Enter exitrons

Staiger D, Simpson GG. Enter exitrons. Genome Biology. 2015;16(1): 136.Exitrons are exon-like introns located within protein-coding exons. Removal or retention of exitrons through alternative splicing increases proteome complexity and thus adds to phenotypic diversity

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Cytoplasmic p21(WAF1/CIP1 )expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

BACKGROUND: HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21(WAFI/CIPI )in cell culture, accompanied by resistance to apoptosis. p21(WAFI/CIPI )is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21(WAFI/CIPI). We previously showed that higher levels of cytoplasmic p21(WAFI/CIPI )in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21(WAFI/CIPI )expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. METHODS: The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21(WAFI/CIPI )staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). RESULTS: HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21(WAFI/CIPI )staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21(WAFI/CIPI )and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21(WAF1/CIP1 )and HER-2. CONCLUSION: This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21(WAFI/CIPI )from the nucleus to the cytoplasm, resulting in a loss of p21(WAFI/CIPI)tumour suppressor functions. Cytoplasmic p21(WAFI/CIPI )may be a surrogate marker of functional HER-2 in vivo

Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation

The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assesse

Organic Geochemical Studies. I. Molecular Criteria for Hydrocarbon Genesis

In recent years the search for life-forms at the earliest periods of geological time has been continued not only at the morphological level but also at the molecular level. This has been possible as a result of the increase in the biochemical knowledge and with the advent of analytical techniques that are capable of describing the intimate molecular architecture of individual molecules in acute detail. The fundamental premises upon which this organic geochemical approach rest are the following: that certain molecules, possessing a characteristic structural skeleton, show a reasonable stability to degradation over long periods of geological time; that their structural specificity can be understood in terms of known biosynthetic sequences; and that their formation by any non-biological means is of negligible probability. In this manuscript it is proposed to critically re-examine these premises and to establish criteria whereby one can differentiate molecules derived from biological systems from those that have their origin in non-biological processes. The importance of establishing such criteria lies in the significance these criteria have in determining whether life exists, or has existed, on other planets. Within the very near future it may be possible to provide an initial answer to this question when the first lunar samples are returned to the earth for analysis

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymousGATA2variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations inGATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymousGATA2substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders

Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors

Target or substrate Rab GTPases are identified for 17 proteins with DENN domains

The MLL recombinome of acute leukemias in 2017

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients