Search

Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.

Tidal Love numbers describe the linear response of a compact object under the presence of external tidal perturbations, and they are found to vanish exactly for black holes within General Relativity. In this paper we investigate the tidal deformability of neutral black holes when non-linearities in the theory are taken into account. As a case in point, we consider scalar tidal perturbations on the black hole background, and find that the tidal Love numbers may be non vanishing depending on the scalar interactions in the bulk theory. Remarkably, for non-linear sigma models, we find that the tidal Love numbers vanish to all orders in perturbation theory., Comment: 30 pages. v2: matching version published in PRD

The Breakthrough Listen Initiative is conducting a program using multiple telescopes around the world to search for "technosignatures": artificial transmitters of extraterrestrial origin from beyond our solar system. The VERITAS Collaboration joined this program in 2018, and provides the capability to search for one particular technosignature: optical pulses of a few nanoseconds duration detectable over interstellar distances. We report here on the analysis and results of dedicated VERITAS observations of Breakthrough Listen targets conducted in 2019 and 2020 and of archival VERITAS data collected since 2012. Thirty hours of dedicated observations of 136 targets and 249 archival observations of 140 targets were analyzed and did not reveal any signals consistent with a technosignature. The results are used to place limits on the fraction of stars hosting transmitting civilizations. We also discuss the minimum-pulse sensitivity of our observations and present VERITAS observations of CALIOP: a space-based pulsed laser onboard the CALIPSO satellite. The detection of these pulses with VERITAS, using the analysis techniques developed for our technosignature search, allows a test of our analysis efficiency and serves as an important proof-of-principle., Comment: 15 pages, 7 figures

Mechanical support of respiration in infants born at less than 30 weeks' gestation during the immediate neonatal period is the topic reviewed. Guidelines for management are recommended. Variation in application of these guidelines is anticipated because of contextual factors with individual cases and new information since the inception of the guideline. Thus, the guideline is not intended to serve as a standard of care. Initial Document: July 2014 Update: August 2018

This document was developed for educational purposes, to guide management decisions and to provide recommendations for clinical care. Variation from the recommendations in the guideline is anticipated based on individual patient and contextual factors and new evidence after the inception of the guideline. Hence, the document is not intended to serve as a standard of care. Initial document: March 2013 Update: March 2018

Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. We characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ∼3-fold decrease in catalytic efficiency and K

Shift-symmetric Horndeski theories admit an interesting class of Schwarzschild-de Sitter black hole solutions exhibiting time-dependent scalar hair. The properties of these solutions may be studied via a bottom-up effective field theory (EFT) based on the background symmetries. This is in part possible by making use of a convenient coordinate choice -- Lema\^itre-type coordinates -- in which the profile of the Horndeski scalar field is linear in the relevant time coordinate. We construct this EFT, and use it to understand the stability of hairy black holes in shift-symmetric Horndeski theories, providing a set of constraints that the otherwise-free functions appearing in the Horndeski Lagrangian must satisfy in order to admit stable black hole solutions. The EFT is analyzed in the decoupling limit to understand potential sources of instability. We also perform a complete analysis of the EFT with odd-parity linear perturbations around general spherically symmetric space-time., Comment: 25 pages, JCAP version

HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PRTri) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri mutant in complex with inhibitor 1 at 1.5 A resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

A sterile neutrino at GeV mass scale is of particular interest in this work. Though not take part in neutrino oscillation, the sterile neutrino can induce flavor violating semileptonic and leptonic decay of $K, D$ and $B$ mesons. We calculated a box diagram contribution in these processes. By making use of current experiment limit of lepton flavor violating decays $M^+_h\to M_l^+\ell_1^+\ell_2^-$ and $M^0\to \ell_1^-\ell_2^+$, we explore the allowed parameter space of $U_{e4}$ and $U_{\mu 4}$ in different mass ranges. Generally speaking, both channels give a limit to the product of $U_{e4}$ and $U_{\mu 4}$. When sterile neutrino mass is located in between pion and kaon mass, $K^+\to \pi^+ e^{\pm}\mu^{\mp}$ gives the strongest constraint while $B^+\to \pi^+ e^{\pm} \mu^{\mp}$ provides the dominated constraint when its mass in between of kaon and B meson. If sterile neutrino is even heavier than B mesons, the $B^0_s\to \mu^{\pm} e^{\mp}$ experiment which is performed at LHCb gives the strongest constraint., Comment: 14 pages, 7 figures

