scholarly journals Defects in the synthesis of human haemoglobin

1978 ◽  
Author(s):  
Ρεγγίνα Σταθοπούλου
Keyword(s):  
Structural Changes ◽  
Molecular Mechanisms ◽  
Bone Marrow Cells ◽  
Red Cells ◽  
Synthesis Rate ◽  
Structural Studies ◽  
Human Haemoglobin ◽  
Abnormal Haemoglobin ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

The work described is concerned with the biosynthesis of haemoglobin in human reticulicytes and bone marrow cells with particular reference to abnormal haemoglobins. The work in abnormal haemoglobins was supported by structural studies and involved a - and ß - chain variants, some of the latter being unstable. In some of the individuals with α or ß - chain variants, as well as in a number of subjects with β- thalassaemia, the estimation of the free α - chian pool was carried out. Using the same methodology, an attempt was made to detect chain fragments in the latter group of subjects. In the α - chian variants, attention was paid to the different proportions of the same α - chian abnormal haemoglobin in different individuals. Notably so in the case of haemoglobin G Philadelphia. The results supported the interpretation that here are four α - chian genes and that the α - G Philadelphia gene may occur together with threee, two or one normal α - chian genes respectively, the number of normal α - chian genes being potentially decreased by α - thalassaemia. With ß - chain variants a number of low proportion abnormal haemoglobins in the blood was studied. The globin chain synthesis pattern in the reticulocytes was compared with the haemoglobin composition in the mature red cells and the clinical condition of the subjects. Structural changes in haemoglobin were related to the rate of its synthesis. In some instances, both the synthesised amount of the variant was low as well as its proportion in the mature red cells. In others, notably haemoglobin E and Haemoglobin newcastle, the synthesis rate of the variant was normal but its proportion in the circulating red cells was low. Possible molecular mechanisms are either instability of the variant ß - chain of defective association into functioning polymer.

scholarly journals Molecular mechanisms of substrate-controlled ring dynamics and sub-stepping in a nucleic-acid dependent hexameric motor

2016 ◽  
Author(s):  
Nathan D. Thomsen ◽  
Michael R. Lawson ◽  
Lea B. Witkowsky ◽  
Song Qu ◽  
James M. Berger
Keyword(s):  
Nucleic Acid ◽  
Conformational Changes ◽  
Molecular Motors ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Ring Closure ◽  
Structural Studies ◽  
Saxs Data ◽  
Structural Methods

ABSTRACTRing-shaped hexameric helicases and translocases support essential DNA, RNA, and protein-dependent transactions in all cells and many viruses. How such systems coordinate ATPase activity between multiple subunits to power conformational changes that drive the engagement and movement of client substrates is a fundamental question. Using the E. coli Rho transcription termination factor as a model system, we have employed solution and crystallographic structural methods to delineate the range of conformational changes that accompany distinct substrate and nucleotide cofactor binding events. SAXS data show that Rho preferentially adopts an open-ring state in solution, and that RNA and ATP are both required to cooperatively promote ring closure. Multiple closed-ring structures with different RNA substrates and nucleotide occupancies capture distinct catalytic intermediates accessed during translocation. Our data reveal how RNA-induced ring closure templates a sequential ATP-hydrolysis mechanism, provide a molecular rationale for how the Rho ATPase domains distinguishes between distinct RNA sequences, and establish the first structural snapshots of substepping events in a hexameric helicase/translocase.SIGNIFICANCEHexameric, ring-shaped translocases are molecular motors that convert the chemical energy of ATP hydrolysis into the physical movement of protein and nucleic acid substrates. Structural studies of several distinct hexameric translocases have provided insights into how substrates are loaded and translocated; however, the range of structural changes required for coupling ATP turnover to a full cycle of substrate loading and translocation has not been visualized for any one system. Here, we combine low-and high-resolution structural studies of the Rho helicase, defining for the first time the ensemble of conformational transitions required both for substrate loading in solution and for substrate movement by a processive hexameric translocase.

scholarly journals Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta- thalassemia

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 928-933 ◽  
Author(s):  
JL Villeval ◽  
P Rouyer-Fessard ◽  
N Blumenfeld ◽  
A Henri ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Bone Marrow Cells ◽  
Elevated Serum ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Alpha Globin ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta- thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta- thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.

scholarly journals Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta- thalassemia

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 928-933 ◽  
Author(s):  
JL Villeval ◽  
P Rouyer-Fessard ◽  
N Blumenfeld ◽  
A Henri ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Bone Marrow Cells ◽  
Elevated Serum ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Alpha Globin ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta- thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta- thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.

scholarly journals Changes in Globin Synthesis With Erythroid Cell Maturation in Sickle Thalassemia

Blood ◽  
1973 ◽  
Vol 41 (3) ◽  
pp. 353-357 ◽  
Author(s):  
A. Bank ◽  
L. W. Dow ◽  
M. G. Farace ◽  
J. V. ÓDonnell ◽  
S. Ford ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Cell Maturation ◽  
Erythroid Cell ◽  
Clinical Symptomatology ◽  
Mild Anemia ◽  
Black Patients ◽  
Biochemical Studies ◽  
Globin Synthesis ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract Biochemical studies of different groups of patients with sickle β-thalassemia (S-thal) are described. In a group of relatively asymptomatic black patients with sickle thalassemia, there is mild anemia and no clinical symptomatology. α and β-type (βA,βS, and γ) globin chain synthesis in these patients is balanced in bone marrow cells, although there is an excess of α-over β-type chain synthesis in peripheral blood. These mildly affected patients are in contrast to two other groups of S-thal patients of both Mediterranean and black extraction who have anemia and clinical symptomatology and in whom there is absent or more decreased βA-chain production.

