Factors regulating Hb F synthesis in thalassemic diseases

BACKGROUND: The thalassemic syndromes originate from mutations of the globin genes that cause, besides the characteristic clinical picture, also an increased Hb F amount. It is not yet clear if there are more factors, besides the beta globin genotype, determining the Hb F production. We have tried to find out if there are relations between total Hb and Hb F, between erythropoietin (Epo) and Hb F, between Hb F and point mutations of the gamma gene promoters. MATERIALS AND METHODS: Hematologic parameters, iron status, alpha/non-alpha globin ratio, Epo level, and thalassemic defects of the alpha-, beta-, and gamma-globin genes were explored using standard methods in patients affected by thalassemic diseases. Ninety-five non thalassemic individuals have been examined as controls. RESULTS: Two clinical variants of beta-thalassemia intermedia referred to as beta-thal int sub-silent and evident are associated with distinct sets of mutations of the beta-globin gene. Silent beta thal mutations are invariably associated with sub-silent beta thal int; beta° or severe beta(+) thal mutations are associated with evident beta thal int (88%) and almost invariably (98%) with thalassemia major. A positive correlation was observed between the severity of the disease and the Hb F level, but no correlation was found between the Hb F and erythropoietin (Epo) level. The mutation Ggamma -158 C→T was detected in 26.9% of patients affected by beta-thal int sub-silent and evident, respectively, but only in 2% of patients with thalassemia major. CONCLUSIONS: The severity of beta-thal int and the increased Hb F level are strictly dependent from the type of beta-globin gene mutations. No relation is found between Hb F synthesis and Epo secretion. The mutation Ggamma -158 C→T, common among patients affected by beta-thal int and very rare in thal major patients, does not seem, in this study, to influence the Hb F content in beta thal int patients

Hb H disease resulting from the association of an α0-thalassemia allele [-(α)20.5] with an unstable α-globin variant [Hb Icaria]: First report on the occurrence in Brazil

Hb H Disease is caused by the loss or inactivation of three of the four functional α-globin genes. Patients present chronic hemolytic anemia and splenomegaly. In some cases, occasional blood transfusions are required. Deletions are the main cause of this type of thalassemia ( α-thalassemia). We describe here an unusual case of Hb H disease caused by the combination of a common α0 deletion [-( α) 20.5 ] with a rare point mutation (c.427T > A), thus resulting in an elongated and unstable α-globin variant, Hb Icaria, (X142K), with 31 additional amino-acid residues. Very high levels of Hb H and Hb Bart's were detected in the patient's red blood cells (14.7 and 19.0%, respectively). This is the first description of this infrequent association in the Brazilian population

‘Inspired and assisted’, or ‘berated and destroyed’? Research leadership, management and performativity in troubled times

Research leadership in Australian universities takes place against a backdrop of policy reforms concerned with measurement and comparison of institutional research performance. In particular, the Excellence in Research in Australian initiative undertaken by the Australian Research Council sets out to evaluate research quality in Australian universities, using a combination of expert review process, and assessment of performance against &lsquo;quality indicators&rsquo;. Benchmarking exercises of this sort continue to shape institutional policy and practice, with inevitable effects on the ways in which research leadership, mentoring and practice are played out within university faculties and departments. In an exploratory study that interviewed 32 Australian academics in universities in four Australian states, we asked participants, occupying formal or informal research leadership roles, to comment on their perceptions of research leadership as envisioned and enacted in their particular workplaces. We found a pervasive concern amongst participants that coalesced around binaries characterized in metaphoric terms of &lsquo;carrots and whips&rsquo;. Research leadership was seen by many as managerial in nature, and as such, largely tethered to instrumentalist notions of productivity and performativity, while research cultures were seen as languishing under the demoralizing weight of reward and punishment systems. Here, we consider what is at stake for the future of the academic workforce under such conditions, arguing that new models of visionary research leadership are urgently needed in the &lsquo;troubled times&rsquo; of techno-bureaucratic university reforms.<br /

Invasive Predators Deplete Genetic Diversity of Island Lizards

Invasive species can dramatically impact natural populations, especially those living on islands. Though numerous examples illustrate the ecological impact of invasive predators, no study has examined the genetic consequences for native populations subject to invasion. Here we capitalize on a natural experiment in which a long-term study of the brown anole lizard (Anolis sagrei) was interrupted by rat invasion. An island population that was devastated by rats recovered numerically following rat extermination. However, population genetic analyses at six microsatellite loci suggested a possible loss of genetic diversity due to invasion when compared to an uninvaded island studied over the same time frame. Our results provide partial support for the hypothesis that invasive predators can impact the genetic diversity of resident island populations

