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Abstract PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

The emergence and rapid growth of tourism paradigms such as ecotourism, sustainable tourism, and nature-based tourism signify a shift towards more environmentally and culturally conscious forms of tourism. We conduct a comparative analysis of these emerging fields with the aim of providing insights to the field and inform future research directions in this dynamic area of study. Our investigation spans diverse geographical regions over an extended period (1986-2022) to provide a comprehensive understanding of the global landscape of alternative tourism. The study utilizes descriptive bibliometrics and scientific mapping techniques using data derived from Scopus to depict changes and contributions over time and identify thematic structures and their evolution. Along with more established regional actors such as the US and European contributors, China and Latin America appear as emergent participants. The analyzed fields seem more prone to interdisciplinary approaches and more impactful than the average Tourism research. Also, international collaboration seems to have played a crucial role in advancing research in these topics. Overall, the study reveals a vibrant field with outstanding features in the context of general Tourism scientific area.

Relevant für die Medienpädagogik ist Design, weil es über die Gestaltung von Medien und Prozessen Strukturen des Handelns und Denkens konfiguriert und hervorbringt. Insbesondere das Interaktionsdesign digitaler Technologien ruft bestimmte Nutzer:innen an, macht Identitätsangebote und offeriert Sinndeutungen und Gesellschaftsentwürfe. In dem Beitrag werden aus designhistorischer Perspektive die programmatischen Gesellschaftsentwürfe und pädagogischen Imaginationen von der Industrialisierung bis zur heutigen Zeit nachverfolgt. In der Industrialisierung wuchsen erste Ideen einer planerisch-materiellen Sequenzierung von Denken und Handeln, die sich dann unter anderem in Strömungen des Bauhauses als Ordnung von Lebenswelten weiterentwickelt. Später kamen mit kybernetischen Ansätzen die Steuerungsprogrammatiken von Verhalten und Gesellschaft durch Technologien hinzu und vermischten sich darauffolgend mit Individualisierungsbestrebungen, der Gestaltung von Erlebniswelten und der Idee, dass Computertechnologie das Denken unterstützen sollte. Die Affordanzen digitaler Technologien – also Sinnangebote und nahegelegte Gebrauchsweisen – spitzen sich in der Delegation der Ordnung und Steuerung sozial-kultureller Lebenswelten immer weiter zu und jene sollen sich qua Design unmerklich durch nutzerfreundliches Design in den Alltag einschmiegen. So werden in stiller Anwesenheit digitaler Technologien eingeschriebene Subjekt- und Gesellschaftsentwürfe unmerklich in der Praxis mithilfe von Technologien aktualisiert. Eine medienpädagogische Möglichkeit, darauf zu reagieren, wird in dem Beitrag mit dem kritischen Design formuliert. Diese zielt darauf ab, die den digitalen Technologien innewohnenden Affordanzen sichtbar und diskutierbar zu machen. Als medienpädagogische Analysemethode und Praxis ist das kritische Design eine Möglichkeit, gestalterisch-kreativ die in Technologien eingeschriebenen Werte und Gesellschafts- und Subjektentwürfe zu analysieren und darauf basierend, unterschiedliche Zukünfte anhand von fiktiven Design-Artefakten und Narrativen aufzuzeigen.

Abstract Background It is well documented that smokers suffer increased risk of postoperative complications after medical surgery, for example delayed healing and increased risk of infection. It is also known that preoperative smoking cessation can reduce the risk of these complications. Because of this there are guidelines regarding preoperative smoking cessation in non-oral medical surgery. There are however no specific guidelines regarding oral surgical procedures, such as surgical extractions, dentoalveolar surgery, periodontal surgery, or dental implantation. Nevertheless, it is common that dentists and oral surgeons recommend smoking cessation pre to oral surgical procedures. The aim with this systematic review was to see if there are any evidence in the literature, supporting preoperative smoking cessation in oral surgical procedures. Methods A systematic search of the electronic databases PubMed, Scopus, Web of Science, and Cochrane was conducted to identify studies addressing the effect of preoperative smoking cessation in oral surgical procedures. Included publications were subjected to preidentified inclusion criterion. Six examiners performed the eligibility and quality assessment of relevant studies. Risk of bias was assessed using ROBINS-I and RoB 2. Certainty assessment was carried out using GRADE. Results The initial search resulted in 2255 records, and after removal of 148 duplicates, 16 articles met an acceptable level of relevance. These were read in full text, whereof 12 articles were excluded, due to different intervention, outcome, or study design than stated in the review protocol. One study remained with moderate risk of bias and three were excluded due to high risk of bias. Conclusion This systematic review could not determine the effect of smoking cessation pre to oral surgical procedures, in smokers. This indicates lack of knowledge in the effects of smoking cessation. We also conclude a lack of knowledge in how to design smoking cessation in the most effective way.

Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancers, the leading cause of cancer associated deaths in the US and worldwide. Within NSCLC tumors, there is a subpopulation of cancer cells termed cancer stem cells (CSCs) which exhibit stem-like properties that drive NSCLC progression, metastasis, relapse, and therapeutic resistance. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells that carry vital messages for short- and long-range intercellular communication. Numerous studies have implicated NSCLC CSC-derived EVs in the factors associated with NSCLC lethality. In this review, we have discussed mechanisms of EV-directed cross-talk between CSCs and cells of the tumor microenvironment that promote stemness, tumor progression and metastasis in NSCLC. The mechanistic studies discussed herein have provided insights for developing novel NSCLC diagnostic and prognostic biomarkers and strategies to therapeutically target the NSCLC CSC niche.

MicroRNAs (miRNAs) play important roles in the regulation of cellular function and fate via post-transcriptional regulation of gene expression. Although several miRNAs are associated with physiological processes and kidney diseases, not much is known about changes in miRNAs in aging kidneys. We previously demonstrated that sodium hydrogen exchanger 1 (NHERF1) expression regulates cellular responses to cisplatin, age-dependent salt-sensitive hypertension, and sodium-phosphate cotransporter trafficking. However, the mechanisms driving these regulatory effects of NHERF1 on cellular processes are unknown. Here, we hypothesize that dysregulation of miRNA-mediated gene regulatory networks that induce fibrosis and cytokines may depend on NHERF1 expression. To address this hypothesis, we compared miRNA expression in kidneys from both male and female old (12–18-month-old) and young (4–7-month-old) wild-type (WT) and NHERF1 knockout (NHERF1−/−) mice. Our results identified that miRNAs significantly decreased in NHERF1−/− mice included miR-669m, miR-590-3p, miR-153, miR-673-3p, and miR-127. Only miR-702 significantly decreased in aged WT mice, while miR-678 decreased in both WT and NHERF1−/− old versus young mice. miR-153 was shown to downregulate transcription factors NFATc2 and NFATc3 which regulate the transcription of several cytokines. Immunohistochemistry and western blotting revealed a significant increase in nuclear NFATc2 and NFATc3 in old NHERF1−/− mice compared to old WT mice. Our data further show that expression of the cytokines IL-1β, IL-6, IL-17A, MCP1, and TNF-α significantly increased in the old NHERF1−/− mice compared to the WT mice. We conclude that loss of NHERF1 expression induces cytokine expression in the kidney through interactive regulation between miR-153 and NFATc2/NFATc3 expression.

Interactive multimedia experiences (IME) can be a pedagogical resource that has a strong potential to enhance learning experiences in early childhood. Learning analytics (LA) has become an important tool that allows us to understand more clearly how these multimedia experiences can contribute to the learning processes of these students. This article proposes a work route that defines a set of activities and techniques, as well as a flow for their application, by taking into consideration the importance of including LA guidelines when designing IMEs for elementary education. The work route’s graphical representation is inspired by the foundations of the Essence standard’s graphical notation language. The guidelines are grouped into five categories, namely (i) a data analytics dashboard, (ii) student data, (iii) teacher data, (iv) learning activity data, and (v) student progress data. The guidelines were validated through two approaches. The first involved a case study, where the guidelines were applied to an IME called Coco Shapes, which was aimed at transition students at the Colegio La Fontaine in Cali (Colombia), and the second involved the judgments of experts who examined the usefulness and clarity of the guidelines. The results from these approaches allowed us to obtain precise and effective feedback regarding the hypothesis under study. Our findings provide promising evidence of the value of our guidelines, which were included in the design of an IME and contributed to the greater personalized monitoring available to teachers to evaluate student learning.

This systematic literature review delves into the extensive landscape of emotion recognition, sentiment analysis, and affective computing, analyzing 609 articles. Exploring the intricate relationships among these research domains, and leveraging data from four well-established sources—IEEE, Science Direct, Springer, and MDPI—this systematic review classifies studies in four modalities based on the types of data analyzed. These modalities are unimodal, multi-physical, multi-physiological, and multi-physical–physiological. After the classification, key insights about applications, learning models, and data sources are extracted and analyzed. This review highlights the exponential growth in studies utilizing EEG signals for emotion recognition, and the potential of multimodal approaches combining physical and physiological signals to enhance the accuracy and practicality of emotion recognition systems. This comprehensive overview of research advances, emerging trends, and limitations from 2018 to 2023 underscores the importance of continued exploration and interdisciplinary collaboration in these rapidly evolving fields.