scholarly journals Hemoglobin Koln occurring in association with a beta zero thalassemia: hematologic and functional consequences

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 496-500
Author(s):  
F Galacteros ◽  
D Loukopoulos ◽  
P Fessas ◽  
J Kister ◽  
N Arous ◽  
...  
Keyword(s):  
Oxygen Affinity ◽  
Red Cells ◽  
Beta Thalassemia ◽  
Oxygen Binding ◽  
Morphological Alterations ◽  
Functional Consequences ◽  
High Oxygen Affinity ◽  
Alkaline Bohr Effect ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Hemoglobin (Hb) Koln-beta zero thalassemia compound heterozygosity was discovered in a young Greek patient. This gave us the unique opportunity for studying the functional properties of this unstable high-oxygen affinity hemoglobin variant in red cells containing almost pure Hb Koln. The red cells of the proposita exhibit morphological alterations and hematologic indices corresponding to the presence of an unstable Hb and beta thalassemia. Globin chain synthesis confirmed the association with a beta zero thalassemia gene. Oxygen-binding curves for these cells were biphasic, indicating the presence of both heme- saturated and of approximately 20% of non-cooperative Hb Koln. The major component exhibits an increased oxygen affinity, reduced cooperativeness, and normal alkaline Bohr effect. The 35-year-old proposita is active, has not been splenectomized, and has not been transfused in several years.

scholarly journals Hemoglobin Koln occurring in association with a beta zero thalassemia: hematologic and functional consequences

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 496-500 ◽  
Author(s):  
F Galacteros ◽  
D Loukopoulos ◽  
P Fessas ◽  
J Kister ◽  
N Arous ◽  
...  
Keyword(s):  
Oxygen Affinity ◽  
Red Cells ◽  
Beta Thalassemia ◽  
Oxygen Binding ◽  
Morphological Alterations ◽  
Functional Consequences ◽  
High Oxygen Affinity ◽  
Alkaline Bohr Effect ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract Hemoglobin (Hb) Koln-beta zero thalassemia compound heterozygosity was discovered in a young Greek patient. This gave us the unique opportunity for studying the functional properties of this unstable high-oxygen affinity hemoglobin variant in red cells containing almost pure Hb Koln. The red cells of the proposita exhibit morphological alterations and hematologic indices corresponding to the presence of an unstable Hb and beta thalassemia. Globin chain synthesis confirmed the association with a beta zero thalassemia gene. Oxygen-binding curves for these cells were biphasic, indicating the presence of both heme- saturated and of approximately 20% of non-cooperative Hb Koln. The major component exhibits an increased oxygen affinity, reduced cooperativeness, and normal alkaline Bohr effect. The 35-year-old proposita is active, has not been splenectomized, and has not been transfused in several years.

Structural Studies of Fibrinolysis by Electron and Light Microscopy

1999 ◽  
Vol 82 (08) ◽  
pp. 277-282 ◽  
Author(s):  
Yuri Veklich ◽  
Jean-Philippe Collet ◽  
Charles Francis ◽  
John W. Weisel
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Plasminogen Activator ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Degradation Products ◽  
Molecular Model ◽  
Three Dimensional ◽  
Tissue Type ◽  
Type Plasminogen Activator

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6 Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15 To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.

scholarly journals Comparative Study of Structural Changes of Polylactide and Poly(ethylene terephthalate) in the Presence of Trichoderma viride

2021 ◽  
Vol 22 (7) ◽  
pp. 3491
Author(s):  
Grażyna B. Dąbrowska ◽  
Zuzanna Garstecka ◽  
Ewa Olewnik-Kruszkowska ◽  
Grażyna Szczepańska ◽  
Maciej Ostrowski ◽  
...  
Keyword(s):  
Structural Changes ◽  
Ethylene Terephthalate ◽  
Molecular Mechanisms ◽  
Blot Hybridization ◽  
Trichoderma Viride ◽  
Cost Effective ◽  
Plastic Pollution ◽  
Scanning Calorimetry ◽  
Poly Ethylene Terephthalate ◽  
Poly Ethylene

Plastic pollution is one of the crucial global challenges nowadays, and biodegradation is a promising approach to manage plastic waste in an environment-friendly and cost-effective way. In this study we identified the strain of fungus Trichoderma viride GZ1, which was characterized by particularly high pectinolytic activity. Using differential scanning calorimetry, Fourier-transform infrared spectroscopy techniques, and viscosity measurements we showed that three-month incubation of polylactide and polyethylene terephthalate in the presence of the fungus lead to significant changes of the surface of polylactide. Further, to gain insight into molecular mechanisms underneath the biodegradation process, western blot hybridization was used to show that in the presence of poly(ethylene terephthalate) (PET) in laboratory conditions the fungus produced hydrophobin proteins. The mycelium adhered to the plastic surface, which was confirmed by scanning electron microscopy, possibly due to the presence of hydrophobins. Further, using atomic force microscopy we demonstrated for the first time the formation of hydrophobin film on the surface of aliphatic polylactide (PLA) and PET by T. viride GZ1. This is the first stage of research that will be continued under environmental conditions, potentially leading to a practical application.

Globin Chain Synthesis in Haemoglobin New York (β 113 Valine→Glutamic acid

1980 ◽  
Vol 46 (4) ◽  
pp. 557-564 ◽  
Author(s):  
D. Todd ◽  
Vivian Chan ◽  
Rose G. Schneider ◽  
Andree M. Dozy ◽  
Y. W. Kan ◽  
...  
Keyword(s):  
New York ◽  
Glutamic Acid ◽  
Globin Chain ◽  
Chain Synthesis ◽  
Globin Chain Synthesis
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