Downstream Actions Research Articles

Brain health is a human right: Implications for policy and research.

The call to synergize brain health with mental health has major ramifications for research and policy. Mental health has been recognized as a universal human right, but no such declaration exists for brain health. Here, I defend the right to lifelong brain health as a derived, intermediary, and generative right. It is derived from the right to physical health because it is reducible to facts about the health of the body. This grounds brain health in the right to physical health, a long-standing right with hard legal status, while avoiding "rights inflation." It is intermediary because it bridges the gap between physical and mental health, since the brain is an organ that is central to both physical and mental health. It is generative because it provides impetus to downstream actions including the creation of health-based "neurorights" and bolstering the right to a healthy environment to protect collective cognitive health. Thus, the right to lifelong brain health would guarantee the right of citizens to live and grow in a brain health-promoting environment. A rights-based approach to brain health also has important consequences for research. It would help to move research away from the disease paradigm that focuses on individual risk and responsibility to the study of deeper contributions to brain health and disease through a population neuroscience approach to public brain health. Until the right to brain health is recognized alongside mental health, their synergy will remain incomplete, and brain health promotion will lack unity.

USP10 deubiquitinates and stabilizes CD44 leading to enhanced breast cancer cell proliferation, stemness and metastasis.

Despite extensive research, strategies to effectively combat breast cancer stemness and achieve a definitive cure remains elusive. CD44, a well-defined cancer stem cell marker is reported to promote breast cancer tumorigenesis, metastasis, and chemoresistance. However, mechanisms leading to its enhanced expression and function is poorly understood. Here, we demonstrate that USP10 positively regulates CD44 protein levels and its downstream actions. While USP10 depletion prominently downregulates CD44 protein levels and functions, its overexpression significantly enhances CD44 protein levels, leading to enhanced cluster tumor cell formation, stemness, and metastasis in breast cancer cells both in vitro and ex vivo in primary human breast tumor cells. USP10 interacts with CD44 and stabilizes it through deubiquitination both in breast cancer cell lines and human breast cancer-derived primary tumor cells. Stabilized CD44 shows enhanced interaction with cytoskeleton proteins Ezrin/Radixin/Moesin and potently activates PDGFRβ/STAT3 signalling which are involved in promoting CSC traits. Using USP10 stably expressing 4T1 cells, we further demonstrate that the USP10-CD44 axis potently promotes tumorigenicity in vivo in mice, while simultaneous depletion of CD44 in these cells renders them ineffective. In line with these findings, we further showed that inhibition of USP10 either through RNAi or the pharmacological inhibitor Spautin-1 significantly mitigated CD44 levels and its downstream function ex vivo in primary breast tumor cells. Finally, we demonstrated that primary breast tumor cells are more susceptible to chemotherapy when co-treated with USP10 inhibitor indicating that the USP10-CD44 axis could be an attractive therapeutic target in combination with chemotherapy in CD44 expressing breast cancers.

Physical activity promotion as intersectoral planning in Milan Health Protection Agency

Abstract Issue/problem Physical activity is a protective factor for preventing Noncommunicable diseases (NCDs) and, for this reason, it plays an important role in all the different guidelines for prevention and health promotion. The Italian Regional Prevention Plans and in particular the Lombardy one promote physical activity with a systemic approach, through both upstream and downstream actions to encourage the role of communities. Description of the problem Based on the regional plan, the Health Protection Agency (HPA) of the Metropolitan City of Milan developed locally validated actions and best practices for the promotion of physical activity, through the cross-sectoral involvement of different stakeholders (health system, companies, universities, local authorities, sports associations, etc.). Results Physical activity is embedded in all lines of health promotion activities in local planning documents. Sustainable and active mobility activities have been implemented in companies and schools with a comprehensive approach. Validated regional programs (Pedibus, Walking Groups, ecc.) have been implemented in the local community, along with the construction of permanent local laboratories for physical activity, structured through the development of specific territorial networks and providing for integration with the socio-sanitary setting. Lessons Promoting physical activity becomes an opportunity to both consolidate territorial networks and to develop evidence-based health promotion actions able to meet the different health needs of the population and to produce a structural change in living contexts. Key messages • Physical activity is both a protective factor for health promotion and a tool for implementing intersectoral and equity-oriented system actions from a life-course perspective. • Promoting physical activity becomes an opportunity to consolidate territorial networks.

7286 Higher Order Associations Linking Tryptophan, Kynurenine, And Tyrosine As Serum Markers Of Glucocorticoid Downstream Action In Adipose Tissue

Abstract Disclosure: K. Bennett: None. T. Garner: None. D. Chantzichristos: Speaker; Self; Sanofi, Takeda. P. Jansson: None. A. Stevens: None. G. Johannsson: Consulting Fee; Self; Novo Nordisk, Shire, AstraZeneca. Speaker; Self; Novo Nordisk, Pfizer, Inc.. Introduction: Treatment of Adrenal Insufficiency (AI) by glucocorticoid (GC) replacement therapy is mainly guided by clinical judgement, as there is no biomarker of GC action to individualise its dosage. Hypergraphs are networks modelling higher order associations (HOAs), which are interactions between more than two ‘omic elements. The aim of this study was to use hypergraphs to identify serum markers that reflect the action of GCs in adipose tissue (AT). Methods: In a randomised, cross-over trial, 10 patients with primary AI received saline i.v. (GC withdrawal), or circadian infusion of hydrocortisone (GC exposure), with > 2 weeks apart. After 26 hours (8AM), AT biopsy and PBMCs were collected for transcriptomic analysis, and abdominal subcutaneous microdialysis and PBMCs were collected for metabolomic profiling using LC/MS. Hypergraph models were generated to integrate serum and AT transcriptomics and metabolomics, identifying clusters of putatively causally linked metabolites which could represent serum markers of downstream GC action in AT. Hypergraph structure was assessed in AT and serum using entropy to infer associations within pre-defined metabolic pathways. Differences in entropy between the interventions was measured using Bayes Factor. Univariate ROC curve analysis was used to calculate AUCs for the serum markers. Results: In AT dialysate, 22 metabolites were identified as significantly different between GC exposure and withdrawal states. These included metabolites found in lipolysis and proteolysis pathways, such as acyl carnitines, lysophosphatidylcholines, fatty acids, and peptide derivatives. Nine metabolites were significantly different between the interventions in the serum. DEGs in AT (n=2048) were found to be enriched in metabolic pathways. Hypergraphs were used to refine clusters in the serum based on their HOAs with AT differentially expressed genes and metabolites. Tryptophan, Kynurenine, and Tyrosine clustered together, demonstrating a relationship between their expression in serum, and the metabolomic and transcriptomic profile of AT. These HOAs were shared with cortisol in the exposure intervention, but not in GC withdrawal, suggesting GC dependent regulation. All 3 metabolites had AUC-ROCs > 0.8, with Kynurenine performing the best at 0.86. Tissue specific differences were seen in the entropy of metabolic pathways between GC exposure and withdrawal, with similar changes seen in lipid and proteolysis pathways, but no difference seen in serum in carbohydrate and amino acid biosynthesis. Conclusions: During near physiological exposure, we identified changes to hypergraph structure and metabolite concentrations in lipid, protein, and carbohydrate pathways in AT and serum, compared to GC withdrawal. Hypergraph integration of multi-omic data identified tryptophan, kynurenine, and tyrosine as potential serum markers reflecting GC action in AT. Presentation: 6/3/2024

27-Hydroxycholesterol contributes to hypercholesterolemia-associated aggravation of apical periodontitis in ovariectomized rats and raloxifene counteracts its action.

