Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.

Small heat shock proteins (sHSPs) are a class of oligomeric molecular chaperones that limit protein aggregation. However, it is often not clear where sHSPs bind on their client proteins or how these protein-protein interactions (PPIs) are regulated. Here, we map the PPIs between human Hsp27 and the microtubule-associated protein tau (MAPT/tau). We find that Hsp27 selectively recognizes two aggregation-prone regions of tau, using the conserved β4-β8 cleft of its alpha-crystallin domain. The β4-β8 region is also the site of Hsp27-Hsp27 interactions, suggesting that competitive PPIs may be an important regulatory paradigm. Indeed, we find that each of the individual PPIs are relatively weak and that competition for shared sites seems to control both client binding and Hsp27 oligomerization. These findings highlight the importance of multiple, competitive PPIs in the function of Hsp27 and suggest that the β4-β8 groove acts as a tunable sensor for clients

Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads

Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics

Strain localisation in mechanically layered rocks beneath detachment zones: insights from numerical modelling.

International audienceFully dynamic numerical simulations have been designed in order to asses how the orientation of mechanical layering in rocks controls the orientation of shear bands and the depth of penetration of strain in the footwall of detachment zones. Two parametric studies are presented. In the first one, the influence of stratification orientation on the occurrence and mode of strain localisation is tested. The second parametric study shows that results are length-scale independent and that orientation of shear bands is not sensitive to the viscosity contrast or the strain rate. Based on the results, a conceptual model for strain localisation under detachment faults is presented. In the early stages, strain localisation occurs at slow rates by viscous shear instabilities but as the layered media is exhumed, the temperature drops and the strong layers start yielding plastically, forming shear bands and localising strain at the top of the shear zone. Once strain localisation has occured, the deformation in the shear band becomes extremely penetrative but the strength cannot drop since the shear zone has a finite thickness

Aerodynamics of aero-engine installation

This paper describes current progress in the development of methods to assess aero-engine airframe installation effects. The aerodynamic characteristics of isolated intakes, a typical transonic transport aircraft as well as a combination of a through-flow nacelle and aircraft configuration have been evaluated. The validation task for an isolated engine nacelle is carried out with concern for the accuracy in the assessment of intake performance descriptors such as mass flow capture ratio and drag rise Mach number. The necessary mesh and modelling requirements to simulate the nacelle aerodynamics are determined. Furthermore, the validation of the numerical model for the aircraft is performed as an extension of work that has been carried out under previous drag prediction research programmes. The validation of the aircraft model has been extended to include the geometry with through flow nacelles. Finally, the assessment of the mutual impact of the through flow nacelle and aircraft aerodynamics was performed. The drag and lift coefficient breakdown has been presented in order to identify the component sources of the drag associated with the engine installation. The paper concludes with an assessment of installation drag for through-flow nacelles and the determination of aerodynamic interference between the nacelle and the aircraft

Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories

In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphse plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered

Limited biomass recovery from gold mining in Amazonian forests

1. Gold mining has rapidly increased across the Amazon Basin in recent years, especially in the Guiana shield, where it is responsible for >90% of total deforestation. However, the ability of forests to recover from gold mining activities remains largely unquantified. 2. Forest inventory plots were installed on recently abandoned mines in two major mining regions in Guyana, and re‐censused 18 months later, to provide the first ground‐based quantification of gold mining impacts on Amazon forest biomass recovery. 3. We found that woody biomass recovery rates on abandoned mining pits and tailing ponds are among the lowest ever recorded for tropical forests, with close to no woody biomass recovery after 3–4 years. 4. On the overburden sites (i.e. areas not mined but where excavated soil is deposited), however, above‐ground biomass recovery rates (0.4–5.4 Mg ha−1 year−1) were within the range of those recorded in other secondary forests across the Neotropics following abandonment of pastures and agricultural lands. 5. Our results suggest that forest recovery is more strongly limited by severe mining‐induced depletion of soil nutrients, especially nitrogen, than by mercury contamination, due to slowing of growth in nutrient‐stripped soils. 6. We estimate that the slow recovery rates in mining pits and ponds currently reduce carbon sequestration across Amazonian secondary forests by ~21,000 t C/year, compared to the carbon that would have accumulated following more traditional land uses such as agriculture or pasture. 7. Synthesis and applications. To achieve large‐scale restoration targets, Guyana and other Amazonian countries will be challenged to remediate previously mined lands. The recovery process is highly dependent on nitrogen availability rather than mercury contamination, affecting woody biomass regrowth. The significant recovery in overburden zones indicates that one potential active remediation strategy to promote biomass recovery may be to backfill mining pits and ponds with excavated soil

Big geochemical data through remote sensing for dynamic mineral resource monitoring in tailing storage facilities

