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CD44-targeted <i>N</i>-benzyltetrahydroisoquinoline derivatives as anticancer agents with high tumor-to-normal cell selectivity
Get PDFCD44, a cell surface glycoprotein, plays a crucial role in cancer progression by enhancing cell proliferation and resistance to apoptosis. Targeting CD44 with small molecules is a promising cancer therapy strategy. Building on our previous work with the tetrahydroisoquinoline (THIQ) derivative SRT1, we designed and synthesized a series of analogues (SRT2-SRT10) to explore their anticancer potential. Among these, the sulfonate esters SRT5 and SRT6 were the most promising in CD44+ MDA-MB-231 breast cancer cells. They effectively inhibited the HA-CD44 interaction, as demonstrated by binding assays and cell viability studies. In addition, molecular dynamics simulations predict that these esters interact with the same key residues within the CD44-HABD domain as those involved in HA recognition. In CD44+ lung cancer cell lines (A549 and NCI-H23), SRT1 exhibited the strongest antiproliferative activity (EC50 = 0.88 and 0.42 μM, respectively), while SRT5 and SRT6 also showed significant efficacy, particularly in NCI-H23 cells. Interestingly, only SRT1 induced apoptosis, suggesting distinct mechanisms of cell death. Kinase profiling revealed that SRT5 and SRT6 inhibited CD44-associated kinases, particularly SRC, contributing to their anticancer effects. In contrast, SRT1 appeared to act through a kinase-independent pathway. All compounds displayed high selectivity for cancer cells over non-tumoral lung cells. ADME predictions suggested favorable pharmacokinetic properties. Overall, our results underscore the potential of N-benzylTHIQ derivatives, as selective agents for targeted therapy of lung cancer and support further in vivo validation and mechanistic investigations.</p
Data collected for "Providing an Eyewitness Testimony as an Individual who Stammers: Examining Accuracy/Completeness and Subjective Experiences"
No full textStammering may impede an individual's eyewitness testimony and reduce jurors' perceptions of their credibility through a complex interplay of bio-psycho-social factors. However, no research to date has explored this. Three co-produced, mixed-methods studies are reported, investigating the evidential quality, lived experiences and perceived credibility of people who stammer (PWS) as witnesses. In pre-registered Study 1, PWS recalled as much correct information as non-stammering witnesses overall. However, during the free – but not cued – recall interview phase, PWS provided fewer correct details. A reflexive thematic analysis of participants' post-testimony reflections captured how PWS experienced a cyclical relationship between communicative pressure, anxiety over listener misperceptions and stammer severity, which they navigated either by employing avoidance strategies at the expense of testimony or by speaking through their stammer. In pre-registered Study 2, mock jurors rated PWS as less confident yet more likeable and trustworthy than non-stammering witnesses. In Study 3, providing jurors with information about stammering further improved their likeability and trustworthiness but had no impact on perceived confidence. Findings provide new insight into communication disorders in legal contexts – and the unique challenges faced by PWS in particular – demonstrating the need for systemic accommodations and targeted training for legal professionals. This dataset contains * A SAV file with participant demographics, cognitive ability scores, and the data on completeness, errors, and accuracy of participants' testimony accounts in overall, free, and cued recall phases. * Another SAV file containing the number of correct details and errors, and accuracy (%) of 12 testimony accounts (6 accounts from each group) coded by two independent raters for inter-rater reliability. * Transcripts (docx) of the semi-structured interviews conducted in Study 1b. * The post-testimony survey responses (pdf) provided by participants who stammer
The Social Multiplier of Leisure:Peer Effects in Museum Attendance
Get PDFThis study uses a unique longitudinal data set on daily museum visits in Northern Italy to investigate how social networks influence leisure consumption. Based on detailed administrative records of museum cardholders, we use repeated joint visits to build a dynamic network of peers. We identify peer effects that exploit exogenous variation in membership prices generated by age-based discounts. We find robust evidence of peer spillovers in both museum attendance and membership renewal, primarily driven by a preference for shared experiences. These results underscore the role of social interactions in shaping leisure demand and support the view that social networks can amplify individual behavior. More broadly, our findings contribute to the understanding of peer dynamics in settings where consumption is inherently social.<br/
