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1.
BMC Infect Dis ; 20(1): 487, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646433

RESUMO

BACKGROUND: Genetic diversity of ABO blood, glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemoglobin type and their ability to protect against malaria vary geographically, ethnically and racially. No study has been carried out in populations resident in malaria regions in western Kenya. METHOD: A total of 574 malaria cases (severe malaria anaemia, SMA = 137 and non-SMA = 437) seeking treatment at Vihiga County and Referral Hospital in western Kenya, were enrolled and screened for ABO blood group, G6PD deficiency and haemoglobin genotyped in a hospital-based cross-sectional study. RESULT: When compared to blood group O, blood groups A, AB and B were not associated with SMA (P = 0.380, P = 0.183 and P = 0.464, respectively). Further regression analysis revealed that the carriage of the intermediate status of G6PD was associated with risk to SMA (OR = 1.52, 95%CI = 1.029-2.266, P = 0.035). There was, however, no association between AS and SS with severe malaria anaemia. Co-occurrence of both haemoglobin type and G6PD i.e. the AA/intermediate was associated with risk to SMA (OR = 1.536, 95%CI = 1.007-2.343, P = 0.046) while the carriage of the AS/normal G6PD was associated with protection against SMA (OR = 0.337, 95%CI = 0.156-0.915, P = 0.031). CONCLUSION: Results demonstrate that blood group genotypes do not have influence on malaria disease outcome in this region. Children in Vihiga with blood group O have some protection against malaria. However, the intermediate status of G6PD is associated with risk of SMA. Further, co-inheritance of sickle cell and G6PD status are important predictors of malaria disease outcome. This implies combinatorial gene function in influencing disease outcome.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Genótipo , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/sangue , Hemoglobinas/genética , Malária Falciparum/sangue , Malária Falciparum/epidemiologia , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Quênia/epidemiologia , Malária Falciparum/parasitologia , Masculino , Fenótipo , Plasmodium falciparum/isolamento & purificação , Polimorfismo Genético , Risco , Traço Falciforme/genética
2.
PLoS One ; 15(6): e0234272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502196

RESUMO

Insects have long been thought to largely not require hemoglobins, with some notable exceptions like the red hemolymph of chironomid larvae. The tubular, branching network of tracheae in hexapods is traditionally considered sufficient for their respiration. Where hemoglobins do occur sporadically in plants and animals, they are believed to be either convergent, or because they are ancient in origin and their expression is lost in many clades. Our comprehensive analysis of 845 Hexapod transcriptomes, totaling over 38 Gbases, revealed the expression of hemoglobins in all 32 orders of hexapods, including the 29 recognized orders of insects. Discovery and identification of 1333 putative hemoglobins were achieved with target-gene BLAST searches of the NCBI TSA database, verifying functional residues, secondary- and tertiary-structure predictions, and localization predictions based on machine learning. While the majority of these hemoglobins are intracellular, extracellular ones were recovered in 38 species. Gene trees were constructed via multiple-sequence alignments and phylogenetic analyses. These indicate duplication events within insects and a monophyletic grouping of hemoglobins outside other globin clades, for which we propose the term insectahemoglobins. These hemoglobins are phylogenetically adjacent and appear structurally convergent with the clade of chordate myoglobins, cytoglobins, and hemoglobins. Their derivation and co-option from early neuroglobins may explain the widespread nature of hemoglobins in various kingdoms and phyla. These results will guide future work involving genome comparisons to transcriptome results, experimental investigations of gene expression, cell and tissue localization, and gas binding properties, all of which are needed to further illuminate the complex respiratory adaptations in insects.


Assuntos
Artrópodes/genética , Perfilação da Expressão Gênica , Hemoglobinas/genética , Sequência de Aminoácidos , Animais , Hemoglobinas/química , Homologia de Sequência do Ácido Nucleico
4.
PLoS Pathog ; 16(6): e1008485, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32589689

RESUMO

Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage ozonide-induced damage.


