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This case study describes and discusses how student-faculty partnerships can be strengthened through design thinking and the establishment of shared ignorance, i.e., an awareness of how none of the involved parties understands the problem or knows the optimum solution of the partnership project. As a case, we use a student-faculty project that aimed to develop course material for an electrical engineering course based on project work involving wicked problems. This project illustrates, through student and faculty reflections, how design thinking and shared ignorance can be used to subvert implicit power structures and strengthen the partnership and project outcomes.

This paper focuses on the sociological and legal analysis of the effects of the development of rapid technological advancements. The focus is on the need to rethink new technologies and the process of hyperconnectivity. The theoretical discussion is embedded in the framework of the chosen philosophical and social approaches. It starts with the attempt to understand the essence of the discussed changes and poses several questions to be answered. The authors analyze several mediating notions such as social values, axionormative order, legal regulations, the human position towards technological advancements, etc. Further analysis leads to a discussion of the legal context of these problems. The authors search for answers to many fundamental questions to open avenues for building coherent legal pillars of social order based on human values. To achieve these goals, they use a sociological and legal approach that is based mainly on criticism of writing and the analytical and synthetic methods.

AIMS: We aimed to explore atrial fibrillation (AF)-induced productivity losses in working-age atrial fibrillation patients and to estimate atrial fibrillation-related indirect costs. METHODS: Between 2014 and 2017, the Swiss Atrial Fibrillation prospective cohort study (Swiss-AF) enrolled 217 working-age patients with documented atrial fibrillation. Self-reported changes in professional activity and the reasons thereof were descriptively analysed over 8 years of follow-up or until patients reached the retirement age. Results were put into perspective, and indirect costs were planned to be estimated, through comparison with a general population-based, age-, sex- and year-matched comparison sample from the Swiss labour force survey (SLFS). RESULTS: Of 217 analysed Swiss-AF patients, 14.7% reported a professional activity change (9.2% stop, 5.5% reduction) due to atrial fibrillation before the end of observation. Of those working at enrolment (n = 157), 3.8% had a subsequent professional activity change due to atrial fibrillation, 11.6% due to other reasons. Patients were more likely to report an impact of atrial fibrillation on professional activity if they had had atrial fibrillation longer and were closer to the retirement age. Slightly fewer Swiss-AF patients were employed (75%) than in the comparison sample (77%). For those working however, the degree of employment was higher (88% vs 83%). Lack of differences between the Swiss-AF patients and the comparison sample indicated no relevant indirect costs of atrial fibrillation due to lost productivity. CONCLUSION: Only a minority of atrial fibrillation patients reported a negative impact of atrial fibrillation on their professional activity. Professional activity changes due to other reasons were reported more frequently. Compared with the general population, atrial fibrillation did not cause distinct differences.

IntroductionInfants with congenital diaphragmatic hernia can suffer severe respiratory insufficiency and pulmonary hypertension after birth. Aerating the lungs before removing placental support (physiologically based cord clamping, PBCC) increases pulmonary blood flow (PBF) and reduces pulmonary vascular resistance (PVR) in lambs with a diaphragmatic hernia (DH). We hypothesized that these benefits of PBCC persist for at least 8 h after birth.MethodsAt ∼138 days of gestation age (dGA), 21 lambs with a surgically induced left-sided DH (∼86 dGA) were delivered via cesarean section. The umbilical cord was clamped either before ventilation onset (immediate cord clamping, ICC, n = 9) or after achieving a tidal volume of 4 ml/kg, with a maximum delay of 10 min (PBCC, n = 12). The lambs were ventilated for 8 h, initially with conventional mechanical ventilation, but were switched to high-frequency oscillatory ventilation after 30 min if required. Ventilatory parameters, cardiopulmonary physiology, and arterial blood gases were measured throughout the study.ResultsPBF increased after ventilation onset in both groups and was higher in the PBCC DH lambs than the ICC DH lambs at 8 h (5.2 ± 1.2 vs. 1.9 ± 0.3 ml/min/g; p

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

The aim of this study is to determine what variables influence consumer purchase intentions regarding preferences for natural cosmetics. Data were collected via an online survey from 197 people completed in April-May 2018 in Hungary. The research used a non-parametric test – the Wilcoxon test. Analyses have shown that gender and consumers’ willingness to purchase natural products influence consumers’ willingness to purchase. Environmentally and health-conscious consumer behavior also influences their purchasing intentions for natural cosmetics. Consumer interest in environmental and health issues is growing today, providing a huge opportunity for the natural and organic cosmetics (N&O Cs) industry to develop a strategy that would encourage many consumers to buy organic or natural body care products. The results may also be useful for marketers, online sellers and professionals in identifying and better understanding new trends in natural cosmetics production.

