Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans

Analysis of periosteal lesions from commingled human remains at the Xagħra Circle hypogeum reveals the first case of probable scurvy from Neolithic Malta

Abstract Objectives Palaeopathological analysis is key for characterising population health at the individual level and across large assemblages but is rarely exploited to unite the remains of disarticulated individuals. This study explores the potential for individual identification through differential diagnosis of periosteal lesions in a commingled deposit, both to ascertain the number of individuals represented and provide a differential diagnosis. Materials and Methods The late Neolithic Xag?ra Circle hypogeum on Gozo contains the remains of more than 800 individuals, most of which were transformed to a collective disarticulated assemblage. Across the excavated population, pathological observations are strikingly low. In one specific 1???1-m area in a single stratigraphic context, fragmented and disarticulated cranial and post-cranial non-adult bones were identified that displayed periosteal new bone formation. To aid differential diagnosis, macroscopic analysis, taphonomic analysis and micro-computed tomography (?CT) imaging were integrated. Results This approach, when combined with osteobiographical analyses, reveals that the elements most likely derive from one individual, a young child, who presents a probable case of scurvy. The potential for micronutrient co-morbidities are explored, but without further microscopic study it cannot be determined if this individual also experienced iron-deficiency anaemia and/or rickets. Discussion In the context of the Mediterranean and Europe in later prehistory, reported cases of scurvy are currently low and often reveal periods of environmental instability and resource insufficiency. Our finding of non-adult scurvy in late 3rd millennium BC Malta contributes to a developing picture of an increasingly unstable palaeoenvironment and declining population health at this time, although it may also indicate an individual case of poor childhood health within this broader context.1 Introduction 1.1 Archaeological context of the Xagħra Circle hypogeum 2 Materials and methods 2.1 Remains presenting periosteal lesions 2.2 Macroscopic and micro-CT analysis 3 Macroscopic and radiological observations of pathology 3.1 Frontal bone (FB0039, FB0040) and zygoma (FB0041) 3.2 Mandible (FB0042) 3.3 Left rib (FB0043) and right rib (FB0044) 3.4 Ulna (FB0045) 4 Differential diagnosis 4.1 Frontal bone (FB0039, FB0040) and zygoma (FB0041) 4.2 Mandible (FB0042) 4.3 Left rib (FB0043) and right rib (FB0044) 4.4 Ulna (FB0045) 5 Discussion 5.1 Scurvy: Causes, consequences and comorbidities 5.2 Scurvy in prehistory 5.3 The Maltese context 6 Conclusio

Mesoscopic Superconducting Disc with Short-Range Columnar Defects

Short-range columnar defects essentially influence the magnetic properties of a mesoscopic superconducting disc.They help the penetration of vortices into the sample, thereby decrease the sample magnetization and reduce the upper critical field. Even the presence of weak defects split a giant vortex state (usually appearing in a clean disc in the vicinity of the transition to a normal state) into a number of vortices with smaller topological charges. In a disc with a sufficient number of strong enough defects vortices are always placed onto defects. The presence of defects lead to the appearance of additional magnetization jumps related to the redistribution of vortices which are already present on the defects and not to the penetration of new vortices.Comment: 14 pgs. RevTex, typos and figures corrected. Submitted to Phys. Rev.

Magnetoresistance of a 2-dimensional electron gas in a random magnetic field

We report magnetoresistance measurements on a two-dimensional electron gas (2DEG) made from a high mobility GaAs/AlGaAs heterostructure, where the externally applied magnetic field was expelled from regions of the semiconductor by means of superconducting lead grains randomly distributed on the surface of the sample. A theoretical explanation in excellent agreement with the experiment is given within the framework of the semiclassical Boltzmann equation.Comment: REVTEX 3.0, 11 pages, 3 Postscript figures appended. The manuscript can also be obtained from our World Wide Web server: http://roemer.fys.ku.dk/randmag.ht

Potent Activity of the HIV-1 Maturation Inhibitor Bevirimat in SCID-hu Thy/Liv Mice

The HIV-1 maturation inhibitor, 3-O-(3',3'-dimethylsuccinyl) betulinic acid (bevirimat, PA-457) is a promising drug candidate with 10 nM in vitro antiviral activity against multiple wild-type (WT) and drug-resistant HIV-1 isolates. Bevirimat has a novel mechanism of action, specifically inhibiting cleavage of spacer peptide 1 (SP1) from the C-terminus of capsid which results in defective core condensation.Oral administration of bevirimat to HIV-1-infected SCID-hu Thy/Liv mice reduced viral RNA by >2 log(10) and protected immature and mature T cells from virus-mediated depletion. This activity was observed at plasma concentrations that are achievable in humans after oral dosing, and bevirimat was active up to 3 days after inoculation with both WT HIV-1 and an AZT-resistant HIV-1 clinical isolate. Consistent with its mechanism of action, bevirimat caused a dose-dependent inhibition of capsid-SP1 cleavage in HIV-1-infected human thymocytes obtained from these mice. HIV-1 NL4-3 with an alanine-to-valine substitution at the N-terminus of SP1 (SP1/A1V), which is resistant to bevirimat in vitro, was also resistant to bevirimat treatment in the mice, and SP1/AIV had replication and thymocyte kinetics similar to that of WT NL4-3 with no evidence of fitness impairment in in vivo competition assays. Interestingly, protease inhibitor-resistant HIV-1 with impaired capsid-SP1 cleavage was hypersensitive to bevirimat in vitro with a 50% inhibitory concentration 140 times lower than for WT HIV-1.These results support further clinical development of this first-in-class maturation inhibitor and confirm the usefulness of the SCID-hu Thy/Liv model for evaluation of in vivo antiretroviral efficacy, drug resistance, and viral fitness

Geographically touring the eastern bloc: British geography, travel cultures and the Cold War

This paper considers the role of travel in the generation of geographical knowledge of the eastern bloc by British geographers. Based on oral history and surveys of published work, the paper examines the roles of three kinds of travel experience: individual private travels, tours via state tourist agencies, and tours by academic delegations. Examples are drawn from across the eastern bloc, including the USSR, Poland, Romania, East Germany and Albania. The relationship between travel and publication is addressed, notably within textbooks, and in the Geographical Magazine. The study argues for the extension of accounts of cultures of geographical travel, and seeks to supplement the existing historiography of Cold War geography

Experiments in vortex avalanches

Avalanche dynamics is found in many phenomena spanning from earthquakes to the evolution of species. It can be also found in vortex matter when a type II superconductor is externally driven, for example, by increasing the magnetic field. Vortex avalanches associated with thermal instabilities can be an undesirable effect for applications, but "dynamically driven" avalanches emerging from the competition between intervortex interactions and quenched disorder constitute an interesting scenario to test theoretical ideas related with non-equilibrium dynamics. However, differently from the equilibrium phases of vortex matter in type II superconductors, the study of the corresponding dynamical phases - in which avalanches can play a role - is still in its infancy. In this paper we critically review relevant experiments performed in the last decade or so, emphasizing the ability of different experimental techniques to establish the nature and statistical properties of the observed avalanche behavior.Comment: To be published in Reviews of Modern Physics April 2004. 17 page