Assuntos
Adamantano/análogos & derivados , Antimaláricos/farmacologia , Eritrócitos , Hemoglobinas/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Peróxidos/farmacologia , Plasmodium falciparum/metabolismo , Compostos de Espiro/farmacologia , Adamantano/farmacologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Hemoglobinas/genética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Plasmodium falciparum/genética , Proteômica
5.
J Nutr ; 150(7): 1943-1950, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32433728

RESUMO

BACKGROUND: Riboflavin is required for erythropoiesis, which is increased in people with hemoglobinopathies due to increased hemolysis and erythrocyte turnover. Dietary intake and status of riboflavin is poor in Cambodia, where hemoglobinopathies are common. OBJECTIVE: We assessed the association between genetic hemoglobin disorders and riboflavin status in women of reproductive age in Cambodia. METHODS: Venous blood samples from 515 Cambodian women of reproductive age, 18-45 y, were analyzed for biomarker status of riboflavin [erythrocyte glutathione reductase activation coefficient (EGRac)], genetic hemoglobin (Hb) disorders, and hematological indices. Linear regression analysis was used to estimate the association between EGRac with Hb, ferritin, and Hb genotypes. EGRac was log transformed in the analyses, and the regression coefficients represent the geometric mean differences. RESULTS: Genetic Hb disorders were present in 57% of the population, with the homozygous hemoglobin E variant (Hb EE) occurring in ∼10% of women (n = 53). Deficient (EGRac ≥1.40) or marginal riboflavin status (EGRac ≥1.30 and <1.40) was observed in 92% (n = 475) of women. The variant Hb EE genotype was associated with 18% (95% CI: 9%, 28%) higher geometric mean EGRac values than the normal Hb AA genotype (P < 0.001). CONCLUSIONS: Although riboflavin biomarker deficiency or marginal status is widely prevalent in Cambodian women, lower riboflavin status was observed more frequently in women with the Hb EE genotype than in women with normal Hb AA. The relation between genetic Hb disorders and riboflavin warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01593423 and NCT02481375.


Assuntos
Variação Genética , Hemoglobinas/genética , Estado Nutricional , Riboflavina/sangue , Adulto , Camboja , Feminino , Predisposição Genética para Doença , Humanos , Deficiência de Riboflavina/epidemiologia , Deficiência de Riboflavina/genética , Adulto Jovem
6.
Sci Rep ; 10(1): 5630, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221409

RESUMO

RNA-Sequencing (RNA-Seq) of peripheral blood can be a valuable source of information for investigating the status and mechanism of diseases. However, blood contains 50-80% unwanted hemoglobin (Hb) transcripts. Lexogen's QuantSeq mRNA-Seq-Kit for Illumina RNA-Seq features a 'Globin Block' (GB) module that depletes Hb cDNAs during library preparation. Here, we aimed to assess GB's effectiveness and checked for technical biases attributable to GB. Using whole blood total RNA samples of 91 healthy individuals, we sequenced 91 pairs of GB and non-blocked samples (noGB) on Illumina HiSeq2500 and 8 pairs of GB/noGB technical replicates on HiSeq4000. GB reduced the fraction of Hb transcripts from 43% (s.d. 14%) to 8.0% (s.d. 4.3%). From GB samples we detected 1,397 more expressed genes at approximately 11 million reads per RNA-isolate. Enrichment and differential expression analyses did not reveal significant differences for GB and noGB samples with respect to molecular function. In contrast to results from studies that have examined the performance of GB during RNA isolation, we were able to assign GB to corresponding noGB samples (from multiple sequencing runs on HiSeq2500) with at least 89.8% accuracy from the complete correlation matrix of all GB/GB, noGB/noGB and GB/noGB pairs. However, the use of different sequencers (HiSeq2500 vs HiSeq4000) impaired assignment of technical replicates, whereas assignment of GB to corresponding noGB samples worked perfectly when sequencing on one lane on HiSeq4000. Lexogen's GB RNA-Seq module is a valuable addition during mRNA-Seq library preparation which works even with low amounts of input total RNA (50 ng per sample). GB facilitated the detection of low abundant transcripts and yielded more non-hemoglobin reads, while preserving biological information. We observed that differences in sequencing run and platform have a far greater effect on technical variation than the use of GB.


Assuntos
Hemoglobinas/genética , RNA Mensageiro/genética , Análise de Sequência de RNA/métodos , Benchmarking/métodos , Perfilação da Expressão Gênica/métodos , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
7.
Biochim Biophys Acta Proteins Proteom ; 1868(6): 140413, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32179182

RESUMO

Only recently it was discovered that haemoglobin (Hb) belongs to the standard gene repertoire of insects, although their tracheal system is used for respiration. A classical oxygen-carrying function of Hb is only obvious for hexapods living in hypoxic environments. In other insect species, including the common fruit fly Drosophila melanogaster, the physiological role of Hb is yet unclear. Here, we study recombinant haemoglobin from the European honeybee Apis mellifera (Ame) and the malaria mosquito Anopheles gambiae (Aga). Spectroscopic evidence shows that both proteins can be classified as hexacoordinate Hbs with a strong affinity for the distal histidine. AgaHb1 is proposed to play a role in oxygen transport or sensing based on its multimeric state, slow autoxidation, and small but significant amount of five-coordinated haem in the deoxy ferrous form. AmeHb appears to behave more like vertebrate neuroglobin with a complex function given its diversified distribution in the genome.


Assuntos
Anopheles/metabolismo , Abelhas/metabolismo , Hemoglobinas/análise , Sistema Respiratório/metabolismo , Análise Espectral/métodos , Animais , Anopheles/genética , Abelhas/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Evolução Molecular , Compostos Férricos/química , Compostos Ferrosos/química , Genoma , Heme/metabolismo , Hemoglobinas/genética , Insetos/genética , Insetos/metabolismo , Ligantes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Oxigênio
8.
Subcell Biochem ; 94: 345-382, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189307

RESUMO

This chapter reviews how allosteric (heterotrophic) effectors and natural mutations impact hemoglobin (Hb) primary physiological function of oxygen binding and transport. First, an introduction about the structure of Hb is provided, including the ensemble of tense and relaxed Hb states and the dynamic equilibrium of Hb multistate. This is followed by a brief review of Hb variants with altered Hb structure and oxygen binding properties. Finally, a review of different endogenous and exogenous allosteric effectors of Hb is presented with particular emphasis on the atomic interactions of synthetic ligands with altered allosteric function of Hb that could potentially be harnessed for the treatment of diseases.


Assuntos
Hemoglobinas/química , Hemoglobinas/metabolismo , Regulação Alostérica/efeitos dos fármacos , Doenças Hematológicas/sangue , Doenças Hematológicas/tratamento farmacológico , Doenças Hematológicas/metabolismo , Hemoglobinas/efeitos dos fármacos , Hemoglobinas/genética , Humanos , Ligantes , Oxigênio/metabolismo
9.
Subcell Biochem ; 94: 297-322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189305

RESUMO

Sickle cell hemoglobin (HbS) is an example of a genetic variant of human hemoglobin where a point mutation in the ß globin gene results in substitution of glutamic acid to valine at sixth position of the ß globin chain. Association between tetrameric hemoglobin molecules through noncovalent interactions between side chain residue of ßVal6 and hydrophobic grooves formed by ßAla70, ßPhe85 and ßLeu88 amino acid residues of another tetramer followed by the precipitation of the elongated polymer leads to the formation of sickle-shaped RBCs in the deoxygenated state of HbS. There are multiple non-covalent interactions between residues across intra- and inter-strands that stabilize the polymer. The clinical phenotype of sickling of RBCs manifests as sickle cell anemia, which was first documented in the year 1910 in an African patient. Although the molecular reason of the disease has been understood well over the decades of research and several treatment procedures have been explored to date, an effective therapeutic strategy for sickle cell anemia has not been discovered yet. Surprisingly, it has been observed that the oxy form of HbS and glutathionylated form of deoxy HbS inhibits polymerization. In addition to describe the residue level interactions in the HbS polymer that provides its stability, here we explain the mechanism of inhibition in the polymerization of HbS in its oxy state. Additionally, we reported the molecular insights of inhibition in the polymerization for glutathionyl HbS, a posttranslational modification of hemoglobin, even in its deoxy state. In this chapter we briefly consider the available treatment procedures of sickle cell anemia and propose that the elevation of glutathionylation of HbS within RBCs, without inducing oxidative stress, might be an effective therapeutic strategy for sickle cell anemia.


