QBI research publications

  • Cortical activity emerges in region-specific patterns during early brain development

  • Complex interactions between distinct Theta oscillatory patterns during sleep deprivation

  • The evolution of the green-light-sensitive visual opsin genes (RH2) in teleost fishes

    Vertebrates have four visual cone opsin classes that mediate sensitivity from ultraviolet to red wavelengths of light. The rhodopsin-like 2 (RH2) opsin is sensitive to the central mostly green part of the spectrum. While lost in some terrestrial vertebrates (mammals), the RH2 opsin gene has proliferated during the evolution of teleost fishes. Here, we investigated the genomes of 132 extant teleosts and found between zero and eight RH2 gene copies per species. The RH2 gene shows a dynamic evolutionary history with repeated gene duplications, gene losses, and gene conversions affecting entire orders, families, and species. At least four ancestral duplications provided the substrate for today's RH2 diversity, with duplications occurring in the common ancestors of Clupeocephala (twice), Neoteleostei, and likely Acanthopterygii as well. Despite these evolutionary dynamics, we identified conserved RH2 synteny in two main gene clusters; the slc6A13/synpr cluster is highly conserved within Percomorpha and also present across most teleosts, including Otomorpha, Euteleostei and in parts in tarpons (Elopomorpha), and the mutSH5 cluster, which is specific for Otomorpha. When comparing the number of visual opsin genes (SWS1, SWS2, RH2, LWS, and total cone opsins) with habitat depth, we found that deeper-dwelling species had less (or none) long-wavelength-sensitive opsins. Using retinal/eye transcriptomes in a phylogenetic representative dataset of 32 species, we show that if present in the genome, RH2 is expressed in most fishes except for some species within the tarpons, characins, and gobies (and Osteoglossomorpha and some other characin species have lost the gene). Those species instead express a green-shifted long-wavelength-sensitive LWS opsin. Our study applies modern genomic and transcriptomic tools within a comparative framework to elucidate the evolutionary history of the visual sensory system in teleost fishes.
  • Living with frontotemporal degeneration: diagnostic journey, symptom experiences, and disease impact

    Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive declines in cognition, behavior, and personality. Hearing directly from individuals living with FTD and their care partners is critical in optimizing care, identifying meaningful clinical trial endpoints, and improving research recruitment and retention. The current paper presents a subset of data from the FTD Insights Survey, chronicling the diagnostic journey, symptoms, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease. Survey respondents included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses. Around half of survey respondents reported seeing three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick's disease. Participating independently in a range of activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the degree to which the lives of these individuals are affected even at the mild and moderate stages of disease. Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop therapies that improve quality of life.
  • Multi-parametric MR for detection of pathological changes in CNS of mouse model of multiple sclerosis in vivo

    Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4 T MRI. Multi-parametric MRI measurements including MR spectroscopy (MRS), diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared to healthy mice, EAE mice showed a significant reduction in N-acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed significant reduction in fractional anisotropy and axial diffusivity and increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM) fractional anisotropy increased. High-resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2-L6), particularly, WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo.
  • Microglial CD68 and L-ferritin upregulation in response to phosphorylated-TDP-43 pathology in the amyotrophic lateral sclerosis brain

    Microglia, the innate immune cells of the brain, are activated by damage or disease. In mouse models of amyotrophic lateral sclerosis (ALS), microglia shift from neurotrophic to neurotoxic states with disease progression. It remains unclear how human microglia change relative to the TAR DNA-binding protein 43 (TDP-43) aggregation that occurs in 97% of ALS cases. Here we examine spatial relationships between microglial activation and TDP-43 pathology in brain tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from the Neurological Foundation Human Brain Bank was obtained from 10 control and 10 ALS cases in parallel with brain tissue from a bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at disease onset, early disease, and late disease stages. The spatiotemporal relationship between microglial activation and ALS pathology was determined by investigating microglial functional marker expression in brain regions with low and high TDP-43 burden at end-stage human disease: hippocampus and motor cortex, respectively. Sections were immunohistochemically labelled with a two-round multiplexed antibody panel against; microglial functional markers (L-ferritin, HLA-DR, CD74, CD68, and Iba1), a neuronal marker, an astrocyte marker, and pathological phosphorylated TDP-43 (pTDP-43). Single-cell levels of microglial functional markers were quantified using custom analysis pipelines and mapped to anatomical regions and ALS pathology. We identified a significant increase in microglial Iba1 and CD68 expression in the human ALS motor cortex, with microglial CD68 being significantly correlated with pTDP-43 pathology load. We also identified two subpopulations of microglia enriched in the ALS motor cortex that were defined by high L-ferritin expression. A similar pattern of microglial changes was observed in the rNLS mouse, with an increase first in CD68 and then in L-ferritin expression, with both occurring only after pTDP-43 inclusions were detectable. Our data strongly suggest that microglia are phagocytic at early-stage ALS but transition to a dysfunctional state at end-stage disease, and that these functional states are driven by pTDP-43 aggregation. Overall, these findings enhance our understanding of microglial phenotypes and function in ALS.
  • Compartment-specific dendritic information processing in striatal cholinergic interneurons is reconfigured by peptide neuromodulation

    Cholinergic interneurons are central hubs of the striatal neuronal network, controlling information processing in a behavioral-state-dependent manner. It remains unknown, however, how such state transitions influence the integrative properties of these neurons. To address this, we made simultaneous somato-dendritic recordings from identified rodent cholinergic interneurons, revealing that action potentials are initiated at dendritic sites because of a dendritic axonal origin. Functionally, this anatomical arrangement ensured that the action potential initiation threshold was lowest at axon-bearing dendritic sites, a privilege efficacy powerfully accentuated at the hyperpolarized membrane potentials achieved in cholinergic interneurons following salient behavioral stimuli. Experimental analysis revealed the voltage-dependent attenuation of the efficacy of non-axon-bearing dendritic excitatory input was mediated by the recruitment of dendritic potassium channels, a regulatory mechanism that, in turn, was controlled by the pharmacological activation of neurokinin receptors. Together, these results indicate that the neuropeptide microenvironment dynamically controls state- and compartment-dependent dendritic information processing in striatal cholinergic interneurons.
  • Anxiety attenuates learning advantages conferred by statistical stability and induces loss of volatility-attuning in brain activity

    Anxiety can alter an individual's perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults while they performed an auditory oddball task under stable and volatile environments and while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to identify the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility. Neurally, we found that threat-of-shock led to attenuation and loss of volatility-attuning of brain activity evoked by surprising sounds across most subcortical and limbic regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and the superior temporal gyrus. Taken together, our findings suggest that threat eliminates learning advantages conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.
  • The Queensland Twin Adolescent Brain Project, a longitudinal study of adolescent brain development

    We describe the Queensland Twin Adolescent Brain (QTAB) dataset and provide a detailed methodology and technical validation to facilitate data usage. The QTAB dataset comprises multimodal neuroimaging, as well as cognitive and mental health data collected in adolescent twins over two sessions (session 1: N = 422, age 9-14 years; session 2: N = 304, 10-16 years). The MRI protocol consisted of T1-weighted (MP2RAGE), T2-weighted, FLAIR, high-resolution TSE, SWI, resting-state fMRI, DWI, and ASL scans. Two fMRI tasks were added in session 2: an emotional conflict task and a passive movie-watching task. Outside of the scanner, we assessed cognitive function using standardised tests. We also obtained self-reports of symptoms for anxiety and depression, perceived stress, sleepiness, pubertal development measures, and risk and protective factors. We additionally collected several biological samples for genomic and metagenomic analysis. The QTAB project was established to promote health-related research in adolescence.
  • PREdiction and Diagnosis using Imaging and Clinical biomarkers Trial in Traumatic Brain Injury (PREDICT-TBI) study protocol: an observational, prospective, multicentre cohort study for the prediction of outcome in moderate-to-severe TBI

    Introduction Traumatic brain injury (TBI) is a heterogeneous condition with a broad spectrum of injury severity, pathophysiological processes and variable outcomes. For moderate-to-severe TBI survivors, recovery is often protracted and outcomes can range from total dependence to full recovery. Despite advances in medical treatment options, prognosis remains largely unchanged. The objective of this study is to develop a machine learning predictive model for neurological outcomes at 6 months in patients with a moderate-to-severe TBI, incorporating longitudinal clinical, multimodal neuroimaging and blood biomarker predictor variables.Methods and analysis A prospective, observational, cohort study will enrol 300 patients with moderate-to-severe TBI from seven Australian hospitals over 3 years. Candidate predictors including demographic and general health variables, and longitudinal clinical, neuroimaging (CT and MRI), blood biomarker and patient-reported outcome measures will be collected at multiple time points within the acute phase of injury. The predictor variables will populate novel machine learning models to predict the Glasgow Outcome Scale Extended 6 months after injury. The study will also expand on current prognostic models by including novel blood biomarkers (circulating cell-free DNA), and the results of quantitative neuroimaging such as Quantitative Susceptibility Mapping and Dynamic Contrast Enhanced MRI as predictor variables.Ethics and dissemination Ethical approval has been obtained by the Royal Brisbane and Women’s Hospital Human Research Ethics Committee, Queensland. Participants or their substitute decision-maker/s will receive oral and written information about the study before providing written informed consent. Study findings will be disseminated by peer-review publications and presented at national and international conferences and clinical networks.
  • Chronic aphasias after left-hemisphere resective surgery

    Surgical resection of brain tumours is associated with an increased risk of aphasia. However, relatively little is known about outcomes in the chronic phase (i.e., >6 months). Using voxel-based lesion symptom mapping (VLSM) in 46 patients, we investigated whether chronic language impairments are related to the location of surgical resection, residual tumour characteristics (e.g., peri-resection treatment effects, progressive infiltration, oedema) or both. Approximately 72% of patients scored below the cut-off for aphasia. Action naming and spoken sentence comprehension deficits were associated with lesions in the left anterior temporal and inferior parietal lobes, respectively. Voxel-wise analyses revealed significant associations between ventral language pathways and action naming deficits. Reading impairments were also associated with increasing disconnection of cerebellar pathways. The results indicate chronic post-surgical aphasias reflect a combination of resected tissue and tumour infiltration of language-related white matter tracts, implicating progressive disconnection as the critical mechanism of impairment.
  • UNC-43/CaMKII-triggered anterograde signals recruit GABAARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs

    Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABARs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABARs remains elusive. Here, we show that UNC-43/CaMKII functions at GABAergic neurons to recruit GABARs and modulate inhibitory synaptic transmission at C. elegans neuromuscular junctions. We demonstrate that UNC-43 promotes presynaptic MADD-4B/Punctin secretion and NRX-1α/Neurexin surface delivery. Together, MADD-4B and NRX-1α recruit postsynaptic NLG-1/Neuroligin and stabilize GABARs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABARs, which depends on UNC-43, MADD-4B, and NRX-1. These data all support that UNC-43 triggers MADD-4B and NRX-1α, which act as anterograde signals to recruit postsynaptic GABARs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity.
  • Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations

    Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.
  • Proceedings of the OHBM Brainhack 2021

  • Expectation violations enhance neuronal encoding of sensory information in mouse primary visual cortex

    The response of cortical neurons to sensory stimuli is shaped both by past events (adaptation) and the expectation of future events (prediction). Here we employed a visual stimulus paradigm with different levels of predictability to characterise how expectation influences orientation selectivity in the primary visual cortex (V1) of male mice. We recorded neuronal activity using two-photon calcium imaging (GCaMP6f) while animals viewed sequences of grating stimuli which either varied randomly in their orientations or rotated predictably with occasional transitions to an unexpected orientation. For single neurons and the population, there was significant enhancement in the gain of orientation-selective responses to unexpected gratings. This gain-enhancement for unexpected stimuli was prominent in both awake and anaesthetised mice. We implemented a computational model to demonstrate how trial-to-trial variability in neuronal responses were best characterised when adaptation and expectation effects were combined.
  • A GNN-based model for capturing spatio-temporal changes in locomotion behaviors of aging C. elegans

    Investigating the locomotion of aging C. elegans is an important way for understanding the basic mechanisms behind age-related changes in organisms. However, the locomotion of aging C. elegans is often quantified using insufficient physical variables, which makes it challenging to capture essential dynamics. To study changes in the locomotion pattern of aging C. elegans, we developed a novel data-driven model based on graph neural networks, in which the C. elegans body is modeled as a long chain with interactions within and between adjacent segments, and their interactions are described by high-dimensional variables. Using this model, we discovered that each segment of the C. elegans body generally tends to maintain its locomotion, i.e., tries to keep the bending angle unchanged, and expects to change the locomotion of the adjacent segments. The ability to maintain its locomotion strengthens with age. Besides, a subtle distinguish in the changes in the locomotion pattern of C. elegans at various aging stages were observed. Our model is anticipated to provide a data-driven method for quantifying the changes in the locomotion pattern of aging C. elegans and for mining the underlying causes of these changes.
  • Evidence for entropy maximisation in human free choice behaviour

    The freedom to choose between options is strongly linked to notions of free will. Accordingly, several studies have shown that individuals demonstrate a preference for choice, or the availability of multiple options, over and above utilitarian value. Yet we lack a decision-making framework that integrates preference for choice with traditional utility maximisation in free choice behaviour. Here we test the predictions of an inference-based model of decision-making in which an agent actively seeks states yielding entropy (availability of options) in addition to utility (economic reward). We designed a study in which participants freely navigated a virtual environment consisting of two consecutive choices leading to reward locations in separate rooms. Critically, the choice of one room always led to two final doors while, in the second room, only one door was permissible to choose. This design allowed us to separately determine the influence of utility and entropy on participants' choice behaviour and their self-evaluation of free will. We found that choice behaviour was better predicted by an inference-based model than by expected utility alone, and that both the availability of options and the value of the context positively influenced participants' perceived freedom of choice. Moreover, this consideration of options was apparent in the ongoing motion dynamics as individuals navigated the environment. In a second study, in which participants selected between rooms that gave access to three or four doors, we observed a similar pattern of results, with participants preferring the room that gave access to more options and feeling freer in it. These results suggest that free choice behaviour is well explained by an inference-based framework in which both utility and entropy are optimised and supports the idea that the feeling of having free will is tightly related to options availability.
  • Intravenous immunoglobulin (IVIG) promotes brain repair and improves cognitive outcomes after traumatic brain injury in a FcγRIIB receptor-dependent manner

    Intravenous immunoglobulin (IVIG) is a promising immune-modulatory therapy for limiting harmful inflammation and associated secondary tissue loss in neurotrauma. Here, we show that IVIG therapy attenuates spatial learning and memory deficits following a controlled cortical impact mouse model of traumatic brain injury (TBI). These improvements in cognitive outcomes were associated with increased neuronal survival, an overall reduction in brain tissue loss, and a greater preservation of neural connectivity. Furthermore, we demonstrate that the presence of the main inhibitory FcγRIIB receptor is required for the beneficial effects of IVIG treatment in TBI, with our results simultaneously highlighting the role of this receptor in reducing secondary damage arising from brain injury.
  • Identification of phosphorylated Tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission

    Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody-mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p-Tau in PSP. Using this proof-of-concept workflow for identifying interacting proteins of interest, we characterized proteins proximal to p-Tau in PSP cases, identifying >84% of previously identified interaction partners of Tau and known modifiers of Tau aggregation, while 19 novel proteins not previously found associated with Tau were identified. Furthermore, our data also identified confidently assigned phosphorylation sites that have been previously reported on p-Tau. Additionally, using ingenuity pathway analysis (IPA) and human RNA-seq datasets, we identified proteins previously associated with neurological disorders and pathways involved in protein degradation, stress responses, cytoskeletal dynamics, metabolism, and neurotransmission. Together, our study demonstrates the utility of biotinylation by antibody recognition (BAR) approach to answer a fundamental question to rapidly identify proteins in proximity to p-Tau from post-mortem tissue. The application of this workflow opens up the opportunity to identify novel protein targets to give us insight into the biological process at the onset and progression of tauopathies.
  • An overview of DNA methylation-derived trait score methods and applications

    Microarray technology has been used to measure genome-wide DNA methylation in thousands of individuals. These studies typically test the associations between individual DNA methylation sites (“probes”) and complex traits or diseases. The results can be used to generate methylation profile scores (MPS) to predict outcomes in independent data sets. Although there are many parallels between MPS and polygenic (risk) scores (PGS), there are key differences. Here, we review motivations, methods, and applications of DNA methylation-based trait prediction, with a focus on common diseases. We contrast MPS with PGS, highlighting where assumptions made in genetic modeling may not hold in epigenetic data.
  • fmr1 mutation alters the early development of sensory coding and hunting and social behaviors in larval zebrafish

    Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in FMR1 Mutation of fmr1 in zebrafish causes anxiety-like behavior, hyperactivity, and hypersensitivity in auditory and visual processing. Here, we show that zebrafish fmr1-/- mutant larvae of either sex also display changes in hunting behavior, tectal coding, and social interaction. During hunting, they were less successful at catching prey and displayed altered behavioral sequences. In the tectum, representations of prey-like stimuli were more diffuse and had higher dimensionality. In a social behavioral assay, they spent more time observing a conspecific but responded more slowly to social cues. However, when given a choice of rearing environment fmr1-/- larvae preferred one with reduced visual stimulation, and rearing them in this environment reduced genotype-specific effects on tectal excitability. Together, these results shed new light on how fmr1-/- changes the early development of neural systems and behavior in a vertebrate.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are caused by changes in early neural development. Animal models of ASDs offer the opportunity to study these developmental processes in greater detail than in humans. Here, we found that a zebrafish mutant for a gene which in humans causes one type of ASD showed early alterations in hunting behavior, social behavior, and how visual stimuli are represented in the brain. However, we also found that mutant fish preferred reduced visual stimulation, and rearing them in this environment reduced alterations in neural activity patterns. These results suggest interesting new directions for using zebrafish as a model to study the development of brain and behavior in ASDs, and how the impact of ASDs could potentially be reduced.
  • The neuroanatomy of visuospatial neglect: A systematic review and analysis of lesion-mapping methodology