Anhydrobiosis-Associated Nuclear DNA Damage and Repair in the Sleeping Chironomid: Linkage with Radioresistance

Anhydrobiotic chironomid larvae can withstand prolonged complete desiccation as well as other external stresses including ionizing radiation. To understand the cross-tolerance mechanism, we have analyzed the structural changes in the nuclear DNA using transmission electron microscopy and DNA comet assays in relation to anhydrobiosis and radiation. We found that dehydration causes alterations in chromatin structure and a severe fragmentation of nuclear DNA in the cells of the larvae despite successful anhydrobiosis. Furthermore, while the larvae had restored physiological activity within an hour following rehydration, nuclear DNA restoration typically took 72 to 96 h. The DNA fragmentation level and the recovery of DNA integrity in the rehydrated larvae after anhydrobiosis were similar to those of hydrated larvae irradiated with 70 Gy of high-linear energy transfer (LET) ions (4He). In contrast, low-LET radiation (gamma-rays) of the same dose caused less initial damage to the larvae, and DNA was completely repaired within within 24 h. The expression of genes encoding the DNA repair enzymes occurred upon entering anhydrobiosis and exposure to high- and low-LET radiations, indicative of DNA damage that includes double-strand breaks and their subsequent repair. The expression of antioxidant enzymes-coding genes was also elevated in the anhydrobiotic and the gamma-ray-irradiated larvae that probably functions to reduce the negative effect of reactive oxygen species upon exposure to these stresses. Indeed the mature antioxidant proteins accumulated in the dry larvae and the total activity of antioxidants increased by a 3–4 fold in association with anhydrobiosis. We conclude that one of the factors explaining the relationship between radioresistance and the ability to undergo anhydrobiosis in the sleeping chironomid could be an adaptation to desiccation-inflicted nuclear DNA damage. There were also similarities in the molecular response of the larvae to damage caused by desiccation and ionizing radiation

An expression meta-analysis of predicted microRNA targets identifies a diagnostic signature for lung cancer

<p>Abstract</p> <p>Background</p> <p>Patients diagnosed with lung adenocarcinoma (AD) and squamous cell carcinoma (SCC), two major histologic subtypes of lung cancer, currently receive similar standard treatments, but resistance to adjuvant chemotherapy is prevalent. Identification of differentially expressed genes marking AD and SCC may prove to be of diagnostic value and help unravel molecular basis of their histogenesis and biologies, and deliver more effective and specific systemic therapy.</p> <p>Methods</p> <p>MiRNA target genes were predicted by union of miRanda, TargetScan, and PicTar, followed by screening for matched gene symbols in NCBI human sequences and Gene Ontology (GO) terms using the PANTHER database that was also used for analyzing the significance of biological processes and pathways within each ontology term. Microarray data were extracted from Gene Expression Omnibus repository, and tumor subtype prediction by gene expression used Prediction Analysis of Microarrays.</p> <p>Results</p> <p>Computationally predicted target genes of three microRNAs, miR-34b/34c/449, that were detected in human lung, testis, and fallopian tubes but not in other normal tissues, were filtered by representation of GO terms and their ability to classify lung cancer subtypes, followed by a meta-analysis of microarray data to classify AD and SCC. Expression of a minimal set of 17 predicted miR-34b/34c/449 target genes derived from the developmental process GO category was identified from a training set to classify 41 AD and 17 SCC, and correctly predicted in average 87% of 354 AD and 82% of 282 SCC specimens from total 9 independent published datasets. The accuracy of prediction still remains comparable when classifying 103 AD and 79 SCC samples from another 4 published datasets that have only 14 to 16 of the 17 genes available for prediction (84% and 85% for AD and SCC, respectively). Expression of this signature in two published datasets of epithelial cells obtained at bronchoscopy from cigarette smokers, if combined with cytopathology of the cells, yielded 89–90% sensitivity of lung cancer detection and 87–90% negative predictive value to non-cancer patients.</p> <p>Conclusion</p> <p>This study focuses on predicted targets of three lung-enriched miRNAs, compares their expression patterns in lung cancer by their GO terms, and identifies a minimal set of genes differentially expressed in AD and SCC, followed by validating this gene signature in multiple published datasets. Expression of this gene signature in bronchial epithelial cells of cigarette smokers also has a great sensitivity to predict the patients having lung cancer if combined with cytopathology of the cells.</p

α-thalassaemia

Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia