Screening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry

The search for therapeutic agents that bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult because many protein precursors of aggregation are partially folded or intrinsically disordered, which rules out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or nonspecific binding, as well as colloidal inhibition. Here we report a high-throughput method based on ion mobility spectrometry–mass spectrometry (IMS–MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human ​islet amyloid polypeptide (​hIAPP) aggregation or ​amyloid-beta 1-40 aggregation as specific, nonspecific, colloidal or non-interacting. We also demonstrate the ability of IMS–MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of ​hIAPP amyloid assembly

A rapid mechanism to remobilize and homogenize highly crystalline magma bodies

International audienceThe largest products of magmatic activity on Earth, the great bodies of granite and their corresponding large eruptions, have a dual nature: homogeneity at the large scale and spatial and temporal heterogeneity at the small scale1-4. This duality calls for amechanism that selectively removes the large-scale heterogeneities associated with the incremental assembly4 of these magmatic systems and yet occurs rapidly despite crystal-rich, viscous conditions seemingly resistant to mixing2,5. Here we show that a simple dynamic template can unify a wide range of apparently contradictory observations from both large plutonic bodies and volcanic systems by a mechanism of rapid remobilization (unzipping) of highly viscous crystalrich mushes. We demonstrate that this remobilization can lead to rapid overturn and produce the observed juxtaposition ofmagmatic materials with very disparate ages and complex chemical zoning. What distinguishes our model is the recognition that the process has two stages. Initially, a stiff mushy magma is reheated from below, producing a reduction in crystallinity that leads to the growth of a subjacent buoyant mobile layer. When the thickening mobile layer becomes sufficiently buoyant, it penetrates the overlying viscous mushy magma. This second stage rapidly exports homogenized material from the lower mobile layer to the top of the system, and leads to partial overturn within the viscous mush itself as an additional mechanism of mixing. Model outputs illustrate that unzipping can rapidly produce large amounts of mobile magma available for eruption. The agreement between calculated and observed unzipping rates for historical eruptions at Pinatubo and at Montserrat demonstrates the general applicability of the model. This mechanism furthers our understanding of both the formation of periodically homogenized plutons (crust building) and of ignimbrites by large eruptions

Living on the edge: utilising lidar data to assess the importance of vegetation structure for avian diversity in fragmented woodlands and their edges

Context: In agricultural landscapes, small woodland patches can be important wildlife refuges. Their value in maintaining biodiversity may, however, be compromised by isolation, and so knowledge about the role of habitat structure is vital to understand the drivers of diversity. This study examined how avian diversity and abundance were related to habitat structure in four small woods in an agricultural landscape in eastern England. Objectives: The aims were to examine the edge effect on bird diversity and abundance, and the contributory role of vegetation structure. Specifically: what is the role of vegetation structure on edge effects, and which edge structures support the greatest bird diversity? Methods: Annual breeding bird census data for 28 species were combined with airborne lidar data in linear mixed models fitted separately at (i) the whole wood level, and (ii) for the woodland edges only. Results: Despite relatively small woodland areas (4.9–9.4 ha), bird diversity increased significantly towards the edges, being driven in part by vegetation structure. At the whole woods level, diversity was positively associated with increased vegetation above 0.5 m and especially with increasing vegetation density in the understorey layer, which was more abundant at the woodland edges. Diversity along the edges was largely driven by the density of vegetation below 4 m. Conclusions: The results demonstrate that bird diversity was maximised by a diverse vegetation structure across the wood and especially a dense understorey along the edge. These findings can assist bird conservation by guiding habitat management of remaining woodland patches

Timescales of Quartz Crystallization and the Longevity of the Bishop Giant Magma Body

Supereruptions violently transfer huge amounts (100 s–1000 s km3) of magma to the surface in a matter of days and testify to the existence of giant pools of magma at depth. The longevity of these giant magma bodies is of significant scientific and societal interest. Radiometric data on whole rocks, glasses, feldspar and zircon crystals have been used to suggest that the Bishop Tuff giant magma body, which erupted ∼760,000 years ago and created the Long Valley caldera (California), was long-lived (>100,000 years) and evolved rather slowly. In this work, we present four lines of evidence to constrain the timescales of crystallization of the Bishop magma body: (1) quartz residence times based on diffusional relaxation of Ti profiles, (2) quartz residence times based on the kinetics of faceting of melt inclusions, (3) quartz and feldspar crystallization times derived using quartz+feldspar crystal size distributions, and (4) timescales of cooling and crystallization based on thermodynamic and heat flow modeling. All of our estimates suggest quartz crystallization on timescales of <10,000 years, more typically within 500–3,000 years before eruption. We conclude that large-volume, crystal-poor magma bodies are ephemeral features that, once established, evolve on millennial timescales. We also suggest that zircon crystals, rather than recording the timescales of crystallization of a large pool of crystal-poor magma, record the extended periods of time necessary for maturation of the crust and establishment of these giant magma bodies

Poor prospects for avian biodiversity in amazonian oil palm

Expansion of oil palm plantations across the humid tropics has precipitated massive loss of tropical forest habitats and their associated speciose biotas. Oil palm plantation monocultures have been identified as an emerging threat to Amazonian biodiversity, but there are no quantitative studies exploring the impact of these plantations on the biome’s biota. Understanding these impacts is extremely important given the rapid projected expansion of oil palm cultivation in the basin. Here we investigate the biodiversity value of oil palm plantations in comparison with other dominant regional land-uses in Eastern Amazonia. We carried out bird surveys in oil palm plantations of varying ages, primary and secondary forests, and cattle pastures. We found that oil palm plantations retained impoverished avian communities with a similar species composition to pastures and agrarian land-uses and did not offer habitat for most forest-associated species, including restricted range species and species of conservation concern. On the other hand, the forests that the oil palm companies are legally obliged to protect hosted a relatively species-rich community including several globally-threatened bird species. We consider oil palm to be no less detrimental to regional biodiversity than other agricultural land-uses and that political pressure exerted by large landowners to allow oil palm to count as a substitute for native forest vegetation in private landholdings with forest restoration deficits would have dire consequences for regional biodiversity

Fault slip and identification of the second fault plane in the Varzeghan earthquake doublet

An intraplate earthquake doublet, with 11-min delay between the events, devastated the city of Varzeghan in northwestern Iran on August 11, 2012. The first Mw 6.5 strike-slip earthquake, which occurred after more than 200 years of low seismicity, was followed by an Mw 6.4 oblique thrust event at an epicentral separation of about 6 km. While the first event can be associated with a distinct surface rupture, the absence of a surface fault trace and no clear aftershock signature makes it challenging to identify the fault plane of the second event. We use teleseismic body wave inversion to deduce the slip distribution in the first event. Using both P and SH waves stabilize the inversion and we further constrain the result with the surface rupture extent and the aftershock distribution. The obtained slip pattern shows two distinct slip patches with dissimilar slip directions where aftershocks avoid high-slip areas. Using the estimated slip for the first event, we calculate the induced Coulomb stress change on the nodal planes of the second event and find a preference for higher Coulomb stress on the N-S nodal plane. Assuming a simple slip model for the second event, we estimate the combined Coulomb stress changes from the two events on the focal planes of the largest aftershocks. We find that 90% of the aftershocks show increased Coulomb stress on one of their nodal planes when the N-S plane of the second event is assumed to be the correct fault plane