Top PDF Defect in messenger RNA for human hemoglobin synthesis in beta thalassemia

Defect in messenger RNA for human hemoglobin synthesis in beta thalassemia

Defect in messenger RNA for human hemoglobin synthesis in beta thalassemia

reticulocyte lysates of patients with homozygous beta thalassemia and sickle cell anemia. The messenger RNA stimulated the synthesis of human globin chains by a cell-free system derived from Krebs mouse ascites cells. In the presence of beta thalassemia messenger RNA, the system synthesized much less beta chain than alpha chain whereas in the presence of sickle cell anemia messenger RNA, nearly equal amounts of alpha and beta chains were synthesized. The beta/alpha synthetic ratios obtained in the cell-free system were similar to those obtained by incubating intact beta thalassemia and sickle cell anemia reticulocytes in the presence of radioactive leucine. The experiments provide direct
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Posttranscriptional defects in beta globin messenger RNA metabolism in beta thalassemia: abnormal accumulation of beta messenger RNA precursor sequences

Posttranscriptional defects in beta globin messenger RNA metabolism in beta thalassemia: abnormal accumulation of beta messenger RNA precursor sequences

sequences hybridizing to a pure DNA probe containing only the large intervening sequence (intron) of the beta-mRNA precursor. Four of the patients exhibited abnormal accumulation of 3H-beta-intron sequences (2-10 times normal), indicating abnormal posttranscriptional processing. In the remaining two patients, one of whom is known to carry a mutation in the small intron of the beta-globin gene, accumulation of large 3H beta-intron RNA and beta- globin [3H]mRNA was normal in nuclei, but the ratio of beta/alpha [3H]mRNA in cytoplasm was reduced, suggesting a different posttranscriptional defect in beta-mRNA processing. These findings imply the existence of heterogeneous posttranscriptional abnormalities in beta-globin mRNA metabolism in different patients with beta-thalassemia. The initial rates of gamma- and delta-mRNA synthesis were low in all patients, suggesting that the low level of expression of these genes in adults is mediated […]
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Hemoglobin Messenger RNA from Human Bone Marrow ISOLATION AND TRANSLATION IN HOMOZYGOUS AND HETEROZYGOUS β THALASSEMIA

Hemoglobin Messenger RNA from Human Bone Marrow ISOLATION AND TRANSLATION IN HOMOZYGOUS AND HETEROZYGOUS β THALASSEMIA

chromatography. The relative synthesis of alpha to beta chains in response to normal hemoglobin mRNA was found to be a function of the amount of mRNA added to the assay system: increasing the amount of mRNA led to a decrease in the alpha-to-beta-chain synthetic ratio. Therefore, assays were carried out at limiting concentrations of mRNA. The molecular defect in homozygous beta thalassemia was shown to be carried in the mRNA of bone marrow cells as well as in the mRNA from peripheral reticulocytes, because much less beta than alpha globin was produced in the cell-free system in response to mRNA from either type of cell. In patients doubly heterozygous for […]
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α Thalassemia in the American Negro

α Thalassemia in the American Negro

In Italian and Chinese patients with the a-thalassemia syndromes the production of a-chain of normal hemoglobin is decreased relative to that of b-chain in reticulocytes. In this study the relative rates of a- and b-chain synthesis were determined in members of three Negro families with a-thalassemia. Two of the families had members with hemoglobin H disease and a-thalassemia trait, while the mother of several children with a-thalassemia trait in the third family was doubly heterozygous for a-thalassemia and an a-chain mutant. The a/b ratios of globin synthesis in the patients with hemoglobin H disease and a-thalassemia trait indicated less severe biochemical defects in the peripheral blood than those previously determined in Italian and Chinese patients. In the third family, there was a heterogeneity of expression of the gene for a-thalassemia, including patients with normal red cell indices and synthesis ratios. These findings differ from those previously described in patients with a-thalassemia from other racial groups. Hydrops fetalis due to homozygous a-thalassemia may not occur in the Negro because of the relatively mild thalassemic defect.
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Beta-thalassemia

