Search

BACKGROUND & AIMS: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Here we aimed to reconcile these conflicting reports by repeating a key lineage tracing study from pericentral hepatocytes and characterised this Axin2CreERT2 model in detail.METHODS: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in depth phenotypic comparison including transcriptomics, metabolomics and analysis of protein through immunohistochemistry of Axin2CreERT2 mice to WT counterparts.RESULTS: We find that after careful definition of a baseline population there is marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We find substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance.CONCLUSIONS: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci.

Number needed to treat (NNT) is a clinically useful "yardstick" used to gauge the efficacy of therapeutic interventions. The objective of this project was to develop and pilot a series of pictograms and assess their impact on pharmacist understanding of the NNT.Three decision aids containing NNT pictograms were developed following a preliminary literature review and three focus groups with current Australian-registered pharmacists and pharmacist interns. Pharmacists then tested the pictograms in a research pilot in clinical encounters until (1) ≥ 3 sessions had occurred or (2) a two-week period had elapsed from commencement. Knowledge assessment was administered both pre- and post-pilot. Transcription and inductive thematic analysis were applied to focus group data. Descriptive statistics, Wilcoxon signed rank, and McNemar's tests were used to analyse the pilot data.Six core themes regarding NNT decision aid development were identified with80% consensus across three focus groups (N = 11). Comparison of the pre-post measures (n = 10) showed an increase in median scores after use of NNT decision aids, correlating to a moderate Cohen classified effect size (d = 0.54). Wilcoxon matched pairs test demonstrated a statistically insignificant influence of NNT pictograms on the knowledge assessment survey (P .05).While the NNT is not a new concept, its incorporation as part of pictograms for health practitioner enrichment is novel. This pilot study suggests that utilizing decision aids with NNT pictograms as counselling adjuncts appears promising in the realm of enhancing pharmacists' understanding of the NNT.

Throughout the COVID-19 pandemic governments across the world including in France, Canada, Lithuania, Austria, Italy, and Ireland imposed ‘vaccine passports’ on the premise that they would curtail transmission of the virus, reduce COVID-19 related mortalities, and enable society to return to neoliberal normality. However, vaccine passports raise several important and troubling issues that have not been given sufficient attention within the social sciences. Therefore, this article offers a critique of vaccine passports. It is structured into three key themes: (a) scientifically and ethically problematic, (b) the death of the social and the ‘Other’, and (c) digital surveillance and freedom. The article begins by exploring how vaccine passports make little scientific sense and further entrench some unvaccinated peoples’ sense of political and medical mistrust. It then discusses how they amplify social divisions, creating the unvaccinated Other in society and intensifying the neoliberal shift towards a post-social, contactless world. The paper closes with an outline of how vaccine passports were cast as enabling a return to neoliberal normality and freedom, hinging upon an assumption of harmlessness while cementing the negative ideology of capitalist realism.

This article explores the problem of sleep deprivation amongst migrant workers in North East England’s night-time economy (NTE). After first outlining some of the physical and psychological effects of sleep loss, the narrative then focuses on primary accounts drawn from unstructured interviews (n = 16) and short vignettes with migrant workers. The article uses a framework grounded in social harm to explicate the declining recognition afforded to sleep and recuperation among night workers, constructing this as a socially corrosive outcome of neoliberal economic relations and the cultural injunctions that accompany it. The forfeiture of sleep among workers can also form an important point of departure for exploring a nexus of harms that suffuse the nocturnal service industry for low-paid migrant workers. These can have far-reaching consequences for well-being, as they expose the fraying of labour relations in the NTE and act as an affront to the possibility of human flourishing.

COVID-19 and the resulting limitations on freedom of movement has been difficult for many, including individuals living with dementia and those who provide support and care. In the summer of 2021, England’s national lockdown measures eased, and regulations were amended to allow indoor social gatherings. With this enabling a return to in-person meetings, this study explored the experiences of people living with dementia and current and former care partners who had previously attended groups at Salford Institute for Dementia (UK). Two phases of research were conducted. In the first phase, during the summer of 2020, telephone interviews were utilised to ask participants ( n = 13) about their views of re-engagement and how the in-person groups might be best reintroduced. Phase two began in the summer of 2021, where mood questionnaires ( n = 10) were administered and observations conducted to explore how participants experienced the return to in-person meetings. Thematic analysis resulted in the construction of three overarching themes: planning for and the reality of transitioning; safety versus autonomy; and tensions and complexities of life in the ‘new normal’. Despite initial concerns about their reintegration into the community, participants all enjoyed resuming in-person meetings. An inclusive and consultative approach to re-engagement allowed all participants to feel valued, safe, and informed about their return to campus. However, individuals living with dementia and care partners experienced the transition to re-engagement in different ways and their perceptions shifted over time. We therefore highlight the complexities of responding to different perceptions of risk and safety, while also promoting engagement and inclusivity after a period of social isolation. In this paper, we consider implications for the re-integration of individuals with dementia and their care partners into in-person social groups and propose further avenues for research.

