ALBERT

Description: A precision measurement of jet cross sections in neutral current deep-inelastic scattering for photon virtualities $$5.5

Description: The strong coupling constant $$alpha _mathrm{s}$$ α s is determined from inclusive jet and dijet cross sections in neutral-current deep-inelastic ep scattering (DIS) measured at HERA by the H1 collaboration using next-to-next-to-leading order (NNLO) QCD predictions. The dependence of the NNLO predictions and of the resulting value of $$alpha _mathrm{s} (m_mathrm{Z})$$ α s ( m Z ) at the Z-boson mass $$m_Z$$ m Z are studied as a function of the choice of the renormalisation and factorisation scales. Using inclusive jet and dijet data together, the strong coupling constant is determined to be $$alpha _mathrm{s} (m_mathrm{Z}) =0.1157,(20)_mathrm{exp},(29)_mathrm{th}$$ α s ( m Z ) = 0.1157 ( 20 ) exp ( 29 ) th . Complementary, $$alpha _mathrm{s} (m_mathrm{Z})$$ α s ( m Z ) is determined together with parton distribution functions of the proton (PDFs) from jet and inclusive DIS data measured by the H1 experiment. The value $$alpha _mathrm{s} (m_mathrm{Z}) =0.1142,(28)_mathrm{tot}$$ α s ( m Z ) = 0.1142 ( 28 ) tot obtained is consistent with the determination from jet data alone. The impact of the jet data on the PDFs is studied. The running of the strong coupling is tested at different values of the renormalisation scale and the results are found to be in agreement with expectations.

Description: A Higgs field of particle physics can play the role of the inflaton in the early universe if it is non-minimally coupled to gravity. The Higgs inflation scenario predicts a small tensor to scalar ratio: \(r\simeq 0.003\) . Although this value is consistent with the upper bound \(r〈0.12\) given by the BICEP2/ Keck Array and Planck data, it is not at their maximum likelihood point: \(r\simeq 0.05\) . Inflationary observables depend not only on the inflationary models, but they also depend on the initial conditions of inflation. Changing the initial state of inflation can improve the value of r . In this work, we study the Higgs inflation model under general initial conditions and show that there is a subset of these general initial conditions which leads to enhancement of r . Then we show that this region of parameter space is consistent with a non-Gaussianity bound.

Description: When Morris and Thorne first proposed that traversable wormholes may be actual physical objects, they concentrated on the geometry by specifying the shape and redshift functions. This mathematical approach necessarily raises questions regarding the determination of the required stress-energy tensor. This paper discusses a natural way to obtain a complete wormhole solution by assuming that the wormhole (1) is supported by generalized Chaplygin gas and (2) admits conformal Killing vectors.

Description: In this article, we study the charmed baryon states \(\Lambda _c(2625)\) and \(\Xi _c(2815)\) with the spin-parity \({3\over 2}^-\) by subtracting the contributions from the corresponding charmed baryon states with the spin-parity \({3\over 2}^+\) using the QCD sum rules, and suggest a formula \( \mu =\sqrt{M_{\Lambda _c/\Xi _c}^2-{\mathbb {M}}_c^2}\) with the effective mass \({\mathbb {M}}_c=1.8\,\mathrm {GeV}\) to determine the energy scales of the QCD spectral densities, and make reasonable predictions for the masses and pole residues. The numerical results indicate that the \(\Lambda _c(2625)\) and \(\Xi _c(2815)\) have at least two remarkable under-structures.

Description: We study the radiative leptonic \(B_c\rightarrow \gamma \ell {\bar{\nu }}\) decays in nonrelativistic QCD effective field theory, and we explore the contribution from a fast-moving photon. As a result, interactions between the photon and the heavy quarks can be integrated out, resulting in the factorization formula for the decay amplitude. We calculate not only the relevant short-distance coefficients at leading order and next-to-leading order in \(\alpha _s\) , but also the nonrelativistic corrections at the order \(|\mathrm {v}|^2\) in our analysis. We find that the QCD corrections can significantly decrease the branching ratio, and this is of great importance in extracting the long-distance operator matrix elements of \(B_c\) . For phenomenological application, we present our results for the photon energy, lepton energy and lepton-neutrino invariant mass distribution.

Description: We point out a weak side of the commonly used determination of scalar cosmological perturbations lying in the fact that their average values can be nonzero for some matter distributions. It is shown that introduction of the finite-range gravitational potential instead of the infinite-range one resolves this problem. The concrete illustrative density profile is investigated in detail in this connection.

Description: A consistent BPS formalism to study the existence of topological axially symmetric vortices in generalized versions of the Born–Infeld–Higgs electrodynamics is implemented. Such a generalization modifies the field dynamics via the introduction of three nonnegative functions depending only in the Higgs field, namely, \(G(|\phi |)\) , \(w(|\phi |) \) , and \(V(|\phi |)\) . A set of first-order differential equations is attained when these functions satisfy a constraint related to the Ampère law. Such a constraint allows one to minimize the system’s energy in such way that it becomes proportional to the magnetic flux. Our results provides an enhancement of the role of topological vortex solutions in Born–Infeld–Higgs electrodynamics. Finally, we analyze a set of models entailing the recovery of a generalized version of Maxwell–Higgs electrodynamics in a certain limit of the theory.

Description: I put forward a qualitatively new dynamical mechanism for solving the electroweak hierarchy problem that does not require new physics at the electroweak scale. I argue that the infrared fluctuations of the gravitational field may provide a partial screening of the Higgs mass, similar to the infrared screening of the electric charge in quantum electrodynamics.

Description: It is thought that the spacetime geometry around black hole candidates is described by the Kerr solution, but an observational confirmation is still missing. Today, the continuum-fitting method and the analysis of the iron K \(\alpha \) line cannot unambiguously test the Kerr paradigm because of the degeneracy among the parameters of the system, in the sense that it is impossible with current X-ray data to distinguish a Kerr black hole from a non-Kerr object with different values of the model parameters. In this paper, we study the possibility of testing the Kerr nature of black hole candidates with X-ray spectropolarimetric measurements. Within our simplified model that does not include the effect of returning radiation, we find that it is impossible to test the Kerr metric and the problem is still the strong correlation between the spin and possible deviations from the Kerr geometry. Moreover, the correlation is very similar to that of the other two techniques, which makes the combination of different measurements not very helpful. Nevertheless, our results cannot be taken as conclusive and, in order to arrive at a final answer, the effect of returning radiation should be properly taken into account.

Description: We investigate unitarity within the complex-mass scheme, a convenient universal scheme for perturbative calculations involving unstable particles in quantum field theory which guarantees exact gauge invariance. Since this scheme requires one to introduce complex masses and complex couplings, the Cutkosky cutting rules, which express perturbative unitarity in theories of stable particles, are no longer valid. We derive corresponding rules for scalar theories with unstable particles based on Veltman’s largest-time equation and prove unitarity in this framework.

Description: We compute the decays \({B\rightarrow D^*_0}\) and \({B\rightarrow D^*_2}\) with finite masses for the b and c quarks. We first discuss the spectral properties of both the B meson as a function of its momentum and the \(D^*_0\) and \(D^*_2\) at rest. We compute the theoretical formulae leading to the decay amplitudes from the three-point and two-point correlators. We then compute the amplitudes at zero recoil of \({B\rightarrow D^*_0}\) , which turns out not to be vanishing contrary to what happens in the heavy quark limit. This opens the possibility to get better agreement with experiment. To improve the continuum limit we have added a set of data with smaller lattice spacing. The \({B\rightarrow D^*_2}\) vanishes at zero recoil and we show a convincing signal but only slightly more than 1 sigma from 0. In order to reach quantitatively significant results we plan to exploit fully smaller lattice spacings as well as another lattice regularisation.

Description: We present a simulation study of the prospects for the mass measurement of TeV-scale light-flavored right-handed squarks at a 3 TeV \(e^+e^-\) collider based on CLIC technology. In the considered model, these particles decay into their standard-model counterparts and the lightest neutralino, resulting in a signature of two jets plus missing energy. The analysis is based on full GEANT4 simulations of the CLIC_ILD detector concept, including Standard Model physics backgrounds and beam-induced hadronic backgrounds from two-photon processes. The analysis serves as a generic benchmark for the reconstruction of highly energetic jets in events with substantial missing energy. Several jet finding algorithms were evaluated, with the longitudinally invariant \(k_t\) algorithm showing a high degree of robustness towards beam-induced background while preserving the features typically found in algorithms developed for \(e^+e^-\) collisions. The presented study of the reconstruction of light-flavored squarks shows that for TeV-scale squark masses, sub-percent accuracy on the mass measurement can be achieved at CLIC.

Description: We evaluate the Hadamard function and the vacuum expectation value (VEV) of the current density for a charged scalar field, induced by flat boundaries in spacetimes with an arbitrary number of toroidally compactified spatial dimensions. The field operator obeys the Robin conditions on the boundaries and quasiperiodicity conditions with general phases along compact dimensions. In addition, the presence of a constant gauge field is assumed. The latter induces Aharonov–Bohm-type effect on the VEVs. There is a region in the space of the parameters in Robin boundary conditions where the vacuum state becomes unstable. The stability condition depends on the lengths of compact dimensions and is less restrictive than that for background with trivial topology. The vacuum current density is a periodic function of the magnetic flux, enclosed by compact dimensions, with the period equal to the flux quantum. It is explicitly decomposed into the boundary-free and boundary-induced contributions. In sharp contrast to the VEVs of the field squared and the energy-momentum tensor, the current density does not contain surface divergences. Moreover, for Dirichlet condition it vanishes on the boundaries. The normal derivative of the current density on the boundaries vanish for both Dirichlet and Neumann conditions and is nonzero for general Robin conditions. When the separation between the plates is smaller than other length scales, the behavior of the current density is essentially different for non-Neumann and Neumann boundary conditions. In the former case, the total current density in the region between the plates tends to zero. For Neumann boundary condition on both plates, the current density is dominated by the interference part and is inversely proportional to the separation.

Description: A small tensor-to-scalar ratio r may lead to distinctive phenomenology of high-scale supersymmetry. Assuming the same origin of SUSY breaking between the inflation and visible sector, we show model independent features. The simplest hybrid inflation, together with a new linear term for the inflaton field which is induced by a large gravitino mass, is shown to be consistent with all experimental data for r of order \(10^{-5}\) . For superpartner masses far above the weak scale we find that the reheating temperature after inflation might be below the value required by thermal leptogenesis if the inflaton decays to its products perturbatively, but above it if the decay is non-perturbatively instead. Remarkably, the gravitino overproduction can be evaded in such high-scale supersymmetry because of the kinematically blocking effect.

Description: We show how leading radiative corrections can be implemented in the general description of \(h\rightarrow 4\ell \) decays by means of pseudo observables (PO). With the inclusion of such corrections, the PO description of \(h\rightarrow 4\ell \) decays can be matched to next-to-leading-order electroweak calculations both within and beyond the Standard Model (SM). In particular, we demonstrate that with the inclusion of such corrections the complete next-to-leading-order SM prediction for the \(h\rightarrow 2e2\mu \) dilepton mass spectrum is recovered within \(1\,\%\) accuracy. The impact of radiative corrections for non-standard PO is also briefly discussed.

Description: A comprehensive review of physics at an \(e^+e^-\) linear collider in the energy range of \(\sqrt{s}=92\)  GeV–3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

Description: We investigate the fragmentation instability of hairy black holes in the theory with a Gauss–Bonnet (GB) term in asymptotically flat spacetime. Our approach is through the non-perturbative fragmentation instability. By this approach, we investigate whether the initial black hole can be broken into two black holes by comparing the entropy of the initial black hole with the sum of those of two fragmented black holes. The relation between the black hole instability and the GB coupling with dilaton hair are presented. We describe the phase diagrams with respect to the mass of the black hole solutions and coupling constants. We find that a perturbatively stable black hole can be unstable under fragmentation.

Description: A pulse-shape discrimination method based on artificial neural networks was applied to pulses simulated for different background, signal and signal-like interactions inside a germanium detector. The simulated pulses were used to investigate variations of efficiencies as a function of used training set. It is verified that neural networks are well-suited to identify background pulses in true-coaxial high-purity germanium detectors. The systematic uncertainty on the signal recognition efficiency derived using signal-like evaluation samples from calibration measurements is estimated to be 5 %. This uncertainty is due to differences between signal and calibration samples.

Description: In this article, we calculate the form factors and the coupling constant of the vertex \(D_{s}^{*}D_{s}\phi \) using the three-point QCD sum rules. We consider the contributions of the vacuum condensates up to dimension 7 in the operator product expansion. And all possible off-shell cases are considered, \(\phi \) , \(D_{s}\) and \(D_{s}^{*}\) , resulting in three different form factors. Then we fit the form factors into analytical functions and extrapolate them into time-like regions, which giving the coupling constant for the process. Our analysis indicates that the coupling constant for this vertex is \(G_{D_{s}^{*}D{_{s}}\phi }=4.12\pm 0.70\,\mathrm{GeV}^{-1}\) . The results of this work are very useful in the other phenomenological analysis. As an application, we calculate the coupling constant for the decay channel \(D_{s}^{*}\rightarrow D_{s}\gamma \) and analyze the width of this decay with the assumption of the vector meson dominance of the intermediate \(\phi (1020)\) . Our final result about the decay width of this decay channel is \(\Gamma =0.59\pm 0.15\,\mathrm{keV}\) .

Description: Extensive N -body simulations are among the key means for the study of numerous astrophysical and cosmological phenomena, so various schemes are developed for possibly higher accuracy computations. We demonstrate the principal possibility for revealing the evolution of a perturbed Hamiltonian system with an accuracy independent on time. The method is based on the Laplace transform and the derivation and analytical solution of an evolution equation in the phase space for the resolvent and using computer algebra.

Description: A search for a standard model Higgs boson produced in association with a top-quark pair and decaying to bottom quarks is presented. Events with hadronic jets and one or two oppositely charged leptons are selected from a data sample corresponding to an integrated luminosity of 19.5 \(\,\text {fb}^\text {-1}\) collected by the CMS experiment at the LHC in \(\mathrm {p}\mathrm {p}\) collisions at a centre-of-mass energy of 8 \(\,\hbox {TeV}\) . In order to separate the signal from the larger \(\hbox {t}\overline{\hbox {t}}\)  + jets background, this analysis uses a matrix element method that assigns a probability density value to each reconstructed event under signal or background hypotheses. The ratio between the two values is used in a maximum likelihood fit to extract the signal yield. The results are presented in terms of the measured signal strength modifier, \(\mu \) , relative to the standard model prediction for a Higgs boson mass of 125 \(\,\hbox {GeV}\) . The observed (expected) exclusion limit at a 95 % confidence level is \(\mu 〈4.2\) (3.3), corresponding to a best fit value \(\hat{\mu }=1.2^{+1.6}_{-1.5}\) .

Description: In this paper we are concerned with the effects of an anisotropic pressure on the boundary conditions of the anisotropic Lane–Emden equation and the homology theorem. Some new exact solutions of this equation are derived. Then some of the theorems governing the Newtonian perfect fluid star are extended, taking the anisotropic pressure into account.

Description: An optimized digital shaping filter has been developed for the Gerda experiment which searches for neutrinoless double beta decay in \(^{76}\) Ge. The Gerda Phase I energy calibration data have been reprocessed and an average improvement of 0.3 keV in energy resolution (FWHM) corresponding to 10 % at the \(Q\) value for \(0\nu \beta \beta \) decay in \(^{76}\) Ge is obtained. This is possible thanks to the enhanced low-frequency noise rejection of this Zero Area Cusp (ZAC) signal shaping filter.

Description: A generalisation of the narrow-width approximation (NWA) is formulated which allows for a consistent treatment of interference effects between nearly mass-degenerate particles in the factorisation of a more complicated process into production and decay parts. It is demonstrated that interference effects of this kind arising in BSM models can be very large, leading to drastic modifications of predictions based on the standard NWA. The application of the generalised NWA is demonstrated both at tree level and at one-loop order for an example process where the neutral Higgs bosons h and H of the MSSM are produced in the decay of a heavy neutralino and subsequently decay into a fermion pair. The generalised NWA, based on on-shell matrix elements or their approximations leading to simple weight factors, is shown to produce UV- and IR-finite results which are numerically close to the result of the full process at tree level and at one-loop order, where an agreement of better than \(1\,\%\) is found for the considered process. The most accurate prediction for this process based on the generalised NWA, taking into account also corrections that are formally of higher orders, is briefly discussed.

Description: A new theory of gravity called Eddington-inspired Born–Infeld (EiBI) gravity was recently proposed by Bañados and Ferreira. This theory leads to some exciting new features, such as free of cosmological singularities. In this paper, we first obtain a charged EiBI black hole solution with a nonvanishing cosmological constant when the electromagnetic field is included in. Then based on it, we study the strong gravitational lensing by the asymptotic flat charged EiBI black hole. The strong deflection limit coefficients and observables are shown to closely depend on the additional coupling parameter \(\kappa \) in the EiBI gravity. It is found that, compared with the corresponding charged black hole in general relativity, the positive coupling parameter \(\kappa \) will shrink the black hole horizon and photon sphere. Moreover, the coupling parameter will decrease the angular position and relative magnitudes of the relativistic images, while increase the angular separation, which may shine new light on testing such gravity theory in near future by the astronomical instruments.

Description: This manuscript is devoted to the investigation of the Bianchi type I universe in the context of f ( R ,  T ) gravity. For this purpose, we explore the exact solutions of locally rotationally symmetric Bianchi type I spacetime. The modified field equations are solved by assuming an expansion scalar \(\theta \) proportional to the shear scalar \(\sigma \) , which gives \(A=B^n\) , where A ,   B are the metric coefficients and n is an arbitrary constant. In particular, three solutions have been found and physical quantities are calculated in each case.

Description: By detecting redshift drift in the spectra of the Lyman- \(\alpha \) forest of distant quasars, the Sandage–Loeb (SL) test directly measures the expansion of the universe, covering the “redshift desert” of \(2 \lesssim z \lesssim 5\) . Thus this method is definitely an important supplement to the other geometric measurements and will play a crucial role in cosmological constraints. In this paper, we quantify the ability of the SL test signal by a CODEX-like spectrograph for constraining interacting dark energy. Four typical interacting dark energy models are considered: (i) \(Q=\gamma H\rho _c\) , (ii) \(Q=\gamma H\rho _{de}\) , (iii) \(Q=\gamma H_0\rho _c\) , and (iv) \(Q=\gamma H_0\rho _{de}\) . The results show that for all the considered interacting dark energy models, relative to the current joint SN  \(+\)  BAO  \(+\)  CMB  \(+\)   \(H_0\) observations, the constraints on \(\Omega _m\) and \(H_0\) would be improved by about 60 and 30–40 %, while the constraints on w and \(\gamma \) would be slightly improved, with a 30-year observation of the SL test. We also explore the impact of the SL test on future joint geometric observations. In this analysis, we take the model with \(Q=\gamma H\rho _c\) as an example, and we simulate future SN and BAO data based on the space-based project WFIRST. We find that with the future geometric constraints, the redshift drift observations would help break the geometric degeneracies in a meaningful way, thus the measurement precisions of \(\Omega _m\) , \(H_0\) , w , and \(\gamma \) could be substantially improved using future probes.

Description: To identify the nature of the newly observed charged resonance \(Z_c(4200)^+\) , we study its hadronic decays \(Z_c(4200)^+\rightarrow J/\psi \pi ^+, Z_c(4200)^+\rightarrow \eta _c\rho ^+\) and \(Z_c(4200)^+\rightarrow D^+\bar{D}^{*0}\) as a charmonium-like tetraquark state. In the framework of the QCD sum rules, we calculate the three-point functions and extract the coupling constants and decay widths for these interaction vertices. Including all these channels, the full decay width of the \(Z_c(4200)^+\) state is consistent with the experimental value reported by the Belle Collaboration, supporting the tetraquark interpretation of this state.

Description: A search for heavy long-lived multi-charged particles is performed using the ATLAS detector at the LHC. Data collected in 2012 at \(\sqrt{s}=8\)  TeV from pp collisions corresponding to an integrated luminosity of 20.3 fb \(^{-1}\) are examined. Particles producing anomalously high ionisation, consistent with long-lived massive particles with electric charges from \(|q|=2e\) to \(|q|=6e\) are searched for. No signal candidate events are observed, and 95 % confidence level cross-section upper limits are interpreted as lower mass limits for a Drell–Yan production model. The mass limits range between 660 and 785 GeV.

Description: We study to which extent SUSY extensions of the Standard Model can describe the excess of events of 3.0 standard deviations observed by ATLAS in the on- Z signal region, respecting constraints by CMS on similar signal channels as well as constraints from searches for jets and \(E^\mathrm{miss}_\text {T}\) . GMSB-like scenarios are typically in conflict with these constraints, and do not reproduce well the shape of the \(E^\mathrm{miss}_\text {T}\) distribution of the data. An alternative scenario with two massive neutralinos can improve fits to the total number of events as well as to the \(H_\text {T}\) and \(E^\mathrm{miss}_\text {T}\) distributions. Such a scenario can be realised within the NMSSM.

Description: Leading-twist operators have a remarkable property that their divergence vanishes in a free theory. Recently it was suggested that this property can be used for an alternative technique to calculate anomalous dimensions of leading-twist operators and allows one to gain one order in perturbation theory so that, i.e., two-loop anomalous dimensions can be calculated from one-loop Feynman diagrams, etc. In this work we study the feasibility of this program by a toy-model example of the \(\varphi ^3\) theory in six dimensions. Our conclusion is that this approach is valid, although it does not seem to present considerable technical simplifications as compared to the standard technique. It does provide one, however, with a very nontrivial check of the calculation as the structure of the contributions is very different.

Description: Recently, a family of interesting analytical brane solutions were found in f ( R ) gravity with \(f(R)=R \,+\, \alpha R^2\) in Bazeia et al. (Phys Lett B 729:127 2014 ). In these solutions, the inner brane structure can be turned on by tuning the value of the parameter \(\alpha \) . In this paper, we investigate how the parameter \(\alpha \) affects the localization and the quasilocalization of the tensorial gravitons around these solutions. It is found that, in a range of \(\alpha \) , despite the brane having an inner structure, there is no graviton resonance. However, in some other regions of the parameter space, although the brane has no internal structure, the effective potential for the graviton Kaluza–Klein (KK) modes has a singular structure, and there exist a series of graviton resonant modes. The contribution of the massive graviton KK modes to Newton’s law of gravity is discussed briefly.

Description: The production of the Standard Model Higgs boson in association with a vector boson, followed by the dominant decay to \(H \rightarrow b\bar{b}\) , is a strong prospect for confirming and measuring the coupling to b -quarks in pp collisions at \(\sqrt{s}=14\)  TeV. We present an updated study of the prospects for this analysis, focussing on the most sensitive highly Lorentz-boosted region. The evolution of the efficiency and composition of the signal and main background processes as a function of the transverse momentum of the vector boson are studied covering the region 200–1000 GeV, comparing both a conventional dijet and jet substructure selection. The lower transverse momentum region (200–400 GeV) is identified as the most sensitive region for the Standard Model search, with higher transverse momentum regions not improving the statistical sensitivity. For much of the studied region (200–600 GeV), a conventional dijet selection performs as well as the substructure approach, while for the highest transverse momentum regions ( \(〉\) 600 GeV), which are particularly interesting for Beyond the Standard Model and high luminosity measurements, the jet substructure techniques are essential.

Description: Massive QED, in contrast with its massless counterpart, possesses two conserved charges; one is a screened (vanishing) Maxwell charge which is directly associated with the massive vector mesons through the identically conserved Maxwell current, while the presence of a particle-antiparticle counting charge depends on the matter. A somewhat peculiar situation arises for couplings of Hermitian matter fields to massive vector potentials; in that case the only current is the screened Maxwell current and the coupling disappears in the massless limit. In the case of self-interacting massive vector mesons the situation becomes even more peculiar in that the usually renormalizability guaranteeing validity of the first order power-counting criterion breaks down in second order and requires the compensatory presence of additional Hermitian H -fields. Some aspect of these observation have already been noticed in the BRST gauge theoretic formulation, but here we use a new setting based on string-local vector mesons which is required by Hilbert space positivity (“off-shell unitarity”). This new formulation explains why spontaneous symmetry breaking cannot occur in the presence of higher spin \(s\ge 1\)  fields. The coupling to H -fields induces Mexican hat-like self-interactions; they are not imposed and bear no relation with spontaneous symmetry breaking; they are rather consequences of the foundational causal localization properties realized in a Hilbert space setting. In the case of self-interacting massive vector mesons their presence is required in order to maintain the first order power-counting restriction of renormalizability also in second order. The presentation of the new Hilbert space setting for vector mesons which replaces gauge theory and extends on-shell unitarity to its off-shell counterpart is the main motivation for this work. The new Hilbert space setting also shows that the second order Lie-algebra structure of self-interacting vector mesons is a consequence of the principles of QFT and promises a deeper understanding of the origin of confinement.

Description: We develop a methodology for the construction of a Hessian representation of Monte Carlo sets of parton distributions, based on the use of a subset of the Monte Carlo PDF replicas as an unbiased linear basis, and of a genetic algorithm for the determination of the optimal basis. We validate the methodology by first showing that it faithfully reproduces a native Monte Carlo PDF set (NNPDF3.0), and then, that if applied to Hessian PDF set (MMHT14) which was transformed into a Monte Carlo set, it gives back the starting PDFs with minimal information loss. We then show that, when applied to a large Monte Carlo PDF set obtained as combination of several underlying sets, the methodology leads to a Hessian representation in terms of a rather smaller set of parameters (MC-H PDFs), thereby providing an alternative implementation of the recently suggested Meta-PDF idea and a Hessian version of the recently suggested PDF compression algorithm (CMC-PDFs). The mc2hessian conversion code is made publicly available together with (through LHAPDF6 ) a Hessian representations of the NNPDF3.0 set, and the MC-H PDF set.

Description: We explore a fermionic dark matter model with a possible extension of Standard Model of particle physics into two Higgs doublet model. Higgs doublets couple to the singlet fermionic dark matter through a non-renormalisable coupling providing a new physics scale. We explore the viability of such dark matter candidate and constrain the model parameter space by collider serach, relic density of DM, direct detection measurements of DM-nucleon scattering cross-section and with the experimentally obtained results from indirect search of dark matter.

Description: An overview of the flavour problem is presented, with emphasis on the theoretical efforts to find a satisfactory description of the fermion masses and the mixing angles.

Description: The production of the massive bosons \(Z^0\) and \(W^{\pm }\) could provide an excellent tool to study cold nuclear matter effects and the modifications of nuclear parton distribution functions (nPDFs) relative to the parton distribution functions (PDFs) of a free proton in high-energy nuclear reactions at the LHC as well as in heavy-ion collisions (HIC) with much higher center-of-mass energies available in the future colliders. In this paper we calculate the rapidity and transverse momentum distributions of the vector boson and their nuclear modification factors in p + Pb collisions at \(\sqrt{s_{NN}}=63\)  TeV and in Pb + Pb collisions at \(\sqrt{s_{NN}}=39\)  TeV in the framework of perturbative QCD by utilizing three parametrization sets of nPDFs: EPS09, DSSZ, and nCTEQ. It is found that in heavy-ion collisions at such high colliding energies, both the rapidity distribution and the transverse momentum spectrum of vector bosons are considerably suppressed in wide kinematic regions with respect to p + p reactions due to large nuclear shadowing effect. We demonstrate that the massive vector boson production processes with sea quarks in the initial state may give more contributions than those with valence quarks in the initial state; therefore in future heavy-ion collisions the isospin effect is less pronounced and the charge asymmetry of the W boson will be reduced significantly as compared to that at the LHC. A large difference between results with nCTEQ and results with EPS09 and DSSZ is observed in nuclear modifications of both rapidity and \(p_T\) distributions of \(Z^0\) and W in the future HIC.

Description: We present a frequentist analysis of the parameter space of the pMSSM10, in which the following ten soft SUSY-breaking parameters are specified independently at the mean scalar top mass scale \(M_\mathrm{SUSY}\equiv \sqrt{m_{\tilde{t}_{1}} m_{\tilde{t}_{2}}}\) : the gaugino masses \(M_{1,2,3}\) , the first-and second-generation squark masses \(m_{\tilde{q}_1}= m_{\tilde{q}_2}\) , the third-generation squark mass \(m_{\tilde{q}_3}\) , a common slepton mass \(m_{\tilde{\ell }}\) and a common trilinear mixing parameter A , as well as the Higgs mixing parameter \(\mu \) , the pseudoscalar Higgs mass \(M_A\) and \(\tan \beta \) , the ratio of the two Higgs vacuum expectation values. We use the MultiNest sampling algorithm with \(\sim \) 1.2 \(\times 10^9\) points to sample the pMSSM10 parameter space. A dedicated study shows that the sensitivities to strongly interacting sparticle masses of ATLAS and CMS searches for jets, leptons \(+\) signals depend only weakly on many of the other pMSSM10 parameters. With the aid of the Atom and Scorpion codes, we also implement the LHC searches for electroweakly interacting sparticles and light stops, so as to confront the pMSSM10 parameter space with all relevant SUSY searches. In addition, our analysis includes Higgs mass and rate measurements using the HiggsSignals code, SUSY Higgs exclusion bounds, the measurements of \(\mathrm{BR}(B_s \rightarrow \mu ^+\mu ^-)\) by LHCb and CMS, other B -physics observables, electroweak precision observables, the cold dark matter density and the XENON100 and LUX searches for spin-independent dark matter scattering, assuming that the cold dark matter is mainly provided by the lightest neutralino \(\tilde{\chi }^0_{1}\) . We show that the pMSSM10 is able to provide a supersymmetric interpretation of \((g-2)_\mu \) , unlike the CMSSM, NUHM1 and NUHM2. As a result, we find (omitting Higgs rates) that the minimum \(\chi ^2 = 20.5\) with 18 degrees of freedom (d.o.f.) in the pMSSM10, corresponding to a \(\chi ^2\) probability of 30.8 %, to be compared with \(\chi ^2/\mathrm{d.o.f.} = 32.8/24 \ (31.1/23) \ (30.3/22)\) in the CMSSM (NUHM1) (NUHM2). We display the one-dimensional likelihood functions for sparticle masses, and we show that they may be significantly lighter in the pMSSM10 than in the other models, e.g., the gluino may be as light as \(\sim \) 1250 \(\,\, \mathrm {GeV}\) at the 68 % CL, and squarks, stops, electroweak gauginos and sleptons may be much lighter than in the CMSSM, NUHM1 and NUHM2. We discuss the discovery potential of future LHC runs, \(e^+e^-\) colliders and direct detection experiments.

Description: We compute the corrections to the Schwarzschild metric necessary to reproduce the Hawking temperature derived from a generalized uncertainty principle (GUP), so that the GUP deformation parameter is directly linked to the deformation of the metric. Using this modified Schwarzschild metric, we compute corrections to the standard general relativistic predictions for the light deflection and perihelion precession, both for planets in the solar system and for binary pulsars. This analysis allows us to set bounds for the GUP deformation parameter from well-known astronomical measurements.

Description: LHC searches for non-standard Higgs bosons decaying into tau lepton pairs constitute a sensitive experimental probe for physics beyond the Standard Model (BSM), such as supersymmetry (SUSY). Recently, the limits obtained from these searches have been presented by the CMS collaboration in a nearly model-independent fashion – as a narrow resonance model – based on the full \(8\,\, \mathrm {TeV}\) dataset. In addition to publishing a \(95~\%~\mathrm {C.L.}\) exclusion limit, the full likelihood information for the narrow resonance model has been released. This provides valuable information that can be incorporated into global BSM fits. We present a simple algorithm that maps an arbitrary model with multiple neutral Higgs bosons onto the narrow resonance model and derives the corresponding value for the exclusion likelihood from the CMS search. This procedure has been implemented into the public computer code HiggsBounds (version 4.2.0 and higher). We validate our implementation by cross-checking against the official CMS exclusion contours in three Higgs benchmark scenarios in the Minimal Supersymmetric Standard Model (MSSM), and find very good agreement. Going beyond validation, we discuss the combined constraints of the \(\tau \tau \) search and the rate measurements of the SM-like Higgs at \(125\,\, \mathrm {GeV}\) in a recently proposed MSSM benchmark scenario, where the lightest Higgs boson obtains SM-like couplings independently of the decoupling of the heavier Higgs states. Technical details for how to access the likelihood information within HiggsBounds are given in the appendix. The program is available at http://higgsbounds.hepforge.org .

