The permanently chaperone-active small heat shock protein Hsp17 from Caenorhabditis elegans exhibits topological separation of its N-terminal regions

Small Heat shock proteins (sHsps) are a family of molecular chaperones that bind nonnative proteins in an ATP-independent manner. Caenorhabditis elegans encodes 16 different sHsps, among them Hsp17, which is evolutionarily distinct from other sHsps in the nematode. The structure and mechanism of Hsp17 and how these may differ from other sHsps remain unclear. Here, we find that Hsp17 has a distinct expression pattern, structural organization, and chaperone function. Consistent with its presence under nonstress conditions, and in contrast to many other sHsps, we determined that Hsp17 is a mono-disperse, permanently active chaperone in vitro, which interacts with hundreds of different C. elegans proteins under physiological conditions. Additionally, our cryo-EM structure of Hsp17 reveals that in the 24-mer complex, 12 N-terminal regions are involved in its chaperone function. These flexible regions are located on the outside of the spherical oligomer, whereas the other 12 N-terminal regions are engaged in stabilizing interactions in its interior. This allows the same region in Hsp17 to perform different functions depending on the topological context. Taken together, our results reveal structural and functional features that further define the structural basis of permanently active sHsps

osm-flex/osm-flex: v1.1.0

<p>This release adds a <code>simplify</code> module for simple cleaning functions of OSM parsing output, and some smaller bugfixes.</p&gt

A generalized natural hazard risk modelling framework for infrastructure failure cascades

Critical infrastructures are more exposed than ever to natural hazards in a changing climate. To understand and manage risk, failure cascades across large, real-world infrastructure networks, and their impact on people, must be captured. Bridging established methods in both infrastructure and risk modelling communities, we develop an open-source modelling framework which integrates a network-based interdependent infrastructure system model into the globally consistent and spatially explicit natural hazard risk assessment platform CLIMADA. The model captures infrastructure damages, triggers failure cascades and estimates resulting basic service disruptions for the dependent population. It flexibly operates on large areas with publicly available hazard, exposure and vulnerability information, for any set of infrastructure networks, hazards and geographies of interest. In a validated case study for 2018’s Hurricane Michael across three US states, the model reproduced important failure dynamics among six infrastructure networks, and provided a novel spatial map where people were likely to experience disruptions in access to healthcare, loss of power and other vital services. Our generalized approach allows for a view on infrastructure risks and their social impacts also in areas where detailed information and risk assessments are traditionally scarce, informing humanitarian activities through hotspot analyses and policy frameworks alike

OpenStreetMap for multi-faceted climate risk assessments

Natural hazards pose significant risks to human lives, infrastructure, and ecosystems. Understanding risks along all these dimensions is critical for effective adaptation planning and risk management. However, climate risk assessments mostly focus on population, economic asset values, and road or building infrastructure, because publicly available data on more diverse exposures are scarce. The increasing availability of crowd-sourced geospatial data, notably from OpenStreetMap, opens up a novel means for assessing climate risk to a large range of physical assets. To this end, we present a stand-alone, lightweight, and highly flexible Python-based OpenStreetMap data extraction tool: OSM-flex. To demonstrate the potential and limitations of OpenStreetMap data for risk assessments, we couple OSM-flex to the open-source natural hazard risk assessment platform CLIMADA and compute winter storm risk and event impacts from winter storm Lothar across Switzerland to forests, UNESCO heritage sites, railways, healthcare facilities, and airports. Contrasting spatial patterns of risks on such less conventional exposure layers with more traditional risk metrics (asset damages and affected population) reveals that risk hot-spots are inhomogeneously and distinctly distributed. For instance, impacts on forestry are mostly expected in Western Switzerland in the Jura mountain chain, whereas economic asset damages are concentrated in the urbanized regions around Basel and Zurich and certain train lines may be most often affected in Central Switzerland and alpine valleys. This study aims to highlight the importance of conducting multi-faceted and high-resolution climate risk assessments and provides researchers, practitioners, and decision-makers with potential open-source software tools and data suggestions for doing so.ISSN:2515-762

