Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286, a novel retinoic acid receptor-ß agonist for treatment of spinal cord injury, in male healthy participants.

AIMS: KCL-286 is an orally available agonist that activates the retinoic acid receptor (RAR) ß2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population. METHODS: The design was a double blind, randomized, placebo-controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARß2 mRNA expression was evaluated in white blood cells. RESULTS: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration-time curve up to 24 h showing a trend to subproportionality with dose. RARß2 was upregulated by the investigational medicinal product in white blood cells. CONCLUSION: KCL-286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL-286 as a novel oral treatment for SCI.

A global portrait of expressed mental health signals towards COVID-19 in social media space.

Globally, the COVID-19 pandemic has induced a mental health crisis. Social media data offer a unique opportunity to track the mental health signals of a given population and quantify their negativity towards COVID-19. To date, however, we know little about how negative sentiments differ across countries and how these relate to the shifting policy landscape experienced through the pandemic. Using 2.1 billion individual-level geotagged tweets posted between 1 February 2020 and 31 March 2021, we track, monitor and map the shifts in negativity across 217 countries and unpack its relationship with COVID-19 policies. Findings reveal that there are important geographic, demographic, and socioeconomic disparities of negativity across continents, different levels of a nation's income, population density, and the level of COVID-19 infection. Countries with more stringent policies were associated with lower levels of negativity, a relationship that weakened in later phases of the pandemic. This study provides the first global and multilingual evaluation of the public's real-time mental health signals to COVID-19 at a large spatial and temporal scale. We offer an empirical framework to monitor mental health signals globally, helping international authorizations, including the United Nations and World Health Organization, to design smart country-specific mental health initiatives in response to the ongoing pandemic and future public emergencies.

Community resilience to crime: A study of the 2011 Brisbane flood.

Understanding and enhancing community resilience is a global priority as societies encounter a rising number of extreme weather events. Given that these events are typically both sudden and unexpected, community resilience is typically examined after the disaster so there can be no before and after comparisons. As such, the extent to which existing community capacities buffer the effects of a traumatic event remains largely unexamined and untested in the literature. Drawing on a longitudinal study of 148 Brisbane suburbs, we examine the key community processes associated with community resilience to the crime before and after the 2011 Brisbane floods. We introduce a novel disaster severity index to simultaneously capture the direct and indirect impacts of the flood and embed this measure within our modeling framework. Results from the models provide important insights for predisaster preparedness and postdisaster rebuilding and recovery.

The socio-spatial determinants of COVID-19 diffusion: the impact of globalisation, settlement characteristics and population.

BACKGROUND: COVID-19 is an emergent infectious disease that has spread geographically to become a global pandemic. While much research focuses on the epidemiological and virological aspects of COVID-19 transmission, there remains an important gap in knowledge regarding the drivers of geographical diffusion between places, in particular at the global scale. Here, we use quantile regression to model the roles of globalisation, human settlement and population characteristics as socio-spatial determinants of reported COVID-19 diffusion over a six-week period in March and April 2020. Our exploratory analysis is based on reported COVID-19 data published by Johns Hopkins University which, despite its limitations, serves as the best repository of reported COVID-19 cases across nations. RESULTS: The quantile regression model suggests that globalisation, settlement, and population characteristics related to high human mobility and interaction predict reported disease diffusion. Human development level (HDI) and total population predict COVID-19 diffusion in countries with a high number of total reported cases (per million) whereas larger household size, older populations, and globalisation tied to human interaction predict COVID-19 diffusion in countries with a low number of total reported cases (per million). Population density, and population characteristics such as total population, older populations, and household size are strong predictors in early weeks but have a muted impact over time on reported COVID-19 diffusion. In contrast, the impacts of interpersonal and trade globalisation are enhanced over time, indicating that human mobility may best explain sustained disease diffusion. CONCLUSIONS: Model results confirm that globalisation, settlement and population characteristics, and variables tied to high human mobility lead to greater reported disease diffusion. These outcomes serve to inform suppression strategies, particularly as they are related to anticipated relocation diffusion from more- to less-developed countries and regions, and hierarchical diffusion from countries with higher population and density. It is likely that many of these processes are replicated at smaller geographical scales both within countries and within regions. Epidemiological strategies must therefore be tailored according to human mobility patterns, as well as countries' settlement and population characteristics. We suggest that limiting human mobility to the greatest extent practical will best restrain COVID-19 diffusion, which in the absence of widespread vaccination may be one of the best lines of epidemiological defense.

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells.