The influence of hypercholesterolemia on the development of apical periodontitis (AP) is inconclusive. Recent studies revealed that cholesterol metabolite 27-hydoxycholesterol (27HC) can affect cellular responses to bacterial infections and oestrogen status and raloxifene may influence its action. Herein, we aimed to examine the impact of 27HC on production of inflammatory mediators by macrophages and the regulatory function of raloxifene. The contribution of 27HC to AP development and the therapeutic effect of raloxifene were evaluated in a rat model. Murine macrophages J774 cells were used. The expression of inducible nitric oxide synthase (iNOS) was examined by Western blot. The concentrations of C-C motif chemokine ligand (CCL) 2 and 27HC were assessed by enzyme-linked immunosorbent assay. Colorimetric assay was used to evaluate cholesterol levels. Experimental AP was induced in ovariectomized (OVX) or un-operated rats receiving high-fat/high-cholesterol diet (HFHCD) or normal diet (ND). Micro-computed tomography and immunohistochemistry were employed to evaluate disease severity and the therapeutic effect of raloxifene. Cholesterol enhanced 27HC production in macrophages. 27HC induced iNOS and CCL2 synthesis by macrophages and estradiol suppressed the responses. In our animal model of AP, HFHCD plus OVX significantly augmented serum and lesion tissue levels of 27HC (p < .05 versus the ND group). Lesion size, infiltration of CD68+ cells, and iNOS+ monocytes were increased in parallel with 27HC accumulation. Raloxifene inhibited pro-inflammatory effects of 27HC on macrophages and suppressed AP progression in HFHCD/OVX rats (p < .05 versus the vehicle control group). Our results suggested that 27HC contributes to AP aggravation associated with hypercholesterolemia. Oestrogen deficiency may both enhance 27HC production and exacerbate its downstream action.

Unsteady vane-rotor secondary flow interaction of the endwall region in a 1.5-stage variable-geometry turbine

Variable-geometry turbines present significant improvements in both off-design cycle efficiency and enhanced engine responsiveness for future adaptive cycle engines. The adjustable vanes regulate the through-flow capacity by varying the installation angle and thus unavoidably require endwall clearance, resulting in profound implications for vane and downstream blade rows. Unsteady numerical simulations are carried out to investigate the vane-rotor flow interaction under the zero and partial clearance type of the adjustable vane in a 1.5-stage variable-geometry turbine. First, specific vortical structures and loss characteristics of upstream adjustable vane leakage flow at turning angles of −5°, 0°, and +5° are described. Then, the basic mechanisms of vane-rotor secondary flow interaction between acquired upstream leakage flow and downstream blade rows secondary flow is explored by the time-resolved method and quantitative detailed analysis method. The results show that adjustable vane vortex core area is the primary cause of internal loss within the vortex, and the mixing and interaction between the leakage vortex and other vortex systems contribute to secondary loss in the vane. Due to the downstream blade shear action caused by different flow velocity on the suction and pressure surfaces, the vane leakage flow fragments upon entering the R1 blade passage and develops downstream of the endwall region. Compared to the vane with zero clearance case at same turning angle, the intensity of the R1 tip leakage vortex at the design turning angle and open turning angle is reduced by 47.4 % and 23.66 % with the upstream partial clearance, respectively. The unsteady vane-rotor secondary flow interaction under different turning angles has large influence on the flow structure and loss characteristics of the downstream blade rows, and results in significant differences in the variation pattern and trend direction of the turbine performance.

ECM-based Ca2+/l-arginine/NO periosteum nourishes bone defect microenvironment, directs macrophage polarity, and accelerates osteogenesis and angiogenesis

The natural periosteum is responsible for supporting bone homeostasis and initiating repair, but is often damaged during bone fracture, causing acute inflammation and loss of a functioning substratum for induction of new bone formation. Here, we propose an ECM-based Ca2+/l-arginine/nitric oxide (NO) electrospun periosteum to reinitiate bone regeneration. The multifaceted action of NO could promote osteoblastic differentiation, angiogenesis and polarization of macrophages, while accelerating new bone formation, enhancing bone quality and reducing inflammation in a rat critical size calvarial defect model, acting as a mainspring that drives the rest of the PI3K-AKT pathway including the downstream action of VEGF, MAPK and mTOR signalling. The modulation of NO cycle by periosteum scaffold is envisioned to be highly efficient at supporting bone grafting surgeries, with simple and clean clinical translation and implications for anti-inflammatory healing.