A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis involves the translation of codons within the mRNA coding sequence into a string of amino acids to form a polypeptide chain. As most amino acids are encoded by multiple codons, the nucleotide sequence of a coding region can vary dramatically without altering the polypeptide sequence of the encoded protein. Although mutations that do not alter the final amino acid sequence are often thought of as silent/synonymous, these can still have dramatic effects on protein output. Because each codon has a distinct translation elongation rate and can differentially impact mRNA stability, each codon has a different degree of ‘optimality’ for protein synthesis. Recent data demonstrates that the codon preference of a transcriptome matches the abundance of tRNAs within the cell and that this supply and demand between tRNAs and mRNAs varies between different cell types. The largest observed distinction is between mRNAs encoding proteins associated with proliferation or differentiation. Nevertheless, precisely how codon optimality and tRNA expression levels regulate cell fate decisions and their role in malignancy is not fully understood. This review describes the current mechanistic understanding on codon optimality, its role in malignancy and discusses the potential to target codon optimality therapeutically in the context of cancer.

Cet article est le premier de deux textes interdépendants issus d’un projet fondé par l’AHRC (R.-U.), Chronotopic Cartographies, dont le but est de cartographier les lieux et l’espace de la littérature. Il cherche à établir la valeur d’une approche topologique pour la cartographie de textes littéraires. Centré sur le concept bakhtinien de chronotope, ou relation espace-temps, qui sert de fondement à la cartographie numérique de la signification spatiale dans les œuvres littéraires, il s’ouvre sur la contextualisation de notre travail en relation au domaine de la géographie et de la cartographie littéraires. Puis il trace une distinction claire entre la cartographie du monde réel au moyen des SIG (comme cela se fait couramment en histoire ou en géographie, par exemple) et la cartographie relative au moyen de topologies, qui est essentielle selon nous à la cartographie des lieux et de l’espace fictionnels. Les modèles numériques actuels qui se rapprochent le plus de ce projet concernent l’analyse des réseaux sociaux et son adaptation à la cartographie des réseaux des personnages dans les textes littéraires. Après la contextualisation de notre travail en relation à ce projet de recherche, nous argumentons en faveur de l’utilisation des modèles topologiques en cartographie littéraire. Une variété de formes topologiques et leur signification pour la littérature sont ensuite examinées dans leurs rapports avec des exemples particuliers tirés du projet Chronotopic Cartographies.

Background: While stroke is becoming increasingly prevalent in young people (Objectives: The purpose of this study was to characterise and appreciate the experience of young stroke survivors. Methods: Qualitative in-depth semi-structured interviews were conducted with 11 stroke survivors aged between 18 and 49 (via virtual conferencing software). Interview data were analysed using interpretative phenomenological analysis. Results: Young stroke survivors experience a sense of alienation when healthcare providers imply their stroke is an anomaly and are surrounded by elderly patients in stroke units. Alienation and additional emotional concerns, coupled with memory and communication difficulties, compromised survivors’ sense of agency. Many participants also developed and exhibited resilience, gratitude, and acceptance, preserving their mental health. Conclusions: The experience of young stroke survivors is distinct. By considering the unique trajectory of young stroke survivors, health services will be better able to facilitate the rehabilitation of this population.

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes which link substrate release and opening of the cytoplasmic gate, and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Standing wave (SW) microscopy is a method that uses an interference pattern to excite fluorescence from labelled cellular structures and produces high-resolution images of three-dimensional objects in a two-dimensional dataset. SW microscopy is performed with high-magnification, high-numerical aperture objective lenses, and while this results in high-resolution images, the field of view is very small. Here we report upscaling of this interference imaging method from the microscale to the mesoscale using the Mesolens, which has the unusual combination of a low-magnification and high-numerical aperture. With this method, we produce SW images within a field of view of 4.4 mm × 3.0 mm that can readily accommodate over 16,000 cells in a single dataset. We demonstrate the method using both single-wavelength excitation and the multi-wavelength SW method TartanSW. We show application of the method for imaging of fixed and living cells specimens, with the first application of SW imaging to study cells under flow conditions.