    While visuospatial neglect is commonly associated with damage to the right posterior parietal cortex, neglect is an anatomically heterogenous syndrome. This project presents a systematic review of 34 lesion-mapping studies reporting on the anatomical correlates of neglect. Specifically, the reported correlates of egocentric versus allocentric, acute versus chronic, personal versus extra-personal, and left versus right hemisphere neglect are summarised. The quality of each included lesion-mapping analysis was then evaluated to identify methodological factors which may help account for the reported variance in correlates of neglect.Overall, the existing literature strongly suggests that egocentric and allocentric neglect represent anatomically dissociable conditions and that the anatomy of these conditions may not be entirely homologous across hemispheres. Studies which have compared the anatomy of acute versus chronic neglect have found that these conditions are associated with distinct lesion loci, while studies comparing the correlates of peripersonal/extrapersonal neglect are split as to whether these neglect subtypes are anatomically dissociable. The included studies employed a wide range of lesion-mapping analysis techniques, each producing results of varying quality and generalisability. This review concludes that the reported underlying anatomical correlates of heterogeneous visuospatial neglect vary considerably. Future, high quality studies are needed to investigate patterns of disconnection associated with clearly defined forms of visuospatial neglect in large and representative samples.
  • Communicating the complex lives of families that include a child with Down syndrome

    Families of children with Down syndrome experience complex lives and needs, yet the few existing studies on these families are written in conventional academic prose that is not optimal for knowledge translation beyond academia, particularly for busy healthcare professionals. In this paper, we Depart Radically in Academic Writing (DRAW) (Mackinlay, 2022) and present data poetry and two case studies that draw upon semi-structured interviews with mothers, fathers, and siblings, who were interviewed separately about their experiences of having a child/sibling with Down syndrome. We introduce our interdisciplinary team that includes academics and clinicians to contextualise our focus on research translation. We demonstrate that writing with creative criticality (i.e. 'DRAWing') contributes an embodied and affective understanding of research participants' stories, which is largely lacking in the academic literature on families of children with Down syndrome and the sociology of health and illness field more broadly. Moreover, DRAWing can impact audiences emotionally as well as intellectually (Richardson, 2003, p. 924), which has important knowledge translation implications for both healthcare professionals and these families. DRAWing can capture healthcare professionals' attention, prompting them to critically reflect on their practices and opportunities for improving care and treatment for these families.
  • Deletion of MyD88 in astrocytes prevents β-amyloid-induced neuropathology in mice

    As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell-specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non-AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady-state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of β-amyloid (Aβ). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune-related proteins, and higher expression of synaptic-related proteins in response to Aβ. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.
  • Higher ultraviolet skin reflectance signals submissiveness in the anemonefish, Amphiprion akindynos

    When signaling submission, it is important to wave the "white flag." In the Barrier Reef anemonefish, ultraviolet color patterns serve to signal submissiveness. In staged contests over dominance between size-matched anemonefish, low ultraviolet skin reflectance strongly predicted fish winning a contest, while high UV skin reflectance predicted losing. We demonstrate that juvenile subordinates benefit by signaling their submissiveness with a naturally higher ultraviolet skin reflectance which evokes less aggression from larger, more-dominant fish and likely aids with social group integration.Ultraviolet (UV) vision is widespread among teleost fishes, of which many exhibit UV skin colors for communication. However, aside from its role in mate selection, few studies have examined the information UV signaling conveys in other socio-behavioral contexts. Anemonefishes (subfamily, Amphiprioninae) live in a fascinating dominance hierarchy, in which a large female and male dominate over non-breeding subordinates, and body size is the primary cue for dominance. The iconic orange and white bars of anemonefishes are highly UV-reflective, and their color vision is well tuned to perceive the chromatic contrast of skin, which we show here decreases in the amount of UV reflectance with increasing social rank. To test the function of their UV-skin signals, we compared the outcomes of staged contests over dominance between size-matched Barrier Reef anemonefish (Amphiprion akindynos) in aquarium chambers viewed under different UV-absorbing filters. Fish under UV-blocking filters were more likely to win contests, where fish under no-filter or neutral-density filter were more likely to submit. For contests between fish in no-filter and neutral density filter treatments, light treatment had no effect on contest outcome (win/lose). We also show that sub-adults were more aggressive toward smaller juveniles placed under a UV filter than a neutral density filter. Taken together, our results show that UV reflectance or UV contrast in anemonefish can modulate aggression and encode dominant and submissive cues, when changes in overall intensity are controlled for.
  • Quantitative proteomics of tau and Aβ in detergent fractions from Alzheimer's disease brains

    The two hallmarks of Alzheimer's disease (AD) are amyloid-beta (A beta) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Ala drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non-fibrillar (oligomeric) forms of A beta mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure-based nosologic classification, but less emphasis was given to non-filamentous co-aggregates of insoluble proteins in the fractions derived from post-mortem human brains. Here, we revisited sarkosyl-soluble and -insoluble extracts to characterize tau and A beta species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl-insoluble pellets were greatly enriched with A beta(42) at almost equimolar levels to N-terminal truncated microtubule-binding region (MTBR) isoforms of tau with multiple site-specific post-translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl-insoluble materials with a 10-fold higher concentration than N-terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation-prone N-terminal and proline-rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site-specific phosphorylation pT(181) (similar to 22%) and pT(217) (similar to 16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non-filamentous form (N-terminal intact tau) co-localized with A beta in the sarkosyl-insoluble pellets along with tau filaments (N-truncated MTBR tau). Our results suggest a model that A beta and tau interact forming globular aggregates, from which filamentous tau and A beta emerge. These characterizations contribute towards unravelling the sequence of events which lead to end-stage AD changes.
  • The empirical evidence for the social-ecological impacts of seaweed farming

    Seaweed farming is widely expected to transform the way we approach sustainable developments, particularly in the context of the ‘Blue Economy’. However, many claims of the social and ecological benefits from seaweed farming have limited or contextually weak empirical grounding. Here we systematically review relevant publications across four languages to form a comprehensive picture of observed—rather than theorised—social and environmental impacts of seaweed farming globally. We show that, while some impacts such as improved water quality and coastal livelihoods are consistently reported, other promulgated benefits vary across cultivation contexts or are empirically unsubstantiated. For some communities, increasing dependence on seaweed farming may improve or worsen the cultural fabric and their vulnerability to economic and environmental shocks. The empirical evidence for the impacts of seaweed farming is also restricted geographically, mainly to East Asia and South-East Asia, and taxonomically. Seaweed farming holds strong potential to contribute to sustainability objectives, but the social and ecological risks associated with scaling up global production remain only superficially understood. These risks require greater attention to ensure just, equitable, and sustainable seaweed industries can be realised.
  • Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose

    The genetic regulation of post-prandial glucose levels is poorly understood. Here, we characterise the genetic architecture of blood glucose variably measured within 0 and 24 h of fasting in 368,000 European ancestry participants of the UK Biobank. We found a near-linear increase in the heritability of non-fasting glucose levels over time, which plateaus to its fasting state value after 5 h post meal (h = 11%; standard error: 1%). The genetic correlation between different fasting times is > 0.77, suggesting that the genetic control of glucose is largely constant across fasting durations. Accounting for heritability differences between fasting times leads to a ~16% improvement in the discovery of genetic variants associated with glucose. Newly detected variants improve the prediction of fasting glucose and type 2 diabetes in independent samples. Finally, we meta-analysed summary statistics from genome-wide association studies of random and fasting glucose (N = 518,615) and identified 156 independent SNPs explaining 3% of fasting glucose variance. Altogether, our study demonstrates the utility of random glucose measures to improve the discovery of genetic variants associated with glucose homeostasis, even in fasting conditions.
  • The anaesthetics isoflurane and xenon reverse the synaptotoxic effects of Aβ1–42 on Megf10-dependent astrocytic synapse elimination and spine density in ex vivo hippocampal brain slices

    It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer’s disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how β-amyloid peptide 1–42 (Aβ), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aβ, Iso or Xe and the combination of Aβ with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aβ elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aβ both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aβ-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation.
  • Disrupted auditory N1, theta power and coherence suppression to willed speech in people with schizophrenia

    The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound. It has further been hypothesized that this suppression is evident primarily in theta band activity. Fifty-one people, half of whom had a diagnosis of schizophrenia, were asked to repeatedly utter a single syllable, which was played back to them concurrently over headphones while EEG was continuously recorded. In other conditions, recordings of the same spoken syllables were played back to participants while they passively listened, or were played back with their onsets preceded by a visual cue. All participants experienced these conditions with their voice artificially shifted in pitch and also with their unaltered voice. Suppression was measured using event-related potentials (N1 component), theta phase coherence and power. We found that suppression was generally reduced on all metrics in the patient sample, and when voice alteration was applied. We additionally observed reduced theta coherence and power in the patient sample across all conditions. Visual cueing affected theta coherence only. In aggregate, the results suggest that sensory self-suppression of theta power and coherence is disrupted in schizophrenia.
  • Application of WGCNA and PloGO2 in the analysis of complex proteomic data

    In this protocol we describe our workflow for analyzing complex, multi-condition quantitative proteomic experiments, with the aim to extract biological insights. The tool we use is an R package, PloGO2, contributed to Bioconductor, which we can optionally precede by running correlation network analysis with WGCNA. We describe the data required and the steps we take, including detailed code examples and outputs explanation. The package was designed to generate gene ontology or pathway summaries for many data subsets at the same time, visualize protein abundance summaries for each biological category examined, help determine enriched protein subsets by comparing them all to a reference set, and suggest key highly correlated hub proteins, if the optional network analysis is employed.
  • The N 6 ‐methyladenosine RNA landscape in the aged mouse hippocampus

    The aged brain is associated with an inevitable decline in cognitive function and increased vulnerability to neurodegenerative disorders. Multiple molecular hallmarks have been associated with the aging nervous system through transcriptomics and proteomic studies. Recently, epitranscriptomic analysis has highlighted the role of RNA chemical modification in various biological processes. In particular, N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNAs, has been functionally linked to multiple aspects of RNA metabolism with the roles of m6A in processes such as learning and memory, leading to our current investigation of how the m6A-transcriptomic landscape is shaped during aging. Using the inbred C57BL/6 line, we compared the m6A-transcriptomic profiles from the hippocampi of young (3-month-old) and aged (20-month-old) mice. Methylated RNA immunoprecipitation (MeRIP)-sequencing analysis revealed hyper- and hypomethylation in 426 and 102 genes, respectively, in the aged hippocampus (fold change >1.5, false discovery rate <0.05). By correlating the methylation changes to their steady-state transcript levels in the RNA-Seq data, we found a significant concordance between m6A and transcript levels in both directions. Notably, the myelin regulator gene Gpr17 was downregulated in the aged hippocampus concomitant with reduced m6A levels in its 3'UTR. Using reporter constructs and mutagenesis analysis, we demonstrated that the putative m6A sites in the 3'UTR of Gpr17 are important for mRNA translation but not for regulating transcript stability. Overall, the positive correlation between m6A and the transcript expression levels indicates a co-transcriptional regulation of m6A with gene expression changes that occur in the aged mouse hippocampus.
  • Animal models of relevance to the schizophrenia prodrome

    Patients with schizophrenia often undergo a prodromal phase prior to diagnosis. Given the absence of significant therapeutic improvements, attention has recently shifted to the possibility of intervention during this early stage to delay or diminish symptom severity or even prevent onset. Unfortunately, the 20 or so trials of intervention to date have not been successful in either preventing onset or improving long-term outcomes in subjects who are at risk of developing schizophrenia. One reason may be that the biological pathways an effective intervention must target are not static. The prodromal phase typically occurs during late adolescence, a period during which a number of brain circuits and structures are still maturing. We propose that developing a deeper understanding of which circuits/processes and brain structures are still maturing at this time and which processes drive the transition to schizophrenia will take us a step closer to developing better prophylactic interventions. Fortunately, such knowledge is now emerging from clinical studies, complemented by work in animal models. Our task here is to describe what would constitute an appropriate animal model to study and to potentially intervene in such processes. Such a model would allow invasive analysis of the cellular and molecular substrates of the progressive neurobiology that defines the schizophrenia prodrome and hopefully offer valuable insights into potential prophylactic targets.
  • Developing and adult reef fish show rapid light‐induced plasticity in their visual system

