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Abstract Background Resilience is an essential psychological trait that empowers individuals to adapt and thrive in the face of challenges. Although it is acknowledged that health professionals need to possess high levels of resilience, there has been limited research comparing how different groups of health students, particularly school leaver undergraduates and mature age graduate entry students, develop resilience in their coursework. Methods This study combines both objective (academic grades with validated survey results) and subjective data (interviews) to compare how resilience is related to academic coursework performance for two groups of pharmacy students: the mature age graduate entry (GE, N = 64) learners and school leaver undergraduate (UG, N = 208) learners. We employed a sequential explanatory mixed methods design using surveys, academic performance data and semi-structured interviews. The survey tapped constructs related to resilience (burnout, stressors and coping methods) while the interviews elicited a more nuanced understanding of individual and environmental factors. Results Although there was no statistical difference in burnout experience between the two groups, GE students exhibited more positive resilience attitudes than UG when selecting resilience statements on the survey. Both cohorts indicated in the survey that engaging in distraction activities (physical exercise, sleeping, listening to music, anything other than the stressor) was their most preferred method of relieving stress. Within UG student survey responses, those who indicated support from partners, friends and family had better academic performance, while those who did not report coping methods did worse academically. The three key environmental factors we identified that contributed to both undergraduate and graduate entry resilience were workload, feedback provision and psychosocial support. Conclusions Currently, there is still a need for resilience programs geared at academic success to be implemented in higher education. This study provides objective evidence of academic success coupled with exploration into the nuances of resilience amongst different student groups. It not only highlights the differing resilience development strategies and burnout coping mechanisms in emerging health professionals, but showcases the juxtaposition of two different learner groups (UG and GE students) within a discipline. The cross-cohort facilitation of learning as in the discipline-specific strategies identified can help both groups develop resilience and inform future innovations. By comparing mature-age graduate students and younger-in-age undergraduate students, we identified a wider range of strategies and more positive attitudes to burnout in mature-age students. Health and clinical educators in university health degrees, clinical placements and clinical workplaces can develop effective training materials based on findings from this study to 1) assist undergraduate younger-age health students with developing resilience and 2) further refine mature-age health students’ and practicing health professionals’ resilience in today’s fast-paced clinical workplaces.

Abstract Two distemper paint samples taken from decorative boards in Uvdal stave church, Norway, were analysed using palaeoproteomics, with an aim of identifying their binder and possible contaminants. The results point at the use of calfskin to produce hide glue as the original paint binder, and are consistent with the instructions of binder production and resource allocation in the historical records of Norway. Although we did not observe any evidence of prior restoration treatments using protein-based materials, we found abundant traces of human saliva proteins, as well as a few oats and barley peptides, likely deposited together on the boards during their discovery in the 1970s. This work illustrates the need to fully consider contamination sources in palaeoproteomics and to inform those working with such objects about the potential for their contamination.

Abstract Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram’s anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.

Artificial intelligence (AI) has shown its effectiveness in helping clinical users meet evolving challenges. Recently, ChatGPT, a newly launched AI chatbot with exceptional text comprehension capabilities, has triggered a global wave of AI popularization and application in seeking answers through human‒machine dialogues. Gastric cancer, as a globally prevalent disease, has a five-year survival rate of up to 90% when detected early and treated promptly. This research aims to explore ChatGPT's potential in disseminating gastric cancer knowledge, providing consultation recommendations, and interpreting endoscopy reports. Through experimentation, the GPT-4 model of ChatGPT achieved an appropriateness of 91.3% and a consistency of 95.7% in a gastric cancer knowledge test. Furthermore, GPT-4 has demonstrated considerable potential in consultation recommendations and endoscopy report analysis.

Over the last 30 years, high-resolution site documentation has rapidly developed, with analogue drawings and film photography being replaced with high-precision digital recordings. Today, most archaeological field data sets are produced using digital tools that store spatial and visual information in various digital formats directly, i.e., born-digital. A fully digital workflow makes the process of combining, comparing, and integrating field datasets quicker, easier, and potentially more analytically powerful. However, at sites where both analogue and born-digital data sets have been produced, additional procedural digitization steps are required before full data interoperability is achieved. In cases where the archaeological sites have a long excavation history, multiple generations of analogue and digital site documentation techniques have often been used, making it particularly challenging to physically reconstruct an excavated site based on its archival material. The Middle Stone Age site of Blombos Cave, South Africa, is a prime example of this type of challenging situation. This site features a more than 3-meter-deep and well-preserved archaeological sequence dated to between 300 and 100 000 years ago. Since it was initially excavated in 1991, multiple archaeological campaigns have been carried out (>15), and the excavations are still ongoing. The field documentation from Blombos Cave has, over the years, produced varied but rich datasets that have never been integrated into a single, coherent, and accessible archive. In this paper we evaluate the changes in excavation protocol at Blombos Cave over time, and we use this knowledge to digitally integrate and map the various stages of excavation within a three-dimensional framework using digital photogrammetry and archival photographs. The archaeological and analytical value of this approach is exemplified through multiple case studies, in which we demonstrate how and why the merging of old and new archaeological field data can lead to new results, specifically by offering more complete mapping and more accurate and analytically dynamic visualisations. The research history at Blombos Cave is not unique or site-specific. Our approach would be applicable to a wide variety of sites and contexts where long-running excavations have produced a mix of analogue and digital field data.

