Health and social care services worldwide need to support ageing populations to live well with advanced progressive conditions while adapting to functional decline and finitude. We aimed to identify and map common elements of effective geriatric and palliative care services and consider their scalability and generalisability to high, middle and low-income countries.Tertiary systematic review  of studies in geriatric or palliative care that demonstrated improved quality of life and/or health service use outcomes among older people with advanced progressive conditions. Using frameworks for health system analysis, service elements were identified. We used a staged, iterative process to develop a ‘common components’ logic model and consulted experts in geriatric or palliative care from high, middle and low-income countries on its scalability.78 studies  spanning all WHO regions were included. Data were available from 17 739 participants. Nearly half the studies recruited patients with heart failure (n=36) and one-third recruited patients with mixed diagnoses (n=26). Common service elements (≥80% of studies) included collaborative working, ongoing assessment, active patient participation, patient/family education and patient self-management. Effective services incorporated patient engagement, patient goal-driven care and the centrality of patient needs. Stakeholders (n=20) emphasised that wider implementation of such services would require access to skilled, multidisciplinary teams with sufficient resource to meet patients’ needs. Identified barriers to scalability included the political and societal will to invest in and prioritise palliative and geriatric care for older people, alongside geographical and socioeconomic factors.Our logic model combines elements of effective services to achieve optimal quality of life and health service use among older people with advanced progressive conditions. The model transcends current best practice in geriatric and palliative care and applies across the care continuum, from prevention of functional decline to end-of-life care.CRD42020150252. We draw on and synthesise a diverse evidence base of geriatric and palliative care for older people with progressive advanced conditions across the globe.The review was conducted by a multidisciplinary and international group representing broad methodological expertise and perspectives.Our common components logic model is a recombination of effective service elements. However, we were unable to assert how outcomes may be influenced by different combinations of components and their interactions.Our stakeholder consultation identified significant barriers to scalability where country health budgets cannot meet the growing population need, and where multidisciplinary care is not available.Globally, more people are living into old ageThe WHO Member States’ commitment to achieve Universal Health Coverage (UHC) by 2030 provides an opportunity to plan health and social care delivery for the future. Palliative care has recently been included as an essential service that is fundamental to achieving UHC.12Our previous meta-review outlined two service delivery models for older people towards the end of life; ‘integrated geriatric care’ and ‘integrated palliative care’.This review aimed to detail service delivery models that optimise quality of life and health services use for older people aged 60 years and over with advanced progressive health conditions. We defined ‘advanced’ to include disease stage, people described as in their last 1 or 2 years of life or people accessing a service typically used in advanced disease stage, such as nursing home or palliative care. Our objectives were to: (1) identify and map common elements of effective service delivery models within primary studies; (2) outline the similarities and differences across models of geriatric care or palliative care and (3) consider the scalability of effective models, attending to implementation and economic requirements.This review builds on our previous meta-review, where the methods are described in detail.Patients and members of the public were not involved in the design, conduct, reporting or dissemination of this research.For the purposes of this tertiary review, in October 2019 we updated our original meta-review search to identify systematic reviews that included a meta-analysis that demonstrated overall effectiveness on at least one outcome for quality of life (including symptom burden and function) and/or health service use outcome. The systematic review eligibility criteria and search terms are reported in 10.1136/bmjopen-2020-048417.supp1Supplementary dataData on study population, outcomes and context were extracted. Service delivery models were classified as either integrated geriatric or palliative care. Data identification and extraction was informed by a framework for healthcare systems analysis, the checklist CATWOE .The methodological quality of systematic reviews and primary studies was appraised using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) toolet al’s guidance on logic models for complex health interventionsWe used a staged and iterative approach following Rohwer 2 tests (or Fisher’s exact tests where counts were low).The frequency and proportion of service elementsWe appraised the potential for the common components of effective interventions to be generalised and scalable, defined as the ability ‘to be expanded under real world conditions to reach a greater proportion of the eligible population while retaining effectiveness’.25We shared an interim logic model and consulted a purposive sample of healthcare researchers, clinical-academics and clinicians from high, middle and low-income countries with expertise in either geriatric or palliative care, hospital or community based. We used the Context and Implementation of Complex Interventions Framework (CICI) to develop a response form with free-text open questions on the barriers and facilitators to providing the elements of care, for their respective country and healthcare settings.14Ten systematic reviews met eligibility, seven from the meta-reviewOf the 78 included studies, 59 were categorised as integrated geriatric care and 19 as integrated palliative care . All WHOThe 10 systematic reviews were assessed as of moderate quality . PrimaryServices most frequently used collaborative working and case management to support integrated working between professionals . PatientComparing between integrated geriatric and palliative care, palliative care interventions had a higher frequency of end-of-life expertise and training, professional psychosocial support, spiritual support and physician home visits. In contrast geriatric care interventions more often featured early rehabilitation assessment and self-management, though the differences were not statistically significant .All interventions were delivered by qualified healthcare professionals , most often working in multidisciplinary teams. Over 90% of studies involved trained medical and nursing clinicians and 59% involved members of the wider healthcare team, including physiotherapists, occupational therapists and social workers. Geriatric care services were delivered by physicians from geriatrics, cardiology and general practice, whereas palliative care services involved physicians from cardiology, neurology, respiratory medicine, oncology, psychiatry, primary care and palliative medicine. While involvement of physiotherapists was reported across all studies, fewer occupational therapists and dietitians were reported in those from palliative care. No studies reported the involvement of volunteers .Forty-five studies (58%) were included based on an effect on quality of life alone. Fifty-seven studies (73%) used a disease or population specific measure to quantify quality of life  and fiveThe interim logic model highlighted key elements present in the majority (<80%) of included studies.Elements more common in integrated palliative care compared with geriatric care studies were; professional psychosocial support, advance care planning, caregiver engagement, joint decision-making and expert consultation with other providers. Elements more common in geriatric care studies included a social worker or dietician as a delivery agent and care planning organised around the service, delivering the same intervention to all patients but with individual tailoring .Elements more common in geriatric care studies included a social worker or dietician as a delivery agent and care planning organised around the service with the same intervention being delivered to all patients with individual tailoring .The context and implementation considerations identified from the stakeholder responses were incorporated into the logic model . StakehoStakeholders from LMICs considered that overall health budgets were inadequate to meet the population need, and multidisciplinary care was considered unaffordable. The voluntary sector was often seen as important to augment publicly funded services. In some contexts, continuity of care is impeded when individually funded services compete for resources rather than collaborate. There are challenges to multidisciplinary working in systems where health workers receive payment directly from patients, as this was considered a financial disincentive to making referrals for expert consultation. Social deprivation was cited as an important barrier to accessing care, especially in health systems with out-of-pocket expenses or private insurance.Stakeholders described how cultural norms influence care provision. Death denying attitudes in some cultures influence uptake of palliative care services. Some countries have limited recognition or respect for the specialties of palliative care and geriatric care. The role of the family and the health system to provide care was identified to vary across countries influenced by cultural beliefs such as filial piety, gender-related norms and changing intergenerational family structures. Acknowledging faith and religion were identified as factors supporting the delivery of individualised care aligned with spiritual needs in hospice and nursing homes.Increasing education levels and internet access were identified as factors that are changing patient and family participation in joint decision-making. Finally, stakeholders recognised an increasing political will to invest in services for older people supported by a growing public and research agenda and established regulatory frameworks. However, this did not always equate to increases in funding. A lack of policies and clinical governance for specialist palliative and geriatric care was reported as a problem, like legal restrictions on opioid prescribing limiting effective medication management of pain.We used rigorous methods to detail service delivery models that optimise quality of life and health service use outcomes among older people with advanced progressive conditions. Effective services commonly used collaborative working between professionals