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.

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.

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.

Urban-rural disparity of social vulnerability to natural hazards in Australia.

Assessing vulnerability to natural hazards is at the heart of hazard risk reduction. However, many countries such as Australia lack measuring systems to quantity vulnerability for hazard risk evaluation. Drawing on 41 indicators from multiple data sources at the finest spatial unit of the Australian census, we re-forged the Cutter's classic vulnerability measuring framework by involving the '4D' quantification of built environment (diversity, design, density and distance), and constructed the first nationwide fine-grained measures of vulnerability for urban and rural locales, respectively. Our measures of vulnerability include five themes-(1) socioeconomic status; (2) demographics and disability; (3) minority and languages; (4) housing characteristics; and (5) built environment-that were further used to assess the inequality of vulnerability to three widely affected natural hazards in Australia (wildfires, floods, and earthquakes). We found the inequality of vulnerability in the affected areas of the three hazards in eight capital cities are more significant than that of their rural counterparts. The most vulnerable areas in capital cities were peri-urban locales which must be prioritised for hazard adaptation. Our findings contribute to the risk profiling and sustainable urban-rural development in Australia, and the broad understanding of place-based risk reduction in South Hemisphere.

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.

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 times, they are a-changin': tracking shifts in mental health signals from early phase to later phase of the COVID-19 pandemic in Australia.

INTRODUCTION: Widespread problems of psychological distress have been observed in many countries following the outbreak of COVID-19, including Australia. What is lacking from current scholarship is a national-scale assessment that tracks the shifts in mental health during the pandemic timeline and across geographic contexts. METHODS: Drawing on 244 406 geotagged tweets in Australia from 1 January 2020 to 31 May 2021, we employed machine learning and spatial mapping techniques to classify, measure and map changes in the Australian public's mental health signals, and track their change across the different phases of the pandemic in eight Australian capital cities. RESULTS: Australians' mental health signals, quantified by sentiment scores, have a shift from pessimistic (early pandemic) to optimistic (middle pandemic), reflected by a 174.1% (95% CI 154.8 to 194.5) increase in sentiment scores. However, the signals progressively recessed towards a more pessimistic outlook (later pandemic) with a decrease in sentiment scores by 48.8% (95% CI 34.7 to 64.9). Such changes in mental health signals vary across capital cities. CONCLUSION: We set out a novel empirical framework using social media to systematically classify, measure, map and track the mental health of a nation. Our approach is designed in a manner that can readily be augmented into an ongoing monitoring capacity and extended to other nations. Tracking locales where people are displaying elevated levels of pessimistic mental health signals provide important information for the smart deployment of finite mental health services. This is especially critical in a time of crisis during which resources are stretched beyond normal bounds.

A data fusion approach to the estimation of temporary populations: An application to Australia.

This study establishes a new method for estimating the monthly Average Population Present (APP) in Australian regions. Conventional population statistics, which enumerate people where they usually live, ignore the significant spatial mobility driving short term shifts in population numbers. Estimates of the temporary or ambient population of a region have several important applications including the provision of goods and services, emergency preparedness and serve as more appropriate denominators for a range of social statistics. This paper develops a flexible modelling framework to generate APP estimates from an integrated suite of conventional and novel data sources. The resultant APP estimates reveal the considerable seasonality in small area populations across Australia's regions alongside the contribution of domestic and international visitors as well as absent residents to the observed monthly variations. The modelling framework developed in the paper is conceived in a manner such that it can be adapted and re-deployed both for use with alternative data sources as well as other situational contexts for the estimation of temporary populations.

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.

Collecting duct cells show differential retinoic acid responses to acute versus chronic kidney injury stimuli.

Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury. In RARE-LacZ mice, Adriamycin-induced heavy albuminuria was associated with reduced RA/RAR activity in CD cells. In cultured CD cells, RA/RAR activity was repressed by acetylcholine, albumin, aldosterone, angiotensin II, high glucose, cisplatin and lipopolysaccharide, but was induced by aristolochic acid I, calcitonin gene-related peptide, endothelin-1, gentamicin, norepinephrine and vasopressin. Compared with age-matched normal human CD cells, CD-derived renal cystic epithelial cells from patients with autosomal recessive polycystic kidney disease (ARPKD) had significantly lower RA/RAR activity. Synthetic RAR agonist RA-568 was more potent than RA in rescuing RA/RAR activity repressed by albumin, high glucose, angiotensin II, aldosterone, cisplatin and lipopolysaccharide. Hence, RA/RAR  in CD cells is a convergence point of regulation by neurotransmitters and mediators of kidney injury, and may be a novel therapeutic target.

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.

RARß Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms.

Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodeling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARß agonist, C286, currently under clinical research, in NP. A 4-week treatment initiated 2 days after the injury normalized pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286-mediated pain modulation, suggests that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore.

Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons.

Alzheimer's disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer's disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer's disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer's disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.

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.

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.

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.