Beta-thalassemia

Treatment of individuals with thalassemia intermedia is symptomatic [4,85]. As hypersplenism may cause wors- ening anemia, retarded growth and mechanical distur- bance from the large spleen, splenectomy is a relevant aspect of the management of thalassemia intermedia. Risks associated with splenectomy include an increased susceptibility to infections mainly from encapsulated bac- teria (Streptococcus Pneumoniae, Haemophilus Influen- zae and Neisseria Meningitidis) and an increase in thromboembolic events. Prevention of post-splenectomy sepsis includes immunization against the above men- tioned bacteria and antibiotic prophylaxis as well as early antibiotic treatment for fever and malaise. Because of the elevated prevalence of cholelithiasis and the risks of cholecystitis in splenectomised patients, the gallbladder should be inspected during splenectomy and removed in case with or to prevent gallstones. Treatment of extramedullary erythropoietic masses, detected by mag- netic resonance imaging, is based on radiotherapy, trans- fusions, or hydroxycarbamide. Once leg ulcer has developed, it is very difficult to manage. Regular blood transfusions, zinc supplementation and pentoxifylline, and the use of an oxygen chamber have been proposed for ulcer treatment. Hydroxycarbamide also has some benefit, either alone or with erythropoietin. Recently promising results have been obtained with platelet derived growth factor. Since patients with thalassemia intermedia have a high risk of thrombosis, exacerbated by splenectomy, it is important to be aware of thrombotic complications. Recommended treatment options include proper anticoagulation prior to surgical or other high- risk procedures, platelet anti-aggregating agents in case of thrombocytosis (platelet count higher than 700,000/ mm 3 ) and low molecular weight heparin in patients with
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Benefits of chronic blood transfusion in hemoglobin E/β thalassemia with pulmonary arterial hypertension

Benefits of chronic blood transfusion in hemoglobin E/β thalassemia with pulmonary arterial hypertension

After the physician advised patients that they may gain some benefit from chronic blood transfusions; patients were classified into one of two groups according to their preference. Group 1 patients were those with a preference for chronic blood transfusions. Patients in this group would receive one to two units of leukocyte-poor packed red cells every 2–4 weeks to maintain the pre-transfusion hemoglobin level of 7.0 g/dL over 1 year. Group 2 patients, compris- ing those patients who indicated a preference for occasional blood transfusions, would receive occasional transfusions not more often than every 4 weeks. All patients were treated with medications following standard guidelines, including intensive chelation therapy when their serum ferritin level was above 1,000 µ g/dL.
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Inhibition of endoplasmic reticulum-to-Golgi traffic by poliovirus protein 3A: genetic and ultrastructural analysis.

Inhibition of endoplasmic reticulum-to-Golgi traffic by poliovirus protein 3A: genetic and ultrastructural analysis.

inhibitor of glycoprotein synthesis, suggested a possible re- quirement for glycosylation of 3A-containing proteins in po- liovirus genome replication (18). Such a glycosylation event would argue that these sequences of 3A (Fig. 1) reside, at least transiently, within the lumen of one or more organelles of the secretory pathway. These authors (18) also suggested that the inhibition of poliovirus by brefeldin A (BFA), an inhibitor of transport through the secretory pathway, might stem from the resulting inhibition of Golgi-specific oligosaccharide modifica- tions in BFA-treated cells. Two pieces of data argued against this hypothesis: glycosylated forms of 3A and 3AB were not detected in extracts of poliovirus-infected cells (18), and tuni- camycin had been reported to have no effect on poliovirus infection, although little documentation of these experiments was actually published (17, 27). Due to the fragmentary nature of the previous tunicamycin experiments, and the possible sig- nificance of the in vitro glycosylation of poliovirus proteins, we tested the effect of tunicamycin on poliovirus growth under conditions in which tunicamycin was shown to be active.
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Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia

Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia

Thalassemic red cells show irregular morphology and maldistribution of glycoproteins and sialic acids. These changes are compatible with damage to the red cell membrane skeleton. To test this possibility, we systematically studied the interconnections of skeletal proteins in patients with a form of alpha thalassemia (HbH disease), in patients with beta thalassemia intermedia, and in normal individuals. Alpha- and beta-thalassemic spectrin functions normally in spectrin self-association, binding to normal inside-out vesicles (IOVs), and binding to actin in the presence and absence of normal protein 4.1. Binding of normal spectrin to beta: thalassemic IOVs is normal but alpha-thalassemic IOVs are defective and bind only half the normal amount of spectrin (66 +/- 5 vs. 120 +/- 16 micrograms spectrin dimer/mg IOV protein, respectively). A different defect is detected in beta thalassemia, in which protein 4.1 shows markedly reduced ability (48 +/- 7% of normal) to enhance the binding of normal spectrin to actin and a decreased ability to bind normal spectrin in a binary interaction, compared with normal protein 4.1 (24 +/- 1 and 43 +/- 1 micrograms protein 4.1/mg spectrin, respectively). As no quantitative deficiency of beta-thalassemic protein 4.1 is detected, we assume an acquired lesion is present, which affects about half of the protein 4.1 molecules. These findings indicate that specific, localized, yet different defects exist in the skeletal […]
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Globin synthesis in fractionated Normoblasts of beta thalassemia heterozygotes

Globin synthesis in fractionated Normoblasts of beta thalassemia heterozygotes

experiments. However, the alpha/beta ratio of the hemoglobin fraction obtained by gel filtration remained constant throughout maturation at an average of 0.65. This latter finding is incompatible with balanced synthesis at any stage of red cell development and excludes the possibility that total beta chain production is higher in the early cells than in the later cells or that alpha chain production in the early cells is reduced to the level of beta chain synthesis. Furthermore, in a Hb S/beta-thalassemia marrow examined, the beta A/beta S ratio remained constant throughout maturation while the alpha/non-alpha ratio showed an increase like that observed in the simple beta-thalassemia heterozygotes. This argues strongly against increased synthesis from […]
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An insight to HTLV 1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high throughput data integration and meta analysis

An insight to HTLV 1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high throughput data integration and meta analysis

A significant increase was observed in the expression of PSMB8 in patients with HAM/TSP in comparison to those who carry the virus and normal subjects. PSMB8 is one of the 17 subunits essential for the synthesis of the 20S proteasome unit [46]. The targeting of proteasome in the HAM/TSP disease is a known mechanism which affects the pathogenicity of HTLV-1 by increasing the activity of genes such as IKBKG [2]. PSMB8 can influence the immune responses due to involvement in the process of apoptosis [47], so its increase in patients with HAM/ TSP may be because of this function. Although previous studies reported the role of apoptosis in the HAM/TSP pathogenesis [2], there is no comprehensive information regarding the role of PSMB8.
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Killing The Messenger: Exploring Novel Triggers For Messenger Rna Decay In Eukaryotes

Killing The Messenger: Exploring Novel Triggers For Messenger Rna Decay In Eukaryotes

The lifecycle of messenger RNAs is regulated by multiple layers beyond their primary sequence. In addition to carrying the information for protein synthesis, mRNAs are decorated with RNA binding proteins, marked with covalent chemical modifications, and fold into intricate secondary structures. However, the full set of information encoded by these “epitranscriptomic” layers is only partially understood, and is often only characterized for select transcripts. Thus, it is crucial to develop and apply transcriptome-wide analytical tools to probe the location and functional relevance of epitranscriptome features. In this dissertation, I focus on applying such methods toward better understanding determinants of mRNA stability, through using 1) High Throughput Annotation of Modified Nucleotides, 2) nuclease-mediated probing of RNA secondary structure, and 3) detection of partial mRNA degradation from RNA sequencing. I observe that chemical modifications tend to mark uncapped and small RNA fragments derived from mRNAs in plants and humans, suggesting a link between modifications and mRNA stability. I then show this link is direct through showing differential stability at Arabidopsis transcripts that change modification status during long-term salt stress. By probing secondary structure, I show a link between structure, smRNA production, and co-translational RNA decay. Finally, I develop a new in silico method to detect partial RNA degradation in mouse oocytes, and identify sequence elements that appear to block complete exonucleolytic transcript cleavage during meiosis. I then identify putative RNA binding proteins that might mediate this partial decay. In summary, I apply
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Control of protein synthesis in Semliki forest virus-infected cells.

