. Os CDAs da matéria seca, proteína bruta e energia bruta do ingrediente foram iguais (P>0,05) nas classes de peso avaliadas. Os CDAs observados nas classes 1 e 2, respectivamente, foram: matéria seca (17,52% e 20,75%), proteína bruta (62,83% e 63,75%) e energia bruta (14,16% e 22,43%). A capacidade do tambaqui para digerir os nutrientes do farelo de palmiste não foi influenciada pelo peso corporal, e o aproveitamento satisfatório da proteína (63,29%) faz desse ingrediente uma potencial fonte alternativa de proteína em dietas para a espécie.
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Yu, Hai-Zhong, Ning-Yan Li, Bing Li, Shahzad Toufeeq, Yan-Xin Xie, Yu-Ling Huang, Yi-Ming Du, Xiang-Dong Zeng, Bo Zhu, and Zhan-Jun Lu. "Immune Functional Analysis of Chitin Deacetylase 3 from the Asian Citrus Psyllid Diaphorina citri." International Journal of Molecular Sciences 21, no. 1 (December 20, 2019): 64. http://dx.doi.org/10.3390/ijms21010064.
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Chitin deacetylase (CDA) is a chitin degradation enzyme that strictly catalyzes the deacetylation of chitin to form chitosan, which plays an important role in regulating growth and development, as well as the immune response. In this study, a chitin deacetylase 3 gene (CDA3) was identified with a complete open reading frame (ORF) of 1362 bp from the genome database of Diaphorina citri, encoding a protein of 453 amino acids. Spatiotemporal expression analysis suggested that D. citri CDA3 (DcCDA3) had the highest expression level in the integument and third-instar nymph stage. Furthermore, DcCDA3 expression level can be induced by 20-hydroxyecdysone (20E). Injection of Escherichia coli and Staphylococcus aureus induced the upregulation of DcCDA3 in the midgut, while DcCDA3 was downregulated in the fat body. After silencing DcCDA3 by RNA interference, there was no influence on the D. citri phenotype. In addition, bactericidal tests showed that recombinant DcCDA3 inhibited gram-positive bacteria, including S. aureus and Bacillus subtilis (B. subtilis). In conclusion, our results suggest that DcCDA3 might play an important role in the immune response of D. citri.
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Boguszewska, Karolina, Michał Szewczuk, Julia Kaźmierczak-Barańska, and Bolesław T. Karwowski. "How (5′S) and (5′R) 5′,8-Cyclo-2′-Deoxypurines Affect Base Excision Repair of Clustered DNA Damage in Nuclear Extracts of xrs5 Cells? A Biochemical Study." Cells 10, no. 4 (March 24, 2021): 725. http://dx.doi.org/10.3390/cells10040725.
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The clustered DNA lesions (CDLs) are a characteristic feature of ionizing radiation’s impact on the human genetic material. CDLs impair the efficiency of cellular repair machinery, especially base excision repair (BER). When CDLs contain a lesion repaired by BER (e.g., apurinic/apyrimidinic (AP) sites) and a bulkier 5′,8-cyclo-2′-deoxypurine (cdPu), which is not a substrate for BER, the repair efficiency of the first one may be affected. The cdPus’ influence on the efficiency of nuclear BER in xrs5 cells have been investigated using synthetic oligonucleotides with bi-stranded CDL (containing (5′S) 5′,8-cyclo-2′-deoxyadenosine (ScdA), (5′R) 5′,8-cyclo-2′-deoxyadenosine (RcdA), (5′S) 5′,8-cyclo-2′-deoxyguanosine (ScdG) or (5′R) 5′,8-cyclo-2′-deoxyguanosine (RcdG) in one strand and an AP site in the other strand at different interlesion distances). Here, for the first time, the impact of ScdG and RcdG was experimentally tested in the context of nuclear BER. This study shows that the presence of RcdA inhibits BER more than ScdA; however, ScdG decreases repair level more than RcdG. Moreover, AP sites located ≤10 base pairs to the cdPu on its 5′-end side were repaired less efficiently than AP sites located ≤10 base pairs on the 3′-end side of cdPu. The strand with an AP site placed opposite cdPu or one base in the 5′-end direction was not reconstituted for cdA nor cdG. CdPus affect the repair of the other lesion within the CDL. It may translate to a prolonged lifetime of unrepaired lesions leading to mutations and impaired cellular processes. Therefore, future research should focus on exploring this subject in more detail.
