QBI research publications

  • Biofluid biomarkers of amyotrophic lateral sclerosis

    Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease that is characterized by the progressive, irreversible loss of upper and lower motor neurons. It is a highly heterogeneous disease and variability in age of onset, site of onset, rate of disease progression, and survival between individuals present significant challenges for diagnosis and clinical care. Research into understanding the cause for ALS, and the clinical management of the disease is limited in part due to the absence of specific, sensitive biomarkers for the disease. To date, studies aimed at identifying reliable and specific biomarkers for ALS have revealed blood, cerebrospinal fluid (CSF), and urine markers as being useful. Here, we summarize some of the most promising fluid biomarkers identified to date, and discuss their proposed utility for improving our approach to ALS diagnosis, care, and research. Overall, while most studies into biomarkers for ALS explore single-marker utility, accurate profiling of individuals with ALS is likely to require a panel of complementary biomarkers providing insight into multiple aspects of the disease.
  • Neuroinflammation in Huntington’s

    Huntington’s disease (HD) is a debilitating inherited neurodegenerative disorder characterized by motor, cognitive and psychiatric deficits. Microglial and astrocyte activation, part of the process termed neuroinflammation, is one hallmark of HD, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. Although the relationship between neuroinflammation markers and the disease pathology is not completely understood, there is now compelling evidence to suggest that microglial and astrocyte activation signatures, identified as soluble factors in the cerebrospinal fluid or blood, or identified using PET imaging, could be used as potential complementary biomarkers to monitor and evaluate disease progression in HD patients. Identification of neuroinflammation markers prior to clinical symptoms opens up the possibility of evaluating disease-modifying treatments in the premanifest phase. Hence, neuroinflammatory biofluid and imaging biomarkers could provide an objective measurement for assessing HD severity and would also be valuable in the clinical care of existing HD patients. Neuroinflammatory biomarkers would also be useful in a clinical trial context, potentially serving as surrogate endpoints. This chapter will explore the evidence of roles for activated microglia, astrocytes, and peripheral immune cells in HD, and explore possible biomarkers of neuroinflammation.
  • Neurogenic-dependent changes in hippocampal circuitry underlie the pro-cognitive effect of exercise in ageing mice

    We have shown that the improvement in hippocampal-based learning in aged mice following physical exercise observed is dependent on neurogenesis in the dentate gyrus (DG) and is regulated by changes in growth hormone levels. The changes in neurocircuitry, however, which may underlie this improvement, remain unclear. Using in vivo multimodal magnetic resonance imaging to track changes in aged mice exposed to exercise, we show the improved spatial learning is due to enhanced DG connectivity, particularly the strengthening of the DG-Cornu Ammonis 3 and the DG-medial entorhinal cortex connections in the dorsal hippocampus. Moreover, we provide evidence that these changes in circuitry are dependent on neurogenesis since they were abrogated by ablation of newborn neurons following exercise. These findings identify the specific changes in hippocampal circuitry that underlie the cognitive improvements resulting from physical activity and show that they are dependent on the activation of neurogenesis in aged animals.
  • Sofosbuvir plus Ribavirin is effective for HCV elimination in people living with HIV from rural area of China

    People living with HIV (PLWH) bear higher prevalence of HCV coinfection. An accessible directly acting antivirals regimen with less drug–drug interaction with antiretroviral therapy (ART) is urgently needed in source limited regions. We aimed to assess the efficacy and safety of SOF + RBV for 24 weeks regimen in HIV–HCV coinfected patients in Liangshan Prefecture, China. PLWH under ART from China’s national free antiretroviral treatment project (CNFATP) and diagnosed with treatment-naïve HCV infection were enrolled. SOF + RBV was administrated for 24 weeks and patients were followed for ≥ 12 weeks. The efficacy and safety were analyzed and related factors were explored. 58 patients completed 24 weeks of SOF + RBV and had all tests done. Genotype prevalence in this population was G3 44.8% (n = 26), G6 31.0% (n = 18) and G1 17.2% (n = 10) respectively. 52/58 (89.7%) patients achieved SVR12 while 10.3% experienced therapeutic failure. However, SVR12 was neither significantly different between groups of different gender, age, transmission routines, CD4 cell count, HIV infection duration, ART duration and HBsAg prevalence nor influenced by HCV viral load, genotypes and hepatic stiffness. The regimen was well-tolerated without any serious AEs or AEs leading to treatment adjustment or discontinuation reported. PLWH in Liangshan showed a high prevalence of HCV coinfection with GT3 and GT6 as the most frequent genotypes. SOF + RBV for 24 weeks could achieve good SVR12 in this population and was well-tolerated. It has great potential to be generalized in coinfected population in source-limited regions.
  • Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.
  • Task-related brain functional network reconfigurations relate to motor recovery in chronic subcortical stroke

    Stroke leads to both regional brain functional disruptions and network reorganization. However, how brain functional networks reconfigure as task demand increases in stroke patients and whether such reorganization at baseline would facilitate post-stroke motor recovery are largely unknown. To address this gap, brain functional connectivity (FC) were examined at rest and motor tasks in eighteen chronic subcortical stroke patients and eleven age-matched healthy controls. Stroke patients underwent a 2-week intervention using a motor imagery-assisted brain computer interface-based (MI-BCI) training with or without transcranial direct current stimulation (tDCS). Motor recovery was determined by calculating the changes of the upper extremity component of the Fugl–Meyer Assessment (FMA) score between pre- and post-intervention divided by the pre-intervention FMA score. The results suggested that as task demand increased (i.e., from resting to passive unaffected hand gripping and to active affected hand gripping), patients showed greater FC disruptions in cognitive networks including the default and dorsal attention networks. Compared to controls, patients had lower task-related spatial similarity in the somatomotor–subcortical, default–somatomotor, salience/ventral attention–subcortical and subcortical–subcortical connections, suggesting greater inefficiency in motor execution. Importantly, higher baseline network-specific FC strength (e.g., dorsal attention and somatomotor) and more efficient brain network reconfigurations (e.g., somatomotor and subcortical) from rest to active affected hand gripping at baseline were related to better future motor recovery. Our findings underscore the importance of studying functional network reorganization during task-free and task conditions for motor recovery prediction in stroke.
  • Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

    Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
  • JM-20 treatment prevents neuronal damage and memory impairment induced by aluminum chloride in rats

    The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.
  • Predicting the retinotopic organization of human visual cortex from anatomy using geometric deep learning

    Whether it be in a single neuron or a more complex biological system like the human brain, form and function are often directly related. The functional organization of human visual cortex, for instance, is tightly coupled with the underlying anatomy with cortical shape having been shown to be a useful predictor of the retinotopic organization in early visual cortex. Although the current state-of-the-art in predicting retinotopic maps is able to account for gross individual differences, such models are unable to account for any idiosyncratic differences in the structure-function relationship from anatomical information alone due to their initial assumption of a template. Here we developed a geometric deep learning model capable of exploiting the actual structure of the cortex to learn the complex relationship between brain function and anatomy in human visual cortex such that more realistic and idiosyncratic maps could be predicted. We show that our neural network was not only able to predict the functional organization throughout the visual cortical hierarchy, but that it was also able to predict nuanced variations across individuals. Although we demonstrate its utility for modeling the relationship between structure and function in human visual cortex, our approach is flexible and well-suited for a range of other applications involving data structured in non-Euclidean spaces.
  • Traumatic brain injury augurs ill for prolonged deficits in the brain’s structural and functional integrity following controlled cortical impact injury

    Previous neuroimaging studies in rodents investigated effects of the controlled cortical impact (CCI) model of traumatic brain injury (TBI) within one-month post-TBI. This study extends this temporal window to monitor the structural–functional alterations from two hours to six months post-injury. Thirty-seven male Sprague–Dawley rats were randomly assigned to TBI and sham groups, which were scanned at two hours, 1, 3, 7, 14, 30, 60 days, and six months following CCI or sham surgery. Structural MRI, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were acquired to assess the dynamic structural, microstructural, and functional connectivity alterations post-TBI. There was a progressive increase in lesion size associated with brain volume loss post-TBI. Furthermore, we observed reduced fractional anisotropy within 24 h and persisted to six months post-TBI, associated with acutely reduced axial diffusivity, and chronic increases in radial diffusivity post-TBI. Moreover, a time-dependent pattern of altered functional connectivity evolved over the six months’ follow-up post-TBI. This study extends the current understanding of the CCI model by confirming the long-term persistence of the altered microstructure and functional connectivity, which may hold a strong translational potential for understanding the long-term sequelae of TBI in humans.
  • Cell-specific mitochondria affinity purification (CS-MAP) from Caenorhabditis elegans

    Cell-Specific Mitochondria Affinity Purification (CS-MAP) enables isolation and purification of intact mitochondria from individual cell types of Caenorhabditis elegans. The approach is based on the cell-specific expression of a recombinant hemagglutinin (HA)-tag fused to the TOMM-20 protein that decorates the surface of mitochondria, thereby allowing their immunomagnetic purification. This protocol describes the CS-MAP procedure performed on large populations of animals. The purified mitochondria are suitable for subsequent nucleic acid, protein, and functional analyses.
  • Functional status and its associated factors among community-dwelling older adults in rural Nepal: findings from a cross-sectional study

    Background: The high burden of chronic conditions, coupled with various physical, mental, and psychosocial changes that accompany the phenomenon of aging, may limit the functional ability of older adults. This study aims to assess the prevalence of poor functional status and investigate factors associated with poor functional status among community-dwelling older adults in rural communities of eastern Nepal. Methods: Data on 794 older adults aged ≥ 60 years from a previous community-based cross-sectional study was used. Participants were recruited from rural municipalities of Morang and Sunsari districts of eastern Nepal using multi-stage cluster sampling. Functional status was assessed in terms of participants’ ability to perform activities of daily living using the Barthel Index. Covariates included sociodemographic characteristics, lifestyle factors, and self-reported chronic conditions. A binary logistic regression model was used to investigate factors associated with poor functional status. Results: The overall prevalence of poor functional status was 8.3 % (male: 7.0 % and female: 9.6 %), with most dependence noted for using stairs (17.3 %), followed by dressing (21.9 %) on Barthel Index. In the adjusted model, oldest age group (odds ratio [OR] = 2.83, 95 %CI: 1.46, 5.50), those unemployed (OR = 2.41, 95 %CI: 1.26, 4.65), having memory/concentration problems (OR = 2.32, 95 %CI: 1.30, 4.13), depressive symptoms (OR = 2.52, 95 %CI: 1.28, 4.95), and hypertension (OR = 1.78, 95 %CI: 1.03, 3.06) had almost or more than two times poor functioning. Conclusions: One in 12 older adults had poor functional status as indicated by their dependency on the items of the Barthel Index; those in the oldest age bracket were more likely to exhibit poor functional status. We suggest future studies from other geographies of the country to supplement our study from the rural setting for comprehensive identification of the problem, which could guide the development of prevention strategies and comprehensive interventions for addressing the unmet needs of the older adults for improving functional status.
  • Reversed and increased functional connectivity in non-REM sleep suggests an altered rather than reduced state of consciousness relative to wake

    Sleep resting state network (RSN) functional connectivity (FC) is poorly understood, particularly for rapid eye movement (REM), and in non-sleep deprived subjects. REM and non-REM (NREM) sleep involve competing drives; towards hypersynchronous cortical oscillations in NREM; and towards wake-like desynchronized oscillations in REM. This study employed simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) to explore whether sleep RSN FC reflects these opposing drives. As hypothesized, this was confirmed for the majority of functional connections modulated by sleep. Further, changes were directional: e.g., positive wake correlations trended towards negative correlations in NREM and back towards positive correlations in REM. Moreover, the majority did not merely reduce magnitude, but actually either reversed and strengthened in the opposite direction, or increased in magnitude during NREM. This finding supports the notion that NREM is best expressed as having altered, rather than reduced FC. Further, as many of these functional connections comprised “higher-order” RSNs (which have been previously linked to cognition and consciousness), such as the default mode network, this finding is suggestive of possibly concomitant alterations to cognition and consciousness.
  • Association between circulating 25-hydroxyvitamin D concentrations and hip replacement for osteoarthritis: a prospective cohort study

    Background: To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study. Methods: This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders. Results: Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women. Conclusions: Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis.
  • Modulatory effects of autophagy on app processing as a potential treatment target for Alzheimer’s disease

    Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate com-posed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and-independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.
  • The evolving gene regulatory landscape—a tinkerer of complex creatures

  • Functional interactions between sensory and memory networks for adaptive behavior

    The brain’s capacity to adapt to sensory inputs is key for processing sensory information efficiently and interacting in new environments. Following repeated exposure to the same sensory input, brain activity in sensory areas is known to decrease as inputs become familiar, a process known as adaptation. Yet, the brain-wide mechanisms that mediate adaptive processing remain largely unknown. Here, we combine multimodal brain imaging (functional magnetic resonance imaging [fMRI], magnetic resonance spectroscopy) with behavioral measures of orientation-specific adaptation (i.e., tilt aftereffect) to investigate the functional and neurochemical mechanisms that support adaptive processing. Our results reveal two functional brain networks: 1) a sensory-adaptation network including occipital and dorsolateral prefrontal cortex regions that show decreased fMRI responses for repeated stimuli and 2) a perceptual-memory network including regions in the parietal memory network (PMN) and dorsomedial prefrontal cortex that relate to perceptual bias (i.e., tilt aftereffect). We demonstrate that adaptation relates to increased occipito-parietal connectivity, while decreased connectivity between sensory-adaptation and perceptual-memory networks relates to GABAergic inhibition in the PMN. Thus, our findings provide evidence that suppressive interactions between sensory-adaptation (i.e., occipito-parietal) and perceptual-memory (i.e., PMN) networks support adaptive processing and behavior, proposing a key role of memory systems in efficient sensory processing.
  • A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity

    While the dire cardiometabolic consequences of the hypercaloric modern ‘Western’ diet are well known, there is not much information on the health impact of a high sucrose diet not inducing weight gain. Here, we tested the hypothesis that rats reared with intermittent binge access to sucrose in addition to normal chow would develop an inflammatory response in brain. To test this hypothesis, we undertook serial PET/MRI scans with the TSPO ligand [F]DPA714 in a group of (n=9) rats at baseline and again after voluntarily consuming 5% sucrose solution three days a week for three months. Compared to a control group fed with normal chow (n=9), the sucrose rats indeed showed widespread increases in the availability of cerebral binding sites for the microglial marker, despite normal weight gain compared to the control diet group. Subsequent immunofluorescence staining of the brains confirmed the PET findings, showing a widespread 20% increase in the abundance of IBA-1-positive microglia with characteristic ‘semi-activated’ morphology in the binge sucrose rats, which had 23% lower density of microglial endpoints and 25% lower mean process length compared to microglia in the control rats with ordinary feeding. GFAP immunofluorescence showed no difference in astroglial coverage in the sucrose rats, except for a slight reduction in hypothalamus. The binge sucrose diet-induced neuroinflammation was associated with a significant elevation of white blood cell counts. Taking these results together, we find that long-term intake of sucrose in a binge paradigm, similar in sucrose content to the contemporary Western diet, triggered a low-grade systemic and central inflammation in non-obese rats. The molecular mechanism of this phenomenon remains to be established.
  • An exercise ‘sweet spot’ reverses cognitive deficits of ageing by growth hormone-induced neurogenesis

    Hippocampal function is critical for spatial and contextual learning, and its decline with age contributes to cognitive impairment. Exercise can improve hippocampal function, however, the amount of exercise and mechanisms mediating improvement remain largely unknown. Here, we show exercise reverses learning deficits in aged (24 months) female mice but only when it occurs for a specific duration, with longer or shorter periods proving ineffective. A spike in the levels of growth hormone (GH) and a corresponding increase in neurogenesis during this sweet spot mediate this effect because blocking GH receptor with a competitive antagonist or depleting newborn neurons abrogates the exercise-induced cognitive improvement. Moreover, raising GH levels with GH-releasing hormone agonist improved cognition in nonrunners. We show that GH stimulates neural precursors directly, indicating the link between raised GH and neurogenesis is the basis for the substantially improved learning in aged animals.
  • Development of synthetic human and mouse C5a: application to binding and functional assays in vitro and in vivo

    The complement activation peptide C5a is a key mediator of inflammation that is associated with numerous immune disorders. C5a binds and activates two seven-transmembrane receptors, C5aR1 and C5aR2. Experimentally, C5a is utilized to investigate C5a receptor biology and to screen for potential C5aR1/C5aR2 therapeutics. Currently, laboratory sources of C5a stem from either isolation of endogenous C5a from human serum or most predominantly via recombinant expression. An alternative approach to C5a production is chemical synthesis, which has several advantages, including the ability to introduce non-natural amino acids and site-specific modifications whilst also maintaining a lower probability of C5a being contaminated with microbial molecules or other endogenous proteins. Here, we describe the efficient synthesis of both human (hC5a) and mouse C5a (mC5a) without the need for ligation chemistry. We validate the synthetic peptides by comparing pERK1/2 signaling in CHO-hC5aR1 cells and primary human macrophages (for hC5a) and in RAW264.7 cells (for mC5a). C5aR2 activation was confirmed by measuring β-arrestin recruitment in C5aR2-transfected HEK293 cells. We also demonstrate the functionalization of synthetic C5a through the introduction of a lanthanide chelating cage to facilitate a screen for the binding of ligands to C5aR1. Finally, we verify that the synthetic ligands are functionally similar to recombinant or native C5a by assessing hC5a-induced neutrophil chemotaxis in vitro and mC5a-mediated neutrophil mobilization in vivo. We propose that the synthetic hC5a and mC5a described herein are valuable alternatives to recombinant or purified C5a for in vitro and in vivo applications and add to the growing complement reagent toolbox.
  • Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease

    The synapse has emerged as a critical neuronal structure in the degenerative process of Alzheimer disease (AD), in which the pathogenic signals of two key players — amyloid-β (Aβ) and tau — converge, thereby causing synaptic dysfunction and cognitive deficits. The synapse presents a dynamic, confined microenvironment in which to explore how key molecules travel, localize, interact and assume different levels of organizational complexity, thereby affecting neuronal function. However, owing to their small size and the diffraction-limited resolution of conventional light microscopic approaches, investigating synaptic structure and dynamics has been challenging. Super-resolution microscopy (SRM) techniques have overcome the resolution barrier and are revolutionizing our quantitative understanding of biological systems in unprecedented spatio-temporal detail. Here we review critical new insights provided by SRM into the molecular architecture and dynamic organization of the synapse and, in particular, the interactions between Aβ and tau in this compartment. We further highlight how SRM can transform our understanding of the molecular pathological mechanisms that underlie AD. The application of SRM for understanding the roles of synapses in AD pathology will provide a stepping stone towards a broader understanding of dysfunction in other subcellular compartments and at cellular and circuit levels in this disease.
  • Predicting subclinical psychotic-like experiences on a continuum using machine learning

    Previous studies applying machine learning methods to psychosis have primarily been concerned with the binary classification of chronic schizophrenia patients and healthy controls. The aim of this study was to use electroencephalographic (EEG) data and pattern recognition to predict subclinical psychotic-like experiences on a continuum between these two extremes in otherwise healthy people. We applied two different approaches to an auditory oddball regularity learning task obtained from N = 73 participants: A feature extraction and selection routine incorporating behavioural measures, event-related potential components and effective connectivity parameters; Regularisation of spatiotemporal maps of event-related potentials. Using the latter approach, optimal performance was achieved using the response to frequent, predictable sounds. Features within the P50 and P200 time windows had the greatest contribution toward lower Prodromal Questionnaire (PQ) scores and the N100 time window contributed most to higher PQ scores. As a proof-of-concept, these findings demonstrate that EEG data alone are predictive of individual psychotic-like experiences in healthy people. Our findings are in keeping with the mounting evidence for altered sensory responses in schizophrenia, as well as the notion that psychosis may exist on a continuum expanding into the non-clinical population.
  • Comparative brain structure and visual processing in octopus from different habitats

