White matter development and language abilities during infancy in autism spectrum disorder.

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

Infant Visual Brain Development and Inherited Genetic Liability in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Semaphorin3F Drives Dendritic Spine Pruning Through Rho-GTPase Signaling.

Dendritic spines of cortical pyramidal neurons are initially overproduced then remodeled substantially in the adolescent brain to achieve appropriate excitatory balance in mature circuits. Here we investigated the molecular mechanism of developmental spine pruning by Semaphorin 3F (Sema3F) and its holoreceptor complex, which consists of immunoglobulin-class adhesion molecule NrCAM, Neuropilin-2 (Npn2), and PlexinA3 (PlexA3) signaling subunits. Structure-function studies of the NrCAM-Npn2 interface showed that NrCAM stabilizes binding between Npn2 and PlexA3 necessary for Sema3F-induced spine pruning. Using a mouse neuronal culture system, we identified a dual signaling pathway for Sema3F-induced pruning, which involves activation of Tiam1-Rac1-PAK1-3 -LIMK1/2-Cofilin1 and RhoA-ROCK1/2-Myosin II in dendritic spines. Inhibitors of actin remodeling impaired spine collapse in the cortical neurons. Elucidation of these pathways expands our understanding of critical events that sculpt neuronal networks and may provide insight into how interruptions to these pathways could lead to spine dysgenesis in diseases such as autism, bipolar disorder, and schizophrenia.

Sampling Properties of color Independent Component Analysis.

Independent Component Analysis (ICA) offers an effective data-driven approach for blind source extraction encountered in many signal and image processing problems. Although many ICA methods have been developed, they have received relatively little attention in the statistics literature, especially in terms of rigorous theoretical investigation for statistical inference. The current paper aims at narrowing this gap and investigates the statistical sampling properties of the colorICA (cICA) method. The cICA incorporates the correlation structure within sources through parametric time series models in the frequency domain and outperforms several existing ICA alternatives numerically. We establish the consistency and asymptotic normality of the cICA estimates, which then enables statistical inference based on the estimates. These asymptotic properties are further validated using simulation studies.

Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex.

Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.

Close Homolog of L1 Regulates Dendritic Spine Density in the Mouse Cerebral Cortex Through Semaphorin 3B.

Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. In vivo CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation.SIGNIFICANCE STATEMENT Dendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.

Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and ß-arrestin 2 in inflammatory macrophages.

Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and ß-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and ß-arrestin 2-deficient mice. These GRK6- and ß-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and ß-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.

Cortical Thinning and Cognitive Impairment in Parkinson's Disease without Dementia.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction (bradykinesia, rigidity, tremor, and postural instability), and pathologically by the loss of dopaminergic neurons in the substantia nigra of the basal ganglia. Growing literature supports that cognitive deficits may also be present in PD, even in non-demented patients. Gray matter (GM) atrophy has been reported in PD and may be related to cognitive decline. This study investigated cortical thickness in non-demented PD subjects and elucidated its relationship to cognitive impairment using high-resolution T1-weighted brain MRI and comprehensive cognitive function scores from 71 non-demented PD and 48 control subjects matched for age, gender, and education. Cortical thickness was compared between groups using a flexible hierarchical multivariate Bayesian model, which accounts for correlations between brain regions. Correlation analyses were performed among brain areas and cognitive domains as well, which showed significant group differences in the PD population. Compared to Controls, PD subjects demonstrated significant age-adjusted cortical thinning predominantly in inferior and superior parietal areas and extended to superior frontal, superior temporal, and precuneus areas (posterior probability >0.9). Cortical thinning was also found in the left precentral and lateral occipital, and right postcentral, middle frontal, and fusiform regions (posterior probability >0.9). PD patients showed significantly reduced cognitive performance in executive function, including set shifting (p = 0.005) and spontaneous flexibility (p = 0.02), which were associated with the above cortical thinning regions (p < 0.05).

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis.

