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Efficient nuclear delivery of DNA remains a significant challenge for non-viral vectors, limiting their broader application in gene therapy. A key intracellular barrier is represented by the nuclear envelope, where the nuclear pore complex (NPC) restricts passive diffusion of macromolecules, and prevents more than 97% of delivered cytosolic DNA from entering the nucleus. Our study addresses this major limitation with a targeted delivery strategy leveraging nuclear localization signaling (NLS) peptides to enhance nuclear import of plasmid DNA (pDNA). NLS peptides were non-covalently complexed with pDNA and co-encapsulated in lipid nanoparticles (LNPs). Using fluorescently labeled LNPs and pDNA, the intracellular trafficking behavior from cellular uptake to endosomal escape and nuclear entry was characterized with and without the co-encapsulation of the NLS peptide. pDNA-NLS-functionalized LNPs achieved a 2.5-fold increase in transfection efficiency compared to non-complexed controls in vitro. Mechanistic studies indicate that cytosolic importins recognize the co-delivered NLS peptides, facilitating active transport of the released pDNA through the nuclear pore complex. In vivo studies in zebrafish larvae and wildtype mice are consistent with an NLS-dependent enhancement in gene expression, displaying a 10-fold increase after 72 h in mice. These findings demonstrate that LNPs can be combined with NLS peptides to promote non-viral DNA delivery to the nucleus by endogenous nuclear import pathways.

Background Ischemia reperfusion injury (IRI) after myocardial infarction (MI) may lead to heart failure. Anti-apoptotic signaling through Fms-like tyrosine kinase 3 ligand (FLT3L) could reduce post-MI left ventricular remodeling. Limited tissue bioavailability is an obstacle for therapies using small protein drugs. Microbubbles (MBs) have been developed for drug delivery. In a hypothesis testing preclinical study we examined whether delivery of FLT3L coupled to MBs would reduce infarct size and improve left ventricular ejection fraction (LVEF) in murine myocardial IRI. Methods FLT3L was conjugated to lipid shelled, decafluorobutane gas core MBs (MBFLT3L) using biotin-streptavidin linkage. Fluorescence labeling of FLT3L was used to optimize and measure drug payload. In vitro activity of FLT3L and of MBFLT3L after ultrasound destruction was assessed in cell cultures using an XTT assay. In vivo activity of MBFLT3L (3x108) with ultrasound destruction was compared to FLT3L only, to control and to sham animals (n = 6-10 per group) in murine myocardial IRI. 7 days after IRI, infarct size on histology and LVEF on echocardioagaphy were assessed. Results Incubation of 1x10 8 MBs with 2.5 μg FLT3L resulted in 1.51 ± 0.38 μg FLT3L/1 × 108 MB with no increase for incubations with higher amounts. XTT assays confirmed similar activity of FLT3L and FLT3L exposed to ultrasound (Effective dose 50 11.3 ± 4.4 ng/ml vs. 9.4 ± 1.0 ng/ml), while activity of MBFLT3L after ultrasound destruction was lower (ED50 154.3 ± 52.4 ng/ml). In control animals about 35% of the myocardium were infarcted whereas sham animals had no infarcts (p < 0.01). However, neither animals treated with FLT3L nor animals treated with MBFLT3L showed a reduction in infarct size, decrease in apoptosis, or an improvement in LVEF compared to controls. Conclusions Conjugation of FLT3L to MBs is possible in dosages relevant for antiapoptotic effects in vitro. In a cell assay, MBFLT3L shows biologic effects attributable to FLT3L after ultrasound destruction. However, this did not translate into improvement in scar size, apoptosis or LVEF after myocardial IRI.

Introduction: Organizational commitment refers to the extent to which employees identify with and are involved with a given organization. It is an important variable for healthcare organizations to consider since it acts as a predictor of job satisfaction, organizational efficiency and effectiveness, health professionals’ absenteeism, and turnover. However, there is a knowledge gap in the health sector about workplace factors that are associated with healthcare provider commitment to their organization. Thus, this study aimed to assess organizational commitment and associated factors among health professionals working in public hospitals in the southwestern Oromia region, Ethiopia. Methods: A facility-based analytical cross-sectional study was conducted from March 30 to April 30, 2021. A multistage sampling technique was employed to select 545 health professionals from public health facilities. Data were collected using a structured self-administered questionnaire. simple and multiple linear regression analyses were employed to assess the association between organizational commitment and explanatory variables after checking the assumptions of factor analysis and linear regression. The statistical significance was declared at a p-value of < 0.05 and Adjusted Odds Ratio (AOR) with a 95% Confidence Interval (CI). Results: Health professionals’ organizational commitment percentage mean score was 48.8% (95% CI: 47.39, 50.24). A higher level of organizational commitment was associated to satisfaction with recognition, work climate, supervisor support, and workload. Besides, good practice of transformational and transactional leadership styles and employee empowerment are significantly associated with high organizational commitment. Conclusion: The overall level of organizational commitment is a bit low. To improve the organizational commitment of health professionals, hospital managers, and healthcare policy-makers need to develop and institutionalize evidence-based satisfaction strategies, practice good leadership styles and empower healthcare providers on the job.

In this article we study the numerical solution of elliptic shape optimization problems with additional constraints, given by domain or boundary integral functionals. A special boundary variational approach combined with a boundary integral formulation of the state equation yields shape gradients and functionals which are expressed only in terms of boundary integrals. Hence, the efficiency of (standard) descent optimization algorithms is considerably increased, especially for the line search. We demonstrate our method for a class of problems from planar elasticity, where the stationary domains are given analytically by Banichuk and Karihaloo in [N.V. Banichuk and B.L. Karihaloo (1976). Minimum-weight design of multi-purpose cylindrical bars. International Journal of Solids and Structures, 12, 267-273.]. In particular, the boundary integral equation is solved by a wavelet Galerkin scheme which offers a powerful tool. For optimization we apply gradient and Quasi-Newton type methods for the penalty as well as for the augmented Lagrangian functional.

Digital technologies have fundamentally transformed the ways in which Cultural Heritage (CH) collections are accessed and engaged with. Linked Open Usable Data (LOUD) specifications, including the International Image Interoperability Framework (IIIF) Presentation API 3.0, Linked Art, and the Web Annotation Data Model (WADM), have emerged as web standards to facilitate the description and dissemination of these valuable resources. Despite the widespread adoption of IIIF, the implementation of LOUD specifications, especially in combination, remains challenging. This is particularly true in the development and assessment of infrastructures, or sites of assemblage, that support these standards. The research is guided by two perspectives, namely community practices and semantic interoperability. The former aims to assess how organisations, individuals, and apparatuses engage with and contribute to the consensus-making processes surrounding LOUD. By examining community practices, the social fabrics of the LOUD ecosystem can be better understood. The latter perspective explores how data can be made meaningful to machines in a standardised and interoperable approach that promotes the exchange of well-formed information. This work is grounded as part of the SNSF-funded research project Participatory Knowledge Practices in Analogue and Digital Image Archives (PIA) (2021-2025), which aims to develop a citizen science platform around three photographic collections from the Cultural Anthropology Switzerland (CAS) archives. The theoretical framework is firmly rooted in Actor-Network Theory (ANT), as one of the aims of the thesis is to describe the collaborative structures of the LOUD ecosystem and to highlight the importance of non-human actors. Beyond the implementation of LOUD standards within the PIA research project, the empirical research includes an analysis of the social fabrics of the IIIF and Linked Art communities, as well as an investigation of LUX, Yale Collections Discovery platform. The research aims to identify the socio-technical requirements for developing specifications consistent with LOUD design principles. It also seeks to understand how the implementation of LOUD standards within PIA contributes to recognising their potential benefits and limitations in terms of facilitating data reuse and wider participation. The thesis further examines the implementation strategies, challenges, and outcomes of Yale University’s large-scale deployment of LOUD standards, focusing on how ensuring the consistency of Linked Art and IIIF resources within the LUX platform contributes to the CH domain. The core methodology of this thesis is an actor- and practice-centred inquiry, focusing on the detailed examination of specific cosmologies within LOUD-driven communities, PIA, and LUX. This approach aims to unravel the intricate web of cultural processes and constellations through a micro-perspective, rich in empirical evidence. Key empirical findings indicate that LOUD improves the discoverability and integration of data in CH, which requires community-driven consensus on model interoperability. Significant challenges include engaging marginalised groups, sustaining long-term engagement, and balancing technological and social considerations. The strategic use of technology and the capture of digital materiality are critical, yet LOUD presents challenges in terms of resource investment, data consistency, and the wider implementation of complex patterns. LOUD should clearly lead efforts to improve the accessibility and usability of CH data. The community-driven methodology of IIIF and Linked Art inherently promotes collaboration and transparency, making these standards critical tools in the ongoing evolution of data management. Even for projects and institutions that do not adopt these specifications, LOUD's socio-technical practices provide crucial insights into effective digital stewardship and community engagement strategies.

The term Decentralized Finance or DeFi refers to an alternative financial infrastructure built on top of the Ethereum Blockchain. DeFi uses smart contracts to create protocols that replicate existing financial services in a more open, interoperable, and transparent way. In this paper, we highlight opportunities and potential risks of the ecosystem. We propose a multi-layered framework to analyze the implicit architecture and the various DeFi building blocks, including token standards, decentralized exchanges, decentralized debt markets, Blockchain derivatives, and on-chain asset management protocols. We conclude that DeFi still is a niche market with certain risks but also has interesting properties in terms of efficiency, transparency, accessibility, and composability. As such, it may potentially contribute to a more robust and transparent financial infrastructure.