    Octopods are masters of camouflage and solve complex tasks, and their cognitive ability is said to approach that of some small mammals. Despite intense interest and some research progress, much of our knowledge of octopus neuroanatomy and its links to behavior and ecology comes from one coastal species, the European common octopus, Octopus vulgaris. Octopod species are found in habitats including complex coral reefs and the relatively featureless mid-water. There they encounter different selection pressures, may be nocturnal or diurnal, and are mostly solitary or partially social. How these different ecologies and behavioral differences influence the octopus central nervous system (CNS) remains largely unknown. Here we present a phylogenetically informed comparison between diurnal and nocturnal coastal and a deep-sea species using brain imaging techniques. This study shows that characteristic neuroanatomical changes are linked to their habits and habitats. Enlargement and division of the optic lobe as well as structural foldings and complexity in the underlying CNS are linked to behavioral adaptation (diurnal versus nocturnal; social versus solitary) and ecological niche (reef versus deep sea), but phylogeny may play a part also. The difference between solitary and social life is mirrored within the brain including the formation of multiple compartments (gyri) in the vertical lobe, which is likened to the vertebrate cortex. These findings continue the case for convergence between cephalopod and vertebrate brain structure and function. Notably, within the current push toward comparisons of cognitive abilities, often with unashamed anthropomorphism at their root, these findings provide a firm grounding from which to work.
  • Autism-related dietary preferences mediate autism-gut microbiome associations

    There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.
  • Global, regional, and national mortality among young people aged 10-24 years, 1950-2019: a systematic analysis for the Global Burden of Disease Study 2019

    Documentation of patterns and long-term trends in mortality in young people, which reflect huge changes in demographic and social determinants of adolescent health, enables identification of global investment priorities for this age group. We aimed to analyse data on the number of deaths, years of life lost, and mortality rates by sex and age group in people aged 10-24 years in 204 countries and territories from 1950 to 2019 by use of estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.

    We report trends in estimated total numbers of deaths and mortality rate per 100 000 population in young people aged 10-24 years by age group (10-14 years, 15-19 years, and 20-24 years) and sex in 204 countries and territories between 1950 and 2019 for all causes, and between 1980 and 2019 by cause of death. We analyse variation in outcomes by region, age group, and sex, and compare annual rate of change in mortality in young people aged 10-24 years with that in children aged 0-9 years from 1990 to 2019. We then analyse the association between mortality in people aged 10-24 years and socioeconomic development using the GBD Socio-demographic Index (SDI), a composite measure based on average national educational attainment in people older than 15 years, total fertility rate in people younger than 25 years, and income per capita. We assess the association between SDI and all-cause mortality in 2019, and analyse the ratio of observed to expected mortality by SDI using the most recent available data release (2017).

    In 2019 there were 1·49 million deaths (95% uncertainty interval 1·39-1·59) worldwide in people aged 10-24 years, of which 61% occurred in males. 32·7% of all adolescent deaths were due to transport injuries, unintentional injuries, or interpersonal violence and conflict; 32·1% were due to communicable, nutritional, or maternal causes; 27·0% were due to non-communicable diseases; and 8·2% were due to self-harm. Since 1950, deaths in this age group decreased by 30·0% in females and 15·3% in males, and sex-based differences in mortality rate have widened in most regions of the world. Geographical variation has also increased, particularly in people aged 10-14 years. Since 1980, communicable and maternal causes of death have decreased sharply as a proportion of total deaths in most GBD super-regions, but remain some of the most common causes in sub-Saharan Africa and south Asia, where more than half of all adolescent deaths occur. Annual percentage decrease in all-cause mortality rate since 1990 in adolescents aged 15-19 years was 1·3% in males and 1·6% in females, almost half that of males aged 1-4 years (2·4%), and around a third less than in females aged 1-4 years (2·5%). The proportion of global deaths in people aged 0-24 years that occurred in people aged 10-24 years more than doubled between 1950 and 2019, from 9·5% to 21·6%.

    Variation in adolescent mortality between countries and by sex is widening, driven by poor progress in reducing deaths in males and older adolescents. Improving global adolescent mortality will require action to address the specific vulnerabilities of this age group, which are being overlooked. Furthermore, indirect effects of the COVID-19 pandemic are likely to jeopardise efforts to improve health outcomes including mortality in young people aged 10-24 years. There is an urgent need to respond to the changing global burden of adolescent mortality, address inequities where they occur, and improve the availability and quality of primary mortality data in this age group.

    Bill & Melinda Gates Foundation.
  • Comorbidity between mood and substance-related disorders: A systematic review and meta-analysis

    Evidence indicates that mood disorders often co-occur with substance-related disorders. However, pooling comorbidity estimates can be challenging due to heterogeneity in diagnostic criteria and in the overall study design. The aim of this study was to systematically review and, where appropriate, meta-analyse estimates related to the pairwise comorbidity between mood disorders and substance-related disorders, after sorting these estimates by various study designs.

    We searched PubMed (MEDLINE), Embase, CINAHL and Web of Science for publications between 1980 and 2017 regardless of geographical location and language. We meta-analysed estimates from original articles in 4 broadly defined mood and 35 substance-related disorders.

    After multiple eligibility steps, we included 120 studies for quantitative analysis. In general, regardless of variations in diagnosis type, temporal order or use of adjustments, there was substantial comorbidity between mood and substance-related disorders. We found a sixfold elevated risk between broadly defined mood disorder and drug dependence (odds ratio = 5.7) and fivefold risk between depression and cannabis dependence (odds ratio = 4.9) while the highest pooled estimate, based on period prevalence risk, was found between broadly defined dysthymic disorder and drug dependence (odds ratio = 11.3). Based on 56 separate meta-analyses, all pooled odds ratios were above 1, and 46 were significantly greater than 1 (i.e. the 95% confidence intervals did not include 1).

    This review found robust and consistent evidence of an increased risk of comorbidity between many combinations of mood and substance-related disorders. We also identified a number of under-researched mood and substance-related disorders, suitable for future scrutiny. This review reinforces the need for clinicians to remain vigilant in order to promptly identify and treat these common types of comorbidity.
  • Biased weighting of temporally discrete visual stimuli in a continuous report decision-making task: a combined behavioral and electrophysiological study

    Integrating evidence from multiple sources to guide decisions is something humans do on a daily basis. Existing research suggests that not all sources of information are weighted equally in decision-making tasks, and that observers are subject to biases in the face of internal and external noise. Here we describe two experiments that measured observers' ability to integrate successive visual signals. Participants viewed pairs of gratings presented sequentially and reproduced their average orientation. Experiment 1 revealed a recency bias in evidence integration, such that observers' average judgments were closer to the orientation of the second grating than the first. Mixture distribution modeling revealed that this was caused by a recency bias in averaging, as well as a tendency to disregard the first stimulus altogether in some trials. In Experiment 2 we replicated these findings, and quantified orientation-specific patterns of neural activity recorded during the task using population-tuning curve modeling of electroencephalography data. This analysis yielded robust orientation tuning to both the presented gratings and observers' decisions, and suggested that observers were storing both grating stimuli for subsequent averaging rather than computing a running average. The neural representation of the second grating was not reliably stronger than that of the first, suggesting that the recency bias is not due to a difference in the strength of encoding of the second stimulus, and instead may arise at a later decision stage where information is retrieved or integrated. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
  • The emerging role of complement in neuromuscular disorders

    The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.
  • Genetic and environmental influences on sleep-wake behaviours in adolescence

    Study ObjectivesTo investigate the influence of genetic and environmental factors on sleep-wake behaviors across adolescence.MethodsFour hundred and ninety-five participants (aged 9–17; 55% females), including 93 monozygotic and 117 dizygotic twin pairs, and 75 unmatched twins, wore an accelerometry device and completed a sleep diary for 2 weeks.ResultsIndividual differences in sleep onset, wake time, and sleep midpoint were influenced by both additive genetic (44%–50% of total variance) and shared environmental (31%–42%) factors, with a predominant genetic influence for sleep duration (62%) and restorative sleep (43%). When stratified into younger (aged 9–14) and older (aged 16–17) subsamples, genetic sources were more prominent in older adolescents. The moderate correlation between sleep duration and midpoint (rP = −.43, rG = .54) was attributable to a common genetic source. Sleep-wake behaviors on school and nonschool nights were correlated (rP = .44–.72) and influenced by the same genetic and unique environmental factors. Genetic sources specific to night-type were also identified, for all behaviors except restorative sleep.ConclusionsThere were strong genetic influences on sleep-wake phenotypes, particularly on sleep timing, in adolescence. Moreover, there may be common genetic influences underlying both sleep and circadian rhythms. The differences in sleep-wake behaviors on school and nonschool nights could be attributable to genetic factors involved in reactivity to environmental context.
  • Contributions of luminance and motion to visual escape and habituation in larval zebrafish

    Animals from insects to humans perform visual escape behavior in response to looming stimuli, and these responses habituate if looms are presented repeatedly without consequence. While the basic visual processing and motor pathways involved in this behavior have been described, many of the nuances of predator perception and sensorimotor gating have not. Here, we have performed both behavioral analyses and brain-wide cellular-resolution calcium imaging in larval zebrafish while presenting them with visual loom stimuli or stimuli that selectively deliver either the movement or the dimming properties of full loom stimuli. Behaviorally, we find that, while responses to repeated loom stimuli habituate, no such habituation occurs when repeated movement stimuli (in the absence of luminance changes) are presented. Dim stimuli seldom elicit escape responses, and therefore cannot habituate. Neither repeated movement stimuli nor repeated dimming stimuli habituate the responses to subsequent full loom stimuli, suggesting that full looms are required for habituation. Our calcium imaging reveals that motion-sensitive neurons are abundant in the brain, that dim-sensitive neurons are present but more rare, and that neurons responsive to both stimuli (and to full loom stimuli) are concentrated in the tectum. Neurons selective to full loom stimuli (but not to movement or dimming) were not evident. Finally, we explored whether movement- or dim-sensitive neurons have characteristic response profiles during habituation to full looms. Such functional links between baseline responsiveness and habituation rate could suggest a specific role in the brain-wide habituation network, but no such relationships were found in our data. Overall, our results suggest that, while both movement- and dim-sensitive neurons contribute to predator escape behavior, neither plays a specific role in brain-wide visual habituation networks or in behavioral habituation.
  • Identification of specific gene modules and candidate signatures in necrotizing enterocolitis disease: Networkbased gene co-expression approach

    Necrotizing enterocolitis (NEC) is a serious disease of the gastrointestinal systems that primarily affects premature newborns' intestine in neonatal intensive care units. The present study aimed to detect NEC molecular signatures and pathways from comprehensive bioinformatics analysis of NEC's RNA-seq transcriptomics. We performed systems biology analysis of RNA-seq transcriptomics data (with accession GSE64801) of NEC from nine NEC and five healthy controls. Differential expression of gene expression was performed using a combination of three R packages "DESeq2", "edgeR", “edger robust”. Gene co-expression analysis was performed using a weighted WGCNA package to identify gene modules, Gene Ontology (GO), pathway analysis, protein-protein interaction, gene-transcription factor, and gene-microRNA interaction analysis was performed. The differential expression analysis identified 966 differentially expressed genes (DEGs) in NEC from the RNA-seq dataset related to corresponding controls. The WGCNA showed the presence of three key gene modules. The GO analysis showed genes are enriched in metabolic processes, regulation of immune response and immune systems, cell communication, and cellular process. The immune and complement pathways are related to co-expressed key modules that were detected. The protein-protein interactions analysis showed the presence of key hub genes related to the modules. Integration of these co-expressed gene modules with regulatory networks showed the presence of significant key transcription factors and microRNAs as hub molecules. The present study's findings suggested the immune systems and complement cascade are key mechanisms of NEC pathogenesis. The comprehensive network analysis showed several key hub molecules that might be potential biomarkers and drug targets in NEC.
  • Modulating neuroplasticity: lessons learned from antidepressants and emerging novel therapeutics