All supplemental figures and legends

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC–dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application.Significance:KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995

There is considerable literature on autism but a paucity of literature on social work with autistic people. This is surprising when autistic people may be overrepresented in the populations that social workers assess and support. This article reports the findings from a qualitative study exploring social workers’ perceptions of training needs about autism through two focus groups involving social workers. Social workers frequently engage with autistic people, either as practitioners in specialist teams but more frequently through generic adult and/or childcare services; therefore, awareness of autism is important. Autism is complex because it is sometimes hidden, which is exacerbated when autistic people may mask and camouflage their autism and any difficulties they experience. Data from the focus groups were thematically analysed to identify themes that highlight how social workers benefit from training about autism and how to work with autistic people, which includes training from autistic people and others with lived experience. The authors of this article represent different perspectives: the first author is a social work educator with over three decades’ practice and personal autism experience, and the second author is a social work manager and practitioner in a specialist service.

Targeted sequencing of untreated DLBCL and TLy

Targeted capture sequencing

targeted sequencing results of rrDLBCL

Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell–type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290–300. ©2015 AACR.

Supplemental methods Supplemental Figures Supplemental Figure S1. Overview of somatic copy number alterations in rrDLBCLs. Supplemental Figure S2. Consistent low coverage in the first exon of FOXO1. Supplemental Figure S3. Overview of FOXO1 mutations in rrDLBCLs. Supplemental Figure S4. VAFs corrected using purity estimates. Supplemental Figure S5. Somatic copy number alterations affecting lymphoma-related genes. Supplemental Figure S6: Recurrent deletions in NFKBIE. Supplemental Tables Supplemental Table S1. Clinical details and sample processing of 38 patients with relapsed or refractory DLBCL and TLy Supplemental Table S2. Characteristics of samples used for exome sequencing and targeted sequencing of selected genes.

exome sequencing results of rrDLBCL

Standing wave (SW) microscopy is a method that uses an interference pattern to excite fluorescence from labelled cellular structures and produces high-resolution images of three-dimensional objects in a two-dimensional dataset. SW microscopy is performed with high magnification, high numerical aperture objective lenses, and while this results in high resolution images, the field of view is very small. Here we report upscaling of this interference imaging method from the microscale to the mesoscale using the Mesolens, which has the unusual combination of a low magnification and high numerical aperture. With this method, we produce SW images within a field of view of 4.4 mm x 3.0 mm that can readily accommodate over 16,000 cells in a single dataset. We demonstrate the method using both single-wavelength excitation and the multi-wavelength SW method TartanSW. We show application of the method for imaging of fixed and living cells specimens, with the first application of SW imaging to study cells under flow conditions.

Disorders of the central nervous system (CNS) represent a global health challenge and an increased understanding of the CNS in both physiological and pathophysiological states is essential to tackle the problem. Modelling CNS conditions is difficult, as traditional in vitro models fail to recapitulate precise microenvironments and animal models of complex disease often have limited translational validity. Microfluidic and organ-on-chip technologies offer an opportunity to develop more physiologically relevant and complex in vitro models of the CNS. They can be developed to allow precise cellular patterning and enhanced experimental capabilities to study neuronal function and dysfunction. To improve ease-of-use of the technology and create new opportunities for novel in vitro studies, we introduce a modular platform consisting of multiple, individual microfluidic units that can be combined in several configurations to create bespoke culture environments. Here, we report proof-of-concept experiments creating complex in vitro models and performing functional analysis of neuronal activity across modular interfaces. This platform technology presents an opportunity to increase our understanding of CNS disease mechanisms and ultimately aid the development of novel therapies.

Consumer stockpiling from pharmacies has been reported by media outlets throughout the course of COVID-19.This study evaluated pharmacists' perceptions of consumer stockpiling from pharmacies, the impact of stockpiling, aggressive or hostile behaviour from customers and preparedness for COVID-19 and future pandemics.A self-administered survey was disseminated between September and November of 2020. The survey comprised four major sections: demographic information, experiences of consumer stockpiling, impact of consumer stockpiling and preparedness for COVID-19 and future pandemics. Survey results were analysed in Microsoft Excel using descriptive statistics.Of the 56 responses analysed, most pharmacists observed consumer stockpiling of over-the-counter products (98.2%), schedule 2 and schedule 3 medications (92.8%) and prescription only medications (94.6%). The most commonly stockpiled items included face masks, hand-sanitisers and wipes, alcohol wipes and antiseptic solutions, thermometers, paracetamol and salbutamol inhalers. Patients also requested the dispensing of several months' supply of regular prescription medications. Customer aggression was observed by 53.6% of pharmacists, with 63% of pharmacists agreeing that hostile behaviour impeded their practice. Only 36.7% of pharmacists felt adequately prepared to cope with the challenges of COVID-19.Consumer stockpiling from pharmacies was observed throughout COVID-19. Stockpiling as well as aggressive and hostile behaviour from customers affected pharmacists, their staff, business and other pharmacy customers. Additional studies are needed to investigate the severity of these issues and to inform policy changes to help mitigate consumer stockpiling and prepare the pharmacy profession for future pandemics.

