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As an interdisciplinary team, “crystallization” is an invaluable methodology for making our writing impactful for a broad readership. The authors show that crystallisation has two key benefits: it enriches understandings of the embodied and affective dimensions of emotional labour, and—as Laurel Richardson insists, is essential for “reach[ing] beyond academia, teaching all of us about social injustice and methods of alleviating it.” Underneath the shimmering surface of the computer screen, Emma senses the glowing jewels, the hailing data, lurking within the matter-of-fact interview transcript. In Australia, government mandates restricted children's physical attendance at ECEC at various points throughout the pandemic. During these restrictions, ECEC services were permitted to provide care and education only for children of essential workers. Emma and Laetitia—feminist researchers and seasoned DRAWers with sociological imaginations—read through the transcripts and were struck by service directors' accounts.
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Neurotransmitter release relies on the regulated fusion of synaptic vesicles (SVs) that are tightly packed within the presynaptic bouton of neurons. The mechanism by which SVs are clustered at the presynapse, while preserving their ability to dynamically recycle to support neuronal communication, remains unknown. Synapsin 2a (Syn2a) tetramerization has been suggested as a potential clustering mechanism. Here, we used Dual-pulse sub-diffractional Tracking of Internalised Molecules (DsdTIM) to simultaneously track single SVs from the recycling and the reserve pools, in live hippocampal neurons. The reserve pool displays a lower presynaptic mobility compared to the recycling pool and is also present in the axons. Triple knockout of Synapsin 1-3 genes (SynTKO) increased the mobility of reserve pool SVs. Re-expression of wild-type Syn2a (Syn2aWT), but not the tetramerization-deficient mutant K337Q (Syn2aK337Q), fully rescued these effects. Single-particle tracking revealed that Syn2aK337QmEos3.1 exhibited altered activity-dependent presynaptic translocation and nanoclustering. Therefore, Syn2a tetramerization controls its own presynaptic nanoclustering and thereby contributes to the dynamic immobilisation of the SV reserve pool.
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Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020-21 COVID-19 pandemic period.22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5-65·1] decline), and increased during the COVID-19 pandemic period (2020-21; 5·1% [0·9-9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98-5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50-6·01) in 2019. An estimated 131 million (126-137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7-17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8-24·8), from 49·0 years (46·7-51·3) to 71·7 years (70·9-72·5). Global life expectancy at birth declined by 1·6 years (1·0-2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67-8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4-52·7]) and south Asia (26·3% [9·0-44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic.
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Background: The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. Methods: Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing. Results: In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1. Conclusion: This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.
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Background: Cognitive screening following stroke is widely recommended, yet few studies have considered the prognostic value of acute domain-specific function for longer-term cognitive outcome. Identifying which post-stroke cognitive impairments more commonly occur, recover, and persist, and which impairments hold prognostic value, could inform care planning, and resource allocation. Aims: This study aimed to determine the prevalence of domain-specific impairment acutely and at 6 months, assess the proportion of change in cognitive performance, and examine the prognostic value of acute domain-specific cognitive screening. Methods: A prospective stroke cohort completed the Oxford Cognitive Screen acutely (⩽2 weeks) and 6 months post-stroke. We determined the prevalence of acute and 6-month domain-specific impairment and proportion of change in performance from acute to 6 months. Hierarchical multivariable regression was used to predict global and domain-specific cognitive impairment at 6 months adjusted for demographic/vascular factors, stroke severity, and lesion volume. Results: A total of 430 stroke survivors (mean/SD age 73.9/12.5 years, 46.5% female, median/interquartile range (IQR) National Institute of Health Stroke Scale (NIHSS) 5/2–10) completed 6-month follow-up. Acutely, domain-specific impairments were highly prevalent ranging from 26.7% (n = 112) in praxis to 46.8% (n = 183) in attention. At 6 months, the proportion of domain-specific recovery was highest in praxis (n = 73, 71%) and lowest in language (n = 89, 46%) and memory (n = 82, 48%). Severity of 6-month cognitive impairment was best predicted by the addition of acute cognitive impairment (adj R = 0.298, p < 0.0001) over demographic and clinical factors alone (adj R = 0.105, p < 0.0001). Acute cognitive function was the strongest predictor of 6-month cognitive performance (p < 0.0001). Acute domain-specific impairments in memory (p < 0.0001), language (p < 0.0001), and praxis (p < 0.0001) significantly predicted overall severity of cognitive impairment at 6 months. Conclusion: Post-stroke cognitive impairment is highly prevalent across all domains acutely, while impairments in language, memory, and attention predominate at 6 months. Early domain-specific screening can provide valuable prognostic information for longer-term cognitive outcomes.
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Background and Aim. Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Methods and Results. Acute administration of a CSF1-Fc fusion protein led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilisation of body fat. The impacts of CSF1 on macrophage abundance, liver size and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. Conclusion. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system and control of liver:body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilisation, without changes in appetence, which may have novel implications for managing metabolic syndrome.
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Bacteria adapt to selective pressure in their immediate environment in multiple ways. One mechanism involves the acquisition of independent mutations that disable or modify a key pathway, providing a signature of adaptation via convergent evolution. Extra-intestinal pathogenic Escherichia coli (ExPEC) belonging to sequence type 95 (ST95) represent a global clone frequently associated with severe human infections including acute pyelonephritis, sepsis, and neonatal meningitis. Here, we analysed a publicly available dataset of 613 ST95 genomes and identified a series of loss-of-function mutations that disrupt cellulose production or its modification in 55.3% of strains. We show the inability to produce cellulose significantly enhances ST95 invasive infection in a rat model of neonatal meningitis, leading to the disruption of intestinal barrier integrity in newborn pups and enhanced dissemination to the liver, spleen and brain. Consistent with these observations, disruption of cellulose production in ST95 augmented innate immune signalling and tissue neutrophil infiltration in a mouse model of urinary tract infection. Mutations that disrupt cellulose production were also identified in other virulent ExPEC STs, Shigella and Salmonella, suggesting a correlative association with many Enterobacteriaceae that cause severe human infection. Together, our findings provide an explanation for the emergence of hypervirulent Enterobacteriaceae clones.
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Mitochondria perform a myriad of essential functions that ensure organismal homeostasis, including maintaining bioenergetic capacity, sensing and signalling the presence of pathogenic threats, and determining cell fate. Their function is highly dependent on mitochondrial quality control and the appropriate regulation of mitochondrial size, shape, and distribution during an entire lifetime, as well as their inheritance across generations. The roundworm Caenorhabditis elegans has emerged as an ideal model organism through which to study mitochondria. The remarkable conservation of mitochondrial biology has allowed C. elegans researchers to investigate complex processes that are challenging to study in higher organisms. In this review, we explore the key recent contributions of C. elegans to mitochondrial biology through the lens of mitochondrial dynamics, organellar removal, and mitochondrial inheritance, as well as their involvement in immune responses, various types of stress, and transgenerational signalling.
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The rapid evolution of different imaging modalities in the last two decades has enabled the investigation of the role of different genes in development and disease to be studied in a range of model organisms. However, selection of the appropriate imaging technique depends on a number of constraints, including cost, time, image resolution, size of the sample, computational complexity and processing power. Here, we use the adult mouse central nervous system to investigate whether High-Resolution Episcopic Microscopy (HREM) can provide an effective means to study the volume of individual subregions within the brain. We find that HREM can provide precise volume quantification of different structures within the mouse brain, albeit with limitations regarding the time involved for analysis and the necessity of some estimations.
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Protein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most cellular physiological processes and their regulations. As for all intracellular proteins, PKs are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PK localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein–protein and protein–lipid interactions, as well as liquid–liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular quantal unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the composition and mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.
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Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform (https://www.neurodesk.org/) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.
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This article investigates the decisional and attentional drivers of the attentional repulsion effect (ARE) using the diffusion decision model (DDM). The ARE is a phenomenon in which a subjective expansion of space is experienced outside the focus of attention. It is thought to occur due to changes in the functioning of visual cell receptive fields. The DDM is a model of the decision-making process that assumes responses are selected by sequentially sampling an encoded representation of a stimulus until sufficient evidence has been accumulated favoring one response alternative over the other. The model decomposes observed choice and response times into different latent variables corresponding to the rate of evidence accumulation, response caution, response bias, and the time course of stimulus encoding and response execution. In this article, we interpret changes in the rate of evidence accumulation as primarily reflecting perceptual-driven changes in stimulus representation. We interpret changes in response bias as primarily reflecting decision-level changes. We utilize the DDM’s ability to estimate these variables independently to explore how they are each affected by cueing manipulations to clarify whether the ARE emerges due to attentional or decisional drivers, or some combination of the two. The results of this study could shed light on the mechanisms underlying the ARE, and has implications in our understanding of spatial attention.
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Munc18-interacting proteins (Mints) are multi-domain adaptors that regulate neuronal membrane trafficking, signalling and neurotransmission. Mint1 and Mint2 are highly expressed in the brain with overlapping roles in the regulation of synaptic vesicle fusion required for neurotransmitter release by interacting with the essential synaptic protein Munc18-1. Here, we have used AlphaFold2 to identify and then validate the mechanisms that underpin both the specific interactions of neuronal Mint proteins with Munc18-1 as well as their wider interactome. We find a short acidic α-helical motif (AHM) within Mint1 and Mint2 is necessary and sufficient for specific binding to Munc18-1 and binds a conserved surface on Munc18-1 domain3b. In Munc18-1/2 double knockout neurosecretory cells mutation of the Mint-binding site reduces the ability of Munc18-1 to rescue exocytosis, and although Munc18-1 can interact with Mint and Sx1a proteins simultaneously in vitro we find they have mutually reduced affinities, suggesting an allosteric coupling between the proteins. Using AlphaFold2 to then examine the entire cellular network of putative Mint interactors provides a structural model for their assembly with a variety of known and novel regulatory and cargo proteins including ARF3/ARF4 small GTPases, and the AP3 clathrin adaptor complex. Validation of Mint1 interaction with a new predicted binder TJAP1 provides experimental support that AlphaFold2 can correctly predict interactions across such large-scale datasets. Overall, our data provides insights into the diversity of interactions mediated by the Mint family and shows that Mints may help facilitate a key trigger point in SNARE complex assembly and vesicle fusion.