Cross-modal learning with multi-modal model for video action recognition based on adaptive weight training

The canonical video action recognition methods usually label categories with numbers or one-hot vectors and train neural networks to classify a fixed set of predefined categories, thereby constraining their ability to recognise complex actions and transferable ability to unseen concepts. In contrast, cross-modal learning can improve the performance of individual modalities. Based on the facts that a better action recogniser can be built by reading the statements used to describe actions, we exploited the recent multimodal foundation model CLIP for action recognition. In this study, an effective Vision-Language action recognition adaptation was implemented based on few-shot examples spanning different modalities. We added semantic information to action categories by treating textual and visual label as training examples for action classifier construction rather than simply labelling them with numbers. Due to the different importance of words in text and video frames, simply averaging all sequential features may result in ignoring keywords or key video frames. To capture sequential and hierarchical representation, a weighted token-wise interaction mechanism was employed to exploit the pair-wise correlations adaptively. Extensive experiments with public datasets show that cross-modal action recognition learning helps for downstream action images classification, in other words, the proposed method can train better action classifiers by reading the sentences describing action itself. The method proposed in this study not only reaches good generalisation and zero-shot/few-shot transfer ability on Out of Distribution (OOD) test sets, but also performs lower computational complexity due to the lightweight interaction mechanism with 84.15% Top-1 accuracy on the Kinetics-400.

Abrocitinib: A Comprehensive Review of its Efficacy and Safety in Dermatology.

Abrocitinib is a novel oral small molecule which acts as a selective JAK-1 inhibitor. Currently approved for use in moderate-to-severe cases of atopic dermatitis, this drug is gaining a rapid impetus for its use across various inflammatory dermatoses for its selective downstream action on cytokines of the JAK-1 pathway. Its efficacy and safety in atopic dermatitis has been established in phase 3 clinical trials. The future implication of this drug will depend largely on feasibility and practical use in Indian scenario.

Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system.

Environmental factors and genetic variation individually impact bone. However, it is not clear how these factors interact to influence peak bone mass accrual. Here we tested whether genetically programmed high bone formation driven by missense mutations in the Lrp5 gene (Lrp5A214V) altered the sensitivity of mice to an environment of inadequate dietary calcium (Ca) intake. Weanling male Lrp5A214V mice and wildtype littermates (control) were fed AIN-93G diets with 0.125%, 0.25%, 0.5% (reference, basal), or 1% Ca from weaning until 12 weeks of age (ie, during bone growth). Urinary Ca, serum Ca, Ca regulatory hormones (PTH, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)), bone parameters (μCT, ash), and renal/intestinal gene expression were analyzed. As expected, low dietary Ca intake negatively impacted bones and Lrp5A214V mice had higher bone mass and ash content. Although bones of Lrp5A214V mice have more matrix to mineralize, their bones were not more susceptible to low dietary Ca intake. In control mice, low dietary Ca intake exerted expected effects on serum Ca (decreased), PTH (increased), and 1,25(OH)2D3 (increased) as well as their downstream actions (ie, reducing urinary Ca, increasing markers of intestinal Ca absorption). In contrast, Lrp5A214V mice had elevated serum Ca with a normal PTH response but a blunted 1,25(OH)2D3 response to low dietary Ca that was reflected in the renal 1,25(OH)2D3 producing/degrading enzymes, Cyp27b1 and Cyp24a1. Despite elevated serum Ca in Lrp5A214V mice, urinary Ca was not elevated. Despite an abnormal serum 1,25(OH)2D3 response to low dietary Ca, intestinal markers of Ca absorption (Trpv6, S100g mRNA) were elevated in Lrp5A214V mice and responded to low Ca intake. Collectively, our data indicate that the Lrp5A214V mutation induces changes in Ca homeostasis that permit mice to retain more Ca and support their high bone mass phenotype.

Using Clinical Simulation to Evaluate AI-Enabled Decision Support.

Clinical simulation is a useful method for evaluating AI-enabled clinical decision support (CDS). Simulation studies permit patient- and risk-free evaluation and far greater experimental control than is possible with clinical studies. The effect of CDS assisted and unassisted patient scenarios on meaningful downstream decisions and actions within the information value chain can be evaluated as outcome measures. This paper discusses the use of clinical simulation in CDS evaluation and presents a case study to demonstrate feasibility of its application.

IL-26 Potentiates Type 2 Skin Inflammation in the Presence of IL-1β

Atopic dermatitis (AD) is a debilitating inflammatory skin disorder. Biologics targeting the IL-4/IL-13 axis are effective in AD, but there is still a large proportion of patients that do not respond to IL-4R blockade. Further exploration of potentially pathogenic T cell-derived cytokines in AD may lead to new effective treatments. This study aimed to investigate the downstream effects of IL-26 on skin in the context of type 2 skin inflammation. We found that IL-26 alone exhibited limited inflammatory activity in skin. However, in presence of IL-1β, IL-26 potentiated the secretion of TSLP, CXCL1 and CCL20 from human epidermis through JAK/STAT signaling. Moreover, in an in vivo AD-like skin inflammation model, IL-26 exacerbated skin pathology and locally increased type 2 cytokines, most notably of Il13 in skin T helper cells. Neutralization of IL-1β abrogated IL-26-mediated effects, indicating that the presence of IL-1β is required for full IL-26 downstream action in vivo. These findings suggest that the presence of IL-1β enables IL-26 to be a key amplifier of inflammation in the skin. As such, IL-26 may contribute to the development and pathogenesis of inflammatory skin disorders such as AD.

Involvement of α-klotho in growth hormone (GH) signaling

Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-klotho was observed in the renal distal tubules and pituitary glands of somatostatin- and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.

A scoping study on the social determinants of health and sugar consumption in the context of policy approaches for improving population health.

To conduct a scoping review of existing research on the social determinants of health, sugar consumption and public health policy responses to address or improve health outcomes. A total of 13 categories were developed to reflect the authors' interest in the overall focus on the social determinants of health, sugar as an independent risk factor, upstream policy action ('whole populations'), downstream policy action ('targeted') and two contemporary policy strategies (namely 'Vulnerable populations' and 'Proportionate Universalism'). The search strategy was then performed on MEDLINE (via Ovid) and Web of Science, and was limited to the English language. No time limits prior to when the database search was conducted in 2022 were set to explore the full extent of the literature in this field. Five hundred and sixty articles were retrieved, of which 181 met the criteria for review. When all categories were applied, the findings showed that 76% of papers focusing on sugar consumption as a risk factor for non-communicable diseases (NCDs) mentioned the social determinants of health. The majority of studies (60%) recommended downstream interventions, with 40% recommending 'upstream' interventions. A limited proportion (12%) of research work was published in dental journals. Research had been done using predominantly quantitative methods (66% of articles), with 24% of studies adopting a mixed methods approach, and 8% being exclusively qualitative. Research on contemporary strategies for sugar reduction were focused on the 'Global North' and 98% of papers used individual level data focused on targeted approaches, highlighting that there is little direct evidence for contemporary strategies aimed at reducing sugar consumption. Whilst the majority of public and dental health research argues that there is a need to address the social determinants of health, the findings from this study highlight that very few empirical studies have been designed to directly inform contemporary strategies for sugar reduction. More research is therefore needed that can directly assess the evidence for contemporary strategies in public health policy.