IntroductionThe human body's response to pain is indicative of a complex adaptive system. Therapeutic yoga potentially represents a similar complex adaptive system that could interact with the pain response system with unique benefits.ObjectivesTo determine the viability of yoga as a therapy for pain and whether pain responses and/or yoga practice should be considered complex adaptive systems.MethodsExamination through 3 different approaches, including a narrative overview of the evidence on pain responses, yoga, and complex system, followed by a network analysis of associated keywords, followed by a mapping of the functional components of complex systems, pain response, and yoga.ResultsThe narrative overview provided extensive evidence of the unique efficacy of yoga as a pain therapy, as well as articulating the relevance of applying complex systems perspectives to pain and yoga interventions. The network analysis demonstrated patterns connecting pain and yoga, while complex systems topics were the most extensively connected to the studies as a whole.ConclusionAll three approaches support considering yoga a complex adaptive system that exhibits unique benefits as a pain management system. These findings have implications for treating chronic, pervasive pain with behavioral medicine as a systemic intervention. Approaching yoga as complex system suggests the need for research of mind-body topics that focuses on long-term systemic changes rather than short-term isolated effects.

Plant development depends on coordination of growth between different cell layers. Coordination may be mediated by molecular signalling or mechanical connectivity between cells, but evidence for genetic control via direct mechanics has been lacking. We show that a brassinosteroid-deficient dwarf mutant of the aquatic plantUtricularia gibbahas twisted internal tissue, likely caused by a mechanical constraint from a slow-growing epidermis creating tissue stresses. This conclusion is supported by showing that inhibition of brassinosteroid action in anArabidopsismutant compromised for cell adhesion, enhances epidermal crack formation, an indicator of increased tissue tension. Thus, genes driving brassinosteroid synthesis can promote growth of internal tissue by reducing mechanical epidermal constraint, showing that tissue mechanics plays a key role in coordinating growth between cell layers.One-Sentence SummaryInternal twists in a mutant carnivorous plant reveal how genes control growth via tissue mechanics.

Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5’UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5’UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.

Supplemental Document

Using concepts from transport and management literature, this thesis provides new insight into policy and management direction into facilitating public transport integration through platforms post Mobility-as-a-Service. Integration discussions are extended via ecosystems and organisational networks that harness actor self-interest to generate service collaboration. The central problem is the effectiveness of public transport systems and its competitive position compared to the private car. Improvements in public transport integration achieved through operator collaboration may provide better transport options for consumers. Transport integration and the failure of broker model MaaS reveals inherent conflicts, concluding sustainability of business models has not been achieved. Integrated ticketing systems show nascent signs of integrating public transport, such as facilitating fare calculation (including discounts) across different operators. Consumers want institutional integration to be undertaken across a wide range of transport consumption, whether for local trips in their own city or in trips that cross geographic lines. Consumers would choose transport options that involve operator collaboration when facilitated by an institutionalised integration system. Consumers would pay for attributes delivered by collaboration (such as reduced transfer times) across both intra-city and inter-city journeys. Operator collaboration is not extensive. Network and proximity theories, explain collaboration through organisational, social, cognitive and technological proximities. Institutional proximity provides stronger explanations, however a new proximity, commercial, explains network formation and collaboration failures. Commercial focus and formal network governance may guide and cultivate the ecosystem for the betterment of all participants.

[Para. 1 of Introduction]: Migration is shaping societies around the world. It has long defined settler countries, such as Canada; it is affecting communities of departure and return, ranging from the Azores to Zimbabwe; and it is increasingly impacting countries that have traditionally not considered themselves as major immigrant destinations, like many European countries. Meanwhile, individual migrants and their families experience departure, migration, and arrival differently than the communities shaped by them. From both societal and individual perspectives, we can ask whether migration accomplishes what it promises to achieve. Does migration contribute to the economic, social, and cultural well-being of societies? Do migrants and their families find a pathway to security, achieve social and economic upward mobility, and gain opportunities to participate in the political and cultural life of their arrival communities? The Promise of Migration addresses these questions through a critical lens.

The Critically Endangered southern corroboree frog Pseudophryne corroboree is dependent upon captive assurance colonies for its continued survival. Although the captive breeding programme for this species has largely been successful, embryonic mortality remains high (40-90% per year). This study aimed to investigate the causes of mortality in P. corroboree embryos in the captive collection at Melbourne Zoo. During the 2021 breeding season, we investigated 108 abnormal embryos to determine the impact of infections and anatomical deformities on survival and used culture and molecular methods to identify microbes. Overall, 100% of abnormal embryos had fungal infections, and of these, 41.6% also had anatomical deformities. The mortality rate in abnormal embryos was 89.8%; however, we detected no difference in survival in any of the 3 observed fungal growth patterns or between deformed and non-deformed embryos. Sanger sequencing of the ITS region identified fungal isolates belonging to the genus Ilyonectria, the first record in a vertebrate host, and another as a Plectosphaerella sp., which is the first record of infection in an embryo. Dominant bacteria identified were of the genera Herbaspirillum and Flavobacterium; however, their role in the mortality is unknown. Fungal infection and deformities have a significant impact on embryo survival in captive-bred P. corroboree. In a species which relies on captive breeding, identifying and reducing the impacts of embryonic mortality can inform conservation efforts and improve reintroduction outcomes.

Effective grazing management in Australia’s semi-arid rangelands requires monitoring landscape conditions and identifying sustainable and productive practice through understanding the interactions of environmental factors and management of soil health. Challenges include extreme rainfall variability, intensifying drought, and inherently nutrient-poor soils. We investigated the impacts of grazing strategies on landscape function—specifically soil health—as the foundation for productive pastures, integrating the heterogenous nature of grass tussocks and the interspaces that naturally exist in between them. At Wambiana—a long-term research site in north-eastern Australia—we studied two soil types, two stocking rates (high, moderate), and resting land from grazing during wet seasons (rotational spelling). Rotational spelling had the highest biocrust (living soil cover), in interspaces and under grass tussocks. Biocrusts were dominated by cyanobacteria that binds soil particles, reduces erosion, sequesters carbon, fixes nitrogen, and improves soil fertility. Rotational spelling with a moderate stocking rate emerged as best practice at these sites, with adjustment of stocking rates in line with rainfall and soil type recommended. In drought-prone environments, monitoring the presence and integrity of biocrusts connects landscape function and soil health. Biocrusts that protect and enrich the soil will support long-term ecosystem integrity and economic profitability of cattle production in rangelands.

Stratospheric water vapor affects the Earth's radiative balance and stratospheric chemistry, yet its future changes are uncertain and not fully understood. The influence of deep convection on stratospheric water vapor remains subject to debate. This letter presents a detailed process‐based model study of the impact of convective ice sublimation on stratospheric water vapor in response to CO2 forced climate change. The influence of convective injection is found to be limited by the vertical profile of temperature and saturation vapor pressure in the tropical tropopause layer, not by the frequency of occurrence. Lagrangian trajectory analysis shows the relative contributions to stratospheric water vapor from sublimation and large‐scale transport are approximately unchanged when CO2 is increased. The results indicate the role of convective ice injection for stratospheric water vapor in a warmer climate remains constrained by large‐scale temperatures.

The resilience of the food supply system has become a vital issue for many countries especially under substantial international supply disturbances (e.g. the effects of COVID-19 restrictions). Regionalizing diets and increasing food self-sufficiency contribute greatly to shortening food supply chains and, therefore, to increasing the resilience of the food system. Simultaneously, food supply disturbances can offer a chance for food system transition toward implementing sustainable management practices in agriculture (e.g. organic farming), increasing the sustainability of food production. In this study, we have proposed a foodshed for the cities of Vienna and Bristol, delineating the spatial extent for such a regionalization and self-sufficiency discussion. We used the Metropolitan Foodshed and Self-sufficiency Scenario model to assess the potential self-sufficiency of these areas under different pathways involving more sustainable and resilient food system scenarios by distinguishing: i) The regionalization, ii) production system, iii) food losses and wastage, and iv) population growth until 2050. Furthermore, we have found the main local food policies and studies involving both cities, linking them to the current self-sufficiency levels and proposing pathways to increase them. Our results suggest that the foodsheds proposed are suitable to achieve a high degree of potential self-sufficiency when shifting consumers’ behavior toward sustainably produced regional products, and reducing food wastes in households and food losses in agriculture. This should be accompanied in parallel by an increase in the diversification of regional crop production managed sustainably. We call for the adoption of the foodshed approach – based on the concept of sustainable city region food systems – so that it can be integrated into the food policies to increase food self-sufficiency sustainably.