and specialties, comprehensive and ongoing assessment, patient/family education and active patient participation. Aligned to this, effective services consistently incorporated patient engagement, patient goal-driven care and the centrality of patient needs in care delivery. Our logic model encompasses a breadth of elements that aim to ‘protect’ , ‘reactivate’ , ‘compensate’  and ‘support’ . Such practices may together support older people to maintain intrinsic capacity and functional ability1This review has several strengths. It was conducted by a large multidisciplinary team with a range of methodological expertise and representation from many regions of the world. We synthesised a diverse literature with studies across different patient populations and needs across the trajectory of advanced disease. We used recognised frameworks to categorise studies, extract data and consult with stakeholders in order to develop a visual logic model applicable to different international settings. There are some limitations to consider. Data on study context is limited to country, country income status and the system for funding healthcare. Further information to support an evaluation of how interventions could be scaled and implemented would be valuable. Stakeholders identified limited applicability for some service elements, including multidisciplinary care, within low-income countries where health budgets cannot meet the growing population need. Change beyond the health system, into education and health promotion, may be required to implement services that meet the challenge of rising incidence in diseases of ageing.et alet al42Our findings build on previous reviews. Bainbridge We also provide new insights into the range of health and social care providers associated with effective services in this population. Services were frequently delivered by multidisciplinary teams of health and social care professionals with formal training in core skills of comprehensive assessment, communication and symptom management. These teams can support people to self-manage a progressive condition and help people close to them to provide care. Investment in training and education is required to achieve greater coverage and ensure the skills base keeps up with the needs of this growing population. Uncoupling skills from professional roles and working towards a generalist skills set may be most beneficial. However, this should ideally be accompanied by access to specialists for ongoing support and supervision. Volunteers may provide additional support that supplements or enhances usual health and social care provision.Service elements that we consider relevant to the target population but not brought forward to our logic model include joint provision across health and social care and early rehabilitation assessment. Neglecting social care can have a considerable negative effect on quality of life for older people, their family and friends and lead to increased patient and carer morbidity and mortality.50 51The logic model is a recombination of different services and we were unable to assert how effectiveness may be influenced by different combinations of components and their interactions. Consequently, the model remains untested as a whole.Box 1Configure services for the whole trajectory of chronic progressive conditions up until the end of life and move away from a focus on acute episodes of care.Plan and deliver education to drive provision of a capable workforce. A broad range of professional education courses and training in core skills of geriatric and palliative care, including comprehensive assessment, communication and symptom management specific to individual need is required.Incentivise interdisciplinary and collaborative working between professional disciplines and across health and social care settings, to optimise high-quality individualised service provision and care coordination. This integrated care, when aligned to need rather than diagnostic condition, will increase the reach and impact of services and promote equitable access.Enable robust evaluation by embedding routine outcome measurement in health and social care settings. These should include measures of intrinsic capacity, functional ability, symptom experience and quality of life. Measures should capture the changes in health and social well-being that are associated with the provision of high quality individualised care across the care continuum from protect to support and end-of-life care.Our logic model brings together common elements of interventions found to optimise quality of life and health service use among older people with advanced progressive conditions. These included collaborative working between professionals and specialties, ongoing assessment, active patient participation, patient/family education and patient self-management, while effective service delivery approaches consistently incorporated patient engagement, patient goal-driven care and the centrality of patient needs.These elements transcend best practices in geriatric care and palliative care to optimise patient outcomes across the continuum, from prevention of functional decline to end-of-life care. The logic model serves as a useful resource for health systems looking to strengthen their response to population ageing. It can guide provision of health and social care that is aligned to the needs of this rapidly growing population. Such care should allow older people across the globe to live fully, with minimal suffering, and to die with dignity.


The ability to store and retrieve learned information over prolonged periods of time is an essential and intriguing property of the brain. Insight into the neurobiological mechanisms that underlie memory consolidation is of utmost importance for our understanding of memory persistence and how this is affected in memory disorders. Recent evidence indicates that a given memory is encoded by sparsely distributed neurons that become highly activated during learning, so-called engram cells. Research by us and others confirms the persistent nature of cortical engram cells by showing that these neurons are required for memory expression up to at least 1 month after they were activated during learning. Strengthened synaptic connectivity between engram cells is thought to ensure reactivation of the engram cell network during retrieval. However, given the continuous integration of new information into existing neuronal circuits and the relatively rapid turnover rate of synaptic proteins, it is unclear whether a lasting learning-induced increase in synaptic connectivity is mediated by stable synapses or by continuous dynamic turnover of synapses of the engram cell network. Here, we first discuss evidence for the persistence of engram cells and memory-relevant adaptations in synaptic plasticity, and then propose models of synaptic adaptations and molecular mechanisms that may support memory persistence through the maintenance of enhanced synaptic connectivity within an engram cell network. Our memories define who we are, help us make decisions and guide our behavior. The ability to effectively encode, store and retrieve information is therefore an essential feature of life. Although the recollection of most experiences fades with time, certain memories are retained for many years or even a lifetime. How the brain is able to process and persistently store learned information has been a topic of intense research for a long time and great progress has been made in recent years toward a better understanding of the mechanisms underlying memory persistence.Memory formation is initiated by the integration of external and interoceptive sensory stimuli in neuronal circuits, forming a cohesive representation of a specific event. Subsequently, the neurons involved are thought to undergo physical changes that enable retrieval of the learned information. The physical representation of experience-driven changes in the brain is collectively referred to as a memory engram , a term Memory engram: the physical representation of learning-induced changes in the brain that are causal to memory storage and retrieval.Engram cells: neurons that encode a memory through consolidation of learning-induced physical adaptations. These neurons are highly activated during learning and subsequently act as a substrate for the storage of a memory engram.Engram cell network: a network of engram cells that persists through the establishment of engram synapses.Engram synapses: synapses between engram cells that are formed or strengthened as a result of learning to ensure reactivation of the engram cell network during memory retrieval.Synaptic connectivity: collection of structural (size and number) and electrophysiological (strength and efficacy) properties of synapses. Learning augments one or more of these properties to enhance synaptic connectivity between engram cells.Global synaptic adaptations: learning-induced changes in synaptic connectivity that have been measured in a random population of neurons in a given brain region, without discriminating between engram and non-engram cells.Engram cell-specific synaptic adaptations: learning-induced changes in synaptic connectivity that have been measured selectively in engram cells in a given brain region, often by comparison with non-engram cells.Cellular feedback loops: recurrent cause-and-effect sequences where the output of an intracellular molecular pathway influences its input.de novo protein synthesis  as a proxy thereof , results in anterograde amnesia for acquisition of new spatial information, as well as the inability to adapt previously stored spatial relationships  of auditory inputs in the lateral amygdala after learning impairs expression of auditory fear memory, which can be rescued by evoking LTP of these inputs  engram cells, which is prevented by post-learning inhibition of protein synthesis . Further neurons , hintingIn addition to the hippocampus, accumulating evidence points to adaptations in synaptic connectivity of engram cells in other brain regions. Lateral amygdala neurons tagged during auditory fear conditioning or discriminative fear learning exhibit enhanced pathway-specific synaptic strength with afferent neurons  and depoTogether, these findings convincingly demonstrate that new learning is associated with enhanced synaptic connectivity involving increased pathway-specific potentiation of synapses between engram cells. Importantly, enhanced synaptic connectivity observed in the first days after learning is necessary for adequate recent memory expression, but whether it contributes to the persistence of an engram cell network is poorly understood.in vivo two-photon imaging  is a transcription factor known to negatively regulate spinogenesis and viral-mediated enhanced expression of MEF2 in ACC pyramidal neurons during the first, but not seventh, week after fear conditioning prevents the learning-induced increase in spine density and subsequently impairs memory expression . The incGRIN1 expression in the