Food practices as part of daily routines: A conceptual framework for analysing networks of practices.

Current debates about the need to change daily practices to address sustainability or health issues often neglect to recognise that single practices like eating are embedded in daily routines and connected to a multitude of other practices that take place within networks. While connections, such as complexes, bundles or nexuses, are mentioned in extant literature, a clear definition of these categories and their operationalisation for empirical research is missing. This conceptual study aims to fill this gap by proposing an analytical framework for a network of practices that joins multiple authors' concepts and supports empirical analyses that aim to understand the complex intertwining of practices in daily life, as well as the challenges to changing them. Inspired by the concepts of 'zooming in and out' (Nicolini, 2012), we propose several explorative steps to support the operationalisation process. 'Zooming in' at practices aims for a deeper understanding of the performance within single practices, exploring their internal variations, including elements (i.e. material, meanings and competences), as well as spatial (i.e. in and outside), temporal (e.g. hours, days) and social (e.g. alone, with friends) dimensions. 'Zooming out' for connections between practices explores the various connections single practices have to other practices as complexes, bundles and nexuses, as well as the role of 'external' contexts influencing those dynamics. The framework's benefits are illustrated with examples that refer to the practice of eating and its interconnectedness with other food practices, with other daily practices and with external contexts, such as the surrounding food distribution systems. Our contribution is centred on how such an operationalisation may support the analysis of current and past networks of practices but also possible changes in daily practices in the future.

Increasing Complexity: A Practical Synthetic Approach to Three-Dimensional, Cyclic Sulfoximines and First Insights into Their in Vitro Properties.

A short synthetic approach with broad scope to access five- to seven-membered cyclic sulfoximines in only two to three steps from readily available thiophenols is reported. Thus, simple building blocks were converted to complex molecular structures by a sequence of S-alkylation and one-pot sulfoximine formation, followed by intramolecular cyclization. Seventeen structurally diverse cyclic sulfoximines were prepared in high overall yields. In vitro evaluation of these underrepresented, three-dimensional, cyclic sulfoximines with respect to properties relevant to medicinal chemistry did not reveal any intrinsic flaw for application in drug discovery.

Exploration of Novel Chemical Space: Synthesis and in vitro Evaluation of N-Functionalized Tertiary Sulfonimidamides.

An unprecedented set of structurally diverse sulfonimidamides (47 compounds) has been prepared by various N-functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N-functionalization reactions of model compound 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X-ray analyses of selected N-functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N-functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences.

A New, Practical One-Pot Synthesis of Unprotected Sulfonimidamides by Transfer of Electrophilic NH to Sulfinamides.

Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one-pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X-ray analysis of NH sulfonimidamide 2 a and its behavior in selected in vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.

Thermodynamic signatures of fragment binding: Validation of direct versus displacement ITC titrations.

BACKGROUND: Detailed characterization of the thermodynamic signature of weak binding fragments to proteins is essential to support the decision making process which fragments to take further for the hit-to-lead optimization. METHOD: Isothermal titration calorimetry (ITC) is the method of choice to record thermodynamic data, however, weak binding ligands such as fragments require the development of meaningful and reliable measuring protocols as usually sigmoidal titration curves are hardly possible to record due to limited solubility. RESULTS: Fragments can be titrated either directly under low c-value conditions (no sigmoidal curve) or indirectly by use of a strong binding ligand displacing the pre-incubated weak fragment from the protein. The determination of Gibbs free energy is reliable and rather independent of the applied titration protocol. CONCLUSION: Even though the displacement method achieves higher accuracy, the obtained enthalpy-entropy profile depends on the properties of the used displacement ligand. The relative enthalpy differences across different displacement experiments reveal a constant signature and can serve as a thermodynamic fingerprint for fragments. Low c-value titrations are only reliable if the final concentration of the fragment in the sample cell exceeds 2-10 fold its K(D) value. Limited solubility often prevents this strategy. GENERAL SIGNIFICANCE: The present study suggests an applicable protocol to characterize the thermodynamic signature of protein-fragment binding. It shows however, that such measurements are limited by protein and fragment solubility. Deviating profiles obtained by use of different displacement ligands indicate that changes in the solvation pattern and protein dynamics most likely take influence on the resulting overall binding signature.

Research note: attitudes of teachers and undergraduate students regarding three augmentative and alternative communication modalities.

The social validity of different communication modalities is a potentially important variable to consider when designing augmentative and alternative communication (AAC) interventions. To assess the social validity of three AAC modes (i.e., manual signing, picture exchange, and an iPad®-based speech-generating device), we asked 59 undergraduate students (pre-service teachers) and 43 teachers to watch a video explaining each mode. They were then asked to nominate the mode they perceived to be easiest to learn as well as the most intelligible, effective, and preferred. Participants were also asked to list the main reasons for their nominations and report on their experience with each modality. Most participants (68-86%) nominated the iPad-based speech-generating device (SGD) as easiest to learn, as well as the most intelligible, effective, and preferred. This device was perceived to be easy to understand and use and to have familiar and socially acceptable technology. Results suggest that iPad-based SGDs were perceived as more socially valid among this sample of teachers and undergraduate students. Information of this type may have some relevance to designing AAC supports for people who use AAC and their current and future potential communication partners.

Healthy, Inclusive and Sustainable Catering in Secondary Schools-An Analysis of a Transformation Process with Multiple Tensions.

Interest in catering for public sector schools is increasing due to its potential role in addressing the prevailing problems of malnutrition, food insecurity and non-sustainable food habits. Based on the case of secondary schools in Berlin, this study aims to explore this potential by focusing on the process of transformation towards healthy, inclusive and sustainable school catering. It employs a multi-perspective analysis based on the two concepts of food environment and social cohesion. Results are based on quantitative and qualitative data collected via an online survey of pupils from 25 secondary schools in Berlin as well as field notes from six stakeholder events. The survey findings were analyzed by descriptive means and provide explanations for the fact that most of the pupils (66.7%) never eat lunch at school. Based on the qualitative analysis of the stakeholder events, key tensions between actors from the federal state, municipal, school and private levels could be identified. Major areas of conflict arise due to (1) a lack of public funding and catering standards, (2) incompatible demands and preferences, (3) a lack of resources and opportunities for complementary education and participation, and (4) peer and parental influence. Transforming school food environments requires integrative strategies with interventions introduced by multiple actors operating on different levels.

Fostering reflective impact orientation in transdisciplinary research-A multi-method workshop format.

The primary objective of transdisciplinary research (TDR) is to contribute to the solution of complex 'real-world' problems by integrating heterogeneous knowledge and achieving societal effects. However, establishing a continuous impact orientation during TDR processes remains a challenge, as the necessary tools are not yet sufficiently available. We developed and tested a half-day workshop format for strengthening the impact-oriented project management and research activities of seven TDR projects. Our findings indicate that the reflective impact workshops supported participants in pursuing societal effects systematically. Applying the methodological approach also fosters TDR process qualities such as knowledge integration. Conducted at different project stages, the results can serve as a basis for monitoring and adapting the project design. The reflective approach•includes scientific and non-scientific TDR project team members,•draws on Theory of Change as a conceptual framework and motivates participants to reflect on plausible impact pathways and make implicit assumptions about interlinkages between different forms of societal effects explicit, and•provides results which enable project partners to adjust their project design for greater societal effectiveness.

PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [18F]DCFPyL (PYLARIFY®, Lantheus Holdings), [18F]rhPSMA-7.3 (POSLUMA®, Blue Earth Diagnostics) and [68Ga]Ga-PSMA-11 (Locametz®, Novartis/ ILLUCCIX®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [177Lu]Lu-PSMA-617 (Pluvicto®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

Bibliometric and scientometric analysis of PSMA-targeted radiotheranostics: knowledge mapping and global standing.

Purpose: Bibliometric and scientometric analyses provide a structured approach to large amounts of data, enabling the prediction of research theme trends over time, the detection of shifts in the boundaries of disciplines, and the identification of the most productive countries, institutions and scholars. In the context of prostate-specific membrane antigen (PSMA)-targeted radiotheranostics, no bibliometric or scientometric analysis has been published thus far. Therefore, this study was conducted to identify key contributors to the literature, assess the global scientific production of related research, and possibly predict future development patterns. Methods: Scientometrics and bibliometrics were utilized to analyze the current body of knowledge while tracking its evolution to support scientific decision-making comprehensively and systematically. Science mapping techniques were employed to visualize research activities. Two different tools, Tableau and VOSviewer, were utilized, with VOSviewer being deemed the most suitable for the research objectives. The Web of Science (WoS) was used as the principal database for the searches. Results: Through the search process over a period of 30 years (January 1993-January 2023), 694 original studies in the English language were subjected to comprehensive analysis. By employing bibliometric and scientometric methods, multiple networks were created that mapped various concepts, such as publication trends, leading countries, cocitations, coauthorship among researchers and scientists, as well as coauthorship among organizations and funding agencies. This study revealed the evolutionary patterns, trends, outliers, and key players in the PSMA field, which enabled a more nuanced understanding of the research landscape. Conclusion: This research contributes to the enrichment of knowledge on PSMA-targeted radiotheranostics through detailed global bibliometric and scientometric analyses. It stresses the necessity for the development of communication platforms, the establishment of supportive infrastructures, and the implementation of proactive solutions to address emerging challenges. This study offers a significant resource for delineating effective strategies and identifying prominent funding bodies essential for continuous advancements in the field of PSMA-based diagnosis and therapy for prostate cancer. It is vital to sustain this momentum to ensure further progress in this pioneering area.

Human ABC and SLC Transporters: The Culprit Responsible for Unspecific PSMA-617 Uptake?