Ryan D Castle,1 Michelle A Williams,2 William C Bushell,3 J Adam Rindfleisch,4 Christine Tara Peterson,5 James Marzolf,6 Kimberly Brouwer,7 Paul J Mills8 1Science Division, Whole Health Institute, Bentonville, AR, USA; 2Harvard T.H. Chan School of Public Health, Department of Global Health and Population, Harvard University, Boston, MA, USA; 3Science Division, Whole Health Institute, New York, NY, USA; 4Education Department, Whole Health School of Medicine and Health Sciences, Bentonville, AR, USA; 5Center of Excellence for Research and Training in Integrative Health, Department of Family Medicine, School of Medicine, University of California, San Diego, CA, USA; 6Health Sector Finance & Policy, Whole Health Institute, Bentonville, AR, USA; 7Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, CA, USA; 8Herbert Wertheim School of Public Health and Human Longevity Science, Center of Excellence for Research and Training in Integrative Health, University of California, San Diego, CA, USACorrespondence: Ryan D CastleScience Division, Whole Health Institute, 900 McClain Road, Bentonville, AR, 72712, USAEmail rcastle@wholehealth.orgIntroduction: COVID-19 poses a chronic threat to inflammatory systems, reinforcing the need for efficient anti-inflammatory strategies. The purpose of this review and analysis was to determine the efficacy of various interventions upon the inflammatory markers most affected by COVID-19. The focus was on the markers associated with COVID-19, not the etiology of the virus itself.Methods: Based on 27 reviewed papers, information was extracted on the effects of COVID-19 upon inflammatory markers, then the effects of standard treatments (Remdesivir, Tocilizumab) and adjunctive interventions (vitamin D3, melatonin, and meditation) were extracted for those markers. These data were used to approximate effect sizes for the disease or interventions via standardized mean differences (SMD).Results: The data that were available indicated that adjunctive interventions affected 68.4% of the inflammatory markers impacted by COVID-19, while standard pharmaceutical medication affected 26.3%.Discussion: Nonstandard adjunctive care appeared to have comparable or superior effects in comparison to Remdesivir and Tocilizumab on the inflammatory markers most impacted by COVID-19. Alongside standards of care, melatonin, vitamin D3, and meditation should be considered for treatment of SARS-COV-2 infection and COVID-19 disease.Keywords: COVID-19, inflammation, cytokine storm, effect size, antivirals, corticosteroids, melatonin, vitamin D, meditation, whole health

Introduction COVID-19 poses a chronic threat to inflammatory systems, reinforcing the need for efficient anti-inflammatory strategies. The purpose of this review and analysis was to determine the efficacy of various interventions upon the inflammatory markers most affected by COVID-19. The focus was on the markers associated with COVID-19, not the etiology of the virus itself. Methods Based on 27 reviewed papers, information was extracted on the effects of COVID-19 upon inflammatory markers, then the effects of standard treatments (Remdesivir, Tocilizumab) and adjunctive interventions (vitamin D3, melatonin, and meditation) were extracted for those markers. These data were used to approximate effect sizes for the disease or interventions via standardized mean differences (SMD). Results The data that were available indicated that adjunctive interventions affected 68.4% of the inflammatory markers impacted by COVID-19, while standard pharmaceutical medication affected 26.3%. Discussion Nonstandard adjunctive care appeared to have comparable or superior effects in comparison to Remdesivir and Tocilizumab on the inflammatory markers most impacted by COVID-19. Alongside standards of care, melatonin, vitamin D3, and meditation should be considered for treatment of SARS-COV-2 infection and COVID-19 disease., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/2i2QG5lT0JI

