Human Immunodeficiency Virus-1 Uses the Mannose-6-Phosphate Receptor to Cross the Blood-Brain Barrier

HIV-1 circulates both as free virus and within immune cells, with the level of free virus being predictive of clinical course. Both forms of HIV-1 cross the blood-brain barrier (BBB) and much progress has been made in understanding the mechanisms by which infected immune cells cross the blood-brain barrier BBB. How HIV-1 as free virus crosses the BBB is less clear as brain endothelial cells are CD4 and galactosylceramide negative. Here, we found that HIV-1 can use the mannose-6 phosphate receptor (M6PR) to cross the BBB. Brain perfusion studies showed that HIV-1 crossed the BBB of all brain regions consistent with the uniform distribution of M6PR. Ultrastructural studies showed HIV-1 crossed by a transcytotic pathway consistent with transport by M6PR. An in vitro model of the BBB was used to show that transport of HIV-1 was inhibited by mannose, mannan, and mannose-6 phosphate and that enzymatic removal of high mannose oligosaccharide residues from HIV-1 reduced transport. Wheatgerm agglutinin and protamine sulfate, substances known to greatly increase transcytosis of HIV-1 across the BBB in vivo, were shown to be active in the in vitro model and to act through a mannose-dependent mechanism. Transport was also cAMP and calcium-dependent, the latter suggesting that the cation-dependent member of the M6PR family mediates HIV-1 transport across the BBB. We conclude that M6PR is an important receptor used by HIV-1 to cross the BBB

Strong Double Higgs Production at the LHC

The hierarchy problem and the electroweak data, together, provide a plausible motivation for considering a light Higgs emerging as a pseudo-Goldstone boson from a strongly-coupled sector. In that scenario, the rates for Higgs production and decay differ significantly from those in the Standard Model. However, one genuine strong coupling signature is the growth with energy of the scattering amplitudes among the Goldstone bosons, the longitudinally polarized vector bosons as well as the Higgs boson itself. The rate for double Higgs production in vector boson fusion is thus enhanced with respect to its negligible rate in the SM. We study that reaction in pp collisions, where the production of two Higgs bosons at high pT is associated with the emission of two forward jets. We concentrate on the decay mode hh -> WW^(*)WW^(*) and study the semi-leptonic decay chains of the W's with 2, 3 or 4 leptons in the final states. While the 3 lepton final states are the most relevant and can lead to a 3 sigma signal significance with 300 fb^{-1} collected at a 14 TeV LHC, the two same-sign lepton final states provide complementary information. We also comment on the prospects for improving the detectability of double Higgs production at the foreseen LHC energy and luminosity upgrades.Comment: 54 pages, 26 figures. v2: typos corrected, a few comments and one table added. Version published in JHE

Does ligament balancing technique affect kinematics in rotating platform, PCL retaining knee arthroplasties?: A prospective randomized study

The goal of this prospective, randomized, blinded trial was to determine if ligament balancing techniques for rotating platform TKA affect postoperative knee kinematics. Sixteen patients with unilateral rotating platform TKA consented to participate in this institutional review board approved study. Eight patients were randomly selected to receive ligament balancing with an instrumented joint spreader device and eight patients received ligament balancing using fixed thickness spacer blocks. A single plane shape matching technique was used for kinematic analysis of static deep knee flexion and dynamic stair activities. There were no differences in knee kinematics between groups during static deep flexion activities. The spreader group demonstrated kinematics more similar to the normal knee during the ascending phase of the dynamic stair activity. Knee kinematics in static knee flexion were unaffected by ligament balancing technique, while knees balanced with the spreader demonstrated a medial pivot motion pattern during stair ascent. This medial pivot motion pattern may improve long-term results by more closely replicating normal knee kinematics

