Correction: A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues.

Correction for 'A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues' by Christopher Adamson et al., Chem. Commun., 2024, 60, 2212-2215, https://doi.org/10.1039/D3CC05807G.

A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues.

To further understand the specificity of muramyl dipeptide (MDP) sensing by NOD2, we evaluated the compatibility of synthetic MDP analogues for cellular uptake and NAGK phosphorylation, the pre-requisite steps of intracellular NOD2 activation. Our results revealed that these two prior steps do not confer ligand stereoselectivity; yet NAGK strictly discriminates against the disaccharide NOD2 agonists for phosphorylation in vitro, despite it being indispensable for the cellular NOD2-stimulating effects of these analogues, implying potential glycosidase cleavage as a novel intermediate step for cellular activation of NOD2.

Chemoenzymatic Probes Reveal Peptidoglycan Recognition and Uptake Mechanisms in Candida albicans.

Candida albicans, the major fungal pathogen in humans, is under the strong influence of bacterial peptidoglycan fragments to undergo the yeast-to-hyphae transition, a key virulent step in C. albicans pathogenesis and infections. However, due to the synthetic difficulties of obtaining peptidoglycan fragments for biological studies, mechanistic details of how C. albicans recognizes and uptakes these peptidoglycan fragments have not been well elucidated. Notably, previous works have solely focused on the synthetic peptidoglycan ligand, muramyl dipeptide (MDP), despite its poor hyphal-inducing activity in C. albicans. In this work, we isolated and purified natural peptidoglycan fragments via enzymatic degradation of bacteria cell wall sacculi and chemoenzymatically installed a series of functional d-amino acids into the natural muropeptide, creating peptidoglycan probes that bear photoaffinity, bio-orthogonal, or fluorescent functionality. Using these chemoenzymatic peptidoglycan probes, we established that natural peptidoglycan fragments, which are potent hyphal-inducers, interact with the C. albicans Cyr1 sensor protein in the in-gel fluorescence assay as well as in in vitro pulldown studies. Moreover, we established that bacterial peptidoglycan probes enter C. albicans cells via an energy-dependent endocytic process.

Association of Prenatal Exposure to Early-Life Adversity With Neonatal Brain Volumes at Birth.

Importance: Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood. Objective: To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding. Design, Setting, and Participants: This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were recruited from local obstetric clinics in St Louis, Missouri from September 1, 2017, to February 28, 2020. Exposures: Maternal social disadvantage and psychosocial stress in pregnancy. Main Outcomes and Measures: Confirmatory factor analyses were used to create latent constructs of maternal social disadvantage (income-to-needs ratio, Area Deprivation Index, Healthy Eating Index, educational level, and insurance status) and psychosocial stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, and Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellum, hippocampus, and amygdala volumes were generated using semiautomated, age-specific, segmentation pipelines. Results: A total of 280 mothers (mean [SD] age, 29.1 [5.3] years; 170 [60.7%] Black or African American, 100 [35.7%] White, and 10 [3.6%] other race or ethnicity) and their healthy, term-born infants (149 [53.2%] male; mean [SD] infant gestational age, 38.6 [1.0] weeks) were included in the analysis. After covariate adjustment and multiple comparisons correction, greater social disadvantage was associated with reduced cortical gray matter (unstandardized ß = -2.0; 95% CI, -3.5 to -0.5; P = .01), subcortical gray matter (unstandardized ß = -0.4; 95% CI, -0.7 to -0.2; P = .003), and white matter (unstandardized ß = -5.5; 95% CI, -7.8 to -3.3; P < .001) volumes and cortical folding (unstandardized ß = -0.03; 95% CI, -0.04 to -0.01; P < .001). Psychosocial stress showed no association with brain metrics. Although social disadvantage accounted for an additional 2.3% of the variance of the left hippocampus (unstandardized ß = -0.03; 95% CI, -0.05 to -0.01), 2.3% of the right hippocampus (unstandardized ß = -0.03; 95% CI, -0.05 to -0.01), 3.1% of the left amygdala (unstandardized ß = -0.02; 95% CI, -0.03 to -0.01), and 2.9% of the right amygdala (unstandardized ß = -0.02; 95% CI, -0.03 to -0.01), no regional effects were found after accounting for total brain volume. Conclusions and Relevance: In this baseline assessment of an ongoing cohort study, prenatal social disadvantage was associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that associations between poverty and brain development begin in utero and are evident early in life. These findings emphasize that preventive interventions that support fetal brain development should address parental socioeconomic hardships.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T 1-w/T 2-w Ratio.