Knowledge-guided pre-training and fine-tuning: Video representation learning for action recognition

Video-based action recognition is an important task in the computer vision community, aiming to extract rich spatial–temporal information to recognize human actions from videos. Many approaches adopt self-supervised learning in large-scale unlabeled datasets and exploit transfer learning in the downstream action recognition task. Though much progress has been made for action recognition with video representation learning, two main issues remain for most existing methods. Firstly, the pre-training with self-supervised pretext tasks usually learns neutral and not much informative representations for the downstream action recognition task. Secondly, the valuable learned knowledge from large-scaled pre-training datasets will be gradually forgotten in the fine-tuning stage. To address such issues, in this paper, we propose a novel video representation learning method with knowledge-guided pre-training and fine-tuning for action recognition, which incorporates external human parsing knowledge for generating informative representation in the pre-training, and preserves the pre-trained knowledge in the fine-tuning stage to avoid catastrophic forgetting via self-distillation. Our model, with contributions from the external human parsing knowledge, video-level contrastive learning, and knowledge preserving self-distillation, achieves state-of-the-art performance on two popular benchmarks, i.e., UCF101 and HMDB51, verifying the effectiveness of the proposed method.

A teacher–student deep learning strategy for extreme low resolution unsafe action recognition in construction projects

A large proportion of construction accidents are caused by workers’ unsafe actions. Due to the complexity of the work environment and excessive demands of safety supervision on construction sites, many modern information technologies, such as computer vision (CV) technologies, have been increasingly applied and gradually replaced the traditional manual supervision to automatically identify unsafe behaviors from surveillance video data. Current models focus on high resolution (HR) video containing high quality features. However, challenges remain for more specific real-world construction scenarios, including but not limited to lack of high-quality data, far-field video recognition, privacy protection, and limited computing resources. To address the challenges, in this paper, a simple but effective method relying on the Teacher–Student Learning Architecture is proposed, where the teacher network assists the student network in effectively capturing useful features for downstream action recognition from extreme low resolution (eLR) video which can be easily transferred to other tasks. In addition, a Knowledge Learning Model and a similarity loss function are proposed to better guide the training of student network. In numerical experiments and case studies, our proposed training strategy achieves an top-1 accuracy of 28.53% and 71.81% on eLR HMDB dataset and eLR CMA dataset, 5.96% and 3.89% higher than the baseline model. The proposed strategy can make the automatic safety monitoring of construction works more accurate and reliable, thereby effectively reducing the accident rate and management cost. In addition, the performance of proposed strategy depends on efficient knowledge distillation methods, which may inspire future applications of CV-based deep learning models in construction management to achieve higher recognition results while maintaining low computational cost.

A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.

Studies have established a correlation between α2-macroglobulin-like 1 (A2ML1) and the prognosis of lung, pancreatic, and breast cancers; however, research on its involvement in the pathogenesis of esophageal carcinoma remains limited. Therefore, in this study, we aimed to investigate the role of A2ML1 in the progression of esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining was employed to assess the expression level of A2ML1 protein in both tumor and adjacent normal tissues of patients with ESCC. The Kaplan-Meier method, along with univariate and multivariate Cox risk ratio analyses, was used to determine survival rates and prognostic factors. Furthermore, two human ESCC cell lines, KYSE30 and KYSE150, were used to assess the effect of A2ML1 overexpression on cell proliferation and apoptosis. A human apoptosis antibody kit was also used to analyze the downstream action proteins of A2ML1, and a nude mouse xenotransplantation model was used to evaluate the effect of A2ML1 on ESCC tumorigenesis in vivo. The protein level of A2ML1 in ESCC tissues was significantly lower than that in normal esophageal tissues, and higher A2ML1 protein levels were associated with smaller ESCC tumor sizes and improved tumor-specific survival rates. Multivariate analysis established A2ML1 as a novel independent prognostic factor for ESCC. Moreover, A2ML1 overexpression significantly inhibited ESCC cell proliferation and promoted apoptosis. A2ML1 consistently inhibited tumor growth in mouse models. Furthermore, the human apoptotic antibody kit results showed increased expression of the proliferation-inhibiting protein p21 downstream of KYSE150 cells overexpressing A2ML1. Our findings demonstrate that a correlation exists between A2ML1 and ESCC prognosis and that A2ML1 plays an antitumor role in ESCC progression. This study underscores the potential of A2ML1 as a novel biomarker for predicting the prognosis of ESCC.