Assuntos
Anemia Falciforme/metabolismo , Hemoglobinas/química , Hemoglobinas/metabolismo , Anemia Falciforme/genética , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Eritrócitos/química , Eritrócitos/metabolismo , Eritrócitos/patologia , Hemoglobinas/genética , Humanos , Polimerização
10.
Subcell Biochem ; 94: 323-344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189306

RESUMO

The diversity of fish hemoglobins and the association with oxygen availability and physiological requirements during the life cycle has attracted scientists since the first report on multiple hemoglobin in fishes (Buhler and Shanks 1959). The functional heterogeneity of the fish hemoglobins enables many species to tolerate hypoxic conditions and exhausting swimming, but also to maintain the gas pressure in the swim bladder at large depths. The hemoglobin repertoire has further increased in various species displaying polymorphic hemoglobin variants differing in oxygen binding properties. The multiplicity of fish hemoglobins as particularly found in the tetraploid salmonids strongly contrasts with the complete loss of hemoglobins in Antarctic icefishes and illustrates the adaptive radiation in the oxygen transport of this successful vertebrate group.


Assuntos
Peixes/genética , Hemoglobinas/química , Hemoglobinas/genética , Polimorfismo Genético , Animais , Regiões Antárticas , Peixes/metabolismo , Hemoglobinas/metabolismo , Oxigênio/química , Oxigênio/metabolismo
11.
Arterioscler Thromb Vasc Biol ; 40(5): 1220-1230, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160775

RESUMO

OBJECTIVE: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antracenos/farmacologia , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Remodelação Vascular/efeitos dos fármacos , Anemia Falciforme/enzimologia , Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , Animais , Artérias Carótidas/enzimologia , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/fisiopatologia , Catepsina K/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Elastina/metabolismo , Hemoglobinas/genética , Homozigoto , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Transgênicos , Mutação , Proteólise , Transdução de Sinais , Fatores de Tempo
12.
Int J Mol Sci ; 21(4)2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32102473

RESUMO

Overexpression of phytoglobins (formerly plant hemoglobins) increases the survival rate of plant tissues under hypoxia stress by the following two known mechanisms: (1) scavenging of nitric oxide (NO) in the phytoglobin/NO cycle and (2) mimicking ethylene priming to hypoxia when NO scavenging activates transcription factors that are regulated by levels of NO and O2 in the N-end rule pathway. To map the cellular and metabolic effects of hypoxia in barley (Hordeum vulgare L., cv. Golden Promise), with or without priming to hypoxia, we studied the proteome and metabolome of wild type (WT) and hemoglobin overexpressing (HO) plants in normoxia and after 24 h hypoxia (WT24, HO24). The WT plants were more susceptible to hypoxia than HO plants. The chlorophyll a + b content was lowered by 50% and biomass by 30% in WT24 compared to WT, while HO plants were unaffected. We observed an increase in ROS production during hypoxia treatment in WT seedlings that was not observed in HO seedlings. We identified and quantified 9694 proteins out of which 1107 changed significantly in abundance. Many proteins, such as ion transporters, Ca2+-signal transduction, and proteins related to protein degradation were downregulated in HO plants during hypoxia, but not in WT plants. Changes in the levels of histones indicates that chromatin restructuring plays a role in the priming of hypoxia. We also identified and quantified 1470 metabolites, of which the abundance of >500 changed significantly. In summary the data confirm known mechanisms of hypoxia priming by ethylene priming and N-end rule activation; however, the data also indicate the existence of other mechanisms for hypoxia priming in plants.


Assuntos
Hemoglobinas/metabolismo , Hordeum/metabolismo , Metaboloma , Oxigênio/metabolismo , Proteínas de Plantas/metabolismo , Proteoma/metabolismo , Anaerobiose , Clorofila/metabolismo , Clorofila A/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Hemoglobinas/genética , Hordeum/genética , Metabolômica/métodos , Óxido Nítrico/metabolismo , Proteínas de Plantas/genética , Proteoma/genética , Proteômica/métodos , Espécies Reativas de Oxigênio/metabolismo , Plântula/genética , Plântula/metabolismo
13.
Nat Genet ; 52(2): 138-145, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959994

RESUMO

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ß-thalassemia1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.


