Superallowed 0+ to 0+ nuclear beta decays: A new survey with precision tests of the conserved vector current hypothesis and the standard model

A new critical survey is presented of all half-life, decay-energy and branching-ratio measurements related to 20 0+ to 0+ beta decays. Compared with our last review, there are numerous improvements: First, we have added 27 recently published measurements and eliminated 9 references; of particular importance, the new data include a number of high-precision Penning-trap measurements of decay energies. Second, we have used the recently improved isospin symmetry-breaking corrections. Third, our calculation of the statistical rate function now accounts for possible excitation in the daughter atom. Finally, we have re-examined the systematic uncertainty associated with the isospin symmetry-breaking corrections by evaluating the radial-overlap correction using Hartree-Fock radial wave functions and comparing the results with our earlier calculations, which used Saxon-Woods wave functions; the provision for systematic uncertainty has been changed as a consequence. The new corrected Ft values are impressively constant and their average, when combined with the muon liftime, yields the up-down quark-mixing element of the Cabibbo-Kobayashi-Maskawa (CKM) matrix, V_{ud} = 0.97425(22). The unitarity test on the top row of the matrix becomes |V_{ud}|^2 + |V_{us}|^2 + |V_{ub}|^2 = 0.99995(61). Both V_{ud} and the unitarity sum have significantly reduced uncertainties compared with our previous survey, although the new value of V_{ud} is statistically consistent with the old one. From these data we also set limits on the possible existence of scalar interactions, right-hand currents and extra Z bosons. Finally, we discuss the priorities for future theoretical and experimental work with the goal of making the CKM unitarity test even more definitive.Comment: 36 pages, 11 tables, 9 figure

Alternative mRNA Editing in Trypanosomes Is Extensive and May Contribute to Mitochondrial Protein Diversity

The editing of trypanosome mitochondrial mRNAs produces transcripts necessary for mitochondrial functions including electron transport and oxidative phosphorylation. Precursor-mRNAs are often extensively edited by specific uridine insertion or deletion that is directed by small guide RNAs (gRNAs). Recently, it has been shown that cytochrome c oxidase subunit III (COXIII) mRNAs can be alternatively edited to encode a novel mitochondrial membrane protein composed of a unique hydrophilic N-terminal sequence of unknown function and the C-terminal hydrophobic segment of COXIII. To extend the analysis of alternative editing in Trypanosoma brucei we have constructed libraries with over 1100 full-length mitochondrial cDNAs and the sequences of over 1200 gRNA genes. Using this data, we show that alternative editing of COXIII, ATPase subunit 6 (A6), and NADH dehydrogenase subunits 7, 8 and 9 (ND7, 8, 9) mRNAs can produce novel open reading frames (ORFs). Several gRNAs potentially responsible for the alternative editing of these mRNAs were also identified. These findings show that alternative editing of mitochondrial mRNAs is common in T. brucei and expands the diversity of mitochondrial proteins in these organisms

Superallowed nuclear beta decays: A critical survey with tests of CVC and the standard model

A complete and critical survey is presented of all half-life, decay-energy and branching-ratio measurements related to 20 superallowed decays; no measurements are ignored, though some are rejected for cause and others updated. A new calculation of the statistical rate function is described and experimental ft values determined. The associated theoretical corrections needed to convert these results into Ft values are discussed, and careful attention is paid to the origin and magnitude of their uncertainties. As an exacting confirmation of the conserved vector current hypothesis, the Ft values are seen to be constant to 3 parts in 10^4. These data are also used to set new limits on any possible scalar interactions or right-hand currents. The average Ft value obtained from the survey, when combined with the muon lifetime, yields the CKM matrix element Vud = 0.9738(4); and the unitarity test on the top row of the matrix becomes |Vud|^2 + |Vus|^2 + |Vub|^2 = 0.9966(14) using the PDG's currently recommended values for Vus and Vub. We discuss the priorities for future theoretical and experimental work with the goal of making the CKM unitarity test more definitive.Comment: 64 pages, 4 postscript figure

Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy

BACKGROUND: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. METHODS: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. RESULTS: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05). CONCLUSION: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment. British Journal of Cancer (2010) 103, 1407-1414. doi: 10.1038/sj.bjc.6605925 www.bjcancer.com Published online 5 October 2010 (C) 2010 Cancer Research U

Native Variants of the MRB1 Complex Exhibit Specialized Functions in Kinetoplastid RNA Editing

We want to thank Kathy Kyler for editing this manuscript, Ken Stuart for supplying monoclonal antisera against RECC subunits, and Laurie K. Read for her gift of polyclonal antisera against GAP1 and RGG2. Funding: National Science Foundation Grant No. NSF1122109 (PI: J.Cruz-Reyes.). NIH/National Institute of Allergies and Infectious Diseases R01 AI088011 (PI: Blaine Mooers). Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103640. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Adaptation and survival of Trypanosoma brucei requires editing of mitochondrial mRNA by uridylate (U) insertion and deletion. Hundreds of small guide RNAs (gRNAs) direct the mRNA editing at over 3,000 sites. RNA editing is controlled during the life cycle but the regulation of substrate and stage specificity remains unknown. Editing progresses in the 3’ to 5’ direction along the pre-mRNA in blocks, each targeted by a unique gRNA. A critical editing factor is the mitochondrial RNA binding complex 1 (MRB1) that binds gRNA and transiently interacts with the catalytic RNA editing core complex (RECC). MRB1 is a large and dynamic complex that appears to be comprised of distinct but related subcomplexes (termed here MRBs). MRBs seem to share a ‘core’ complex of proteins but differ in the composition of the ‘variable’ proteins. Since some proteins associate transiently the MRBs remain imprecisely defined. MRB1 controls editing by unknown mechanisms, and the functional relevance of the different MRBs is unclear. We previously identified two distinct MRBs, and showed that they carry mRNAs that undergo editing. We proposed that editing takes place in the MRBs because MRBs stably associate with mRNA and gRNA but only transiently interact with RECC, which is RNA free. Here, we identify the first specialized functions in MRBs: 1) 3010-MRB is a major scaffold for RNA editing, and 2) REH2-MRB contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function in 3010-MRB. These trans effects of the REH2 include loading of unedited mRNA and editing in the first block and in subsequent blocks as editing progresses. REH2 binds its own MRB via RNA, and conserved domains in REH2 were critical for REH2 to associate with the RNA and protein components of its MRB. Importantly, REH2 associates with a ~30 kDa RNA-binding protein in a novel ~15S subcomplex in RNA-depleted mitochondria. We use these new results to update our model of MRB function and organization.Yeshttp://www.plosone.org/static/editorial#pee

A leucine aminopeptidase is involved in kinetoplast DNA segregation in <i>Trypanosoma brucei</i>

The kinetoplast (k), the uniquely packaged mitochondrial DNA of trypanosomatid protists is formed by a catenated network of minicircles and maxicircles that divide and segregate once each cell cycle. Although many proteins involved in kDNA replication and segregation are now known, several key steps in the replication mechanism remain uncharacterized at the molecular level, one of which is the nabelschnur or umbilicus, a prominent structure which in the mammalian parasite Trypanosoma brucei connects the daughter kDNA networks prior to their segregation. Here we characterize an M17 family leucyl aminopeptidase metalloprotease, termed TbLAP1, which specifically localizes to the kDNA disk and the nabelschur and represents the first described protein found in this structure. We show that TbLAP1 is required for correct segregation of kDNA, with knockdown resulting in delayed cytokinesis and ectopic expression leading to kDNA loss and decreased cell proliferation. We propose that TbLAP1 is required for efficient kDNA division and specifically participates in the separation of daughter kDNA networks

Commuting and happiness: What ways feel best for what kinds of people?