    The visual capabilities of fish are optimized for their ecology and light environment over evolutionary time. Similarly, fish vision can adapt to regular changes in light conditions within their lifetime, e.g., ontogenetic or seasonal variation. However, we do not fully understand how vision responds to irregular short-term changes in the light environment, e.g., algal blooms and light pollution. In this study, we investigated the effect of short-term exposure to unnatural light conditions on opsin gene expression and retinal cell densities in juvenile and adult diurnal reef fish (convict surgeonfish; Acanthurus triostegus). Results revealed phenotypic plasticity in the retina across ontogeny, particularly during development. The most substantial differences at both molecular and cellular levels were found under constant dim light, while constant bright light and simulated artificial light at night had a lesser effect. Under dim light, juveniles and adults increased absolute expression of the cone opsin genes, sws2a, rh2c and iws, within a few days and juveniles also decreased densities of cones, inner nuclear layer cells and ganglion cells. These changes potentially enhanced vision under the altered light conditions. Thus, our study suggests that plasticity mainly comes into play when conditions are extremely different to the species' natural light environment, i.e., a diurnal fish in "constant night", Finally, in a rescue experiment on adults, shifts in opsin expression were reverted within 24 h. Overall, our study showed rapid, reversible light-induced changes in the retina of A. triostegus, demonstrating phenotypic plasticity in the visual system of a reef fish throughout life.
  • The brain structure and the neural network features of the diurnal cuttlefish Sepia plangon

    Cuttlefish are known for their rapid changes of appearance enabling camouflage and con-specific communication for mating or agonistic display. However, interpretation of their sophisticated behaviors and responsible brain areas is based on the better-studied squid brain atlas. Here we present the first detailed description of the neuroanatomical features of a tropical and diurnal cuttlefish, Sepia plangon, coupled with observations on ontogenetic changes in its visual and learning centers using a suite of MRI-based techniques and histology. We then make comparisons to a loliginid squid, treating it as a ‘baseline’, and also to other cuttlefish species to help construct a connectivity map of the cuttlefish brain. Differences in brain anatomy and the previously unknown neural connections associated with camouflage, motor control and chemosensory function are described. These findings link brain heterogeneity to ecological niches and lifestyle, feeding hypotheses and evolutionary history, and provide a timely, new technology update to older literature.
  • High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile

    Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual’s polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) (n = 407,800, 40–69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study (n = 2122, 55–85 years), Older Australian Twins Study (n = 539, 65–90 years) and Sydney Memory and Ageing Study (n = 925, 70–90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies (n = 2273, 70–93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22–30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10) and its components (p < 2.30 × 10). Meta-analyses of the replication cohorts showed nominal associations with MetS (p = 0.028) and 3 MetS components (p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.
  • Demographic and symptom correlates of initial idiopathic psychiatric diagnosis in frontotemporal dementia

    Introduction This study aims to measure frequency and correlates of initial idiopathic psychiatric diagnosis in a cohort of 147 patients with Frontotemporal Dementia (FTD)-spectrum disorders. Methods Participants were evaluated at the National Institutes of Health in Bethesda, Maryland. Initial participant diagnoses were determined by chart review and patient and informant interviews. Logistic regression was used to assess the relationships between diagnosis and age of symptom onset, gender, education, family history of psychiatric illness, and family history of dementia. Additional exploratory analyses investigated patients' first symptom type. Results 25% (n=43) of all the patients reviewed were initially misdiagnosed with an idiopathic psychiatric illness, which is less than half the commonly cited 50% rate.(3) Depression was the most common misdiagnosis (46.5%). Family history of dementia, family history of mental illness and an exploratory analysis of behavioral first symptoms suggested significant association with a greater likelihood of initial idiopathic psychiatric diagnosis in FTD patients. Discussion This data confirms patterns of initial idiopathic psychiatric diagnosis in FTD and elucidates potential factors underlying misdiagnosis. Potential implications for patient outcomes, caregiver burden and healthcare costs are discussed.
  • Signaling and function of death receptors of the tumor necrosis factor receptor superfamily

    Programmed cell death or apoptosis is a genetically based mechanism that has evolved to eliminate superfluous cells. Upon activation of the extrinsic apoptotic pathway, an extracellular apoptotic signal is transmitted to the cytosol via transmembrane death receptors (DRs) of the tumor necrosis factor receptor superfamily. The apoptotic signal emanating from the DRs initiates one of the two cascades that activate multiple caspases, which eventually dismantle the cell from the inside. However, despite their name, most DRs are also engaged in non-apoptotic signaling pathways, with recent research revealing their important role in a number of biological processes, including development and inflammation.
  • Association of subjective cognitive decline with progression to dementia in a cognitively unimpaired multiracial community sample

    This prospective study seeks to examine the utility of SCD as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black and Latinx individuals. Debate surrounds the utility of Subjective Cognitive Decline (SCD), the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer's disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia.

    Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project (WHICAP) if they were cognitively unimpaired, had baseline measurement of SCD and self-identified as non-Latinx White, non-Latinx Black or Latinx. SCD was measured as a continuous sum of 10-items assessing cognitive complaints. Competing risk models tested main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort and baseline memory test performance with death jointly modelled as a function of race/ethnicity.

    A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black and 1,713 Latinx) participants were selected for this study with mean age of 75 years, 67% women and with a mean follow up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (HR=1.085, CI=1.047, 1.125, p<.001) as well as within Latinx (HR=1.084, CI=1.039, 1.130, p<.001) and Black individuals (HR=1.099, CI=1.012, 1.194, p=.024).

    Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. As models examining the risk of dementia were adjusted for baseline memory test performance, results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD.
  • Impairment in novelty-promoted memory via behavioral tagging and capture before apparent memory loss in a knock-in model of Alzheimer’s disease

    Alzheimer’s disease (AD) is associated with cognitive impairments and age-dependent memory deficits which have been studied using genetic models of AD. Whether the processes for modulating memory persistence are more vulnerable to the influence of amyloid pathology than the encoding and consolidation of the memory remains unclear. Here, we investigated whether early amyloid pathology would affect peri-learning novelty in promoting memory, through a process called behavioral tagging and capture (BTC). AppNL-G-F/NL-G-F mice and wild-type littermates were trained in an appetitive delayed matching-to-place (ADMP) task which allows for the assessment of peri-learning novelty in facilitating memory. The results show that novelty enabled intermediate-term memory in wild-type mice, but not in AppNL-G-F/NL-G-F mice in adulthood. This effect preceded spatial memory impairment in the ADMP task seen in middle age. Other memory tests in the Barnes maze, Y-maze, novel object or location recognition tasks remained intact. Together, memory modulation through BTC is impaired before apparent deficits in learning and memory. Relevant biological mechanisms underlying BTC and the implication in AD are discussed.
  • Long-wavelength-sensitive (lws) opsin gene expression, foraging and visual communication in coral reef fishes

    Coral reef fishes are diverse in ecology and behaviour and show remarkable colour variability. Investigating the visual pigment gene (opsin) expression in these fishes makes it possible to associate their visual genotype and phenotype (spectral sensitivities) to visual tasks, such as feeding strategy or conspecific detection. By studying all major damselfish clades (Pomacentridae) and representatives from five other coral reef fish families, we show that the long-wavelength-sensitive (lws) opsin is highly expressed in algivorous and less or not expressed in zooplanktivorous species. Lws is also upregulated in species with orange/red colours (reflectance >520 nm) and expression is highest in orange/red-coloured algivores. Visual models from the perspective of a typical damselfish indicate that sensitivity to longer wavelengths does enhance the ability to detect the red to far-red component of algae and orange/red-coloured conspecifics, possibly enabling social signalling. Character state reconstructions indicate that in the early evolutionary history of damselfishes, there was no lws expression and no orange/red coloration. Omnivory was most often the dominant state. Although herbivory was sometimes dominant, zooplanktivory was never dominant. Sensitivity to long wavelength (increased lws expression) only emerged in association with algivory but never with zooplanktivory. Higher lws expression is also exploited by social signalling in orange/red, which emerged after the transition to algivory. Although the relative timing of traits may deviate by different reconstructions and alternative explanations are possible, our results are consistent with sensory bias whereby social signals evolve as a correlated response to natural selection on sensory system properties in other contexts.
  • Computer-aided measurement system using image processing for measuring Cobb angle in scoliosis

    Background: One of the spine deformities is scoliosis, and Cobb angle is generally used to assess it. Objectives: In this study, a computer-aided measurement system (CAMS) was presented as a new repeatable and reproducible approach to assess the Cobb angle in idiopathic scoliosis patients. Methods: Python libraries, including OpenCV and Numpy were used for image processing and design of the software. To assess the repeatability and reproducibility of the CAMS, a series of 98 anterior-posterior radiographs from patients with idiopathic scoliosis were used. Assessments were done by five independent observers. Each radiograph was assessed by each observer three times with a minimum break of two weeks among assessment. The single measure intraclass correlation coefficient (ICC), the mean absolute difference (MAD), and the standard error measurement (SEM) values were used for intra-and inter-observer reliability. Results: The inter-observer analysis indicated that the ICCs ranged from 0.94-0.99, and the MAD between manual and CAMS were less than 3°. For intra-observer measurements, the combined SEM between all observers for the manual and CAMS was 1.79° and 1.27°, respectively. An ICC value of 0.97 with 95% confidence interval (CI) was excellent in CAMS for inter-observer reliability. The MAD of CAMS was 2.18 ± 2.01 degrees. Conclusions: The CAMS is an effective and reliable approach for assessing scoliotic curvature in the standing radiographs of thoraco-lumbar. Moreover, CAMS can accelerate clinical visits, and its calculation results are reliable.
  • Neurophysiological evidence against attentional suppression as the source of the same-location cost in spatial cueing

    Spatial cues that mismatch the colour of a subsequent target have been shown to slow responses to targets that share their location. The source of this 'same location cost' (SLC) is currently unknown. Two potential sources are attentional signal suppression and object-file updating. Here, we tested a direct prediction of the suppression account using data from a spatial-cueing study in which we recorded brain activity using electroencephalography (EEG), and focusing on the event-related P-D component, which is thought to index attentional signal suppression. Correlating P-D amplitude with SLC magnitude, we tested the prediction that if attentional signal suppression is the source of the SLC, then the SLC should be positively correlated with P-D amplitude. Across 48 participants, SLC and P-D magnitudes were negatively correlated, in direct contradiction to a suppression account of the SLC. These results are compatible with an object-file updating account of the SLC in which updating is facilitated by reactive suppression of the to-be-updated stimulus information.
  • Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells

    Induced pluripotent stem cells (iPSCs) can in principle differentiate into any cell of the body, and have revolutionized biomedical research and regenerative medicine. Unlike their human counterparts, mouse iPSCs (miPSCs) are reported to silence transposable elements and prevent transposable element-mediated mutagenesis. Here we apply short-read or Oxford Nanopore Technologies long-read genome sequencing to 38 bulk miPSC lines reprogrammed from 10 parental cell types, and 18 single-cell miPSC clones. While single nucleotide variants and structural variants restricted to miPSCs are rare, we find 83 de novo transposable element insertions, including examples intronic to Brca1 and Dmd. LINE-1 retrotransposons are profoundly hypomethylated in miPSCs, beyond other transposable elements and the genome overall, and harbor alternative protein-coding gene promoters. We show that treatment with the LINE-1 inhibitor lamivudine does not hinder reprogramming and efficiently blocks endogenous retrotransposition, as detected by long-read genome sequencing. These experiments reveal the complete spectrum and potential significance of mutations acquired by miPSCs.
  • Anemonefish have finer color discrimination in the ultraviolet

    In many animals, ultraviolet (UV) vision guides navigation, foraging, and communication, but few studies have addressed the contribution of UV vision to color discrimination, or behaviorally assessed UV discrimination thresholds. Here, we tested UV-color vision in an anemonefish (Amphiprion ocellaris) using a novel five-channel (RGB-V-UV) LED display designed to test UV perception. We first determined that the maximal sensitivity of the A. ocellaris UV cone was at ∼386 nm using microspectrophotometry. Three additional cone spectral sensitivities had maxima at ∼497, 515, and ∼535 nm, which together informed the modelling of the fish’s color vision. Anemonefish behavioral discrimination thresholds for nine sets of colors were determined from their ability to distinguish a colored target pixel from grey distractor pixels of varying intensity. We found that A. ocellaris used all four cones to process color information and is therefore tetrachromatic, and fish were better at discriminating colors (i.e., color discrimination thresholds were lower, or more acute) when targets had UV chromatic contrast elicited by greater stimulation of the UV cone relative to other cone types. These findings imply that a UV component of color signals and cues improves their detectability, that likely increases the salience of anemonefish body patterns used in communication and the silhouette of zooplankton prey.
  • Interleukin-8 and depressive responses to an inflammatory challenge: secondary analysis of a randomized controlled trial

    Emerging evidence suggests that interleukin (IL)-8 has a protective role in the context of depression. Higher levels of IL-8 are associated with lower depressive symptom severity among depressed patients, and treatment-related increases in IL-8 correlate with a positive response in depressed patients. This study (a secondary analysis of a completed randomized controlled trial) aimed to examine whether higher levels of IL-8 mitigate increases in depressed mood in response to an experimental model of inflammation induced depression. Given epidemiologic relationships identified between IL-6, tumor necrosis factor (TNF)- α, and subsequent depression, levels of these pro-inflammatory cytokines were also explored as potential moderators of depressed mood response to endotoxin. Secondary analyses were completed on data from healthy adults (n = 114) who completed a double-blind, placebo-controlled randomized trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). IL-8, as well as IL-6 and TNF- α, were measured at baseline prior to infusion, and depressed mood and feelings of social disconnection were assessed approximately hourly. Baseline levels of IL-8, but not IL-6 or TNF-α, moderated depressed mood (β = − 0.274, p =.03) and feelings of social disconnection (β = − 0.307, p =.01) responses, such that higher baseline IL-8 was associated with less increase in depressed mood and feelings of social disconnection in the endotoxin, but not placebo, condition. IL-8 had threshold effects, in which highest quartile IL-8 (≥ 2.7 pg/mL) attenuated increases in depressed mood in response to endotoxin as compared to lower IL-8 quartiles (p =.02). These findings suggest that IL-8 may be a biological factor that mitigates risk of inflammation-associated depression. Clinical trials registration: ClinicalTrials.gov NCT01671150, registration date 23/08/2012.
  • Plasma biomarkers inclusive of α-synuclein/amyloid-beta40 ratio strongly correlate with Mini-Mental State Examination score in Parkinson’s disease and predict cognitive impairment

    Plasma biomarkers for Parkinson’s disease (PD) diagnosis that carry predictive value for cognitive impairment are valuable. We explored the relationship of Mini-Mental State Examination (MMSE) score with plasma biomarkers in PD patients and compared results to vascular dementia (VaD) and normal controls. The predictive accuracy of an individual biomarker on cognitive impairment was evaluated using area under the receiver operating characteristic curve (AUROC), and multivariate logistic regression was applied to evaluate predictive accuracy of biomarkers on cognitive impairment; 178 subjects (41 PD, 31 VaD and 106 normal controls) were included. In multiple linear regression analysis of PD patients, α-synuclein, anti-α-synuclein, α-synuclein/Aβ40 and anti-α-synuclein/Aβ40 were highly predictive of MMSE score in both full model and parsimonious model (R = 0.838 and 0.835, respectively) compared to non-significant results in VaD group (R = 0.149) and in normal controls (R = 0.056). Α-synuclein and anti-α-synuclein/Aβ40 were positively associated with MMSE score, and anti-α-synuclein, α-synuclein/Aβ40 were negatively associated with the MMSE score among PD patients (all Ps < 0.005). In the AUROC analysis, anti-α-synuclein (AUROC = 0.788) and anti-α-synuclein/Aβ40 (AUROC = 0.749) were significant individual predictors of cognitive impairment. In multivariate logistic regression, full model of combined biomarkers showed high accuracy in predicting cognitive impairment (AUROC = 0.890; 95%CI 0.796–0.984) for PD versus controls, as was parsimonious model (AUROC = 0.866; 95%CI 0.764–0.968). In conclusion, simple combination of biomarkers inclusive of α-synuclein/Aβ40 strongly correlates with MMSE score in PD patients versus controls and is highly predictive of cognitive impairment.
  • Chronicling the diagnostic journey, symptom experiences, and disease impact in frontotemporal degeneration

  • Nanopore Sequencing to Identify Transposable Element Insertions and Their Epigenetic Modifications

    Over the past 20 years, high-throughput genomic assays have fundamentally changed how transposable elements (TEs) are studied. While short-read DNA sequencing has been at the heart of these efforts, novel technologies that generate longer reads are driving a shift in the field. Long-read sequencing now permits locus-specific approaches to locate individual TE insertions and understand their epigenetic and transcriptional regulation, while still profiling TE activity genome-wide. Here we provide detailed guidelines to implement Oxford Nanopore Technologies (ONT) sequencing to identify polymorphic TE insertions and profile TE epigenetic landscapes. Using human long interspersed element-1 (LINE-1, L1) as an example, we explain the procedures involved, including final visualization, and potential bottlenecks and pitfalls. ONT sequencing will be, in our view, a workhorse technology for the foreseeable future in the TE field.
  • Analysis of the distribution of vagal afferent projections from different peripheral organs to the nucleus of the solitary tract in rats

    Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno-associated virus that transports retrogradely and exhibits selective tropism for vagal afferents, to map their soma location and central termination sites within the nucleus of the solitary tract (NTS). We examined the vagal sensory afferents innervating the trachea, duodenum, stomach, or heart, and in some animals, from two organs concurrently. We observed no obvious somatotopy in the somata distribution within the nodose ganglion. The central termination patterns of afferents from different organs within the NTS overlap substantially. Convergence of vagal afferent inputs from different organs onto single NTS neurons is observed. Abdominal and thoracic afferents terminate throughout the NTS, including in the rostral NTS, where the 7th cranial nerve inputs are known to synapse. To address whether the axonal labeling produced by viral transduction is so widespread because it fills axons traveling to their targets, and not just terminal fields, we labeled pre and postsynaptic elements of vagal afferents in the NTS . Vagal afferents form multiple putative synapses as they course through the NTS, with each vagal afferent neuron distributing sensory signals to multiple second-order NTS neurons. We observe little selectivity between vagal afferents from different visceral targets and NTS neurons with common neurochemical phenotypes, with afferents from different organs making close appositions with the same NTS neuron. We conclude that specific viscerosensory information is distributed widely within the NTS and that the coding of this input is probably determined by the intrinsic properties and projections of the second-order neuron.