[177Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,ß-3H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives.

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence.

BACKGROUND: We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data. METHODS: A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden. RESULTS: Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks. CONCLUSIONS: This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

The chemistry and biology of soluble guanylate cyclase stimulators and activators.

The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. Still today, NO-donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and nonspecific effects, such as post-translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme-containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO-independent manner, the so-called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone Phase III clinical trials for different forms of pulmonary hypertension.

Synthesis of tritium-labeled Lu-PSMA-617: Alternative tool for biological evaluation of radiometal-based pharmaceuticals.

This project focuses on the generation and evaluation of functional alternatives to radiometal-based pharmaceuticals supporting basic research and the in vitro developmental phase. Employing robust tritium chemistry and non-radioactive metal surrogates in two synthetic and labeling strategies resulted in ([ring-3H]Nal)PSMA-617 and ([α,ß-3H]Nal)PSMA-617. In particular, ([α,ß-3H]Nal)Lu-PSMA-617 exhibited high radiolytic as well as metal-complex stability and was compared to the clinically-established radiopharmaceutical [177Lu]Lu-PSMA-617. The cell-based assays confirmed the applicability of ([α,ß-3H]Nal)Lu-PSMA-617 as a substitute of [177Lu]Lu-PSMA-617 in pre-clinical biological settings.

Stuttering characteristics of German-English bilingual speakers.

The purpose of this study was to examine stuttering behavior in German-English bilingual people who stutter (PWS), with particular reference to the frequency of stuttering on content and function words. Fifteen bilingual PWS were sampled who spoke German as the first language (L1) and English as a second language (L2). Conversational speech was sampled in each language and analyzed for the percentage of overall stuttering-like disfluencies and distribution of stuttering on content and function words. Significantly more stuttering was found to occur in L2 compared to L1. Stuttering occurred significantly more often on content words compared to function words in L1. No significant difference between stuttering on function and content words was observed in L2. Examination across L1 and L2 found a significantly greater percentage of stuttering on function words in L2 compared to L1, and a significantly lower percentage of stuttering on content words in L2 compared to L1. The characteristics of stuttering in L2 could not be differentiated on the basis of an L2 proficiency measure. The differences observed in the amount of stuttering between L1 and L2 suggest that stuttering in bilingual speakers is closely related to language dominance, with features of stuttering in L2 indicative of a less developed language system.

A crystallographic fragment screen identifies cinnamic acid derivatives as starting points for potent Pim-1 inhibitors.

A crystallographic fragment screen was carried out to identify starting points for the development of inhibitors of protein kinase Pim-1, a potential target for tumour therapy. All fragment hits identified via soaking in this study turned out to bind to the unusually hydrophobic pocket at the hinge region. The most potent fragments, two cinnamic acid derivatives (with a best IC(50) of 130 µM), additionally form a well defined hydrogen bond. The balance between hydrophobic and polar interactions makes these molecules good starting points for further optimization. Pim-2 inhibitors from a recently reported high-throughput screening campaign also feature a cinnamic acid moiety. Two of these Pim-2 inhibitors were synthesized, their potencies against Pim-1 were determined and their cocrystal structures were elucidated in order to determine to what degree the binding modes identified by fragment screening are conserved in optimized inhibitors. The structures show that the cinnamic acid moieties indeed adopt the same binding mode. Fragment screening thus correctly identified binding modes which are maintained when fragments are grown into larger and higher affinity inhibitors. The high-throughput screening-derived compound (E)-3-{3-[6-(4-aminocyclohexylamino)-pyrazin-2-yl]phenyl}acrylic acid (compound 1) is the most potent inhibitor of the cinnamic acid series for which the three-dimensional binding mode is known (IC(50) = 17 nM, K(d) = 28 nM). The structure reveals the molecular basis for the large gain in potency between the initial fragment hit and this optimized inhibitor.

Transstadial transmission of Francisella tularensis holarctica in mosquitoes, Sweden.

In Sweden, human cases of tularemia caused by Francisella tularensis holarctica are assumed to be transmitted by mosquitoes, but how mosquito vectors acquire and transmit the bacterium is not clear. To determine how transmission of this bacterium occurs, mosquito larvae were collected in an area where tularemia is endemic, brought to the laboratory, and reared to adults in their original pond water. Screening of adult mosquitoes by real-time PCR demonstrated F. tularensis lpnA sequences in 14 of the 48 mosquito pools tested; lpnA sequences were demonstrated in 6 of 9 identified mosquito species. Further analysis confirmed the presence of F. tularensis holarctica-specific 30-bp deletion region sequences (FtM19inDel) in water from breeding containers and in 3 mosquito species (Aedes sticticus, Ae. vexans, and Ae. punctor) known to take blood from humans. Our results suggest that the mosquitoes that transmit F. tularensis holarctica during tularemia outbreaks acquire the bacterium already as larvae.

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer.

Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.