Publications by authors named "John D Lee"

100 Publications

Glucose clearance and uptake is increased in the SOD1 mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism.

FASEB J 2021 07;35(7):e21707

School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia.

Metabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS). However, the molecular events that drive energy imbalances in ALS are not completely understood. In this study, we aimed to elucidate deficits in energy homeostasis in the SOD1 mouse model of ALS. SOD1 mice and their wild-type littermates underwent indirect calorimetry and intraperitoneal glucose/insulin tolerance tests at both the onset and mid-symptomatic stages of the disease. Glucose uptake and the plasma glucoregulatory hormone profiles were analyzed. Pancreatic islet cell mass and function were assessed by measuring hormone concentrations and secretion in isolated islets, and pancreatic α- and β-cell immunoreactive areas. Finally, we profiled liver glycogen metabolism by measuring glucagon concentrations and liver metabolic gene expressions. We identified that mid-symptomatic SOD1 mice have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. The capacity for pancreatic islets to secrete insulin appears intact, however, islet cell insulin concentrations and β-cell mass were reduced. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signaling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilized efficiently in SOD1 mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1 mice, which is linked to an increase in insulin-independent glucose uptake, and a loss of β-cells, insulin production, and glucagon sensitivity. This suggests that the hormonal regulation of glucose concentrations may contribute to the progression of disease in this ALS mouse model.
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http://dx.doi.org/10.1096/fj.202002450RDOI Listing
July 2021

Trusting Automation: Designing for Responsivity and Resilience.

Hum Factors 2021 Apr 27:187208211009995. Epub 2021 Apr 27.

5228 University of Wisconsin Madison, USA.

Objective: This paper reviews recent articles related to human trust in automation to guide research and design for increasingly capable automation in complex work environments.

Background: Two recent trends-the development of increasingly capable automation and the flattening of organizational hierarchies-suggest a reframing of trust in automation is needed.

Method: Many publications related to human trust and human-automation interaction were integrated in this narrative literature review.

Results: Much research has focused on calibrating human trust to promote appropriate reliance on automation. This approach neglects relational aspects of increasingly capable automation and system-level outcomes, such as cooperation and resilience. To address these limitations, we adopt a relational framing of trust based on the decision situation, semiotics, interaction sequence, and strategy. This relational framework stresses that the goal is not to maximize trust, or to even calibrate trust, but to support a process of trusting through automation responsivity.

Conclusion: This framing clarifies why future work on trust in automation should consider not just individual characteristics and how automation influences people, but also how people can influence automation and how interdependent interactions affect trusting automation. In these new technological and organizational contexts that shift human operators to co-operators of automation, automation responsivity and the ability to resolve conflicting goals may be more relevant than reliability and reliance for advancing system design.

Application: A conceptual model comprising four concepts-situation, semiotics, strategy, and sequence-can guide future trust research and design for automation responsivity and more resilient human-automation systems.
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http://dx.doi.org/10.1177/00187208211009995DOI Listing
April 2021

The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist.

Front Pharmacol 2020 21;11:591398. Epub 2021 Jan 21.

School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.

Innate immune complement activation generates the C3 and C5 protein cleavage products C3a and C5a, defined classically as anaphylatoxins. C3a activates C3aR, while C5a activates two receptors (C5aR1 and C5aR2) to exert their immunomodulatory activities. The non-peptide compound, SB290157, was originally reported in 2001 as the first C3aR antagonist. In 2005, the first report on the non-selective nature of SB290157 was published, where the compound exerted clear agonistic, not antagonistic, activity in variety of cells. Other studies also documented the non-selective activities of this drug in vivo. These findings severely hamper data interpretation regarding C3aR when using this compound. Unfortunately, given the dearth of C3aR inhibitors, SB290157 still remains widely used to explore C3aR biology (>70 publications to date). Given these issues, in the present study we aimed to further explore SB290157's pharmacological selectivity by screening the drug against three human anaphylatoxin receptors, C3aR, C5aR1 and C5aR2, using cell models. We identified that SB290157 exerts partial agonist activity at C5aR2 by mediating -arrestin recruitment at higher compound doses. This translated to a functional outcome in both human and mouse primary macrophages, where SB290157 significantly dampened C5a-induced ERK signaling. We also confirmed that SB290157 acts as a potent agonist at human C3aR in transfected cells, but as an antagonist in primary human macrophages. Our results therefore provide even more caution against using SB290157 as a research tool to explore C3aR function. Given the reported immunomodulatory and anti-inflammatory activities of C5aR2 agonism, any function observed with SB290157 could be due to these off-target activities.
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http://dx.doi.org/10.3389/fphar.2020.591398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859635PMC
January 2021