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van den Berg, Renate J., Norbert Vaessen, Hubert P. Endtz, Tanja Schülin, Eric R. van der Vorm, and Ed J. Kuijper. "Evaluation of real-time PCR and conventional diagnostic methods for the detection of Clostridium difficile-associated diarrhoea in a prospective multicentre study." Journal of Medical Microbiology 56, no. 1 (January 1, 2007): 36–42. http://dx.doi.org/10.1099/jmm.0.46680-0.
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In this prospective multicentre study, an enzyme-linked fluorescent assay (VIDAS CDA2; bioMérieux), an enzyme-linked assay [Premier Toxins A and B (PTAB); Meridian] and an in-house real-time PCR amplifying the tcdB gene were compared with the cell cytotoxicity assay used as the ‘gold standard’ for diagnosis of Clostridium difficile-associated diarrhoea (CDAD). Faecal samples from patients with a request for C. difficile diagnosis and samples from patients with diarrhoea hospitalized for at least 72 h were collected for 3 consecutive months from four university medical centres in The Netherlands. In total, 547 faecal samples were obtained from 450 patients. Of 540 samples available for all of the assays, 84 (15.6 %) showed a positive result in one or more assays. The cell cytotoxicity assay was positive in 31 samples (5.7 %) from 28 patients. A diagnosis of CDAD was not considered by the physician in 5 (23.8 %) of 21 patients with CDAD who were hospitalized for at least 72 h. Compared with the cell cytotoxicity assay, the sensitivity of VIDAS, PTAB and PCR was 83.9, 96.8 and 87.1 %, respectively. The specificity of VIDAS, PTAB and PCR was 97.1, 94.3 and 96.5 %, respectively. The positive and negative predictive values for VIDAS, PTAB and PCR were 63.4 and 99.0 %, 50.9 and 99.8 %, and 60.0 and 99.2 %, respectively. Of 61 samples that were positive in one, two or three of the assays, 56 were available for discordance analysis. Discordance analysis was performed by culture of toxinogenic strains. The concordance of VIDAS, PTAB and PCR with culture was 53.6 % (30/56), 55.4 % (31/56) and 71.4 % (40/56), respectively. It was concluded that real-time PCR had the highest concordance with toxinogenic culture and is therefore the preferred method for diagnosing CDAD in faecal samples. It was also concluded that diagnosis of patients with diarrhoea who have been hospitalized for more than 72 h should focus mainly on the detection of C. difficile, irrespective of the physician's request.
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Manian, Farrin A., Lynn Meyer, Mary M. Olson, Carol J. Shanholtzer, James T. Lee, and Dale N. Gerding. "CDAD Rates." Infection Control and Hospital Epidemiology 16, no. 2 (February 1995): 63–65. http://dx.doi.org/10.2307/30140942.
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Koshy, Beena. "CDPU Hypergraphs." International Journal of Mathematics Trends and Technology 66, no. 5 (May 25, 2020): 150–54. http://dx.doi.org/10.14445/22315373/ijmtt-v66i5p520.
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Manian, Farrin A., Lynn Meyer, Mary M. Olson, Carol J. Shanholtzer, James T. Lee, and Dale N. Gerding. "CDAD Rates." Infection Control and Hospital Epidemiology 16, no. 2 (February 1995): 63–65. http://dx.doi.org/10.1086/647056.
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Shemer, Orna Steinberg, Yu Yao, Gary M. Kupfer, Hannah Tamary, and Mitchell J. Weiss. "Modeling Congenital Dyserythropoietic Anemia Type I Through Patient-Derived Induced Pluripotent Stem Cells." Blood 120, no. 21 (November 16, 2012): 3196. http://dx.doi.org/10.1182/blood.v120.21.3196.3196.