In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARß) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARß agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARß and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARß) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARß agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca2+ pathway. Although RARß has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARß and RARα in remyelination.

Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities. METHODS: We measured levels of the integrin α4ß7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts. RESULTS: We found that Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4ß7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium. CONCLUSIONS: Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4ß7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.

The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor ß signaling.

Neuronal regeneration is a highly energy-demanding process that greatly relies on axonal mitochondrial transport to meet the enhanced metabolic requirements. Mature neurons typically fail to regenerate after injury, partly because of mitochondrial motility and energy deficits in injured axons. Retinoic acid receptor (RAR)-ß signaling is involved in axonal and neurite regeneration. Here we investigate the effect of RAR-ß signaling on mitochondrial trafficking during neurite outgrowth and find that it enhances their proliferation, speed, and movement toward the growing end of the neuron via hypoxia-inducible factor 1α signaling. We also show that RAR-ß signaling promotes the binding of the mitochondria to the anchoring protein, glucose-related protein 75, at the growing tip of neurite, thus allowing them to provide energy and metabolic roles required for neurite outgrowth.-Trigo, D., Goncalves, M. B., Corcoran, J. P. T. The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor ß signaling.

Recent advances in the design of RAR α and RAR ß agonists as orally bioavailable drugs. A review.

Retinoic acid receptors (RARs) α, ß, and γ are members of the nuclear receptor superfamily. Compounds which bind to and activate the RARs are termed retinoids which regulate a wide variety of biological processes such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation, and apoptosis, as well as their disorders. Although many synthetic selective RARα, RARß, and RARγ agonists have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARß agonists with low lipophilicity that are orally bioavailable and less toxic have been developed, that have a range of potential therapeutic uses. This review covers these new advances.

Transport-related walking among young adults: when and why?

BACKGROUND: The existing smartphones' technology allows for the objective measurement of a person's movements at a fine-grained level of geographic and temporal detail, and in doing so, it mitigates the issues associated with self-report biases and lack of spatial details. This study proposes and evaluates the advantages of using a smartphone app for collecting accurate, fine-grained, and objective data on people's transport-related walking. METHODS: A sample of 142 participants (mostly young adults) was recruited in a large Australian university, for whom the app recorded all their travel activities over two weekdays during August-September 2014. We identified eight main activity nodes which operate as transport-related walking generators. We explored the participants' transport-related walking patterns around and between these activity nodes through the use of di-graphs to better understand patterns of incidental physical activity and opportunities for intervention to increase incidental walking. RESULTS: We found that the educational node - in other samples may be represented by the workplace - is as important as the residential node for generating walking trips. We also found that the likelihood of transport-related walking trips is larger during the daytime, whereas at night time walking trips tend to be longer. We also showed that patterns of transport-related walking relate to the presence of 'chaining' trips in the afternoon period. CONCLUSIONS: The findings of this study show how the proposed data collection and analytic approach can inform urban design to enhance walkability at locations that are likely to generate walking trips. This study's insights can help to shape public education and awareness campaigns that aim to encourage walking trips throughout the day by suggesting locations and times of the day when engaging in these forms of exercise is easiest and least intrusive.

Discovery and lead optimisation of a potent, selective and orally bioavailable RARß agonist for the potential treatment of nerve injury.

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.

Community social capital and individual functioning in the post-disaster context.

Disasters can have severe and long-lasting consequences for individuals and communities. While scholarly evidence indicates that access to social support can ameliorate their negative impacts, less understood is whether or not neighbourhood social capital can facilitate recovery. This study uses two waves of survey data-collected before and after a significant flood in Brisbane, Australia, in 2011-to examine the relationship between the severity of the event at the individual and neighbourhood level, access to neighbourhood social capital and individual-level social support, and functioning in the post-disaster environment. In line with previous research, the results indicate that the severity of the flood is the most salient predictor of post-disaster functioning. No evidence was unearthed to show that neighbourhood social capital amassed before the flood leads to better functioning subsequently, but the findings do suggest that individual-level social support can moderate the effect of flood severity on functioning.

Retinoic acid synthesis by NG2 expressing cells promotes a permissive environment for axonal outgrowth.

Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor ß (RARß) is required for this process. Here we identify a novel mechanism by which neuronal RARß activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARß induced axonal regeneration, we show that neuronal RARß activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth. This hitherto unidentified RA paracrine signalling is required for axonal/neurite outgrowth and is initiated by the activation of neuronal RARß signalling.

Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist.