Description: Nucleobase modifications dramatically alter nucleic acid structure and thermodynamics. 2-thiouridine (s 2 U) is a modified nucleobase found in tRNAs and known to stabilize U:A base pairs and destabilize U:G wobble pairs. The recently reported crystal structures of s 2 U-containing RNA duplexes do not entirely explain the mechanisms responsible for the stabilizing effect of s 2 U or whether this effect is entropic or enthalpic in origin. We present here thermodynamic evaluations of duplex formation using ITC and UV thermal denaturation with RNA duplexes containing internal s 2 U:A and s 2 U:U pairs and their native counterparts. These results indicate that s 2 U stabilizes both duplexes. The stabilizing effect is entropic in origin and likely results from the s 2 U-induced preorganization of the single-stranded RNA prior to hybridization. The same preorganizing effect is likely responsible for structurally resolving the s 2 U:U pair-containing duplex into a single conformation with a well-defined H-bond geometry. We also evaluate the effect of s 2 U on single strand conformation using UV- and CD-monitored thermal denaturation and on nucleoside conformation using 1 H NMR spectroscopy, MD and umbrella sampling. These results provide insights into the effects that nucleobase modification has on RNA structure and thermodynamics and inform efforts toward improving both ribozyme-catalyzed and nonenzymatic RNA copying.

Description: DNA interstrand crosslinks (ICLs) are the primary mechanism for the cytotoxic activity of many clinical anticancer drugs, and numerous strategies for forming ICLs have been developed. One such method is using crosslink-forming oligonucleotides (CFOs). In this study, we designed a 4-amino-6-oxo-2-vinylpyrimidine (AOVP) derivative with an acyclic spacer to react selectively with guanine. The AOVP CFO exhibited selective crosslinking reactivity with guanine and thymine in DNA, and with guanine in RNA. These crosslinking reactions with guanine were accelerated in the presence of CoCl 2 , NiCl 2 , ZnCl 2 and MnCl 2 . In addition, we demonstrated that the AOVP CFO was reactive toward 8-oxoguanine opposite AOVP in the duplex DNA. The structural analysis of each guanine and 8-oxoguanine adduct in the duplex DNA was investigated by high-resolution NMR. The results suggested that AOVP reacts at the N2 amine in guanine and at the N1 or N2 amines in 8-oxoguanine in the duplex DNA. This study demonstrated the first direct determination of the adduct structure in duplex DNA without enzyme digestion.

Description: The sequencing of the full transcriptome (RNA-seq) has become the preferred choice for the measurement of genome-wide gene expression. Despite its widespread use, challenges remain in RNA-seq data analysis. One often-overlooked aspect is normalization. Despite the fact that a variety of factors or ‘batch effects’ can contribute unwanted variation to the data, commonly used RNA-seq normalization methods only correct for sequencing depth. The study of gene expression is particularly problematic when it is influenced simultaneously by a variety of biological factors in addition to the one of interest. Using examples from experimental neuroscience, we show that batch effects can dominate the signal of interest; and that the choice of normalization method affects the power and reproducibility of the results. While commonly used global normalization methods are not able to adequately normalize the data, more recently developed RNA-seq normalization can. We focus on one particular method, RUVSeq and show that it is able to increase power and biological insight of the results. Finally, we provide a tutorial outlining the implementation of RUVSeq normalization that is applicable to a broad range of studies as well as meta-analysis of publicly available data.

Description: Many antiproliferative G-quadruplexes (G4s) arise from the folding of GT-rich strands. Among these, the Thrombin Binding Aptamer (TBA), as a rare example, adopts a monomolecular well-defined G4 structure. Nevertheless, the potential anticancer properties of TBA are severely hampered by its anticoagulant action and, consequently, no related studies have appeared so far in the literature. We wish to report here that suitable chemical modifications in the TBA sequence can preserve its antiproliferative over anticoagulant activity. Particularly, we replaced one residue of the TT or TGT loops with a dibenzyl linker to develop seven new quadruplex-forming TBA based sequences (TBA-bs), which were studied for their structural (CD, CD melting, 1D NMR) and biological (fibrinogen, PT and MTT assays) properties. The three-dimensional structures of the TBA-bs modified at T13 (TBA-bs13) or T12 (TBA-bs12), the former endowed with selective antiproliferative activity, and the latter acting as potently as TBA in both coagulation and MTT assays, were further studied by 2D NMR restrained molecular mechanics. The comparative structural analyses indicated that neither the stability, nor the topology of the G4s, but the different localization of the two benzene rings of the linker was responsible for the loss of the antithrombin activity for TBA-bs13.

Description: A structural and functional classification of H/ACA and H/ACA-like motifs is obtained from the analysis of the H/ACA guide RNAs which have been identified previously in the genomes of Euryarchaea (Pyrococcus) and Crenarchaea (Pyrobaculum). A unified structure/function model is proposed based on the common structural determinants shared by H/ACA and H/ACA-like motifs in both Euryarchaea and Crenarchaea. Using a computational approach, structural and energetic rules for the guide:target RNA-RNA interactions are derived from structural and functional data on the H/ACA RNP particles. H/ACA(-like) motifs found in Pyrococcus are evaluated through the classification and their biological relevance is discussed. Extra-ribosomal targets found in both Pyrococcus and Pyrobaculum might support the hypothesis of a gene regulation mediated by H/ACA(-like) guide RNAs in archaea.

Description: Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson–Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine–thymine (A–T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events.

Description: Sequence alignment is a long standing problem in bioinformatics. The Basic Local Alignment Search Tool (BLAST) is one of the most popular and fundamental alignment tools. The explosive growth of biological sequences calls for speedup of sequence alignment tools such as BLAST. To this end, we develop high speed BLASTN (HS-BLASTN), a parallel and fast nucleotide database search tool that accelerates MegaBLAST—the default module of NCBI-BLASTN. HS-BLASTN builds a new lookup table using the FMD-index of the database and employs an accurate and effective seeding method to find short stretches of identities (called seeds) between the query and the database. HS-BLASTN produces the same alignment results as MegaBLAST and its computational speed is much faster than MegaBLAST. Specifically, our experiments conducted on a 12-core server show that HS-BLASTN can be 22 times faster than MegaBLAST and exhibits better parallel performance than MegaBLAST. HS-BLASTN is written in C++ and the related source code is available at https://github.com/chenying2016/queries under the GPLv3 license.

Description: Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo . Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.

Description: Ten eleven translocation (Tet) family-mediated DNA oxidation on 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) represents a novel epigenetic modification that regulates dynamic gene expression during embryonic stem cells (ESCs) differentiation. Through the role of Tet on 5hmC regulation in stem cell development is relatively defined, how the Tet family is regulated and impacts on ESCs lineage development remains elusive. In this study, we show non-coding RNA regulation on Tet family may contribute to epigenetic regulation during ESCs differentiation, which is suggested by microRNA-29b (miR-29b) binding sites on the Tet1 3' untranslated region (3' UTR). We demonstrate miR-29b increases sharply after embyoid body (EB) formation, which causes Tet1 repression and reduction of cellular 5hmC level during ESCs differentiation. Importantly, we show this miR-29b/Tet1 regulatory axis promotes the mesendoderm lineage formation both in vitro and in vivo by inducing the Nodal signaling pathway and repressing the key target of the active demethylation pathway, Tdg. Taken together, our findings underscore the contribution of small non-coding RNA mediated regulation on DNA demethylation dynamics and the differential expressions of key mesendoderm regulators during ESCs lineage specification. MiR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells.

Description: The emergence of multidrug-resistant pathogens will make current antibiotics ineffective. For linezolid, a member of the novel oxazolidinone class of antibiotics, 10 nucleotide mutations in the ribosome have been described conferring resistance. Hypotheses for how these mutations affect antibiotics binding have been derived based on comparative crystallographic studies. However, a detailed description at the atomistic level of how remote mutations exert long-distance effects has remained elusive. Here, we show that the G2032A-C2499A double mutation, located 〉 10 Å away from the antibiotic, confers linezolid resistance by a complex set of effects that percolate to the binding site. By molecular dynamics simulations and free energy calculations, we identify U2504 and C2452 as spearheads among binding site nucleotides that exert the most immediate effect on linezolid binding. Structural reorganizations within the ribosomal subunit due to the mutations are likely associated with mutually compensating changes in the effective energy. Furthermore, we suggest two main routes of information transfer from the mutation sites to U2504 and C2452. Between these, we observe cross-talk, which suggests that synergistic effects observed for the two mutations arise in an indirect manner. These results should be relevant for the development of oxazolidinone derivatives that are active against linezolid-resistant strains.

Description: Genes from yeast to mammals are frequently subject to non-coding transcription of their antisense strand; however the genome-wide role for antisense transcription remains elusive. As transcription influences chromatin structure, we took a genome-wide approach to assess which chromatin features are associated with nascent antisense transcription, and contrast these with features associated with nascent sense transcription. We describe a distinct chromatin architecture at the promoter and gene body specifically associated with antisense transcription, marked by reduced H2B ubiquitination, H3K36 and H3K79 trimethylation and increased levels of H3 acetylation, chromatin remodelling enzymes, histone chaperones and histone turnover. The difference in sense transcription between genes with high or low levels of antisense transcription is slight; thus the antisense transcription-associated chromatin state is not simply analogous to a repressed state. Using mutants in which the level of antisense transcription is reduced at GAL1 , or altered genome-wide, we show that non-coding transcription is associated with high H3 acetylation and H3 levels across the gene, while reducing H3K36me3. Set1 is required for these antisense transcription-associated chromatin changes in the gene body. We propose that nascent antisense and sense transcription have fundamentally distinct relationships with chromatin, and that both should be considered canonical features of eukaryotic genes.

Description: Clonal populations accumulate mutations over time, resulting in different haplotypes. Deep sequencing of such a population in principle provides information to reconstruct these haplotypes and the frequency at which the haplotypes occur. However, this reconstruction is technically not trivial, especially not in clonal systems with a relatively low mutation frequency. The low number of segregating sites in those systems adds ambiguity to the haplotype phasing and thus obviates the reconstruction of genome-wide haplotypes based on sequence overlap information. Therefore, we present EVORhA, a haplotype reconstruction method that complements phasing information in the non-empty read overlap with the frequency estimations of inferred local haplotypes. As was shown with simulated data, as soon as read lengths and/or mutation rates become restrictive for state-of-the-art methods, the use of this additional frequency information allows EVORhA to still reliably reconstruct genome-wide haplotypes. On real data, we show the applicability of the method in reconstructing the population composition of evolved bacterial populations and in decomposing mixed bacterial infections from clinical samples.