BACKGROUND AND OBJECTIVES: To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T 1- and T 2-weighted MRI (T 1-w/T 2-w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years. METHODS: Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T 1-w/T 2-w images were parcellated into 48 white matter regions of interest. RESULTS: Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T 1-w/T 2-w data from at least one timepoint. T 1-w/T 2-w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T 1-w/T 2-w values in childhood and adolescence. Increased T 1-w/T 2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T 1-w/T 2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1-w/T 2-w values at 7 years were associated with poorer mathematics performance. DISCUSSION: VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T 1-w/T 2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1-w/T 2-w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance.

The Structural Connectome and Internalizing and Externalizing Symptoms at 7 and 13 Years in Individuals Born Very Preterm and Full Term.

BACKGROUND: Children born very preterm (VP) are at higher risk of emotional and behavioral problems compared with full-term (FT) children. We investigated the neurobiological basis of internalizing and externalizing symptoms in individuals born VP and FT by applying a graph theory approach. METHODS: Structural and diffusion magnetic resonance imaging data were combined to generate structural connectomes and calculate measures of network integration and segregation at 7 (VP: 72; FT: 17) and 13 (VP: 125; FT: 44) years. Internalizing and externalizing symptoms were assessed at 7 and 13 years using the Strengths and Difficulties Questionnaire. Linear regression models were used to relate network measures and internalizing and externalizing symptoms concurrently at 7 and 13 years. RESULTS: Lower network integration (characteristic path length and global efficiency) was associated with higher internalizing symptoms in VP and FT children at 7 years, but not at 13 years. The association between network integration (characteristic path length) and externalizing symptoms at 7 years was weaker, but there was some evidence for differential associations between groups, with lower integration in the VP group and higher integration in the FT group associated with higher externalizing symptoms. At 13 years, there was some evidence that associations between network segregation (average clustering coefficient, transitivity, local efficiency) and externalizing symptoms differed between the VP and FT groups, with stronger positive associations in the VP group. CONCLUSIONS: This study provides insights into the neurobiological basis of emotional and behavioral problems after preterm birth, highlighting the role of the structural connectome in internalizing and externalizing symptoms in childhood and adolescence.

Live-Cell Protein Modification by Boronate-Assisted Hydroxamic Acid Catalysis.

Selective methods for introducing protein post-translational modifications (PTMs) within living cells have proven valuable for interrogating their biological function. In contrast to enzymatic methods, abiotic catalysis should offer access to diverse and new-to-nature PTMs. Herein, we report the boronate-assisted hydroxamic acid (BAHA) catalyst system, which comprises a protein ligand, a hydroxamic acid Lewis base, and a diol moiety. In concert with a boronic acid-bearing acyl donor, our catalyst leverages a local molarity effect to promote acyl transfer to a target lysine residue. Our catalyst system employs micromolar reagent concentrations and affords minimal off-target protein reactivity. Critically, BAHA is resistant to glutathione, a metabolite which has hampered many efforts toward abiotic chemistry within living cells. To showcase this methodology, we installed a variety of acyl groups in E. coli dihydrofolate reductase expressed within human cells. Our results further establish the well-known boronic acid-diol complexation as a bona fide bio-orthogonal reaction with applications in chemical biology and in-cell catalysis.

Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke.

Background and Purpose: Recent studies using automated perfusion imaging software have identified adults most likely to benefit from reperfusion therapies in extended time windows. The time course of penumbral tissue is poorly characterized in childhood arterial ischemic stroke (AIS). We explore the feasibility of using automated perfusion-diffusion imaging software to characterize penumbra in childhood AIS. Methods: An observational cohort study of children with acute unilateral AIS presenting to our institution. Diffusion-weighted imaging and dynamic susceptibility contrast perfusion magnetic resonance imaging performed within 72 hours of symptom onset were necessary for inclusion. Perfusion-diffusion mismatch was estimated using RAPID software. Ischemic core was defined as apparent diffusion coefficient <620×10−6 mm2/s and hypoperfusion as Tmax >6 seconds. Favorable mismatch profile was defined as core volume <70 mL, mismatch volume ≥15 mL, and a mismatch ratio ≥1.8. Results: Twenty-nine children (median 8 years old, interquartile range, 4.4­14.6) were included (26 unilateral middle cerebral artery and 3 unilateral cerebellar infarcts). Median Pediatric National Institutes of Health Stroke Scale was 4 (interquartile range, 3­11). Most cases had cryptogenic (n=11) or focal cerebral arteriopathy (n=9) causes. Median time-to-imaging =13.7 hours (interquartile range, 7.5­25.3). RAPID detected an ischemic core in 19 (66%) patients. In the remaining cases, the mean apparent diffusion coefficient values were mostly higher than the threshold as the majority of these presentations were delayed (median >21 hours) and infarct volumes were small (<3.5 mL). Overall, 3 children, imaged at 3.75, 11, and 23.5 hours had favorable mismatch profiles. Conclusions: This study demonstrates it is feasible to rapidly assess perfusion-diffusion mismatch in childhood AIS using automated software. Favorable mismatch profiles, using adult-based parameters, persisted beyond the standard 4.5 hours window for thrombolysis, suggesting potential therapeutic benefit of RAPID use. Further work is required to determine the utility of perfusion-based imaging to guide clinical decision making, whether adult thresholds require modification in childhood AIS, and to investigate the effect of time-delay and cause on mismatch characteristics.

