Surface-based morphometry of the corpus callosum in young children of ages 1-5.

The corpus callosum (CC) is a large white matter fiber bundle in the brain and is involved in various cognitive, sensory, and motor processes. While implicated in various developmental and psychiatric disorders, much is yet to be uncovered about the normal development of this structure, especially in young children. Additionally, while sexual dimorphism has been reported in prior literature, observations have not necessarily been consistent. In this study, we use morphometric measures including surface tensor-based morphometry (TBM) to investigate local changes in the shape of the CC in children between the ages of 12 and 60 months, in intervals of 12 months. We also analyze sex differences in each of these age groups. We observed larger significant clusters in the earlier ages between 12 v 24 m and between 48 v 60 m and localized differences in the anterior region of the body of the CC. Sex differences were most pronounced in the 12 m group. This study adds to the growing literature of work aiming to understand the developing brain and emphasizes the utility of surface TBM as a useful tool for analyzing regional differences in neuroanatomical morphometry.

Pain, but not Physical Activity, is Associated with Gray Matter Volume Differences in Gulf War Veterans with Chronic Pain.

Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWV (all p<0.05). GWV with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (p<0.05adjusted). Gray matter volumes in the left insula were associated with pain symptoms (rpartial=0.26, -0.29; p<0.05adjusted). No significant associations were observed for either PA or sedentary time (p>0.05adjusted). GWV with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing which may reflect pain chronification.Significance Statement:The pathophysiology of chronic pain in Gulf War Veterans is understudied and not well understood. In a large sample of Gulf War Veterans, we report Veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared to otherwise healthy Gulf War Veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.

How we get a grip: Microstructural neural correlates of manual grip strength in children.

Maximal grip strength is associated with a variety of health-related outcome measures and thus may be reflective of the efficiency of foundational brain-body communication. Non-human primate models of grip strength strongly implicate the cortical lateral grasping network, but little is known about the translatability of these models to human children. Further, it is unclear how supplementary networks that provide proprioceptive information and cerebellar-based motor command modification are associated with maximal grip strength. Therefore, this study employed high resolution, multi-shell diffusion and quantitative T1 imaging to examine how variations in lateral grasping, proprioception input, and cortico-cerebellar modification network white matter microstructure are associated with variations in grip strength across 70 children. Results indicated that stronger grip strength was associated with higher lateral grasping and proprioception input network fractional anisotropy and R1, indirect measures consistent with stronger microstructural coherence and increased myelination. No relationships were found in the cerebellar modification network. These results provide a neurobiological mechanism of grip behavior in children which suggests that increased myelination of cortical sensory and motor pathways is associated with stronger grip. This neurobiological mechanism may be a signature of pediatric neuro-motor behavior more broadly as evidenced by the previously demonstrated relationships between grip strength and behavioral outcome measures across a variety of clinical and non-clinical populations.

White matter microstructure predicts individual differences in infant fear (But not anger and sadness).

We examine neural correlates of discrete expressions of negative emotionality in infants to determine whether the microstructure of white matter tracts at 1 month of age foreshadows the expression of specific negative emotions later in infancy. Infants (n = 103) underwent neuroimaging at 1-month, and mothers reported on infant fear, sadness, and anger at 6, 12, and 18 months using the Infant Behavior Questionnaire-Revised. Levels and developmental change in fear, sadness, and anger were estimated from mother reports. Relations between MRI and infant emotion indicated that 1-month white matter microstructure was differentially associated with level and change in infant fear, but not anger or sadness, in the left stria terminalis (p < 0.05, corrected), a tract that connects frontal and tempo-parietal regions and has been implicated in emerging psychopathology in adults. More relaxed constraints on significance (p < 0.10, corrected) revealed that fear was associated with lower white matter microstructure bilaterally in the inferior portion of the stria terminalis and regions within the sagittal stratum. Results suggest the neurobehavioral uniqueness of fear as early as 1 month of age in regions that are associated with potential longer-term outcomes. This work highlights the early neural precursors of fearfulness, adding to literature explaining the psychobiological accounts of affective development. HIGHLIGHTS: Expressions of infant fear and anger, but not sadness, increase from 6 to 18 months of age. Early neural architecture in the stria terminalis is related to higher initial levels and increasing fear in infancy. After accounting for fear, anger and sadness do not appear to be associated with differences in early white matter microstructure. This work identifies early neural precursors of fearfulness as early as 1-month of age.

Neuroimaging and biomarker evidence of neurodegeneration in asthma.