Osteoinduction and -conduction through absorbable bone substitute materials based on calcium sulfate:in vivo biological behavior in a rabbit model

Calcium sulfate (CS) can be used as an antibiotically impregnated bone substitute in a variety of clinical constellations. Antibiotically loaded bone substitutes find specific application in orthopedic and trauma surgery to prevent or treat bone infections especially in relation to open bone defects. However, its use as a structural bone graft reveals some concerns due to its fast biodegradation. The addition of calcium carbonate and tripalmitin makes CS formulations more resistant to resorption leaving bone time to form during a prolonged degradation process. The aim of the present study was the evaluation of biocompatibility and degradation properties of newly formulated antibiotically impregnated CS preparations. Three different types of CS bone substitute beads were implanted into the tibial metaphysis of rabbits (CS dihydrate with tripalmitin, containing gentamicin (Group A) or vancomycin (Group B); Group C: tobramycin-loaded CS hemihydrate). Examinations were performed by means of x-ray, micro-computed tomography (micro-CT) and histology after 4, 6, 8 and 12 weeks. Regarding biocompatibility of the formulations, no adverse reactions were observed. Histology showed formation of vital bone cells attached directly to the implanted materials, while no cytotoxic effect in the surrounding of the beads was detected. All CS preparations showed osteogenesis associated to implanted material. Osteoblasts attached directly to the implant surface and revealed osteoid production, osteocytes were found in newly mineralized bone. Group C implants (Osteoset®) were subject to quick degradation within 4 weeks, after 6-8 weeks there were only minor remnants with little osteogenesis demonstrated by histological investigations. Group A implants (Herafill®-G) revealed similar degradation within atleast 12 weeks. In contrast, group B implants (CaSO4-V) were still detectable after 12 weeks with the presence of implant-associated osteogenesis atlatest follow-up. In all of these preparations, giant cells were found during implant degradation on surface and inside of resorption lacunae. None of the analyzed CS preparations triggered contact activation. All implants demonstrated excellent biocompatibility, with implants of Group A and B showing excellent features as osteoconductive and -inductive scaffolds able to improve mechanical stability

Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble.

Hsp26 is a small heat shock protein (sHsp) from S. cerevisiae. Its chaperone activity is activated by oligomer dissociation at heat shock temperatures. Hsp26 contains 9 phosphorylation sites in different structural elements. Our analysis of phospho-mimetic mutations shows that phosphorylation activates Hsp26 at permissive temperatures. The cryo-EM structure of the Hsp26 40mer revealed contacts between the conserved core domain of Hsp26 and the so-called thermosensor domain in the N-terminal part of the protein, which are targeted by phosphorylation. Furthermore, several phosphorylation sites in the C-terminal extension, which link subunits within the oligomer, are sensitive to the introduction of negative charges. In all cases, the intrinsic inhibition of chaperone activity is relieved and the N-terminal domain becomes accessible for substrate protein binding. The weakening of domain interactions within and between subunits by phosphorylation to activate the chaperone activity in response to proteotoxic stresses independent of heat stress could be a general regulation principle of sHsps

The co-chaperone Cnsl and the recruiter protein Hgh1 Link Hsp90 to translation elongation via chaperoning elongation factor 2.

The Hsp90 chaperone machinery in eukaryotes comprises a number of distinct accessory factors. Cns1 is one of the few essential co-chaperones in yeast, but its structure and function remained unknown. Here, we report the X-ray structure of the Cns1 fold and NMR studies on the partly disordered, essential segment of the protein. We demonstrate that Cns1 is important for maintaining translation elongation, specifically chaperoning the elongation factor eEF2. In this context, Cns1 interacts with the novel co-factor Hgh1 and forms a quaternary complex together with eEF2 and Hsp90. The in vivo folding and solubility of eEF2 depend on the presence of these proteins. Chaperoning of eEF2 by Cns1 is essential for yeast viability and requires a defined subset of the Hsp90 machinery as well as the identified eEF2 recruiting factor Hgh1