Irish consumers attitudes and behaviors to transitioning to more sustainable dietary

Abstract Background The evidence on the environmental, socio-cultural and economic impacts of current diets highlights the need for countries to develop food based dietary guidelines incorporating sustainability. This study assessed consumers current beliefs, attitudes, and behaviours to transitioning to more sustainable dietary practices. Methods An online quantitative survey was developed. An all-Island sample in Ireland, representative of national age and gender distribution was recruited by Qualtrics XM market research company. Ethical approval for the study was granted by the Social Research Ethics Committee of UCC and reaffirmed by Queens University Belfast. Data were analysed using STATA SE Version 17.0. Results Affordability, accessibility, nutrition, and health were the most important characteristics of sustainable diets reported by participants that influence food purchases. Almost half of respondents were not interested in eating less animal-based food (45%) and more plant-based foods (51%). However, 22% reported to have started reducing red and processed meat consumption ‘some of the time'. The most popular sustainable dietary behaviours that people were already engaged with are: eating more home-cooked meals (59%), reducing food waste through prevention (41%), and eating less discretionary foods (55%). Conclusions Facilitating dietary change is a critical component of the transition towards more sustainable diets. A multi-pronged strategy is needed to transition to food environments that empower people to choose healthier and more sustainable options. This includes downstream actions at the individual level, including awareness and education campaigns, but more importantly upstream where strong leadership through public policies taking a whole of population approach is imperative. Key messages • Much work has to be done to reconnect human and ecological health, building awareness and knowledge of sustainable diets, and to make the more sustainable choice the easier, and acceptable choice. • Affordability, accessibility and nutrition and health are important characteristics of sustainable diets influencing food purchases. These need to be considered in the development of key messages.

Targeted metabolome and transcriptome analyses reveal changes in gibberellin and related cell wall-acting enzyme-encoding genes during stipe elongation in Flammulina filiformis.

Flammulina filiformis, a typical agaric fungus, is a widely cultivated and consumed edible mushroom. Elongation of its stipe (as the main edible part) is closely related to its yield and commercial traits; however, the endogenous hormones during stipe elongation and their regulatory mechanisms are not well understood. Gibberellin (GA) plays an important role in the regulation of plant growth, but little has been reported in macro fungi. In this study, we first treated F. filiformis stipes in the young stage with PBZ (an inhibitor of GA) and found that PBZ significantly inhibited elongation of the stipe. Then, we performed GA-targeted metabolome and transcriptome analyses of the stipe at both the young and elongation stages. A total of 13 types of GAs were detected in F. filiformis; the contents of ten of them, namely, GA3, GA4, GA8, GA14, GA19, GA20, GA24, GA34, GA44, and GA53, were significantly decreased, and the contents of three (GA5, GA9, and GA29) were significantly increased during stipe elongation. Transcriptome analysis showed that the genes in the terpenoid backbone biosynthesis pathway showed varying expression patterns: HMGS, HMGR, GPS, and FPPS were significantly upregulated, while CPS/KS had no significant difference in transcript level during stipe elongation. In total, 37 P450 genes were annotated to be involved in GA biosynthesis; eight of them were upregulated, twelve were downregulated, and the rest were not differentially expressed. In addition, four types of differentially expressed genes involved in stipe elongation were identified, including six signal transduction genes, five cell cycle-controlling genes, twelve cell wall-related enzymes and six transcription factors. The results identified the types and content of GAs and the expression patterns of their synthesis pathways during elongation in F. filiformis and revealed the molecular mechanisms by which GAs may affect the synthesis of cell wall components and the cell cycle of the stipe through the downstream action of cell wall-related enzymes, transcription factors, signal transduction and cell cycle control, thus regulating stipe elongation. This study is helpful for understanding the roles of GAs in stipe development in mushrooms and lays the foundation for the rational regulation of stipe length in agaric mushrooms during production.

DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway.

Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.