Assuntos
Hemoglobinas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/genética , Adulto , Animais , Sítios de Ligação , Células Cultivadas , Células Eritroides/metabolismo , Eritropoese/genética , Regulação da Expressão Gênica , Hemoglobinas/genética , Humanos , Recém-Nascido , MicroRNAs/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , RNA Ribossômico 18S/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/metabolismo , Ribossomos/genética , Ribossomos/metabolismo
14.
BMC Med Genet ; 21(1): 6, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906886

RESUMO

BACKGROUND: Thalassemia is a group of inherited hemoglobic disorders resulting from defects in the synthesis of one or more of the hemoglobin chains, which is one of the most prevalent inherited disorders in southern China. Only few studies reported the molecular characterization of α- and ß-Thalassemia in Hubei Province in the central of China. METHODS: A total of 4889 clinically suspected cases of thalassemia were analyzed by Gap-PCR, PCR-based reverse dot blot (RDB). RESULTS: 1706 (33.8%) subjects harbored thalassemia mutations, including 539 (11.0%) subjects with α-thalassemia, 1140 (23.3%) subjects with ß-thalassemia mutations, and 25 (0.51%) subjects with both α- and ß-thalassemia mutations. Seven genotypes of α-thalassemia mutations and 29 genotypes of ß-thalassemia mutations were characterized. --SEA/αα (66.05%), -α3.7/αα (24.12%), and -α4.2/αα (3.71%) accounted for 93.88% of the α-thalassemia mutations. ßIVS-II-654/ßN, ßCD41-42/ßN, ßCD17/ßN, ßCD27-28/ßN, ßCD71-72/ßN, ß - 28/ßN, ß - 29/ßN, ßCD43/ßN, ßE/ßN, accounting for 96.40% of all ß-thalassemia genotypes. Furthermore, mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) were sensitive markers for both ß-thalassemia and α-thalassemia with --SEA/αα, but not -α3.7/αα and -α4.2/αα. CONCLUSIONS: Our data indicated great heterogeneity and extensive spectrum of thalassemias in Hubei province of China.


Assuntos
Genética Populacional , Hemoglobinas/genética , Talassemia alfa/genética , Talassemia beta/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China , Feminino , Heterogeneidade Genética , Genótipo , Hemoglobinas/biossíntese , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem , Talassemia alfa/epidemiologia , Talassemia beta/sangue , Talassemia beta/epidemiologia
15.
Mar Genomics ; 49: 100724, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31735579

RESUMO

The ancient origins and functional versatility of globins make them ideal subjects for studying physiological adaptation to environmental change. Our goals in this review are to describe the evolution of the vertebrate globin gene superfamily and to explore the structure/function relationships of hemoglobin, myoglobin, neuroglobin and cytoglobin in teleost fishes. We focus on the globins of Antarctic notothenioids, emphasizing their adaptive features as inferred from comparisons with human proteins. We dedicate this review to Guido di Prisco, our co-author, colleague, friend, and husband of C.V. Ever thoughtful, creative, and enthusiastic, Guido spearheaded study of the structure, function, and evolution of the hemoglobins of polar fishes - this review is testimony to his wide-ranging contributions. Throughout his career, Guido inspired younger scientists to embrace polar biological research, and he challenged researchers of all ages to explore evolutionary adaptation in the context of global climate change. Beyond his scientific contributions, we will miss his warmth, his culture, and his great intellect. Guido has left an outstanding legacy, one that will continue to inspire us and our research.