    Purpose of review: Antidepressants share a common mechanism of action downstream of pharmacological drug targets. Rapid-acting antidepressants, such as ketamine, have highlighted the immense clinical potential of directly targeting neurotrophic signalling pathways. In turn, these neurotrophic mechanisms effectively reverse the deleterious effects of stress and other factors implicated in the aetiology of mood disorders at the cellular level. Treatments that target synaptic plasticity can restore functional synaptic connections in stress-sensitive neural circuits to improve mood regulation and cognitive function. Here, we describe the neurotrophic mechanisms of antidepressants and describe current and novel treatment modalities that can restore neural circuit function by directly engaging neuroplasticity. Recent findings: The discovery of ketamine as a rapid modulator of synaptic plasticity with associated therapeutic actions for major depressive disorder and other psychiatric disorders has accelerated interest in the potential surrounding the direct targeting of neurotrophic pathways. Targets to the glutamatergic system currently seem to be the most promising area of novel drug discovery and development. Other systems such as the cholinergic and inflammatory systems are gaining traction as well. While cellular and animal studies have provided exquisite insights into the molecular mechanisms that influence plasticity, ongoing work demonstrating the therapeutic impact of targeting these mechanisms with neuromodulation, pharmacological, and/or behavioural interventions in human subjects is needed. Summary: Targeting the neurobiological mechanisms that regulate neuroplasticity will be of relevance to a range of neurological and neuropsychiatric disorders beyond depression. However, the factors responsible for disrupting synaptic integrity across the disorders will vary. Consequently, the treatments targeting plasticity need to be optimally aligned to the specific pathophysiological context of the illness, which can vary even within a specific diagnostic category.
  • Hippocampus-prefrontal coupling regulates recognition memory for novelty discrimination

    Recognition memory provides the ability to distinguish familiar from novel objects and places and is important for recording and updating events to guide appropriate behaviour. The hippocampus (HPC) and medial prefrontal cortex (mPFC) have both been implicated in recognition memory, but the nature of HPC-mPFC interactions, and its impact on local circuits in mediating this process is not known. Here we show that novelty discrimination is accompanied with higher theta (4-10 Hz) activity and increased c-Fos expression in both these regions. Moreover, theta oscillations were highly coupled between the HPC and mPFC during recognition memory retrieval for novelty discrimination, with the HPC leading the mPFC, but not during initial learning. Principal neurons and interneurons in the mPFC responded more strongly during recognition memory retrieval compared to learning. Optogenetic silencing of HPC input to the mPFC disrupted coupled theta activity between these two structures, as well as the animals’ (male Sprague-Dawley rats) ability to differentiate novel from familiar objects. These results reveal a key role of monosynaptic connections between the HPC and mPFC in novelty discrimination via theta coupling and identify neural populations that underlie this recognition memory-guided behaviour.
  • Cavin4 interacts with Bin1 to promote T-tubule formation and stability in developing skeletal muscle

    The cavin proteins are essential for caveola biogenesis and function. Here, we identify a role for the muscle-specific component, Cavin4, in skeletal muscle T-tubule development by analyzing two vertebrate systems, mouse and zebrafish. In both models, Cavin4 localized to T-tubules, and loss of Cavin4 resulted in aberrant T-tubule maturation. In zebrafish, which possess duplicated cavin4 paralogs, Cavin4b was shown to directly interact with the T-tubule-associated BAR domain protein Bin1. Loss of both Cavin4a and Cavin4b caused aberrant accumulation of interconnected caveolae within the T-tubules, a fragmented T-tubule network enriched in Caveolin-3, and an impaired Ca2+ response upon mechanical stimulation. We propose a role for Cavin4 in remodeling the T-tubule membrane early in development by recycling caveolar components from the T-tubule to the sarcolemma. This generates a stable T-tubule domain lacking caveolae that is essential for T-tubule function.
  • Polygenic burden could explain high rates of affective disorders in a community with restricted founder population

    This study investigates if genetic factors could contribute to the high rate of mood disorders reported in a U.S. community known to have a restricted early founder population (confirmed here through runs of homozygosity analysis). Polygenic scores (PGSs) for eight common diseases, disorders, or traits, including psychiatric disorders, were calculated in 274 participants (125 mood disorder cases) who each reported three or four grandparents born in the community. Ancestry-matched controls were selected from the UK Biobank (UKB; three sets of N = 1,822 each). The mean PGSs were significantly higher in the community for major depression PRS (p = 2.1 × 10, 0.56 SD units), bipolar disorder (p = 2.5 × 10, 0.56 SD units), and schizophrenia (p = 3.8 × 10, 0.64 SD units). The PGSs were not significantly different between the community participants and UKB controls for the traits of body mass index, Type 2 diabetes, coronary artery disease, and chronotype. The mean PGSs for height were significantly lower in the community sample compared to controls (−0.21 SD units, p = 1.2 × 10). The results are consistent with enrichment of polygenic risk factors for psychiatric disorders in this community.
  • Slow wave transcranial electrical stimulation during wake to investigate the consolidation of new learning

  • Citrullination of Amyloid-β peptides in Alzheimer's disease

    Protein citrullination (deimination of arginine residue) is a well-known biomarker of inflammation. Elevated protein citrullination has been shown to colocalize with extracellular amyloid plaques in postmortem AD patient brains. Amyloid-β (Aβ) peptides which aggregate and accumulate in the plaques of Alzheimer's disease (AD) have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration, and dityrosine cross-linking. However, no conclusive biochemical evidence exists whether citrullinated Aβ is present in AD brains. In this study, using high-resolution mass spectrometry, we have identified citrullination of Aβ in sporadic and familial AD brains by characterizing the tandem mass spectra of endogenous N-truncated citrullinated Aβ peptides. Our quantitative estimations demonstrate that ∼35% of pyroglutamate3-Aβ pool was citrullinated in plaques in the sporadic AD temporal cortex and ∼22% in the detergent-insoluble frontal cortex fractions. Similarly, hypercitrullinated pyroglutamate3-Aβ (∼30%) was observed in both the detergent-soluble as well as insoluble Aβ pool in familial AD cases. Our results indicate that a common mechanism for citrullination of Aβ exists in both the sporadic and familial AD. We establish that citrullination of Aβ is a remarkably common PTM, closely associated with pyroglutamate3-Aβ formation and its accumulation in AD. This may have implications for Aβ toxicity, autoantigenicity of Aβ, and may be relevant for the design of diagnostic assays and therapeutic targeting.
  • Unsupervised quantification of naturalistic animal behaviors for gaining insight into the brain

    Neural computation has evolved to optimize the behaviors that enable our survival. Although much previous work in neuroscience has focused on constrained task behaviors, recent advances in computer vision are fueling a trend toward the study of naturalistic behaviors. Automated tracking of fine-scale behaviors is generating rich datasets for animal models including rodents, fruit flies, zebrafish, and worms. However, extracting meaning from these large and complex data often requires sophisticated computational techniques. Here we review the latest methods and modeling approaches providing new insights into the brain from behavior. We focus on unsupervised methods for identifying stereotyped behaviors and for resolving details of the structure and dynamics of behavioral sequences.
  • Mindfulness based cognitive therapy for youth with inflammatory bowel disease and depression - Findings from a pilot randomised controlled trial

    Background: Mindfulness-based cognitive therapy (MBCT) is a promising adjunctive treatment for adolescents and young adults (AYAs) with Inflammatory Bowel Disease (IBD) and comorbid depression. Objectives: This pilot randomised controlled trial (RCT) aimed to evaluate feasibility and efficacy of an adapted MBCT program for AYA, aged 16-29, with IBD. Methods: Sixty-four AYAs were randomly allocated to MBCT (n = 33) or treatment as usual (TAU) (n = 31). Primary outcome measure was the depression score on Depression, Anxiety and Stress Scale. Secondary outcomes included anxiety, stress, IBD-related quality of life, coping, mindfulness, post-traumatic growth, medication adherence, IBD activity, inflammatory markers, microbiome characteristics and brain functional connectivity. Results: Study recruitment rate was 75%, retention rate 70%, and session attendance 92%. Intention to treat analyses revealed that, compared to TAU group, MBCT group had significantly lower depression ( increment = -6.0; 95% CI = -10.8 to -1.2; P = 0.015) and stress ( increment = -5.1; 95%CI = -10.1 to -0.0; P = 0.049), higher active coping ( increment = 1.0;95%CI = 0.1-1.9; P = 0.022), and total mindfulness scores ( increment = 10.9;95%CI = 1.1-20.8; P = 0.030) at 8 weeks (post-therapy), and improved coping by positive reframing ( increment = 1.1;95%CI = 0.0-2.2; P = 0.043) and planning ( increment = 0.9;95%CI = 0.0-1.9; P = 0.045), mindful awareness ( increment = 5.2.;95%CI = 2.0-8.5; P = 0.002) and total mindfulness scores ( increment = 10.8.;95%CI = 0.4-21.1; P = 0.042) at 20 weeks. On per protocol analysis, MBCT group had significantly lower depression ( increment = -6.3; 95%CI = -11.4 to -1.2; P = 0.015), stress ( increment = -6.0; 95% CI = -11.2 to -0.5; P = 0.032), increased active coping ( increment = 0.9;95%CI = 0-1.7; P = 0.05) at 8 weeks, and mindful awareness ( increment = 5.4; 95%CI = 2.1-8.6; P = 0.001) at 20 weeks. Conclusion: In AYAs with IBD, MBCT is feasible and beneficial in improving depression, stress, mindfulness and adaptive coping. It holds promise as an important component of integrated IBD care. Trial registration number ACTRN12617000876392, U1111-1197-7370; Pre-results.
  • Hcv activates somatic l1 retrotransposition—a potential hepatocarcinogenesis pathway

    Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance.
  • Does self-reassurance reduce neural and self-report reactivity to negative life events?

    Whilst research has shown how self-criticism may increase both neural and self-report markers of negative emotion, less well-known is how self-reassurance—a compassionately-motivated cognitive self-relating style—may regulate negative emotion. Using fMRI, we invited participants to engage in self-criticism and self-reassurance toward written descriptions of negative life events (mistakes, setbacks, failures). Our results identify that neural markers of negative emotion and self-report markers of trial intensity during fMRI are down-regulated under conditions of self-reassurance, relative to self-criticism. Future work to control for autobiographical memory during this fMRI task is needed, as are controls for how well participants can engage in both thinking styles, to explore how memory/task engagement can contribute to self-reassurance and self-criticism. Engagement in self-reassurance can reduce the “sting” of negative life-events, both neural and self-report, which holds important implications for therapy.
  • Processed pseudogenes: a substrate for evolutionary innovation. Retrotransposition contributes to genome evolution by propagating pseudogene sequences with rich regulatory potential throughout the genome

    Processed pseudogenes may serve as a genetic reservoir for evolutionary innovation. Here, we argue that through the activity of long interspersed element-1 retrotransposons, processed pseudogenes disperse coding and noncoding sequences rich with regulatory potential throughout the human genome. While these sequences may appear to be non-functional, a lack of contemporary function does not prohibit future development of biological activity. Here, we discuss the dynamic evolution of certain processed pseudogenes into coding and noncoding genes and regulatory elements, and their implication in wide-ranging biological and pathological processes.
  • Discovery and implications of polygenicity of common diseases

    The sequencing of the human genome has allowed the study of the genetic architecture of common diseases: the number of genomic variants that contribute to risk of disease and their joint frequency and effect size distribution. Common diseases are polygenic, with many loci contributing to phenotype, and the cumulative burden of risk alleles determines individual risk in conjunction with environmental factors. Most risk loci occur in noncoding regions of the genome regulating cell- and context-specific gene expression. Although the effect sizes of most risk alleles are small, their cumulative effects in individuals, quantified as a polygenic (risk) score, can identify people at increased risk of disease, thereby facilitating prevention or early intervention.
  • Transcranial direct current stimulation of three cortical targets is no more effective than placebo as treatment for fibromyalgia: a double-blind sham-controlled clinical trial

    Transcranial Direct Current Stimulation (tDCS) over the primary motor cortex (M1) and the Dorsolateral Prefrontal Cortex (DLPFC) seem to improve pain and other symptoms of fibromyalgia (FM), although the evidence on the effectiveness of tDCS and the optimal stimulation target is not robust enough. Our main objective was to establish the optimal area of stimulation, comparing the two classical targets and a novel pain-related area, the Operculo Insular Cortex (OIC), in a sham-controlled trial. Using a double-blind design, we randomly assigned 130 women with FM to four treatment groups (M1, DLPFC, OIC, Sham), each receiving fifteen 20-minute sessions of 2mA anodal tDCS over the left hemisphere. Our primary outcome was pain intensity. The secondary outcomes were the other core symptoms of FM (fatigue, mood, cognitive and sleep disorders, hyperalgesia measured by pressure pain threshold). We performed the assessment at 3 time points (before, immediately after treatment, and at 6 months follow-up). The linear mixed-model ANOVAs showed significant treatment effects across time for clinical pain and for fatigue, cognitive and sleep disturbances, and experimental pain, irrespective of the group. In mood, the three active tDCS groups showed a significantly larger improvement in anxiety and depression than sham. Our findings provide evidence of a placebo effect, support the use of tDCS for the treatment of affective symptoms, and challenge the effectiveness of tDCS as treatment of FM.
  • Slow-oscillatory tACS does not modulate human motor cortical response to repeated plasticity paradigms

  • The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons

    Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.
  • Effects of slow oscillatory transcranial alternating current stimulation on motor cortical excitability assessed by transcranial magnetic stimulation

    Converging evidence suggests that transcranial alternating current stimulation (tACS) may entrain endogenous neural oscillations to match the frequency and phase of the exogenously applied current and this entrainment may outlast the stimulation (although only for a few oscillatory cycles following the cessation of stimulation). However, observing entrainment in the electroencephalograph (EEG) during stimulation is extremely difficult due to the presence of complex tACS artifacts. The present study assessed entrainment to slow oscillatory (SO) tACS by measuring motor cortical excitability across different oscillatory phases during (i.e., online) and outlasting (i.e., offline) stimulation. 30 healthy participants received 60 trials of intermittent SO tACS (0.75 Hz; 16 s on/off interleaved) at an intensity of 2 mA peak-to-peak. Motor cortical excitability was assessed using transcranial magnetic stimulation (TMS) of the hand region of the primary motor cortex (M1HAND) to induce motor evoked potentials (MEPs) in the contralateral thumb. MEPs were acquired at four time-points within each trial – early online, late online, early offline, and late offline – as well as at the start and end of the overall stimulation period (to probe longer-lasting aftereffects of tACS). A significant increase in MEP amplitude was observed from pre- to post-tACS (paired-sample t-test; t29 = 2.64, P = 0.013, d = 0.48) and from the first to the last tACS block (t29 = −2.93, P = 0.02, d = 0.54). However, no phase-dependent modulation of excitability was observed. Therefore, although SO tACS had a facilitatory effect on motor cortical excitability that outlasted stimulation, there was no evidence supporting entrainment of endogenous oscillations as the underlying mechanism.
  • Pipeline for generating stable large genomic deletions in zebrafish, from small domains to whole gene excisions

    Here we describe a short feasibility study and methodological framework for the production of stable, CRISPR/Cas9-based, large genomic deletions in zebrafish, ranging from several base pairs (bp) to hundreds of kilobases (kb). Using a cocktail of four sgRNAs targeting a single genomic region mixed with a marker-sgRNA against the pigmentation gene tyrosinase (tyr), we demonstrate that one can easily and accurately excise genomic regions such as promoters, protein domains, specific exons or whole genes. We exemplify this technique with a complex gene family, neurexins, composed of three duplicated genes with multiple promoters and intricate splicing processes leading to thousands of isoforms. We precisely deleted small regions such as their transmembrane domains (150 bp deletion in average) to their entire genomic locus (300 kb deletion for nrxn1a for instance). We find that both the concentration and ratio of Cas9/sgRNAs are critical for the successful generation of these large deletions and, interestingly, that in our study their transmission frequency does not seem to decrease with increasing distance between sgRNA target sites. Considering the growing reports and debate about genetically compensated small indel mutants, the use of large-deletion approaches is likely to be widely adopted in studies of gene function. This strategy will also be key to the study of non-coding genomic regions. Note that we are also describing here a custom method to produce the sgRNAs, which proved to be faster and more robust than the ones traditionally used in the community to date.
  • Stimulus reliability automatically biases temporal integration of discrete perceptual targets in the human brain

    Many decisions, from crossing a busy street to choosing a profession, require integration of discrete sensory events. Previous studies have shown that integrative decision-making favours more reliable stimuli, mimicking statistically optimal integration. It remains unclear, however, whether reliability biases operate even when they lead to suboptimal performance. To address this issue, we asked human observers to reproduce the average motion direction of two suprathreshold coherent motion signals presented successively and with varying levels of reliability, while simultaneously recording whole-brain activity using electroencephalography. By definition, the averaging task should engender equal weighting of the two component motion signals, but instead we found robust behavioural biases in participants' average decisions that favoured the more reliable stimulus. Using population-tuning modelling of brain activity we characterised tuning to the average motion direction. In keeping with the behavioural biases, the neural tuning profiles also exhibited reliability biases. A control experiment revealed that observers were able to reproduce motion directions of low-and high-reliability with equal precision, suggesting that unbiased integration in this task was not only theoretically optimal but demonstrably possible. Our findings reveal that temporal integration of discrete sensory events in the brain is automatically and sub-optimally weighted according to stimulus reliability.Many everyday decisions require integration of several sources of information. To safely cross a busy road, for example, one must consider the movement of vehicles with different speeds and trajectories. Previous research has shown that individual stimuli are weighted according to their reliability. Whereas reliability biases typically yield performance that closely mimic statistically optimal integration, it remains unknown whether such biases arise even when they lead to suboptimal performance. Here we combined a novel integrative decision-making task with concurrent brain recording and modelling to address this question. While unbiased decisions were optimal in the task, observers nevertheless exhibited robust reliability biases in both behaviour and brain activity, suggesting that reliability-weighted integration is automatic and dissociable from statistically optimal integration.
  • Analysis of SYK gene as a prognostic biomarker and suggested potential bioactive phytochemicals as an alternative therapeutic option for colorectal cancer: an in-silico pharmaco-informatics investigation

    Background: SYK gene regulates the expression of SYK kinase (Spleen tyrosine kinase), an important non-receptor protein-tyrosine kinase for immunological receptor-mediated signaling, which is also considered a tumor growth metastasis initiator. An onco-informatics analysis was adopted to evaluate the expression and prognostic value of the SYK gene in colorectal cancer (CRC), the third most fatal cancer type; of late, it may be a biomarker as another targeted site for CRC. In addition, identify the potential phytochemicals that may inhibit the overexpression of the SYK kinase protein and minimize the human CRC. Materials & Methods: The differential expression of the SYK gene was analyzed using several transcriptomic databases, including Oncomine, UALCAN, GENT2, and GEPIA2. The server cBioPortal was used to analyze the mutations and copy number alterations, whereas GENT2, Gene Expression Profiling Interactive Analysis (GEPIA), Onco-Lnc, and PrognoScan were used to examine the survival rate. The protein-protein interaction network of SYK kinase and its co-expressed genes was conducted via Gene-MANIA. Considering the SYK kinase may be the targeted site, the selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. Molecular interactions were also observed by following the Ligplot+ version 2.2. YASARA molecular dynamics simulator was applied for the post-validation of the selected phytochemicals. Results: Our result reveals an increased level of mRNA expression of the SYK gene in colorectal adenocarcinoma (COAD) samples compared to those in normal tissues. A significant methylation level and various genetic alterations recurrence of the SYK gene were analyzed where the fluctuation of the SYK alteration frequency was detected across different CRC studies. As a result, a lower level of SYK expression was related to higher chances of survival. This was evidenced by multiple bioinformatics platforms and web resources, which demonstrated that the SYK gene can be a potential biomarker for CRC. In this study, aromatic phytochemicals, such as kaempferol and glabridin that target the macromolecule (SYK kinase), showed higher stability than the controls, and we have estimated that these bioactive potential phytochemicals might be a useful option for CRC patients after the clinical trial. Conclusions: Our onco-informatics investigation suggests that the SYK gene can be a potential prognostic biomarker of CRC. On the contrary, SYK kinase would be a major target, and all selected compounds were validated against the protein using in-silico drug design approaches. Here, more in vitro and in vivo analysis is required for targeting SYK protein in CRC.