Regional Conformational Flexibility Couples Substrate Specificity and Scissile Phosphate Diester Selectivity in Human Flap Endonuclease 1

Human flap endonuclease-1 (hFEN1) catalyzes the divalent metal ion-dependent removal of single-stranded DNA protrusions known as flaps during DNA replication and repair. Substrate selectivity involves passage of the 5′-terminus/flap through the arch and recognition of a single nucleotide 3′-flap by the α2–α3 loop. Using NMR spectroscopy, we show that the solution conformation of free and DNA-bound hFEN1 are consistent with crystal structures; however, parts of the arch region and α2–α3 loop are disordered without substrate. Disorder within the arch explains how 5′-flaps can pass under it. NMR and single-molecule FRET data show a shift in the conformational ensemble in the arch and loop region upon addition of DNA. Furthermore, the addition of divalent metal ions to the active site of the hFEN1–DNA substrate complex demonstrates that active site changes are propagated via DNA-mediated allostery to regions key to substrate differentiation. The hFEN1–DNA complex also shows evidence of millisecond timescale motions in the arch region that may be required for DNA to enter the active site. Thus, hFEN1 regional conformational flexibility spanning a range of dynamic timescales is crucial to reach the catalytically relevant ensemble

Modified gravity with negative and positive powers of the curvature: unification of the inflation and of the cosmic acceleration

The modified gravity, which eliminates the need for dark energy and which seems to be stable, is considered. The terms with positive powers of the curvature support the inflationary epoch while the terms with negative powers of the curvature serve as effective dark energy, supporting current cosmic acceleration. The equivalent scalar-tensor gravity may be compatible with the simplest solar system experiments.Comment: 23 pages, 3 figures, discussion is extended, references added, version to appear in PR

Constraints on diffuse neutrino background from primordial black holes

We calculated the energy spectra and the fluxes of electron neutrino emitted in the process of evaporation of primordial black holes (PBHs) in the early universe. It was assumed that PBHs are formed by a blue power-law spectrum of primordial density fluctuations. We obtained the bounds on the spectral index of density fluctuations assuming validity of the standard picture of gravitational collapse and using the available data of several experiments with atmospheric and solar neutrinos. The comparison of our results with the previous constraints (which had been obtained using diffuse photon background data) shows that such bounds are quite sensitive to an assumed form of the initial PBH mass function.Comment: 18 pages,(with 7 figures

Kaluza-Klein Type Robertson Walker Cosmological Model With Dynamical Cosmological Term Λ\Lambda

In this paper we have analyzed the Kaluza-Klein type Robertson Walker (RW) cosmological models by considering three different forms of variable $\Lambda$: $\Lambda\sim(\frac{\dot{a}}{a})^2$,$\Lambda\sim(\frac{\ddot{a}} {a})$ and $\Lambda \sim \rho$. It is found that, the connecting free parameters of the models with cosmic matter and vacuum energy density parameters are equivalent, in the context of higher dimensional space time. The expression for the look back time, luminosity distance and angular diameter distance are also derived. This work has thus generalized to higher dimensions the well-known results in four dimensional space time. It is found that there may be significant difference in principle at least, from the analogous situation in four dimensional space time.Comment: 16 pages, no figur

Acute cocoa flavanol supplementation improves muscle macro- and microvascular but not anabolic responses to amino acids in older men

The anabolic effects of nutrition on skeletal muscle may depend on adequate skeletal muscle perfusion, which is impaired in older people. Cocoa flavanols have been shown to improve flow-mediated dilation, an established measure of endothelial function. However, their effect on muscle microvascular blood flow is currently unknown. Therefore, the objective of this study was to explore links between the consumption of cocoa flavanols, muscle microvascular blood flow and muscle protein synthesis (MPS) in response to nutrition in older men. To achieve this objective leg blood flow (LBF), muscle microvascular blood volume (MBV) and MPS were measured under postabsorptive and postprandial (I.V glamin, dextrose to sustain glucose ~7.5 mmol·l-1) conditions in 20 older men. Ten of these men were studied with no cocoa flavanol intervention and a further 10 were studied with the addition of 350 mg of cocoa flavanols at the same time as nutrition began. Leg [femoral artery] blood flow was measured by Doppler ultrasound, muscle MBV by contrast-enhanced ultrasound (CEUS) using DefinityTM perflutren contrast agent and MPS using [1, 2-13C2] leucine tracer techniques. Our results show that although older individuals do not show an increase in LBF or MBV in response to feeding, these absent responses are apparent when cocoa flavanols are given acutely with nutrition. However this restoration in vascular responsiveness is not associated with improved MPS responses to nutrition. We conclude that acute cocoa flavanol supplementation improves muscle macro- and microvascular responses to nutrition, independently of modifying muscle protein anabolism

The CPLEAR detector at CERN

The CPLEAR collaboration has constructed a detector at CERN for an extensive programme of CP-, T- and CPT-symmetry studies using ${\rm K}^0$ and $\bar{\rm K}^0$ produced by the annihilation of $\bar{\rm p}$'s in a hydrogen gas target. The ${\rm K}^0$ and $\bar{\rm K}^0$ are identified by their companion products of the annihilation ${\rm K}^{\pm} \pi^{\mp}$ which are tracked with multiwire proportional chambers, drift chambers and streamer tubes. Particle identification is carried out with a liquid Cherenkov detector for fast separation of pions and kaons and with scintillators which allow the measurement of time of flight and energy loss. Photons are measured with a lead/gas sampling electromagnetic calorimeter. The required antiproton annihilation modes are selected by fast online processors using the tracking chamber and particle identification information. All the detectors are mounted in a 0.44 T uniform field of an axial solenoid of diameter 2 m and length 3.6 m to form a magnetic spectrometer capable of full on-line reconstruction and selection of events. The design, operating parameters and performance of the sub-detectors are described.