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Abstract Abstract 3196 Congenital dyserythropoietic anemias (CDAs) are rare inherited disorders characterized by impaired red blood cell formation (dyserythropoiesis) and signature cytopathologies. CDA type I is an autosomal recessive disease with macrocytic anemia and occasional bone abnormalities. Erythroid precursors exhibit pathognomonic abnormalities including internuclear chromatin bridges and spongy (“Swiss cheese”) heterochromatin. The disease is caused by biallelic mutations in the gene CDANI (Dgany et al., 2002), which encodes codanin-1, a ubiquitously expressed protein that is believed to have fundamental roles in cell cycle control and chromatin structure (Noy-Lotan et. al, 2009). Animal models for the study of CDA I are suboptimal and clinical samples are scarce. Thus, we have developed an experimental model for the study of CDA I by generating induced pluripotent stem cells (iPSCs) from affected patients. We reprogrammed fibroblasts from CDA I patients and normal subjects using a single lentiviral vector encoding OCT4, KLF4, SOX2, and MYC. The resultant iPSCs exhibited standard criteria for pluripotency and the integrated reprogramming vector was excised using Cre-lox technology. We differentiated CDA I and control iPSCs into erythroid progenitors by inducing the formation of embryoid bodies (EBs) with stepwise additions of supportive cytokines. Beginning at about day 8, hematopoietic progenitors with erythroid potential were detected within EBs and as free-floating cells in the medium. Our differentiation protocol showed two waves of erythroid precursor production. Early EBs (days 12 to 23) produced erythroid cells that expressed mainly epsilon globin, resembling early yolk sac type “primitive” erythropoiesis. In contrast, erythroblasts produced from later EBs (days 27 to 50) expressed mainly gamma globins, resembling “definitive” erythroid cells produced by late stage yolk sac and fetal liver. Our preliminary studies, indicate that CDA I iPSCs produce normal numbers of primitive and definitive erythrocytes. No defects in survival or maturation were detected by flow cytometry assessing the expression of annexin V and the developmental stage markers CD235/CD71/forward scatter. However, definitive type (but not primitive) erythroblasts derived from CDA I iPSCs exhibit some characteristic pathological features including occasional internuclear chromatin bridging visible by light microscopy and spongy “Swiss cheese” heterochromatin revealed by transmission electron microscopy. Thus, patient-derived iPSCs can model at least some aspects of CDA I and provide the basis for future studies to define the actions of codanin-1 and the pathophysiology of this disorder. Figure: Patient iPSC-derived erythroblasts recapitulate CDA I pathology. Light microscopy and transmission electron microscopy (TEM) of normal and CDA I iPSC-derived erythroblasts generated in ∼30 day differentiation cultures. Inserts show higher magnification of the marked areas. CDA I cells exhibit occasional internuclear bridges on light microscopy (third panel). TEM showed abnormal spongy chromatin structure in most CDA I erythroid precursors (fourth panel). Figure:. Patient iPSC-derived erythroblasts recapitulate CDA I pathology. Light microscopy and transmission electron microscopy (TEM) of normal and CDA I iPSC-derived erythroblasts generated in ∼30 day differentiation cultures. Inserts show higher magnification of the marked areas. CDA I cells exhibit occasional internuclear bridges on light microscopy (third panel). TEM showed abnormal spongy chromatin structure in most CDA I erythroid precursors (fourth panel). Disclosures: No relevant conflicts of interest to declare.
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Duncan, Fraser. "A Decade of Christian Democratic Decline: The Dilemmas of the CDU, ÖVP and CDA in the 1990s." Government and Opposition 41, no. 4 (2006): 469–90. http://dx.doi.org/10.1111/j.1477-7053.2006.00200.x.
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AbstractThis article explores Christian Democratic electoral decline in the 1990s through an examination of the key problems faced by the CDU, the ÖVP and the CDA. Although the problems of Christian Democracy in this period are identified as arising from exogenous changes, the article goes beyond a mechanistic approach by also scrutinizing the response of the various parties. It is argued that the contraction of core support bases, intensified party competition and the rise of problematic issues created a series of dilemmas for the parties but also that the unconvincing reaction of the parties contributed to their electoral predicament.
