Magnetic transport in a straight parabolic channel

We study a charged two-dimensional particle confined to a straight parabolic-potential channel and exposed to a homogeneous magnetic field under influence of a potential perturbation $W$. If $W$ is bounded and periodic along the channel, a perturbative argument yields the absolute continuity of the bottom of the spectrum. We show it can have any finite number of open gaps provided the confining potential is sufficiently strong. However, if $W$ depends on the periodic variable only, we prove by Thomas argument that the whole spectrum is absolutely continuous, irrespectively of the size of the perturbation. On the other hand, if $W$ is small and satisfies a weak localization condition in the the longitudinal direction, we prove by Mourre method that a part of the absolutely continuous spectrum persists

D10.6 - Final Version of NanoCommons Sustainability Plan

NanoCommons was funded as an infrastructure project for a starting community. This means that it was supposed to build the concepts and foundation on which the community can continue to build solutions and services; in the case of NanoCommons, the infrastructure goal was to address the starting community’s data and nanoinformatics needs. NanoCommons did not start entirely from scratch, as it was building on efforts of the Nanosafety Cluster’s Working Group F on data management, and benefited from a general appreciation of the value of data reuse and computational predictions in the community. The push towards increasing use of chemoinformatics and nanoinformatics approaches was also endorsed by the public, regulatory and funding agencies, including being accelerated by the European ban on animal testing in the cosmetics industry and the European Green Deal. Similarly, industry is increasingly acting as a driver: fostering implementation and adoption of data harmonisation, FAIRness (Findability, Accessibility, Interoperability and Reusability of data) and openness and recognising that these activities require targeted and centralised efforts, which were provided by NanoCommons. However, a starting community is just that: a start upon which the community can build, a coalescence point around which collective efforts can nucleate. Our journey is still at the earliest stages, and much is needed in terms of automation, tooling, and continued training and education to drive the mindset changes within the community to fully embed data management at the start of the data lifecycle. Sustained and continuous support will be needed to achieve sufficient levels of digitalisation, global adoption of reporting standards both in scientific and regulatory settings, and machine-readability and machine-actionable data, all of which will lead to better quality and reproducible research, and more trust in the data and understanding of its applicability and suitability for reuse thus enhancing the value of the data and knowledge generated. This starts with sustaining what we already have, which in our case is the NanoCommons Knowledge Infrastructure, the implemented services from NanoCommons, as well as other associated partners and projects, and the collaboration with other projects established beyond the borders of nanosafety research. The term sustainability can be described as “the ability to be maintained at a certain rate or level”. Applied to NanoCommons, this means that the services/tools/materials that were designed and developed during the project and are already being offered to support the nanosafety community will continue to be maintained and ideally further developed, beyond the end of the funded period of the project, ensuring future accessibility for users and potential customers. Since there will be no direct public funding for these services anymore (pending further applications via Horizon Europe for example), planning for sustainability and creation of a (not necessarily commercial) business model were started very early in the project as a central task of WP10 and possible options were continuously evaluated and adapted based on stakeholder feedback coming from surveys and, more importantly, from users of the starting infrastructure services and expertise who received support in the form of Transnational Access (TA) projects or as part of the Demonstration Cases (see deliverable reports D9.3 and D9.4 for details of the first and second round Demonstration Cases, respectively). Deliverable D10.6 presented here builds on the previous deliverables D10.4 “First Testing and Evaluation Results of NanoCommons Sustainability Plan” and D10.5 “Second Testing and Evaluation Results on the NanoCommons Sustainability Plan”, proposing the first version of the business model and analysing all project activities related to sustainability during the last period, respectively. Together, these three reports outline the considerations and activities undertaken with the aim of ensuring the sustained existence and utilisation of the NanoCommons project outcomes beyond the project lifetime. A major NanoCommons objective has been to achieve a sustainable and open knowledge infrastructure for the whole nanosafety community, and thus a considerable effort was invested in exploring the options and approaches, focussing on those business models consistent with the ethos of openness and accessibility, given the public funding used to develop the services, and the critical importance of access to Environmental Health and Safety (EHS) data globally. In this final deliverable, evaluation of the TAs and Demonstration Cases with respect to their (potential) contributions to the UN Sustainable Development Goals (SDGs) is completed by looking at the results from the third funding period. Additionally, the targeted activities with the strategic partners most of whom were previously identified as significant routes via which to sustain and further develop the NanoCommons tools and services, are summarised. The NanoCommons focus areas for short/long term sustainability are presented, along with the justifications of these choices. All of this information is then condensed into the final NanoCommons sustainability plan