forebrain abolishes LTP and when its expression is temporarily suppressed at 6 months after learning, this impairs the expression of a 9-month-old contextual and auditory fear memory  in neurons in the NAc, which reverses into synaptic potentiation at 10–14 days after the last cocaine treatment . Increasr memory .Taken together, memory persistence is associated with enhanced synaptic connectivity through persistent changes in structural and physiological properties in brain regions that are engaged in a particular experience and prevention or reversal of these alterations disrupts memory retention. In the examples above, random neurons were selected and analyzed in relevant brain areas and therefore it remains to be determined whether the lasting adaptations described represent the engram in neurons that are activated during memory acquisition and retrieval.Arc-TRAP mouse line) with retrograde and anterograde tracing of activated neurons, Whereas fear memory-encoding engram cells in the hippocampal DG develop a rapid increase in spine density that diminishes within 2 weeks after learning, a more gradual increase in spine density occurs on engram cells in the mPFC which lasts for a least 2 weeks . NotablyWe will now discuss how enhanced synaptic connectivity, through structural and/or physiological adaptations (pre- and postsynaptic), could be maintained over time . UnfortuIn this model, enhanced learning-induced connectivity would endure immutably over the lifetime of a given memory due to unvarying size and strength of either (1a) all, or (1b) a subset of synaptic connections triggered by learning . A handfThe importance of activity-dependent synaptic pruning for the optimization of cortical network function and capacity during critical periods of development is well-established  and is aAn alternative view to a fixed synaptic connectivity configuration is a fluid model in which individual synapses on engram cells can be continually calibrated and reorganized , while mSimilar to structural connectivity, persistent physiological changes in synaptic strength can be supported by a stable or dynamic population of synapses between engram cells. So far, identified augmentation of synaptic strength has been measured by whole cell patch-clamp recordings, which do not provide insight into the specific synapses that are altered as a result of learning. Moreover, physiological adaptations likely also commensurate with the duration of engagement of engram cells in memory expression. For instance, DG engram cells exhibit enhanced synaptic strength the first days after fear conditioning , but thiThe models we propose represent a dormant state of the memory after learning. Depending on epochs of retrieval and the conditions under which retrieval occurs, synaptic connectivity within the engram cell network may be altered, enabling updating of memory strength and content. This process is likely associated with modulation of physiological properties of existing synapses between engram cells , as wellWe will discuss a few of many possible mechanisms that can perpetuate synaptic connectivity within an engram cell network over weeks to months   providesr memory . This sur memory . This por memory . Next, fr memory ].Regulated transcriptional/translational programs within engram cells that are ongoing long after learning/stimulation occurs are considered to contribute to a lasting increase in synaptic connectivity. Indeed, transcriptome profiling of mPFC cells activated by cocaine exposure  or fear As described above, synaptic triggers can lead to epigenetic modifications that regulate transcriptional signatures supporting remote memory. In line with this, learning-induced chromatin modifications  have been measured at a global level in the hippocampus and prefrontal cortex , and recAccumulating evidence indicates that expression of remote memory depends on cortical neurons that are activated at the time of memory acquisition. After learning, consolidation is thought to enhance synaptic connectivity within the engram cell network through structural and physiological adaptations, thereby supporting memory retention. Based on this, we propose that the connectivity patterns that support persistence of an engram cell network can be perpetuated over time in different ways. Whether augmented connectivity is indeed maintained by stable or dynamic synapses and whether it involves synaptic pruning is an important topic for future research. To date, experimental evidence that provides detailed insight into the mechanisms that contribute to the persistence of synaptic connectivity between engram cells, such as the role of synapse turnover, and the identity of molecular mechanisms that coordinate and sustain these processes, is limited. A handful of interconnected synaptic and (epi)genetic feedback loops have been identified for specific types of memory at a global level of analysis. However, the picture remains incomplete, and the palette of recursive mechanisms that direct plasticity to specific sites and connections within the engram cell network long after learning occurs, remains largely unknown. Furthermore, even though we have focused mainly on mechanisms of enhanced synaptic connectivity underlying memory retention, non-synaptic mechanisms  may also play a role and need to be further investigated in order to obtain a comprehensive picture of the cellular and molecular processes that support memory persistence.in vivo imaging techniques to measure brain circuit dynamics, permanent cell/synapse-specific tagging methods, ultrasensitive -omics techniques, and spatio-temporally precise manipulation tools (in vivo imaging of engram cell synapse dynamics over time-scales that reflect the persistency of remote memories. This might also reveal whether enhanced connectivity occurs in functional clusters exclusive to synapses between engram cells of interconnected brain regions, or whether this is maintained by engram synapses that function as single units. Next, the identification of synaptic tags, signaling mechanisms, epigenetic modifications and transcriptional/translational events specific to engram cells would require temporal molecular analysis of these neurons and the specific synapses between them. This could be addressed by combining permanent fluorescent tagging of engram cells/synapses with the generation of molecular profiles of these compartments. Finally, causal manipulation of identified molecular adaptations specifically in engram cells is crucial to elucidate how changes that maintain enhanced synaptic connectivity support the stabilization of an engram cell network over time. It is noteworthy that thus far, the majority of studies focused on Fos- or Arc-expressing engram cells. Fos- and Arc-expressing neurons overlap to a large extent after learning (The field of learning and memory is currently in a fortunate position, with a highly specialized and rapidly developing technical toolbox; including, but not limited to, on tools . Althouglearning , but evilearning . DistincAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Stromal cells provide structural support and nutrients in secondary lymphoid organs and non-lymphoid tissues. However, accumulating evidence suggests that a complex relationship exists between stromal cells and immune cells. Interactions between immune cells and stromal cells have been shown to influence the pathology of both autoimmunity and cancer. This review examines the heterogeneity of stromal cells within the lymph node and non-lymphoid tissues during both homeostatic and inflammatory conditions, in particular autoimmunity and cancer, with the goal of better understanding the complex and apparently paradoxical relationship between these two classes of diseases. The review surveys potential novel mechanisms involving the interactions between stromal cells and immune cells which may contribute to the development, pathology and underlying connection between autoimmunity and cancer, including potential pathways from autoimmune inflammation to either “hot” or “cold” tumors. These interactions may provide some insights to explain the rising incidence of both autoimmunity and cancer in young women in industrialized countries and have the potential to be exploited in the development of new interventions for preventions and treatments of both autoimmune diseases and cancer. Stromal cells are commonly known for their role in providing support and nutrients in both the secondary lymphoid organs and non-lymphoid tissues. However, recent studies have illustrated the expansive role of stromal cells along with the characterization of the diverse group of cells that constitute the stromal cell compartment. The stromal cell compartment is comprised of many types of cells including but not limited to endothelial cells, mesenchymal stromal cells, and pericytes. Within these larger categories are even more subsets of cells which help shape both the stromal compartment and organ microenvironments . This heOn the “surface” autoimmunity and cancer appear to be at the opposite end of the spectrum of immune-related diseases. Autoimmune diseases are caused by the immune system wreaking havoc on the body’s healthy tissues, while cancer represents a failure of the immune system to destroy malignant cells. The recent breakthrough in cancer immune therapy coincidently brought a broader attention to at least one aspect of the intricacy in the relationship between autoimmunity and cancer — autoimmune damage is not just off-target toxicity but also an indicator of effective anti-tumor immunity . More peNevertheless, it remains largely unclear how exactly T cells in inflammatory settings may promote cancer development. In this review, we explore that question from the angle of the stromal cell biology with a focus on stromal–immune interactions, keeping in mind that the extensive changes in the stromal compartment, such as tissue remodeling and fibrosis, are often associated with both autoimmune disorders and cancer.Stromal cells are essential components in both lymphoid and non-lymphoid tissues. In central lymphoid organs such as the thymus and bone marrow, it has been well-recognized that they play an essential role in supporting lymphocyte development and selection . In the Within the lymph node, stromal cells are derived from either mesenchymal or endothelial origins . These tLymphatic endothelial cell can be found lining both the afferent and efferent lymphatic vessels. Traditionally, it was believed that their main role was to drain lymph from surrounding tissues in and out of the lymph node, but more recently exciting new functions in antigen presentation and immune tolerance induction have been discovered along with the identification of multiple new subsets of LEC .Recent studies in both mice and humans have found transcriptionally distinct populations of LEC residing in distinct geographic location within the lymph node . The lym+ T cells , which also express LTβR, or required by other T cell populations. These results illustrated a novel mechanism for Treg migration through interactions with LEC  independent manner. Peripheral antigens presented by the LEC subset include melanocyte-specific tyrosinase, intestinal epithelial protein A33, and pancreatic prohormone (PYY) . LEC als T cells . Additiowith LEC .The other major endothelial cell lineage in lymph nodes is BEC. BEC are comprised of two main groups. These groups include the endothelial cells within the HEV and the non-HEV cells. Within the lymph node BEC expand and create a capillary network. This network is responsible for the delivery of solutes, metabolites, and oxygen to the lymphocytes along with control of fluid between tissues. In the lymph node this network of vessels ends at the HEV , whereinLike LEC, BEC are comprised of diverse subsets in terms of both phenotype and function. Gja5 and Gja4 which encode connexin 37 (CX37) and connexin 40 (CX40)  . Capillaal cells  -FDC population represented the classical FDC profile expressing both complement and Fc-receptors as well as genes associated with intracellular stiffness. The LZ-FDC gene profile supported the mechanical properties needed to present antigen. The dark zone (DZ)-FDC were shown to express lower levels of these receptors and tended to express a somewhat hybrid phenotype between the LZ-FDC and other B cell region reticular cell . This population can be identified by the expression of CCL19 and CCL21 . The TRC T cells   differentiation and is crucial for proper function of the lung  mesothelial and fibroblastic stromal cells helps to maintain both homeostasis and the GATA6 transcriptional program in cavity resident macrophages . Additiothe lung .Mesenchymal stromal cells are also important in immune cell differentiation as well as tissue health within the liver environment. Hepatic stellate cells, a type of liver-specific stromal cell (pericytes), produce CSF-1, IL-34, and bone morphogenetic proteins which play a role in the differentiation of monocytes into Kupffer cells . KupfferMost types of non-lymphoid tissues, especially the skin dermis and various mucosal membranes are drained through an extensive network of lymphatic vasculature . The lym+ dendritic cells migrate into the intestinal lymphatic system via the CCL21 gradient generated by intestinal LEC. Trafficking of these dendritic cells to the mesenteric lymph node help generate Treg cells and induce tolerance . Within the TME, stromal cells can play an important role in modulating immune cells. TME stromal cells are not derived from a malignant cell lineage; therefore theoretically these cells should function similarly to their counterparts in healthy tissues . HoweverThe BEC subset plays an important role in the migration of immune cells into tissues. Within the tumor, it has been shown that trafficking of antigen specific T cells is dysfunctional. Some of this immune trafficking dysfunction can be contributed to abnormal structure of vasculature within the tumor . Tumor Breg cells. Of note, Treg infiltration has been associated with decreased survival in many types of cancer. One example is the increased expression of CLEVER-1 in the BEC population found in human hepatocellular carcinoma. CLEVER-1 was found to preferentially mediate the infiltration of Treg populations into the tumor  cells  cells .+ T cells to CD4+ Treg cells in the periphery (reg phenotype in conventional CD4+ T cells, therefore indicating a potential role for stromal cells to directly influence T cell lineage commitment in the periphery (The mechanisms underlying these lineage conversions are still mostly unknown, but there is suggestive evidence for a role of MHC expression in stromal cells. It has been shown that MHCII expression is required for the conversion of CD8eriphery . As disceriphery  (Figureseriphery . Antigeneriphery . This meeriphery , and theeriphery . Explora+ PDPN+ fibroblasts in the cancer setting may mediate the exclusion of T cells from tumor infiltration, through TGFβ signaling and fibrosis as well as nitric oxide-mediated T cell suppression (Of note, in the tumor microenvironment, the presence of the various immune constituents, regardless of effectiveness, characterizes the tumor as “hot” and in general a more likely target responding to immune therapy, unlike its “cold” counterpart that is largely devoid of immune cell infiltrates. How a tumor microenvironment evolves to be immune “cold” remains essentially unknown ? It is ppression . OverallBoth autoimmune diseases and cancer are heterogeneous diseases which vary greatly from patient to patient. With this heterogeneity comes difficulty in identifying common causative mechanisms and universal treatments for either category of the diseases. Nevertheless, recent studies suggest that there may be a number of mechanisms linking these two complicated diseases together. One of the major advances is the discovery of new roles for stromal cells in immunological and metabolic regulation that are far beyond their traditionally assigned functions in providing structural and nutritional support. Thus, stromal cells could present attractive therapeutic targets against both autoimmunity and cancer, with immune therapy as well as metabolic interventions. A better understanding of stromal cell intrinsic and extrinsic regulation of immune cells, such as T cell exhaustion, contraction or lineage conversion, will likely lead to a plethora of novel therapeutic approaches. New discoveries in metabolic reprograming of both stromal and immune compartments will also likely lead to novel and exciting venues for preventions and treatments of autoimmune disorders and cancer. Those approaches could substantially help curtail the rising incidences of both autoimmunity and cancer, especially among the young, and thus reduce the burden of these two major types of diseases on humanity.AH researched and wrote the manuscript. AH and ZC designed the figures and conceived the theme and framework. ZC reviewed and edited the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


During inflammation, inflammatory cells are rapidly recruited to sites of infection or injury, where they cross physiological barriers around the infected site and further infiltrate into the tissues. Other cells, such as erythrocytes, endothelial cells and stem cells, also play prominent roles in host defense and tissue repair. In recent years, nanotechnology has been exploited to deliver drugs to sites of inflammation. For example, nanoparticles camouflaged with a cell membrane are a novel drug-delivery platform that can interact with the immune system and that show great potential for treating inflammation. Encapsulating drugs inside plasma membranes derived from various cells involved in inflammatory processes can be effective against inflammation. This review describes the preparation, characterization, and properties of various types of cell membrane-camouflaged biomimetic nanoparticles. It also summarizes preclinical research into their efficacy against inflammation. Inflammation is the normal immune response against harmful factors and insults such as pathogens, injuries and irritants , prolonging their circulation in the bloodstream and therefore drug delivery to the targeted site   (PLGA), poly(ε-caprolactone), gelatin, nanogel, liposome, porous silicon, gold nanoparticles and iron oxide nanoparticles  and zeta potential of the camouflaged nanoparticles are determined using dynamic light scattering  , they can cross physiological barriers to permeate tissue. Their surface receptors can bind to ligands on endothelium, allowing them to migrate to sites of inflammation  kill cancer cells and other infected cells. CTLs can promote target cell death (apoptosis) through a granule- and receptor-mediated mechanism (Qin et al., Platelets are enucleated blood cells that are derived from megakaryocytes. Platelets are major actors in hemostasis, thrombosis, inflammation as well as host and adaptive immune responses (Anitua et al., Staphylococcus aureus strain 252.Nanoparticles cloaked in platelet membrane have been shown to adhere selectively to damaged blood vessels and to bacteria that normally interact with platelets (Hu et al., Stem and precursor cells regulate differentiation and remodeling through paracrine effects, especially their capacity to migrate to damaged tissues, which is important for tissue repair and regeneration (Rennert et al. Biomimetic PLGA nanoparticles coated with stem cell membrane have been shown to selectively interact with damaged cardiac cells to protect the remaining myocardium and improve cardiac function in a mouse model of myocardial infarction (Tang et al., Escherichia coli OMVs to yield nanoparticles with a diameter of 41.9 ± 0.5 nm (Gao et al., OMVs from bacteria resemble–to the host–the bacteria from which they came, and the many bacterial surface antigens that they contain can stimulate a protective immune response (Gagliardi, Helicobacter pylori (Angsantikul et al., Helicobacter pylori infection in mice.Endothelial cells are widely present in the body and participate in a number of pathophysiological processes such as inflammation and tumors. Pathogens often act on molecules on the surface of endothelial cell membranes. For example, polymeric nanoparticles were loaded with the antibiotic clarithromycin and coated with membrane from gastric epithelial cells, allowing them to adhere to Staphylococcus aureus, which normally bind to platelets, and that neutralized pore-forming toxins such as α-toxin (Esteban-Fernández de Ávila et al., Researchers have broadened the possible characteristics and functions of membrane-camouflaged nanoparticles by fuzing membranes from multiple types of source cells. For example, wrapping gold nanowires in membranes mixed from RBCs and platelets generated nanoparticles that bound to Cell membrane-camouflaged biomimetic nanoparticles combine the intrinsic properties of the cells that served as the membrane source, with the functional versatility of the nanomaterial in the core. This provides new opportunities for prolonging time in circulation, reducing immunogenicity and targeting drug cargo. Better than synthetic drug delivery systems, natural cell membranes can avoid eliciting an immune response and their surface components can interact with receptors on target cells, such as at sites of inflammation or infection. Optimizing the source of the membranes and the composition of the nanoparticle core can lead to biomimetic nanoparticles with unique properties. Applying cell membrane-camouflaged biomimetic nanotechnology to inflammation has shown promise but its implementation in clinical treatments will be challenging because of the complexity and heterogeneity of the inflammatory microenvironment, as well as costly because of the design and production processes involved. By integrating nanotechnology, medicine, materials science, bioengineering and pharmaceutical science, it may be possible to reduce these costs and close the gap between preclinical research and clinical application.