TDP-43 Puts the STING in ALS.

Trends Neurosci 2021 02 20;44(2):81-82. Epub 2020 Dec 20.

School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia; Queensland Brain Institute, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia. Electronic address:

In a recent study, Yu et al. demonstrated that TAR DNA-binding protein of 43 kDa (TDP-43) causes inflammation in amyotrophic lateral sclerosis (ALS) by triggering mitochondrial (mt)DNA release into the cytoplasm, which subsequently activates the cytoplasmic DNA-sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. These results suggest that inhibition of cGAS/STING could help mitigate inflammation-related neuropathology in ALS.
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http://dx.doi.org/10.1016/j.tins.2020.12.001DOI Listing
February 2021

Complement: a global immunometabolic regulator in amyotrophic lateral sclerosis.

Neural Regen Res 2021 Jun;16(6):1210-1211

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland, Australia.

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http://dx.doi.org/10.4103/1673-5374.300441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224118PMC
June 2021

Clinical and electrophysiological examination of pinch strength in patients with amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 9;63(1):108-113. Epub 2020 Nov 9.

Department of Neurology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.

Background: The split-hand concept has highlighted the preferential wasting of the thenar side of the hand in amyotrophic lateral sclerosis (ALS). Our objective is to re-explore pinch grip strength to assess whether it has the potential to be a practical biomarker of ALS.

Methods: We measured different pinch grip strengths (thumb, index, and fifth) using a pinch gauge from both hands of 54 ALS patients and correlated this with the Medical Research Council (MRC) score, the upper-limb component of the revised ALS Functional Rating Scale - Revised (ALSFRS-R) score, and compound muscle action potentials (CMAPs) that comprise the split-hand index.

Results: Pinch grip strength using any of the three fingers showed a positive correlation with its corresponding CMAP, MRC grading, and upper-limb ALSFRS-R score. The thumb pinch showed the strongest correlation with the split-hand index and MRC grading.

Conclusions: Pinch grip strength test using a simple gauge deserves further study as a potentially practical biomarker of ALS.
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http://dx.doi.org/10.1002/mus.27111DOI Listing
January 2021

Is the C3a receptor antagonist SB290157 a useful pharmacological tool?

Br J Pharmacol 2020 12 18;177(24):5677-5678. Epub 2020 Oct 18.

School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.

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http://dx.doi.org/10.1111/bph.15264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707084PMC
December 2020

Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration.

J Immunol 2020 11 7;205(10):2834-2839. Epub 2020 Oct 7.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia

Neutrophil infiltration to ischemic tissues following reperfusion worsens injury. A key driver of neutrophil recruitment and activation is the complement factor C5a, which signals through two receptors, C5aR1 and C5aR2. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to investigate the underexplored role of C5aR2 in neutrophil mobilization, recruitment, and disease outcomes. We show that intestinal IR induces rapid neutrophil mobilization along with a concomitant reduction in plasma C5a levels that is driven by both C5aR1 and C5aR2. Intestinal IR in C5aR2 mice led to worsened intestinal damage and increased neutrophil infiltration. Inhibition of C5aR1 signaling in C5aR2 mice with PMX53 prevented neutrophil accumulation and reduced IR pathology, suggesting a key requirement for enhanced neutrophil C5aR1 activation in the absence of C5aR2 signaling. Interestingly, C5aR2 deficiency also reduced circulating neutrophil numbers after IR, as well as following G-CSF-mediated bone marrow mobilization, which was independent of C5aR1, demonstrating that C5aR2 has unique and distinct functions from C5aR1 in neutrophil egress. Despite enhanced tissue injury in C5aR2 IR mice, there were significant reductions in intestinal proinflammatory cytokines, highlighting complicated dual protective/pathogenic roles for C5aR2 in pathophysiology. Collectively, we show that C5aR2 is protective in intestinal IR by inhibiting C5aR1-mediated neutrophil recruitment to the ischemic tissue. This is despite the potentially local pathogenic effects of C5aR2 in increasing intestinal proinflammatory cytokines and enhancing circulating neutrophil numbers in response to mobilizing signals. Our data therefore suggest that this balance between the dual pro- and anti-inflammatory roles of C5aR2 ultimately dictates disease outcomes.
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http://dx.doi.org/10.4049/jimmunol.2000778DOI Listing
November 2020

Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function.

Biochem Pharmacol 2020 10 17;180:114156. Epub 2020 Jul 17.

School of Biomedical Sciences, Australia; Queensland Brain Institute, Australia. Electronic address:

The complement fragment C5a is a core effector of complement activation. C5a, acting through its major receptor C5aR1, exerts powerful pro-inflammatory and immunomodulatory functions. Dysregulation of the C5a-C5aR1 axis has been implicated in numerous immune disorders, and the therapeutic inhibition of this axis is therefore imperative for the treatment of these diseases. A myriad of small-molecule C5aR1 inhibitors have been developed and independently characterised over the past two decades, however the pharmacological properties of these compounds has been difficult to directly compare due to the wide discrepancies in the model, read-out, ligand dose and instrumentation implemented across individual studies. Here, we performed a systematic characterisation of the most commonly reported and clinically advanced small-molecule C5aR1 inhibitors (peptidic: PMX53, PMX205 and JPE1375; non-peptide: W545011, NDT9513727, DF2593A and CCX168). Through signalling assays measuring C5aR1-mediated cAMP and ERK1/2 signalling, and β-arrestin 2 recruitment, this study highlighted the signalling-pathway dependence of the rank order of potencies of the C5aR1 inhibitors. Functional experiments performed in primary human macrophages demonstrated the high insurmountable antagonistic potencies for the peptidic inhibitors as compared to the non-peptide compounds. Finally, wash-out studies provided novel insights into the duration of inhibition of the C5aR1 inhibitors, and confirmed the long-lasting antagonistic properties of PMX53 and CCX168. Overall, this study revealed the potent and prolonged antagonistic activities of selected peptidic C5aR1 inhibitors and the unique pharmacological profile of CCX168, which thus represent ideal candidates to fulfil diverse C5aR1 research and clinical therapeutic needs.
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http://dx.doi.org/10.1016/j.bcp.2020.114156DOI Listing
October 2020

Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1 Mouse Model of Amyotrophic Lateral Sclerosis.

Mol Neurobiol 2020 Oct 16;57(10):4143-4155. Epub 2020 Jul 16.

School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1 mice lacking RAGE and compared them with SOD1 transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1 pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.
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http://dx.doi.org/10.1007/s12035-020-02019-9DOI Listing
October 2020

A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models.

J Neurochem 2020 Jul 6. Epub 2020 Jul 6.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Qld, Australia.

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are highly specialized structures that limit molecule entry from the blood and maintain homeostasis within the central nervous system (CNS). BBB and BSCB breakdown are associated with multiple neurodegenerative diseases. Given the key role of neuroprotective barrier impairment in neurodegeneration, it is important to identify an effective quantitative method to assess barrier integrity in animal models. In this study, we developed and validated a quantitative method for assessing BBB and BSCB integrity using sodium fluorescein, a compound that outperformed other fluorescent dyes. We demonstrated using this method that multiple CNS regions progressively increase in permeability in models of Huntington's disease and amyotrophic lateral sclerosis, whereas biphasic disruption occurred in a mouse model of Alzheimer's disease with disease progression. Collectively, we report a quantitative fluorometric marker with validated reproducible experimental methods that allows the effective assessment of BBB and BSCB integrity in animal models. This method could be useful to further the understanding of the contribution of these neuroprotective barriers to neurodegeneration processes.
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http://dx.doi.org/10.1111/jnc.15119DOI Listing
July 2020

The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

Front Neurol 2020 21;11:279. Epub 2020 Apr 21.

Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.
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http://dx.doi.org/10.3389/fneur.2020.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186478PMC
April 2020

The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis.

FASEB J 2020 06 19;34(6):7225-7233. Epub 2020 Apr 19.

School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, Australia.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating the defective energy metabolism and components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the mechanisms by which the energy metabolism and the complement system are altered during the disease progression of ALS and how it can contribute to disease. Furthermore, it will also examine how complement activation can modify the energy metabolism in metabolic disorders, in order to highlight how the complement system and energy metabolism may be linked in ALS.
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http://dx.doi.org/10.1096/fj.201901781DOI Listing
June 2020

Preface to the Special Issue on Human Factors and Advanced Vehicle Automation: Of Benefits, Barriers, and Bridges to Safe and Effective Implementation.

Hum Factors 2020 03;62(2):189-193

5228 University of Wisconsin-Madison, USA.

Objective: The aim of this special issue is to bring together the latest research related to driver interaction with various types of vehicle automation.

Background: Vehicle technology has undergone significant progress over the past decade, bringing new support features that can assist the driver and take on more and more of the driving responsibilities.

Method: This issue is comprised of eight articles from international research teams, focusing on different types of automation and different user populations, including driver support features through to highly automated driving systems.

Results: The papers comprising this special issue are clustered into three categories: (a) experimental studies of driver interactions with advanced vehicle technologies; (b) analysis of existing data sources; and (c) emerging human factors issues. Studies of currently available and pending systems highlight some of the human factors challenges associated with the driver-system interaction that are likely to become more prominent in the near future. Moreover, studies of more nascent concepts (i.e., those that are still a long way from production vehicles) underscore many attitudes, perceptions, and concerns that will need to be considered as these technologies progress.

Conclusions: Collectively, the papers comprising this special issue help fill some gaps in our knowledge. More importantly, they continue to help us identify and articulate some of the important and potential human factors barriers, design considerations, and research needs as these technologies become more ubiquitous.
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http://dx.doi.org/10.1177/0018720820901542DOI Listing
March 2020

Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice.

ACS Omega 2020 Feb 30;5(5):2345-2354. Epub 2020 Jan 30.

School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.

The cyclic hexapeptides PMX53 and PMX205 are potent noncompetitive inhibitors of complement C5a receptor 1 (C5aR1). They are widely utilized to study the role of C5aR1 in mouse models, including central nervous system (CNS) disease, and are dosed through a variety of routes of administration. However, a comprehensive pharmacokinetics analysis of these drugs has not been reported. In this study, the blood and CNS pharmacokinetics of PMX53 and PMX205 were performed in mice following intravenous, intraperitoneal, subcutaneous, and oral administration at identical doses. The absorption and distribution of both drugs were rapid and followed a two-compartment model with elimination half-lives of ∼20 min for both compounds. Urinary excretion was the major route of elimination following intravenous dosing with ∼50% of the drug excreted unchanged within the first 12 h. Oral bioavailability of PMX205 was higher than that of PMX53 (23% versus 9%), and PMX205 was also more efficient than PMX53 at entering the intact CNS. In comparison to other routes, subcutaneous administration of PMX205 resulted in high bioavailability (above 90%), as well as prolonged plasma and CNS exposure. Finally, repeated daily oral or subcutaneous administration of PMX205 demonstrated no accumulation of drug in blood, the brain, or the spinal cord, promoting its safety for chronic dosing. These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.
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http://dx.doi.org/10.1021/acsomega.9b03735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017397PMC
February 2020

Designing for the Extremes: Modeling Drivers' Response Time to Take Back Control From Automation Using Bayesian Quantile Regression.

Hum Factors 2021 May 24;63(3):519-530. Epub 2019 Dec 24.