BACKGROUND: Epidemiologic studies have shown that Alzheimer's disease (AD) and related dementias (ADRD) are seen more frequently with asthma, especially with greater asthma severity or exacerbation frequency. OBJECTIVE: To examine the changes in brain structure that may underlie this phenomenon, we examined diffusion-weighted magnetic resonance imaging (dMRI) and blood-based biomarkers of AD (phosphorylated tau 181, p-Tau181), neurodegeneration (neurofilament light chain, NfL), and glial activation (glial fibrillary acidic protein, GFAP). METHODS: dMRI data were obtained in 111 individuals with asthma, ranging in disease severity from mild to severe, and 135 healthy controls. Regression analyses were used to test the relationships between asthma severity and neuroimaging measures, as well as AD pathology, neurodegeneration, and glial activation, indexed by plasma p-Tau181, NfL, and GFAP, respectively. Additional relationships were tested with cognitive function. RESULTS: Asthma participants had widespread and large-magnitude differences in several dMRI metrics, which were indicative of neuroinflammation and neurodegeneration, and which were robustly associated with GFAP and, to a lesser extent, NfL. The AD biomarker p-Tau181 was only minimally associated with neuroimaging outcomes. Further, asthma severity was associated with deleterious changes in neuroimaging outcomes, which in turn were associated with slower processing speed, a test of cognitive performance. CONCLUSIONS: Asthma, particularly when severe, is associated with characteristics of neuroinflammation and neurodegeneration, and may be a potential risk factor for neural injury and cognitive dysfunction. There is a need to determine how asthma may affect brain health and whether treatment directed toward characteristics of asthma associated with these risks can mitigate these effects.

Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch.

Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining their viability.

Longitudinal assessment of early-life white matter development with quantitative relaxometry in nonhuman primates.

Alterations in white matter (WM) development are associated with many neuropsychiatric and neurodevelopmental disorders. Most MRI studies examining WM development employ diffusion tensor imaging (DTI), which relies on estimating diffusion patterns of water molecules as a reflection of WM microstructure. Quantitative relaxometry, an alternative method for characterizing WM microstructural changes, is based on molecular interactions associated with the magnetic relaxation of protons. In a longitudinal study of 34 infant non-human primates (NHP) (Macaca mulatta) across the first year of life, we implement a novel, high-resolution, T1-weighted MPnRAGE sequence to examine WM trajectories of the longitudinal relaxation rate (qR1) in relation to DTI metrics and gestational age at scan. To the best of our knowledge, this is the first study to assess developmental WM trajectories in NHPs using quantitative relaxometry and the first to directly compare DTI and relaxometry metrics during infancy. We demonstrate that qR1 exhibits robust logarithmic growth, unfolding in a posterior-anterior and medial-lateral fashion, similar to DTI metrics. On a within-subject level, DTI metrics and qR1 are highly correlated, but are largely unrelated on a between-subject level. Unlike DTI metrics, gestational age at birth (time in utero) is a strong predictor of early postnatal qR1 levels. Whereas individual differences in DTI metrics are maintained across the first year of life, this is not the case for qR1. These results point to the similarities and differences in using quantitative relaxometry and DTI in developmental studies, providing a basis for future studies to characterize the unique processes that these measures reflect at the cellular and molecular level.

Edited magnetic resonance spectroscopy in the neonatal brain.

J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.

Study Protocol: Multimodal Longitudinal Assessment of Infant Brain Organization and Recovery in Perinatal Brain Injury.

PURPOSE: Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in lifelong motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. METHODS: Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to noninvasively measure CST functional and structural integrity across multiple time points in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. DISCUSSION: This protocol will identify bioindicators of motor outcome and neuroplasticity and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds, and related diagnoses.

A 16-year study of longitudinal volumetric brain development in males with autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unknown brain etiology. Our knowledge to date about structural brain development across the lifespan in ASD comes mainly from cross-sectional studies, thereby limiting our understanding of true age effects within individuals with the disorder that can only be gained through longitudinal research. The present study describes FreeSurfer-derived volumetric findings from a longitudinal dataset consisting of 607 T1-weighted magnetic resonance imaging (MRI) scans collected from 105 male individuals with ASD (349 MRIs) and 125 typically developing male controls (258 MRIs). Participants were six to forty-five years of age at their first scan, and were scanned up to 5 times over a period of 16 years (average inter-scan interval of 3.7 years). Atypical age-related volumetric trajectories in ASD included enlarged gray matter volume in early childhood that approached levels of the control group by late childhood, an age-related increase in ventricle volume resulting in enlarged ventricles by early adulthood and reduced corpus callosum age-related volumetric increase resulting in smaller corpus callosum volume in adulthood. Larger corpus callosum volume was related to a lower (better) ADOS score at the most recent study visit for the participants with ASD. These longitudinal findings expand our knowledge of volumetric brain-based abnormalities in males with ASD, and highlight the need to continue to examine brain structure across the lifespan and well into adulthood.