Diversity-oriented synthesis of glycomimetics.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.

Integrating abiotic chemical catalysis and enzymatic catalysis in living cells.

Life emerges from networks of multiple chemical reactions mediated by enzymes. If abiotic chemical catalysis is implanted into the reaction network of life, such an integration would produce organisms generating unique secondary metabolites and value-added materials from feedstocks or even air, or new diagnostics and therapeutics against diseases. In this review, we introduce selected papers in this emerging field of catalysis research.

Cortisol is not associated with pre-treatment medial temporal lobe volume or volume changes after electroconvulsive therapy in patients with late-life depression.

Accumulating evidence suggests that late-life depression is associated with reduced hippocampal volume and that cortisol might be related to this volumetric reduction. We explored whether cortisol awaking response (CAR), which is the increase in cortisol after awakening, was associated with volumetric changes in the medial temporal lobe (MTL) after electroconvulsive therapy (ECT) in 41 patients (age ≥ 55) treated for major depressive disorder (MDD) with ECT. Cortisol was measured before the start of the ECT treatment and was related to MTL volumes derived from structural T1-weighted images. The study assessed associations between CAR and pre-treatment MTL volumes, and CAR and ECT-induced MTL volumetric changes. There were no significant correlations found between CAR, operationalized as Area Under the Curve with respect to ground (AUCg) and Area Under the Curve with respect to increase (AUCi), and pre-treatment MTL volumes. Neither was there an association between AUCg or AUCi and the ECT-induced changes in MTL volumes after correction for multiple comparisons. Finally, neither AUCg or AUCi were able to predict ECT-induced volumetric changes in the MTL. Hence, we conclude that CAR is unrelated to pre-treatment hippocampus and amygdala volumes, and to the volumetric changes in the aforementioned areas following ECT.

Marker-based watershed transform method for fully automatic mandibular segmentation from CBCT images.

OBJECTIVES:: To propose a reliable and practical method for automatically segmenting the mandible from CBCT images. METHODS:: The marker-based watershed transform is a region-growing approach that dilates or "floods" predefined markers onto a height map whose ridges denote object boundaries. We applied this method to segment the mandible from the rest of the CBCT image. The height map was generated to enhance the sharp decreases of intensity at the mandible/tissue border and suppress noise by computing the intensity gradient image of the CBCT itself. Two sets of markers, "mandible" and "background" were automatically placed inside and outside the mandible, respectively in a novel image using image registration. The watershed transform flooded the gradient image by dilating the markers simultaneously until colliding at watershed lines, estimating the mandible boundary. CBCT images of 20 adolescent subjects were chosen as test cases. Segmentation accuracy of the proposed method was evaluated by measuring overlap (Dice similarity coefficient) and boundary agreement against a well-accepted interactive segmentation method described in the literature. RESULTS:: The Dice similarity coefficient was 0.97 ± 0.01 (mean ± SD), indicating almost complete overlap between the automatically and the interactively segmented mandibles. Boundary deviations were predominantly under 1 mm for most of the mandibular surfaces. The errors were mostly from bones around partially erupted wisdom teeth, the condyles and the dental enamels, which had minimal impact on the overall morphology of the mandible. CONCLUSIONS:: The marker-based watershed transform method produces segmentation accuracy comparable to the well-accepted interactive segmentation approach.

Corpus callosum macro and microstructure in late-life depression.

