A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity

The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC50 of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans

The motion of point particles in curved spacetime

This review is concerned with the motion of a point scalar charge, a point electric charge, and a point mass in a specified background spacetime. In each of the three cases the particle produces a field that behaves as outgoing radiation in the wave zone, and therefore removes energy from the particle. In the near zone the field acts on the particle and gives rise to a self-force that prevents the particle from moving on a geodesic of the background spacetime. The field's action on the particle is difficult to calculate because of its singular nature: the field diverges at the position of the particle. But it is possible to isolate the field's singular part and show that it exerts no force on the particle -- its only effect is to contribute to the particle's inertia. What remains after subtraction is a smooth field that is fully responsible for the self-force. Because this field satisfies a homogeneous wave equation, it can be thought of as a free (radiative) field that interacts with the particle; it is this interaction that gives rise to the self-force. The mathematical tools required to derive the equations of motion of a point scalar charge, a point electric charge, and a point mass in a specified background spacetime are developed here from scratch. The review begins with a discussion of the basic theory of bitensors (part I). It then applies the theory to the construction of convenient coordinate systems to chart a neighbourhood of the particle's word line (part II). It continues with a thorough discussion of Green's functions in curved spacetime (part III). The review concludes with a detailed derivation of each of the three equations of motion (part IV).Comment: LaTeX2e, 116 pages, 10 figures. This is the final version, as it will appear in Living Reviews in Relativit

Self-force: Computational Strategies

Building on substantial foundational progress in understanding the effect of a small body's self-field on its own motion, the past 15 years has seen the emergence of several strategies for explicitly computing self-field corrections to the equations of motion of a small, point-like charge. These approaches broadly fall into three categories: (i) mode-sum regularization, (ii) effective source approaches and (iii) worldline convolution methods. This paper reviews the various approaches and gives details of how each one is implemented in practice, highlighting some of the key features in each case.Comment: Synchronized with final published version. Review to appear in "Equations of Motion in Relativistic Gravity", published as part of the Springer "Fundamental Theories of Physics" series. D. Puetzfeld et al. (eds.), Equations of Motion in Relativistic Gravity, Fundamental Theories of Physics 179, Springer, 201

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Search for dark matter candidates and large extra dimensions in events with a jet and missing transverse momentum with the ATLAS detector

Open Access, Copyright CERN, for the benefit of the ATLAS collaboration. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited

Unresolved antiretroviral treatment management issues in HIV-infected children.

Geneeskunde en GesondheidswetenskappePediatrie En KindergesondheidPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]