Spatiotemporal dynamics of nonhuman primate white matter development during the first year of life.

White matter (WM) development early in life is a critical component of brain development that facilitates the coordinated function of neuronal pathways. Additionally, alterations in WM have been implicated in various neurodevelopmental disorders, including psychiatric disorders. Because of the need to understand WM development in the weeks immediately following birth, we characterized changes in WM microstructure throughout the postnatal macaque brain during the first year of life. This is a period in primates during which genetic, developmental, and environmental factors may have long-lasting impacts on WM microstructure. Studies in nonhuman primates (NHPs) are particularly valuable as a model for understanding human brain development because of their evolutionary relatedness to humans. Here, 34 rhesus monkeys (23 females, 11 males) were imaged longitudinally at 3, 7, 13, 25, and 53 weeks of age with T1-weighted (MPnRAGE) and diffusion tensor imaging (DTI). With linear mixed-effects (LME) modeling, we demonstrated robust logarithmic growth in FA, MD, and RD trajectories extracted from 18 WM tracts across the brain. Estimated rate of change curves for FA, MD, and RD exhibited an initial 10-week period of exceedingly rapid WM development, followed by a precipitous decline in growth rates. K-means clustering of raw DTI trajectories and rank ordering of LME model parameters revealed distinct posterior-to-anterior and medial-to-lateral gradients in WM maturation. Finally, we found that individual differences in WM microstructure assessed at 3 weeks of age were significantly related to those at 1 year of age. This study provides a quantitative characterization of very early WM growth in NHPs and lays the foundation for future work focused on the impact of alterations in early WM developmental trajectories in relation to human psychopathology.

Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles.

Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of Zeb1 accelerated tumor growth. Mechanistically, ZEB1 expression in TAMs induced their polarization toward an F4/80low pro-tumor phenotype, including direct activation of Ccr2 In turn, expression of ZEB1 by TAMs induced Ccl2, Cd74, and a mesenchymal/stem-like phenotype in cancer cells. In human ovarian carcinomas, TAM infiltration and CCR2 expression correlated with ZEB1 in tumor cells, where along with CCL2 and CD74 determined poorer prognosis. Importantly, ZEB1 in TAMs was a factor of poorer survival in human ovarian carcinomas. These data establish ZEB1 as a key factor in the tumor microenvironment and for maintaining TAMs' tumor-promoting functions.

Yap1 is required for maintenance of adult RPE differentiation.

Nuclear YAP1 plays a critical role in regulation of stem cell proliferation, tissue regeneration, and organ size in many types of epithelia. Due to rapid turnover of most epithelial cell types, the cytoplasmic function of YAP1 in epithelial cells has not been well studied. The retinal pigment epithelium (RPE) is a highly polarized epithelial cell type maintained at a senescence state, and offers an ideal cell model to study the active role of YAP1 in maintenance of the adult epithelial phenotype. Here, we show that the cytoplasmic function of YAP1 is essential to maintain adult RPE differentiation. Knockout of Yap1 in the adult mouse RPE caused cell depolarization and tight junction breakdown, and led to inhibition of RPE65 expression, diminishment of RPE pigments, and retraction of microvilli and basal infoldings. These changes in RPE further prompted the loss of adjacent photoreceptor outer segments and photoreceptor death, which eventually led to decline of visual function in older mice between 6 and 12 months of age. Furthermore, nuclear ß-catenin and its activity were significantly increased in mutant RPE. These results suggest that YAP1 plays an important role in active inhibition of Wnt/ß-catenin signaling, and is essential for downregulation of ß-catenin nuclear activity and prevention of dedifferentiation of adult RPE.

Cortical Microstructural Alterations in Mild Cognitive Impairment and Alzheimer's Disease Dementia.

In Alzheimer's disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI-but not cortical thickness-was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.

Longitudinal white matter and cognitive development in pediatric carriers of the apolipoprotein ε4 allele.