Evolution in geoscientific data provides the mineral industry with new opportunities. A direction of geochemical data generation evolution is towards big data to meet the demands of data-driven usage scenarios that rely on data velocity. This direction is more significant where traditional geochemical data are not ideal, which is the case for evaluating unconventional resources, such as tailing storage facilities (TSFs), because they are not static due to sedimentation, compaction and changes associated with hydrospheric and lithospheric processes (e.g., erosion, saltation and mobility of chemical constituents). In this paper, we generate big secondary geochemical data derived from Sentinel-2 satellite-remote sensing data to showcase the benefits of big geochemical data using TSFs from the Witwatersrand Basin (South Africa). Using spatially fused remote sensing and legacy geochemical data on the Dump 20 TSF, we trained a machine learning model to predict in-situ gold grades. Subsequently, we deployed the model to the Lindum TSF, which is 3 km away, over a period of a few years (2015-2019). We were able to visualize and analyze the temporal variation in the spatial distributions of the gold grade of the Lindum TSF. Additionally, we were able to infer extraction sequencing (to the resolution of the data), acid mine drainage formation and seasonal migration. These findings suggest that dynamic mineral resource models and live geochemical monitoring (e.g., of elemental mobility and structural changes) are possible without additional physical sampling

Quaternary geology of the Northern Great Plains

The Great Plains physiographic province lies east of the Rocky Mountains and extends from southern Alberta and Saskatchewan nearly to the United States-Mexico border. This chapter covers only the northern part of the unglaciated portion of this huge region, from Oklahoma almost to the United StatesCanada border, a portion that herein will be referred to simply as the Northern Great Plains (Fig. 1). This region is in the rain shadow of the Rocky Mountains. Isoheyets are roughly longitudinal, and mean annual precipitation decreases from about 750 mm at the southeastern margin to less than 380 mm in the western and northern parts (Fig. 2). Winters typically are cold with relatively little precipitation, mostly as snow; summers are hot with increased precipitation, chiefly associated with movement of Pacific and Arctic air masses into warm, humid air masses from the Gulf of Mexico. Vegetation is almost wholly prairie grassland, due to the semiarid, markedly seasonal climate. The Northern Great Plains is a large region of generally low relief sloping eastward from the Rocky Mountains toward the Missouri and Mississippi Rivers. Its basic bedrock structure is a broad syncline, punctuated by the Black Hills and a few smaller uplifts, and by structural basins such as the Williston, Powder River, and Denver-Julesburg Basins (Fig. 3). Its surface bedrock is chiefly Cretaceous and Tertiary sediments, with small areas of older rocks in the Black Hills, central Montana, and eastern parts of Wyoming, Kansas, and Oklahoma. During the Laramide orogeny (latest Cretaceous through Eocene), while the Rocky Mountains and Black Hills were rising, synorogenic sediments (frequently with large amounts of volcanic ash from volcanic centers in the Rocky Mountains) were deposited in the subsiding Denver-Julesburg, Powder River, and other basins. From Oligocene to Miocene time, sedimentation generally slowed with declining tectonism and volcanism in the Rocky Mountains. However, since the later Miocene, epeirogenic uplift, probably associated with the East Pacific Rise, affected the Great Plains and particularly the Rocky Mountains. During the last 10 m.y. the Rocky Mountain front has risen 1.5 to 2 km, and the eastern margin of the Great Plains 100 to 500 m (Gable and Hatton, 1983), with half to one-quarter of these amounts during the last 5 m.y. Thus, during the later Miocene the Great Plains became a huge aggrading piedmont sloping gently eastward from the Rocky Mountains and Black Hills, with generally eastward drainage, on which the Ogallala Formation and equivalents was deposited. The Ogallala underlies the High Plains Surface, the highest and oldest geomorphic surface preserved in this region. It has been completely eroded along some parts of the western margin of the region (e.g., the Colorado Piedmont), but eastward, it (and its equivalents, such as the Flaxville gravels in Montana) locally is preserved as caprock or buried by Quaternary sediments (Alden, 1924, 1932; Howard, 1960; Stanley, 1971, 1976; Pearl, 1971; Scott, 1982; Corner and Diffendal, 1983; Diffendal and Corner, 1984; Swinehart and others, 1985; Aber, 1985). During the Pliocene, regional aggradation slowly changed to dissection by the principal rivers. In the western part of the region the rivers flowed eastward, but the continental drainage divide Figure 3. Major bedrock structures of the Northern Great Plains. extended northeast from the Black Hills through central South Dakota, far south of its present position. The ancestral upper Missouri, Little Missouri, Yellowstone, and Cheyenne Rivers drained northeast to Hudson Bay, whereas the ancestral White, Platte, and Arkansas Rivers went to the Gulf of Mexico (Fig 4A). Their courses are marked by scattered surface and subsurface gravel remnants; in Montana and North Dakota, deposits of the preglacial Missouri River and its tributaries are buried deeply beneath glacial and other sediments (Howard, 1960; Bluemle, 1972)

Molecular dynamics simulations reveal the mechanisms of allosteric activation of Hsp90 by designed ligands

Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone's active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators