Context-dependent TGFß family signalling in cell fate regulation.

The transforming growth factor-ß (TGFß) family are a large group of evolutionarily conserved cytokines whose signalling modulates cell fate decision-making across varying cellular contexts at different stages of life. Here we discuss new findings in early embryos that reveal how, in contrast to our original understanding of morphogen interpretation, robust cell fate specification can originate from a noisy combination of signalling inputs and a broad range of signalling levels. We compare this evidence with novel findings on the roles of TGFß family signalling in tissue maintenance and homeostasis during juvenile and adult life, spanning the skeletal, haemopoietic and immune systems. From these comparisons, it emerges that in contrast to robust developing systems, relatively small perturbations in TGFß family signalling have detrimental effects at later stages in life, leading to aberrant cell fate specification and disease, for example in cancer or congenital disorders. Finally, we highlight novel strategies to target and amend dysfunction in signalling and discuss how gleaning knowledge from different fields of biology can help in the development of therapeutics for aberrant TGFß family signalling in disease.

Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-ß family type I receptor. ACVR1R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A-mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild-type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1R206H activation does not require upstream kinases, but is predominantly activated via Activin A-dependent receptor clustering, which induces its auto-activation. We use optogenetics and live-imaging approaches to demonstrate Activin A-induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.

A network of transcription factors governs the dynamics of NODAL/Activin transcriptional responses.

SMAD2, an effector of the NODAL/Activin signalling pathway, regulates developmental processes by sensing distinct chromatin states and interacting with different transcriptional partners. However, the network of factors that controls SMAD2 chromatin binding and shapes its transcriptional programme over time is poorly characterised. Here, we combine ATAC-seq with computational footprinting to identify temporal changes in chromatin accessibility and transcription factor activity upon NODAL/Activin signalling. We show that SMAD2 binding induces chromatin opening genome wide. We discover footprints for FOXI3, FOXO3 and ZIC3 at the SMAD2-bound enhancers of the early response genes, Pmepa1 and Wnt3, respectively, and demonstrate their functionality. Finally, we determine a mechanism by which NODAL/Activin signalling induces delayed gene expression, by uncovering a self-enabling transcriptional cascade whereby activated SMADs, together with ZIC3, induce the expression of Wnt3. The resultant activated WNT pathway then acts together with the NODAL/Activin pathway to regulate expression of delayed target genes in prolonged NODAL/Activin signalling conditions. This article has an associated First Person interview with the first author of the paper.

Older adults' lived experiences of physical rehabilitation for acquired brain injury and their perceptions of well-being: A qualitative phenomenological study.

AIM: To explore the experiences of older adults (65+) living with acquired brain injury regarding their sense of well-being during physical rehabilitation within the Greek Healthcare System. BACKGROUND: With the increasing ageing population and the life-changing effects of acquired brain injury, there is a need to focus on care for older people and their potential to live well. Rehabilitation systems deserve greater attention, especially in improving the well-being of those who are using them. DESIGN: A qualitative study design with a hermeneutic phenomenological approach was used. METHODS: Fourteen older adults living with acquired brain injury and undergoing physical rehabilitation in Greece were purposively sampled. Semi-structured interviews were conducted to collect data and were thematically analysed using van Manen's and Clarke and Braun's methods. The COREQ checklist was followed. RESULTS: Four themes emerged from the analysis: (1) Challenges of new life situation, (2) Seeking emotional and practical support through social interaction, (3) Identifying contextual processes of rehabilitation, (4) Realising the new self. CONCLUSIONS: The subjective experiences, intersubjective relations and contextual conditions influence the sense of well-being among older adults living with acquired brain injury, thus impacting the realisation of their new self. The study makes the notion of well-being a more tangible concept by relating it to the degree of adaptation to the new situation and the potential for older adults to create a future whilst living with acquired brain injury. RELEVANCE FOR CLINICAL PRACTICE: Identifying the factors that impact older adults' sense of well-being during rehabilitation can guide healthcare professionals in enhancing the quality of care offered and providing more dignified and humanising care. PATIENT OR PUBLIC CONTRIBUTION: Older adults living with acquired brain injury were involved in the study as participants providing the research data.

Sulfur compounds: From plants to humans and their role in chronic disease prevention.

Sulfur is essential for the health of plants and is an indispensable dietary component for human health and disease prevention. Its incorporation into our food supply is heavily reliant upon the uptake of sulfur into plant tissue and our subsequent intake. Dietary requirements for sulfur are largely calculated based upon requirements for the sulfur-containing amino acids (SAA), cysteine and methionine, to meet the demands for synthesis of proteins, enzymes, co-enzymes, vitamins, and hormones. SAA are found in abundance in animal sources and are relatively low in plants. However, some plants, particularly cruciferous and allium vegetables, produce many protective sulfur-containing secondary metabolites, such as glucosinolates and cysteine sulfoxides. The variety and quantity of these sulfur-containing metabolites are extensive and their effects on human health are wide-reaching. Many benefits appear to be related to sulfur's role in redox biochemistry, protecting against uncontrolled oxidative stress and inflammation; features consistent within cardiometabolic dysfunction and many chronic metabolic diseases of aging. This narrative explores the origins and importance of sulfur, its incorporation into our food supply and dietary sources. It also explores the overarching potential of sulfur for human health, particularly around the amelioration of oxidative stress and chronic inflammation, and subsequent chronic disease prevention.

S-methyl cysteine sulfoxide and its potential role in human health: a scoping review.

Higher intakes of cruciferous and allium vegetables are associated with a lower risk of cardiometabolic-related outcomes in observational studies. Whilst acknowledging the many healthy compounds within these vegetables, animal studies indicate that some of these beneficial effects may be partially mediated by S-methyl cysteine sulfoxide (SMCSO), a sulfur-rich, non-protein, amino acid found almost exclusively within cruciferous and alliums. This scoping review explores evidence for SMCSO, its potential roles in human health and possible mechanistic action. After systematically searching several databases (EMBASE, MEDLINE, SCOPUS, CINAHL Plus Full Text, Agricultural Science), we identified 21 original research articles meeting our inclusion criteria. These were limited primarily to animal and in vitro models, with 14/21 (67%) indicating favorable anti-hyperglycemic, anti-hypercholesterolemic, and antioxidant properties. Potential mechanisms included increased bile acid and sterol excretion, altered glucose- and cholesterol-related enzymes, and improved hepatic and pancreatic ß-cell function. Raising antioxidant defenses may help mitigate the oxidative damage observed in these pathologies. Anticancer and antibacterial effects were also explored, along with one steroidogenic study. SMCSO is frequently overlooked as a potential mediator to the benefits of sulfur-rich vegetables. More research into the health benefits of SMCSO, especially for cardiometabolic and inflammatory-based pathology, is warranted. Human studies are especially needed.

A Sense of Control and Wellbeing in Older People Living with Frailty: A Scoping Review.

A sense of control is important for supporting older people living with frailty to develop adaptive functioning to optimize wellbeing. This scoping review examined the literature on the sense of control and wellbeing in older people living with frailty within their everyday life and care service use. Nine databases were searched using the timeframe 2000 to 2021 to identify key ideas regarding control and wellbeing in older people with frailty. The review highlighted three major themes: a) Control as conveyed in bodily expressions and daily activities, b) Sense of control and influence of place of residence, and c) Control within health and social care relationships. Maintaining a sense of control is not only an internal feeling but is impacted by physical and social environments. Greater focus is needed on the nature of relationships between older people living with frailty and those who work alongside them, which support control and wellbeing.

Russian Orthodox framing of abortion in online journalism on religion.

When making public statements about abortion, those serving in the Russian Orthodox Church are beholden to the legacy of the Soviet health care system and the need to connect with audiences whose religious sentiments are largely nominal. This article explores framing of abortion by clerics and others serving in the Church in 150 Russian online newspaper articles. Said framing was analyzed according to typologies from prior research of morality policy and church-state relations in Russia. The frequency with which these frames were employed was measured and cross-referenced with article genres. The results show that rational-instrumental frames rooted in secular reasoning surpassed religious argumentation and appeals for state intervention, and that frames expressing disillusionment with the Russian government outpaced positive assessments of the state.

Lorsqu'ils font des déclarations publiques sur l'avortement, les membres de l'Église orthodoxe russe ont à assumer l'héritage du système de santé soviétique et la nécessité de se rapprocher d'un public dont les sentiments religieux sont en grande partie nominaux. Cet article explore le cadrage de l'avortement par des religieux et d'autres personnes servant dans l'Église dans 150 articles de journaux en ligne russes. Ce cadrage a été analysé selon des typologies issues de recherches antérieures sur la politique de la morale et les relations entre l'Église et l'État en Russie. La fréquence d'utilisation de ces cadres a été mesurée et croisée avec les genres d'articles. Les résultats montrent que les cadres rationnels-instrumentaux ancrés dans le raisonnement séculier ont dépassé l'argumentation religieuse et les appels à l'intervention de l'État, et que les cadres exprimant une désillusion à l'égard du gouvernement russe ont dépassé les évaluations positives de l'État.

A review of trial and real-world data applying elements of a realist approach to identify behavioural mechanisms supporting practitioners to taper opioids.

This evidence synthesis applying realist concepts and behavioural science aimed to identify behavioural mechanisms and contexts that facilitate prescribers tapering opioids. We identified relevant opioid-tapering interventions and services from a 2018 international systematic review and a 2019 England-wide survey, respectively. Interventions and services were eligible if they provided information about contexts and/or behavioural mechanisms influencing opioid-tapering success. A stakeholder group (n = 23) generated draft programme theories based around the 14 domains of the Theoretical Domains Framework. We refined these using the trial and service data. From 71 articles and 21 survey responses, 56 and 16 respectively were included, representing primary care, hospital, specialist pain facilities and prison services. We identified 6 programme theories comprising 5 behavioural mechanisms: prescribers' knowledge about how to taper; build prescribers' beliefs about capabilities to initiate tapering discussions and manage psychological consequences of tapering; perceived professional role in tapering; the environmental context enabling referral to specialists; and facilitating positive social influence by aligning patient: prescriber expectations of tapering. No interventions are addressing all 6 mechanisms supportive of tapering. Work is required to operationalise programme theories according to organisational structures and resources. An example operationalisation is combining tapering guidelines with information about local excess opioid problems and endorsing these with organisational branding. Prescribers being given the skills and confidence to initiate tapering discussions by training them in cognitive-based interventions and incorporating access to psychological and physical support in the patient pathway. Patients being provided with leaflets about the tapering process and informed about the patient pathway.

A systematic review of the qualitative literature on older individuals' experiences of care and well-being during physical rehabilitation for acquired brain injury.

AIMS: To acquire an in-depth understanding of how older individuals diagnosed with acquired brain injury (ABI) experience their well-being and care when undergoing physical rehabilitation. DESIGN: Systematic literature review. DATA SOURCES: The electronic databases of PubMed, CINAHL, APA PsycInfo, ASSIA and SCOPUS were searched from 2005 to 2020. Extensive reference checking was also conducted. REVIEW METHODS: A systematic review was conducted following PRISMA guidelines, including predominantly qualitative studies. Studies' quality was appraised using the critical apraisal skills programme (CASP) tool. RESULTS: Seventeen studies met the inclusion criteria. Following methods of thematic synthesis, four overarching interpretive themes were identified: (a) Rehabilitation processes and their impact on older individuals' well-being; (b) Identity and embodiment concerns of older individuals during rehabilitation; (c) Institutional factors affecting older individuals' care and well-being experiences; and (d) Older individuals' participation in creative activities as part of rehabilitation. CONCLUSION: Organizational and structural care deficiencies as well as health disparities can adversely impact older individuals' autonomous decision-making and goal-setting potentials. The discrepancy between older individuals' expectations and the reality of returning home along with the illusionary wish to return to a perceived normality, can further negatively affect older individuals' sense of well-being. Constructive communication, emotional support, family involvement in rehabilitation and creating a stimulating, enriching social environment can humanize and facilitate older individuals' adjustment to their new reality following ABI. IMPACT: There is a lack of qualitative research on older individuals' ABI rehabilitation experiences, especially traumatic brain injury incidents. Further study should consider patients' concerns over their involvement in decision-making and goal setting about their care. Overall, this review reveals the need to examine further the significance of humanizing care and the factors that affect older individuals' sense of well-being.

Making the invisible more visible: Reflections on practice-based humanising lifeworld-led research - existential opportunities for supporting dignity, compassion and wellbeing.

BACKGROUND: The need for dignity and compassion in healthcare is enshrined in policy, but is often difficult to enact in practice and what is precisely meant by these concepts is unclear. In this paper, we have explored theoretical underpinnings which form the basis of a lifeworld-led approach which was used in a research study to support the humanity of service providers and users alike. AIM: In this article, we share our analysis of what we have learnt after undertaking an innovative appreciative action research project with patients and staff in a stroke ward with the aim of exploring if a novel phenomenologically driven and philosophically derived humanising framework could be applied in health care. Following the research, we wanted to develop a theoretical understanding of the processes occurring during the research in order to provide a framework and language which could be used to support practical lifeworld developments in the future. We analysed the approach through Participatory and Appreciative Action Reflection. FINDINGS: As researchers, we found that the approach was underpinned by four key existential principles. The first principle was recognising a mutually arising reality rather than a reality 'out there'. The second was recognising a reality which was constantly changing rather than 'fixed'. The third was recognising that we needed to work from within, as part of a human living system rather than trying to control reality from the 'outside'. Finally, we recognised that this reality could only be accessed through human knowing, including embodied knowing rather than intellectual knowing alone. These principles challenged many of the usual ways of thinking and working within research and healthcare contexts. CONCLUSION: Understanding the processes and reality in this way gave new perspectives; enhancing our understandings and views of ourselves, what is important and most importantly what is possible in caring systems.

TGF-ß family ligands exhibit distinct signalling dynamics that are driven by receptor localisation.

Growth factor-induced signal transduction pathways are tightly regulated at multiple points intracellularly, but how cells monitor levels of extracellular ligand and translate this information into appropriate downstream responses remains unclear. Understanding signalling dynamics is thus a key challenge in determining how cells respond to external cues. Here, we demonstrate that different TGF-ß family ligands, namely activin A and BMP4, signal with distinct dynamics, which differ profoundly from those of TGF-ß itself. The signalling dynamics are driven by differences in the localisation and internalisation of receptors for each ligand, which in turn determine the capability of cells to monitor levels of extracellular ligand. By using mathematical modelling, we demonstrate that the distinct receptor behaviours and signalling dynamics observed may be primarily driven by differences in ligand-receptor affinity. Furthermore, our results provide a clear rationale for the different mechanisms of pathway regulation found in vivo for each of these growth factors.

A criteria-based rehabilitation program for chronic mid-portion Achilles tendinopathy: study protocol for a randomised controlled trial.

BACKGROUND: Achilles tendinopathy (AT) is a common overuse injury in running-related sports where patients experience pain and impaired function which can persist. A graded rehabilitation program has been successful in reducing pain and improving function to enable a return to sport. The aim of this study is to compare the effectiveness of a criteria-based rehabilitation program including strength and reactive strength targets, with a previously successful rehabilitation program on changes in pain and function using the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire. Secondary aims will be to assess changes in calf strength, reactive strength, and lower limb running and forward hop biomechanics over the course of a 12-week rehabilitation program, and long-term follow-up investigations. METHODS: Sixty eligible participants with chronic mid-portion AT who train in running-based sports will be included in this study. They will be randomly assigned to a group that will follow an evidence-based rehabilitation program of daily exercises with progression guided by symptoms or a group performing 3 high-intensity rehabilitation sessions per week with individualised load targets progressing to reactive strength exercises. Testing will take place at baseline, week 6 and 12. Plantar flexor peak torque will be measured using isokinetic dynamometry, reactive strength will be measured using a drop jump and lower limb biomechanical variables will be measured during a single leg forward hurdle hop test and treadmill running using 3D motion analysis. Follow-up interviews will take place at 6, 12 and 24 months after beginning the program which will assess patient participation in sport and possible re-injury. DISCUSSION: This is the first study to propose an individualised criteria-based graded rehabilitation program in patients in with chronic mid-portion Achilles tendinopathy where progression is guided by strength and reactive strength outcome measures. This study will provide a comprehensive assessment of plantar flexor strength, reactive strength and lower limb biomechanical variables in running and forward hopping with the VISA-A questionnaire as the primary outcome measure and long term post-intervention follow-up assessments performed. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT04384874 ). Registered retrospectively on April 23rd 2020.

Facile CO2 separation and subsequent H2 production via chemical-looping combustion over ceria-zirconia solid solutions.

A novel chemical-looping combustion scheme is proposed, where facile gas separation via steam condensation enables the production of sequestrable CO2 from alkanes, such as CH4, and pure H2 from H2O. This cycle consists of two steps, namely, (1) the endothermic reduction of a ceria-based solid solution via the complete oxidation of CH4, followed by (2) the exothermic oxidation of the reduced metal oxide via H2O splitting. Relative to iron oxide-based materials and undoped ceria, ceria-zirconia solid solutions possess favorable partial molar enthalpic and entropic properties; this promotes selective production of complete combustion products, H2O and CO2, during the reforming reaction. Thermodynamic predictions suggest that the complete oxidation of CH4 is possible by increasing the Zr content to 20 mol%, operating below 600 °C, increasing total pressure, or reducing the amount of delivered reactant. Furthermore, any H2, CO, or unreacted CH4 that may persist is thermodynamically favored to oxidize if exposed to unreacted oxide downstream, as is typical for a packed-bed or downer reactor configuration. Experiments were performed to validate the thermodynamic trends using isothermal thermogravimetry coupled with residual gas analysis, which confirmed that high selectivity towards H2O and CO2 is attainable for methane-driven reduction of Ce0.9Zr0.1O2; selectivities greater than 0.70 were observed at initial reaction extents. Importantly, metal oxide oxidation via H2O splitting and selective production of H2 (or CO if CO2 is the delivered oxidant) is also thermodynamically favored at the operating conditions considered for the first step. This work ultimately presents a viable avenue for the carbon-neutral conversion of CH4 (or other alkanes) to H2 if a renewable energy resource, such as solar energy, is leveraged to supply process heat.

Inhibiting the inhibitor: the role of RNF12 in TGF-ß superfamily signaling.

In this issue of Molecular Cell, Zhang et al. (2012) identify the E3 ubiquitin ligase RNF12 as a new component of the TGF-ß superfamily signaling pathways, which functions by targeting the negative regulator Smad7 for proteasomal degradation and thus potentiates pathway activity.

TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.

Ligands of the transforming growth factor-beta (TGFbeta) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?

Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities.

The interplay between sequence-specific DNA-binding transcription factors, histone-modifying enzymes, and chromatin-remodeling enzymes underpins transcriptional regulation. Although it is known how single domains of chromatin "readers" bind specific histone modifications, how combinations of histone marks are recognized and decoded is poorly understood. Moreover, the role of histone binding in regulating the enzymatic activity of chromatin readers is not known. Here we focus on the TGF-ß superfamily transcriptional repressor TIF1γ/TRIM33/Ectodermin and demonstrate that its PHD finger-bromodomain constitutes a multivalent histone-binding module that specifically binds histone H3 tails unmethylated at K4 and R2 and acetylated at two key lysines. TIF1γ's ability to ubiquitinate its substrate Smad4 requires its PHD finger-bromodomain, as does its transcriptional repressor activity. Most importantly, TIF1γ's E3 ubiquitin ligase activity is induced by histone binding. We propose a model of TIF1γ activity in which it dictates the residence time of activated Smad complexes at promoters of TGF-ß superfamily target genes.

We are not the same people we used to be: An exploration of family biographical narratives and identity change following traumatic brain injury.

Subjective changes are increasingly recognised as important in recovery and rehabilitation following traumatic brain injury. Accumulation of subjective changes over time has led many to examine the question of "continuity of self" post-injury. Vacillation between feeling the same and different is common and often at odds with the medical narrative preparing families for permanent change. This position of ambiguity was examined in a qualitative narrative study. The aim of this paper is to describe the narrative structures used by uninjured members of a family to understand change. These changes relate primarily, to their perspective of whether and how the injured person had changed, but also secondarily to whether and why they themselves felt they had changed in the first year post-injury. Nine uninjured family members from three families took part in three unstructured interviews during the first twelve months post-injury. In-depth narrative analysis showed family members used biographical attendance; biographical disruption; biographical continuity; and biographical reconstruction to understand change. Drawing on these findings it is argued that concentrating on a narrative of change is too limiting and that engaging in biographical narratives may help humanise care provided to injured individuals and their families. Implications for research and practice are discussed.

Calreticulin is a secreted BMP antagonist, expressed in Hensen's node during neural induction.

Hensen's node is the "organizer" of the avian and mammalian early embryo. It has many functions, including neural induction and patterning of the ectoderm and mesoderm. Some of the signals responsible for these activities are known but these do not explain the full complexity of organizer activity. Here we undertake a functional screen to discover new secreted factors expressed by the node at this time of development. Using a Signal Sequence Trap in yeast, we identify several candidates. Here we focus on Calreticulin. We show that in addition to its known functions in intracellular Calcium regulation and protein folding, Calreticulin is secreted, it can bind to BMP4 and act as a BMP antagonist in vivo and in vitro. Calreticulin is not sufficient to account for all organizer functions but may contribute to the complexity of its activity.