Assuntos
Adaptação Fisiológica , Evolução Molecular , Peixes/genética , Globinas/genética , Sequência de Aminoácidos , Animais , Regiões Antárticas , Citoglobina/genética , Hemoglobinas/genética , Família Multigênica , Mioglobina/genética , Neuroglobina/genética , Sintenia
16.
Acta méd. costarric ; 61(4): 160-165, oct.-dic. 2019. tab
Artigo em Espanhol | LILACS | ID: biblio-1054725

RESUMO

Resumen Justificación: La genética en las variantes de hemoglobina en Costa Rica es resultado del cruce de caracteres autóctonos indígenas con poblaciones inmigrantes de europeos, africanos y otros, desde el periodo de la Conquista, que contribuyeron a la mezcla genética presente en la población de Costa Rica. Las hemoglobinopatías mayormente distribuidas en la población humana son: hemoglobina S, C, D y E, siendo la hemoglobina S la más frecuente y la que presenta consecuencias más graves. Objetivo: Detectar variantes de hemoglobina en pacientes examinados por hemoglobina A1c, en la sección de Química Clínica del laboratorio de la Clínica de Filadelfia de la Caja Costarricense de Seguro Social, en el Cantón de Carrillo, Guanacaste, Costa Rica, durante el período de enero a octubre de 2018. Métodos: Se analizaron 2775 muestras sanguíneas de pacientes de los nueve equipos básicos de salud que conforman el Área de Salud de Carrillo, y que además requieren estudio por hemoglobina glicosilada en el período de enero a octubre de 2018. El análisis se realizó en el Laboratorio del Área de Salud de Carrillo. Las muestras fueron recolectadas en tubos vacutainer con EDTA y analizadas en el equipo automatizado TOSOH HLC-723GX, utilizando la metodología HPLC cromatografía de intercambio catiónico con la separación y cuantificación de las diferentes fracciones de hemoglobina. Los datos se analizaron en plantilla de Microsoft Excel. Resultados: En 2775 pacientes examinados por hemoglobina A1c, 167 (6,0 %) fueron portadores de variantes de hemoglobina, con una frecuencia de 1/17, en donde el 97 % correspondió a heterocigotos para hemoglobina un 3% a heterocigotos para hemoglobina C y ninguno para la variante D. La presencia de variantes se observó en los 9 equipos básicos de atención integral en salud del área. La distribución de portadores por equipo básico de atención en el Área de Salud de Carrillo varió de un 4,0 % a un 9,3 %. Conclusiones: Un 6 % de las muestras analizadas presentó variantes de hemoglobina, siendo la hemoglobina S la predominante. Esta característica presente en la población del cantón de Carrillo merece atención a nivel de salud pública; la metodología existente a nivel de área permite estudiar a un grupo de población (costo efectivo) en riesgo que precisa vigilancia y asesoramiento genético, con el fin de concienciar a la población respecto al problema, reducir la incidencia de la enfermedad y prolongar la supervivencia de los afectados.


Abstract Background: The genetics in hemoglobin variants in Costa Rica are a result of the crossing of autochthonous indigenous characters with European, African and other immigrant populations. All of these contributed to the genetic mixture that is currently present in Costa Rica's population. The most distributed hemoglobinopathies in the human population are: hemoglobin S, C, D, and E, with hemoglobin S being the most frequent and having the most serious consequences. Objective: Detection of hemoglobin variants in patients who were examined for hemoglobin A1c in the Clinical Chemistry section of the Filadelfia Clinic Laboratory, from January to October 2018. The clinic is in Canton of Carrillo, Guanacaste (Costa Rica), and it is part of the social security system. Methods: 2775 blood samples and their respective data were analyzed from patients of the nine basic health teams that make up the Carrillo Health Area and required a study for glycosylated hemoglobin from January to October 2018. The analysis was performed in the Carrillo Health Area Laboratory. The samples were collected in vacutainer tubes containing EDTA and analyzed in the TOSOH HLC-723GX automated equipment, using the HPLC cation exchange chromatography methodology with the separation and quantification of the different hemoglobin fractions. The data was then analyzed in a Microsoft Excel template. Results: In the 2775 patients examined for hemoglobin A1c, 167 (6.0%) were found to be carriers of hemoglobin variants, with a frequency of 1/17, where 97% corresponded to heterozygotes for hemoglobin S, 3% heterozygous for hemoglobin C, and none for variant D. The presence of variants was observed in the 9 basic teams of integral health care of the area, and the distribution varied from 4% to 9,3% between them. Conclusions: A total of 6% of the samples analyzed showed a hemoglobin variant, being hemoglobin S the most predominant. This characteristic present in the population of Canton of Carrillo deserves attention at the public health level. The existing methodology at the level area allows professionals to study a population group at risk that deserves surveillance and genetic counseling, in order to raise awareness about the problem, reduce the incidence of the disease, and prolong the survival of those affected by it.