BackgroundIndividuals reporting self-injury are at greater risk of several adverse outcomes, including suicide. There is reason to be concerned how these individuals cope when stressful life events increase. This study aimed to investigate the trajectories of anxiety and depressive symptoms and the predictive value of self-injury history in individuals with psychiatric symptoms during the unique and stressful conditions of the COVID-19 pandemic.MethodsIn a longitudinal population cohort study (N = 1810) ranging from 2020 to 2022, anxiety (measured by Generalized Anxiety Disorder, GAD-7) and depressive symptoms (measured by Patient Health Questionnaire, PHQ-9) were self-reported monthly during 12 months. Latent growth curve models with and without self-reported self-injury history as predictors were conducted.ResultsOverall, anxiety and depressive symptoms decreased from baseline, but remained at moderate severity at follow-up. Individuals reporting suicidal or nonsuicidal self-injury reported significantly higher symptom severity at baseline. In addition, individuals reporting suicidal self-injury demonstrated a slower rate of decline in the symptom load over the course of 12 months.ConclusionsOver the course of 12 months, anxiety and depressive symptoms decreased in individuals with psychiatric symptoms, but still indicate a psychiatric burden. Individuals with a history of self-injury could be more vulnerable in face of stressful conditions such as those experienced during the COVID-19 pandemic.

Abstract Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

Abstract Prior laboratory research has suggested that humans may become more prosocial in stressful or threatening situations, but it is unknown whether the link between prosociality and defense generalizes to real-life. Here, we examined the association between defensive responses to a real-world threat (the COVID-19 pandemic) and everyday altruism. Four independent samples of 150 (N = 600) US residents were recruited online at 4 different timepoints, and self-report measures of perceived COVID-19 threat, defensive emotions (e.g., stress and anxiety), and everyday altruism were collected. Our operationalization of defensive emotions was inspired by the threat imminence framework, an ecological model of how humans and animals respond to varying levels of threat. We found that perceived COVID-19 threat was associated with higher levels of everyday altruism (assessed by the Self-report Altruism scale). Importantly, there was a robust association between experiencing acute anxiety and high physiological arousal during the pandemic (responses typically characteristic of higher perceived threat imminence), and propensity to engage in everyday altruism. Non-significant or negative associations were found with less acute defensive responses like stress. These findings support a real-life relation between defensive and altruistic motivation in humans, which may be modulated by perceived threat imminence.

Abstract Luffa is a genus of tropical and subtropical vines belonging to the Cucurbitaceae family. Sponge gourd (Luffa cylindrica) and ridge gourd (Luffa acutangula) are two important species of the genus Luffa and are good sources of human nutrition and herbal medicines. As a vegetable, aromatic luffa is more preferred by consumers than nonaromatic luffa. While the aroma trait is present in the sponge gourd, the trait is not present in the ridge gourd. In this study, we identified Luffa cylindrica’s betaine aldehyde dehydrogenase (LcBADH) as a gene associated with aroma in the sponge gourd based on a de novo assembly of public transcriptome data. A single nucleotide polymorphism (SNP: A > G) was identified in exon 5 of LcBADH, causing an amino acid change from tyrosine to cysteine at position 163, which is important for the formation of the substrate binding pocket of the BADH enzyme. Based on the identified SNP, a TaqMan marker, named AroLuff, was developed and validated in 370 F2 progenies of the sponge gourd. The marker genotypes were perfectly associated with the aroma phenotypes, and the segregation ratios supported Mendelian’s simple recessive inheritance. In addition, we demonstrated the use of the AroLuff marker in the introgression of LcBADH from the aromatic sponge gourd to the ridge gourd to improve aroma through interspecific hybridization. The marker proved to be useful in improving the aroma characteristics of both Luffa species.