BACKGROUND: Differences in corpus callosum (CC) morphology and microstructure have been implicated in late-life depression and may distinguish between late and early-onset forms of the illness. However, a multimodal approach using complementary imaging techniques is required to disentangle microstructural alterations from macrostructural partial volume effects. METHODS: 107 older adults were assessed: 55 currently-depressed patients without dementia and 52 controls without cognitive impairment. We investigated group differences and clinical associations in 7 sub-regions of the mid-sagittal corpus callosum using T1 anatomical data, white matter hyperintensity (WMH) quantification and two different diffusion MRI (dMRI) models (multi-tissue constrained spherical deconvolution, yielding apparent fibre density, AFD; and diffusion tensor imaging, yielding fractional anisotropy, FA and radial diffusivity, RD). RESULTS: Callosal AFD was lower in patients compared to controls. There were no group differences in CC thickness, surface area, FA, RD, nor whole brain or WMH volume. Late-onset of depression was associated with lower FA, higher RD and lower AFD. There were no associations between any imaging measures and psychotic features or depression severity as assessed by the geriatric depression scale. WMH volume was associated with lower FA and AFD, and higher RD in patients. LIMITATIONS: Patients were predominantly treatment-resistant. Measurements were limited to the mid-sagittal CC. dMRI analysis was performed on a smaller cohort, n=77. AFD was derived from low b-value data. CONCLUSIONS: Callosal structure is largely preserved in LLD. WMH burden may impact on CC microstructure in late-onset depression suggesting vascular pathology has additional deleterious effects in these patients.

Brain connectivity networks and longitudinal trajectories of depression symptoms in adolescence.

High levels of depression during adolescence may contribute to the risk for future depression later in life. This study examined the relationship between the developmental timing of depressive symptoms, and brain structural outcomes in late adolescence. In a prior work, we examined longitudinal trajectories of depressive symptoms in 243 adolescents (121 males and 122 females), and identified four subgroups: a normative group with stable low levels of depression, two groups with declining symptoms, and one group with increasing symptoms. For the current paper, diffusion-weighted MRI images were acquired at the final wave of the study, and used to perform white matter tractography and brain network analysis. The four depression trajectory groups were tested for differences in brain connectivity variables. This revealed differences in several frontal and temporal regions. The groups that had experienced elevated depression symptoms in early adolescence differed from the normative group in a greater number of areas than the group who had experienced depression later. Affected tracts corresponded to areas of white matter that are still maturing during this period, particularly frontolimbic regions. These findings support the proposition that the timing and duration of depression symptoms during adolescence are associated with brain structural outcomes.

Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars.

Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in 2 H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2 H3 half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.

Axon density and axon orientation dispersion in children born preterm.

BACKGROUND: Very preterm birth (VPT, <32 weeks' gestation) is associated with altered white matter fractional anisotropy (FA), the biological basis of which is uncertain but may relate to changes in axon density and/or dispersion, which can be measured using Neurite Orientation Dispersion and Density Imaging (NODDI). This study aimed to compare whole brain white matter FA, axon dispersion, and axon density between VPT children and controls (born ≥37 weeks' gestation), and to investigate associations with perinatal factors and neurodevelopmental outcomes. METHODS: FA, neurite dispersion, and neurite density were estimated from multishell diffusion magnetic resonance images for 145 VPT and 33 control 7-year-olds. Diffusion values were compared between groups and correlated with perinatal factors (gestational age, birthweight, and neonatal brain abnormalities) and neurodevelopmental outcomes (IQ, motor, academic, and behavioral outcomes) using Tract-Based Spatial Statistics. RESULTS: Compared with controls, VPT children had lower FA and higher axon dispersion within many major white matter fiber tracts. Neonatal brain abnormalities predicted lower FA and higher axon dispersion in many major tracts in VPT children. Lower FA, higher axon dispersion, and lower axon density in various tracts correlated with poorer neurodevelopmental outcomes in VPT children. CONCLUSIONS: FA and NODDI measures distinguished VPT children from controls and were associated with neonatal brain abnormalities and neurodevelopmental outcomes. This study provides a more detailed and biologically meaningful interpretation of white matter microstructure changes associated with prematurity. Hum Brain Mapp 37:3080-3102, 2016. © 2016 Wiley Periodicals, Inc.

Structural connectivity relates to perinatal factors and functional impairment at 7years in children born very preterm.

OBJECTIVE: To use structural connectivity to (1) compare brain networks between typically and atypically developing (very preterm) children, (2) explore associations between potential perinatal developmental disturbances and brain networks, and (3) describe associations between brain networks and functional impairments in very preterm children. METHODS: 26 full-term and 107 very preterm 7-year-old children (born <30weeks' gestational age and/or <1250g) underwent T1- and diffusion-weighted imaging. Global white matter fibre networks were produced using 80 cortical and subcortical nodes, and edges were created using constrained spherical deconvolution-based tractography. Global graph theory metrics were analysed, and regional networks were identified using network-based statistics. Cognitive and motor function were assessed at 7years of age. RESULTS: Compared with full-term children, very preterm children had reduced density, lower global efficiency and higher local efficiency. Those with lower gestational age at birth, infection or higher neonatal brain abnormality score had reduced connectivity. Reduced connectivity within a widespread network was predictive of impaired IQ, while reduced connectivity within the right parietal and temporal lobes was associated with motor impairment in very preterm children. CONCLUSIONS: This study utilised an innovative structural connectivity pipeline to reveal that children born very preterm have less connected and less complex brain networks compared with typically developing term-born children. Adverse perinatal factors led to disturbances in white matter connectivity, which in turn are associated with impaired functional outcomes, highlighting novel structure-function relationships.