Potato protein isolate hydrogels as potential scaffolds for bone tissue engineering
Get PDFIntroduction/Objectives:Potato protein isolate (PPI), enriched with patatin, shows comparable gelation ability to egg protein. This study aimed to investigate the potential of PPI hydrogels as a scaffold for bone tissue engineering.Methods:Potato protein isolate powder, Solanic 200, was provided by Royal Avebe U.A. PPI films were generated in multiwell plates by oven-baking a 5% w/w PPI suspension at 70 °C for 3 hours. MG-63 cells were used as a model cell line and cultured on PPI films with adhesion and cell proliferation measured using the resazurin assay. Cell viability was measured on day 10 post-seeding using LIVE/DEAD stain and quantified using FIJI software. PPI hydrogels were formed by heating 10%, 15%, or 20% w/w PPI in a 90 °C water bath for 30 mins. For crosslinked gels, 5% w/w 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 5% w/w Nhydroxysuccinimide (NHS) relative to PPI were added to the solutions immediately prior to heating. The water-holding capacity of hydrogels was evaluated by weighing the gel mass before and after soaking in water at room temperature for 24 hours. Hydrogel degradation was examined by incubating 20% w/w PPI hydrogels in 0.1% v/v trypsin solution at 37 °C and weighing the gels at 1, 3, 6, and 10 days. Young’s modulus was calculated based on the stress-strain curve of both natural and crosslinked PPI gels under compression.Results:The adhesion of MG-63 cells to PPI films relative to tissue culture plastic was over 95% and cells showed steady growth over time. At 10 days post-seeding, the cell viability on PPI films was approximately 100%. For hydrogels, when soaked in water, the mass of all concentrations of natural PPI gels increased no more than 5%. Crosslinked hydrogels increased by 16.63% and 8.63% for 10 and 20% crosslinked hydrogels, respectively. In the degradation test, both natural and crosslinked PPI gels steadily decreased in mass from day 1 to day 10. Crosslinked hydrogels increased in mass on day 1 due to water absorption. From day 1 to day 6, crosslinked gels had higher mass percentages than natural gels. However, on day 10, natural PPI gels retained 70% of the original mass while crosslinked gels were 60%, which was significantly lower. The Young’s modulus of hydrogels increased with increasing protein concentration, reaching 0.2 MPa in 20% gels. The stress-strain curve of crosslinked PPI gels showed a non-linear relationship, suggesting viscoelastic properties, which will be further investigated. Conclusions:PPI films were cytocompatible with MG-63 cells. The crosslinked PPI hydrogels showed promising biodegradable properties and water-holding ability. The viscoelasticity, porosity, interconnectivity, and biocompatibility of crosslinked hydrogels with MG63 cells will be evaluated in the future. Overall, heat-induced PPI hydrogel is a simple prepared, inexpensive, and renewable material for bone tissue engineering applications
Deconstructing and reconstructing African development studies through student engagement and cross-cultural collaboration at a UK university
Get PDFThis paper reflects on the authors’ experience of seeking student feedback and peer recommendations to reconstruct learning content for the delivery of a module on African development studies at a university in the United Kingdom (UK). This restructuring process relied on a form of Appreciative Inquiry that covered the four stages of discovery, dreaming, delivery, and destiny. The paper finds that most students enter university with a limited understanding of Africa framed by overwhelmingly negative associations and have difficulty accessing positive narratives about African countries in their programmes of study. Consequently, problematizing generalised perceptions of Africa must form an obligatory part of transformative change in UK universities, so that students can gain an education that provides them with a more rounded understanding of and appreciation for the continent and its people. The paper also highlights that for sustained, transformative change to occur, efforts to decolonise teaching must go beyond the fragility of siloed initiatives to institution-wide efforts that include establishing training programs and the targeted recruitment of staff with specialised knowledge. Through a discussion of its key findings, the paper seeks to contribute to a growing body of literature providing practical examples of how universities in the UK (and beyond) can decolonise, diversify, and update their social science curricula
Probabilistic forecasting of residential electric vehicle charging demand for low voltage distribution network planning
No full textDual-Unsaturated Transition Metal-Main Group (TM-M’) Heterometallic Complexes for Cooperative Reactivity
No full textHeritage Language and Literacy Development in a Digital Age: The Case of Multilingual Transnational Chinese-English Families in the UK
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