QBI research publications

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Signaling and function of death receptors of the tumor necrosis factor receptor superfamily

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Rapid development of an integrated remote programming platform for neuromodulation systems through the biodesign process

    Treating chronic symptoms for pain and movement disorders with neuromodulation therapies involves fine-tuning of programming parameters over several visits to achieve and maintain symptom relief. This, together with challenges in access to trained specialists, has led to a growing need for an integrated wireless remote care platform for neuromodulation devices. In March of 2021, we launched the first neuromodulation device with an integrated remote programming platform. Here, we summarize the biodesign steps taken to identify the unmet patient need, invent, implement, and test the new technology, and finally gain market approval for the remote care platform. Specifically, we illustrate how agile development aligned with the evolving regulatory requirements can enable patient-centric digital health technology in neuromodulation, such as the remote care platform. The three steps of the biodesign process applied for remote care platform development are: (1) Identify, (2) Invent, and (3) Implement. First, we identified the unmet patient needs through market research and voice-of-customer (VOC) process. Next, during the concept generation phase of the invention step, we integrated the results from the VOC into defining requirements for prototype development. Subsequently, in the concept screening phase, ten subjects with PD participated in a clinical pilot study aimed at characterizing the safety of the remote care prototype. Lastly, during the implementation step, lessons learned from the pilot experience were integrated into final product development as new features. Following final product development, we completed usability testing to validate the full remote care system and collected preliminary data from the limited market release experience. The VOC data, during prototype development, helped us identify thresholds for video quality and needs priorities for clinicians and patients. During the pilot study, one subject reported anticipated remote–care-related adverse events that were resolved without sequelae. For usability analysis following final product development, the failure rates for task completion for both user groups were about 1%. Lastly, during the initial 4 weeks of the limited market release experience, a total of 858 remote care sessions were conducted with a 93% success rate. Overall, we developed a remote care platform by adopting a user-centric approach. Although the system intended to address pre-COVID19 challenges associated with disease management, the unforeseen overlap of the study with the pandemic elevated the importance of such a system and an innovative development process enabled us to advance a patient-centric platform to gain regulatory approval and successfully launch the remote care platform to market.
  • Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors

    Background: Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABA subunits promote misfolding and inefficient assembly of the GABA receptors, limiting receptor expression and activity at the plasma membrane. However, GABA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy. Results: Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis. Conclusions: These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases.
  • On the relations between letter, word, and sentence-level processing during reading

    Much prior research on reading has focused on a specific level of processing, with this often being letters, words, or sentences. Here, for the first time in adult readers, we provide a combined investigation of these three key component processes of reading comprehension. We did so by testing the same group of participants in three tasks thought to reflect processing at each of these levels: alphabetic decision, lexical decision, and grammatical decision. Participants also performed a non-reading classification task, with an aim to partial-out common binary decision processes from the correlations across the three main tasks. We examined the pairwise partial correlations for response times (RTs) in the three reading tasks. The results revealed strong significant correlations across adjacent levels of processing (i.e., letter-word; word-sentence) and a non-significant correlation between non-adjacent levels (letter-sentence). The results provide an important new benchmark for evaluating computational models that describe how letters, words, and sentences contribute to reading comprehension.
  • 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.
  • 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.
  • Diversity and evolution of optically complex eyes in a family of deep-sea fish: ocular diverticula in barreleye spookfish (Opisthoproctidae)

    Several families of mesopelagic fish have tubular eyes that are usually upwardly directed. These maximise sensitivity to dim downwelling sunlight and dorsal bioluminescence, as well as facilitating the detection of dark silhouettes above the animal. Such eyes, however, have a much-reduced field of view and will not be sensitive to, for example, lateral and ventral bioluminescent stimuli. All mesopelagic Opisthoproctidae so far examined have evolved mechanisms for extending the limited visual field of their eyes using approximately ventrolaterally directed, light-sensitive, diverticula. Some genera have small rudimentary lateral retinal areas capable of detecting only unfocussed illumination. Others have more extensive structures resulting in eyes that simultaneously focus light from above onto the main retina of the tubular eye using a lens, while diverticula produce focussed images of ventrolateral illumination using either reflection or possibly refraction. These bipartite structures represent perhaps the most optically complex of all vertebrate eyes. Here we extend the limited previous data on the ocular morphology of five Opisthoproctidae (Opisthoproctus soleatus, Winteria telescopa, Dolichopteryx longipes, Rhynchohyalus natalensis, and Bathylychnops exilis) using a combination of histology and magnetic resonance imaging and provide a preliminary description of the eyes of Macropinna microstoma. We note an increase in diverticular complexity over the life span of some species and quantify the contribution of the diverticulum to the eye’s total neural output in D. longipes and R. natalensis (25 and 20%, respectively). To help understand the evolution of Opisthoproctidae ocular diversity, a phylogeny, including all the species whose eye types are known, was reconstructed using DNA sequences from 15 mitochondrial and four nuclear genes. Mapping the different types of diverticula onto this phylogeny suggests a process of repeated evolution of complex ocular morphology from more rudimentary diverticula.
  • Retrospective genomics highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population

    Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark (Galeocerdo cuvier) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates.
  • The time-course of feature-based attention effects dissociated from temporal expectation and target-related processes

    Selective attention prioritises relevant information amongst competing sensory input. Time-resolved electrophysiological studies have shown stronger representation of attended compared to unattended stimuli, which has been interpreted as an effect of attention on information coding. However, because attention is often manipulated by making only the attended stimulus a target to be remembered and/or responded to, many reported attention effects have been confounded with target-related processes such as visual short-term memory or decision-making. In addition, attention effects could be influenced by temporal expectation about when something is likely to happen. The aim of this study was to investigate the dynamic effect of attention on visual processing using multivariate pattern analysis of electroencephalography (EEG) data, while (1) controlling for target-related confounds, and (2) directly investigating the influence of temporal expectation. Participants viewed rapid sequences of overlaid oriented grating pairs while detecting a “target” grating of a particular orientation. We manipulated attention, one grating was attended and the other ignored (cued by colour), and temporal expectation, with stimulus onset timing either predictable or not. We controlled for target-related processing confounds by only analysing non-target trials. Both attended and ignored gratings were initially coded equally in the pattern of responses across EEG sensors. An effect of attention, with preferential coding of the attended stimulus, emerged approximately 230 ms after stimulus onset. This attention effect occurred even when controlling for target-related processing confounds, and regardless of stimulus onset expectation. These results provide insight into the effect of feature-based attention on the dynamic processing of competing visual information.
  • 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.
  • The when, what, and how of observing practice in Early Childhood Education and Care: development of the Assisting Observations Toolkit for Authorised Officers

  • Teacher vs child: an interactional tug of war to decide their next activity

  • Eliciting and responding to young children's talk: a systematic review

  • Challenging behaviour of children and its impact on educators

  • Multiple rod layers increase the speed and sensitivity of vision in nocturnal reef fishes

    Multibank retinas have rod photoreceptors stacked into multiple layers. They are found in many species of fish that inhabit dim environments and are one of the most common visual adaptations in the deep-sea. Despite its prevalence, the function of multibank retinas remained unknown. Two predominant theories, neither of which has been tested, have emerged: 1) they enhance sensitivity in dim light, and 2) they allow colour vision in dim light. To investigate the sensitivity hypothesis, we performed electrophysiological recordings and compared the rod pigments of three species of nocturnal reef fishes, two with a multibank retina (Neoniphon sammara and Myripristis violacea) and a control species with a single rod bank (Ostorhinchus compressus). Results indicated that nocturnal reef fishes with a multibank retina have higher temporal resolution of vision, as indicated by electrophysiology, and that their rhodopsin proteins likely also have faster retinal release kinetics, as suggested by amino acid substitutions. Electrophysiology also showed that the multibank retina conferred greater sensitivity to both dim and bright intensities than a single rod bank and this occurred at times when rod-derived signals usually dominate the visual response. This study provides the first functional evidence for enhanced dim-light sensitivity using a multibank retina while also suggesting novel roles for the adaptation in enhancing bright-light sensitivity and the speed of vision.
  • Management-induced distress syndrome

  • Absence of age differences in emotion perception and gaze patterns using a contextually rich film-based assessment

    Age differences in emotion perception are now well documented. However, a key limitation of many studies in this literature is the reliance on highly artificial tasks that lack context and consequently have poor ecological validity. This study reports two separate experiments that investigated age differences in emotion perception abilities using a highly contextualised film-based assessment along with a traditional emotion perception task. Experiment 2 additionally included a middle-aged sample and an assessment of eye-gaze patterns to the emotional films. The inclusion of eye-tracking in Experiment 2 was motivated by the fact that older adults consistently show visual biases to static emotion stimuli, yet it remains unclear whether biases also emerge in response to dynamic contextualised emotion stimuli. Experiment 1 identified age effects recognising displays of anger in the traditional emotion perception task but no age differences emerged on the film-based task. This finding was replicated in Experiment 2 with significant group differences on the traditional emotion perception task but no age differences on the film-based task. Experiment 2 also showed that there were no age differences in gaze patterns to these stimuli, showing for the first time that age-related visual biases to emotion stimuli may be task dependent. These findings highlight the fact that task-related features play a key role in the evaluation of age effects in emotion perception.
  • Visual representations: insights from neural decoding

    Patterns of brain activity contain meaningful information about the perceived world. Recent decades have welcomed a new era in neural analyses, with computational techniques from machine learning applied to neural data to “decode” information represented in the brain. In this article, we review how decoding approaches have advanced our understanding of visual representations, and discuss efforts to characterize both their complexity and behavioral relevance. We outline the current consensus regarding the spatiotemporal structure of visual representations, and review recent findings that suggest visual representations are at once robust to perturbations, yet sensitive to different mental states. Beyond representations of the physical world, recent decoding work has shone a light on how the brain instantiates internally-generated states, for example during imagery and prediction. Going forward, decoding has remarkable potential to assess how visual representations function for behavior, during development and aging, and in various mental disorders.
  • Novel plasma and brain proteins that are implicated in multiple sclerosis

    Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown.Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening.We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases.The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.
  • 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.
  • tDCS augments decision-making efficiency in an intensity dependent manner: a training study

    The application of transcranial direct current stimulation (tDCS) to the prefrontal cortex has the potential to improve performance more than cognitive training alone. Such stimulation-induced performance enhancements can generalize beyond trained tasks, leading to benefits for untrained tasks/processes. We have shown evidence that stimulation intensity has non-linear effects on augmenting cognitive training outcomes. However, it is currently unclear how stimulation intensity augments cognitive processing to impact training and transfer effects. Here, we applied decision-making modelling via the linear ballistic accumulator framework to understand what aspects of cognitive processes underlying speeded single-/dual-task decision-making performance change with tDCS intensity. One hundred and twenty-three participants were split into four groups: sham, 0.7 mA, 1.0 mA and 2.0 mA stimulation intensities. Participants completed four training sessions whilst tDCS was delivered. The 0.7 mA & 1.0 mA intensities provided the greatest benefit for performance (increased decision-making efficiency as measured by drift rates) on the trained task - more than sham or 2.0 mA stimulation. The latent decision components integrated both accuracy and reaction times to estimate performance more broadly. We see an inverted u-shaped function of stimulation intensity and cognitive performance in the trained-on task, where either no stimulation or too much stimulation is sub-optimal for performance. By contrast, 1.0 mA and 2.0 mA intensities led to increased drift rates in an untrained (transfer) single task. In sum, tDCS intensity non-linearly modulates cognitive processes related to decision-making efficiency.
  • Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer’s disease

    Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer’s disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.
  • Optical tweezers across scales in cell biology

    Optical tweezers (OT) provide a noninvasive approach for delivering minute physical forces to targeted objects. Controlling such forces in living cells or in vitro preparations allows for the measurement and manipulation of numerous processes relevant to the form and function of cells. As such, OT have made important contributions to our understanding of the structures of proteins and nucleic acids, the interactions that occur between microscopic structures within cells, the choreography of complex processes such as mitosis, and the ways in which cells interact with each other. In this review, we highlight recent contributions made to the field of cell biology using OT and provide basic descriptions of the physics, the methods, and the equipment that made these studies possible.
  • SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

    Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
  • Rapid reconstruction of neural circuits using tissue expansion and light sheet microscopy

    Brain function is mediated by the physiological coordination of a vast, intricately connected network of molecular and cellular components. The physiological properties of neural network components can be quantified with high throughput. The ability to assess many animals per study has been critical in relating physiological properties to behavior. By contrast, the synaptic structure of neural circuits is presently quantifiable only with low throughput. This low throughput hampers efforts to understand how variations in network structure relate to variations in behavior. For neuroanatomical reconstruction there is a methodological gulf between electron-microscopic (EM) methods, which yield dense connectomes at considerable expense and low throughput, and light-microscopic (LM) methods, which provide molecular and cell-type specificity at high throughput but without synaptic resolution. To bridge this gulf, we developed a high-throughput analysis pipeline and imaging protocol using tissue expansion and light sheet microscopy (ExLLSM) to rapidly reconstruct selected circuits across many animals with single-synapse resolution and molecular contrast. Using Drosophila to validate this approach, we demonstrate that it yields synaptic counts similar to those obtained by EM, enables synaptic connectivity to be compared across sex and experience, and can be used to correlate structural connectivity, functional connectivity, and behavior. This approach fills a critical methodological gap in studying variability in the structure and function of neural circuits across individuals within and between species.
  • Colour vision in stomatopod crustaceans

    The stomatopod crustaceans, or mantis shrimps, are colourful marine invertebrate predators. Their unusual compound eyes have dorsal and ventral regions resembling typical crustacean apposition designs separated by a unique region called the midband that consists of from two to six parallel rows of ommatidia. In species with six-row midbands, the dorsal four rows are themselves uniquely specialized for colour analysis. Rhabdoms of ommatidia in these rows are longitudinally divided into three distinct regions: an apical ultraviolet (UV) receptor, a shorter-wavelength middle tier receptor and a longer-wavelength proximal tier receptor. Each of the total of 12 photoreceptors has a different spectral sensitivity, potentially contributing to a colour-vision system with 12 channels. Mantis shrimps can discriminate both human-visible and UV colours, but with limited precision compared to other colour-vision systems. Here, we review the structure and function of stomatopod colour vision, examining the types of receptors present in a species, the spectral tuning of photoreceptors both within and across species, the neural analysis of colour and the genetics underlying the multiple visual pigments used for colour vision. Even today, after many decades of research into the colour vision of stomatopods, much of its operation and its use in nature remain a mystery. This article is part of the theme issue 'Understanding colour vision: molecular, physiological, neuronal and behavioural studies in arthropods'.