Hemipiperazines - Novel Photochromic Cyclic Dipeptides for Bioactivity Photomodulation

Nach Angaben der Internationalen Agentur für Krebsforschung, einer Einrichtung der Weltgesundheitsorganisation, wurden im Jahr 2020 schätzungsweise 19,3 Millionen Menschen Krebs diagnostiziert, von denen 9,96 Millionen den Kampf gegen diese Krankheit verlieren werden. Krebstherapien werden häufig durch schwere Nebenwirkungen beeinträchtigt, die die anwendbare Dosis einschränken und die Lebensqualität der Patienten stark einschränken können. Die Entwicklung neuer, effizienter Therapeutika, die selektiv wirken und weniger Nebenwirkungen haben, ist daher von großer Bedeutung. Die Photopharmakologie stellt ein vielversprechendes Forschungsgebiet dar, um diesen Anforderungen gerecht zu werden, indem neue Medikamente entwickelt werden, die lokal und bioorthogonal mit Licht aktiviert werden können. In dieser Arbeit stelle ich die Identifizierung und Charakterisierung von 3-Aryliden-2,5-diketopiperazinen (Hemipiperazine, HPIs) als eine neue Klasse von molekularen Photoschaltern vor. Ein HPI ist in Plinabulin enthalten, einem zytotoxischen Wirkstoff, der auf Mikrotubuli abzielt und sich derzeit in einer Phase-III-Studie zur Krebsbehandlung befindet. Es wurde entdeckt, dass die Bioaktivität von Plinabulin mit sichtbarem Licht moduliert werden kann, was eine biorthogonale Aktivierung dieses Medikaments mit räumlicher und zeitlicher Präzision ermöglichen kann. Außerdem wurden Derivate mit verbesserten photophysikalischen und pharmakologischen Eigenschaften identifiziert. Das photochrome Kernfragment von Plinabulin enthält ein zyklisches Dipeptid (2,5-Diketopiperazin, DKP), welches selbst ein wichtiges Pharmakophor darstellt und auch in zahlreichen biokompatiblen intelligenten Materialien zu finden ist. Der Photochromismus von HPIs und der Einfluss von elektronenziehenden und -schiebenden Gruppen auf die photophysikalischen Eigenschaften wurde systematisch untersucht. Darüber hinaus wurde gezeigt, dass HPI-Photoschalter in andere molekulare Gerüste eingebaut werden können und eine reversible Photomodulation der Fluoreszenzintensität ermöglichen. Es wurde festgestellt, dass fluoreszierende Derivate von Zellen aufgenommen und mittels konfokaler Mikroskopie innerhalb dieser Zellen sichtbar gemacht werden können. Diese Ergebnisse könnten die Grundlage für die Entwicklung neuartiger photoschaltbarer Fluoreszenzmarker bilden

Photopharmacology of Antimitotic Agents

Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents

An Exploratory Analysis on the Risk to be Offended on the Internet

Questionnaire data is used to identify socio-demographic as well as the risk-awareness characteristics of users offended on the Internet. The data comprises a representative sample of 3,000 individuals, containing information on employment, education, age, the frequency of Internet usage and security measures taken by the users. Probit and logit regressions show that, conditional on using the Internet, being female and abstaining from using social media significantly reduces the risk to be offended on the Internet

Digitalisierung. Digitalisierung im Öffentlichen Dienst Österreichs

Zielsetzung dieser Studie ist eine Analyse von aktuellen Herausforderungen für den Öffentlichen Dienst Österreichs. Den Hintergrund bildet die Digitalisierung, die auch für den Öffentlichen Dienst in mehrfacher Hinsicht Bedeutung hat, sowie allgemeine Entwicklungen wie zum Beispiel die bevorstehenden Pensionierungen der geburtenstarken Jahrgänge. In methodischer Hinsicht wurden sekundärstatistische Daten aus gängigen internationalen und nationalen Daten- und Webportalen wie Eurostat, Europäische Kommission, Europäisches Parlament, etc. herangezogen sowie Studienergebnisse renommierter Institute, die aktuelle Erhebungen und Ergebnisse zum Thema Digitalisierung publizierten. Parallel zu den Sekundärerhebungen konnten Expert:innen-Interviews durchgeführt werden. Der künstlichen Intelligenz wurde ein eigenes Kapitel gewidmet. Auch die allgemeinen Auswirkungen auf den Arbeitsmarkt wurden thematisiert. Die Beschreibung des aktuellen Standes der Digitalisierung im Rahmen der österreichischen Verwaltung erfolgte anhand von Beispielen sowie durch Ländervergleiche mittels standardisierter Indikatoren. Die Fragestellungen im Zusammenhang mit der Digitalisierung des Öffentlichen Dienstes fokussieren auf die Themengebiete: Digitalisierung und Personalsituation, Digitalisierung und Aus- und Weiterbildung, Digitalisierung und Datenschutz, Digitalisierung und Infrastruktur sowie den mit der künstlichen Intelligenz verbundenen Herausforderungen

