Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

Meteoric smoke fallout over the Holocene epoch revealed by iridium and platinum in Greenland ice

An iridium anomaly at the Cretaceous/Tertiary boundary layer has been attributed to an extraterrestrial body that struck the Earth some 65 million years ago. It has been suggested that, during this event, the carrier of iridium was probably a micrometre-sized silicate-enclosed aggregate or the nanophase material of the vaporized impactor. But the fate of platinum-group elements (such as iridium) that regularly enter the atmosphere via ablating meteoroids remains largely unknown. Here we report a record of iridium and platinum fluxes on a climatic-cycle timescale, back to 128,000 years ago, from a Greenland ice core. We find that unexpectedly constant fallout of extraterrestrial matter to Greenland occurred during the Holocene, whereas a greatly enhanced input of terrestrial iridium and platinum masked the cosmic flux in the dust-laden atmosphere of the last glacial age. We suggest that nanometre-sized meteoric smoke particles, formed from the recondensation of ablated meteoroids in the atmosphere at altitudes >70 kilometres, are transported into the winter polar vortices by the mesospheric meridional circulation and are preferentially deposited in the polar ice caps. This implies an average global fallout of 14 +/- 5 kilotons per year of meteoric smoke during the Holocene.     

Acrylamide from Maillard reaction products

The discovery of the adventitious formation of the potential cancer-causing agent acrylamide in a variety of foods during cooking has raised much concern, but the chemical mechanism(s) governing its production are unclear. Here we show that acrylamide can be released by the thermal treatment of certain amino acids (asparagine, for example), particularly in combination with reducing sugars, and of early Maillard reaction products (N-glycosides). Our findings indicate that the Maillard-driven generation of flavour and colour in thermally processed foods can -- under particular conditions -- be linked to the formation of acrylamide.     

Survival of stressed rats following experimental cardiac necrosis

Résumé Une nécrose myocardique a été produite chez. le rat mâle adulte avec de l'isoprotérénol. Aucune différence de survie significative n'a été constatée entre les individus traités et les non traités lorsque les uns et les autres ont été soumis à l'hypoxémie, la nage forcée dans l'eau froide, ou la restriction par attache.

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This work was conducted in the Department of Chemical Pharmacology. We wish to thank Dr.D. A. Buyske for his interest and suggestions.     

Synthetic homeostatic materials with chemo-mechano-chemical self-regulation

Living organisms have unique homeostatic abilities, maintaining tight control of their local environment through interconversions of chemical and mechanical energy and self-regulating feedback loops organized hierarchically across many length scales. In contrast, most synthetic materials are incapable of continuous self-monitoring and self-regulating behaviour owing to their limited single-directional chemomechanical or mechanochemical modes. Applying the concept of homeostasis to the design of autonomous materials would have substantial impacts in areas ranging from medical implants that help stabilize bodily functions to 'smart' materials that regulate energy usage. Here we present a versatile strategy for creating self-regulating, self-powered, homeostatic materials capable of precisely tailored chemo-mechano-chemical feedback loops on the nano- or microscale. We design a bilayer system with hydrogel-supported, catalyst-bearing microstructures, which are separated from a reactant-containing 'nutrient' layer. Reconfiguration of the gel in response to a stimulus induces the reversible actuation of the microstructures into and out of the nutrient layer, and serves as a highly precise 'on/off' switch for chemical reactions. We apply this design to trigger organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles synchronized with the motion of the microstructures and the driving external chemical stimulus. By exploiting a continuous feedback loop between various exothermic catalytic reactions in the nutrient layer and the mechanical action of the temperature-responsive gel, we then create exemplary autonomous, self-sustained homeostatic systems that maintain a user-defined parameter--temperature--in a narrow range. The experimental results are validated using computational modelling that qualitatively captures the essential features of the self-regulating behaviour and provides additional criteria for the optimization of the homeostatic function, subsequently confirmed experimentally. This design is highly customizable owing to the broad choice of chemistries, tunable mechanics and its physical simplicity, and may lead to a variety of applications in autonomous systems with chemo-mechano-chemical transduction at their core.     

Self-directed self-assembly of nanoparticle/copolymer mixtures

The organization of inorganic nanostructures within self-assembled organic or biological templates is receiving the attention of scientists interested in developing functional hybrid materials. Previous efforts have concentrated on using such scaffolds to spatially arrange nanoscopic elements as a strategy for tailoring the electrical, magnetic or photonic properties of the material. Recent theoretical arguments have suggested that synergistic interactions between self-organizing particles and a self-assembling matrix material can lead to hierarchically ordered structures. Here we show that mixtures of diblock copolymers and either cadmium selenide- or ferritin-based nanoparticles exhibit cooperative, coupled self-assembly on the nanoscale. In thin films, the copolymers assemble into cylindrical domains, which dictate the spatial distribution of the nanoparticles; segregation of the particles to the interfaces mediates interfacial interactions and orients the copolymer domains normal to the surface, even when one of the blocks is strongly attracted to the substrate. Organization of both the polymeric and particulate entities is thus achieved without the use of external fields, opening a simple and general route for fabrication of nanostructured materials with hierarchical order.     

Die Wirkung von Eiweissfraktionen normaler menschlicher Sera auf die Thrombocytenzahl der Maus

Summary We investigated the thrombocytosis-producing activity of different protein-fractions of human sera in mice. The whole sera, the albumin,- and-globulins were ineffective, whereas the-globulins caused a more or less exact thrombocytosis in mice. The effectiveness of the thrombopoetic activity present in normal human sera is probably inhibited by a factor connected with another protein-fraction.