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Ryding, N. Jamie, Todd B. Anderson, and Wendy C. Champness. "Regulation of the Streptomyces coelicolor Calcium-Dependent Antibiotic by absA, Encoding a Cluster-Linked Two-Component System." Journal of Bacteriology 184, no. 3 (February 1, 2002): 794–805. http://dx.doi.org/10.1128/jb.184.3.794-805.2002.
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ABSTRACT The Streptomyces coelicolor absA two-component system was initially identified through analysis of mutations in the sensor kinase absA1 that caused inhibition of all four antibiotics synthesized by this strain. Previous genetic analysis had suggested that the phosphorylated form of AbsA2 acted as a negative regulator of antibiotic biosynthesis in S. coelicolor (T. B. Anderson, P. Brian, and W. C. Champness, Mol. Microbiol. 39:553–566, 2001). Genomic sequence data subsequently provided by the Sanger Centre (Cambridge, United Kingdom) revealed that absA was located within the gene cluster for production of one of the four antibiotics, calcium-dependent antibiotic (CDA). In this paper we have identified numerous transcriptional start sites within the CDA cluster and have shown that the original antibiotic-negative mutants used to identify absA exhibit a stronger negative regulation of promoters upstream of the proposed CDA biosynthetic genes than of promoters in the clusters responsible for production of actinorhodin and undecylprodigiosin. The same antibiotic-negative mutants also showed an increase in transcription from a promoter divergent to that of absA, upstream of a putative ABC transporter, in addition to an increase in transcription of absA itself. Interestingly, the negative regulation of the biosynthetic transcripts did not appear to be mediated by transcriptional regulation of cdaR (a gene encoding a homolog of the pathway-specific regulators of the act and red clusters) or by any other recognizable transcriptional regulator associated with the cluster. The role of absA in regulating the expression of the diverse antibiotic biosynthesis clusters in the genome is discussed in light of its location in the cda cluster.
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Kohara, Hiroshi, Hiromi Ogura, Takako Aoki, Chika Sakamoto, Yoshie Ogawa, Shohei Miyamoto, Hitoshi Kanno, and Kenzaburo Tani. "Generation and Functional Analysis of Congenital Dyserythropoietic Anemia (CDA) Patient-Specific Induced Pluripotent Stem Cells." Blood 128, no. 22 (December 2, 2016): 2426. http://dx.doi.org/10.1182/blood.v128.22.2426.2426.
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Abstract The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders representing ineffective erythropoiesis and dyserythropoietic changes in the bone marrow. We recently diagnosed a female patient with undiagnosed congenital anemia as type IV CDA caused by a heterozygous missense mutation of the erythroid-specific transcription factor, KLF1; c.973G>A, p. E325K. Although the mutation has been reported in a male patient characterized as hydrops fetalis, severe neonatal jaundice and transfusion-dependent anemia (Arnaud L et al., Am J Hum Genet, 2010), the proband showed relatively mild phenotype showing moderate dyserythropoietic anemia. In order to investigate the pathological significance of mutant KLF1 during erythroid cell development and differentiation, we generated induced pluripotent stem cells (iPSCs) from peripheral blood of the CDA patient (CDA-iPSCs), and utilized these cells to establish in vitro CDA model for better understanding of its molecular basis. CDA-iPSCs were generated from T lymphocytes in peripheral blood mononuclear cells. Hematopoietic precursors were induced from CDA-iPSCs by embryoid bodies formation. CD34(+) precursor cells were isolated and further cultured in liquid culture with cytokine cocktail (erythropoietin (EPO), interleukin (IL)-3, and stem cell factor (SCF)) for additional 1-3 weeks. Flow cytometric analysis showed that CDA-iPSC-derived cells contained significantly lower percentage of