Abstract Background The non-classical human leukocyte antigen (HLA)-G is a strong immunomodulatory molecule. Under physiological conditions, HLA-G induces immunological tolerance in immune privileged tissues, while under pathophysiological situations it contributes to immune escape mechanisms. Therefore, HLA-G could act as a potential immune checkpoint for future anti-cancer immunotherapies. Recent data suggest an aberrant expression of the cAMP response element binding protein (CREB) in clear cell renal cell carcinoma (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary reports demonstrated a connection of CREB as a control variable of HLA-G transcription due to CREB binding sites in the HLA-G promoter region. This study investigates the interaction between CREB and HLA-G in different renal cell carcinoma (RCC) subtypes and its correlation to clinical parameters. Methods The direct interaction of CREB with the HLA-G promoter was investigated by chromatin immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) consisting of 453 RCC samples of distinct subtypes. Staining results were assessed for correlations to clinical parameters as well as to the composition of the immune cell infiltrate. Results There exists a distinct expression pattern of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were positively associated to the overall survival of RCC patients. A slightly, but significantly elevated number of tumor infiltrating regulatory T cells was observed in tumors of high CREB expression. Whether this small increase is of clinical relevance has to be further investigated. Conclusions An interaction of CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the first time the expression of CREB and its interaction with the HLA-G in human RCCs has been shown, which might be of clinical relevance.

Introduction General Practitioners (GPs) and allied healthcare professionals working in primary care are regularly required to make decisions with, for and on behalf of patients who lack capacity. In England and Wales, these decisions are made for incapacitated adult patients under the Mental Capacity Act 2005, which primarily requires that decisions are made in the patient’s ‘best interests’. Regarding children, decisions are also made in their best interests but are done so under the Children Act 1989, which places paramount importance on the welfare of the child. Decisions for children are usually made by parents, but a GP may become involved if he or she feels a parent is not acting in the best interests of the child. Internationally, including elsewhere in the UK, different approaches are taken. We hypothesise that, despite the legislation and professional guidelines, there are many different approaches taken by GPs and allied healthcare professionals in England and Wales when making these complex decisions with, for and on behalf of patients who lack capacity. To better understand what is known about how these decisions are made, we plan to undertake a scoping review and directed content analysis of the literature. While the majority of decisions made in primary care are made by GPs, for completeness, this review will include all allied healthcare professionals working in primary care.Methods and analysis To ensure a wide breadth of literature is captured, a scoping review will be undertaken as described by Arksey and O’Malley (2005). A five-stage approach will be taken when conducting this review: (1) identifying the research question; (2) identifying relevant papers; (3) study selection; (4) data extraction and (5) summarising and synthesis. The final stage will include a directed content analysis of the data to help establish the cross-cutting themes.Ethics and dissemination The scoping review will be disseminated through conferences and peer-reviewed publications. This scoping review is the first (mapping) phase in a proposed larger study to explore how GPs make decisions with, for and on behalf of those who lack capacity. Qualitative research with GPs, patients and their families will follow, before all the results are synthesised using an ‘empirical bioethics’ methodology.

Maximum lifespan for most animal species is difficult to define. This is challenging for wildlife management as it is critical for estimating important aspects of population biology such as mortality rate, population viability, and period of reproductive potential. Recently, it has been shown cytosine-phosphate-guanine (CpG) density is predictive of maximum lifespan in vertebrates. This has made it possible to predict lifespan in long-lived species, which are generally the most intractable. In this study, we use gene promoter CpG density to predict the lifespan of five marine turtle species. Marine turtles are a particularly difficult group for lifespan estimation because of their migratory behaviour, longevity and high juvenile mortality rates, which all restrict individual tracking over their lifespan. Sanger sequencing was used to determine the CpG density in selected promoters. We predicted the lifespans for marine turtle species ranged from 50.4 years (flatback turtle, Natator depressus) to 90.4 years (leatherback turtle, Dermochelys coriacea). These lifespan predictions have broad applications in marine turtle research such as better understanding life cycles and determining population viability.

The breast cancer (BC) biomarker HER2 (Human Epidermal Receptor 2) is overexpressed in 25% of BC. Only patients with HER2-positive tumors receive HER2-targeting therapies, like trastuzumab (Herceptin). However, some women with a HER2-negative BC could benefit from trastuzumab. This could be explained by the activation/phosphorylation of HER2 that can be recognized by trastuzumab. The aim of this study is to examine trastuzumab effects on HER2 phosphorylation at tyrosine Y877 (pHER2Y877). HER2 and pHER2Y877 status were evaluated in a cohort of BC patients representative of molecular subtypes distribution (n = 497) and in a series of BC cell lines (n = 7). Immunohistochemistry against pHER2Y877 was performed on tissue micro arrays. Cellular proliferation assays were performed on BC cell lines presenting different combinations of HER2 and pHER2Y877 status and treated with increasing doses of trastuzumab (0-150 μg/ml). The prevalence of pHER2Y877 in this cohort was 6%. Nearly 5% of patients with HER2-negative tumors (n = 406, 82%) overexpressed pHER2Y877. Among triple negative BC patients (n = 39, 8%), 7.7% expressed pHER2Y877. Trastuzumab treatment decreased cell proliferation in HER2-/pHER2Y877+ BC cell lines, to an extent comparable to what occurs in HER2+ cell lines, but did not affect HER2-/pHER2Y877- cell lines. Trastuzumab sensitivity in HER2-/pHER2Y877+ cell line is specific to HER2 tyrosine 877 phosphorylation. Hence, with further confirmation in a bigger cohort, trastuzumab treatment could be envisaged as a treatment option to women presenting with HER2-/pHER2+ tumors, representing more than 1000 BC women in Canada in 2019.

Abstract Background Investigating fetal development in mice necessitates the determination of fetal sex. However, whilst the sex of adult and juvenile mice can be readily distinguished from anogenital distance, the sex of fetal and neonatal mice cannot be identified visually. Instead, genetic sex must be determined by PCR amplification of X chromosome genes with divergent Y chromosome gametologs. Existing simplex PCR methods are confounded by small size differences between amplicons, amplification of unexpected products, and biased amplification of the shorter amplicon. Results Primers were designed flanking an 84 bp deletion of the X-linked Rbm31x gene relative to its Y-linked gametolog Rbm31y. A single product was amplified from XX samples, with two products amplified from XY samples. Amplicons were resolved by gel electrophoresis for 20 min, with unbiased amplification of both products observed in XY samples. Conclusion This method achieves rapid and unequivocal genetic sex determination of mice in low volume PCR reactions, reducing reagent usage and simultaneously eliminating shortcomings of previous methods.

Increased levels of pro-inflammatory markers and decreased levels of anti-inflammatory markers in the breast tissue can result in local inflammation. We aimed to investigate whether local inflammation in the breast tissue is associated with age-related lobular involution, a process inversely related to breast cancer risk. Levels of eleven pro- and anti-inflammatory markers were assessed by immunohistochemistry in normal breast tissue obtained from 164 pre- and postmenopausal breast cancer patients. Involution status of the breast (degree of lobular involution and the predominant lobule type) was microscopically assessed in normal breast tissue on hematoxylin-eosin stained mastectomy slides. Multivariate generalized linear models were used to assess the associations. In age-adjusted analyses, higher levels of pro-inflammatory markers IL-6, TNF-α, CRP, COX-2, leptin, SAA1 and IL-8; and anti-inflammatory marker IL-10, were inversely associated with the prevalence of complete lobular involution (all P≤0.04). Higher levels of the pro-inflammatory marker COX-2 were also associated with lower prevalence of predominant type 1/no type 3 lobules in the breast, an indicator of complete involution, in age-adjusted analysis (P = 0.017). Higher tissue levels of inflammatory markers, mainly the pro-inflammatory ones, are associated with less involuted breasts and may consequently be associated with an increased risk of developing breast cancer.

Antarctic krill (Euphausia superba) is a key species in the Southern Ocean with an estimated biomass between 100 and 500 million tonnes. Changes in krill population viability would have catastrophic effect on the Antarctic ecosystem. One looming threat due to elevated levels of anthropogenic atmospheric carbon dioxide (CO2) is ocean acidification (lowering of sea water pH by CO2 dissolving into the oceans). The genetics of Antarctic krill has long been of scientific interest for both for the analysis of population structure and analysis of functional genetics. However, the genetic resources available for the species are relatively modest. We have developed the most advanced genetic database on Euphausia superba, KrillDB, which includes comprehensive data sets of former and present transcriptome projects. In particular, we have built a de novo transcriptome assembly using more than 360 million Illumina sequence reads generated from larval krill including individuals subjected to different CO2 levels. The database gives access to: 1) the full list of assembled genes and transcripts; 2) their level of similarity to transcripts and proteins from other species; 3) the predicted protein domains contained within each transcript; 4) their predicted GO terms; 5) the level of expression of each transcript in the different larval stages and CO2 treatments. All references to external entities (sequences, domains, GO terms) are equipped with a link to the appropriate source database. Moreover, the software implements a full-text search engine that makes it possible to submit free-form queries. KrillDB represents the first large-scale attempt at classifying and annotating the full krill transcriptome. For this reason, we believe it will constitute a cornerstone of future approaches devoted to physiological and molecular study of this key species in the Southern Ocean food web.

We describe laboratory-confirmed influenza A pandemic (H1N1) 2009 in 17 hospitalized recipients of a hematopoietic stem cell transplant (HSCT) (8 allogeneic) and in 15 patients with malignancy treated at 6 Australian tertiary centers during winter 2009. Ten (31.3%) patients were admitted to intensive care, and 9 of them were HSCT recipients. All recipients of allogeneic HSCT with infection 4 days of oseltamivir therapy. Three of these 4 patients were critically ill. Oseltamivir resistance in 4 (13.3%) of 30 patients who were administered oseltamivir highlights the need for ongoing surveillance of such resistance and further research on optimal antiviral therapy in the immunocompromised.

T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.