Description: Upon stable cell line generation, chromosomal integration site of the vector DNA has a major impact on transgene expression. Here we apply an active gene environment, rather than specified genetic elements, in expression vectors used for random integration. We generated a set of Bacterial Artificial Chromosome (BAC) vectors with different open chromatin regions, promoters and gene regulatory elements and tested their impact on recombinant protein expression in CHO cells. We identified the Rosa26 BAC as the most efficient vector backbone showing a nine-fold increase in both polyclonal and clonal production of the human IgG-Fc. Clonal protein production was directly proportional to integrated vector copy numbers and remained stable during 10 weeks without selection pressure. Finally, we demonstrated the advantages of BAC-based vectors by producing two additional proteins, HIV-1 glycoprotein CN54gp140 and HIV-1 neutralizing PG9 antibody, in bioreactors and shake flasks reaching a production yield of 1 g/l.

Description: Recent releases of genome three-dimensional (3D) structures have the potential to transform our understanding of genomes. Nonetheless, the storage technology and visualization tools need to evolve to offer to the scientific community fast and convenient access to these data. We introduce simultaneously a database system to store and query 3D genomic data ( 3DBG ), and a 3D genome browser to visualize and explore 3D genome structures ( 3DGB ). We benchmark 3DBG against state-of-the-art systems and demonstrate that it is faster than previous solutions, and importantly gracefully scales with the size of data. We also illustrate the usefulness of our 3D genome Web browser to explore human genome structures. The 3D genome browser is available at http://3dgb.cs.mcgill.ca/ .

Description: Due to their relatively low-cost per sample and broad, gene-centric coverage of CpGs across the human genome, Illumina's 450k arrays are widely used in large scale differential methylation studies. However, by their very nature, large studies are particularly susceptible to the effects of unwanted variation. The effects of unwanted variation have been extensively documented in gene expression array studies and numerous methods have been developed to mitigate these effects. However, there has been much less research focused on the appropriate methodology to use for accounting for unwanted variation in methylation array studies. Here we present a novel 2-stage approach using RUV-inverse in a differential methylation analysis of 450k data and show that it outperforms existing methods.

Description: Telomerase is a reverse transcriptase that maintains telomeres on the ends of chromosomes, allowing rapidly dividing cells to proliferate while avoiding senescence and apoptosis. Understanding telomerase gene expression and splicing at the single cell level could yield insights into the roles of telomerase during normal cell growth as well as cancer development. Here we use droplet-based single cell culture followed by single cell or colony transcript abundance analysis to investigate the relationship between cell growth and transcript abundance of the telomerase genes encoding the RNA component (hTR) and protein component (hTERT) as well as hTERT splicing. Jurkat and K562 cells were examined under normal cell culture conditions and during exposure to curcumin, a natural compound with anti-carcinogenic and telomerase activity-reducing properties. Individual cells predominantly express single hTERT splice variants, with the α+/β– variant exhibiting significant transcript abundance bimodality that is sustained through cell division. Sub-lethal curcumin exposure results in reduced bimodality of all hTERT splice variants and significant upregulation of alpha splicing, suggesting a possible role in cellular stress response. The single cell culture and transcript abundance analysis method presented here provides the tools necessary for multiparameter single cell analysis which will be critical for understanding phenotypes of heterogeneous cell populations, disease cell populations and their drug response.

Description: We investigate inflation within \(f(R,\phi )\) -theories, where a dynamical scalar field is coupled to gravity. A class of models which can support early-time acceleration with the emerging of an effective cosmological constant at high curvature is studied. The dynamics of the field allow for exit from inflation leading to the correct amount of inflation in agreement with cosmological data. Furthermore, the spectral index and tensor-to-scalar ratio of the models are carefully analyzed. A generalization of the theory to incorporate dark matter in the context of mimetic gravity, and further extensions of the latter, are also discussed.

Description: The existence of both a minimum mass and a minimum density in nature, in the presence of a positive cosmological constant, is one of the most intriguing results in classical general relativity. These results follow rigorously from the Buchdahl inequalities in four-dimensional de Sitter space. In this work, we obtain the generalized Buchdahl inequalities in arbitrary space–time dimensions with \(\Lambda \ne 0\) and consider both the de Sitter and the anti-de Sitter cases. The dependence on D , the number of space–time dimensions, of the minimum and maximum masses for stable spherical objects is explicitly obtained. The analysis is then extended to the case of dark energy satisfying an arbitrary linear barotropic equation of state. The Jeans instability of barotropic dark energy is also investigated, for arbitrary D , in the framework of a simple Newtonian model with and without viscous dissipation, and we determine the dispersion relation describing the dark energy–matter condensation process, along with estimates of the corresponding Jeans mass (and radius). Finally, the quantum mechanical implications of the mass limits are investigated, and we show that the existence of a minimum mass scale naturally leads to a model in which dark energy is composed of a ‘sea’ of quantum particles, each with an effective mass proportional to \(\Lambda ^{1/4}\) .

Description: We study multi-soliton solutions of the four-dimensional SU(N) Skyrme model by combining the hedgehog ansatz for SU(N) based on the harmonic maps of \(S^{2}\) into \(CP^{N-1}\) and a geometrical trick which allows to analyze explicitly finite-volume effects without breaking the relevant symmetries of the ansatz. The geometric set-up allows to introduce a parameter which is related to the ’t Hooft coupling of a suitable large N limit, in which \(N\rightarrow \infty \) and the curvature of the background metric approaches zero, in such a way that their product is constant. The relevance of such a parameter to the physics of the system is pointed out. In particular, we discuss how the discrete symmetries of the configurations depend on it.

Description: The effects of color reconnection (CR) at \({\mathrm e}^+{\mathrm e}^-\) colliders are revisited, with focus on recently developed CR models. The new models are compared with the LEP2 measurements for \({\mathrm e}^+{\mathrm e}^- \rightarrow {\mathrm W}^+{\mathrm W}^- \rightarrow {\mathrm q}_1 \overline{\mathrm q}_2 {\mathrm q}_3 \overline{\mathrm q}_4\) and found to lie within their limits. Prospects for constraints from new high-luminosity \({\mathrm e}^+{\mathrm e}^-\) colliders are discussed. The novel arena of CR in Higgs decays is introduced, and it is illustrated by shifts in angular correlations that would be used to set limits on a potential CP -odd admixture of the 125 GeV Higgs state.

Description: The Lorentz transformation properties of the equal-time bound-state Bethe–Salpeter amplitude in the two-dimensional massless quantum electrodynamics (the so-called Schwinger model) are considered. It is shown that while boosting a bound state (a ‘meson’) this amplitude is subject to approximate Lorentz contraction. The effect is exact for large separations of constituent particles (‘quarks’), while for small distances the deviation is more significant. For this phenomenon to appear, the full function, i.e. with the inclusion of all instanton contributions, has to be considered. The amplitude in each separate topological sector does not exhibit such properties.

Description: The canonical Aharonov–Bohm effect is usually studied with time-independent potentials. In this work, we investigate the Aharonov–Bohm phase acquired by a charged particle moving in time-dependent potentials. In particular, we focus on the case of a charged particle moving in the time-varying field of a plane electromagnetic wave. We work out the Aharonov–Bohm phase using both the potential (i.e. \(\oint A_\mu \mathrm{d}x ^\mu \) ) and the field (i.e. \(\frac{1}{2}\int F_{\mu \nu } \mathrm{d}\sigma ^{\mu \nu }\) ) forms of the Aharonov–Bohm phase. We give conditions in terms of the parameters of the system (frequency of the electromagnetic wave, the size of the space–time loop, amplitude of the electromagnetic wave) under which the time-varying Aharonov–Bohm effect could be observed.

Description: The LHC data on jet fragmentation function and jet shapes in PbPb collisions at center-of-mass energy 2.76 TeV per nucleon pair are analyzed and interpreted in the frameworks of PYthia QUENched (PYQUEN) jet quenching model. A specific modification of longitudinal and radial jet profiles in most central PbPb collisions as compared with pp data is close to that obtained with PYQUEN simulations, taking into account wide-angle radiative and collisional partonic energy losses. The contribution of radiative and collisional loss to the medium-modified intra-jet structure is estimated.

Description: When averages of different experimental determinations of the same quantity are computed, each with statistical and systematic error components, then frequently the statistical and systematic components of the combined error are quoted explicitly. These are important pieces of information since statistical errors scale differently and often more favorably with the sample size than most systematical or theoretical errors. In this communication we describe a transparent procedure by which the statistical and systematic error components of the combination uncertainty can be obtained. We develop a general method and derive a general formula for the case of Gaussian errors with or without correlations. The method can easily be applied to other error distributions, as well. For the case of two measurements, we also define disparity and misalignment angles, and discuss their relation to the combination weight factors.

Description: In this work, we have studied the accretion of the \((n+2)\) -dimensional charged BTZ black hole (BH). The critical point and square speed of sound have been obtained. The mass of the BTZ BH has been calculated and we have observed that the mass of the BTZ BH is related with the square root of the energy density of the dark energy which accretes onto the BH in our accelerating FRW universe. We have assumed modified Chaplygin gas (MCG) as a candidate of dark energy which accretes onto the BH and we have found the expression of BTZ BH mass. Since in our solution of MCG, this model generates only quintessence dark energy (not phantom) and so BTZ BH mass increases during the whole evolution of the accelerating universe. Next we have assumed five kinds of parametrizations of well-known dark-energy models. These models generate both quintessence and phantom scenarios i.e., phantom crossing models. So if these dark energies accrete onto the BTZ BH, then in the quintessence stage, the BH mass increases up to a certain value (finite value) and then decreases to a certain finite value for the phantom stage during the whole evolution of the universe. We have shown these results graphically.

Description: We consider lepton-flavour violating decays of the top quark, mediated by 4-fermion operators. We compile constraints on a complete set of SU(3)  \(\times \)  U(1)-invariant operators, arising from their loop contributions to rare decays and from HERA’s single-top search. The bounds on e – \(\mu \) flavour change are more restrictive than on \(\ell \) – \(\tau \) ; nonetheless the top could decay to a jet \({+} e \bar{\mu }\) with a branching ratio of order \(10^{-3}\) . We estimate that the currently available LHC data (20 fb \(^{-1}\) at 8 TeV) could be sensitive to \(BR(t \rightarrow e \bar{\mu }\) + jet) \( {\sim } 6\times 10^{-5}\) , and we extrapolate that 100 fb \(^{-1}\) at 13 TeV could reach a sensitivity of \({\sim } 1 \times 10^{-5}\) .