CD235a(+)/CD71(+) erythroid lineage cells than the cells derived from control iPSCs, and lack expression of the adhesion molecule CD44, which is known to be down regulated in peripheral blood erythroid cells of CDA patients (Arnaud L et al., Am J Hum Genet, 2010). In addition, colony-forming unit (CFU) assay indicated that CD34(+) fraction derived from CDA-iPSCs contained a lower number of erythroid colony-forming cells and the most of the cells in these colonies are morphologically abnormal, in comparison with control iPSCs. We next evaluated mRNA expression levels of fetal (HBG1 and HBG2), embryonic (HBE), and adult (HBB) globins, resulting that HBG1 and HBG2 were significantly increased in CDA-iPSCs-derived erythroid lineage cells, whereas HBE showed no significant change and HBB was decreased in CDA-iPSCs-derived erythroid lineage cells. However, BCL11A, one of the target genes of KLF1 and also known as a suppressor of HBG1 and HBG2, was not decreased in the presence KLF1 gene mutation, indicating that elevated HBG1 and HBG2 in CDA-iPSCs-derived erythroid cells was mediated by other mechanism like Leukemia/lymphoma Related Factor (LRF; Masuda T et al., Science, 2016). Here we suggest that our model provides insights on understanding the mechanisms of type IV CDA and the effect of KLF1 gene mutation on clinical phenotype and it would be a useful tool for drug screening and identification of novel biomarker for the rare congenital anemia. Figure 1 Induction of erythroid differentiation from human iPSCs Figure 2 Flow cytometric analysis of erythroid cells induced from CDA-iPSCs Figure 3 RT-PCR analysis of erythroid cells induced from CDA-iPSCs Disclosures Kohara: SBI Pharmaceuticals: Research Funding. Miyamoto:SBI Pharmaceuticals: Research Funding. Tani:Oncolys BioPharma: Equity Ownership; SymBio Pharmaceuticals: Consultancy, Equity Ownership; SBI Pharmaceuticals: Research Funding; Shinnihonseiyaku: Research Funding.
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Peng, Ching-Tien. "Whole Exome Sequencing Identifies a Novel Variant in the Pklr Gene Which Worsen the Anemia Status in a Congenital Dyserthropoietic Anemia Patient." Blood 132, Supplement 1 (November 29, 2018): 4880. http://dx.doi.org/10.1182/blood-2018-99-112743.
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Abstract Congenital dyserythropoietic anemia (CDAs) is a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Diagnosis of CDA is based primarily on the morphology of bone marrow erythroblasts but genetic tests might have more and more important roles recently. Here, we describe a 31-year old female with atypical CDA under regular blood transfusions. The results of blood tests were as followed: RBC: 3080000/µL, Hb: 9.9 g/dL, Hct: 26.8%, MCV: 87.0 fl, MCH:32.2 pg, and MCHC: 36.9 g/L. In this study, analysis of CDA-related genes, including SEC23B, CDAN1, KLF1, and C15orf41, were analyzed by exome sequencing but no pathogenic variant was found. In additional, we analyzed RBC-related genes and a novel variant in the PKLR p.A468G (NP_000289) was found which was also confirmed by Sanger sequence. Variant of PKLR gene has been reported as the cause of pyruvate kinase (PK) deficiency anemia. PK deficiency is the most cause of congenital nonspherocytic hemolytic anemia with GMAF (global minor allele frequency) of 0.0001. The clinical features of PK-deficient patients are highly variable degree of chronic hemolysis with severe neonatal jaundice and fetal anemia at birth. In this case, PKLR p.A468G heterozygous variant was detected in a patient with PK deficiency, as an example of precision diagnosis by exome sequencing. Disclosures No relevant conflicts of interest to declare.
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Giger Seu, Katie, Lisa Trump, Sana Emberesh, Robert B. Lorsbach, Clarissa E. Johnson, Jessica Meznarich, Hunter Underhill, et al. "VPS4A mutations Cause a Syndrome with Dyserythropoiesis, Hemolytic Anemia, and Neurodevelopmental Delay." Blood 134, Supplement_1 (November 13, 2019): 339. http://dx.doi.org/10.1182/blood-2019-128230.