Abstract Background Gonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling. Methods We used clonal murine pituitary αT3-1 and LβT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LβT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHβ. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LβT2 migration responses to GnRH and AXL. Results We observed AXL, along with the GnRH receptor, expression in αT3-1 and LβT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LβT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LβT2 cells, Gas6/AXL signaling stimulated LHβ production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration. Conclusions Altogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling. Video Abstract

Abstract BackgroundTolvaptan is the only US Food and Drug Administration–approved drug to slow the progression of autosomal dominant polycystic kidney disease (ADPKD), but it requires strict clinical monitoring due to potential serious adverse events. ObjectiveWe aimed to share our experience in developing and implementing an electronic health record (EHR)–based application to monitor patients with ADPKD who were initiated on tolvaptan. MethodsThe application was developed in collaboration with clinical informatics professionals based on our clinical protocol with frequent laboratory test monitoring to detect early drug-related toxicity. The application streamlined the clinical workflow and enabled our nursing team to take appropriate actions in real time to prevent drug-related serious adverse events. We retrospectively analyzed the characteristics of the enrolled patients. ResultsAs of September 2022, a total of 214 patients were enrolled in the tolvaptan program across all Mayo Clinic sites. Of these, 126 were enrolled in the Tolvaptan Monitoring Registry application and 88 in the Past Tolvaptan Patients application. The mean age at enrollment was 43.1 (SD 9.9) years. A total of 20 (9.3%) patients developed liver toxicity, but only 5 (2.3%) had to discontinue the drug. The 2 EHR-based applications allowed consolidation of all necessary patient information and real-time data management at the individual or population level. This approach facilitated efficient staff workflow, monitoring of drug-related adverse events, and timely prescription renewal. ConclusionsOur study highlights the feasibility of integrating digital applications into the EHR workflow to facilitate efficient and safe care delivery for patients enrolled in a tolvaptan program. This workflow needs further validation but could be extended to other health care systems managing chronic diseases requiring drug monitoring.

Summary: Mosaic analysis with double markers (MADM) technology enables the generation of genetic mosaic tissue in mice and high-resolution phenotyping at the individual cell level. Here, we present a protocol for isolating MADM-labeled cells with high yield for downstream molecular analyses using fluorescence-activated cell sorting (FACS). We describe steps for generating MADM-labeled mice, perfusion, single-cell suspension, and debris removal. We then detail procedures for cell sorting by FACS and downstream analysis. This protocol is suitable for embryonic to adult mice.For complete details on the use and execution of this protocol, please refer to Contreras et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The article ‘EGFR/Ras-induced CCL20 production modulates the tumour microenvironment’, written by Andreas Hippe, Stephan Alexander Braun, Péter Oláh, Peter Arne Gerber, Anne Schorr, Stephan Seeliger, Stephanie Holtz, Katharina Jannasch, Andor Pivarcsi, Bettina Buhren, Holger Schrumpf, Andreas Kislat, Erich Bünemann, Martin Steinhoff, Jens Fischer, Sérgio A. Lira, Petra Boukamp, Peter Hevezi, Nikolas Hendrik Stoecklein, Thomas Hoffmann, Frauke Alves, Jonathan Sleeman, Thomas Bauer, Jörg Klufa, Nicole Amberg, Maria Sibilia, Albert Zlotnik, Anja Müller- Homey and Bernhard Homey, was originally published electronically on the publisher’s internet portal on 30 June 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 16 September 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. Open Access funding enabled and organized by Projekt DEAL.

The COVID-19 pandemic dramatically affected transportation systems, including the ability of localities to pay for them. We explore the effects of the pandemic and the associated economic turbulence on local option sales taxes (LOSTs), an increasingly common revenue source for transportation in California and across the U.S. LOSTs have many advantages over alternative finance instruments, and they can raise prodigious amounts of revenue. However, LOST funding relies on consumer spending. During times of economic weakness, spending and therefore LOST revenues will lag. This is precisely the pattern we observe in California counties during the initial months of the pandemic. Fortunately for local transportation budgets, LOST revenues recovered after the initial economic shock of COVID-19, albeit at a lower level than they likely would have otherwise. LOST revenue trends during the pandemic were affected by national and regional economic conditions and government policy as well. This public health crisis illustrates both the pitfalls and resilience of LOSTs during economic downturns and recoveries. The lessons from the pandemic’s effects on LOSTs will be useful for policymakers and analysts in preparing for inevitable future economic fluctuations.