Description: We carry out ADM splitting in the Lagrangian formulation and establish a procedure in which (almost) all of the unphysical components of the metric are removed by using the 4D diffeomorphism and the measure-zero 3D symmetry. The procedure introduces a constraint that corresponds to the Hamiltonian constraint of the Hamiltonian formulation, and its solution implies that the 4D dynamics admits an effective description through 3D hypersurface physics. As far as we can see, our procedure implies potential renormalizability of the ADM formulation of 4D Einstein gravity for which a complete gauge-fixing in the ADM formulation and hypersurface foliation of geometry are the key elements. If true, this implies that the alleged unrenormalizability of 4D Einstein gravity may be due to the presence of the unphysical fields. The procedure can straightforwardly be applied to quantization around a flat background; the Schwarzschild case seems more subtle. We discuss a potential limitation of the procedure when applying it to explicit time-dependent backgrounds.

Description: Here, we present a simple, modular and efficient strategy that allows the 3'-terminal labeling of DNA, regardless of whether it has been chemically or enzymatically synthesized or isolated from natural sources. We first incorporate a range of modified nucleotides at the 3'-terminus, using terminal deoxynucleotidyl transferase. In the second step, we convert the incorporated nucleotides, using either of four highly efficient click chemistry-type reactions, namely copper-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, Staudinger ligation or Diels-Alder reaction with inverse electron demand. Moreover, we create internal modifications, making use of either ligation or primer extension, after the nucleotidyl transferase step, prior to the click reaction. We further study the influence of linker variants on the reactivity of azides in different click reactions. We find that different click reactions exhibit distinct substrate preferences, a fact that is often overlooked, but should be considered when labeling oligonucleotides or other biomolecules with click chemistry. Finally, our findings allowed us to extend our previously published RNA labeling strategy to the use of a different copper-free click chemistry, namely the Staudinger ligation.

Description: Despite the increasing knowledge about DNA methylation, the understanding of human epigenome evolution is in its infancy. Using whole genome bisulfite sequencing we identified hundreds of differentially methylated regions (DMRs) in humans compared to non-human primates and estimated that ~25% of these regions were detectable throughout several human tissues. Human DMRs were enriched for specific histone modifications and the majority were located distal to transcription start sites, highlighting the importance of regions outside the direct regulatory context. We also found a significant excess of endogenous retrovirus elements in human-specific hypomethylated. We reported for the first time a close interplay between inter-species genetic and epigenetic variation in regions of incomplete lineage sorting, transcription factor binding sites and human differentially hypermethylated regions. Specifically, we observed an excess of human-specific substitutions in transcription factor binding sites located within human DMRs, suggesting that alteration of regulatory motifs underlies some human-specific methylation patterns. We also found that the acquisition of DNA hypermethylation in the human lineage is frequently coupled with a rapid evolution at nucleotide level in the neighborhood of these CpG sites. Taken together, our results reveal new insights into the mechanistic basis of human-specific DNA methylation patterns and the interpretation of inter-species non-coding variation.

Description: The product of the Plasmodium falciparum genes clag3.1 and clag3.2 plays a fundamental role in malaria parasite biology by determining solute transport into infected erythrocytes. Expression of the two clag3 genes is mutually exclusive, such that a single parasite expresses only one of the two genes at a time. Here we investigated the properties and mechanisms of clag3 mutual exclusion using transgenic parasite lines with extra copies of clag3 promoters located either in stable episomes or integrated in the parasite genome. We found that the additional clag3 promoters in these transgenic lines are silenced by default, but under strong selective pressure parasites with more than one clag3 promoter simultaneously active are observed, demonstrating that clag3 mutual exclusion is strongly favored but it is not strict. We show that silencing of clag3 genes is associated with the repressive histone mark H3K9me3 even in parasites with unusual clag3 expression patterns, and we provide direct evidence for heterochromatin spreading in P. falciparum . We also found that expression of a neighbor ncRNA correlates with clag3.1 expression. Altogether, our results reveal a scenario where fitness costs and non-deterministic molecular processes that favor mutual exclusion shape the expression patterns of this important gene family.

Description: MicroRNAs are a class of small regulatory RNAs that are generated from primary miRNA (pri-miRNA) transcripts with a stem-loop structure. Accuracy of the processing of pri-miRNA into mature miRNA in plants can be enhanced by SERRATE (SE) and HYPONASTIC LEAVES 1 (HYL1). HYL1 activity is regulated by the FIERY2 (FRY2)/RNA polymerase II C-terminal domain phosphatase-like 1 (CPL1). Here, we discover that HIGH OSMOTIC STRESS GENE EXPRESSION 5 (HOS5) and two serine/arginine-rich splicing factors RS40 and RS41, previously shown to be involved in pre-mRNA splicing, affect the biogenesis of a subset of miRNA. These proteins are required for correct miRNA strand selection and the maintenance of miRNA levels. FRY2 dephosphorylates HOS5 whose phosphorylation status affects its subnuclear localization. HOS5 and the RS proteins bind both intronless and intron-containing pri-miRNAs. Importantly, all of these splicing-related factors directly interact with both HYL1 and SE in nuclear splicing speckles. Our results indicate that these splicing factors are directly involved in the biogenesis of a group of miRNA.

Description: AlgR is a key transcriptional regulator required for the expression of multiple virulence factors, including type IV pili and alginate in Pseudomonas aeruginosa . However, the regulon and molecular regulatory mechanism of AlgR have yet to be fully elucidated. Here, among 157 loci that were identified by a ChIP-seq assay, we characterized a gene, mucR , which encodes an enzyme that synthesizes the intracellular second messenger cyclic diguanylate (c-di-GMP). A algR strain produced lesser biofilm than did the wild-type strain, which is consistent with a phenotype controlled by c-di-GMP. AlgR positively regulates mucR via direct binding to its promoter. A algR mucR double mutant produced lesser biofilm than did the single algR mutant, demonstrating that c-di-GMP is a positive regulator of biofilm formation. AlgR controls the levels of c-di-GMP synthesis via direct regulation of mucR . In addition, the cognate sensor of AlgR, FimS/AlgZ, also plays an important role in P. aeruginosa virulence. Taken together, this study provides new insights into the AlgR regulon and reveals the involvement of c-di-GMP in the mechanism underlying AlgR regulation.

Description: Phosphorylation of the C-terminal domain of the largest subunit of RNA polymerase II (Pol II), especially Ser2 and Ser5 residues, plays important roles in transcription and mRNA processing, including 5' end capping, splicing and 3' end processing. These phosphorylation events stimulate mRNA processing, however, it is not clear whether splicing activity affects the phosphorylation status of Pol II. In this study, we found that splicing inhibition by potent splicing inhibitors spliceostatin A (SSA) and pladienolide B or by antisense oligos against snRNAs decreased phospho-Ser2 level, but had little or no effects on phospho-Ser5 level. In contrast, transcription and translation inhibitors did not decrease phospho-Ser2 level, therefore inhibition of not all the gene expression processes cause the decrease of phospho-Ser2. SSA treatment caused early dissociation of Pol II and decrease in phospho-Ser2 level of chromatin-bound Pol II, suggesting that splicing inhibition causes downregulation of phospho-Ser2 through at least these two mechanisms.

Description: Facioscapulohumeral dystrophy (FSHD) is an epi/genetic satellite disease associated with at least two satellite sequences in 4q35: (i) D4Z4 macrosatellite and (ii) β-satellite repeats (BSR), a prevalent part of the 4qA allele. Most of the recent FSHD studies have been focused on a DUX4 transcript inside D4Z4 and its tandem contraction in FSHD patients. However, the D4Z4-contraction alone is not pathological, which would also require the 4qA allele. Since little is known about BSR, we investigated the 4qA BSR functional role in the transcriptional control of the FSHD region 4q35. We have shown that an individual BSR possesses enhancer activity leading to activation of the Adenine Nucleotide Translocator 1 gene ( ANT1 ), a major FSHD candidate gene. We have identified ZNF555, a previously uncharacterized protein, as a putative transcriptional factor highly expressed in human primary myoblasts that interacts with the BSR enhancer site and impacts the ANT1 promoter activity in FSHD myoblasts. The discovery of the functional role of the 4qA allele and ZNF555 in the transcriptional control of ANT1 advances our understanding of FSHD pathogenesis and provides potential therapeutic targets.

Description: The roles of translesion synthesis (TLS) DNA polymerases in bypassing the C8–2'-deoxyguanosine adduct (dG-C8-IQ) formed by 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ), a highly mutagenic and carcinogenic heterocyclic amine found in cooked meats, were investigated. Three plasmid vectors containing the dG-C8-IQ adduct at the G 1 -, G 2 - or G 3 -positions of the Nar I site (5'-G 1 G 2 CG 3 CC-3') were replicated in HEK293T cells. Fifty percent of the progeny from the G 3 construct were mutants, largely G-〉T, compared to 18% and 24% from the G 1 and G 2 constructs, respectively. Mutation frequency (MF) of dG-C8-IQ was reduced by 38–67% upon siRNA knockdown of pol , whereas it was increased by 10–24% in pol knockdown cells. When pol and pol were simultaneously knocked down, MF of the G 1 and G 3 constructs was reduced from 18% and 50%, respectively, to 〈3%, whereas it was reduced from 24% to 〈1% in the G 2 construct. In vitro TLS using yeast pol showed that it can extend G 3 *:A pair more efficiently than G 3 *:C pair, but it is inefficient at nucleotide incorporation opposite dG-C8-IQ. We conclude that pol and pol cooperatively carry out the majority of the error-prone TLS of dG-C8-IQ, whereas pol is involved primarily in its error-free bypass.

Description: The MRE11/RAD50/NBS1 (MRN) complex plays a central role as a sensor of DNA double strand breaks (DSB) and is responsible for the efficient activation of ataxia-telangiectasia mutated (ATM) kinase. Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival. We report here that MRE11 is also phosphorylated by ATM at S676 and S678 in response to agents that induce DNA DSB, is dependent on the presence of NBS1, and does not affect the association of members of the complex or ATM activation. A phosphosite mutant (MRE11S676AS678A) cell line showed decreased cell survival and increased chromosomal aberrations after radiation exposure indicating a defect in DNA repair. Use of GFP-based DNA repair reporter substrates in MRE11S676AS678A cells revealed a defect in homology directed repair (HDR) but single strand annealing was not affected. More detailed investigation revealed that MRE11S676AS678A cells resected DNA ends to a greater extent at sites undergoing HDR. Furthermore, while ATM-dependent phosphorylation of Kap1 and SMC1 was normal in MRE11S676AS678A cells, there was no phosphorylation of Exonuclease 1 consistent with the defect in HDR. These results describe a novel role for ATM-dependent phosphorylation of MRE11 in limiting the extent of resection mediated through Exonuclease 1.