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The Congenital Dyserythropoietic Anemia Registry (CDAR, ClinicalTrials.gov Identifier: NCT02964494) was created to investigate the natural history, biology, and molecular pathogenetic mechanisms of CDA. To date, there are 6 genes known to cause CDA (CDAN1, C15orf41, SEC23B, KIF23, KLF1, GATA1). However, 57% of patients registered in CDAR so far (17 out of 33 patients) have an unidentified genetic cause. We have utilized whole exome sequencing (WES) in family-trio design to search for novel candidate gene mutations that may be responsible for the disease. Three unrelated patients with dyserythropoiesis, hemolytic anemia, and neurodevelopmental delay were found to have missense mutations in the gene VPS4A which encodes an ATPase that participates with the ESCRT III machinery in endosomal vesicle trafficking, centrosome localization, and the abscission step of cytokinesis. It has been shown to play an essential role in division of HeLa cells in vitro where it concentrates at the spindle poles during mitosis and at the midbody during cytokinesis. The aim of this work is to validate the pathogenetic role of these VPS4A variants in CDA and further investigate the role of VPS4A in erythropoiesis. Patients 1 and 3 had de novo mutations (R284W and G203A) and transfusion-dependent anemia with presence of binucleated erythroblasts in the bone marrow resembling CDA type I. Of note, the patients' erythroblasts exhibited cytoplasmic bridges (Figure 1A) rather than the nuclear chromatin bridges observed in CDA-I. Patient 2, offspring of consanguineous parents, presented with hemolytic anemia and was found to have a homozygous mutation (A28V) in a highly conserved alanine residue in the microtubule-interacting domain (MIT) of VPS4A. She had rare evidence of dyserythropoiesis with fewer than 3% binucleated erythroblasts in bone marrow studies. All three patients had significant neurodevelopmental delay with axial hypotonia and appendicular hypertonia. Flow cytometry analysis of peripheral blood from each of these patients revealed a unique cell population which is negative for RNA (by thiazole orange) but still CD71 positive suggesting that loss of VPS4A function also impacts reticulocyte maturation, likely because of defective endosomal vesicle trafficking. Using CD34+ cells in ex vivo erythropoiesis cultures, we first confirmed that VPS4A is expressed in human erythroblasts and localizes at the spindle poles and midbody during mitosis and cytokinesis in these cells. RNA isolated from reticulocytes from patients 1 and 2 was assessed for expression of VPS4A and the paralogous VPS4B. Samples from patient 1 had reduced expression of VPS4A (<50%) and only slight increase (2-3%) in VPS4B while samples from patient 2 had normal expression of VPS4A, but 10-20x increase in VPS4B highlighting the variable effects of these mutations on protein expression, function, and disease phenotype. Using iPSCs derived from patient 1 peripheral blood mononuclear cells (PBMCs), we have modeled the disease with in vitro erythropoiesis cultures. We observed decreased VPS4A expression and mislocalization in dividing erythroblasts produced from the patient-derived iPSCs. Moreover, the erythroblasts cultured from patient 1 demonstrated an increased rate of being binucleated and frequently maintained cytoplasmic bridges as seen in the patient's bone marrow (Figure 1B). In summary, VPS4A plays a critical role in human erythroblast mitosis, cytokinesis, and reticulocyte maturation and mutations in VPS4A cause congenital dyserythropoietic and hemolytic anemia. The CDA registry is critical to allow systematic gene and pathway evaluation, enable novel treatment considerations, and reveal molecular mechanisms essential for erythropoiesis. Disclosures Kalfa: Agios: Other: local PI of clinical research trial; FORMA: Other: sponsored research agreement.
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Schölmerich, Jürgen, Harro Jenss, Franz Hartmann, and Hanne Döpfer. "Oral 5-Aminosalicyclic Acid Versus 6-Methylprednisolone in Active Crohn's Disease." Canadian Journal of Gastroenterology 4, no. 7 (1990): 446–51. http://dx.doi.org/10.1155/1990/260563.