Many people with neurological conditions experience challenges with movement. Although rehabilitation is often provided acutely and sub-acutely following the onset of a condition, motor deficits commonly persist in the long-term and are exacerbated by disuse and inactivity. Notably, motor rehabilitation approaches that incorporate exercise and physical activity can support gains in motor function even in the chronic stages of many neurological conditions. However, delivering motor rehabilitation on a long-term basis to people with chronic neurological conditions is a challenge within health care systems, and the onus is often placed on patients to find and pay for services. While neurological motor rehabilitation is largely the domain of physical and occupational therapists, kinesiologists may be able to complement existing care and support delivery of long-term neurological motor rehabilitation, specifically through provision of supported exercise and physical activity programs. In this perspective style review article, we discuss potential contributions of kinesiologists to advancing the field through exercise programming, focusing on community-based interventions that increase physical activity levels. We conclude with recommendations on how kinesiologists’ role might be further optimized towards improving long-term outcomes for people with chronic neurological conditions, considering issues related to professional regulation and models of care. An estimated 1 billion people live with neurological conditions, ranging from stroke and traumatic brain injury to neurodegenerative diseases . For sudPersistent and progressive losses in motor function commonly propel people with neurological conditions into a cycle of ever-declining health. Motor deficits interfere with performance of activities of daily living –10 and pThe primary aim of the article is to initiate conversation on whether long-term motor rehabilitation for adults with chronic neurological conditions might be advanced through greater and more deliberate integration of kinesiologists into the field. We begin with a brief overview of motor rehabilitation for people with chronic neurological conditions, discussing its premise, its relationship to exercise and physical activity, and barriers to participation. Next, we describe the scope of practice of a kinesiologist with consideration of where kinesiologists might fit within the traditional neurological motor rehabilitation team. Finally, we provide recommendations on how kinesiologists might be better utilized to complement existing motor rehabilitation services for people with chronic neurological conditions. We consider limitations of kinesiologists in working in the neurological rehabilitation field and acknowledge alternative approaches to improving access to long-term neurological motor rehabilitation. The discussion is framed within our research and clinical experiences with neurological rehabilitation in Canada and the United States but are relevant to other countries with similar health care resources.Most recovery of motor function after sudden neurological damage occurs in the initial 3 to 6 months post-injury during in- and out-patient rehabilitation . While tGiven that chronic neurological motor rehabilitation benefits are partly dependent on physical conditioning, there is a degree of overlap with what might be considered “exercise” or “physical activity” services. A distinction could be made that “rehabilitation” is delivered to improve function or reduce disability associated with a specific underlying condition or impairment , while “Generally, the neurological motor rehabilitation team includes an inter-disciplinary group of physiatrists, physical therapists, and occupational therapists, with supporting contributions from other health care providers such as recreational therapists, psychologists, and nurses , 4, 36. Kinesiology broadly refers to the scientific study of human movement . It is aThe broad scope of practice of kinesiologists could be perceived as a strength in terms of versatility of the profession; however, it also contributes to confusion about the distinct role of a kinesiologist relative to other health care professions , 44, parTo our knowledge, the practical contributions of kinesiologists to the neurological motor rehabilitation process have traditionally been minimal. With increased evidence that exercise and physical activity benefits most chronic health conditions including neurological conditions , there iA valuable and appropriate contribution that kinesiologists can make through a role in chronic neurological motor rehabilitation is in the delivery of community-based exercise programs. The relatively recent development of community-based exercise programs for people with chronic neurological conditions represents a positive shift in the field towards addressing the need for long-term, affordable motor rehabilitation services. Of note, some existing community-based programs, mainly targeted to people with chronic stroke, already utilize instructors with skillsets consistent with kinesiologist training –52. HereTIME™ is a community-based group exercise program that serves people who are ambulatory but experience balance and mobility challenges, including people with neurological conditions . In the Use of kinesiologists in community settings could move beyond general exercise programming to also include programs focused on re-acquisition of motor skills through task-oriented motor skill practice. Researchers in kinesiology-related departments across the world have advanced understanding of the neural control of movement and skill acquisition, and influenced the field of neurological rehabilitation e.g., –61. LikeOutside of community-based group program delivery, kinesiologists commonly work alongside physical and occupational therapists in private practice . In clinAlthough on a generally small scale that is inconsistent across locales, the examples we provided demonstrate that kinesiologists and people with related skillsets  are already being used to support exercise programming for people with chronic neurological conditions. Given the contributions that kinesiologists can, and to some extent already do, make to chronic neurological motor rehabilitation, development of established roles for kinesiologists could be a constructive step for the field toward enhancing long-term functional outcomes for people with neurological conditions. Specifically, the examples provided indicate that kinesiologists could play a crucial role in the expansion of community care for people with chronic neurological conditions. In this role, kinesiologists could complement the traditional neurological rehabilitation team towards providing increased opportunity for people to participate in motor rehabilitation activities on a long-term basis.A major challenge for the kinesiology profession in working with clinical populations in general is the lack of regulatory bodies that protect the public , such asAlthough more widespread regulation of kinesiologists is a critical step for the recognition of the profession, kinesiologists’ formal adoption into the neurological motor rehabilitation team may also depend on the establishment of neurological motor rehabilitation as a sub-field within kinesiology. Many undergraduate kinesiology programs offer concentrations of study, with some common concentrations including content relevant to chronic neurological motor rehabilitation . Likewise, related academic programs in “kinesiotherapy” that focus on using exercise as rehabilitation for people with functional limitations have a rich history in the United States . DevelopGiven the long-term nature of efforts to create regulatory bodies and establish concentrations of study, it is our current recommendation that kinesiologists working within a neurological motor rehabilitation team should have, at a minimum, an undergraduate degree in kinesiology from an accredited institution and be registered with a local professional association that requires participation in a professional liability insurance program . With tUltimately, the need for ongoing and often life-long exercise and motor rehabilitation services for people with neurological conditions , 5 suggeIn advance of this formal model of care, Fig. The use of remote technologies to deliver rehabilitation services could provide an efficient means of delivering in-home motor rehabilitation services to people with mobility and transportation barriers, or those who are geographically isolated from direct services . Beyond It could be argued that long-term neurological motor rehabilitation needs would be better met by expanding access to regulated health professionals, such as physical and occupational therapists, than by increasing the use of kinesiologists. The more advanced training of these therapists is critical for management of complex clinical issues and use of various relevant treatment techniques and modalities. Potential approaches to expanding access to physical and occupational therapists could involve increasing educational funding, development of programs that do not repeat training acquired by prior kinesiology program graduates, or modification of restrictive reimbursement patterns for therapeutic services. In our view, these are also necessary steps for the field of neurological motor rehabilitation but should not be considered exclusive alternatives to advancing the kinesiologist role. Instead, our view is that a more established role for kinesiologists that respects their proficiencies and limitations in working with this population will support increased access to, and more efficient use of, therapists’ skills and expertise.Long-term exercise and physical activity supports for motor rehabilitation for people with chronic neurological conditions are needed. Kinesiologists are movement practitioners with a skillset well-suited to contribute to such strategies, particularly through community-based exercise and physical activity programming. These programs supported by kinesiologists and targeted to people with neurological conditions benefit motor function but are not yet widely offered. Development of relationships among the traditional neurological rehabilitation team and kinesiologists through clinic-to-community models of care could be a step toward advancing kinesiologists’ role in improving long-term outcomes of people with chronic neurological conditions. Yet, lack of professional regulation in most jurisdictions remains a key challenge. Overall, this viewpoint is meant to serve as a starting point for further discussion as we work towards improving long-term motor rehabilitation outcomes for individuals with chronic neurological conditions.