Assuntos
Humanos , Hemoglobinas/genética , Costa Rica , Hemoglobinopatias , Anemia Falciforme
18.
Genome Biol Evol ; 11(11): 3291-3308, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31687752

RESUMO

The Gasterosteidae fish family hosts several species that are important models for eco-evolutionary, genetic, and genomic research. In particular, a wealth of genetic and genomic data has been generated for the three-spined stickleback (Gasterosteus aculeatus), the "ecology's supermodel," whereas the genomic resources for the nine-spined stickleback (Pungitius pungitius) have remained relatively scarce. Here, we report a high-quality chromosome-level genome assembly of P. pungitius consisting of 5,303 contigs (N50 = 1.2 Mbp) with a total size of 521 Mbp. These contigs were mapped to 21 linkage groups using a high-density linkage map, yielding a final assembly with 98.5% BUSCO completeness. A total of 25,062 protein-coding genes were annotated, and about 23% of the assembly was found to consist of repetitive elements. A comprehensive analysis of repetitive elements uncovered centromere-specific tandem repeats and provided insights into the evolution of retrotransposons. A multigene phylogenetic analysis inferred a divergence time of about 26 million years ago (Ma) between nine- and three-spined sticklebacks, which is far older than the commonly assumed estimate of 13 Ma. Compared with the three-spined stickleback, we identified an additional duplication of several genes in the hemoglobin cluster. Sequencing data from populations adapted to different environments indicated potential copy number variations in hemoglobin genes. Furthermore, genome-wide synteny comparisons between three- and nine-spined sticklebacks identified chromosomal rearrangements underlying the karyotypic differences between the two species. The high-quality chromosome-scale assembly of the nine-spined stickleback genome obtained with long-read sequencing technology provides a crucial resource for comparative and population genomic investigations of stickleback fishes and teleosts.


Assuntos
Genoma , Perciformes/genética , Animais , Elementos de DNA Transponíveis , Evolução Molecular , Feminino , Proteínas de Peixes/genética , Hemoglobinas/genética , Masculino , Repetições de Microssatélites , Anotação de Sequência Molecular , Perciformes/classificação , Filogenia , Recombinação Genética
19.
Proc Natl Acad Sci U S A ; 116(44): 22282-22287, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31619570

RESUMO

Sympathetic activation of ß-adrenoreceptors (ß-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p). H3S28p was increased by inhibition of the catecholamine-sensitive protein phosphatase 1 and decreased by ß-blocker pretreatment. By a series of in vitro and in vivo experiments, we show that the ß-AR downstream protein kinase CaM kinase II (CaMKII) directly binds and phosphorylates H3S28. Whereas, in CaMKII-deficient myocytes, acute catecholaminergic stimulation resulted in some degree of H3S28p, sustained catecholaminergic stimulation almost entirely failed to induce H3S28p. Genome-wide analysis of CaMKII-mediated H3S28p in response to chronic ß-AR stress by chromatin immunoprecipitation followed by massive genomic sequencing led to the identification of CaMKII-dependent H3S28p target genes. Forty percent of differentially H3S28p-enriched genomic regions were associated with differential, mostly increased expression of the nearest genes, pointing to CaMKII-dependent H3S28p as an activating histone mark. Remarkably, the adult hemoglobin genes showed an H3S28p enrichment close to their transcriptional start or end sites, which was associated with increased messenger RNA and protein expression. In summary, we demonstrate that chronic ß-AR activation leads to CaMKII-mediated H3S28p in cardiomyocytes. Thus, H3S28p-dependent changes may play an unexpected role for cardiac hemoglobin regulation in the context of sympathetic activation. These data also imply that CaMKII may be a yet unrecognized stress-responsive regulator of hematopoesis.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/metabolismo , Hemoglobinas/genética , Código das Histonas , Histonas/metabolismo , Miocárdio/metabolismo , Sistema Nervoso Simpático/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Animais , Catecolaminas/farmacologia , Células Cultivadas , Feminino , Insuficiência Cardíaca/genética , Hemoglobinas/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos
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