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Guiding protein-ligand docking with different experimental NMR-data

Today's scoring functions are one of the main reasons that state-of-the-art protein-ligand dockings fail in about 20 % to 40 % of the targets due to the sometimes severe approximations they make. However these approximations are necessary for performance reasons. One possibility to overcome these problems is the inclusion of additional, preferably experimental information in the docking process. Especially ligand-based NMR experiments that are far less demanding than the solution of the whole complex structure are helpful.Here we present the inclusion of three different types of NMR-data into the ChemPLP scoring function of our docking tool PLANTS. First, STD and intra-ligand trNOE spectra were used to obtain distant constraints between ligand and protein atoms. This approach proved beneficial for the docking of larger peptide ligands i. e. the epitope of MUC-1 glycoprotein to the SM3 antibody.In the second part the usefulness of INPHARMA data is shown by combinig a score, evaluating the agreement between simulated and measured INPHARMA spectra, with the PLANTS ChemPLP scoring function. First results from rescoring after local optimization of the poses and full docking experiments are shown

The role of FAIR nanosafety data and nanoinformatics in achieving the UN sustainable development goals: the NanoCommons experience†

The increasing focus on open and FAIR (Findable, Accessible, Interoperable and Re-useable) data is driving a step-change in how research communities and governments think about data and knowledge, and the potential for re-use of data. It has long been recognised that international data sharing is essential for regulatory harmonisation and commercialisation, via the Mutual Acceptance of Data (MAD) principle of the Organisation for Economic Cooperation and Development (OECD) for example. However, it is interesting to note that despite the power of data and data-driven software to support the achievement of the United Nations Sustainable Development Goals (UN SDGs), there appears to be limited awareness of how nanomaterials environmental health and safety (nano EHS) data can drive progress towards many of the SDGs. The goal of the NanoCommons research infrastructure project was to increase FAIRness and impact of nanoEHS data through development of services, including data shepherding to support researchers across the data life cycle and tools such as user-friendly nanoinformatics predictive models. We surveyed both service providers and service users on their ideas regarding how nanoEHS data might support the SDGs, and discovered a significant lack of awareness of the SDGs in general, and the potential for impact from NanoCommons tools and services. To address this gap, a workshop on the SDGs was prepared and delivered to support the NanoCommons service providers to understand the SDGs and how nanosafety data and nanoinformatics can support their achievement. Following the workshop, providers were invited to update their questionnaire responses. The results from the workshop discussions are presented, along with a summary of the 12 SDGs identified where increasingly accessible nanoEHS data will have a significant impact, and the 5 that are indirectly benefited along with some recommendations for EU-funded projects on how they can maximise and monitor their contributions to the SDGs

Metadata stewardship in nanosafety research: learning from the past, preparing for an "on-the-fly" FAIR future