In this review, we attempt to connect past research studies to new findings with animal models of cellular and neurotransmitter mediators of stress buffering to extreme fear generalization onto testable research and clinical concepts. Drawing on the greater impact of inescapability over unpredictability in animal models, we propose a mechanism by which ELA aggravates an exhaustive cycle of amygdala expansion and subsequent toxic-metabolic damage. We connect this neurobiological sequela to psychosocial mal/adaptation after ELA, bridging to behavioral studies of attachment, emotion processing, and social functioning. Lastly, we conclude this review by proposing a multitude of future directions in preclinical work and studies of humans that suffered ELA.Early life adversity (ELA), such as child maltreatment or child poverty, engenders problems with emotional and behavioral regulation. In the quest to understand the neurobiological sequelae and mechanisms of risk, the amygdala has been of major focus. While the basic functions of this region make it a strong candidate for understanding the multiple mental health issues common after ELA, extant literature is marked by profound inconsistencies, with reports of larger, smaller, and no differences in regional volumes of this area. We believe integrative models of stress neurodevelopment, grounded in “ The amygdala has been the focus of a great deal of attention in research aimed at understanding the effects of Early Life Adversity (ELA). The fact that this evolutionarily ancient brain structure is of interest is perhaps not surprising given this region's essential role in socioemotional functioning , extreme household dysfunction , and poverty . These and related negative experiences have been referred to using different umbrella terms, such as “early life stress,” “child trauma,” “toxic stress,” “early adversity,” and “Adverse Childhood Experiences (ACEs).” An important starting question is whether to lump adversities together, think about specific experiences , or examine potential shared dimensions of ELAs. Initial research took a purely cumulative exposure approach, summing up the total number of adversities suffered, or looking at child trauma externalizing psychopathology”). For example, greater disruptive behavior and conduct problems have been found in victims of child sexual abuse  being associated with child maltreatment , collectively the amygdala calculates the intensity of response to positive and negative emotional stimuli ; post-traumatic stress disorder (PTSD)] and some samples with autism have shown greater amygdala relative to brain volume continue to increase through adolescence, reaching maximum volumes in the late teens or early twenties. The exact age of these peaks is, however, dependent on the sex and pubertal dynamics of an individual  that found participants who reported two or more early-life events had significantly smaller amygdalae with increasing age  with these patterns should likely be greeted with skepticism. Moving away from hand-tracing, there are now many commonly available automated methods for amygdala volumetric quantification  often yield unsatisfactory results with high-variability and low-validity . When these investigators examined the full cohort, there were no significant effects detected. But, looking at age X ELA interactions, these investigators found that lower family income was significantly associated with smaller amygdala volumes in adolescence (13–21 years old). However, this relation was not seen for younger age children (3–12 years), suggesting important neurodevelopmental associations may only be revealed when considering ELA and developmental stage(s).Turning to issues with study designs, many investigations in humans have had a large age range of participants ; this is particularly important to note given amygdala developmental trajectories reviewed earlier. For example, LoPilato et al.  examinedU allostatic growth trajectory. High levels of stress initially increase amygdala volume, but the most extreme (or chronic) levels of adversity may result in smaller volumes. Support for this idea comes from multiple avenues. First, cross-sectional studies suggest complex associations between amygdala structure, the intensity of ELA, and developmental consequences of stress. For example, Mehta et al.  the amygdala is not a unitary brain area, but rather heterogenous subnuclei with unique functions and developmental trajectories , there is interruption of the normal excitation-inhibition balance in the amygdala. This may occur through multiple pathways and may explain a portion of the heterogeneity of structural results seen previously. First, stress may cause higher excitability in the basolateral amygdala, due to: increases in the number of spontaneously firing neurons , suggesting a common amygdala response in disorders of sustained distress  demonstrate atrophy. We believe research in rodents and non-human primates suggest a testable model about the factors driving this enlargement. As McEwen detailed in multiple reports about allostatic load, the body increases certain functions to meet the demands of the stress, but long-term adaptation is costlier than true homeostasis. Connected to this, Ghosh and Chattarji  examinedr et al.  demonstrIt is as yet unclear if there is an equivalent fear generalization in primates proportional to the intensity of an aversive stimulus, but this is likely the mechanism by which individuals suffering ELA proportionally over-activate their amygdalae. We predict that this metabolically costly effort to map the environmental space surrounding an intense aversive event represents a key function of the basolateral amygdala as defining the boundaries of danger cues so that safety can be achieved. This is in line with imaging findings and neural network modeling that suggest greatest recruitment in situations of uncertain danger  are related to either withdrawal from or overt aggression toward peers. While many may consider these divergent phenotypes, both may be appropriate (and learned) responses to environmental entrapment and an inability to map safety signals. Youth either fight, attempting to escape perceived entrapment; or eventually surrender under the belief that breaking free is not possible. Furthermore, ELA-exposed youth often make errors in encoding social cues, exhibit biases toward attributing hostile intent, generate more aggressive responses, and positively evaluate aggression as an appropriate response  can paradoxically produce an We can take this model one step further and consider how social buffering could lower the excitation:inhibition ratio of the amygdala so as not to rush experience-dependent plasticity during development. Zhang et al.  mapped rFeedforward safety signals likely reduce the average excitation:inhibition ratio of the amygdala, permitting a slower maturation throughout adolescence and possibly more DARPP-32 cells that could activate positive affects in safe contexts. If an environment offers few to no safety signals, this maturation is accelerated according to the allostatic load model, progressing more rapidly to dendritic outgrowth, higher excitation:inhibition and an early allostatic peak that likely compresses stress buffering periods. It is unknown, however if the lack of any parental safety signals during this critical period, most exemplified by institutional neglect, leads to amygdala shrinkage in the absence of additional adversity. This is particularly challenging given the high incidence of further adversity in foster care and may be better studied in children with diffuse attachment disorder. We speculate that the lack of safety learning during critical periods leads to limited psychological and emotion regulation resources, represented by the safety learning possibilities wired through the DARPP-32+ cells, to overcome challenges. Lack of social safety learning likely leads to inability to detect and avoid dangerous environments and individuals, ultimately leading to similar outcomes.Fortunately, future treatments may be able to mimic the temporal dynamics of dopamine signaling and repair or renew DARPP-32 cells in the basolateral complex, re-opening a window of plasticity for social safety learning. Consistent with this model, a single dose of the dopamine precursor L-DOPA/carbidopa facilitates fear extinction in rodents and humans through enhanced negative connectivity between ventromedial prefrontal regions and amygdala  when they are in these settings, and the global neglect they are experiencing may impinge upon attachment processes  experiences may not rise to the level of a “formal ELA.” For example, there is a litany of research on “expressed emotion” and risk for poor mental health  may be compensatory efforts to map environmental features to detect safety in the context of these stressors; however, with high-levels of psychosocial burden and/or limited social support (limited formation of DARPP-32+ escape solutions), no safety can be achieved so the amygdala churns away, reaching a terminal toxic-metabolic shrinkage. These psychosocial perceptions and neurobiological changes may indeed explain many “Deaths of Despair” in populations exposed to ELA  to probe markers of amygdala neurobiology, including cell density, membrane phosphocholines, second messenger turnover, and other critical molecular markers. The second author and his colleagues at University of Wisconsin-Madison . The seminal studies by Vyas et al. motivated a host of human studies on ELA; however, this work was completed in young adult rodents. Additional work that is often less highlighted, by Rosenkranz et al. completed similar stress manipulations and found many critical differences  in animals exposed to stress as juveniles vs. in adulthood. Little work, in our opinion, goes far enough to truly understand the true developmental impact of ELA. In line with recommendations from Callaghan et al. , it is aIn particular, we believe it will be important to consider the interaction of ELAs with stressors during childhood and also later in life. ELA may affect how individuals respond to subsequent life stressors and heighten risk for poor mental health  multiple, different stages of development. In addition, there may be psychosocial consequences of ELA that may increase the likelihood of volumetric shrinkage in exposed individuals. Such a developmental incorporation may have important insights for the prediction, prevention, and treatment of negative outcomes related to ELA. ELA may cause psychosocial  alterations at one time point, but individuals who have suffered these adversities keep engaging in, as well as creating, different experiences. Outcomes at later time points may be related to this initial adaptation, but also could be due to the interaction of early changes and current situational experiences. Clinically, those working with adversity-exposed populations often know that previous (negative) adaptations in their clients may create later residue that individuals who have suffered bring to the different situations that subsequently greet them. Connected to the ideas we advance above, future work will need to consider not just age and duration of a stressor, but also the “escapability” or proportion of contexts affected . Thoughtful execution of these multiple ideas, across preclinical and human studies, could significantly advance our understanding of the neurobiological sequelae of ELA, the mediating connections between ELA and psychopathology, and more basic science questions such as nature vs. nurture.Here, we put forward an integrated model of amygdala neurodevelopment to think about inconsistencies in research on ELA, as well as the behavioral consequences of adversity. We must all continue to dissect heterogeneity, think about theoretical integrations of stress neurobiology and developmental psychology, and clarify complex relationships between ELA and related long-term mental health challenges. We are excited to pursue many of the future directions we proposed here and would be excited about improvements in preclinical and human studies focused on early stress exposure. Continued progress in these spaces, potentially guided by the theoretical model laid out here could be particularly important for predicting, preventing, and treating the consequences of ELA.https://github.com/jlhanson5/Hanson_Nacewicz_Frontiers_Amygdala_Review_Data.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The authors owe a great debt to the late Dr. Bruce McEwen, whose careful measurement of the effects of sustained stress and theoretical extrapolation far beyond the timescale of typical research studies led to the model of Allostasis. His bridge from basic science studies of rodent neurons and synapses to human neuroimaging and behavior inspired us as neuroscientists. As this model has developed, it has become a fantastic tool for patient education in psychiatric practice (of BN) as a tangible mechanism by which fears expand or improve with treatment.Both authors contributed equally to the outlining, drafting, and writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cancer arises from a single cell through a series of acquired mutations and epigenetic alterations. Tumors gradually develop into a complex tissue comprised of phenotypically heterogeneous cancer cell populations, as well as noncancer cells that make up the tumor microenvironment. The phenotype, or state, of each cancer and stromal cell is influenced by a plethora of cell-intrinsic and cell-extrinsic factors. The diversity of these cellular states promotes tumor progression, enables metastasis, and poses a challenge for effective cancer treatments. Thus, the identification of strategies for the therapeutic manipulation of tumor heterogeneity would have significant clinical implications. A major barrier in the field is the difficulty in functionally investigating heterogeneity in tumors in cancer patients. Here we review how mouse models of human cancer can be leveraged to interrogate tumor heterogeneity and to help design better therapeutic strategies. Human tumors develop from single cells in which an accumulation of genetic and epigenetic alterations results in uncontrolled expansion. As cancer cells divide and tumor mass grows, several levels of tissue complexity and heterogeneity emerge .First, not all cancer cells are genetically identical within a tumor. Cancer cells constantly accumulate genetic differences during normal DNA replication and cell division and also as a direct consequence of environmental mutagens—including some cancer therapies. This genetic heterogeneity exists temporally as tumors expand, spread, and metastasize, but also spatially, with clones and subclones localizing in different areas of a tumor. Genetic heterogeneity has been shown to be a key factor driving tumor evolution and determining response to therapy. An impressive body of literature generated through analysis of human tumors has been reviewed extensively .Second, cells that are genetically identical (or highly similar) can generate diversity because of epigenetic differences. Changes in DNA methylation or chromatin structure can result in changes in cell fate and differentiation and can profoundly affect the biology of cancer cells. This epigenetic heterogeneity forms the basis for cell state differences between so-called cancer stem cells, which drive the long-term growth of tumors, and their progeny, which are often less capable of long-term expansion due to loss of stem-like features such as self-renewal and extended proliferative capacity ?These questions are often challenging to address in cancer patients because we nearly always lack the ability to investigate human tumors spatially and temporally. Some exceptions include cancers such as breast and colon cancer, in which samples are easier to obtain due to tissue site, or studies like TRACERx [TRAcking Cancer Evolution through therapy (Rx)], in which repeat biopsies are included . Still, Genetically engineered mouse models (GEMMs) of human disease can help bridge some of the major gaps in human studies. In the past three decades following the development of the first transgenic mice expressing oncogenes, mouse models of human cancer have reached a great level of sophistication and accuracy. The development of inducible models in which oncogenes can be activated and tumor suppressors can be inactivated in a spatially and temporally controlled manner has allowed human cancer development to be modeled very precisely . While tSome aspects of human cancer development are difficult to model in mice, including large tumor size or the long period of tumor development  has recently emerged as the contemporary gold standard approach for molecularly defining cell states (or phenotypes) . The senhttps://github.com/arnavm/multimodal-scRNA-seq for a list of these technologies).These approaches can be combined or substituted with other methods such as mass cytometry  and mulAn important issue in tumor heterogeneity is to understand mechanisms underlying cell fate determination. To do this, one must be able to connect the cell’s present  state with its ancestry. scRNA-seq, coupled to an expanding set of sophisticated computational methods, provides a platform for inferring clonal relationships based on the similarity (or dissimilarity) of the cells’ transcriptional profiles . These cAlthough increasingly powerful, computational inference methods do not provide definitive information on clonal relationships in tissues. Spontaneous somatic mutations enable the retrospective reconstruction of lineage trees in tissues, which has been widely applied to both human and mouse tumors e.g., . RecentlA gold standard approach for determining the fate of a particular cellular lineage in developmental biology studies is to use lineage tracing . In such experiments, a subset of cancer or stromal cells can be genetically labeled by a heritable genetic mark . Thus, any descendants of labeled cells will inherit this genetic mark, enabling evaluation of the potential of a cell type to contribute to tumor growth or various components of the stroma . This clRecent years have witnessed an explosion in the number and versatility of available lineage-tracing techniques . One app+ or CD8+ T cells, B cells, or natural killer cells , is placed under the control of gene regulatory elements that specifically mark a cell type of interest. Mouse cells are not sensitive to diphtheria toxin (DT), an extremely potent cytotoxic peptide, because they do not express DTR. This enables the selective ablation of a cancer or stromal cell subpopulation of interest by systemic delivery of DT . In addils e.g., . In addils e.g., . Cell-abls e.g., .This combination of approaches to investigate single cells and genetic tools to model cancer and to trace cell lineages offers extremely promising avenues to track heterogeneity in tumors in mouse models.The field of mouse models of cancer is vast, and an increasing number of studies have begun to interrogate cancer heterogeneity. Here we chose to discuss specific examples in which mouse models have already provided novel insights into cancer biology linked to the three types of heterogeneity discussed above . We have chosen to focus predom-inantly, but not exclusively, on lung cancer, which accounts for more deaths worldwide than breast, prostate, colon, kidney, and liver cancer combined; lung cancer thus continues to be a challenge for therapeutic interventions and an area of intense study. Notably, GEMMs for lung cancer provide accurate models of multiple aspects of lung cancer biology.Early detection of cancer is usually associated with better survival rates for patients, as small tumors are easier to resect and early-stage cancer has often not spread to other sites. For many human cancers, however, the earliest stages of tumorigenesis are challenging if not impossible to investigate. In particular, it is virtually impossible in most cases to identify the cell type from which a solid tumor arises—a notable exception includes recent studies on human retinoblastoma, which led to the identification of cone precursors in the fetal retina as a cell type of origin . The ideKras oncogene (KrasG12D) in different epithelial cell types in the lung epithelium, such as alveolar type II cells or bronchiolar club cells, gives rise to cancerous adenoma lesions that initially appear histologically distinct  and had increased metastatic potential. Transcriptional and chromatin profiling experiments indicate that the hair follicle stem cells are epigenetically primed to undergo EMT during tumorigenesis  shows that these tumors can arise from distinct cell populations in the lung epithelium  . The tumThese observations of an epigenetic memory of the cell type of origin months after cancer initiation, and of different genetic mechanisms of tumorigenesis dependent on the cell type of origin, emphasize the critical need to better understand the early stages of cancer development in patients.The large majority of cancer patients die from metastases seeded by the primary tumor. In many cases, patients with metastases do not undergo resection of these disseminated tumors, as resection poses some risks and, in most cases, does not improve survival. This limited tissue access is one major reason why the mechanisms of metastasis remain less well understood than other mechanisms of tumorigenesis  as a suppressor of metastatic progression  to full-blown PDAC, as well as the development of a fibrous, desmoplastic stroma that hinders drug delivery and impairs the infiltration of cytotoxic T lymphocytes  have also been developed. In these models, Kras is activated and p53 is mutated by using a Cre-Lox strategy, where Cre is expressed under a pancreatic epithelial cell-specific phocytes . PDAC inphocytes . Subsequphocytes . The traphocytes .Thus, the ability to track and isolate pure populations of cancer cells and the comparative analysis of primary tumors and their metastases in mouse models can help identify key genetic and epigenetic changes during tumor progression that control the metastatic spread of lung cancer cells. These experiments define several levels of intra- and intertumoral heterogeneity that are difficult to identify in cancer patients.An appealing model of tumor growth is based on cancer stem cells . In this model, cancer is a hierarchical structure in which a subset of cancer cells are critical for the long-term expansion of a tumor; through their ability to give rise to differentiated progeny, these cancer stem cells, like stem cells in normal tissues, are also responsible for the cellular heterogeneity of tumors (reviewed by high mesenchymal SCLC cells (For example, the aggressive nature of SCLC may suggest that these tumors do not follow the hierarchical cancer stem cell model—perhaps all types of cancer cells can propagate tumors in the long term? However, it has been known for a long time that SCLC cell populations show heterogeneity in the expression of cell surface receptors . Indeed,LC cells . ImportaLC cells . Thus, wLgr5 is specifically expressed in stem cells in various epithelial tissues (+ cell subset suppressed tumor growth and eradicated liver metastases (+ cells were depleted, a subset of the Krt20+/Lgr5− colon cancer cells were capable of reverting to Lgr5+ stem-like cells by entering the niche vacated by the ablated Lgr5+ cells (Stem cells have the capacity to self-renew while also producing differentiated cells. In normal tissues, these choices are primarily dictated by extrinsic signaling factors, which, together with the cells that produce them, comprise a niche with a short range of action, which limits the number of stem cells. Among the niche signals that promote stem cell phenotypes, secreted Wnt proteins are notable due to their function in multiple stem cell compartments. The Wnt target gene  tissues . Lineage tissues . Convers tissues . In colotastases . Interes5+ cells . These fG12D and loss of p53, we demonstrated that these tumors showed hierarchical features with two distinct cancer cell subpopulations: one with increased Wnt signaling activity, and another forming a niche that provides the Wnt signal (Signals that induce and maintain stem-like cells in cancer can present useful targets for therapeutically targeting tumor heterogeneity. Using a lung adenocarcinoma model driven by activation of Krast signal . We fount signal . The celt signal .+ glioblastoma stem cells (+ glioblastoma cells in combination with chemotherapy resulted in an inhibition of glioma progression in the cerebra of treated mice (The diversity of cellular states within tumors poses a challenge for effective cancer treatments: Cancer cells capable of withstanding and adapting to therapies invariably exist. The identification and therapeutic manipulation of such intrinsically resistant cellular subtypes can lead to improved outcomes . For exaem cells . These cted mice .These studies highlight the power of mouse models in enabling discoveries with profound translational potential that would be impossible in human patients. Future studies will continue to leverage these models to improve the design of therapies in patients and to enable identification of fundamental mechanisms of tumorigenesis.


Results illustrate that the short video, as part of our food communications, positively shapes consumer perception towards meat quality, labelling and traceability trust of Australian beef but has only slight or even negative effects on WTP. This could be due to the short video offering consumers a sense of supply chain visibility but not delivering the right messages to meet their expectation of blockchain credentials. Furthermore, short video storytelling effects vary among consumers with different socio-economic characteristics. Our results posit that short video storytelling can be a useful tool in communicating blockchain-credentialed food products but require the design of a tailor-made storytelling experience for diverse consumers.Short videos have become the most-liked medium for Chinese consumers to learn about a brand’s products or services. This paper assesses how short video storytelling shapes Chinese consumers’ perceptions towards blockchain-credentialed Australian beef and their willingness to pay (WTP). A controlled experiment with a one-minute short video was implemented in an online survey. Respondents in the treatment group watched the video before filling out the survey, whereas respondents in the control group did not. The paper analyses and compares the empirical results from local ( Globally consumers are looking for authentic food products that are safe and healthy . This isAustralian beef products are exposed to a higher counterfeiting risk in China . To builDigital technology has significantly changed the way to access and consume information. It is reported that 72% of people prefer watching a video over texts to learn about a product or service . ChineseThis paper fills these research gaps and examines the effects of short video storytelling in delivering blockchain-credentialed Australian beef products following an exploratory research approach. The study investigates the effects of a one-minute short video storytelling on consumer perceptions with respect to meat quality, trust in labelling and traceability data, and willingness to pay (WTP) using an in-field survey administered in control and treatment settings. The contribution of this study is two-fold. First, it offers an understanding of how a one-minute short video can shape Chinese consumers’ quality and trust perceptions towards blockchain-credentialed Australian beef products and its impact on WTP from a storytelling perspective. Second, it identifies those effects of short video storytelling vary among consumers with different socio-economic characteristics, which highlights the need for using diverse video strategies when targeting different groups of consumers.Following the introduction section, We review relevant literature pertaining to digital storytelling and short videos  and foodDigital storytelling refers to the way of using digital tools to tell stories, and store and exchange those stories on websites and social media networks in the Internet era ,22. The Digital technology has changed the ways of creating and consuming narrative stories ,35. AlthConsumer perception refers to an information process involving consumer exposure and attention to marketing stimuli and consumer interpretation to create a meaningful image and brand identity ,43. WhilA growing number of studies have explored customer perception of food products in terms of quality, label, traceability, authenticity and so on ,54,55,56The effects of how short video storytelling shapes consumers’ perceptions towards food quality, label trust and traceability of blockchain-credentialed Australian beef and affects their willingness to pay (WTP) were measured with a controlled experiment. The controlled experiment is exploratory in nature, consisting of a one-minute short video and six questions  that comThe one-minute video -illustrated the use of blockchain to verify key stages from paddock to plate and introduced people and stakeholders from local food production communities in regional South Australia and other supply chain participants. To ascertain food quality perception, the study examined whether Chinese consumers perceive Australian beef products cut and packed in Australia to be superior to those processed in China. Consumer trust in food labelling was measured by examining consumers’ level of certainty in the food provenance of the beef labelled ‘Australian cut and packed.’ The traceability trust refers to the level of consumer trust in the traceability information attached with the beef package via a digital fingerprint . The WTPRespondents were randomly assigned into either the control or the treatment group to answer the questions illustrated in wj.qq.com) that allows the delivery via WeChat to invited event attendees.The survey was conducted during a series of showcase dinner events across China’s four metropolitan cities Shanghai, Shenzhen, Beijing and Guangzhou from 18 to 25 November 2019. The survey was administered using an online survey platform  with respect to trust and meat quality perceptions between the control and treatment groups are found at a 95% confidence level for both local and foreign respondents. In other words, while our short video storytelling increases consumer perceptions towards meat quality, label trust and traceability trust, it did not yield significantly comparative differences.U test for WTP variables between groups. No significant differences  for WTP between the control and treatment groups were observed at a 95% confidence level for both local and foreign respondents. This means that our short video intervention did not yield significant differences.Little is known about the effect of digital storytelling on consumer perceptions and behaviours in the food industry. Our results corroborate findings of previous studies that focuses on consumer perceptions and purchase decisions but also demonstrate new insights into the use of digital video storytelling in a new field. Comparing the responses from the control and treatment groups shows that our short video storytelling intervention increases consumer trust in the Australian ‘portion cut and packaged’ label and traceability information. This can be attributed to the improved transparency of the supply chain processes, which has been revealed in previous work . Most loFüzesi et al.  found a U tests for consumer trust and quality perceptions between the control and treatment groups show no significant differences at a 95% confidence level for both local and foreign respondents. Similarly, there are no significant differences at a 95% confidence level between treatments and controls in WTP price thresholds. These results show that while our current short video storytelling intervention increases consumer perceptions towards trust in food labelling and traceability data as well as quality, it is not powerful enough to yield significant differences when comparing results between the control and treatment groups.Our research investigated consumer trust and perception research in a comparative setting, which differs from early research. The Mann–Whitney Aligning with early consumer behaviour research in the food industry, our study explored if the effect of short video storytelling differs among consumers’ social-demographic characteristics. Our results contradict previous studies exploring consumers’ willingness to pay a premium for traceability certified beef  and consThis study underpins the Stimulus-Organism-Response (S-O-R) theory from the perspective of a short video storytelling intervention. The S-O-R theory posits that an individual’s response is driven by their exposure to environmental stimuli  and therThis study also offers practical contributions to knowledge. Videos have become a powerful marketing tool, which is used by 86% businesses surveyed in 2021 . AccordiUsing short video storytelling to interpret blockchain credentials leads to changes in consumer confidence and trust in Australian beef products processed in Australia and China. This finding provides additional benefits to Australian businesses building China-based processing plants and Chinese food importers. Our ANOVA results reveal that short video storytelling effects vary among consumers according to different socio-economic characteristics. With this understanding, businesses should be aware of the importance of identifying how to deliver the right digital content information to the targeted population when they use short video for product storytelling. Furthermore, short videos can be an effective and entertaining tool to convey authentic food provenance stories and offer a new and emerging genre of consumer information in the complex and rapidly changing digital world, where consumers are already exposed to an overabundance of information in their everyday lives.This present study implemented and tested a controlled experiment to investigate the effects of a short video storytelling intervention on consumer perceptions of meat quality, label, and traceability trust and on willingness to pay among consumers in China. By comparing the responses from local and foreign respondents in the control and treatment settings, our exploratory study revealed that while the short video storytelling intervention did not yield significant differences between the control and treatment groups, it did have a positive influence on consumer  perception of quality and trust of Australian beef. Further, the effect of the short video storytelling intervention varies among consumers according to different socio-economic characteristics. The novelty of this study lies in offering an understanding of how short video storytelling can shape consumers’ quality and trust perceptions towards Blockchain-credentialed Australian beef and affect WTP from a short video storytelling perspective.Although offering valuable early insights, this study has a few limitations that can prompt inspiration for further research. First, our study is exploratory in nature with a relatively small sample of 103 consumers situated in four metropolitan cities in China, which could lead to biased results. Accordingly, further research is required in order to produce findings generalisable to a broader context. Additionally, comparative research looking at potential differences in consumer perceptions depending on residency in different Chinese city tiers may deliver interesting results . Second,Given the exploratory nature of our study and the abovementioned limitations, further studies are suggested to evaluate the role and impact of short video storytelling more comprehensively, with either more controlled experiments or qualitative research approaches. Measuring the effectiveness of short videos in comparison with other multimedia tools is also a promising research direction. As short videos can be presented with user-generated content (UGC) and professional-generated content (PGC), future research could also be tasked with providing new insights into the value of short video storytelling by comparing the effects of UGC and PGC. Finally, as consumer perceptions are not stable but rapidly evolving over time , future