PVR (poliovirus receptor) functions as a ligand that signals through TIGIT and CD96 to induce suppression of T-cell and NK-cell responses. Alternatively, PVR binds to CD226, resulting in a ...co-stimulatory signal. To date, TIGIT antibody antagonists have been developed to restore immune functions and allow PVR to signal though CD226 in the context of cancer immunotherapy. Due to PVR receptor heterogeneity, agonizing either of these pathways with a recombinant form of the PVR extracellular domain represents a therapeutic strategy for either immunosuppression or activation. Here, we developed a minimal murine PVR-Fc fusion construct, consisting of only the IgV domain of PVR (vdPVR-Fc), and assessed its ability to dampen inflammatory responses in a murine model of psoriasis. vdPVR-Fc and PVR-Fc containing the full-length extracellular domain bound to TIGIT, CD96 and CD226 with similar low nanomolar affinities as defined by surface plasmon resonance. vdPVR-Fc was also able to suppress the in-vitro proliferation of murine CD4
and CD8
T-cells in mixed splenocyte cultures. Importantly, vdPVR-Fc delayed the onset, and reduced inflammatory responses (scaling and thickness) in a murine model of psoriasis. Collectively, our results suggest that the minimal IgV domain of PVR is sufficient to dampen immune responses in-vitro and attenuate symptoms of psoriasis in-vivo.
Depression is a disease driven by dynamic processes both at the individual- and system-level. System dynamics (SD) models are a useful tool to capture this complexity, project the future prevalence ...of depression and understand the potential impact of interventions and policies. SD models have been used to model infectious and chronic disease, but rarely applied to mental health. This scoping review aimed to identify population-based SD models of depression and report on their modelling strategies and applications to policy and decision-making to inform research in this emergent field.
We searched articles in MEDLINE, Embase, PsychInfo, Scopus, MedXriv, and abstracts from the System Dynamics Society from inception to October 20, 2021 for studies of population-level SD models of depression. We extracted data on model purpose, elements of SD models, results, and interventions, and assessed the quality of reporting.
We identified 1899 records and found four studies that met the inclusion criteria. Studies used SD models to assess various system-level processes and interventions, including the impact of antidepressant use on population-level depression in Canada; the impact of recall error on lifetime estimates of depression in the USA; smoking-related outcomes among adults with and without depression in the USA; and the impact of increasing depression incidence and counselling rates on depression in Zimbabwe. Studies included diverse stocks and flows for depression severity, recurrence, and remittance, but all models included flows for incidence and recurrence of depression. Feedback loops were also present in all models. Three studies provided sufficient information for replicability.
The review highlights the usefulness of SD models to model the dynamics of population-level depression and inform policy and decision-making. These results can help guide future applications of SD models to depression at the population-level.
Abstract Integrating hydrogeomorphological (HGM) principles into the restoration of degraded rivers can achieve sustainable results and provide various human benefits. HGM principles mainly involve ...understanding the context and processes that shape a fluvial system before any intervention, in order to support its dynamism and to align with its potential functioning and uses. Despite recent management approaches inspired by HGM principles, most restoration projects carried out in Quebec (Canada) are not process‐based and target specific one‐dimensional objectives. Although there is an overall lack of post‐project monitoring, several projects appear to have failed or had mixed success. This research aims to shed light on the diversity of societal drivers behind river restoration projects and to examine how they influence the integration of HGM principles and human benefits. Four restoration projects were characterized through participant observation and interviews with the organizations running them. Representatives of two ministries involved in river restoration and management were also interviewed. The results show that projects were mainly shaped by public acceptance disregarding HGM principles, which can lead to poorly‐informed action. Project funding and stakeholders' expertise have also challenged project implementation and played a key role in defining their objectives. The addition of these components improve the current analytical frameworks for identifying river restoration objectives. Depending on specific sociocultural, political and legislative contexts, funding programs and stakeholders' expertise may either facilitate or restrict the integration of HGM principles and human benefits in the projects. Recognizing these key drivers reframes river restoration as a fundamentally social activity and enlightens how they could impel innovative approaches towards more sustainable results.