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Traumatic brain injury (TBI) results in prolonged and non-resolving activation of microglia. Forced turnover of these cells during the acute phase of TBI aids recovery, but the cell-intrinsic pathways that underpin the pro-repair phenotype of these repopulating microglia remain unclear. Here, we show that selective targeting of ROCK2 with the small molecule inhibitor KD025 impairs the proliferative response of microglia after TBI as well as during genetically induced turnover of microglia. KD025 treatment abolished the substantial neuroprotective and cognitive benefits conferred by repopulating microglia, preventing these cells from replenishing the depleted niche during the early critical time window post-injury. Delaying KD025 treatment to the subacute phase of TBI allowed microglial repopulation to occur, but this did not enhance the benefits conferred by repopulating microglia. Taken together, our data indicate that ROCK2 mediates neuronal survival and microglial population dynamics after TBI, including the emergence of repopulating microglia with a pro-repair phenotype.
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Older adults often have difficulty in making decisions under uncertainty, increasing the risk of financial exploitation. However, it is still under investigation about the extent to which cognitive decline influences risky decision-making and the underlying neural correlates. We hypothesized that the individual differences of risk-taking behavior depend on cognitive integrity, in which the dorsal and ventral fronto-amygdala connectivity would play dissociable roles. In the current study, thirty-six young and 51 older adults were tested with the Iowa gambling task combing resting-state and task-related functional magnetic resonance imaging. The results showed significant changes in behaviors and the fronto-amygdala network in older adults relative to young adults. More importantly, age-effect on risk-taking behaviors was remarkably different in cognitively normal and impaired older adults. In resting-state analysis, task performance was positively correlated with the ventral fronto-amygdala connectivity and negatively correlated with the dorsal fronto-amygdala connectivity in cognitively impaired older adults, compared with cognitively normal individuals. Furthermore, task-related analysis confirmed the relationships between dorsal/ventral fronto-amygdala network and risk-taking behaviors depending on cognitive integrity. These findings indicate that the fronto-amygdala network is crucial for understanding altered risky decision-making in aging, suggesting dissociable contributions of the dorsal and ventral pathways in the context of cognitive decline.
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Although significant differences in soil nitrogen levels exist under different paddy-upland rotations, the main reason for this is unclear. The nitrogen retention capacity and loss of ammonia volatilisation, leaching, etc. of paddy soil with large differences in nitrogen levels from two long-term rotations, garlic-rice and wheat-rice, were measured using the soil column simulation method. The results showed that the loss rate of leaching was only 5.4%, whereas that of ammonia volatilisation was up to 22.8%, which was the main nitrogen loss way of paddy soil under the two rotations. The average ammonia volatilisation rates under wheat-rice rotation with high and low nitrogen application rates were 12.1% and 40.2% higher than that under garlic-rice rotation, leading to a decrease in the total nitrogen loss amount and rate through ammonia volatilisation by 29.8% and 8.8%, respectively. As a result, nitrogen retention in the soil under garlic-rice rotation increased by 12.7%. In conclusion, the long-term garlic-rice rotation could significantly inhibit ammonia volatilisation, thus improving the soil nitrogen retention capacity. The straw return may increase soil organic matter content, reduce ammonia volatilisation loss, and enhance soil nitrogen retention capacity and productivity.
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This project investigated healthcare professionals’ experiences of explaining prenatal screening and delivering genetic syndrome diagnoses, and their perspectives on the new Prenatal Screening website (https://prenatalscreening.org.au) developed by Down Syndrome Queensland (DSQ) to support healthcare professionals in these areas.
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Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.
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In this presentation, we thoroughly discuss organic semiconductors and their role in printing technologies to manufacture the next-generation of sustainable optoelectronic devices. Focusing on organic photodetectors (OPDs), we study multidimensional factors affecting the device impact on the environment. Low-temperature processing and solution-processed printing technologies strongly reduce the environmental footprint of OPDs as compared to inorganic photodetectors. That being said, there is still room to further improve their sustainability by using polymers with simplified synthesis and non-halogenated solvents, as well as by using novel light detection methodologies requiring simple instrumentation.
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BackgroundIt has been proposed that cat ownership may be a risk-modifying factor for schizophrenia-related disorders and psychotic-like experiences (PLE). This study aimed to systematically review and meta-analyze publications that reported the relationship between cat ownership and schizophrenia-related outcomes.MethodologyWe searched Medline, Embase, CINAHL, Web of Science, and gray literature for publications between January 1, 1980, and May 30, 2023, regardless of geographical location and language. Backward citation search methods were used to locate additional articles. We included studies that reported original data on cat ownership and schizophrenia-related outcomes. We meta-analyzed estimates based on broad definitions (cat ownership, cat bites, and cat contact) with estimates with or without covariate adjustments. We pooled comparable estimates using random-effects models and assessed the risk of bias, heterogeneity, and study quality.ResultsWe identified 1915 studies, of which 106 were chosen for full-text review, ultimately resulting in the inclusion of 17 studies. We found an association between broadly defined cat ownership and increased odds of developing schizophrenia-related disorders. The unadjusted pooled odds ratio (OR) was 2.35 (95% CI: 1.38–4.01), while the adjusted pooled estimate was 2.24 (95% CI: 1.61–3.12). We were unable to aggregate the estimates for the PLE outcomes because of the broad range of measures.ConclusionsOur findings support an association between cat exposure and an increased risk of broadly defined schizophrenia-related disorders; however, the findings related to PLE as an outcome are mixed. There is a need for more high-quality studies in this field.
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Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.
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The recruitment of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors underlies the strengthening of neuronal connectivity during learning and memory. This process is triggered by N-methyl-D-aspartate (NMDA) receptor-dependent postsynaptic Ca2+ influx. Synaptotagmin (Syt)-1 and -7 have been proposed as Ca2+ sensors for AMPA receptor exocytosis but are functionally redundant. Here, we identify a cytosolic C2 domain-containing Ca2+-binding protein, Copine-6, that forms a complex with AMPA receptors. Loss of Copine-6 expression impairs activity-induced exocytosis of AMPA receptors in primary neurons, which is rescued by wild-type Copine-6 but not Ca2+-binding mutants. In contrast, Copine-6 loss of function does not affect steady-state expression or tetrodotoxin-induced synaptic upscaling of surface AMPA receptors. Loss of Syt-1/Syt-7 significantly reduces Copine-6 protein expression. Interestingly, overexpression of wild-type Copine-6, but not the Ca2+-binding mutants, restores activity-dependent exocytosis of AMPA receptors in Syt-1/Syt-7 double-knockdown neurons. We conclude that Copine-6 is a postsynaptic Ca2+ sensor that mediates AMPA receptor exocytosis during synaptic potentiation.
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Background: We present a cross-sectional, case-matched, and pair-wise comparison of structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) measures in vivo and ex vivo in a mouse model of concussion, thus aiming to establish the concordance of structural and diffusion imaging findings in living brain and after fixation. Methods: We allocated 28 male mice aged 3–4 months to sham injury and concussion (CON) groups. CON mice had received a single concussive impact on day 0 and underwent MRI at day 2 (n = 9) or 7 (n = 10) post-impact, and sham control mice likewise underwent imaging at day 2 (n = 5) or 7 (n = 4). Immediately after the final scanning, we collected the perfusion-fixed brains, which were stored for imaging ex vivo 6–12 months later. We then compared the structural imaging, DTI, and NODDI results between different methods. Results: In vivo to ex vivo structural and DTI/NODDI findings were in notably poor agreement regarding the effects of concussion on structural integrity of the brain. Comparison with existing methods: ex vivo imaging was frequently done to study the effects of diseases and treatments, but our results showed that ex vivo and in vivo imaging can detect completely opposite and contradictory results. This is also the first study that compares in vivo and ex vivo NODDI. Conclusion: Our findings call for caution in extrapolating translational capabilities obtained ex vivo to physiological measurements in vivo. The divergent findings may reflect fixation artefacts and the contribution of the glymphatic system changes.
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Background: Child feeding practices during the first two years of life are crucial to ensure good health and nutrition status. This study aimed to assess the factors influencing inappropriate child feeding practices in children aged 6 − 23 months in families receiving nutrition allowance in the remote Mugu district, Nepal. Methods: A community-based cross-sectional study was conducted among 318 mothers who had children aged 6 − 23 months of age in the seven randomly selected wards. Systematic random sampling technique was used to select the desired number of respondents. Data were collected using pre-tested semi-structured questionnaire. Bivariate and multivariable binary logistic regression was used to estimate crude odds ratio (cOR), and adjusted odds ratio (aOR), and 95% confidence intervals (CIs) to understand factor associated with child feeding practices. Results: Almost half of the children aged 6 − 23 months were not consuming a diverse diet (47.2%; 95% CI: 41.7%, 52.7%), did not meet the recommended minimum meal frequency (46.9%; 95% CI: 41.4%, 52.4%) and did not consume minimum acceptable diet (51.7%; 95% CI: 46.1%, 57.1%). Only 27.4% (95% CI: 22.7%, 32.5%) of children met the recommended complementary feeding practices. Multivariable analysis showed maternal characteristics such as mothers who gave birth at home (aOR = 4.70; 95% CI: 1.03, 21.31) and mothers in unpaid employment (aOR = 2.56; 95% CI: 1.06, 6.19) were associated with increased odds of inappropriate child feeding practices. Household economy (i.e. family with < 150 USD monthly income) was also associated with increased odds of inappropriate child feeding practices (aOR = 1.19; 95% CI: 1.05, 2.42). Conclusion: Despite the receipt of nutritional allowances, child feeding practices among 6 − 23 months children were not optimal. Additional context-specific behavior change strategies on child nutrition targeting mothers may be required.
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Microglia regulate multiple processes in the central nervous system, exhibiting a considerable level of cellular plasticity which is facilitated by an equally dynamic transcriptional environment. While many gene networks that regulate microglial functions have been characterised, the influence of epigenetic regulators such as small non-coding microRNAs (miRNAs) is less well defined. We have sequenced the miRNAome and mRNAome of mouse microglia during brain development and adult homeostasis, identifying unique profiles of known and novel miRNAs. Microglia express both a consistently enriched miRNA signature as well as temporally distinctive subsets of miRNAs. We generated robust miRNA-mRNA networks related to fundamental developmental processes, in addition to networks associated with immune function and dysregulated disease states. There was no apparent influence of sex on miRNA expression. This study reveals a unique developmental trajectory of miRNA expression in microglia during critical stages of CNS development, establishing miRNAs as important modulators of microglial phenotype.
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Evoked brain oscillations in the gamma range have been shown to assist in stroke recovery. However, the causal relationship between evoked oscillations and neuroprotection is not well understood. We have used optogenetic stimulation to investigate how evoked gamma oscillations modulate cortical dynamics in the acute phase after stroke. Our results reveal that stimulation at 40 Hz drives activity in interneurons at the stimulation frequency and phase-locked activity in principal neurons at a lower frequency, leading to increased cross-frequency coupling. In addition, 40-Hz stimulation after stroke enhances interregional communication. These effects are observed up to 24 h after stimulation. Our stimulation protocol also rescues functional synaptic plasticity 24 h after stroke and leads to an upregulation of plasticity genes and a downregulation of cell death genes. Together these results suggest that restoration of cortical dynamics may confer neuroprotection after stroke.