Computer werden leistungsfähiger und können komplizierte Probleme immer schneller lösen. Gleichzeitig stehen, dank Internet und Smartphones, grosse Mengen an Daten zur Verfügung. Beides fördert die Entwicklung von künstlicher Intelligenz (KI). Anspruchsvolle Aufgaben, an denen bisherige Computerprogramme gescheitert sind, löst künstliche Intelligenz scheinbar mühelos. Bekannte Beispiele sind KI-Systeme, die Sprachen übersetzen oder menschliche Gegner in Spielen aller Art bezwingen. Stetig wird die künstliche Intelligenz verbessert und übernimmt Tätigkeiten, die bisher Menschen vorbehalten waren, etwa Steuerbetrug identifizieren oder Krankheiten diagnostizieren. Künstliche Intelligenz gilt daher als wichtiger Treiber des digitalen Wandels. Die Studie von TA-SWISS beschäftigt sich eingehend mit den Chancen und Risiken dieser Technologie in den Anwendungsbereichen Arbeit, Bildung und Forschung, Konsum, Medien und Verwaltung. Zur Sprache kommen insbesondere auch allgemeine ethische und rechtliche Aspekte. Das Hauptaugenmerk liegt auf Anwendungen, bei denen KI Entscheidungsprozesse unterstützt - Prozesse, die zu Entscheidungen mit direkten Auswirkungen auf Bürgerinnen und Bürger sowie auf unsere Gesellschaft als Ganzes führen.

Eines der grössten Probleme der modernen Geburtshilfe stellt trotz grosser Bemühungen in den letzten Jahren immer noch die vorzeitige Wehentätigkeit und die mit ihr verbundene drohende Frühgeburt¨ dar. Es wird stets nach neuen Möglichkeiten gesucht, diese zu verhindern und die Risikofaktoren auszuschalten. Vorzeitige Wehen werden symptomatisch mittels medikamentöser Wehenhemmung = Tokolyse behandelt. Mit Nifedipin, das zur Tokolyse weltweit im off-label verwendet wird, steht eine orale Applikation zur Verfügung, die, wenn immer möglich, aus Gründen der Vereinfachung einer intravenösen Tokolyse vorgezogen wird. In der anthroposophischen Medizin werden zur Tokolyse seit ca. 30 Jahren Präparate verwendet, die Auszüge der Pflanze Bryophyllum pinnatum enthalten und in der Schweiz als anthroposophische Heilmittel gehandelt werden, im engeren Sinn aber Phytotherapeutika darstellen. Das Nebenwirkungspotenzial dieser Phytotherapeutika ist sehr klein. Der direkte Vergleich zu einem synthetisch hergestellten Tokolytikum wurde nun mit der klinischen Studie „Bryophyllum pinnatum versus Nifedipin zur Behandlung vorzeitiger Wehentätigkeit“ gezogen. An einem Patientinnenkollektiv von knapp 30 Patientinnen konnte eine gleichwertige Wirkung zur Hemmung der vorzeitigen Wehentätigkeit bezüglich der Hauptzielparameter gezeigt werden. Der Presssaft von Bryophyllum pinnatum, aus dem die Kautabletten für die klinische Studie hergestellt werden, wurde gleichzeitig in-vitro an Myometriumstreifen von Patientinnen getestet, die sich einer Sectio caesarea am Termin unterzogen und der Forschung ein Stück Gewebe ihres Uterus zur Verfügung stellten. Dabei konnte gezeigt werden, dass der Presssaft und Fraktionen davon sehr wohl in der Lage sind, Kontraktionen dieses potenten Muskelgewebes zu hemmen. Um die Fraktionen für die Myometriumstreifenexperimente zu erhalten, wurde der Presssaft lyophilisiert und anschliessend mittels Mitteldruck-Flüssigchromatographie (MPLC) aufgetrennt. Als stationäre Phase zur Chromatographie wurde Sephadex LH-20 eingesetzt. Das Monitoring der Fraktionen erfolgte mittels Dünnschichtchromatographie (DC). Die Fraktionen wurden anschliessend entsprechend vereinigt und eingeengt. Der Presssaft, sowie 3 Fraktionen davon wurden mittels Hochleistungs-Flüssigchromatographie (HPLC) aufgetrennt. Anhand der Diodenarray-UV-Spektren (DAD-UV) wurden einzelne Peaks der Fingerprint-Profile den jeweiligen Substanzklassen (Flavonoide, Bufadienolidderivate oder Zimtsäuren) zugeordnet. Bevor mittels Massenspektrometrie (HPLC-MS) versucht wurde, einzelne Peaks aufgrund ihrer Massenspektren Stoffen zuzuordnen, wurde eine Literatursuche zur Bestimmung der bereits in Bryophyllum pinnatum bekannten Inhaltsstoffe durchgeführt.