Hofmann Clathrates: A "Blue Box" Approach to Modulate Spin-Crossover Properties.

Hofmann coordination polymers (CPs) with cationic ligands provide an innovative strategy for recognizing π-electron-rich aromatic molecules - similar to the "little blue box". In this study, we demonstrate that hydroquinone molecules can be incorporated into these coordination polymers when redox-active bipyridinium derivatives are used as axial ligands. The insertion leads to a significant structural modification, resulting in a shift of the spin transition by 150 K and an approximate 23 % increase in volume, caused by the strong donor-acceptor π-π stacking interaction formed between the ligands and the guest molecule. These findings have been confirmed through temperature-dependent single crystal X-ray diffraction, magnetic measurements and optical reflectivity measurements.

Harmonization after the GDPR? Divergences in the rules for genetic and health data sharing in four member states and ways to overcome them by EU measures: Insights from Germany, Greece, Latvia and Sweden.

The EU member states' healthcare and health-related research sectors are both characterized by an emerging infrastructural coalescence on a national and European level. The culmination of this coalescence is the planned creation of a European Health Data Space, an EU-wide infrastructure for the processing of personal data for healthcare and for secondary uses such as scientific research. In contrast to growing technical interoperability, the legal framework for such integration is not yet defined in detail, particularly with regard to data protection law. Its development is accompanied by discussions about divergent member state implementations of the EU General Data Protection Regulation (GDPR) that affect data sharing between healthcare and scientific research actors and across various sectors driven by divergent processing purposes. The article presents four member states' main rules on data sharing based on the respective provision of the GDPR in six health-related contexts regarding data sharing across the healthcare and research sector and between the main actors of those sectors. The striking differences are then evaluated from the perspective of their factual effect on European data sharing depending on the legal characteristics of the GDPR provisions they rely on. Against this backdrop, the planned regulatory measures for the setup of the European Health Data Space are introduced and evaluated with regard to further harmonization between member states' laws and possibilities to overcome divergences in data protection rules relevant for European data sharing. The results of the analysis point to the conclusion that the destructive effect of divergent member state rules depends on the legal qualification of the EU provisions they rely on and that this qualification also determines which further EU regulatory measure would be the most effective to set the framework for the European Health Data Space.

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.

Three-Year Follow-Up after Intrauterine mTOR Inhibitor Administration for Fetus with TSC-Associated Rhabdomyoma.

Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies.

Minding Rights: Mapping Ethical and Legal Foundations of 'Neurorights'.

The rise of neurotechnologies, especially in combination with artificial intelligence (AI)-based methods for brain data analytics, has given rise to concerns around the protection of mental privacy, mental integrity and cognitive liberty - often framed as "neurorights" in ethical, legal, and policy discussions. Several states are now looking at including neurorights into their constitutional legal frameworks, and international institutions and organizations, such as UNESCO and the Council of Europe, are taking an active interest in developing international policy and governance guidelines on this issue. However, in many discussions of neurorights the philosophical assumptions, ethical frames of reference and legal interpretation are either not made explicit or conflict with each other. The aim of this multidisciplinary work is to provide conceptual, ethical, and legal foundations that allow for facilitating a common minimalist conceptual understanding of mental privacy, mental integrity, and cognitive liberty to facilitate scholarly, legal, and policy discussions.

[Protecting the rights and freedoms of individuals with regard to health data processing: the risk approach of the EU General Data Protection Regulation (GDPR)]. / Schutz der Rechte und Freiheiten von Personen bei der Datenverarbeitung im Gesundheitsbereich: Der Risikoansatz der EU-Datenschutz-Grundverordnung (DGSVO).

Merging sensitive data and tracing their analysis results back to the data subjects is an essential part of data processing in the health sector. This challenges the protection of the data and thus its very purpose, the protection of the data subjects, since the scientific and health findings are often based on certain characteristics in the datasets, which should be preserved in their property as personal in order to make the results of the data analysis fruitful. The EU General Data Protection Regulation (GDPR) establishes a risk-based approach that determines both the identifiability of data and the proportionality of their processing.This paper analyses how the risk-based approach opens the scope of the GDPR and relates it to the risks for the rights and freedoms of data subjects posed by the processing of personal data. Furthermore, the question is explored to what extent the risk-based approach of the GDPR influences the rules for international data transfer and how international data processing in the health sector is currently organised on its basis.Overall, the present analysis sheds light on how the technical measures of data processing and the organisational measures for handling them can contribute to maintaining the proportionality of data processing under the GDPR, which can essentially be determined on a risk-based basis, while at the same time taking into account the specificity of data processing in the health sector.

Pressure Tuning of Coupled Structural and Spin State Transitions in the Molecular Complex [Fe(H2B(pz)2)2(phen)].

The large volume change, which accompanies the molecular spin crossover (SCO) phenomenon in some transition metal complexes, prompts frequently the coupling of the SCO with other instabilities. Understanding the driving mechanism(s) of such coupled phase transitions is not only important for fundamental reasons but also provides scope for the development of multifunctional materials. The general theoretical expectation is that the coupling has elastic origin, and the sequence of transitions can be tuned by an externally applied pressure, but dedicated experiments remain scarce. Here, we used high-pressure and low-temperature single-crystal X-ray diffraction to investigate the high-spin (HS) to low-spin (LS) transitions in the molecular complexes [FeII(H2B(pz)2)2(bipy)] and [FeII(H2B(pz)2)2(phen)]. In the bipyridine complex, the SCO is continuous and isostructural over the whole T, P-range (100-300 K, 0-2 GPa). In the phenanthroline derivative, however, the SCO is concomitant with a symmetry-breaking transition (C2/c to P1̅). Structural analysis reveals that the coupling between the two phenomena can be tuned by external pressure from a virtually simultaneous HSC2/c-LSP1̅ transition to the sequence of HSC2/c-LSC2/c-LSP1̅ transitions. The correlation of spontaneous strain and order parameter behaviors highlights that the "separated" transitions remain still connected via strain coupling, whereas the "simultaneous" transitions are partially split.

Broadband high-contrast visible optical switches based on a spin-crossover material.

Visible optical switches embedding a spin-crossover thin film and exploiting the frustrated total internal reflection operation principle are studied and optimized numerically with a view to obtain broadband high-contrast devices. A practical implementation using uncoated SF11 prisms embedding a 1-µm-thick layer of iron-triazolyl-borate complex as the thermo-active phase-change material is shown to support p-polarized modulation with contrast in excess of 90% over a spectral bandwidth greater than 270 nm and over an angular acceptance bandwidth of 0.45°, surpassing the performance achievable with optically resonant devices.

Bridging the European Data Sharing Divide in Genomic Science.

In this viewpoint, we argue for the importance of creating data spaces for genomic research that are detached from contexts in which fundamental rights concerns related to surveillance measures override a purpose-specific balancing of fundamental rights. Genomic research relies on molecular and phenotypic data, on comparing findings within large data sets, on searchable metadata, and on translating research results into a clinical setting. These methods require sensitive genetic and health data to be shared across borders. International data sharing between the European Union (EU) or the European Economic Area and third countries has accordingly become a cornerstone of genomics. The EU General Data Protection Regulation contains rules that accord privileged status to data processing for research purposes to ensure that strict data protection requirements do not impede biomedical research. However, the General Data Protection Regulation rules applicable to international transfers of data accord no such preferential treatment to international data transfers made in the research context. The rules that govern the international transfer of data create considerable barriers to international data sharing because of the cost-intensive procedural and substantive compliance burdens that they impose. For certain jurisdictions and select use cases, there exist practically no lawful mechanisms to enable the international transfer of data because of concerns about the protection of fundamental rights. The proposed solutions further fail to address the need to share large data sets of local and regional cohorts across national borders to enable joint analyses. The European Health Data Space is an emerging federated, EU-wide data infrastructure that is intended to function as an infrastructure bringing together EU health data to improve patient care and enable the secondary use of health-related data for research purposes. Such infrastructure is implementing new institutions to support its functioning and is being implemented in reliance on a new enabling law, the regulation on the European Health Data Space. This innovation provides the opportunity to facilitate EU contribution to international genomic research efforts. The draft regulation for this data space provides for a concept of data infrastructure intended to enable cross-border data exchange and access, including access to genetic and health data for scientific analysis purposes. The draft regulation also provides for obligations of national actors aimed at making data widely available. This effort is laudable. However, in the absence of further, more fundamental changes to the manner in which the EU regulates the secondary use of health data, it is reasonable to believe that EU participation in international genomic research efforts will remain impeded.

Rapid capillary gel electrophoresis analysis of human milk oligosaccharides for food additive manufacturing in-process control.