Lower urinary tract, renal, and bloodstream infections caused by phylogroup B2 extraintestinal pathogenic Escherichia coli (ExPEC) are a leading cause of morbidity and mortality. ST1193 is a phylogroup B2, multidrug-resistant sequence type that has risen to prominence globally, but a comprehensive analysis of the F virulence plasmids it carries is lacking. We performed a phylogenomic analysis of ST1193 (n = 707) whole-genome sequences from EnteroBase using entries with comprehensive isolation metadata. The data set comprised isolates from humans (n = 634 [90%]), including 339 (48%) from extraintestinal infection sites, and isolates from companion animals, wastewater, and wildlife. Phylogenetic analyses combined with gene detection and genotyping resolved an ST1193 clade structure segregated by serotype and F plasmid carriage. Most F plasmids fell into one of three related plasmid subtypes: F-:A1:B10 (n = 444 [65.97%]), F-:A1:B1 (n = 84 [12.48%]), and F-:A1:B20 (n = 80 [11.89%]), all of which carry the virulence genes cjrABC colocalized with senB (cjrABC-senB), a trademark signature of F29:A-:B10 subtype plasmids (pUTI89). To examine the phylogenetic relationship of these plasmids with pUTI89, complete sequences of F-:A1:B1 and F-:1:B20 plasmids were resolved. Unlike pUTI89, the most dominant and widely disseminated F plasmid that carries cjrABC-senB, F plasmids in ST1193 often carry a complex resistance region with an integron truncation (intI1Δ745) signature embedded within a structure assembled by IS26. Plasmid analysis shows that ST1193 has F plasmids that carry cjrABC-senB and ARG-encoding genes but lack tra regions and are likely derivatives of pUTI89. Further epidemiological investigation of ST1193 should seek to confirm its presence in human-associated environments and identify any potential agricultural links, which are currently lacking. IMPORTANCE We have generated an updated ST1193 phylogeny using publicly available sequences, reinforcing previous assertions that Escherichia coli ST1193 is a human-associated lineage, with many examples sourced from human extraintestinal infections. ST1193 from urban-adapted birds, wastewater, and companion animals are frequent, but isolates from animal agriculture are notably absent. Phylogenomic analysis identified several clades segregated by serogroup, all noted to carry highly similar F plasmids and antimicrobial resistance (AMR) signatures. Investigation of these plasmids revealed virulence regions with similarity to pUTI89, a key F virulence plasmid among dominant pandemic extraintestinal pathogenic E. coli lineages, and encoding a complex antibiotic resistance structure mobilized by IS26. This work has uncovered a series of F virulence plasmids in ST1193 and shows that the lineage mimics the host range and virulence attributes of other E. coli strains that carry pUTI89. These observations have significant ramifications for epidemiological source tracking of emerging and established pandemic ExPEC lineages.

A Code Red has been declared for the planet and human health. Climate change (e.g., increasing temperatures, adverse weather events, rising sea levels) threatens the planet's already declining ecosystems. Without urgent action, all of Earth's inhabitants face an existential threat. Health professions education should therefore prepare learners to not only practice in a changing world, but authentic educational activities should also develop competencies for global and planetary citizenship. Planetary health has been integrated across the five-year Bond University (Australia) medical curriculum. It begins in the second week of Year 1 and ends with a session on Environmentally Sustainable Healthcare in the General Practice rotation in the final year. The purpose of this article is to describe the outcomes of the first 5 years (2018–2022) of a learner-centered planetary health assignment, underpinned by the 2030 United Nations (UN) Sustainable Development Goals (SDGs), in the second year of a five-year medical program. Using systems and/or design thinking with a focus on SDG13 (Climate Action) plus a second SDG of choice, self-selected teams of 4–6 students submit a protocol (with feedback) to develop a deliverable “product” for an intended audience. Data analysis of the first 5 years of implementation found that the most frequently selected SDGs in addition to SDG13 were: SDG12 Sustainable Production and Consumption (41% of teams), mostly relating to healthcare emissions and waste; SDG3 Health and Well-being (22%), generally involving the impact of air pollution; and SDG6 Clean Water and Sanitation (15%). A survey at the concluding conference garnered student feedback across various criteria. The planetary health assignment is authentic in that teams provide solutions to address climate change. Where appropriate, final “products” are sent to local or federal ministers for consideration (e.g., policy proposals) or integrated into the curriculum (e.g., learning modules). We believe that the competencies, attitudes, and values fostered through engagement with planetary health. Throughout the medical program, as evidenced by their evaluations, stands students in good stead to be change agents, not only in clinical practice but in society. An awareness has been created about the need for planetary citizenship in addition to global citizenship.

Background: Vaccine pharmacovigilance is at the forefront of the public eye. Shoulder Injuries Related to Vaccine Administration (SIRVA) is a poorly understood Adverse Event Following Immunisation, with iatrogenic origins. Criteria for medicolegal diagnosis of SIRVA is conflicting, current literature and educational materials are lacking, and healthcare practitioner knowledge of the condition is unknown. Methods: A cross-sectional, convenience sampled survey, utilising a validated online questionnaire assessed practitioner knowledge of SIRVA, safe injecting, and upper limb anatomy, and preferred definition for SIRVA. Results: Mean scores were moderate for safe injecting knowledge (69%), and poor for knowledge of anatomy (42%) and SIRVA (55%). Non-immunising healthcare practitioners scored significantly (p = 0.01, and < 0.05, respectively) higher than immunising practitioners for anatomy (2.213 ± 1.52 vs. 3.12 ± 1.50), and safe injecting knowledge (6.70 ± 1.34 vs. 7.14 ± 1.27). Only 52% of authorised vaccinators accurately selected a 40 × 20 mm area recommended for safe injecting. Majority (91.7%) of respondents thought nerve injuries should be included in the diagnostic criteria for SIRVA. Discussion and conclusions: Greater education and awareness of SIRVA is needed in all healthcare disciplines. Consensus regarding SIRVA definition is paramount for accurate reporting and improved future understanding of all aspects of SIRVA.