Barriers and facilitators of healthcare access for long COVID-19 patients in a universal healthcare system: qualitative evidence from Austria

Background: Long COVID-19 challenges health and social systems globally. International research finds major inequalities in prevalence and healthcare utilization as patients describe difficulties with accessing health care. In order to improve long-term outcomes it is vital to understand any underlying access barriers, for which relevant evidence on long COVID-19 is thus far lacking in a universal healthcare system like Austria. This study aims to comprehensively identify access barriers and facilitators faced by long COVID-19 patients in Austria and explore potential socioeconomic and demographic drivers in health and social care access. Methods: Applying an exploratory qualitative approach, we conducted semi-structured interviews with 15 experts including medical professionals and senior health officials as well as focus groups with 18 patients with confirmed long COVID-19 diagnosis reflecting varying participant characteristics (age, gender, urbanicity, occupation, education, insurance status) (July-Nov 2023). Data were analysed following a thematic framework approach, drawing on a comprehensive ‘access to health care’ model. Results: Based on expert and patient experiences, several access barriers and facilitators emerged along all dimensions of the model. Main themes included scepticism and stigma by medical professionals, difficulties in finding knowledgeable doctors, limited specialist capacities in the ambulatory care sector, long waiting times for specialist care, and limited statutory health insurance coverage of treatments resulting in high out-of-pocket payments. Patients experienced constant self-organization of their patient pathway as stressful, emphasizing the need for multidisciplinary care and centralized coordination. Facilitators included supportive social environments, telemedicine, and informal information provided by a nationwide patient-led support group. Differences in patient experiences emerged, among others, as women and younger patients faced gender- and age-based stigmatization. Complementary health insurance reduced the financial strain, however, did not ease capacity constraints, which were particularly challenging for those living in rural areas. Conclusions: The findings of this study indicate a call for action to improve the long COVID-19 situation in Austria by empowering both providers and patients via increased information offerings, strengthened interdisciplinary treatment structures and telemedicine offerings as well as research funding. Our insights on potentially relevant socioeconomic and demographic drivers in access barriers lay the necessary foundation for future quantitative inequality research

Anatomy of the bacitracin resistance network in <i>Bacillus subtilis</i>

Protection against antimicrobial peptides (AMPs) often involves the parallel production of multiple, well-characterized resistance determinants. So far, little is known about how these resistance modules interact and how they jointly protect the cell. Here, we studied the interdependence between different layers of the envelope stress response of Bacillus subtilis when challenged with the lipid II cycle-inhibiting AMP bacitracin. The underlying regulatory network orchestrates the production of the ABC transporter BceAB, the UPP phosphatase BcrCand the phage-shock proteins LiaIH. Our systems-level analysis reveals a clear hierarchy,allowing us to discriminate between primary (BceAB) and secondary (BcrC and LiaIH) layers ofbacitracin resistance. Deleting the primary layer provokes an enhanced induction of the secondary layer to partially compensate for this loss. This study reveals a direct role of LiaI H inbacitracin resistance, provides novel insights into the feedback regulation of the Lia system, anddemonstrates a pivotal role of BcrC in maintaining cell wall homeostasis. The compensatory regulation within the bacitracin network can also explain how gene expression noise propagates between resistance layers. We suggest that this active redundancy in the bacitracin resistance network of B. subtilis is a general principle to be found in many bacterial antibiotic resistance networks

Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity

The development of photochromic systems is an important and growing area of research, in particular for bioactive molecular photoswitches. Here, the authors report on photopharmacological antimitotic agents, operational under visible light, based on a peptide-derived hemipiperazine photochrome. Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude-all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.Peer reviewe

Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity

The development of photochromic systems is an important and growing area of research, in particular for bioactive molecular photoswitches. Here, the authors report on photopharmacological antimitotic agents, operational under visible light, based on a peptide-derived hemipiperazine photochrome. Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude-all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.Peer reviewe

Fluorinated Azobenzenes Switchable with Red Light

Molecular photoswitches triggered with red or NIR light are optimal for photomodulation of complex biological systems, including efficient penetration of the human body for therapeutic purposes (“therapeutic window”). Yet, they are rarely reported, and even more rarely functional under aqueous conditions. In this work, fluorinated azobenzenes are shown to exhibit efficient E→Z photoisomerization with red light (PSS660nm >75 % Z) upon conjugation with unsaturated substituents. Initially demonstrated for aldehyde groups, this effect was also observed in a more complex structure by incorporating the chromophore into a cyclic dipeptide with propensity for self-assembly. Under physiological conditions, the latter molecule formed a supramolecular material that reversibly changed its viscosity upon irradiation with red light. Our observation can lead to design of new photopharmacology agents or phototriggered materials for in vivo use