Common carotid artery intima-media thickness (IMT) progression was compared between 4 years of treatment with nifedipine and diuretic.
This study, ancillary to the International Nifedipine GITS ...Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), involved nifedipine 30 mg or co-amilozide (hydrochlorothiazide 25 mg and amiloride 2.5 mg) with optional subsequent titration. Among 439 randomized hypertensive patients, 324 had >/=1 year of follow-up (intent-to-treat group), and 242 completed follow-up (until-end-of-study group). Ultrasonography was performed at baseline, 4 months later, and then every year. Central computerized reading provided far-wall IMT, diameter, and cross-sectional area IMT (CSA-IMT). The primary outcome was IMT progression rate (slope of IMT-time regression). Secondary outcomes were changes from baseline (Delta) in IMT, diameter, and CSA-IMT. In the until-end-of-study population, between-treatment differences existed in IMT progression rate (P=0.002), Delta IMT (P=0.001), and Delta CSA-IMT (P=0.006), because IMT progressed on co-amilozide but not on nifedipine. In the intent-to-treat population, treatment differences existed in Delta IMT (P=0.004) and Delta CSA-IMT (P=0.04) but not in IMT progression rate (P=0.09). Patients with >/=2, 3, or 4 years of follow-up showed treatment differences in IMT progression rate (P=0.04, 0.004, 0.007, respectively), Delta IMT (P=0.005, 0.001, 0.005), and Delta CSA-IMT (P=0.025, 0.013, 0.015). Diameter decreased more on co-amilozide than on nifedipine in the intent-to-treat population (P<0.05), whereas blood pressure decreased similarly on both treatments.
A difference in early carotid wall changes is shown between 2 equally effective antihypertensive treatments.
Protein-based nanobubbles such as halophilic archaeabacterial gas vesicles (GVs) represent a new class of stable, homogeneous nanoparticles with acoustic properties that allow them to be visualized ...by ultrasound (US) waves. To design GVs as theranostic agents, we modified them to respond to light, with a view to locally generate reactive oxygen species that can kill cancer cells. Specifically, up to 60,000 photoreactive chlorin e6 (Ce6) molecules were chemically attached to lysine ε-amino groups present on the surface of each purified Halobacterium sp. NRC-1 GV. The resulting fluorescent NRC-1 Ce6-GVs have dimensions comparable to that of native GVs and were efficiently taken up by human breast MCF-7 and human hypopharyngeal FaDu-GFP cancer cells as monitored by confocal microscopy and flow cytometry. When exposed to light, internalized Ce6-GVs were 200-fold more effective on a molar basis than free Ce6 at killing cells. These results demonstrate the potential of Ce6-GVs as novel and promising nanomaterials for image-guided photodynamic therapy.
Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with recurrent thunderclap headaches and is characterized by multifocal and reversible vasoconstriction of cerebral arteries that ...can sometimes evolve to severe cerebral ischemia and stroke. We describe the case of a patient who presented with a clinically typical RCVS and developed focal neurological symptoms and signs despite oral treatment with calcium channel blockers. Within hours of neurological deterioration, she was treated with intra‐arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained neurological improvement.