Question: How happy we are, depends partly on how we live our life and part of our way of life is how we commute between home and work. In that context, we are faced with the question of how much time spent on commuting is optimal happiness wise and with what means of transportation we will feel best. Decisions about commuting are typically made as a side issue in job choice and there are indications that we are bad in predicting how such decisions will work out on our happiness in the long-run. For that reason, it is helpful to know how commuting has worked out on the happiness of other people and on people like you in particular. Earlier research: Several cross-sectional studies found lower happiness among long-distance commuters and among users of public transportation. Yet these differences could be due to selection effects, such as unhappy people opting more often for distant jobs without having a car. Still another limitation is that earlier research has focused on the average effect of commuting, rather than specifying what is optimal for whom. Method: Data of the Dutch ‘Happiness Indicator’ study was analyzed, in the context of which 5000 participants recorded what they had done in the previous day and how happy they had felt during these activities. This data allows comparison between how the same person feels at home and during commute, which eliminates selection effects. The number of participants is large enough to allow a split-up between different kinds of people, in particular among the many well-educated women who participated in this study. Results: People feel typically less happy when commuting than at home, and that the negative difference is largest when commuting with public transportation and smallest when commuting by bike. It is not per se the commuting time that causes happiness loss, but specific combinations of commuting time and commuting mode. Increasing commuting times can even lead to a gain in happiness for certain types of women, when the commute is by bike. Split-up by different kinds of people shows considerable differences, such as an optimal commute alone or even by public transport for some highly educated women. Optimal ways of commuting for different kinds of people are presented in a summary table, from which individuals can read what will fit them best. The differences illustrate that research focusing on average effects of happiness will not help individuals in making a more informed choice. Keywords: happiness, commuting, experience utility, informed choice, DRM

Gene and genon concept: coding versus regulation: A conceptual and information-theoretic analysis of genetic storage and expression in the light of modern molecular biology

We analyse here the definition of the gene in order to distinguish, on the basis of modern insight in molecular biology, what the gene is coding for, namely a specific polypeptide, and how its expression is realized and controlled. Before the coding role of the DNA was discovered, a gene was identified with a specific phenotypic trait, from Mendel through Morgan up to Benzer. Subsequently, however, molecular biologists ventured to define a gene at the level of the DNA sequence in terms of coding. As is becoming ever more evident, the relations between information stored at DNA level and functional products are very intricate, and the regulatory aspects are as important and essential as the information coding for products. This approach led, thus, to a conceptual hybrid that confused coding, regulation and functional aspects. In this essay, we develop a definition of the gene that once again starts from the functional aspect. A cellular function can be represented by a polypeptide or an RNA. In the case of the polypeptide, its biochemical identity is determined by the mRNA prior to translation, and that is where we locate the gene. The steps from specific, but possibly separated sequence fragments at DNA level to that final mRNA then can be analysed in terms of regulation. For that purpose, we coin the new term “genon”. In that manner, we can clearly separate product and regulative information while keeping the fundamental relation between coding and function without the need to introduce a conceptual hybrid. In mRNA, the program regulating the expression of a gene is superimposed onto and added to the coding sequence in cis - we call it the genon. The complementary external control of a given mRNA by trans-acting factors is incorporated in its transgenon. A consequence of this definition is that, in eukaryotes, the gene is, in most cases, not yet present at DNA level. Rather, it is assembled by RNA processing, including differential splicing, from various pieces, as steered by the genon. It emerges finally as an uninterrupted nucleic acid sequence at mRNA level just prior to translation, in faithful correspondence with the amino acid sequence to be produced as a polypeptide. After translation, the genon has fulfilled its role and expires. The distinction between the protein coding information as materialised in the final polypeptide and the processing information represented by the genon allows us to set up a new information theoretic scheme. The standard sequence information determined by the genetic code expresses the relation between coding sequence and product. Backward analysis asks from which coding region in the DNA a given polypeptide originates. The (more interesting) forward analysis asks in how many polypeptides of how many different types a given DNA segment is expressed. This concerns the control of the expression process for which we have introduced the genon concept. Thus, the information theoretic analysis can capture the complementary aspects of coding and regulation, of gene and genon