Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis. During resolution, specific omega-3 polyunsaturated fatty-acid-derived mediators are generated within resolving exudates, including resolvin E1 (RvE1) and protectin D1 (PD1). It is thus important to pinpoint specific actions of RvE1 and PD1 in regulating tissue resolution. Here we report that RvE1 and PD1 in nanogram quantities promote phagocyte removal during acute inflammation by regulating leukocyte infiltration, increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, and enhancing the appearance of phagocytes carrying engulfed zymosan in lymph nodes and spleen. In this tissue terrain, inhibition of either cyclooxygenase or lipoxygenases--pivotal enzymes in the temporal generation of both pro-inflammatory and pro-resolving mediators--caused a 'resolution deficit' that was rescued by RvE1, PD1 or aspirin-triggered lipoxin A4 analogue. Also, new resolution routes were identified that involve phagocytes traversing perinodal adipose tissues and non-apoptotic polymorphonuclear neutrophils carrying engulfed zymosan to lymph nodes. Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues.     

Abrupt onset of a second energy gap at the superconducting transition of underdoped Bi2212

The superconducting gap--an energy scale tied to the superconducting phenomena--opens on the Fermi surface at the superconducting transition temperature (T(c)) in conventional BCS superconductors. In underdoped high-T(c) superconducting copper oxides, a pseudogap (whose relation to the superconducting gap remains a mystery) develops well above T(c) (refs 1, 2). Whether the pseudogap is a distinct phenomenon or the incoherent continuation of the superconducting gap above T(c) is one of the central questions in high-T(c) research. Although some experimental evidence suggests that the two gaps are distinct, this issue is still under intense debate. A crucial piece of evidence to firmly establish this two-gap picture is still missing: a direct and unambiguous observation of a single-particle gap tied to the superconducting transition as function of temperature. Here we report the discovery of such an energy gap in underdoped Bi2Sr2CaCu2O8+delta in the momentum space region overlooked in previous measurements. Near the diagonal of Cu-O bond direction (nodal direction), we found a gap that opens at T(c) and has a canonical (BCS-like) temperature dependence accompanied by the appearance of the so-called Bogoliubov quasi-particles, a classical signature of superconductivity. This is in sharp contrast to the pseudogap near the Cu-O bond direction (antinodal region) measured in earlier experiments.     

Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.     

Aggregation and vesiculation of membrane proteins by curvature-mediated interactions

Membrane remodelling plays an important role in cellular tasks such as endocytosis, vesiculation and protein sorting, and in the biogenesis of organelles such as the endoplasmic reticulum or the Golgi apparatus. It is well established that the remodelling process is aided by specialized proteins that can sense as well as create membrane curvature, and trigger tubulation when added to synthetic liposomes. Because the energy needed for such large-scale changes in membrane geometry significantly exceeds the binding energy between individual proteins and between protein and membrane, cooperative action is essential. It has recently been suggested that curvature-mediated attractive interactions could aid cooperation and complement the effects of specific binding events on membrane remodelling. But it is difficult to experimentally isolate curvature-mediated interactions from direct attractions between proteins. Moreover, approximate theories predict repulsion between isotropically curving proteins. Here we use coarse-grained membrane simulations to show that curvature-inducing model proteins adsorbed on lipid bilayer membranes can experience attractive interactions that arise purely as a result of membrane curvature. We find that once a minimal local bending is realized, the effect robustly drives protein cluster formation and subsequent transformation into vesicles with radii that correlate with the local curvature imprint. Owing to its universal nature, curvature-mediated attraction can operate even between proteins lacking any specific interactions, such as newly synthesized and still immature membrane proteins in the endoplasmic reticulum.     

A link between large mantle melting events and continent growth seen in osmium isotopes

Although Earth's continental crust is thought to have been derived from the mantle, the timing and mode of crust formation have proven to be elusive issues. The area of preserved crust diminishes markedly with age, and this can be interpreted as being the result of either the progressive accumulation of new crust or the tectonic recycling of old crust. However, there is a disproportionate amount of crust of certain ages, with the main peaks being 1.2, 1.9, 2.7 and 3.3 billion years old; this has led to a third model in which the crust has grown through time in pulses, although peaks in continental crust ages could also record preferential preservation. The 187Re-187Os decay system is unique in its ability to track melt depletion events within the mantle and could therefore potentially link the crust and mantle differentiation records. Here we employ a laser ablation technique to analyse large numbers of osmium alloy grains to quantify the distribution of depletion ages in the Earth's upper mantle. Statistical analysis of these data, combined with other samples of the upper mantle, show that depletion ages are not evenly distributed but cluster in distinct periods, around 1.2, 1.9 and 2.7 billion years. These mantle depletion events coincide with peaks in the generation of continental crust and so provide evidence of coupled, global and pulsed mantle-crust differentiation, lending strong support to pulsed models of continental growth by means of large-scale mantle melting events.     

A current filamentation mechanism for breaking magnetic field lines during reconnection

During magnetic reconnection, the field lines must break and reconnect to release the energy that drives solar and stellar flares and other explosive events in space and in the laboratory. Exactly how this happens has been unclear, because dissipation is needed to break magnetic field lines and classical collisions are typically weak. Ion-electron drag arising from turbulence, dubbed 'anomalous resistivity', and thermal momentum transport are two mechanisms that have been widely invoked. Measurements of enhanced turbulence near reconnection sites in space and in the laboratory support the anomalous resistivity idea but there has been no demonstration from measurements that this turbulence produces the necessary enhanced drag. Here we report computer simulations that show that neither of the two previously favoured mechanisms controls how magnetic field lines reconnect in the plasmas of greatest interest, those in which the magnetic field dominates the energy budget. Rather, we find that when the current layers that form during magnetic reconnection become too intense, they disintegrate and spread into a complex web of filaments that causes the rate of reconnection to increase abruptly. This filamentary web can be explored in the laboratory or in space with satellites that can measure the resulting electromagnetic turbulence.