Decreased MCM2-6 in Drosophila S2 cells does not generate significant DNA damage or cause a marked increase in sensitivity to replication interference.

A reduction in the level of some MCM proteins in human cancer cells (MCM5 in U20S cells or MCM3 in Hela cells) causes a rapid increase in the level of DNA damage under normal conditions of cell proliferation and a loss of viability when the cells are subjected to replication interference. Here we show that Drosophila S2 cells do not appear to show the same degree of sensitivity to MCM2-6 reduction. Under normal cell growth conditions a reduction of >95% in the levels of MCM3, 5, and 6 causes no significant short term alteration in the parameters of DNA replication or increase in DNA damage. MCM depleted cells challenged with HU do show a decrease in the density of replication forks compared to cells with normal levels of MCM proteins, but this produces no consistent change in the levels of DNA damage observed. In contrast a comparable reduction of MCM7 levels has marked effects on viability, replication parameters and DNA damage in the absence of HU treatment

Alterations in vascular function in primary aldosteronism - a cardiovascular magnetic resonance imaging study

Introduction: Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV).<p></p> Methods: We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass.<p></p> Results: Subjects with PA had significantly lower aortic distensibilty and higher PWV compared to EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including aging. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular aging. As expected, aortic distensibility and PWV were closely correlated.<p></p> Conclusion: These results demonstrate that PA patients display increased arterial stiffness compared to EH, independent of vascular aging. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.<p></p&gt

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Rhythmic dynamics and synchronization via dimensionality reduction : application to human gait

Reliable characterization of locomotor dynamics of human walking is vital to understanding the neuromuscular control of human locomotion and disease diagnosis. However, the inherent oscillation and ubiquity of noise in such non-strictly periodic signals pose great challenges to current methodologies. To this end, we exploit the state-of-the-art technology in pattern recognition and, specifically, dimensionality reduction techniques, and propose to reconstruct and characterize the dynamics accurately on the cycle scale of the signal. This is achieved by deriving a low-dimensional representation of the cycles through global optimization, which effectively preserves the topology of the cycles that are embedded in a high-dimensional Euclidian space. Our approach demonstrates a clear advantage in capturing the intrinsic dynamics and probing the subtle synchronization patterns from uni/bivariate oscillatory signals over traditional methods. Application to human gait data for healthy subjects and diabetics reveals a significant difference in the dynamics of ankle movements and ankle-knee coordination, but not in knee movements. These results indicate that the impaired sensory feedback from the feet due to diabetes does not influence the knee movement in general, and that normal human walking is not critically dependent on the feedback from the peripheral nervous system

Carbon-fiber tips for scanning probe microscopes and molecular electronics experiments

We fabricate and characterize carbon-fiber tips for their use in combined scanning tunneling and force microscopy based on piezoelectric quartz tuning fork force sensors. An electrochemical fabrication procedure to etch the tips is used to yield reproducible sub-100-nm apex. We also study electron transport through single-molecule junctions formed by a single octanethiol molecule bonded by the thiol anchoring group to a gold electrode and linked to a carbon tip by the methyl group. We observe the presence of conductance plateaus during the stretching of the molecular bridge, which is the signature of the formation of a molecular junction.Comment: Conference Proceeding (Trends in NanoTechnology 2011, Tenerife SPAIN); Nanoscale Research Letters, (2012) 7:25

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Search for rare and forbidden decays of charm and charmed-strange mesons to final states h^+- e^-+ e^+

We have searched for flavor-changing neutral current decays and lepton-number-violating decays of D^+ and D^+_s mesons to final states of the form h^+- e^-+ e^+, where h is either \pi or K. We use the complete samples of CLEO-c open-charm data, corresponding to integrated luminosities of 818 pb^-1 at the center-of-mass energy E_CM = 3.774 GeV containing 2.4 x 10^6 D^+D^- pairs and 602 pb^-1 at E_CM = 4.170 GeV containing 0.6 x 10^6 D^*+-_s D^-+_s pairs. No signal is observed in any channel, and we obtain 90% confidence level upper limits on branching fractions B(D^+ --> \pi^+ e^+ e^-) < 5.9 x 10^-6, B(D^+ --> \pi^- e^+ e^+) K^+ e^+ e^-) < 3.0 x 10^-6, B(D^+ --> K^- e^+ e^+) \pi^+ e^+ e^-) < 2.2 x 10^-5, B(D^+_s --> \pi^- e^+ e^+) K^+ e^+ e^-) < 5.2 x 10^-5, and B(D^+_s --> K^- e^+ e^+) < 1.7 x 10^-5.Comment: 9 pages, available through http://www.lns.cornell.edu/public/CLNS

Determination of the D0 -> K+pi- Relative Strong Phase Using Quantum-Correlated Measurements in e+e- -> D0 D0bar at CLEO

We exploit the quantum coherence between pair-produced D0 and D0bar in psi(3770) decays to study charm mixing, which is characterized by the parameters x and y, and to make a first determination of the relative strong phase \delta between doubly Cabibbo-suppressed D0 -> K+pi- and Cabibbo-favored D0bar -> K+pi-. We analyze a sample of 1.0 million D0D0bar pairs from 281 pb^-1 of e+e- collision data collected with the CLEO-c detector at E_cm = 3.77 GeV. By combining CLEO-c measurements with branching fraction input and time-integrated measurements of R_M = (x^2+y^2)/2 and R_{WS} = Gamma(D0 -> K+pi-)/Gamma(D0bar -> K+pi-) from other experiments, we find \cos\delta = 1.03 +0.31-0.17 +- 0.06, where the uncertainties are statistical and systematic, respectively. In addition, by further including external measurements of charm mixing parameters, we obtain an alternate measurement of \cos\delta = 1.10 +- 0.35 +- 0.07, as well as x\sin\delta = (4.4 +2.7-1.8 +- 2.9) x 10^-3 and \delta = 22 +11-12 +9-11 degrees.Comment: 37 pages, also available through http://www.lns.cornell.edu/public/CLNS/2007/. Incorporated referee's comment