A New MRI-Based Pediatric Subcortical Segmentation Technique (PSST).

Volumetric and morphometric neuroimaging studies of the basal ganglia and thalamus in pediatric populations have utilized existing automated segmentation tools including FIRST (Functional Magnetic Resonance Imaging of the Brain's Integrated Registration and Segmentation Tool) and FreeSurfer. These segmentation packages, however, are mostly based on adult training data. Given that there are marked differences between the pediatric and adult brain, it is likely an age-specific segmentation technique will produce more accurate segmentation results. In this study, we describe a new automated segmentation technique for analysis of 7-year-old basal ganglia and thalamus, called Pediatric Subcortical Segmentation Technique (PSST). PSST consists of a probabilistic 7-year-old subcortical gray matter atlas (accumbens, caudate, pallidum, putamen and thalamus) combined with a customized segmentation pipeline using existing tools: ANTs (Advanced Normalization Tools) and SPM (Statistical Parametric Mapping). The segmentation accuracy of PSST in 7-year-old data was compared against FIRST and FreeSurfer, relative to manual segmentation as the ground truth, utilizing spatial overlap (Dice's coefficient), volume correlation (intraclass correlation coefficient, ICC) and limits of agreement (Bland-Altman plots). PSST achieved spatial overlap scores ≥90% and ICC scores ≥0.77 when compared with manual segmentation, for all structures except the accumbens. Compared with FIRST and FreeSurfer, PSST showed higher spatial overlap (p FDR < 0.05) and ICC scores, with less volumetric bias according to Bland-Altman plots. PSST is a customized segmentation pipeline with an age-specific atlas that accurately segments typical and atypical basal ganglia and thalami at age 7 years, and has the potential to be applied to other pediatric datasets.

Longitudinal growth and morphology of the hippocampus through childhood: Impact of prematurity and implications for memory and learning.

The effects of prematurity on hippocampal development through early childhood are largely unknown. The aims of this study were to (1) compare the shape of the very preterm (VPT) hippocampus to that of full-term (FT) children at 7 years of age, and determine if hippocampal shape is associated with memory and learning impairment in VPT children, (2) compare change in shape and volume of the hippocampi from term-equivalent to 7 years of age between VPT and FT children, and determine if development of the hippocampi over time predicts memory and learning impairment in VPT children. T1 and T2 magnetic resonance images were acquired at both term equivalent and 7 years of age in 125 VPT and 25 FT children. Hippocampi were manually segmented and shape was characterized by boundary point distribution models at both time-points. Memory and learning outcomes were measured at 7 years of age. The VPT group demonstrated less hippocampal infolding than the FT group at 7 years. Hippocampal growth between infancy and 7 years was less in the VPT compared with the FT group, but the change in shape was similar between groups. There was little evidence that the measures of hippocampal development were related to memory and learning impairments in the VPT group. This study suggests that the developmental trajectory of the human hippocampus is altered in VPT children, but this does not predict memory and learning impairment. Further research is required to elucidate the mechanisms for memory and learning difficulties in VPT children.

Brain extraction using the watershed transform from markers.

Isolation of the brain from other tissue types in magnetic resonance (MR) images is an important step in many types of neuro-imaging research using both humans and animal subjects. The importance of brain extraction is well appreciated-numerous approaches have been published and the benefits of good extraction methods to subsequent processing are well known. We describe a tool-the marker based watershed scalper (MBWSS)-for isolating the brain in T1-weighted MR images built using filtering and segmentation components from the Insight Toolkit (ITK) framework. The key elements of MBWSS-the watershed transform from markers and aggressive filtering with large kernels-are techniques that have rarely been used in neuroimaging segmentation applications. MBWSS is able to reliably isolate the brain without expensive preprocessing steps, such as registration to an atlas, and is therefore useful as the first stage of processing pipelines. It is an informative example of the level of accuracy achievable without using priors in the form of atlases, shape models or libraries of examples. We validate the MBWSS using a publicly available dataset, a paediatric cohort, an adolescent cohort, intra-surgical scans and demonstrate flexibility of the approach by modifying the method to extract macaque brains.