This report presents research into the funding categories and other characteristics of active Local Option Sales Taxes (LOSTs) throughout California, with specific focus on the extent to which they make resources available for public transit and the political context that makes it so. LOSTs have grown increasingly popular as a funding mechanism for transportation in California in the context of declining funding from other sources.We find that while LOSTs are increasingly common in California, they vary widely with regards to how they fund transit. In general, LOSTs in rural areas of the state fund transit less, with some of our conversations revealing a preference for additional funds in those areas but others asserting that between LOST funding and other resources such as Transportation Development Act (TDA) funds, rural transit has adequate resources, at least to provide the current level of service. In attempting to characterize which resources are available to transit from each LOST, we also looked closely at local return funds—funds passed on to cities and other local jurisdictions to spend as they see fit, often within some sort of eligibility constraint. Depending on the LOST measure, these funds can either make up a small component or most of the funding program. While our research did reveal that in many cases these funds could be put towards transit, or at least transit-supportive infrastructure such as bus lanes and shelters, we find no evidence of local jurisdictions doing so. Our findings suggest that this is due to local officials and voters seeing road maintenance as the top priority, coupled in some cases with a lack of familiarity with how to support effective public transit.

The aim of the article is to provide an overview of the international and EU law framework concerning the relation between the research and teaching. The analysis of internal regulations of selected European states is provided for a broader vision and comparative perspective. Such an overview constitutes the initial ground for further research and evaluation of the applicable law and its implementation. The article constitutes a summary of the initial phase of the research project dedicated to the impact of the legal research on legal education based on the projects funded by the Polish National Science Centre.

Eukaryotic cells rely on actin to support cellular structure, motility, transport, and a wide variety of other cytoplasmic functions and nuclear activities. Humans and other mammals express six closely related isoforms of actin, four of which are found primarily in skeletal, cardiac, and smooth muscle tissues. The final two isoforms, β and γ, are found in non-muscle cells. Due to the ease of purification, many biochemical studies surveying the functions of actin and its regulators have been carried out with protein purified from skeletal muscle. However, it has become increasingly clear that some activities are isoform specific, necessitating more accessible sources of non-muscle actin isoforms. Recent innovations permit the purification of non-muscle actins from human cell culture and heterologous systems, such as insect cell culture and the yeast Pichia pastoris. However, these systems generate mixtures of actin types or require additional steps to remove purification-related tags. We have developed strains of Saccharomyces cerevisiae (budding yeast) that express single untagged isoforms of either human non-muscle actin (β or γ) as their sole actin, allowing the purification of individual homogeneous actin isoforms by conventional purification techniques.Key features• Easy growth of yeast as a source of human cytoplasmic actin isoforms.• Uses well-established actin purification methods.• The tag-free system requires no post-purification processing.Graphical overviewIsolating human cytoplasmic actins from yeast

This is the second study of voter-approved transportation sales taxes in Los Angeles County performed by the UCLA Institute of Transportation Studies with support from the Haynes Foundation. The earlier study examined the history of the four half cent sales taxes enacted by voters in Los Angeles County between 1980 and 2016. The current study looked in depth at four issues raised but not addressed in the first one. We report on the extent to which the “local return” provisions of the four measures fund transportation programs and projects in the cities and unincorporated areas of the county. We also explored tradeoffs between accountability to the voters through audits and taxpayer advisory committees in comparison with the county’s flexibility to change program elements through amendments when conditions change. Accountability to the voters was enhanced in the later sales tax measures but amendment procedures have been used to respond to changing needs in the county. We examined lawsuits brought against Metro regarding implementation of the sales taxes and found that there have been rather few. The COVID-19 pandemic struck while the study was underway and in response the report also explores the impacts of the pandemic on transportation sales tax revenues and program expenditures. The transportation sales taxes through the end of year 2020 have been the most important and resilient LA Metro funding sources during the pandemic. Sales tax revenue declined but far less than did federal and state sources of finance and revenues from fares paid by passengers.

BackgroundThe activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.MethodsThe effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.ResultsTumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.ConclusionWe propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.