String theoretic QCD axions in the light of PLANCK and BICEP2

The QCD axion solving the strong CP problem may originate from antisymmetric tensor gauge fields in compactified string theory, with a decay constant around the GUT scale. Such possibility appears to be ruled out now by the detection of tensor modes by BICEP2 and the PLANCK constraints on isocurvature density perturbations. A more interesting and still viable possibility is that the string theoretic QCD axion is charged under an anomalous U(1)_A gauge symmetry. In such case, the axion decay constant can be much lower than the GUT scale if moduli are stabilized near the point of vanishing Fayet-Illiopoulos term, and U(1)_A-charged matter fields get a vacuum value far below the GUT scale due to a tachyonic SUSY breaking scalar mass. We examine the symmetry breaking pattern of such models during the inflationary epoch with the Hubble expansion rate 10^{14} GeV, and identify the range of the QCD axion decay constant, as well as the corresponding relic axion abundance, consistent with known cosmological constraints. In addition to the case that the PQ symmetry is restored during inflation, there are other viable scenarios, including that the PQ symmetry is broken during inflation at high scales around 10^{16}-10^{17} GeV due to a large Hubble-induced tachyonic scalar mass from the U(1)_A D-term, while the present axion scale is in the range 10^{9}-5\times 10^{13} GeV, where the present value larger than 10^{12} GeV requires a fine-tuning of the axion misalignment angle. We also discuss the implications of our results for the size of SUSY breaking soft masses.Comment: 29 pages, 1 figure; v3: analysis updated including the full anharmonic effects, references added, version accepted for publication in JHE

Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry

It is well known that R-symmetric models dramatically alleviate the SUSY flavor and CP problems. We study particular modifications of existing R-symmetric models which share the solution to the above problems, and have interesting consequences for electroweak baryogenesis and the Dark Matter (DM) content of the universe. In particular, we find that it is naturally possible to have a strongly first-order electroweak phase transition while simultaneously relaxing the tension with EDM experiments. The R-symmetry (and its small breaking) implies that the gauginos (and the neutralino LSP) are pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role in making the electroweak phase transition strongly first-order. The pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac particle during freeze-out, but like a Majorana particle for annihilation today and in scattering against nuclei, thus being consistent with current constraints. Assuming a standard cosmology, it is possible to simultaneously have a strongly first-order phase transition conducive to baryogenesis and have the LSP provide the full DM relic abundance, in part of the allowed parameter space. However, other possibilities for DM also exist, which are discussed. It is expected that upcoming direct DM searches as well as neutrino signals from DM annihilation in the Sun will be sensitive to this class of models. Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure

Transplanckian axions !?

We discuss quantum gravitational effects in Einstein theory coupled to periodic axion scalars to analyze the viability of several proposals to achieve superplanckian axion periods (aka decay constants) and their possible application to large field inflation models. The effects we study correspond to the nucleation of euclidean gravitational instantons charged under the axion, and our results are essentially compatible with (but independent of) the Weak Gravity Conjecture, as follows: Single axion theories with superplanckian periods contain gravitational instantons inducing sizable higher harmonics in the axion potential, which spoil superplanckian inflaton field range. A similar result holds for multi-axion models with lattice alignment (like the Kim-Nilles-Peloso model). Finally, theories with $N$ axions can still achieve a moderately superplanckian periodicity (by a $\sqrt{N}$ factor) with no higher harmonics in the axion potential. The Weak Gravity Conjecture fails to hold in this case due to the absence of some instantons, which are forbidden by a discrete $\mathbf{Z}_N$ gauge symmetry. Finally we discuss the realization of these instantons as euclidean D-branes in string compactifications.Comment: 46 pages, 6 figures. Added references, clarifications, and missing factor of 1/2 to instanton action. Conclusions unchange

The Cosmological Constant

This is a review of the physics and cosmology of the cosmological constant. Focusing on recent developments, I present a pedagogical overview of cosmology in the presence of a cosmological constant, observational constraints on its magnitude, and the physics of a small (and potentially nonzero) vacuum energy.Comment: 50 pages. Submitted to Living Reviews in Relativity (http://www.livingreviews.org/), December 199

Non-Supersymmetric String Theory

A class of non-supersymmetric string backgrounds can be constructed using twists that involve space-time fermion parity. We propose a non-perturbative definition of string theory in these backgrounds via gauge theories with supersymmetry softly broken by twisted boundary conditions. The perturbative string spectrum is reproduced, and qualitative effects of the interactions are discussed. Along the way, we find an interesting mechanism for inflation. The end state of closed string tachyon condensation is a highly excited state in the gauge theory which, in all likelihood, does not have a geometric interpretation.Comment: 35 pages, 2 figures; revision adds a computation of the relevant orbifold state