Background: COVID-19 impacted higher education (HE) students studying health degrees with an embedded placement in a unique way. At the height of the pandemic AHPRA declared that health students completing placements were required to be vaccinated against COVID-19 and be competent at providing advice and information about the COVID-19 vaccine to the public. It is yet to be determined if there is hesitancy amongst students studying health degrees. This study aimed to determine if offering an evidence-based targeted educational intervention changes health student knowledge, attitudes, and willingness to have the vaccine. Methods: An evidence-based educational intervention was developed and delivered to students studying health. A purpose developed survey was designed to assess health students’ knowledge, and willingness to have the COVID-19 vaccine, before and after this targeted educational intervention. Results: A total of 290 students from eight health disciplines completed the intervention and pre- and post-surveys. Analyses demonstrated a statistically significant increase in participants’ willingness to receive the COVID-19 vaccine, and how confident participants felt about explaining Covid vaccines and their safety, with an increase in accuracy of knowledge about professional responsibility. Conclusion: This study shows that targeted educational intervention can positively influence HE health care students. Increasing the knowledge and confidence of our trainee health professionals is paramount to enable them to be sources of accurate information and advice in relation to Covid vaccination.

This article is a preprint and has not been certified by peer review; DNA Double-Strand Breaks (DSBs) repair is essential to safeguard genome integrity but the contribution of chromosome folding into this process remains elusive. Here we unveiled basic principles of chromosome dynamics upon DSBs in mammalian cells, controlled by key kinases from the DNA Damage Response. We report that ATM is responsible for the reinforcement of topologically associating domains (TAD) that experience a DSB. ATM further drives the formation of a new chromatin sub-compartment (“D” compartment) upon clustering of damaged TADs decorated with γH2AX and 53BP1. “D” compartment formation mostly occurs in G1, is independent of cohesin and is enhanced upon DNA-PK pharmacological inhibition. Importantly, a subset of DNA damage responsive genes that are upregulated following DSBs also physically localize in the D sub-compartment and this ensures their optimal activation, providing a function for DSB clustering in activating the DNA Damage Response. However, these DSB-induced changes in genome organization also come at the expense of an increased translocations rate, which we could also detect on cancer genomes. Overall, our work provides a function for DSB-induced compartmentalization in orchestrating the DNA Damage Response and highlights the critical impact of chromosome architecture in genomic instability.

Cerium oxide nanoparticles are promising materials as novel nanoscale therapeutics and are commonly used materials in industrial processes. Most cytotoxicity studies on cerium oxide nanoparticles are made from in-lab prepared materials making comparison between studies challenging, especially when performed on unique cell lines under non-standard conditions. Using commercially available nanoparticles we show that particle stability/agglomeration may be critical in determining the cytotoxicity in some cell lines, while in other cell lines, larger sized primary particles are linked to higher cytotoxicity, contrasting what has been reported in the literature for smaller cerium nanoparticles. To accelerate the development of cerium oxide enabled commercial processes and biomedical innovations, a clearer understanding of the interactions between cerium oxide nanoparticles and cells is needed to better understand their fate in and impact on biological systems.

Proteins with RNA-binding activity are increasingly being implicated in DNA damage responses (DDR). Additionally, DNA:RNA-hybrids are rapidly generated around DNA double-strand breaks (DSBs), and are essential for effective repair. Here, using a meta-analysis of proteomic data, we identify novel DNA repair proteins and characterise a novel role for DDX17 in DNA repair. We found DDX17 to be required for both cell survival and DNA repair in response to numerous agents that induce DSBs. Analysis of DSB repair factor recruitment to damage sites suggested a role for DDX17 early in the DSB ubiquitin cascade. Genome-wide mapping of R-loops revealed that while DDX17 promotes the formation of DNA:RNA-hybrids around DSB sites, this role is specific to loci that have low levels of pre-existing hybrids. We propose that DDX17 facilitates DSB repair at loci that are inefficient at forming DNA:RNA-hybrids by catalysing the formation of DSB-induced hybrids, thereby allowing propagation of the damage response.