HIV affects the lives of about 37 million patients worldwideincluding around one million Americans. Infection is treated via drugs that inhibit several targets in the virus life cycle such as the HIV protease, which is essential for processing viral polyproteins. Antiviral therapy has been successful; however, emergence of drug resistance is a serious problem for the increasing population of HIV patients. It is unquestionable that there is an urgent need to design new inhibitors against drug-resistant targets in the virus, including HIV proteases. To meet this challenge, molecular mechanisms of resistance must be understood to provide suggestions for drug design. Mutation L76V in the protease is associated with major resistance towards clinical inhibitors darunavir and lopinavir, which are two of the three protease inhibitors that are prescribed in combination therapy. The prevalence of L76V increases from 1.5-3.2% to 5.4% in patients undergoing treatment failure; the mutation causes impaired autoprocessing and decreased protease stability. We tested the effectiveness of antivirals including clinical protease inhibitors (saquinavir, tipranavir and lopinavir) and promising investigational drugs (GRL-519 and GRL-5010) on the single mutant protease bearing L76V. We solved 6 crystal structures at high-resolution and proposed a mechanism of drug resistance at the structural level in which the mutation alters interactions at the interface of the hydrophobic core with the flap base. L76V as a single mutation is rare in the clinic with a frequency of 0.04% and is often found in combination with other resistance mutations. Compensatory mutations rescue weakened viral fitness and impaired autoprocessing caused by L76V. Structural studies on mutants bearing L76V in addition to other mutations are not available. We applied biochemical and biophysical analysis on a clinical isolate bearing over 20 mutations in addition to L76V. This cross-resistant mutant exhibited greater loss of susceptibility towards a panel of inhibitors and experienced partial compensation of protease stability.We solved the first crystal structures of ligand-free and inhibitor-complex for this multiple mutant. The structures display alterations of intramolecular interactions and extreme conformations. The present work on molecular mechanisms of drug resistance provides clues for structure-guided drug design.

The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease-catalyzed processing of the Gag-Pol precursor.

We give a deterministic nearly-linear time algorithm for approximating any point inside a convex polytope with a sparse convex combination of the polytope's vertices. Our result provides a constructive proof for the Approximate Carath��odory Problem, which states that any point inside a polytope contained in the $\ell_p$ ball of radius $D$ can be approximated to within $��$ in $\ell_p$ norm by a convex combination of only $O\left(D^2 p/��^2\right)$ vertices of the polytope for $p \geq 2$. We also show that this bound is tight, using an argument based on anti-concentration for the binomial distribution. Along the way of establishing the upper bound, we develop a technique for minimizing norms over convex sets with complicated geometry; this is achieved by running Mirror Descent on a dual convex function obtained via Sion's Theorem. As simple extensions of our method, we then provide new algorithms for submodular function minimization and SVM training. For submodular function minimization we obtain a simplification and (provable) speed-up over Wolfe's algorithm, the method commonly found to be the fastest in practice. For SVM training, we obtain $O(1/��^2)$ convergence for arbitrary kernels; each iteration only requires matrix-vector operations involving the kernel matrix, so we overcome the obstacle of having to explicitly store the kernel or compute its Cholesky factorization.

We study a racetrack model in the presence of the leading alpha'-correction in flux compactification in Type IIB string theory, for the purpose of getting conceivable de-Sitter vacua in the large compactified volume approximation. Unlike the K��hler Uplift model studied previously, the alpha'-correction is more controllable for the meta-stable de-Sitter vacua in the racetrack case since the constraint on the compactified volume size is very much relaxed. We find that the vacuum energy density ��for de-Sitter vacua approaches zero exponentially as the volume grows. We also analyze properties of the probability distribution of ��in this class of models. As in other cases studied earlier, the probability distribution again peaks sharply at ��=0. We also study the Racetrack K��hler Uplift model in the Swiss-Cheese type model., 23 pages, 4 figures

In this paper, we explicitly study the online vertex cover problem, which is a natural generalization of the well-studied ski-rental problem. In the online vertex cover problem, we are required to maintain a monotone vertex cover in a graph whose vertices arrive online. When a vertex arrives, all its incident edges to previously arrived vertices are revealed to the algorithm. For bipartite graphs with the left vertices offline (i.e. all of the left vertices arrive first before any right vertex), there are algorithms achieving the optimal competitive ratio of $\frac{1}{1-1/e}\approx 1.582$. Our first result is a new optimal water-filling algorithm for this case. One major ingredient of our result is a new charging-based analysis, which can be generalized to attack the online fractional vertex cover problem in general graphs. The main contribution of this paper is a 1.901-competitive algorithm for this problem. When the underlying graph is bipartite, our fractional solution can be rounded to an integral solution. In other words, we can obtain a vertex cover with expected size at most 1.901 of the optimal vertex cover in bipartite graphs. The next major result is a primal-dual analysis of our algorithm for the online fractional vertex cover problem in general graphs, which implies the dual result of a 0.526-competitive algorithm for online fractional matching in general graphs. Notice that both problems admit a well-known 2-competitive greedy algorithm. Our result in this paper is the first successful attempt to beat the greedy algorithm for these two problems. On the hardness side, we show that no randomized online algorithm can achieve a competitive ratio better than 1.753 and 0.625 for the online fractional vertex cover problem and the online fractional matching problem respectively, even for bipartite graphs., Comment: 21 pages