We have previously demonstrated cross-sectional differences in magnetic resonance imaging (MRI) measurements of white matter myelin and gray matter in infants with or without the apolipoprotein ε4 allele, a major genetic risk factor for late-onset Alzheimer's disease (AD). In this study, we sought to compare longitudinal MRI white matter myelin and cognitive-behavioral changes in infants and young children with and without this allele. Serial MRI and cognitive tests were obtained on 223 infants and young children, including 74 ε4 carriers and 149 non-carriers, 2-68 months of age, matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated brain mapping algorithms and non-linear mixed models were used to characterize and compare trajectories of white matter myelin and cognitive-behavioral test scores. The APOE ε4 carriers had statistically significant differences in white matter myelin development, in the uncinate fasciculus, temporal lobe, internal capsule and occipital lobe. Additionally, ε4 carriers had a slightly greater rate of development in early learning composite a surrogate measure of IQ representative of expressive language, receptive language, fine motor, and visual skills, but displayed slightly lower non verbal development quotient scores a composite measure of fine motor and visual skills across the entire age range. This study supports the possibility that ε4 carriers have slightly altered rates of white matter and cognitive development in childhood. It continues to raise questions about the role of APOE in human brain development and the relevance of these developmental differences to the predisposition to AD.

ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells.

OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1ß). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1ß production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.

A simple sleep EEG marker in childhood predicts brain myelin 3.5 years later.

Epidemiological research reveals that insufficient sleep in children has negative cognitive and emotional consequences; however, the physiological underpinnings of these observations remain understudied. We tested the hypothesis that the topographical distribution of deep sleep slow wave activity during the childhood predicts brain white matter microstructure (myelin) 3.5 y later. Healthy children underwent sleep high-density EEG at baseline (n = 13; ages 2.4-8.0 y) and follow-up (n = 14; ages 5.5-12.2 y). At follow-up, myelin (myelin water fraction) and cortical morphology were also quantified. Our investigation revealed 3 main findings. (1) The Frontal/Occipital (F/O)-ratio at baseline strongly predicted whole brain myelin at follow-up. (2) At follow-up, the F/O-ratio was only minimally (negatively) linked to brain myelin. (3) Cortical morphology was not related to the F/O-ratio, neither at baseline nor at follow-up. Our results support the hypothesis that during child development EEG markers during sleep longitudinally predict brain myelin content. Data extend previous findings reporting a link between EEG markers of sleep need and cortical morphology, by supporting the hypothesis that sleep is a necessary component to underlying processes of brain, and specifically myelin, maturation. In line with the overarching theory that sleep contributes to neurodevelopmental processes, it remains to be investigated whether chronic sleep loss negatively affects white matter myelin microstructure growth during sensitive periods of development.

Early nutrition influences developmental myelination and cognition in infants and young children.

Throughout early neurodevelopment, myelination helps provide the foundation for brain connectivity and supports the emergence of cognitive and behavioral functioning. Early life nutrition is an important and modifiable factor that can shape myelination and, consequently, cognitive outcomes. Differences in the nutritional composition between human breast and formula milk may help explain the functional and cognitive disparity often observed between exclusively breast versus formula-fed children. However, past cognitive and brain imaging studies comparing breast and formula feeding are often: cross-sectional; performed in older children and adolescents relying on parental recall of infant feeding; and generally treat formula-fed children as a single group despite the variability between formula compositions. Here we address some of these weakness by examining longitudinal trajectories of brain and neurocognitive development in children who were exclusively breastfed versus formula-fed for at least 3 months. We further examine development between children who received different formula compositions. Results reveal significantly improved overall myelination in breastfed children accompanied by increased general, verbal, and non-verbal cognitive abilities compared to children who were exclusively formula-fed. These differences were found to persist into childhood even with groups matched for important socioeconomic and demographic factors. We also find significant developmental differences depending on formula composition received and that, in particular, long-chain fatty acids, iron, choline, sphingomyelin and folic acid are significantly associated with early myelination trajectories. These results add to the consensus that prolonged and exclusive breastfeeding plays an important role in early neurodevelopment and childhood cognitive outcomes.

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008.

Sphere-Induced Rejuvenation of Swine and Human Müller Glia Is Primarily Caused by Telomere Elongation.

Müller cells are the major supportive and protective glial cells in the retina with important functions in histogenesis and synaptogenesis during development, and in maintenance of mature neurons as they show to secrete various cytokines and manifest potentials of self-renewal and transdifferentiation into retinal neurons following injury in the vertebrate retinas. The swine retina has a visual streak structure similar to the human macular where cone photoreceptors are highly concentrated, thereby can serve as a better model for studying retinal diseases and for formulating cell-based therapeutics than the rodent retinas. Like most differentiated somatic mammalian cells, the isolated swine and human Müller glia become senescent over passages in culture, which restricts their potential application in basic and clinic researches. Here, we demonstrate that the senescence of swine and human Müller cells is caused by telomere attrition upon multiplications in vitro; and the senescent cells can be rejuvenated by sphere suspension culture. We also provide evidence that sphere-induced extension of telomeres in swine and human Müller glia is achieved by alternative lengthening of telomeres or/and by telomerase activation. Stem Cells 2017;35:1579-1591.