Publications

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.

The data-driven approach of supervised learning methods has limited applicability in solving dipole inversion in Quantitative Susceptibility Mapping (QSM) with varying scan parameters across different objects. To address this generalization issue in supervised QSM methods, we propose a novel training-free model-based unsupervised method called MoDIP (Model-based Deep Image Prior). MoDIP comprises a small, untrained network and a Data Fidelity Optimization (DFO) module. The network converges to an interim state, acting as an implicit prior for image regularization, while the optimization process enforces the physical model of QSM dipole inversion. Experimental results demonstrate MoDIP's excellent generalizability in solving QSM dipole inversion across different scan parameters. It exhibits robustness against pathological brain QSM, achieving over 32 % accuracy improvement than supervised deep learning methods. It is also 33 % more computationally efficient and runs 4 times faster than conventional DIP-based approaches, enabling 3D high-resolution image reconstruction in under 4.5 min.

Accumulating evidence underscores the pivotal role of heightened inflammation in the pathophysiology of stress-related diseases, yet the underlying mechanisms remain elusive. The complement system, a key effector of the innate immune system, produces the C5-cleaved activation product C5a upon activation, initiating inflammatory responses through the canonical C5a receptor 1 (C5aR1). While C5aR1 is expressed in stress-responsive brain regions, its role in stress responsiveness remains unknown.MethodsTo investigate C5a-C5aR1 signaling in stress responses, mice underwent acute and chronic stress paradigms. Circulating C5a levels and mRNA expression of C5aR1 in the hippocampus and adrenal gland were measured. C5aR1-deficient mice were utilized to elucidate the effects of disrupted C5a-C5aR1 signaling across behavioral, hormonal, metabolic, and inflammation parameters.ResultsChronic restraint stress elevated circulating C5a levels, while reducing C5aR1 mRNA expression in the hippocampus and adrenal gland. Notably, the absence of C5aR1 signaling enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH), concurrently reducing pituitary ACTH production, enhancing the response to acute stress. C5aR1-deficient mice exhibited attenuated reductions in locomotor activity and body weight under chronic stress. Additionally, these mice displayed increased glucocorticoid receptor sensitivity and disrupted glucose and insulin homeostasis. Chronic stress induced an increase in C5aR1-expressing microglia in the hippocampus, a response mitigated in C5aR1-deficient mice.ConclusionC5a-C5aR1 signaling emerges as a key metabolic regulator during stress, suggesting that complement activation and dysfunctional C5aR1 signaling may contribute to neuroinflammatory phenotypes in stress-related disorders. The results advocate for further exploration of complement C5aR1 as a potential therapeutic target for stress-related conditions.

Objective: How abnormal brain signaling impacts cognition in autism spectrum disorder (ASD) remained elusive. This study aimed to investigate the local and global brain signaling in ASD indicated by theta-band functional excitation-inhibition (fE/I) ratio and explored psychophysiological relationships between fE/I, cognitive deficits, and ASD symptomatology.Methods: A total of 83 ASD and typically developing (TD) individuals participated in this study. Participants’ interference control and set-shifting abilities were assessed. Resting-state electroencephalography (EEG) was used for estimating theta-band fE/I ratio.Results: ASD individuals (n = 31 without visual EEG abnormality; n = 22 with visual EEG abnormality) generally performed slower in a cognitive task tapping interference control and set-maintenance abilities, but only ASD individuals with visually abnormal EEG performed significantly slower than their TD counterparts (Bonferroni-corrected ps < .001). Heightened theta-band fE/I ratios at the whole-head level, left and right hemispheres were observed in the ASD subgroup without visual EEG abnormality only (Bonferroni-corrected ps < .001), which remained highly significant when only data from medication-naïve participants were analyzed. In addition, higher left hemispheric fE/I ratios in ASD individuals without visual EEG abnormality were significantly correlated with faster interference control task performance, in turn faster reaction time was significantly associated with less severe restricted, repetitive behavior (Bonferroni-corrected ps ≤ .0017).Conclusions: Differential theta-band fE/I within the ASD population. Heightened theta-band fE/I in ASD without visual EEG abnormality may be associated with more efficient filtering of distractors and a less severe ASD symptom manifestation.Significance: Brain signaling, indicated by theta-band fE/I, was different in ASD subgroups. Only ASD with visually-normal EEG showed heightened theta-band fE/I, which was associated with faster processing of visual distractors during a cognitive task. More efficient distractor filtering was associated with less restricted, repetitive behaviors.