Control of protein synthesis in Semliki forest virus-infected cells.

The viral structural proteins were detectable with certainty at 3.5 h postinfection, and their rate of synthesis increased linearly parallel to the amount of their messenger, the 26S RNA[r]

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Up-regulation of circ_LARP4 suppresses cell proliferation and migration in ovarian cancer by regulating miR-513b-5p/LARP4 axis

Up-regulation of circ_LARP4 suppresses cell proliferation and migration in ovarian cancer by regulating miR-513b-5p/LARP4 axis

LARP4 gene existed in some protists and all animals tested, while not in plants and yeasts [18]. LARP4 of mammal, which was also called LARP4A, had close inter- action with poly (A) RNA. It indicated that LARP4 could bind to poly (A) tail. As a matter of fact, overexpressing LARP4 induces the increase of mRNA stability, whereas cutting down LARP4 leads to translation declined by 15 percent to 20 percent. It presented the promotion of LARP4 on mRNA stability [19]. Therefore, LARP4 could regulate cellular morphology through the bind with mRNA and translation. Besides, under the condi- tion, LARP4 may specially correlated to the interaction of RACK1, because there has reporter said that RACK1 exerted important effect on cell adhesion and migration [20]. In this research, LARP4 worked as the host gene of
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Genotype–phenotype correlation among beta-thalassemia and beta-thalassemia/HbE disease in Thai children: predictable clinical spectrum using genotypic analysis

Genotype–phenotype correlation among beta-thalassemia and beta-thalassemia/HbE disease in Thai children: predictable clinical spectrum using genotypic analysis

The present study revealed the distribution of the HBB gene mutations causing beta-thalassemia along with a geno- type–phenotype correlation in a Thai pediatrics population. Beta-thalassemia/HbE is the major thalassemia problem in Thailand and can be associated with various clinical pheno- types ranging from thalassemia intermedia to thalassemia major. In our study, the numbers of beta-thalassemia/HbE patients (90%) are higher than the number of homozygous/ compound heterozygous beta-thalassemia patients (10%). Knowledge of the molecular basis of the HBB gene muta- tions elucidates the diversity of clinical manifestations. Beta (zero)-thalassemia apparently has a more severe clinical presentation, causing thalassemia major in homozygous and compound heterozygous states, whereas beta( + )-thalassemia are observed as milder cases of thalassemia intermedia. 11
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Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy  Interaction between hemodynamic and thyroid hormone induced signals

Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy Interaction between hemodynamic and thyroid hormone induced signals

response to aortic coarctation, there was a rapid induction of the beta-MHC mRNA followed by the appearance of comparable levels of the beta-MHC protein in parallel to an increase in the left ventricular weight. Administration of thyroxine to coarctated animals caused a rapid deinduction of beta-MHC and induction of alpha-MHC, both at the mRNA and protein levels, despite progression of left ventricular hypertrophy. These results suggest that the MHC isozyme transition during hemodynamic overload is mainly regulated by

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A RETROSPECTIVE STUDY ON THALASSEMIA IN SOUTH INDIAN TERTIARY CARE TEACHING HOSPITALJ.Lavanya*, S. Arshiya Banu, A.Lokesh, S. Asadulla2, M. Venkata SubbaiahDOWNLOAD/VIEW