Introduction: Significant progress has been made in terms of best practice in research data management for nanosafety. Some of the underlying approaches to date are, however, overly focussed on the needs of specific research projects or aligned to a single data repository, and this "silo" approach is hampering their general adoption by the broader research community and individual labs.Methods: State-of-the-art data/knowledge collection, curation management FAIrification, and sharing solutions applied in the nanosafety field are reviewed focusing on unique features, which should be generalised and integrated into a functional FAIRification ecosystem that addresses the needs of both data generators and data (re)users.Results: The development of data capture templates has focussed on standardised single-endpoint Test Guidelines, which does not reflect the complexity of real laboratory processes, where multiple assays are interlinked into an overall study, and where non-standardised assays are developed to address novel research questions and probe mechanistic processes to generate the basis for read-across from one nanomaterial to another. By focussing on the needs of data providers and data users, we identify how existing tools and approaches can be re-framed to enable "on-the-fly" (meta) data definition, data capture, curation and FAIRification, that are sufficiently flexible to address the complexity in nanosafety research, yet harmonised enough to facilitate integration of datasets from different sources generated for different research purposes. By mapping the available tools for nanomaterials safety research (including nanomaterials characterisation, nonstandard (mechanistic-focussed) methods, measurement principles and experimental setup, environmental fate and requirements from new research foci such as safe and sustainable by design), a strategy for integration and bridging between silos is presented. The NanoCommons KnowledgeBase has shown how data from different sources can be integrated into a one-stop shop for searching, browsing and accessing data (without copying), and thus how to break the boundaries between data silos.Discussion: The next steps are to generalise the approach by defining a process to build consensus (meta)data standards, develop solutions to make (meta)data more machine actionable (on the fly ontology development) and establish a distributed FAIR data ecosystem maintained by the community beyond specific projects. Since other multidisciplinary domains might also struggle with data silofication, the learnings presented here may be transferrable to facilitate data sharing within other communities and support harmonization of approaches across disciplines to prepare the ground for cross-domain interoperability

Harmonising knowledge for safer materials via the “NanoCommons” Knowledge Base

In mediaeval Europe, the term “commons” described the way that communities managed land that was held “in common” and provided a clear set of rules for how this “common land” was used and developed by, and for, the community. Similarly, as we move towards an increasingly knowledge-based society where data is the new oil, new approaches to sharing and jointly owning publicly funded research data are needed to maximise its added value. Such common management approaches will extend the data’s useful life and facilitate its reuse for a range of additional purposes, from modelling, to meta-analysis to regulatory risk assessment as examples relevant to nanosafety data. This “commons” approach to nanosafety data and nanoinformatics infrastructure provision, co-development, and maintenance is at the heart of the “NanoCommons” project and underpins its post-funding transition to providing a basis on which other initiatives and projects can build. The present paper summarises part of the NanoCommons infrastructure called the NanoCommons Knowledge Base. It provides interoperability for nanosafety data sources and tools, on both semantic and technical levels. The NanoCommons Knowledge Base connects knowledge and provides both programmatic (via an Application Programming Interface) and a user-friendly graphical interface to enable (and democratise) access to state of the art tools for nanomaterials safety prediction, NMs design for safety and sustainability, and NMs risk assessment, as well. In addition, the standards and interfaces for interoperability, e.g., file templates to contribute data to the NanoCommons, are described, and a snapshot of the range and breadth of nanoinformatics tools and models that have already been integrated are presented Finally, we demonstrate how the NanoCommons Knowledge Base can support users in the FAIRification of their experimental workflows and how the NanoCommons Knowledge Base itself has progressed towards richer compliance with the FAIR principles

The Mitochondrial Fusion-Promoting Factor Mitofusin Is a Substrate of the PINK1/Parkin Pathway

Loss-of-function mutations in the PINK1 or parkin genes result in recessive heritable forms of parkinsonism. Genetic studies of Drosophila orthologs of PINK1 and parkin indicate that PINK1, a mitochondrially targeted serine/threonine kinase, acts upstream of Parkin, a cytosolic ubiquitin-protein ligase, to promote mitochondrial fragmentation, although the molecular mechanisms by which the PINK1/Parkin pathway promotes mitochondrial fragmentation are unknown. We tested the hypothesis that PINK1 and Parkin promote mitochondrial fragmentation by targeting core components of the mitochondrial morphogenesis machinery for ubiquitination. We report that the steady-state abundance of the mitochondrial fusion-promoting factor Mitofusin (dMfn) is inversely correlated with the activity of PINK1 and Parkin in Drosophila. We further report that dMfn is ubiquitinated in a PINK1- and Parkin-dependent fashion and that dMfn co-immunoprecipitates with Parkin. By contrast, perturbations of PINK1 or Parkin did not influence the steady-state abundance of the mitochondrial fission-promoting factor Drp1 or the mitochondrial fusion-promoting factor Opa1, or the subcellular distribution of Drp1. Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn

Mitochondrial Alterations in PINK1 Deficient Cells Are Influenced by Calcineurin-Dependent Dephosphorylation of Dynamin-Related Protein 1

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential