206 research outputs found

    Chemical genetic analysis of the regulatory role of Cdc2p in the S. pombe septation initiation network

    Get PDF
    The protein kinase Cdc2p is the master regulator of cell cycle progression in the fission yeast Schizosaccharomyces pombe. It is required both for entry into mitosis and for onset of DNA replication. Cdc2p must be inactivated to permit exit from mitosis, licensing of replication origins and cytokinesis. To study the role of Cdc2p in greater detail, we generated a cdc2 allele that is sensitive to an inhibitory ATP analogue. We show that the inhibitor-induced cell cycle arrest is reversible and examine the effect of inhibiting Cdc2p on the regulation of the septation initiation network (SIN), which controls the initiation of cytokinesis in S. pombe. We found that specific inactivation of Cdc2p in a mitotically arrested cell promotes the asymmetrical recruitment of SIN proteins to the spindle poles and the recruitment of the most downstream SIN components and beta-(1,3) glucan synthase to the contractile ring. Thus, we conclude that inactivation of Cdc2p is sufficient to activate the SIN and promote cytokinesis

    Measuring track vertical stiffness through dynamic monitoring

    Full text link
    [EN] This paper proposes a methodology for the evaluation of the track condition by means of the measurement of the track stiffness. This magnitude is calculated from vertical acceleration data measured at the axle box of trains during their normal operation. From the corresponding vertical acceleration spectra, the dominant vibration frequencies for each track stretch are identified and the combined stiffness is then determined. Then the stiffness without the contribution of the rail is calculated. The results obtained for a High Speed ballasted track in several track stretches are within the range 120-130 kN/mm, a result consistent with direct stiffness measurements taken during previous studies. Therefore, the proposed methodology may be used to obtain a first insight to the track condition by means of a continuous measurement of the track combined stiffness. This offers an alternative to traditional stationary stiffness measuring devices and might be a useful complement to dedicated continuous monitoring vehicles.Cano, MJ.; Martínez Fernández, P.; Insa Franco, R. (2016). Measuring track vertical stiffness through dynamic monitoring. Proceedings of the Institution of Civil Engineers - Transport. 169(1). doi:10.1680/jtran.14.00081S169

    Analysis of the performance of under-sleeper pads in highspeed line transition zones

    Full text link
    [EN] In many high-speed railway lines, the zones between embankments and structures may present some discontinuities, in terms of track geometry and track stiffness, which may create discomfort for passengers, induce deterioration of track and vehicle materials and even raise the risk of derailment to dangerous levels. In the attempt to attenuate the consequences of such problems, some solutions pointing at progressively changing the vertical stiffness in the railway track have been tested, such as transition zones or pads placed either between the rails and the sleepers or under the sleepers. The contribution of under-sleeper pads in transition regions and their effect on the railway infrastructure is specifically analysed in the present paper. The results obtained are of interest since they provide useful information for railway managers on infrastructure design and justify the need to implement such transition ones.Insa Franco, R.; Salvador Zuriaga, P.; Inarejos Mesa, J.; Medina González, L. (2014). Analysis of the performance of under-sleeper pads in highspeed line transition zones. Proceedings of the Institution of Civil Engineers - Transport. 167(2):63-77. doi:10.1680/tran.11.00033S6377167

    Responses to systemic therapy in metastatic pheochromocytoma/paraganglioma: a retrospective multicenter cohort study

    Get PDF
    OBJECTIVE The therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) include chemotherapy with cyclophosphamide/vincristine/dacarbazine (CVD), temozolomide monotherapy, radionuclide therapies, and tyrosine kinase inhibitors such as sunitinib. The objective of this multicenter retrospective study was to evaluate and compare the responses of mPPGLs including those with pathogenic variants in succinate dehydrogenase subunit B (SDHB), to different systemic treatments. DESIGN This is a retrospective analysis of treatment responses of mPPGL patients (n = 74) to systemic therapies. METHODS Patients with mPPGLs treated at 6 specialized national centers were selected based on participation in the ENSAT registry. Survival until detected progression (SDP) and disease-control rates (DCRs) at 3 months were evaluated based on imaging reports. RESULTS For the group of patients with progressive disease at baseline (83.8% of 74 patients), the DCR with first-line CVD chemotherapy was 75.0% (n = 4, SDP 11 months; SDHB [n = 1]: DCR 100%, SDP 30 months), with somatostatin peptide receptor-based radionuclide therapy (PPRT) 85.7% (n = 21, SDP 17 months; SDHB [n = 10]: DCR 100%, SDP 14 months), with 131I-meta-iodobenzylguanidine (131I-MIBG) 82.6% (n = 23, SDP 43 months; SDHB [n = 4]: DCR 100%, SDP 24 months), with sunitinib 100% (n = 7, SDP 18 months; SDHB [n = 3]: DCR 100%, SDP 18 months), and with somatostatin analogs 100% (n = 4, SDP not reached). The DCR with temozolomide as second-line therapy was 60.0% (n = 5, SDP 10 months; SDHB [n = 4]: DCR 75%, SDP 10 months). CONCLUSIONS We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations

    Adolescents' health and health behaviour as predictors of injury death. A prospective cohort follow-up of 652,530 person-years

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Injuries represent an important cause of mortality among young adults. Longitudinal studies on risk factors are scarce. We studied associations between adolescents' perceived health and health behaviour and injury death.</p> <p>Methods</p> <p>A prospective cohort of 57,407 Finns aged 14 to 18 years was followed for an average of 11.4 years. The end-point of study was injury death or termination of follow-up in 2001. The relationships of eight health and health behaviour characteristics with injury death were studied with adjusted Cox's proportional hazard model.</p> <p>Results</p> <p>We identified 298 (0.5%) injury deaths, 232 (0.9%) in men and 66 (0.2%) in women. The mean age at death was 23.8 years. In the models adjusted for age, sex and socioeconomic background, the strongest risk factors for injury death were recurring drunkenness (HR 2.1; 95% CI: 1.4–3.1) and daily smoking (HR 1.7; 95% CI: 1.3–2.2). Poor health did not predict injury death. Unintentional and intentional injury deaths had similar health and health behavioural risk factors.</p> <p>Conclusion</p> <p>Health compromising behaviour adopted at adolescence has a clear impact on the risk of injury death in adulthood independent from socioeconomic background. On the other hand, poor health as such is not a significant predictor of injury death. Promotion of healthy lifestyle among adolescents as part of public health programmes would seem an appropriate way to contribute to adolescent injury prevention.</p

    Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Enzymes in the radical SAM (rSAM) domain family serve in a wide variety of biological processes, including RNA modification, enzyme activation, bacteriocin core peptide maturation, and cofactor biosynthesis. Evolutionary pressures and relationships to other cellular constituents impose recognizable grammars on each class of rSAM-containing system, shaping patterns in results obtained through various comparative genomics analyses.</p> <p>Results</p> <p>An uncharacterized gene cluster found in many Actinobacteria and sporadically in Firmicutes, Chloroflexi, Deltaproteobacteria, and one Archaeal plasmid contains a PqqE-like rSAM protein family that includes Rv0693 from <it>Mycobacterium tuberculosis</it>. Members occur clustered with a strikingly well-conserved small polypeptide we designate "mycofactocin," similar in size to bacteriocins and PqqA, precursor of pyrroloquinoline quinone (PQQ). Partial Phylogenetic Profiling (PPP) based on the distribution of these markers identifies the mycofactocin cluster, but also a second tier of high-scoring proteins. This tier, strikingly, is filled with up to thirty-one members per genome from three variant subfamilies that occur, one each, in three unrelated classes of nicotinoproteins. The pattern suggests these variant enzymes require not only NAD(P), but also the novel gene cluster. Further study was conducted using SIMBAL, a PPP-like tool, to search these nicotinoproteins for subsequences best correlated across multiple genomes to the presence of mycofactocin. For both the short chain dehydrogenase/reductase (SDR) and iron-containing dehydrogenase families, aligning SIMBAL's top-scoring sequences to homologous solved crystal structures shows signals centered over NAD(P)-binding sites rather than over substrate-binding or active site residues. Previous studies on some of these proteins have revealed a non-exchangeable NAD cofactor, such that enzymatic activity <it>in vitro </it>requires an artificial electron acceptor such as N,N-dimethyl-4-nitrosoaniline (NDMA) for the enzyme to cycle.</p> <p>Conclusions</p> <p>Taken together, these findings suggest that the mycofactocin precursor is modified by the Rv0693 family rSAM protein and other enzymes in its cluster. It becomes an electron carrier molecule that serves <it>in vivo </it>as NDMA and other artificial electron acceptors do <it>in vitro</it>. Subclasses from three different nicotinoprotein families show "only-if" relationships to mycofactocin because they require its presence. This framework suggests a segregated redox pool in which mycofactocin mediates communication among enzymes with non-exchangeable cofactors.</p
    • …
    corecore