Industrial production of human milk oligosaccharides (HMOs) represents a recently growing interest since they serve as key ingredients in baby formulas and are also utilized as dietary supplements for all age groups. Despite their short oligosaccharide chain lengths, HMO analysis is challenging due to extensive positional and linkage variations. Capillary gel electrophoresis primarily separates analyte molecules based on their hydrodynamic volume to charge ratios, thus, offers excellent resolution for most of such otherwise difficult-to-separate isomers. In this work, two commercially available gel compositions were evaluated on the analysis of a mixture of ten synthetic HMOs. The relevant respective separation matrices were then applied to selected analytical in-process control examples. The conventionally used carbohydrate separation matrix was applied for the in-process analysis of bacteria-mediated production of 3-fucosyllactose, lacto-N-tetraose, and lacto-N-neotetraose. The other example showed the suitability of the method for the in vivo in-process control of a shake flask and fermentation approach of 2'-fucosyllactose production. In this latter instance, borate complexation was utilized to efficiently separate the 2'- and 3-fucosylated lactose positional isomers. In all instances, the analysis of the HMOs of interest required only a couple of minutes with high resolution and excellent migration time and peak area reproducibility (average RSD 0.26% and 3.56%, respectively), features representing high importance in food additive manufacturing in-process control.

On the Spin-State Dependence of Redox Potentials of Spin Crossover Complexes.

Resistance switching properties of nanoscale junctions of spin crossover molecules have received recently much interest. In many cases, this property has been traced back to the variation of molecular orbital energies upon spin transition. However, one can also expect a substantial reorganization of the molecular structure due to charge localization, which calls for a better understanding of the relationship between the redox potential and the spin state of the molecule. To investigate this issue, we carried out a detailed density functional theory and variable temperature cyclic voltammetry investigation of the benchmark compound [Fe(HB(1,2,4-triazol-1-yl)3)2] in solution. We show that, for a correct thermodynamical picture, it is necessary to take into account the charge transfer-induced electronic and structural reorganization as well as spin equilibria in the oxidized and reduced species.

Thermochromic Meltable Materials with Reverse Spin Transition Controlled by Chemical Design.

We report a series of meltable FeII complexes, which, depending on the length of aliphatic chains, display abrupt forward low-spin to high-spin transition or unprecedented melting-triggered reverse high-spin to low-spin transition on temperature rise. The reverse spin transition is perfectly reproducible on thermal cycling and the obtained materials are easily processable in the form of thin film owing to their soft-matter nature. We found that the discovered approach represents a potentially generalizable new avenue to control both the location in temperature and the direction of the spin transition in meltable compounds.

Expression of GLP-1 receptors in insulin-containing interneurons of rat cerebral cortex.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 (GLP-1) receptors are expressed by pancreatic beta cells and GLP-1 receptor signalling promotes insulin secretion. GLP-1 receptor agonists have neural effects and are therapeutically promising for mild cognitive impairment and Alzheimer's disease. Our previous results showed that insulin is released by neurogliaform neurons in the cerebral cortex, but the expression of GLP-1 receptors on insulin-producing neocortical neurons has not been tested. In this study, we aimed to determine whether GLP-1 receptors are present in insulin-containing neurons. METHODS: We harvested the cytoplasm of electrophysiologically and anatomically identified neurogliaform interneurons during patch-clamp recordings performed in slices of rat neocortex. Using single-cell digital PCR, we determined copy numbers of Glp1r mRNA and other key genes in neurogliaform cells harvested in conditions corresponding to hypoglycaemia (0.5 mmol/l glucose) and hyperglycaemia (10 mmol/l glucose). In addition, we performed whole-cell patch-clamp recordings on neurogliaform cells to test the effects of GLP-1 receptor agonists for functional validation of single-cell digital PCR results. RESULTS: Single-cell digital PCR revealed GLP-1 receptor expression in neurogliaform cells and showed that copy numbers of mRNA of the Glp1r gene in hyperglycaemia exceeded those in hypoglycaemia by 9.6 times (p < 0.008). Moreover, single-cell digital PCR confirmed co-expression of Glp1r and Ins2 mRNA in neurogliaform cells. Functional expression of GLP-1 receptors was confirmed with whole-cell patch-clamp electrophysiology, showing a reversible effect of GLP-1 on neurogliaform cells. This effect was prevented by pre-treatment with the GLP-1 receptor-specific antagonist exendin-3(9-39) and was absent in hypoglycaemia. In addition, single-cell digital PCR of neurogliaform cells revealed that the expression of transcription factors (Pdx1, Isl1, Mafb) are important in beta cell development. CONCLUSIONS/INTERPRETATION: Our results provide evidence for the functional expression of GLP-1 receptors in neurons known to release insulin in the cerebral cortex. Hyperglycaemia increases the expression of GLP-1 receptors in neurogliaform cells, suggesting that endogenous incretins and therapeutic GLP-1 receptor agonists might have effects on these neurons, similar to those in pancreatic beta cells.

Direct Visualization of Local Spin Transition Behaviors in Thin Molecular Films by Bimodal AFM.