The synapse is the communication unit of the brain, linking billions of neurons through trillions of synaptic connections. The lipid landscape of the synaptic membrane underpins neurotransmitter release through the exocytic fusion of neurotransmitter-containing vesicles, endocytic recycling of these synaptic vesicles, and the postsynaptic response following binding of the neurotransmitter to specialized receptors. How the connected brain can learn and acquire memories through synaptic plasticity is unresolved. Phospholipases, and especially the phospholipase A1 isoform DDHD2, have recently been shown to play a critical role in memory acquisition through the generation of saturated free fatty acids such as myristic and palmitic acids. This emerging synaptic plasticity pathway suggests that phospholipases cannot only respond to synaptic activity by altering the phospholipid landscape but also contribute to the establishment of long-term memories in our brain.

Understanding the molecular changes associated with the aged brain forms the basis for developing potential strategies for slowing cognitive decline associated with normal aging. Focusing on the hippocampus, a critical brain region involved in learning and memory, we employed tandem mass tag methodology to investigate global proteomic changes that occur in advanced-aged (20-month) versus young (3-month) C57BL/6 male mice. Our analysis revealed the upregulation of 236 proteins in the old hippocampal proteome, including those enriched within several age-related processes, such as the adaptive immune response and molecular metabolic pathways, whereas downregulated proteins (88 in total) are mainly involved in axonogenesis and growth cone-related processes. Categorizing proteins by cell-type enrichment in the brain identified a general upregulation of proteins preferentially expressed in microglia, astrocytes, and oligodendrocytes. In contrast, proteins with neuron-specific expression displayed an overall age-related downregulation. By integrating our proteomic with our previously published transcriptomic data, we discovered a mild but significant positive correlation between mRNA and protein expression changes in the aged hippocampus. Therefore, this proteomic data is a valuable additional resource for further understanding age-related molecular mechanisms.

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Accurate assessments of current and future fertility-including overall trends and changing population age structures across countries and regions-are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.

To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10-54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression-Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values-a metric assessing gain in forecasting accuracy-by comparing predicted versus observed ASFRs from the past 15 years (2007-21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.

During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63-5·06) to 2·23 (2·09-2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137-147), declining to 129 million (121-138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1-canonically considered replacement-level fertility-in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7-29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59-2·08) in 2050 and 1·59 (1·25-1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6-43·1) in 2050 and 54·3% (47·1-59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions-decreasing, for example, in south Asia from 24·8% (23·7-25·8) in 2021 to 16·7% (14·3-19·1) in 2050 and 7·1% (4·4-10·1) in 2100-but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40-1·92) in 2050 and 1·62 (1·35-1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.

Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.

Bill & Melinda Gates Foundation.

A prevalent view in treating age-dependent disorders including Alzheimer’s disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits in the APP23 mouse model of AD without reducing amyloid-β (Aβ) burden. Different from previous studies that had shown Aβ clearance as a consequence of blood-brain barrier (BBB) opening, here, the BBB was not opened as no microbubbles were used. Quantitative SWATH proteomics and functional magnetic resonance imaging revealed that ultrasound induced long-lasting functional changes that correlate with the improvement in memory. Intriguingly, the treatment was more effective at a higher frequency (1 MHz) than at a frequency within the range currently explored in clinical trials in AD patients (286 kHz). Together, our data suggest frequency-dependent bio-effects of ultrasound and a dissociation of cognitive improvement and Aβ clearance, with important implications for the design of trials for AD therapies.

The complexity of localising the epileptogenic zone (EZ) contributes to surgical resection failures in achieving seizure freedom. The distinct patterns of epileptiform activity during interictal and ictal phases, varying across patients, often lead to suboptimal localisation using electroencephalography (EEG) features. We posed two key questions: whether neural signals reflecting epileptogenicity generalise from interictal to ictal time windows within each patient, and whether epileptiform patterns generalise across patients. Utilising an intracranial EEG dataset from 55 patients, we extracted a large battery of simple to complex features from stereo-EEG (SEEG) and electrocorticographic (ECoG) neural signals during interictal and ictal windows. Our features (n = 34) quantified many aspects of the signals including statistical moments, complexities, frequency-domain and cross-channel network attributes. Decision tree classifiers were then trained and tested on distinct time windows and patients to evaluate the generalisability of epileptogenic patterns across time and patients, respectively. Evidence strongly supported generalisability from interictal to ictal time windows across patients, particularly in signal power and high-frequency network-based features. Consistent patterns of epileptogenicity were observed across time windows within most patients, and signal features of epileptogenic regions generalised across patients, with higher generalisability in the ictal window. Signal complexity features were particularly contributory in cross-patient generalisation across patients. These findings offer insights into generalisable features of epileptic neural activity across time and patients, with implications for future automated approaches to supplement other EZ localisation methods.