Polycationic macromolecules and cationic peptides acting as PTDs (protein transduction domains) and CPPs (cell-penetrating peptides) represent important classes of agents used for the import and ...delivery of a wide range of molecular cargoes into cells. Their entry into cells is typically initiated through interaction with cell-surface HS (heparan sulfate) molecules via electrostatic interactions, followed by endocytosis of the resulting complexes. However, the endocytic mechanism employed (clathrin-mediated endocytosis, caveolar uptake or macropinocytosis), defining the migration of these peptides into cells, depends on parameters such as the nature of the cationic agent itself and complex formation with cargo, as well as the nature and distribution of proteoglycans expressed on the cell surface. Moreover, a survey of the literature suggests that endocytic pathways should not be considered as mutually exclusive, as more than one entry mechanism may be operational for a given cationic complex in a particular cell type. Specifically, the observed import may best be explained by the distribution and uptake of cell-surface HSPGs (heparan sulfate proteoglycans), such as syndecans and glypicans, which have been shown to mediate the uptake of many ligands besides cationic polymers. A brief overview of the roles of HSPGs in ligand internalization is presented, as well as mechanistic hypotheses based on the known properties of these cell-surface markers. The identification and investigation of interactions made by glycosaminoglycans and core proteins of HSPGs with PTDs and cationic polymers will be crucial in defining their uptake by cells.
In the wake of prominent theoreticians in developmental science, whose contributions we review in this article, many developmental psychologists came to endorse a systems approach to understanding ...how the individual, as it develops, establishes functional relationships to social ecological contexts that from birth to school entry rapidly increase in complexity. The concept of developmental cascade has been introduced in this context to describe lawful processes by which antecedent conditions may be related with varying probabilities to specified outcomes. These are understood as processes by which function at one level or in one domain of behavior affect the organization of competency in later developing domains of general adaptation. Here we propose a developmental sequence by which the developing child acquires regulative capacities that are key to adjustment to a society that demands considerable control of emotional and cognitive functions early in life. We report empirical evidence showing that the acquisition of regulative capacities may be understood as a cascade of shifts in control parameters induced by the progressive integration of biological, transactional, and socioaffective systems over development. We conclude by suggesting how the developmental process may be accessed for effective intervention in populations deemed "at risk" for later problems of psychosocial adjustment.
Photovoice is a participatory action research method in which participants take and narrate photographs to share their experiences and perspectives. This method is gaining in popularity among health ...researchers. Few studies, however, have described virtual photovoice data collection despite the growing interest among qualitative health researchers for online data collection. As such, the aim of this article is to discuss the implementation of a virtual photovoice study and presents some of the challenges of this design and potential solutions. The study examined issues of social isolation and mental health among older adults during the COVID-19 pandemic in the Canadian province of Québec. Twenty-six older adults took photographs depicting their experience of the pandemic that were then shared in virtual discussion groups. In this article, we discuss three key challenges arising from our study and how we navigated them. First, we offer insights into managing some of the technical difficulties related to using online meeting technologies. Second, we describe the adjustments we made during our study to foster and maintain positive group dynamics. Third, we share our insights into the process of building and maintaining trust between both researchers and participants, and amongst participants. Through a discussion of these challenges, we offer suggestions to guide the work of health promotion researchers wishing to conduct virtual photovoice studies, including with older adults.
Understanding the principles by which agents interact with both complex environments and each other is a key goal of decision neuroscience. However, most previous studies have used experimental ...paradigms in which choices are discrete (and few), play is static, and optimal solutions are known. Yet in natural environments, interactions between agents typically involve continuous action spaces, ongoing dynamics, and no known optimal solution. Here, we seek to bridge this divide by using a "penalty shot" task in which pairs of monkeys competed against each other in a competitive, real-time video game. We modeled monkeys' strategies as driven by stochastically evolving goals, onscreen positions that served as set points for a control model that produced observed joystick movements. We fit this goal-based dynamical system model using approximate Bayesian inference methods, using neural networks to parameterize players' goals as a dynamic mixture of Gaussian components. Our model is conceptually simple, constructed of interpretable components, and capable of generating synthetic data that capture the complexity of real player dynamics. We further characterized players' strategies using the number of change points on each trial. We found that this complexity varied more across sessions than within sessions, and that more complex strategies benefited offensive players but not defensive players. Together, our experimental paradigm and model offer a powerful combination of tools for the study of realistic social dynamics in the laboratory setting.
PDF
