852 research outputs found

    Real-time MR tracking of AAV gene therapy with betagal-responsive MR probe in a murine model of GM1-gangliosidosis

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    Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber\u27s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (betagal) using a self-immolative betagal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1(-/-)) correlates with betagal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With \u3e 1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field

    Four Generations: SUSY and SUSY Breaking

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    We revisit four generations within the context of supersymmetry. We compute the perturbativity limits for the fourth generation Yukawa couplings and show that if the masses of the fourth generation lie within reasonable limits of their present experimental lower bounds, it is possible to have perturbativity only up to scales around 1000 TeV. Such low scales are ideally suited to incorporate gauge mediated supersymmetry breaking, where the mediation scale can be as low as 10-20 TeV. The minimal messenger model, however, is highly constrained. While lack of electroweak symmetry breaking rules out a large part of the parameter space, a small region exists, where the fourth generation stau is tachyonic. General gauge mediation with its broader set of boundary conditions is better suited to accommodate the fourth generation.Comment: 27 pages, 5 figure

    Decaying Dark Matter in the Supersymmetric Standard Model with Freeze-in and Seesaw mechanims

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    Inspired by the decaying dark matter (DM) which can explain cosmic ray anomalies naturally, we consider the supersymmetric Standard Model with three right-handed neutrinos (RHNs) and R-parity, and introduce a TeV-scale DM sector with two fields \phi_{1,2} and a Z3Z_3 discrete symmetry. The DM sector only interacts with the RHNs via a very heavy field exchange and then we can explain the cosmic ray anomalies. With the second right-handed neutrino N_2 dominant seesaw mechanism at the low scale around 10^4 GeV, we show that \phi_{1,2} can obtain the vacuum expectation values around the TeV scale, and then the lightest state from \phi_{1,2} is the decay DM with lifetime around \sim 10^{26}s. In particular, the DM very long lifetime is related to the tiny neutrino masses, and the dominant DM decay channels to \mu and \tau are related to the approximate \mu-\tau symmetry. Furthermore, the correct DM relic density can be obtained via the freeze-in mechanism, the small-scale problem for power spectrum can be solved due to the decays of the R-parity odd meta-stable states in the DM sector, and the baryon asymmetry can be generated via the soft leptogensis.Comment: 24 pages,3 figure

    Flavor Mediation Delivers Natural SUSY

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    If supersymmetry (SUSY) solves the hierarchy problem, then naturalness considerations coupled with recent LHC bounds require non-trivial superpartner flavor structures. Such "Natural SUSY" models exhibit a large mass hierarchy between scalars of the third and first two generations as well as degeneracy (or alignment) among the first two generations. In this work, we show how this specific beyond the standard model (SM) flavor structure can be tied directly to SM flavor via "Flavor Mediation". The SM contains an anomaly-free SU(3) flavor symmetry, broken only by Yukawa couplings. By gauging this flavor symmetry in addition to SM gauge symmetries, we can mediate SUSY breaking via (Higgsed) gauge mediation. This automatically delivers a natural SUSY spectrum. Third-generation scalar masses are suppressed due to the dominant breaking of the flavor gauge symmetry in the top direction. More subtly, the first-two-generation scalars remain highly degenerate due to a custodial U(2) symmetry, where the SU(2) factor arises because SU(3) is rank two. This custodial symmetry is broken only at order (m_c/m_t)^2. SUSY gauge coupling unification predictions are preserved, since no new charged matter is introduced, the SM gauge structure is unaltered, and the flavor symmetry treats all matter multiplets equally. Moreover, the uniqueness of the anomaly-free SU(3) flavor group makes possible a number of concrete predictions for the superpartner spectrum.Comment: 17 pages, 7 figures, 2 tables. v2 references added, minor changes to flavor constraints and a little discussion adde

    A Pedagogical Review of Electroweak Symmetry Breaking Scenarios

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    We review different avenues of electroweak symmetry breaking explored over the years. This constitutes a timely exercise as the world's largest and the highest energy particle accelerator, namely, the Large Hadron Collider (LHC) at CERN near Geneva, has started running whose primary mission is to find the Higgs or some phenomena that mimic the effects of the Higgs, i.e. to unravel the mysteries of electroweak phase transition. In the beginning, we discuss the Standard Model Higgs mechanism. After that we review the Higgs sector of the Minimal Supersymmetric Standard Model. Then we take up three relatively recent ideas: Little Higgs, Gauge-Higgs Unification, and Higgsless scenarios. For the latter three cases, we first present the basic ideas and restrict our illustration to some instructive toy models to provide an intuitive feel of the underlying dynamics, and then discuss, for each of the three cases, how more realistic scenarios are constructed and how to decipher their experimental signatures. Wherever possible, we provide enough pedagogical details, which the beginners might find useful.Comment: 45 pages, Review based on a series of lectures; v2: 63 pages, substantially expanded, references added, to appear in `Reports on Progress in Physics