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The response to 5-aminosalicylic acid (5-ASA) in active Crohn's disease was studied in comparison to methylprednisolone in a 24 week randomized double-blind multicentre study. Sixty-two patients were included in the analysis. Thirty were treated with 500 mg 5-ASA qid and 32 with methylprednisolone (starting dose 48 mg for one week, then reduced weekly to 32, 24, 20, 16 and 12 mg with maintenance at 8 mg/day for the remaining 18 weeks). Mean age, earlier surgical intervention, localization of Crohn's disease and extraintestinal manifestations were not different in both groups. The Crohn's disease activity index (CDAI) and the van Hees index were not significantly different in both treatment groups at the entrance examination (median CDAI 232 in the 5-ASA group and 220 in the methylprednisolone group). According to the protocol, treatment was stopped due to insufficient efficacy in 73% of the patients receiving 5-ASA and in 34% of the patients receiving methylprednisolone (x2test P=0.0019). The area under the curve for the CDAl was significantly greater in 5-ASA (median 170) than in methylprednisolone (P≤0.007) (68). Eleven per cent of patients taking 5-ASA and 26% of patients taking methylprednisolone presented relevant side effects to treatment (not significant). It is concluded from these data that 5-ASA at the dose used in this study is not efficient in the treatment of active Crohn's disease. Considering recent studies in ulcerative colitis, a trial using a higher dose is indicated.
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Pecoraro, Fabrizio, Daniela Luzi, and Fabrizio L. Ricci. "Developing HL7 CDA-Based Data Warehouse for the Use of Electronic Health Record Data for Secondary Purposes." ACI Open 03, no. 01 (January 2019): e44-e62. http://dx.doi.org/10.1055/s-0039-1688936.
Full textAbstract:
Background The growing availability of clinical and administrative data collected in electronic health records (EHRs) have led researchers and policy makers to implement data warehouses to improve the reuse of EHR data for secondary purposes. This approach can take advantages from a unique source of information that collects data from providers across multiple organizations. Moreover, the development of a data warehouse benefits from the standards adopted to exchange data provided by heterogeneous systems. Objective This article aims to design and implement a conceptual framework that semiautomatically extracts information collected in Health Level 7 Clinical Document Architecture (CDA) documents stored in an EHR and transforms them to be loaded in a target data warehouse. Results The solution adopted in this article supports the integration of the EHR as an operational data store in a data warehouse infrastructure. Moreover, data structure of EHR clinical documents and the data warehouse modeling schemas are analyzed to define a semiautomatic framework that maps the primitives of the CDA with the concepts of the dimensional model. The case study successfully tests this approach. Conclusion The proposed solution guarantees data quality using structured documents already integrated in a large-scale infrastructure, with a timely updated information flow. It ensures data integrity and consistency and has the advantage to be based on a sample size that covers a broad target population. Moreover, the use of CDAs simplifies the definition of extract, transform, and load tools through the adoption of a conceptual framework that load the information stored in the CDA in the data warehouse.
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Shin, Bo-Moon, Eun-Joo Lee, Eun-Young Kuak, and Soo Jin Yoo. "Comparison of VIDAS CDAB and CDA immunoassay for the detection of Clostridium difficile in a tcdA− tcdB+ C. difficile prevalent area." Anaerobe 15, no. 6 (December 2009): 266–69. http://dx.doi.org/10.1016/j.anaerobe.2009.09.008.
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Parsons, SF, J. Jones, DJ Anstee, PA Judson, B. Gardner, E. Wiener, J. Poole, N. Illum, and SN Wickramasinghe. "A novel form of congenital dyserythropoietic anemia associated with deficiency of erythroid CD44 and a unique blood group phenotype [In(a-b- ), Co(a-b-)]." Blood 83, no. 3 (February 1, 1994): 860–68. http://dx.doi.org/10.1182/blood.v83.3.860.860.