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Genomic regulation of cardiomyocyte differentiation is central to heart development and function. This study uses genetic loss-of-function human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the genomic regulatory basis of the non-DNA-binding homeodomain protein HOPX. We show that HOPX interacts with and controls cardiac genes and enhancer networks associated with diverse aspects of heart development. Using perturbation studies in vitro, we define how upstream cell growth and proliferation control HOPX transcription to regulate cardiac gene programs. We then use cell, organoid, and zebrafish regeneration models to demonstrate that HOPX-regulated gene programs control cardiomyocyte function in development and disease. Collectively, this study mechanistically links cell signaling pathways as upstream regulators of HOPX transcription to control gene programs underpinning cardiomyocyte identity and function.
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Objectives: Early childhood education and care (ECEC) services are attended by most children before school entry, reaching many living in circumstances of poverty and providing opportunity to support their nutrition. In this study, we examine the extent to which this opportunity is being met, comparing two common types of service provision: centre- versus family- provided food. Methods: Intensive in-situ observations were undertaken across 10 ECEC services in highly disadvantaged Australian communities. All meals provided to children aged 3.5–5 years across an ECEC day (N = 48), of which 11% were experiencing severe food insecurity, were photographed and analysed to assess nutritional adequacy with reference to national dietary standards. Results: Meals provided did not meet national dietary recommendations for quality or quantity. Nutrition was least adequate in services with policies of family-provided food. These services were also those that served families experiencing the highest levels of severe food insecurity (29%). Conclusions: In the absence of policies for the provision of food in ECEC, services are not realising their potential to support child nutrition in the context of poverty presenting increased risk to lifetime trajectories of health and wellbeing. System level policy interventions are required to facilitate equitable access to nutritious food and attendant life chances.
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Spatial transcriptomics (ST) technologies generate multiple data types from biological samples, namely gene expression, physical distance between data points, and/or tissue morphology. Here we developed three computational-statistical algorithms that integrate all three data types to advance understanding of cellular processes. First, we present a spatial graph-based method, pseudo-time-space (PSTS), to model and uncover relationships between transcriptional states of cells across tissues undergoing dynamic change (e.g. neurodevelopment, brain injury and/or microglia activation, and cancer progression). We further developed a spatially-constrained two-level permutation (SCTP) test to study cell-cell interaction, finding highly interactive tissue regions across thousands of ligand-receptor pairs with markedly reduced false discovery rates. Finally, we present a spatial graph-based imputation method with neural network (stSME), to correct for technical noise/dropout and increase ST data coverage. Together, the algorithms that we developed, implemented in the comprehensive and fast stLearn software, allow for robust interrogation of biological processes within healthy and diseased tissues.
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The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential.
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Organic photodetectors (OPDs) detecting light in the near-infrared (NIR) range from 900 to 1200 nm offer numerous applications in biomedical imaging and health monitoring. However, an ultra-low bandgap of the electron donor compound required to achieve NIR detection poses a unique challenge in selecting a complementary acceptor material with a suitable energy-level offset. To tackle this, a solution-processed, fullerene-dominated, ternary device is engineered by adding an ultra-low bandgap (0.6–0.8 eV) ambipolar polymer, polybenzobisthiadiazole-dithienocyclopentane (PBBTCD), into the active layer of visible-light-responsive OPDs (bandgap of 1.8 eV) to form a ternary blend. The resulting OPD benefits from the extended absorption beyond 1000 nm. The cascaded energy level alignment within the ternary blend and the applied reverse bias both improve the overall NIR photocurrent responsivity by 2 orders of magnitude, reaching 0.4 mA W−1 at 1050 nm and −2 V for ternary devices. Furthermore, a photovoltage responsivity of 0.3 mV m2 W−1 along with significant open-circuit voltage (Voc) of 0.12 V allow NIR detection in the Voc mode. Prominently, this ability is accomplished with a minimal presence of PBBTCD. Taken together, this work indicates potential strategies for extending the spectral activity of conventional OPDs through introduction of an ambipolar ultra-low bandgap polymer as a minor element.
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Most vertebrates have one layer of the dim-light active rod photoreceptors. However, multiple rod layers, known as a multibank retina, can be found in over 100 species of fish, including several deep-sea species and one family of nocturnally active reef fish, the Holocentridae. Although seemingly associated with increased photon catch, the function of multibank retinas remained unknown. We used an integrative approach, combining histology, electrophysiology and amino acid sequence analysis, applied to three species of nocturnal reef fishes, two holocentrids with a multibank retina (Neoniphon sammara and Myripristis violacea) and an apogonid with a single rod bank (Ostorhinchus compressus), to determine the sensory advantage of multiple rod layers. Our results showed that fish with multibank retinas have both faster vision and enhanced responses to bright- and dim-light intensities. Faster vision was indicated by higher flicker fusion frequencies during temporal resolution electroretinography as well as faster retinal release rates estimated from their rhodopsin proteins. Enhanced sensitivity was demonstrated by broadened intensity-response curves derived from luminous sensitivity electroretinography. Overall, our findings provide 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.
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Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules that are involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are localized to the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq, we identified a specific set of lncRNAs that accumulate in the synaptic compartment within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these was a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single-molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3BP2 and CAPRIN1, regulates the activity-dependent trafficking and clustering of RNA granules. In addition, we found that cell-type-specific, activity-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and RNA condensates in the synaptic compartment.
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ObjectiveAdverse effects of sleep disruption are identified in parents who live with a child with Down Syndrome (DS), yet there is no research on siblings’ experiences. This study addresses this knowledge gap.DesignA qualitative research study using semi-structured interviews to understand the experiences of siblings of a child with DS and sleep difficulties from the perspectives of parents and siblings.ParticipantsEleven siblings aged 5-15 years old, and 11 parents, from 8 families with a child with DS in Australia.MethodsSemi-structured sibling interviews explored what it was like to have a sibling with DS and sleep difficulties; the participant’s own sleep; how their sleep affected how they felt during the day; how sleep impacted their family; and advice that they would give to other siblings. Parent interviews included similar topics; here we report on excerpts in which parents reference siblings. Interviews were audio recorded, transcribed verbatim, and analyzed using a reflexive thematic analysis.ResultsSiblings and parents acknowledge sleep disruption for siblings; yet sleep disruption is normalized, viewed with acceptance and inevitability. Siblings report adverse effects from sleep disruption, view sleep in a relational way, and cope with sleep disruption. Parents can underestimate siblings’ sleep disruption and are uncertain whether siblings’ symptoms result from sleep disruption or other causes.ConclusionsSiblings of a child with DS experience sleep disruption and may be at risk of developing long-term health problems without focused support.
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This paper describes the longitudinal change in sleep, functional, and behavioural characteristics in a cohort of children with Down syndrome, including the effect of sleep interventions in a subset. A prospective longitudinal cohort study was undertaken in children with Down syndrome aged 3-16 years comparing (1) children referred to a tertiary sleep medicine clinic who received sleep hygiene advice and an additional sleep treatment (DSref_I) with (2) children attending the same clinic who only received sleep hygiene advice (DSref_N) and (3) children recruited from the community who, were not receiving any treatment (DScomm). Data collected included demographic and medical history information, Child Sleep Habits Questionnaire-Abbreviated (CSHQ-A), Life-Habits Questionnaire (Life-H) and Child Behaviour Checklist (CBCL) at baseline and then 6-monthly for a total of 18 months. Any sleep interventions during this time were recorded. A total of 57 children were included (DSref_I, n = 16; DSref_N, n = 25; DScomm, n = 16). At recruitment, the median CSHQ-A total score was high (>41) in all three subgroups, but highest in the DSref_I subgroup (median [interquartile range] Dsref_I score 58 [53-66] versus DSref_N score 49 [43-53], p = 0.019). Although improved, 80% of participants in the DSref_I subgroup still had a CSHQ-A total score >41 at the last assessment point. The median total Life-H and total CBCL scores were not significantly different between groups at baseline and there was no significant time, group, or interaction effect seen through the study. Over an 18-month period, sleep problems were seen to persist in children with Down syndrome. Treatment resulted in only modest improvements in sleep.
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Vitamin D status–a complex trait influenced by environmental and genetic factors–is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)–the main circulating form of vitamin D–in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D.
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Neuronal communication relies on the release of neurotransmitters from various populations of synaptic vesicles. Despite displaying vastly different release probabilities and mobilities, the reserve and recycling pool of vesicles co-exist within a single cluster suggesting that small synaptic biomolecular condensates could regulate their nanoscale distribution. Here, we performed a large-scale activity-dependent phosphoproteome analysis of hippocampal neurons in vitro and identified Tau as a highly phosphorylated and disordered candidate protein. Single-molecule super-resolution microscopy revealed that Tau undergoes liquid-liquid phase separation to generate presynaptic nanoclusters whose density and number are regulated by activity. This activity-dependent diffusion process allows Tau to translocate into the presynapse where it forms biomolecular condensates, to selectively control the mobility of recycling vesicles. Tau, therefore, forms presynaptic nano-biomolecular condensates that regulate the nanoscale organization of synaptic vesicles in an activity-dependent manner.
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Pareidolias, or the misperception of ambiguous stimuli as meaningful objects, are complex visual illusions thought to be phenomenologically similar to Visual Hallucination (VH). VH are a major predictor of dementia in Parkinson’s Disease (PD) and are included as a core clinical feature in Dementia with Lewy Bodies (DLB). A newly developed Noise Pareidolia Test (NPT) was proposed as a possible surrogate marker for VH in DLB patients as increased pareidolic responses correlated with informant-corroborated accounts of VH. This association could, however, be mediated by visuoperceptual impairment. To understand the drivers of performance on the NPT, we contrasted performances in patient groups that varied both in terms of visuoperceptual ability and rates of VH. N = 43 patients were studied of whom n = 13 had DLB or PD with Dementia (PDD); n = 13 had PD; n = 12 had typical, memory-onset Alzheimer’s Disease (tAD); and n = 5 had Posterior Cortical Atrophy (PCA) due to Alzheimer’s disease. All patient groups reported pareidolias. Within the Lewy body disorders (PD, DLB, PDD), there was no significant difference in pareidolic response rates between hallucinating and non-hallucinating patients. Visuoperceptual deficits and pareidolic responses were most frequent in the PCA group—none of whom reported VH. Regression analyses in the entire patient cohort indicated that pareidolias were strongly predicted by visuoperceptual impairment but not by the presence of VH. These findings suggest that pareidolias reflect the underlying visuoperceptual impairment of Lewy body disorders, rather than being a direct marker for VH.
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The corpus callosum is the largest axonal tract in the human brain, connecting the left and right cortical hemipheres. This structure is affected in myriad human neurodevelopmental disorders, and can be entirely absent as a result of congenital or surgical causes. The age when callosal loss occurs, for example via surgical section in cases of refractory epilepsy, correlates with resulting brain morphology and neuropsychological outcomes, whereby an earlier loss generally produces relatively improved interhemispheric connectivity compared to a loss in adulthood (known as the “Sperry’s paradox”). However, the mechanisms behind these age-dependent differences remain unclear. Perhaps the best documented and most striking of the plastic changes that occur due to developmental, but not adult, callosal loss is the formation of large, bilateral, longitudinal ectopic tracts termed Probst bundles. Despite over 100 years of research into these ectopic tracts, which are the largest and best described stereotypical ectopic brain tracts in humans, much remains unclear about them. Here, we review the anatomy of the Probst bundles, along with evidence for their faciliatory or detrimental function, the required conditions for their formation, patterns of etiology, and mechanisms of development. We provide hypotheses for many of the remaining mysteries of the Probst bundles, including their possible relationship to preserved interhemispheric communication following corpus callosum absence. Future research into naturally occurring plastic tracts such as Probst bundles will help to inform the general rules governing axon plasticity and disorders of brain miswiring.
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Few treatment options are available for targeting core symptoms of autism spectrum disorder (ASD). The development of treatments that target common neural circuit dysfunctions caused by known genetic defects, namely, disruption of the excitation/inhibition (E/I) balance, is promising. Transcranial direct current stimulation (tDCS) is capable of modulating the E/I balance in healthy individuals, yet its clinical and neurobiological effects in ASD remain elusive.
This double-blind, randomized, sham-controlled trial investigated the effects of multisession cathodal prefrontal tDCS coupled with online cognitive remediation on social functioning, information processing efficiency and the E/I balance in ASD patients aged 14-21 years.
Sixty individuals were randomly assigned to receive either active or sham tDCS (10 sessions in total, 20 min/session, stimulation intensity: 1.5 mA, cathode: F3, anode: Fp2, size of electrodes: 25 cm) combined with 20 min of online cognitive remediation. Social functioning, information processing efficiency during cognitive tasks, and theta- and gamma-band E/I balance were measured one day before and after the treatment.
Compared to sham tDCS, active cathodal tDCS was effective in enhancing overall social functioning [F(1, 58) = 6.79, p = .012, η = 0.105, 90% CI: (0.013, 0.234)] and information processing efficiency during cognitive tasks [F(1, 58) = 10.07, p = .002, η = 0.148, 90% CI: (0.034, 0.284)] in these individuals. Electroencephalography data showed that this cathodal tDCS protocol was effective in reducing the theta-band E/I ratio of the cortical midline structures [F(1, 58) = 4.65, p = .035, η = 0.074, 90% CI: (0.010, 0.150)] and that this reduction significantly predicted information processing efficiency enhancement (b = -2.546, 95% BCa CI: [-4.979, -0.113], p = .041).
Our results support the use of multisession cathodal tDCS over the left dorsolateral prefrontal cortex combined with online cognitive remediation for reducing the elevated theta-band E/I ratio in sociocognitive information processing circuits in ASD patients, resulting in more adaptive regulation of global brain dynamics that is associated with enhanced information processing efficiency after the intervention.
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Reactive oxygen species (ROS) such as superoxide radicals O-2(-), hydroxyl radicals OH-, and hydrogen peroxide H2O2 may have detrimental effects on marine organisms, including their integuments and visual appearances. Although some studies have described the impact of ROS on marine ecosystems and species ecology, the influence on the optical response of the integuments of marine species and on their visual appearances remains unknown. In this article, we used histology and optical characterisation to show, for the first time, that skin melanophores (melanin-containing chromophores) of the coral reef fish, Stegastes apicalis, change their shapes and fluorescent proprieties upon oxidation with H2O2 radicals. Our observations also suggest that pheomelanosomes may occur in fish integuments, where, previously, it was thought that fish melanosomes only contain eumelanin. This investigation relied on light and electron microscopy and steady-state fluorimetry, as well as time-resolved streak imaging systems. We suggest that the changes in the morphological and spectral characteristics of melanophores can be used as a marker of physiological stress induced by environmental factors such as ROS. Moreover, S. apicalis may be used as a potential model for studying the interaction between the surrounding environment and natural organisms in biologically diverse ecosystems, such as the Great Barrier Reef in Australia.
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Traditional approaches for learning on categorical data underexploit the dependencies between columns (a.k.a. fields) in a dataset because they rely on the embedding of data points driven alone by the classification/regression loss. In contrast, we propose a novel method for learning on categorical data with the goal of exploiting dependencies between fields. Instead of modelling statistics of features globally (i.e., by the covariance matrix of features), we learn a global field dependency matrix that captures dependencies between fields and then we refine the global field dependency matrix at the instance-wise level with different weights (so-called local dependency modelling) w.r.t. each field to improve the modelling of the field dependencies. Our algorithm exploits the meta-learning paradigm, i.e., the dependency matrices are refined in the inner loop of the meta-learning algorithm without the use of labels, whereas the outer loop intertwines the updates of the embedding matrix (the matrix performing projection) and global dependency matrix in a supervised fashion (with the use of labels). Our method is simple yet it outperforms several state-of-the-art methods on six popular dataset benchmarks. Detailed ablation studies provide additional insights into our method.
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Liver cancer (LC) ranks as the second most prevalent cause of cancer-related deaths. Herbaceous plants are valuable sources of complementary, adjuvant, or alternative anti-tumor therapy as they contain natural active ingredients with anti-cancer potential. Although the clinical use of 3, 3′-Diindolylmethane (DIM) has been established, its low chemical stability and bioavailability, limits its therapeutic applications. Increasing effort has been undertaken to improve DIM's biological activity including nanoformulations. Here, we evaluated the efficacy of DIM nanoparticles (DIM-NPs) coated with PEG/chitosan for the treatment of liver cancer and elucidated the underlying molecular mechanisms contributing to its anti-tumor activity. DIM-PLGA-PEG/chitosan NPs were synthesized and characterized using dynamic light scattering (DLS). The effect of newly synthesized DIM-NPs was evaluated in HepG-2 and HUH-7 hepatocarcinoma cells and compared to THLE-2 immortal normal liver cells and WI-38 (normal lung fibroblast cells). These cells were treated with different non-cytotoxic concentrations of DIM-NPs and MTT assay and other functional assays were performed. Compared to normal cells, DIM-NPs induced cytotoxicity in HepG-2 cells at 6.25 µg/mL after 48 h of treatment. Treatment of HepG-2 cells with the 50 % inhibitory concentration (IC50) 12.5 µg/mL of DIM-NPs inhibited cell migration (p < 0.001). Treatment of chicken embryo with 5ug/ml DIM-NPs reduced (p < 0.001) angiogenesis at day 4. Notably, at the molecular level, DIM-NPs upregulated Bax and p53 and downregulated Bcl-2 in a dose-dependent manner. DIM-NPs also induced cell apoptosis in HepG-2 cells. Treatment of hepatic cells with DIM-NPs decreased cell proliferation, migration and angiogenesis, and induced cell death via up-regulation of Bax and p53, and down-regulation of Bcl-2 in HepG-2 cells. Further investigations are necessitated to determine the pharmacokinetics of DIM-NPs using a preclinical cancer model.
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Background: Paternal perinatal distress is receiving increasing attention. The Edinburgh Postnatal Depression Scale (EPDS) is the predominant screening tool for paternal perinatal distress. Research using the large Avon Longitudinal Study of Parents and Children (ALSPAC) cohort demonstrated that a three-factor EPDS structure is appropriate among mothers, with anhedonia, anxiety and depression factors emerging consistently across perinatal timepoints. Method: We employed confirmatory factor (CFA; n = 6170 to 9848) analysis to determine if this structure was appropriate for ALSPAC fathers, and the extent of invariance between mother and father groups. Results: At 18-weeks gestation, and 8-weeks, 8-months and 21-months postpartum, the three-factor model had consistently superior fit to other proposed models. Consistent with interpretation of a total distress score, factors were highly correlated. The model exhibited configural invariance in both the first (8-months) and second (21-months) post-partum years. Metric and scalar invariance were not supported, however, non-invariance was largely attributable to item 9 canvassing “crying”. Limitations: While the study employs a large cohort, the data collection in 1991 to 1992 in the United Kingdom may not account for the diverse gender roles, family structures and societal changes seen since that time. Conclusions: Interpretation of the EPDS as representing perinatal distress, reflecting anhedonia, anxiety and depression aspects, is appropriate for mothers and fathers. The experience of distress has nuanced gender-based differences. Implications for EPDS interpretation and cut-off scores among fathers are discussed.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which patients lose motor functions due to progressive loss of motor neurons in the cortex, brainstem, and spinal cord. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytes play an important role in maintaining ion homeostasis in the extracellular milieu and regulate multiple brain functions by altering their extracellular concentrations. In this study, we have investigated the ability of astrocytes to maintain K+ homeostasis in the brain via direct measurement of the astrocytic K+ clearance rate in the motor and somatosensory cortices of an ALS mouse model (SOD1(G93A)). Using electrophysiological recordings from acute brain slices, we show region-specific alterations in the K+ clearance rate, which was significantly reduced in the primary motor cortex but not the somatosensory cortex. This decrease was accompanied by significant changes in astrocytic morphology, impaired conductivity via Kir4.1 channels and low coupling ratio in astrocytic networks in the motor cortex, which affected their ability to form the K+ gradient needed to disperse K+ through the astrocytic syncytium. These findings indicate that the supportive function astrocytes typically provide to motoneurons is diminished during disease progression and provides a potential explanation for the increased vulnerability of motoneurons in ALS.
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Approximately 300–550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom *25–30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2–3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2–3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2–3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2–3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2–3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.
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The RNA modification N6-methyladenosine (m6A) regulates the interaction between RNA and various RNA binding proteins within the nucleus and other subcellular compartments and has recently been shown to be involved in experience-dependent plasticity, learning, and memory. Using m6A RNA-sequencing, we have discovered a distinct population of learning-related m6A- modified RNAs at the synapse, which includes the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6A readers in the medial prefrontal cortex of male C57/BL6 mice, with m6A-modified Malat1 binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell-type- and synapse-specific, and state-dependent, reduction of m6A on Malat1 impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between Malat1 and DPYSL2 and an associated decrease in dendritic spine formation. These findings highlight the critical role of m6A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience- dependent m6A readers in the synaptic compartment.
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Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO/FiO ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO/FiO ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.