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.

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.

Objective: The objective of this study was to examine variations in age at nap cessation and identify whether there is an association with social-emotional functioning (SEF) as measured by internalizing/externalizing behavior, child temperament, and social skills in a sample of early childhood education and care–attending children.Methods: The sample comprised 1117 children from the Australian Effectiveness Early Educational Experiences for Children longitudinal early childhood study. We used children's age at nap cessation as retrospectively recalled by caregivers in 2011 or 2013 when children were between ages 2 and 7 years. Each child's SEF was reported by a caregiver using the Strengths and Difficulties Questionnaire, the Short Temperament Scale for Children, and the Social Skills Inventory Scale. Associations between children's age of nap cessation and SEF were tested using linear regressions.Results: The children's age at nap cessation ranged from 6 months to 6 years. For each additional year of napping, children's total, conduct, externalizing, and peer behavior problems decreased by 0.39 (95% confidence interval [CI], −0.70 to −0.09), 0.11 (95% CI, −0.21 to −0.01), 0.11 (95% CI, −0.51 to −0.06), and 0.11 (95% CI, −0.20 to −0.02) units on the Strengths and Difficulties Questionnaire scale, respectively. No further significant associations were found.Conclusion: This is the first study reporting the age range of nap cessation and its associations with social-emotional functioning. Our findings demonstrate earlier cessation ages in Australian children attending Early Childhood Education and Care programs than previously reported and a small association with externalizing and peer problems.

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.

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.

Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-023-36392-5, published online 15 February 2023 The original version of this article contained an error in the second paragraph of the ‘Assay of DBP concentration’ section of the ‘Methods’, which incorrectly read ‘The lower and upper detection limits for DBP were 2.07 and 79.8 mg/L respectively’. The correct version states ‘2.07 µg/L’ in place of ‘2.07’. This has been corrected in both the PDF and HTML versions of the article.

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.

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.

Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.

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.

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.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

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.

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.

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.

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.

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.

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.

Over the last 20 years, there has been growing interest in the impact of vitamin D on the developing brain. The evidence linking gestational and/or neonatal vitamin D deficiency with an increased risk of neurodevelopmental disorders such as schizophrenia and autism continues to accrue. Underpinning this research is a large body of developmental studies in animals that demonstrates early life vitamin D deficiency leads to a broad range of alterations in the developing brain. Many of these effects persist into adulthood with altered brain function. Considering how prevalent vitamin D deficiency is in pregnant women, optimizing vitamin D status in this at-risk group may reduce the overall incidence of adverse neuropsychiatric outcomes in offspring. Just as prenatal folate supplementation has reduced the incidence of spina bifida, we believe that prenatal vitamin D supplementation may reduce the incidence of neurodevelopmental disorders such as autism and schizophrenia.

There is a broad understanding that vitamin D deficiency at various points across the life span is associated with a range of adverse health outcomes, including brain disorders. The mechanisms through which vitamin D deficiency impacts behavior and cognition, however, are yet to be fully elucidated. A better understanding of how vitamin D deficiency impacts the adult brain may allow the targeting of specific pathways to prevent or ameliorate cascading effects of low vitamin D. In this review, we examine the evidence from epidemiological and animal studies linking adult vitamin D deficiency with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Although supplementation with vitamin D is readily available, recent clinical trials have had mixed results, highlighting the need for further research.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. Objective: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. Methods: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. Results: Overall, people with PD had a regionally smaller posterior lobe (d = −0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (d = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (d = −0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = −0.17). Conclusions: We provide evidence of a dissociation between anterior “motor” lobe and posterior “non-motor” lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions.

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-β (Aβ) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aβ-PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and Aβ status (Aβ−, Aβ+). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high Aβ levels correlated with faster volume loss in the BF and hippocampus, and the effect of Aβ varied within BF subregions. Compared to CU Aβ+ individuals, Aβ-related loss among CI Aβ+ adults was much greater in the predominantly cholinergic subregion of Ch4p, whereas no difference was observed for the Ch1/Ch2 region. The findings support early and substantial vulnerability of the BF and further reveal distinctive degeneration of BF subregions during early AD.

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.

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.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

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.