Full textAbstract:
Abstract We have used a panel of well-characterized monoclonal antibodies (MoAbs) to examine the blood cells of a patient with a novel form of congenital dyserythropoietic anemia (CDA) characterized by intra- erythroblastic and intra-erythrocytic membranous inclusions. Twelve antibodies defining three nonoverlapping epitope groups on the extracellular domain of CD44 all failed to react with the red blood cells (RBCs) of the patient. A rabbit antibody to the cytoplasmic domain of CD44 from normal RBCs failed to react with the patient's RBC ghosts. In contrast, the patient's lymphocytes, granulocytes, and monocytes showed apparently normal CD44 expression. Bone marrow preparations stained with CD44 antibodies and visualized with 125I antimouse Ig (F(ab')2) followed by autoradiography showed positive staining of lymphocytes and myeloid cells but not of most orthotolidine- positive erythroblasts. The patient's RBCs also gave weaker than normal reactions with MoAbs of anti-LWab specificity while MoAbs to glycophorins A, B, and C, Rh polypeptides, CD47, CD55, CD58, CD59, acetylcholinesterase, and Lutheran and Kell glycoproteins all gave normal reactions. Agglutination tests with human blood grouping sera demonstrated that the RBCs of the patient have the unique phenotype In(a-b-), Co(a-b-) and that they also lack the high incidence RBC antigen AnWj. The phenotype In(a-b-) would be expected because these antigens are known to be expressed on CD44. There is also some evidence associating the AnWj antigen with CD44. However, the CO blood group locus is on chromosome 7p whereas that for CD44 is on chromosome 11p. Quantitative binding assays using 125I-labeled Fab fragments of CD44 antibodies did not show any evidence for reduced levels of CD44 on RBCs from the parents of the patient or from her unaffected sister. The parents and sister had the common Colton blood group phenotype [Co(a+b- )]. Neither deficiency of CD44 nor absence of Colton antigens are general features of CDA because erythrocytes from patients with CDA I, CDA II, CDA III, and two other unclassified CDAs had normal expression of CD44 and normal Colton blood group phenotypes. Further analysis of the defect(s) present in the patient's erythroid cells may provide useful information regarding membrane assembly and the regulation of differentiation in normal erythroid cells.
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Parsons, SF, J. Jones, DJ Anstee, PA Judson, B. Gardner, E. Wiener, J. Poole, N. Illum, and SN Wickramasinghe. "A novel form of congenital dyserythropoietic anemia associated with deficiency of erythroid CD44 and a unique blood group phenotype [In(a-b- ), Co(a-b-)]." Blood 83, no. 3 (February 1, 1994): 860–68. http://dx.doi.org/10.1182/blood.v83.3.860.bloodjournal833860.
Full textAbstract:
We have used a panel of well-characterized monoclonal antibodies (MoAbs) to examine the blood cells of a patient with a novel form of congenital dyserythropoietic anemia (CDA) characterized by intra- erythroblastic and intra-erythrocytic membranous inclusions. Twelve antibodies defining three nonoverlapping epitope groups on the extracellular domain of CD44 all failed to react with the red blood cells (RBCs) of the patient. A rabbit antibody to the cytoplasmic domain of CD44 from normal RBCs failed to react with the patient's RBC ghosts. In contrast, the patient's lymphocytes, granulocytes, and monocytes showed apparently normal CD44 expression. Bone marrow preparations stained with CD44 antibodies and visualized with 125I antimouse Ig (F(ab')2) followed by autoradiography showed positive staining of lymphocytes and myeloid cells but not of most orthotolidine- positive erythroblasts. The patient's RBCs also gave weaker than normal reactions with MoAbs of anti-LWab specificity while MoAbs to glycophorins A, B, and C, Rh polypeptides, CD47, CD55, CD58, CD59, acetylcholinesterase, and Lutheran and Kell glycoproteins all gave normal reactions. Agglutination tests with human blood grouping sera demonstrated that the RBCs of the patient have the unique phenotype In(a-b-), Co(a-b-) and that they also lack the high incidence RBC antigen AnWj. The phenotype In(a-b-) would be expected because these antigens are known to be expressed on CD44. There is also some evidence associating the AnWj antigen with CD44. However, the CO blood group locus is on chromosome 7p whereas that for CD44 is on chromosome 11p. Quantitative binding assays using 125I-labeled Fab fragments of CD44 antibodies did not show any evidence for reduced levels of CD44 on RBCs from the parents of the patient or from her unaffected sister. The parents and sister had the common Colton blood group phenotype [Co(a+b- )]. Neither deficiency of CD44 nor absence of Colton antigens are general features of CDA because erythrocytes from patients with CDA I, CDA II, CDA III, and two other unclassified CDAs had normal expression of CD44 and normal Colton blood group phenotypes. Further analysis of the defect(s) present in the patient's erythroid cells may provide useful information regarding membrane assembly and the regulation of differentiation in normal erythroid cells.