116612 Toyota Collaborative Safety Research Center, Ann Arbor, USA.

Objective: Understanding the factors that affect drivers' response time in takeover from automation can help guide the design of vehicle systems to aid drivers. Higher quantiles of the response time distribution might indicate a higher risk of an unsuccessful takeover. Therefore, assessments of these systems should consider upper quantiles rather than focusing on the central tendency.

Background: Drivers' responses to takeover requests can be assessed using the time it takes the driver to take over control. However, all the takeover timing studies that we could find focused on the mean response time.

Method: A study using an advanced driving simulator evaluated the effect of takeover request timing, event type at the onset of a takeover, and visual demand on drivers' response time. A mixed effects model was fit to the data using Bayesian quantile regression.

Results: Takeover request timing, event type that precipitated the takeover, and the visual demand all affect driver response time. These factors affected the 85th percentile differently than the median. This was most evident in the revealed stopped vehicle event and conditions with a longer time budget and scenes with lower visual demand.

Conclusion: Because the factors affect the quantiles of the distribution differently, a focus on the mean response can misrepresent actual system performance. The 85th percentile is an important performance metric because it reveals factors that contribute to delayed responses and potentially dangerous outcomes, and it also indicates how well the system accommodates differences between drivers.
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http://dx.doi.org/10.1177/0018720819893429DOI Listing
May 2021

Complement dysregulation in the central nervous system during development and disease.

Semin Immunol 2019 10 7;45:101340. Epub 2019 Nov 7.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia. Electronic address:

The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1016/j.smim.2019.101340DOI Listing
October 2019

Assessing Drivers' Trust of Automated Vehicle Driving Styles With a Two-Part Mixed Model of Intervention Tendency and Magnitude.

Hum Factors 2021 Mar 9;63(2):197-209. Epub 2019 Oct 9.

University of Wisconsin-Madison, USA.

Objective: This study examines how driving styles of fully automated vehicles affect drivers' trust using a statistical technique-the two-part mixed model-that considers the frequency and magnitude of drivers' interventions.

Background: Adoption of fully automated vehicles depends on how people accept and trust them, and the vehicle's driving style might have an important influence.

Method: A driving simulator experiment exposed participants to a fully automated vehicle with three driving styles (aggressive, moderate, and conservative) across four intersection types (with and without a stop sign and with and without crossing path traffic). Drivers indicated their dissatisfaction with the automation by depressing the brake or accelerator pedals. A two-part mixed model examined how automation style, intersection type, and the distance between the automation's driving style and the person's driving style affected the frequency and magnitude of their pedal depression.

Results: The conservative automated driving style increased the frequency and magnitude of accelerator pedal inputs; conversely, the aggressive style increased the frequency and magnitude of brake pedal inputs. The two-part mixed model showed a similar pattern for the factors influencing driver response, but the distance between driving styles affected how often the brake pedal was pressed, but it had little effect on how much it was pressed.

Conclusion: Eliciting brake and accelerator pedal responses provides a temporally precise indicator of drivers' trust of automated driving styles, and the two-part model considers both the discrete and continuous characteristics of this indicator.

Application: We offer a measure and method for assessing driving styles.
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http://dx.doi.org/10.1177/0018720819880363DOI Listing
March 2021

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins.

Glia 2020 02 9;68(2):407-421. Epub 2019 Oct 9.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia.

Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β-amyloid and α-synuclein trigger microglial NLRP3 activation, leading to caspase-1 activation and IL-1β secretion. Both caspase-1 and IL-1β contribute to disease progression in the mouse SOD1 model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1 mice microglia do not express NLRP3, and SOD1 protein generated IL-1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3-GFP gene knock-in mice that microglia express NLRP3 in SOD1 mice. We show that both aggregated and soluble SOD1 activates inflammasome in primary mouse microglia leading caspase-1 and IL-1β cleavage, ASC speck formation, and the secretion of IL-1β in a dose- and time-dependent manner. Importantly, SOD1 was unable to induce IL-1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1-induced microglial IL-1β secretion. Microglial NLRP3 upregulation was also observed in the TDP-43 ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1 -mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.
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http://dx.doi.org/10.1002/glia.23728DOI Listing
February 2020

Exploring Trust in Self-Driving Vehicles Through Text Analysis.

Hum Factors 2020 03 10;62(2):260-277. Epub 2019 Sep 10.

158055 J.D. Power, Troy, Michigan, USA.

Objective: This study examined attitudes toward self-driving vehicles and the factors motivating those attitudes.

Background: Self-driving vehicles represent potentially transformative technology, but achieving this potential depends on consumers' attitudes. Ratings from surveys estimate these attitudes, and open-ended comments provide an opportunity to understand their basis.

Method: A nationally representative sample of 7,947 drivers in 2016 and 8,517 drivers in 2017 completed the J.D. Power U.S. Tech Choice Study, which included a rating for level of trust with self-driving vehicles and associated open-ended comments. These open-ended comments are qualitative data that can be analyzed quantitatively using structural topic modeling. Structural topic modeling identifies common themes, extracts prototypical comments for each theme, and assesses how the survey year and rating affect the prevalence of these themes.

Results: Structural topic modeling identified 13 topics, such as "Tested for a long time," which was strongly associated with positive ratings, and "Hacking & glitches," which was strongly associated with negative ratings. The topics of "Self-driving accidents" and "Trust when mature" were more prominent in 2017 compared with 2016.

Conclusion: Structural topic modeling reveals reasons underlying consumer attitudes toward vehicle automation. These reasons align with elements typically associated with trust in automation, as well as elements that mediate perceived risk, such as the desire for control as well as societal, relational, and experiential bases of trust.

Application: The analysis informs the debate concerning how safe is safe enough for automated vehicles and provides initial indicators of what makes such vehicles feel safe and trusted.
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http://dx.doi.org/10.1177/0018720819872672DOI Listing
March 2020

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma.

FASEB J 2019 10 12;33(10):11060-11071. Epub 2019 Jul 12.

Australian Institute of Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia.

The canonical complement component 5a (C5a) receptor (C5aR) 1 has well-described roles in tumorigenesis but the contribution of the second receptor, C5aR2, is unclear. The present study demonstrates that B16.F0 melanoma cells express mRNA for both and and signal through ERK and p38 MAPKs in response to C5a. Despite this, C5a had no impact on melanoma cell proliferation or migration . studies demonstrated that the growth of B16.F0 melanoma tumors was increased in C5aR2 mice but reduced in C5aR1 mice and wild-type mice treated with a C5aR1 antagonist. Analysis of tumor-infiltrating leukocyte populations showed no significant differences between wild-type and C5aR2 mice. Conversely, percentages of myeloid-derived suppressor cells, macrophages, and regulatory T lymphocytes were lower in tumors from C5aR1 mice, whereas total (CD3) T lymphocytes and CD4 subsets were higher. Analysis of cytokine and chemokine levels also showed plasma IFN-γ was higher and tumor C-C motif chemokine ligand 2 was lower in the absence of C5aR1. The results suggest that C5aR1 signaling supports melanoma growth by promoting infiltration of immunosuppressive leukocyte populations into the tumor microenvironment, whereas C5aR2 has a more restricted but beneficial role in limiting tumor growth. Overall, these data support the potential of C5aR1-inhibitory therapies for melanoma.-Nabizadeh, J. A., Manthey, H. D., Panagides, N., Steyn, F. J., Lee, J. D., Li, X. X., Akhir, F. N. M., Chen, W., Boyle, G. M., Taylor, S. M., Woodruff, T. M., Rolfe, B. E. C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma.
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http://dx.doi.org/10.1096/fj.201800980RRDOI Listing
October 2019

Moving Into the Loop: An Investigation of Drivers' Steering Behavior in Highly Automated Vehicles.

Hum Factors 2020 06 10;62(4):671-683. Epub 2019 Jun 10.

5228 University of Wisconsin-Madison, USA.

Objective: This paper investigates driver engagement with vehicle automation and the transition to manual control in the context of a phenomenon that we have termed vicarious steering-drivers steering when the vehicle is under automated control.