A RETROSPECTIVE STUDY ON THALASSEMIA IN SOUTH INDIAN TERTIARY CARE TEACHING HOSPITALJ.Lavanya*, S. Arshiya Banu, A.Lokesh, S. Asadulla2, M. Venkata SubbaiahDOWNLOAD/VIEW

Thalassemia is the genetic disorder occur primarily due to defective formation of globin chain of the hemoglobin moiety of the RBC. It is a specific type of blood disease which results in consequences of excessive destruction of red blood cells which in turn leads to anemia. In this, RBC breakdown occur at an early stage due to abnormal globin chain unable to protect RBC in oxidative stress. Ultimately, resulting in destruction of RBC. In thalassemia the rate of destruction of RBC is so rapid that it exceeds the liver capacity to metabolize the excess billirubin. Thalassemia is a major health problem, and approximately 1 in 14 of the population is carriers for one of the sub types.
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Sex steroid hormone regulation of follicle stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat

Sex steroid hormone regulation of follicle stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat

Follicle-stimulating hormone (FSH) beta, luteinizing hormone (LH) beta, and alpha subunit messenger RNA (mRNA) levels were examined in rats after castration and sex-steroid replacement. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta complementary DNA (cDNA). Rat FSH beta mRNA is 1.7 kilobase in size. After ovariectomy, female FSH beta mRNA levels increased fourfold, whereas those of LH beta and alpha increased twenty- and eightfold, respectively. With estradiol, all subunits returned toward normal levels. Male LH beta and alpha mRNA levels rose eight- and fourfold, respectively, 40 d postcastration, but FSH beta mRNA levels increased minimally. After 7 d of testosterone propionate, LH beta and alpha mRNAs
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EFFICACY OF HEMOGLOBIN LEVEL IN DIAGNOSING OF BETA THALASSEMIA

EFFICACY OF HEMOGLOBIN LEVEL IN DIAGNOSING OF BETA THALASSEMIA

A study done among Sicily population which is an endemic area for thalassemia involving 23,485 samples from year of 2000 to 2006 found that 16.75% of the samples showed borderline HbA2 level, defined between 3.1- 3.9 by HPLC. Out of that, 410 samples were proceed with molecular test which showed that 22.9% were positive for molecular defect in β, α (or) δ-globin genes. [11]

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In Patients with Minor Beta-Thalassemia, Cognitive Performance Is Related to Length of Education, But not to Minor Beta-Thalassemia or Hemoglobin Levels

In Patients with Minor Beta-Thalassemia, Cognitive Performance Is Related to Length of Education, But not to Minor Beta-Thalassemia or Hemoglobin Levels

Individuals with known minor beta-thalassemia undergoing risk-analysis for marriage were asked to participate in the study. A total of 41 people was approached and 25 (61%) agreed to participate. Inclusion criteria were as follow: (a) age 18-40 years; (b) willing and able to follow the study protocol; (c) written informed consent; (d) known and medically confirmed minor beta-thalassemia. Exclusion criteria were as follow: (a) known and confirmed mental impairments, such as psychiatric disorders (eg, major depressive disorders, bipolar disorders, substance use disorders, neurodegenerative disorders, autism spectrum disorders, schizophrenia), or mental retardation; (b) acute suicidality; (c). Illiteracy.
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Instability of beta E messenger RNA during erythroid cell maturation in hemoglobin E homozygotes

Instability of beta E messenger RNA during erythroid cell maturation in hemoglobin E homozygotes

Hemoglobin E interacts with beta-thalassemia to produce a disorder of variable severity that is the most common form of symptomatic thalassemia in Southeast Asia. The beta E-globin gene acts as a mild thalassemia gene; there are low levels of beta E-messenger RNA (mRNA) in reticulocytes, and preliminary evidence had suggested that this might be due to instability of the beta E-mRNA. Analysis of beta E-mRNA levels in the nuclei and cytoplasm of bone marrow erythroblasts compared with reticulocytes has shown higher levels of beta E-mRNA in the former, providing direct evidence that this is the case.
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