    Excluding Electroweak Baryogenesis in the MSSM

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    In the context of the MSSM the Light Stop Scenario (LSS) is the only region of parameter space that allows for successful Electroweak Baryogenesis (EWBG). This possibility is very phenomenologically attractive, since it allows for the direct production of light stops and could be tested at the LHC. The ATLAS and CMS experiments have recently supplied tantalizing hints for a Higgs boson with a mass of ~ 125 GeV. This Higgs mass severely restricts the parameter space of the LSS, and we discuss the specific predictions made for EWBG in the MSSM. Combining data from all the available ATLAS and CMS Higgs searches reveals a tension with the predictions of EWBG even at this early stage. This allows us to exclude EWBG in the MSSM at greater than (90) 95% confidence level in the (non-)decoupling limit, by examining correlations between different Higgs decay channels. We also examine the exclusion without the assumption of a ~ 125 GeV Higgs. The Higgs searches are still highly constraining, excluding the entire EWBG parameter space at greater than 90% CL except for a small window of m_h ~ 117 - 119 GeV.Comment: 24 Pages, 4 Figures (v3: fixed typos, minor corrections, added references

    Triggering of the 2014 M_w7.3 Papanoa earthquake by a slow slip event in Guerrero, Mexico

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    Since their discovery two decades ago, slow slip events have been shown to play an important role in accommodating strain in subduction zones. However, the physical mechanisms that generate slow slip and the relationships with earthquakes are unclear. Slow slip events have been recorded in the Guerrero segment of the Cocos–North America subduction zone. Here we use inversion of position time series recorded by a continuous GPS network to reconstruct the evolution of aseismic slip on the subduction interface of the Guerrero segment. We find that a slow slip event began in February 2014, two months before the magnitude (M_w) 7.3 Papanoa earthquake on 18 April. The slow slip event initiated in a region adjacent to the earthquake hypocentre and extended into the vicinity of the seismogenic zone. This spatio-temporal proximity strongly suggests that the Papanoa earthquake was triggered by the ongoing slow slip event. We demonstrate that the triggering mechanism could be either static stress increases in the hypocentral region, as revealed by Coulomb stress modelling, or enhanced weakening of the earthquake hypocentral area by the slow slip. We also show that the plate interface in the Guerrero area is highly coupled between slow slip events, and that most of the accumulated strain is released aseismically during the slow slip episodes

    It takes two: Evidence for reduced sexual conflict over parental care in a biparental canid

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    In biparental systems, sexual conflict over parental investment predicts that the parent providing care experiences greater reproductive costs. This inequality in parental contribution is reduced when offspring survival is dependent on biparental care. However, this idea has received little empirical attention. Here, we determined whether mothers and fathers differed in their contribution to care in a captive population of coyotes (Canis latrans). We performed parental care assays on 8 (n = 8 males, 8 females) mated pairs repeatedly over a 10-week period (i.e., 5–15 weeks of litter age) when pairs were first-time breeders (2011), and again as experienced breeders (2013). We quantified consistent individual variation (i.e., repeatability) in 8 care behaviors and examined within- and among-individual correlations to determine if behavioral plasticity within or parental personality across seasons varied by sex. Finally, we extracted hormone metabolites (i.e., cortisol and testosterone) from fecal samples collected during gestation to describe potential links between hormonal mechanisms and individual consistency in parental behaviors. Parents differed in which behaviors were repeatable: mothers demonstrated consistency in provisioning and pup-directed aggression, whereas fathers were consistent in pup checks. However, positive within-individual correlations for identical behaviors (e.g., maternal versus paternal play) suggested that the rate of change in all behaviors except provisioning was highly correlated between the sexes. Moreover, positive among-individual correlations among 50% of identical behaviors suggested that personality differences across parents were highly correlated. Lastly, negative among-individual correlations among pup-directed aggression, provisioning, and gestational testosterone in both sexes demonstrated potential links between preparental hormones and labile parental traits. We provide novel evidence that paternal contribution in a biparental species reaches near equivalent rates of their partners

    Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

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    The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal
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