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

Neuronal RARß Signaling Modulates PTEN Activity Directly in Neurons and via Exosome Transfer in Astrocytes to Prevent Glial Scar Formation and Induce Spinal Cord Regeneration.

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor ß (RARß) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARß agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARß-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARß signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT: Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor ß (RARß), which modulates these two aspects of the postinjury physiological response. Activation of RARß in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs.

The Resettlement Journey: Understanding The Role of Social Connectedness on Well-being and Life Satisfaction among (Im)migrants and Refugees: A Systematic Review.

In the context of rising global migration and/or forced displacement, there is a pressing need to consider the well-being and life satisfaction of (im)migrants and refugees during resettlement. Research highlights the importance of social connectedness for (im)migrants and refugees during the resettlement phase. Yet, a critical gap remains in our understanding of the key characteristics through which social connections exert their influence on well-being and life satisfaction. This systematic review provides a comprehensive overview of the existing international literature on social connectedness and its impact on the well-being and life satisfaction of (im)migrants and refugees in post-migration contexts. Our analysis of 43 studies finds that social connectedness, in the form of social support and social networks, is beneficial for well-being and life satisfaction during resettlement. In addition to social support from individual network ties, community engagement can also enhance well-being by facilitating a sense of belonging. All 43 studies focused on psychological well-being and 69.8% relied on cross-sectional data. The findings of this review emphasise the need for longitudinal studies and standardised measurement tools to capture the dynamic interplay between social connectedness and well-being across various domains (psychological, physical, general/subjective) in migrant populations. We draw on the findings to propose a new conceptual model of the dynamic association between social connectedness and well-being/life satisfaction that seeks to explore these relationships in future empirical studies.

Amyloid ß inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist.

The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aß), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aß clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aß and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

Scale mismatches, conservation planning, and the value of social-network analyses.

Many of the challenges conservation professionals face can be framed as scale mismatches. The problem of scale mismatch occurs when the planning for and implementation of conservation actions is at a scale that does not reflect the scale of the conservation problem. The challenges in conservation planning related to scale mismatch include ecosystem or ecological process transcendence of governance boundaries; limited availability of fine-resolution data; lack of operational capacity for implementation; lack of understanding of social-ecological system components; threats to ecological diversity that operate at diverse spatial and temporal scales; mismatch between funding and the long-term nature of ecological processes; rate of action implementation that does not reflect the rate of change of the ecological system; lack of appropriate indicators for monitoring activities; and occurrence of ecological change at scales smaller or larger than the scale of implementation or monitoring. Not recognizing and accounting for these challenges when planning for conservation can result in actions that do not address the multiscale nature of conservation problems and that do not achieve conservation objectives. Social networks link organizations and individuals across space and time and determine the scale of conservation actions; thus, an understanding of the social networks associated with conservation planning will help determine the potential for implementing conservation actions at the required scales. Social-network analyses can be used to explore whether these networks constrain or enable key social processes and how multiple scales of action are linked. Results of network analyses can be used to mitigate scale mismatches in assessing, planning, implementing, and monitoring conservation projects.

Violent assault geographies in northeastern Australia.

As climate change produces more extreme weather, it is increasingly important to understand the impacts of these changes on social behaviour. The relationship between weather and crime has been studied across numerous contexts. However, few studies examine the correlation between weather and violence in southern, non-temperate climates. In addition, the literature lacks longitudinal research that controls for international changes in crime trends. In this study, we examine over 12 years of assault-related incidents in the state of Queensland, Australia. Controlling for deviations in trend for temperature and rainfall, we explore the relationship between violent crime and weather across Köppen climate classifications. Findings provide important insight into the impact of weather on violence across temperate, tropical, and arid climate regions.

Neighbourhood correlates of average population walking: using aggregated, anonymised mobile phone data to identify where people walk.

Understanding and monitoring socio-spatial patterns of population walking mobility can inform urban planning and geographically targeted health promotion strategies aimed at increasing population levels of physical activity. In this study we use aggregated, anonymous mobile phone mobility data to examine the association between neighbourhood physical and social characteristics and residents' weekly walking behaviour across 313 neighbourhoods in a large metropolitan region of Queensland, Australia. We find that residents in neighbourhoods that are highly fragmented by streets with speed limits above 50 kmph, residents in neighbourhoods with high retail density and those living is economically disadvantaged neighbourhoods walk fewer kilometres and minutes on average per week than their counterparts. These findings can inform urban planning policy on the minimum specifications required in newly developing neighbourhoods and provide targets for retro-fitting features into existing neighbourhoods.