White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of ...cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals aged 8–28, who received annual scans for up to 5years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical–subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition–emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.
•We find hierarchical white matter (WM) development in a longitudinal sample.•Maturation of most frontal connectivity in adolescence supports cognitive function.•Late maturation of corticolimbic connectivity supports socioemotional interactions.•Males showed WM growth from childhood to adulthood, females mainly in mid-adolescence.•Delayed maturation of WM was associated with poorer cognitive performance.
Response inhibition refers to the suppression of actions that are inappropriate in a given context and that interfere with goal-driven behavior. Studies using a range of methodological approaches ...have implicated executive control processes mediated by frontal-subcortical circuits as being critical to response inhibition; however, localization within the frontal lobe has been inconsistent. In this review, we present evidence from behavioral, lesion, neuroimaging, electrophysiology, and neurological population studies. The findings lay the foundation for a construct in which response inhibition is akin to response selection, such that pre-SMA circuits are critical to selection of appropriate behavior, including both selecting to engage appropriate motor responses and selecting to withhold (inhibit) inappropriate motor responses. Recruitment of additional prefrontal and posterior cortical circuits, necessary to guide response selection, varies depending on the cognitive and behavioral demands of the task.
Pacific Biosciences HiFi read technology is currently the industry standard for high accuracy long-read sequencing that has been widely adopted by large sequencing and assembly initiatives for ...generation of de novo assemblies in non-model organisms. Though adapter contamination filtering is routine in traditional short-read analysis pipelines, it has not been widely adopted for HiFi workflows.
Analysis of 55 publicly available HiFi datasets revealed that a read-sanitation step to remove sequence artifacts derived from PacBio library preparation from read pools is necessary as adapter sequences can be erroneously integrated into assemblies.
Here we describe the nature of adapter contaminated reads, their consequences in assembly, and present HiFiAdapterFilt, a simple and memory efficient solution for removing adapter contaminated reads prior to assembly.
Cystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk ...factors for progressive disease.
A longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008-2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression.
Prevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008-2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5-53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis.
This study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.
Working memory (WM), the ability to hold information on-line to guide planned behavior, improves through adolescence in parallel with continued maturation of critical brain systems supporting ...cognitive control. Initial developmental neuroimaging studies with one or two timepoints have provided important though varied results limiting our understanding of which and how neural systems change during this transition into mature WM. In this study, we leverage functional magnetic resonance imaging (fMRI) longitudinal data spanning up to 9 years in 129 normally developing individuals to identify which systems demonstrate growth changes that accompany improvements in WM performance. We used a memory guided saccade task that allowed us to probe encoding, pure maintenance, and retrieval neural processes of WM. Consistent with prior research, we found that WM performance continued to improve into the early 20's. fMRI region of interest (ROI) analyses revealed developmental (1) increases in sensorimotor-related (encoding/retrieval) activity in visual cortex from childhood through early adulthood that were associated with WM accuracy and (2) decreases in sustained (maintenance) activity in executive regions from childhood through mid-adolescence that were associated with response latency in childhood and early adolescence. Together these results provide compelling evidence that underlying the maturation of WM is a transition from reliance on executive systems to specialized regions related to the domain of mnemonic requirements of the task leading to optimal performance.
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•Protracted development of working memory and underlying neural processes into 20's.•Increases in encoding/retrieval activity in visual cortex.•Decreases in maintenance activity in prefrontal/subcortical regions.•Association of precision error and encoding activity reflecting mnemonic processing.•Association of latency and maintenance activity reflecting executive processing.
Although motor deficits are common in autism, the neural correlates underlying the disruption of even basic motor execution are unknown. Motor deficits may be some of the earliest identifiable signs ...of abnormal development and increased understanding of their neural underpinnings may provide insight into autism-associated differences in parallel systems critical for control of more complex behaviour necessary for social and communicative development. Functional magnetic resonance imaging was used to examine neural activation and connectivity during sequential, appositional finger tapping in 13 children, ages 8–12 years, with high-functioning autism (HFA) and 13 typically developing (TD), age- and sex-matched peers. Both groups showed expected primary activations in cortical and subcortical regions associated with motor execution contralateral primary sensorimotor cortex, contralateral thalamus, ipsilateral cerebellum, supplementary motor area (SMA); however, the TD group showed greater activation in the ipsilateral anterior cerebellum, while the HFA group showed greater activation in the SMA. Although activation differences were limited to a subset of regions, children with HFA demonstrated diffusely decreased connectivity across the motor execution network relative to control children. The between-group dissociation of cerebral and cerebellar motor activation represents the first neuroimaging data of motor dysfunction in children with autism, providing insight into potentially abnormal circuits impacting development. Decreased cerebellar activation in the HFA group may reflect difficulty shifting motor execution from cortical regions associated with effortful control to regions associated with habitual execution. Additionally, diffusely decreased connectivity may reflect poor coordination within the circuit necessary for automating patterned motor behaviour. The findings might explain impairments in motor development in autism, as well as abnormal and delayed acquisition of gestures important for socialization and communication.
The innate immune response is critical for animal homeostasis and is conserved from invertebrates to vertebrates. This response depends on specialized cells that recognize, internalize, and destroy ...microbial invaders through phagocytosis. This is coupled to autonomous or non-autonomous cellular signaling via reactive oxygen species (ROS) and cytokine production. Lipids are known signaling factors in this process, as the acute phase response of macrophages is accompanied by systemic lipid changes that help resolve inflammation. We found that peroxisomes, membrane-enclosed organelles central to lipid metabolism and ROS turnover, were necessary for the engulfment of bacteria by Drosophila and mouse macrophages. Peroxisomes were also required for resolution of bacterial infection through canonical innate immune signaling. Reduced peroxisome function impaired the turnover of the oxidative burst necessary to fight infection. This impaired response to bacterial challenge affected cell and organism survival and revealed a previously unknown requirement for peroxisomes in phagocytosis and innate immunity.
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•Peroxisomes are necessary for phagocytosis by Drosophila and mouse macrophages•Peroxisomes are required for resolution of microbial infection•Peroxisomes modulate innate immune pathways necessary to fight infection•Lack of functional peroxisomes affects organism survival in response to infection
Peroxisomes are organelles involved in lipid metabolism and reactive oxygen species turnover. Di Cara et al. now show that peroxisomes are required to resolve microbial infection by innate immunity. Peroxisomes assist in the progression of phagocytosis and activate innate immune signaling to promote survival in the face of microbial challenge.
Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with ...reduced EF (HFrEF), heart failure with mid-range-also called mildly reduced EF- (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF.
The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this ...study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).
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