Description: To gain a wider view of the pathways that regulate mitochondrial function, we combined the effect of heat stress on respiratory capacity with the discovery potential of a genome-wide screen in Saccharomyces cerevisiae . We identified 105 new genes whose deletion impairs respiratory growth at 37°C by interfering with processes such as transcriptional regulation, ubiquitination and cytosolic tRNA wobble uridine modification via 5-methoxycarbonylmethyl-2-thiouridine formation. The latter process, specifically required for efficient decoding of AA-ending codons under stress conditions, was covered by multiple genes belonging to the Elongator (e.g. ELP3 ) and urmylation (e.g., NCS6 ) pathways. ELP3 or NCS6 deletants had impaired mitochondrial protein synthesis. Their respiratory deficiency was selectively rescued by overexpression of tRNA Lys UUU as well by overexpression of genes ( BCK1 and HFM1 ) with a strong bias for the AAA codon read by this tRNA. These data extend the mitochondrial regulome, demonstrate that heat stress can impair respiration by disturbing cytoplasmic translation of proteins critically involved in mitochondrial function and document, for the first time, the involvement in such process of the Elongator and urmylation pathways. Given the conservation of these pathways, the present findings may pave the way to a better understanding of the human mitochondrial regulome in health and disease.

Description: Recent studies strongly suggest that in bacterial cells the order of genes along the chromosomal origin-to-terminus axis is determinative for regulation of the growth phase-dependent gene expression. The prediction from this observation is that positional displacement of pleiotropic genes will affect the genetic regulation and hence, the cellular phenotype. To test this prediction we inserted the origin-proximal dusB-fis operon encoding the global regulator FIS in the vicinity of replication terminus on both arms of the Escherichia coli chromosome. We found that the lower fis gene dosage in the strains with terminus-proximal dusB-fis operons was compensated by increased fis expression such that the intracellular concentration of FIS was homeostatically adjusted. Nevertheless, despite unchanged FIS levels the positional displacement of dusB-fis impaired the competitive growth fitness of cells and altered the state of the overarching network regulating DNA topology, as well as the cellular response to environmental stress, hazardous substances and antibiotics. Our finding that the chromosomal repositioning of a regulatory gene can determine the cellular phenotype unveils an important yet unexplored facet of the genetic control mechanisms and paves the way for novel approaches to manipulate bacterial physiology.

Description: In bacteria and archaea, short fragments of foreign DNA are integrated into Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) loci, providing a molecular memory of previous encounters with foreign genetic elements. In Escherichia coli , short CRISPR-derived RNAs are incorporated into a multi-subunit surveillance complex called Cascade (CRISPR-associated complex for antiviral defense). Recent structures of Cascade capture snapshots of this seahorse-shaped RNA-guided surveillance complex before and after binding to a DNA target. Here we determine a 3.2 Å x-ray crystal structure of Cascade in a new crystal form that provides insight into the mechanism of double-stranded DNA binding. Molecular dynamic simulations performed using available structures reveal functional roles for residues in the tail, backbone and belly subunits of Cascade that are critical for binding double-stranded DNA. Structural comparisons are used to make functional predictions and these predictions are tested in vivo and in vitro . Collectively, the results in this study reveal underlying mechanisms involved in target-induced conformational changes and highlight residues important in DNA binding and protospacer adjacent motif recognition.

Description: DNA damage, arising from endogenous metabolism or exposure to environmental agents, may perturb the transmission of genetic information by blocking DNA replication and/or inducing mutations, which contribute to the development of cancer and likely other human diseases. Hydroxyl radical attack on the C1', C3' and C4' of 2-deoxyribose can give rise to epimeric 2-deoxyribose lesions, for which the in vivo occurrence and biological consequences remain largely unexplored. Through independent chemical syntheses of all three epimeric lesions of 2'-deoxyguanosine (dG) and liquid chromatography-tandem mass spectrometry analysis, we demonstrated unambiguously the presence of substantial levels of the α-anomer of dG (α-dG) in calf thymus DNA and in DNA isolated from mouse pancreatic tissues. We further assessed quantitatively the impact of all four α-dN lesions on DNA replication in Escherichia coli by employing a shuttle-vector method. We found that, without SOS induction, all α-dN lesions except α-dA strongly blocked DNA replication and, while replication across α-dA was error-free, replicative bypass of α-dC and α-dG yielded mainly C-〉A and G-〉A mutations. In addition, SOS induction could lead to markedly elevated bypass efficiencies for the four α-dN lesions, abolished the G-〉A mutation for α-dG, pronouncedly reduced the C-〉A mutation for α-dC and triggered T-〉A mutation for α-dT. The preferential misincorporation of dTMP opposite the α-dNs could be attributed to the unique base-pairing properties of the nucleobases elicited by the inversion of the configuration of the N -glycosidic linkage. Our results also revealed that Pol V played a major role in bypassing α-dC, α-dG and α-dT in vivo . The abundance of α-dG in mammalian tissue and the impact of the α-dNs on DNA replication demonstrate for the first time the biological significance of this family of DNA lesions.

Description: We have examined the three-dimensional organization of the yeast genome during quiescence by a chromosome capture technique as a means of understanding how genome organization changes during development. For exponentially growing cells we observe high levels of inter-centromeric interaction but otherwise a predominance of intrachromosomal interactions over interchromosomal interactions, consistent with aggregation of centromeres at the spindle pole body and compartmentalization of individual chromosomes within the nucleoplasm. Three major changes occur in the organization of the quiescent cell genome. First, intrachromosomal associations increase at longer distances in quiescence as compared to growing cells. This suggests that chromosomes undergo condensation in quiescence, which we confirmed by microscopy by measurement of the intrachromosomal distances between two sites on one chromosome. This compaction in quiescence requires the condensin complex. Second, inter-centromeric interactions decrease, consistent with prior data indicating that centromeres disperse along an array of microtubules during quiescence. Third, inter-telomeric interactions significantly increase in quiescence, an observation also confirmed by direct measurement. Thus, survival during quiescence is associated with substantial topological reorganization of the genome.

Description: Cross-talk between competitive endogenous RNAs (ceRNAs) through shared miRNAs represents a novel layer of gene regulation that plays important roles in the physiology and development of cancers. However, a global view of their system-level properties across various types of cancers is still unknown. Here, we constructed the mRNA related ceRNA–ceRNA interaction landscape across 20 cancer types by systematically analyzing molecular profiles of 5203 tumors and miRNA regulations. Our study highlights the conserved features shared by pan-cancer and higher similarity within similar origin cell type. Moreover, a core ceRNA network was identified. Function analysis identified a common theme of cancer hallmarks, however they exhibit phenotype-specific connectivity patterns. Besides, we found a marked rewiring in the ceRNA program between various cancers, and further revealed conserved and rewired network ceRNA hubs in each cancer, which were tensely competitive interactions to constitute conserved and cancer-specific modules. By providing mechanistic linkage between known cancer miRNAs, their mediated ceRNA–ceRNA interactions, and the associations with known cancer hallmarks, the inferred cancer ceRNA–ceRNA interaction landscape will serve as a powerful public resource for further biological discoveries of tumorigenesis.

Description: Replicative helicases are essential ATPases that unwind DNA to initiate chromosomal replication. While bacterial replicative DnaB helicases are hexameric, Helicobacter pylori DnaB ( Hp DnaB) was found to form double hexamers, similar to some archaeal and eukaryotic replicative helicases. Here we present a structural and functional analysis of Hp DnaB protein during primosome formation. The crystal structure of the Hp DnaB at 6.7 Å resolution reveals a dodecameric organization consisting of two hexamers assembled via their N-terminal rings in a stack-twisted mode. Using fluorescence anisotropy we show that Hp DnaB dodecamer interacts with single-stranded DNA in the presence of ATP but has a low DNA unwinding activity. Multi-angle light scattering and small angle X-ray scattering demonstrate that interaction with the DnaG primase helicase-binding domain dissociates the helicase dodecamer into single ringed primosomes. Functional assays on the proteins and associated complexes indicate that these single ringed primosomes are the most active form of the helicase for ATP hydrolysis, DNA binding and unwinding. These findings shed light onto an activation mechanism of Hp DnaB by the primase that might be relevant in other bacteria and possibly other organisms exploiting dodecameric helicases for DNA replication.

Description: Microcalorimetric studies of DNA duplexes and their component single strands showed that association enthalpies of unfolded complementary strands into completely folded duplexes increase linearly with temperature and do not depend on salt concentration, i.e. duplex formation results in a constant heat capacity decrement, identical for CG and AT pairs. Although duplex thermostability increases with CG content, the enthalpic and entropic contributions of an AT pair to duplex formation exceed that of a CG pair when compared at the same temperature. The reduced contribution of AT pairs to duplex stabilization comes not from their lower enthalpy, as previously supposed, but from their larger entropy contribution. This larger enthalpy and particularly the greater entropy results from water fixed by the AT pair in the minor groove. As the increased entropy of an AT pair exceeds that of melting ice, the water molecule fixed by this pair must affect those of its neighbors. Water in the minor groove is, thus, orchestrated by the arrangement of AT groups, i.e. is context dependent. In contrast, water hydrating exposed nonpolar surfaces of bases is responsible for the heat capacity increment on dissociation and, therefore, for the temperature dependence of all thermodynamic characteristics of the double helix.

Description: Small RNAs (sRNAs) are important regulators of gene expression during bacterial stress and pathogenesis. sRNAs act by forming duplexes with mRNAs to alter their translation and degradation. In some bacteria, duplex formation is mediated by the Hfq protein, which can bind the sRNA and mRNA in each pair in a random order. Here we investigate the consequences of this random-order binding and experimentally demonstrate that it can counterintuitively cause high Hfq concentrations to suppress rather than promote sRNA activity in Escherichia coli . As a result, maximum sRNA activity occurs when the Hfq concentration is neither too low nor too high relative to the sRNA and mRNA concentrations (‘Hfq set-point’). We further show with models and experiments that random-order binding combined with the formation of a dead-end mRNA–Hfq complex causes high concentrations of an mRNA to inhibit its own duplex formation by sequestering Hfq. In such cases, maximum sRNA activity requires an optimal mRNA concentration (‘mRNA set-point’) as well as an optimal Hfq concentration. The Hfq and mRNA set-points generate novel regulatory properties that can be harnessed by native and synthetic gene circuits to provide greater control over sRNA activity, generate non-monotonic responses and enhance the robustness of expression.

Description: A prolonged expansion of GGGGCC repeat within non-coding region of C9orf72 gene has been identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which are devastating neurodegenerative disorders. Formation of unusual secondary structures within expanded GGGGCC repeat, including DNA and RNA G-quadruplexes and R-loops was proposed to drive ALS and FTD pathogenesis. Initial NMR investigation on DNA oligonucleotides with four repeat units as the shortest model with the ability to form an unimolecular G-quadruplex indicated their folding into multiple G-quadruplex structures in the presence of K + ions. Single dG to 8Br-dG substitution at position 21 in oligonucleotide d[(G 4 C 2 ) 3 G 4 ] and careful optimization of folding conditions enabled formation of mostly a single G-quadruplex species, which enabled determination of a high-resolution structure with NMR. G-quadruplex structure adopted by d[(G 4 C 2 ) 3 GG Br GG] is composed of four G-quartets, which are connected by three edgewise C-C loops. All four strands adopt antiparallel orientation to one another and have alternating syn-anti progression of glycosidic conformation of guanine residues. One of the cytosines in every loop is stacked upon the G-quartet contributing to a very compact and stable structure.

Description: Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania , resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3 , as a prospective therapeutic candidate for the treatment of VL.

Description: Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by the silencing of the FMR1 gene encoding an RNA-binding protein (FMRP) mainly involved in translational control. We characterized the interaction between FMRP and the mRNA of GRK4 , a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase super-family, both in vitro and in vivo . While the mRNA level of GRK4 is unchanged in the absence or in the presence of FMRP in different regions of the brain, GRK4 protein level is increased in Fmr1 -null cerebellum, suggesting that FMRP negatively modulates the expression of GRK4 at the translational level in this brain region. The C-terminal region of FMRP interacts with a domain of GRK4 mRNA, that we called G4RIF, that is folded in four stem loops. The SL1 stem loop of G4RIF is protected by FMRP and is part of the S1/S2 sub-domain that directs translation repression of a reporter mRNA by FMRP. These data confirm the role of the G4RIF/FMRP complex in translational regulation. Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors.

Description: Alternative splicing is an important and ancient feature of eukaryotic gene structure, the existence of which has likely facilitated eukaryotic proteome expansions. Here, we have used intron lariat sequencing to generate a comprehensive profile of splicing events in Schizosaccharomyces pombe , amongst the simplest organisms that possess mammalian-like splice site degeneracy. We reveal an unprecedented level of alternative splicing, including alternative splice site selection for over half of all annotated introns, hundreds of novel exon-skipping events, and thousands of novel introns. Moreover, the frequency of these events is far higher than previous estimates, with alternative splice sites on average activated at ~3% the rate of canonical sites. Although a subset of alternative sites are conserved in related species, implying functional potential, the majority are not detectably conserved. Interestingly, the rate of aberrant splicing is inversely related to expression level, with lowly expressed genes more prone to erroneous splicing. Although we validate many events with RNAseq, the proportion of alternative splicing discovered with lariat sequencing is far greater, a difference we attribute to preferential decay of aberrantly spliced transcripts. Together, these data suggest the spliceosome possesses far lower fidelity than previously appreciated, highlighting the potential contributions of alternative splicing in generating novel gene structures.

Description: Hexameric helicases are processive DNA unwinding machines but how they engage with a replication fork during unwinding is unknown. Using electron microscopy and single particle analysis we determined structures of the intact hexameric helicase E1 from papillomavirus and two complexes of E1 bound to a DNA replication fork end-labelled with protein tags. By labelling a DNA replication fork with streptavidin (dsDNA end) and Fab (5' ssDNA) we located the positions of these labels on the helicase surface, showing that at least 10 bp of dsDNA enter the E1 helicase via a side tunnel. In the currently accepted ‘steric exclusion’ model for dsDNA unwinding, the active 3' ssDNA strand is pulled through a central tunnel of the helicase motor domain as the dsDNA strands are wedged apart outside the protein assembly. Our structural observations together with nuclease footprinting assays indicate otherwise: strand separation is taking place inside E1 in a chamber above the helicase domain and the 5' passive ssDNA strands exits the assembly through a separate tunnel opposite to the dsDNA entry point. Our data therefore suggest an alternative to the current general model for DNA unwinding by hexameric helicases.

Description: A well-established phenomenon in general relativity is the dragging of inertial frames by a spinning object. In particular, due to the dragging of inertial frames by a ring orbiting a central black hole, the angular velocity \(\Omega ^{\text {BH-ring}}_{\text {H}}\) of the black-hole horizon in the composed black-hole–ring system is no longer related to the black-hole angular momentum \(J_{\text {H}}\) by the simple Kerr-like (vacuum) relation \(\Omega ^{\text {Kerr}}_{\text {H}}(J_{\text {H}})=J_{\text {H}}/2M^2R_{\text {H}}\) (here M and \(R_{\text {H}}\) are the mass and horizon-radius of the black hole, respectively). Will has performed a perturbative treatment of the composed black-hole–ring system in the regime of slowly rotating black holes and found the explicit relation \(\Omega ^{\text {BH-ring}}_{\text {H}}(J_{\text {H}}=0,J_{\text {R}},R)=2J_{\text {R}}/R^3\) for the angular velocity of a central black hole with zero angular momentum, where \(J_{\text {R}}\) and R are respectively the angular momentum of the orbiting ring and its proper circumferential radius. Analyzing a sequence of black-hole–ring configurations with adiabatically varying (decreasing) circumferential radii, we show that the expression found by Will for \(\Omega ^{\text {BH-ring}}_{\text {H}}(J_{\text {H}}=0,J_{\text {R}},R)\) implies a smooth transition of the central black-hole angular velocity from its asymptotic near-horizon value \(\Omega ^{\text {BH-ring}}_{\text {H}}(J_{\text {H}}=0,J_{\text {R}},R\rightarrow R^{+}_{\text {H}})\rightarrow 2J_{\text {R}}/R^3_{\text {H}}\) (that is, just before the assimilation of the ring by the central black hole), to its final Kerr (vacuum) value \(\Omega ^{\text {Kerr}}_{\text {H}}(J^{\text {new}}_{\text {H}})= J^{\text {new}}_{\text {H}}/2{M^{\text {new}}}^2R^{\text {new}}_{\text {H}}\) [that is, after the adiabatic assimilation of the ring by the central black hole. Here \(J^{\text {new}}_{\text {H}}=J_{\text {R}}\) , \(M^{\text {new}}\) , and \(R^{\text {new}}_{\text {H}}\) are the new parameters of the resulting Kerr (vacuum) black hole after it assimilated the orbiting ring]. We use this important observation in order to generalize the result of Will to the regime of black-hole–ring configurations in which the central black holes possess non-zero angular momenta. In particular, it is shown that the continuity argument (namely, the characteristic smooth evolution of the black-hole angular velocity during an adiabatic assimilation process of the ring into the central black hole) yields a concrete prediction for the angular-velocity/angular-momentum asymptotic functional relation \(\Omega ^{\text {BH-ring}}_{\text {H}}=\Omega ^{\text {BH-ring}}_{\text {H}}(J_{\text {H}},J_{\text {R}},R\rightarrow R^{+}_{\text {H}})\) of generic (that is, with \(J_{\text {H}}\ne 0\) ) black-hole–ring configurations. Remarkably, we find the simple universal relation \(\Delta \Omega _{\text {H}}\equiv \Omega ^{\text {BH-ring}}_{\text {H}}(J_{\text {H}},J_{\text {R}},R\rightarrow R^{+}_{\text {H}})-\Omega ^{\text {Kerr}}_{\text {H}}(J_{\text {H}})={{J_{\text {R}}}/{4M^3}}\) for the asymptotic deviation of the black-hole angular velocity in the composed black-hole–ring system from the corresponding angular velocity of the unperturbed (vacuum) Kerr black hole with the same angular momentum.

Description: As an extension of previous works on classical tests of Kaluza–Klein (KK) gravity and as an attempt to find more stringent constraints on this theory, its effects on physical experiments and astronomical observations conducted in the Solar System are studied. We investigate the gravitational time delay at inferior conjunction caused by KK gravity, and use new Solar System ephemerides and the observation of Cassini to strengthen constraints on KK gravity by up to two orders of magnitude. These improved upper bounds mean that the fifth-dimensional space in the soliton case is a very flat extra dimension in the Solar System, even in the vicinity of the Sun.

Description: The normalized differential cross section for top quark pair ( \({\mathrm{t}}\overline{{\mathrm{t}}}\) ) production is measured in pp collisions at a centre-of-mass energy of 8 \(\,\text {TeV}\) at the CERN LHC using the CMS detector in data corresponding to an integrated luminosity of 19.7 \(\,\text {fb}^{-1}\) . The measurements are performed in the lepton \(+\) jets ( \(\mathrm {e}/\mu \) \(+\) jets) and in the dilepton ( \(\mathrm {e}^+\mathrm {e}^-\) , \(\mu ^+ \mu ^- \) , and \(\mathrm {e}^\pm \mu ^{\mp }\) ) decay channels. The \({\mathrm{t}}\overline{{\mathrm{t}}}\) cross section is measured as a function of the kinematic properties of the charged leptons, the jets associated to b quarks, the top quarks, and the \({\mathrm{t}}\overline{{\mathrm{t}}}\) system. The data are compared with several predictions from perturbative quantum chromodynamic up to approximate next-to-next-to-leading-order precision. No significant deviations are observed relative to the standard model predictions.

Description: Recently we have shown that for \(2+1\) -dimensional thin-shell wormholes a non-circular throat may lead to a physical wormhole in the sense that the energy conditions are satisfied. By the same token, herein we consider an angular dependent throat geometry embedded in a \(2+1\) -dimensional flat spacetime in polar coordinates. It is shown that, remarkably, a generic, natural example of the throat geometry is provided by a hypocycloid. That is, two flat \(2+1\) dimensions are glued together along a hypocycloid. The energy required in each hypocycloid increases with the frequency of the roller circle inside the large one.

Description: We propose a parametrization for interpreting some of the presently available data of the \(B^{\pm } \rightarrow K^{\pm } p {\bar{p}}\) decay, in particular those by the LHCb and Belle Collaborations. The model is inspired by the well-known current and transition contributions, usually assumed in this kind of decay. However, in the light of considerations as regards the dominant diagrams and final state interactions, we modify some parameters of the model, determining them by means of a best fit to the data. We show the results, which we discuss in some detail. Moreover, we give some predictions on other observables relative to the decays.

Description: We have set up a light scattering spectrometer to study the depolarization of light scattering in linear alkylbenzene. The scattering spectra show that the depolarized part of light scattering is due to Rayleigh scattering. The additional depolarized Rayleigh scattering can make the effective transparency of linear alkylbenzene much better than expected. Therefore, sufficient scintillation photons can transmit through large liquid scintillator detector, such as that of the JUNO experiment. Our study is crucial to achieving an unprecedented energy resolution of 3 %/ \(\sqrt{E\mathrm {(MeV)}}\) required for the JUNO experiment to determine the neutrino mass hierarchy. The spectroscopic method can also be used to examine the depolarization of other organic solvents used in neutrino experiments.