Selective cell death of latently HIV-infected CD4+ T cells mediated by autosis inducing nanopeptides.

Despite significant advances in the treatment of human immunodeficiency virus type-1 (HIV) infection, antiretroviral therapy only suppresses viral replication but is unable to eliminate infection. Thus, discontinuation of antiretrovirals results in viral reactivation and disease progression. A major reservoir of HIV latent infection resides in resting central memory CD4+ T cells (TCM) that escape clearance by current therapeutic regimens and will require novel strategies for elimination. Here, we evaluated the therapeutic potential of autophagy-inducing peptides, Tat-Beclin 1 and Tat-vFLIP-α2, which can induce a novel Na+/K+-ATPase dependent form of cell death (autosis), to kill latently HIV-infected TCM while preventing virologic rebound. In this study, we encapsulated autophagy inducing peptides into biodegradable lipid-coated hybrid PLGA (poly lactic-co-glycolic acid) nanoparticles for controlled intracellular delivery. A single dose of nanopeptides was found to eliminate latent HIV infection in an in vitro primary model of HIV latency and ex vivo using resting CD4+ T cells obtained from peripheral blood mononuclear cells of HIV-infected patients on antiretroviral with fully suppressed virus for greater than 12 months. Notably, increased LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase activity characteristic of autosis, were detected in nanopeptide treated latently HIV-infected cells compared to untreated uninfected or infected cells. Nanopeptide-induced cell death could be reversed by knockdown of autophagy proteins, ATG5 and ATG7, and inhibition or knockdown of Na+/K+-ATPase. Importantly, viral rebound was not detected following the induction of the Na+/K+-ATPase dependent form of cell death induced by the Tat-Beclin 1 and Tat-vFLIP-α2 nanopeptides. These findings provide a novel strategy to eradicate HIV latently infected resting memory CD4+ T cells, the major reservoir of HIV latency, through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells

Circumbinary disk evolution in the presence of an outer companion star

We consider a hierarchical triple system consisting of an inner eccentric binary with an outer companion. A highly misaligned circumbinary disk around the inner binary is subject to two competing effects: (i) nodal precession about the inner binary eccentricity vector that leads to an increase in misalignment (polar alignment) and (ii) Kozai-Lidov (KL) oscillations of eccentricity and inclination driven by the outer companion that leads to a reduction in the misalignment. The outcome depends upon the ratio of the timescales of these effects. If the inner binary torque dominates, then the disk aligns to a polar orientation. If the outer companion torque dominates, then the disk undergoes KL oscillations. In that case, the highly eccentric and misaligned disk is disrupted and accreted by the inner binary, while some mass is transferred to the outer companion. However, when the torques are similar, the outer parts of the circumbinary disk can undergo large eccentricity oscillations while the inclination remains close to the polar orientation. The range of initial disk inclinations that evolve to a polar orientation is smaller in the presence of the outer companion. Disk breaking is also more likely, at least temporarily, during the polar alignment process. The stellar orbits in HD 98800 have parameters such that polar alignment of the circumbinary disk is expected. In the absence of the gas, solid particles are unstable at much smaller radii than the gas disk inner tidal truncation radius because KL driven eccentricity leads to close encounters with the binary.Comment: Accepted for publication in ApJ

Cost Analysis of Outpatient Anterior Cruciate Ligament Reconstruction: Autograft versus Allograft

Prior studies suggest the cost of allograft anterior cruciate ligament (ACL) reconstruction is less than that for autograft reconstruction. Charges in these studies were influenced by patients requiring inpatient hospitalization. We therefore determined if allograft ACL reconstruction would still be less costly if all procedures were performed in a completely outpatient setting. We retrospectively reviewed 155 patients who underwent ACL reconstruction in an ambulatory surgery center between 2001 and 2004; 105 had an autograft and 50 had an allograft. Charges were extracted from itemized billing records, standardized to eliminate cost increases, and categorized for comparison. Surgeon and anesthesiologist fees were not included in the analysis. Groups were compared for age, gender, mean total cost, mean cost of implants, and several other cost categories. The mean total cost was $5465 for allograft ACL reconstruction and$4872 for autograft ACL reconstruction. There were no differences in complications between the two groups. Allograft ACL reconstruction was more costly than autograft ACL reconstruction in the outpatient setting. The cost of the allograft outweighs the increased surgical time needed for harvesting an autograft. Level II, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence

Longitudinal Evaluation of Fatty Acid Metabolism in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic MicroSPECT Imaging

The goal of this project is to develop radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify changes in cardiac metabolism using the spontaneously hypertensive rat (SHR) as a model of hypertensive-related pathophysiology. This paper quantitatively compares fatty acid metabolism in hearts of SHR and Wistar-Kyoto normal rats as a function of age and thereby tracks physiological changes associated with the onset and progression of heart failure in the SHR model. The fatty acid analog, 123I-labeled BMIPP, was used in longitudinal metabolic pinhole SPECT imaging studies performed every seven months for 21 months. The uniqueness of this project is the development of techniques for estimating the blood input function from projection data acquired by a slowly rotating camera that is imaging fast circulation and the quantification of the kinetics of 123I-BMIPP by fitting compartmental models to the blood and tissue time-activity curves

Multi-scale mechanical characterization of highly swollen photo-activated collagen hydrogels

Biological hydrogels have been increasingly sought after as wound dressings or scaffolds for regenerative medicine, owing to their inherent biofunctionality in biological environments. Especially in moist wound healing, the ideal material should absorb large amounts of wound exudate while remaining mechanically competent in situ. Despite their large hydration, however, current biological hydrogels still leave much to be desired in terms of mechanical properties in physiological conditions. To address this challenge, a multi-scale approach is presented for the synthetic design of cyto-compatible collagen hydrogels with tunable mechanical properties (from the nano- up to the macro-scale), uniquely high swelling ratios and retained (more than 70%) triple helical features. Type I collagen was covalently functionalized with three different monomers, i.e. 4-vinylbenzyl chloride, glycidyl methacrylate and methacrylic anhydride, respectively. Backbone rigidity, hydrogen-bonding capability and degree of functionalization (F: 16 ± 12–91 ± 7 mol%) of introduced moieties governed the structure–property relationships in resulting collagen networks, so that the swelling ratio (SR: 707 ± 51–1996 ± 182 wt%), bulk compressive modulus (Ec: 30 ± 7–168 ± 40 kPa) and atomic force microscopy elastic modulus (EAFM: 16 ± 2–387 ± 66 kPa) were readily adjusted. Because of their remarkably high swelling and mechanical properties, these tunable collagen hydrogels may be further exploited for the design of advanced dressings for chronic wound care

Computation in Classical Mechanics

There is a growing consensus that physics majors need to learn computational skills, but many departments are still devoid of computation in their physics curriculum. Some departments may lack the resources or commitment to create a dedicated course or program in computational physics. One way around this difficulty is to include computation in a standard upper-level physics course. An intermediate classical mechanics course is particularly well suited for including computation. We discuss the ways we have used computation in our classical mechanics courses, focusing on how computational work can improve students' understanding of physics as well as their computational skills. We present examples of computational problems that serve these two purposes. In addition, we provide information about resources for instructors who would like to include computation in their courses.Comment: 6 pages, 3 figures, submitted to American Journal of Physic