Thin films of the molecular spin-crossover complex [Fe(HB(1,2,4-triazol-1-yl)3 )2 ] undergo spin transition above room temperature, which can be exploited in sensors, actuators, and information processing devices. Variable temperature viscoelastic mapping of the films by atomic force microscopy reveals a pronounced decrease of the elastic modulus when going from the low spin (5.2 ± 0.4 GPa) to the high spin (3.6 ± 0.2 GPa) state, which is also accompanied by increasing energy dissipation. This technique allows imaging, with high spatial resolution, of the formation of high spin puddles around film defects, which is ascribed to local strain relaxation. On the other hand, no clustering process due to cooperative phenomena was observed. This experimental approach sets the stage for the investigation of spin transition at the nanoscale, including phase nucleation and evolution as well as local strain effects.

Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex.

In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3-5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2-3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning.

Model consent clauses for rare disease research.

BACKGROUND: Rare Disease research has seen tremendous advancements over the last decades, with the development of new technologies, various global collaborative efforts and improved data sharing. To maximize the impact of and to further build on these developments, there is a need for model consent clauses for rare diseases research, in order to improve data interoperability, to meet the informational needs of participants, and to ensure proper ethical and legal use of data sources and participants' overall protection. METHODS: A global Task Force was set up to develop model consent clauses specific to rare diseases research, that are comprehensive, harmonized, readily accessible, and internationally applicable, facilitating the recruitment and consent of rare disease research participants around the world. Existing consent forms and notices of consent were analyzed and classified under different consent themes, which were used as background to develop the model consent clauses. RESULTS: The IRDiRC-GA4GH MCC Task Force met in September 2018, to discuss and design model consent clauses. Based on analyzed consent forms, they listed generic core elements and designed the following rare disease research specific core elements; Rare Disease Research Introductory Clause, Familial Participation, Audio/Visual Imaging, Collecting, storing, sharing of rare disease data, Recontact for matching, Data Linkage, Return of Results to Family Members, Incapacity/Death, and Benefits. CONCLUSION: The model consent clauses presented in this article have been drafted to highlight consent elements that bear in mind the trends in rare disease research, while providing a tool to help foster harmonization and collaborative efforts.

Complete Set of Elastic Moduli of a Spin-Crossover Solid: Spin-State Dependence and Mechanical Actuation.

Molecular spin crossover complexes are promising candidates for mechanical actuation purposes. The relationships between their crystal structure and mechanical properties remain, however, not well understood. In this study, combining high pressure synchrotron X-ray diffraction, nuclear inelastic scattering, and micromechanical measurements, we assessed the effective macroscopic bulk modulus ( B = 11.5 ± 1.5 GPa), Young's modulus ( Y = 10.9 ± 1.0 GPa), and Poisson's ratio (ν = 0.34 ± 0.04) of the spin crossover complex [FeII(HB(tz)3)2] (tz = 1,2,4-triazol-1-yl). Crystal structure analysis revealed a pronounced anisotropy of the lattice compressibility, which was correlated with the difference in spacing between the molecules as well as by the distribution of the stiffest C-H···N interactions in different crystallographic directions. Switching the molecules from the low spin to the high spin state leads to a remarkable drop of the Young's modulus to 7.1 ± 0.5 GPa both in bulk and thin film samples. The results highlight the application potential of these films in terms of strain (ε = -0.17 ± 0.05%), recoverable stress (σ = -21 ± 1 MPa), and work density ( W/V = 15 ± 6 mJ/cm3).

Germany: a fair balance between scientific freedom and data subjects' rights?

With the German Bundestag's adoption of the Data Protection Adaptation and Implementation Act EU (DSAnpUG-EU) on 30 June 2017, the adaptation of German law to the General Data Protection Regulation (GDPR) has begun (Gesetz zur Anpassung des Datenschutzrechts an die Verordnung (EU) 2016/679 und zur Umsetzung der Richtlinie (EU) 2016/680 (Datenschutz-Anpassungs- und -Umsetzungsgesetz-DSAnpUG-EU) v. 30. Juni 2017, BGBl. 2017 I p. 2097 et seq.). Despite being directly binding on all EU member states, the GDPR does not render national data protection provision obsolete-they are covered by the GDPR's opening clauses which include regulatory mandates and room for derogation. This creates considerable need for national legislative adaptation. Art. 1 DSAnpUG-EU contains the necessary amendments to the Federal Data Protection Law (BDSG(neu)), thus creating the second major building block of future German data protection alongside the GDPR itself. Nevertheless, there are still numerous sector-specific regulations in other federal laws and the data protection laws of the 16 states also need amendments. Adjustment in Germany is well on its way, but implementation in general is still ongoing, with further consequences for data processing and sharing.

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.

To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.