Background: Automated vehicles introduce many challenges, including disengagement from the driving task and out-of-the-loop performance decrement. We examine drivers' steering behavior when the automation is engaged, and steering input has no effect on the vehicle state. Such vicarious steering is a potential indicator of engagement for evaluating automated vehicles.

Method: A total of 32 female and 32 male drivers between 25 and 55 years of age participated in this experiment. A 2 × 2 between-subject design combined control algorithms and instructed responsibility. The control algorithms (lane centering and adaptive) were intended to convey the capability of the automation. The adaptive algorithm drifted across the lane center when latent hazards were present. The instructed levels of responsibility (driver primarily responsible and automation primarily responsible) were intended to replicate the admonitions of owners' manuals.

Results: The adaptive algorithm increased vicarious steering ( < .001), but instructed responsibility did not ( = .67), and there was no interaction between the algorithm and the responsibility ( = .75). Vicarious steering was associated with an increase in transitions to manual control and glances to the road but was negatively associated with driving performance immediately after the transition to manual control.

Conclusion: Vicarious steering is a promising indicator of driver engagement when the vehicle is under automated control and automation algorithms can promote engagement.
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http://dx.doi.org/10.1177/0018720819850283DOI Listing
June 2020

The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity.

J Immunol 2019 06;202(12):3339-3348

School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia; and

Complement activation generates the core effector protein C5a, a potent immune molecule that is linked to multiple inflammatory diseases. Two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, GPR77), mediate the biological activities of C5a. Although C5aR1 has broadly acknowledged proinflammatory roles, C5aR2 remains at the center of controversy, with existing findings supporting both immune-activating and immune-dampening functions. Recent progress has been made toward resolving these issues. Instead of being a pure recycler and sequester of C5a, C5aR2 is capable of mediating its own set of signaling events and through these events exerting significant immunomodulatory effects not only toward C5aR1 but also other pattern recognition receptors and innate immune systems, such as NLRP3 inflammasomes. This review highlights the existing knowns and unknowns concerning C5aR2 and provides a timely update on recent breakthroughs which are expected to have a substantial impact on future fundamental and translational C5aR2 research.
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http://dx.doi.org/10.4049/jimmunol.1900371DOI Listing
June 2019

Gut microbiota in ALS: possible role in pathogenesis?

Expert Rev Neurother 2019 09 29;19(9):785-805. Epub 2019 May 29.

Centre for Clinical Research, The University of Queensland , Brisbane , Australia.

: The gut microbiota has important roles in maintaining human health. The microbiota and its metabolic byproducts could play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). : The authors evaluate the methods of assessing the gut microbiota, and also review how the gut microbiota affects the various physiological functions of the gut. The authors then consider how gut dysbiosis could theoretically affect the pathogenesis of ALS. They present the current evidence regarding the composition of the gut microbiota in ALS and in rodent models of ALS. Finally, the authors review therapies that could improve gut dysbiosis in the context of ALS. : Currently reported studies suggest some instances of gut dysbiosis in ALS patients and mouse models; however, these studies are limited, and more information with well-controlled larger datasets is required to make a definitive judgment about the role of the gut microbiota in ALS pathogenesis. Overall this is an emerging field that is worthy of further investigation. The authors advocate for larger studies using modern metagenomic techniques to address the current knowledge gaps.
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http://dx.doi.org/10.1080/14737175.2019.1623026DOI Listing
September 2019

Challenges for Older Drivers in Urban, Suburban, and Rural Settings.

Geriatrics (Basel) 2018 Mar 22;3(2). Epub 2018 Mar 22.

Department of Industrial and Systems Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.

Along with age-related factors, geographical settings-urban, suburban, and rural areas-also contribute to the differences in fatal crashes among older drivers. These differences in crash outcomes might be attributed to the various driving challenges faced by older drivers residing in different locations. To understand these challenges from the perspective of the older driver, a focus group study was conducted with drivers 65 and older from urban, suburban, and rural settings. Guided-group interviews were used to assess driving challenges, mobility options, opportunities for driver support systems (DSS), and alternate transportation needs. Content analysis of the interview responses resulted in four categories representing common challenges faced by older drivers across the settings: behavior of other drivers on the road, placement of road signs, reduced visibility of road signs due to age-related decline, and difficulties using in-vehicle technologies. Six categories involved location-specific challenges such as heavy traffic situations for urban and suburban drivers, and multi-destination trips for rural drivers. Countermeasures implemented by older drivers to address these challenges primarily involved route selection and avoidance. Technological advances of DSS systems provide a unique opportunity to support the information needs for route selection and avoidance preferences of drivers. Using the content analysis results, a framework was built to determine additional and modified DSS features to meet the specific challenges of older drivers in urban, suburban, and rural settings. These findings suggest that there is heterogeneity in the driving challenges and preferences of older drivers based on their location. Consequently, DSS technologies and vehicle automation need to be tailored to not only meet the driving safety and mobility needs of older drivers as a population, but also to their driving environment.
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http://dx.doi.org/10.3390/geriatrics3020014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319240PMC
March 2018

Trust and the teleology of technology.

Authors:
John D Lee

Ergonomics 2019 04 7;62(4):500-501. Epub 2019 Apr 7.

a Department of Industrial and Systems Engineering , University of Wisconsin-Madison.

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http://dx.doi.org/10.1080/00140139.2019.1563332DOI Listing
April 2019

Revisiting the role of the innate immune complement system in ALS.

Neurobiol Dis 2019 07 6;127:223-232. Epub 2019 Mar 6.

School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; University of Queensland Centre for Clinical Research, The University of Queensland, Herston, QLD 4029, Australia. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.
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http://dx.doi.org/10.1016/j.nbd.2019.03.003DOI Listing
July 2019

Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1 mouse model of amyotrophic lateral sclerosis.

J Neuroinflammation 2019 Feb 19;16(1):45. Epub 2019 Feb 19.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4.

Methods: The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1 transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1.

Results: We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1 mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation.

Conclusions: In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1 mouse model of ALS.
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http://dx.doi.org/10.1186/s12974-019-1435-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380064PMC
February 2019

Using Topic Modeling to Develop Multi-level Descriptions of Naturalistic Driving Data from Drivers with and without Sleep Apnea.

Transp Res Part F Traffic Psychol Behav 2018 Oct 9;58:25-38. Epub 2018 Jun 9.

University of Nebraska Medical Center, 42nd and Emile, Omaha, NE 68198.

One challenge in using naturalistic driving data is producing a holistic analysis of these highly variable datasets. Typical analyses focus on isolated events, such as large g-force accelerations indicating a possible near-crash. Examining isolated events is ill-suited for identifying patterns in continuous activities such as maintaining vehicle control. We present an alternative approach that converts driving data into a text representation and uses topic modeling to identify patterns across the dataset. This approach enables the discovery of non-linear patterns, reduces the dimensionality of the data, and captures subtle variations in driver behavior. In this study topic models are used to concisely described patterns in trips from drivers with and without untreated obstructive sleep apnea (OSA). The analysis included 5000 trips (50 trips from 100 drivers; 66 drivers with OSA; 34 comparison drivers). Trips were treated as documents, and speed and acceleration data from the trips were converted to "driving words." The identified patterns, called topics, were determined based on regularities in the co-occurrence of the driving words within the trips. This representation was used in random forest models to predict the driver condition (i.e., OSA or comparison) for each trip. Models with 10, 15 and 20 topics had better accuracy in predicting the driver condition, with a maximum AUC of 0.73 for a model with 20 topics. Trips from drivers with OSA were more likely to be defined by topics for smaller lateral accelerations at low speeds. The results demonstrate topic modeling as a useful tool for extracting meaningful information from naturalistic driving datasets.
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http://dx.doi.org/10.1016/j.trf.2018.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294309PMC
October 2018

Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance.

Mol Immunol 2018 09 27;101:176-181. Epub 2018 Jun 27.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia. Electronic address:

The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain.
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http://dx.doi.org/10.1016/j.molimm.2018.06.271DOI Listing
September 2018
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