Tissue-specific immune responses play an important role in the pathology of autoimmune diseases. In systemic lupus erythematosus, deposits of IgG-immune complexes and the activation of complement in the kidney have long been thought to promote inflammation and lupus nephritis. However, the events that localize cells in non-lymphoid tertiary organs and sustain tissue-specific immune responses remain undefined. In this manuscript, we show that BAFF promotes events leading to lupus nephritis. Using an inducible model of systemic lupus erythematosus, we found that passive transfer of antinucleosome IgG into AID-/-MRL/lpr mice elevated autoantibody levels and promoted lupus nephritis by inducing BAFF production in the kidneys, and the formation of renal tertiary lymphoid structures (TLSs). Reducing BAFF in vivo prevented the formation of TLSs and lupus nephritis; however, it did not reduce immune cell infiltrates, or the deposits of IgG and complement in the kidney. Mechanistically, lowering BAFF levels also diminished the number of T cells positioned inside the glomeruli and reduced inflammation. Thus, BAFF plays a previously unappreciated role in lupus nephritis by inducing renal TLSs and regulating the position of T cells within the glomeruli.

School Entry Requirements and Coverage of Nontargeted Adolescent Vaccines.

BACKGROUND: Low human papillomavirus (HPV) vaccination coverage is an urgent public health problem requiring action. To identify policy remedies to suboptimal HPV vaccination, we assessed the relationship between states' school entry requirements and adolescent vaccination. METHODS: We gathered data on states' school entry requirements for adolescent vaccination (tetanus, diphtheria, and pertussis [Tdap] booster; meningococcal; and HPV) from 2007 to 2012 from Immunization Action Coalition. The National Immunization Survey-Teen provided medical record-verified vaccination data for 99 921 adolescents. We calculated coverage (among 13- to 17-year-olds) for individual vaccinations and concomitant vaccination. HPV vaccination outcomes were among female adolescents. Analyses used weighted longitudinal multivariable models. RESULTS: States with requirements for Tdap booster and meningococcal vaccination had 22 and 24 percentage point increases in coverage for these vaccines, respectively, compared with other states (both P < .05). States with HPV vaccination requirements had <1 percentage point increase in coverage for this vaccine (P < .05). Tdap booster and meningococcal vaccination requirements, respectively, were associated with 8 and 4 percentage point spillover increases for HPV vaccination coverage (both P < .05) and with increases for concomitant vaccination (all P < .05). CONCLUSIONS: Ensuring all states have meningococcal vaccination requirements could improve the nation's HPV vaccination coverage, given that many states already require Tdap booster but not meningococcal vaccination for school entry. Vaccination programs and clinicians should capitalize on changes in adolescent vaccination, including concomitant vaccination, that may arise after states adopt vaccination requirements. Additional studies are needed on the effects of HPV vaccination requirements and opt-out provisions.

Evaluating Substance Use and Insulin Misuse in Adolescents With Type 1 Diabetes.

PURPOSE: Substance use behaviors often emerge during adolescence, and adolescents with type 1 diabetes (T1D) may be at risk for engaging in traditional substance use (eg, alcohol, tobacco, and illicit substances) as well as a unique form of substance use: insulin misuse. The purpose of this exploratory study was to examine substance use and insulin misuse in adolescents with T1D. METHODS: Sixty adolescents aged 12 to 20 years with T1D (n = 60) completed surveys on substance use, insulin misuse, and diabetes self-management during a routine diabetes appointment. Demographic measures were summarized by mean (SD) or percentage. Prevalence of substance use and insulin misuse was calculated and stratified by demographic and clinical characteristics. Two-sample t test (continuous variables) and chi-square analysis (categorical variables) determined statistically significant differences. RESULTS: The prevalence of ever using substances was 36.7%, and that for ever misusing insulin was 19%. Older participants (17.1 ± 1.8 vs 15.6 ± 1.9 years; P < .01) and those with depression (31.8% vs 7.9%; P = .02) were more likely to use substances. Disordered eating behaviors were the most frequently reported reason for insulin misuse. Self-harm intent was reported by one-third of insulin misusers. Substance use and insulin misuse were not related to glycemic control or diabetes self-management behaviors. CONCLUSIONS: The diabetes care team should be aware that substance use and insulin misuse are common in adolescents with T1D. Screening for these risky behaviors is critical in those who are older or have mental health disorders. Effective education, prevention, and treatment strategies targeted at these behaviors are needed to improve the overall health of this population.

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus.

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.

G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis.

Triple negative breast cancer (TNBC) is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine receptor interactions are important modulators of breast cancer metastasis; however, it is now recognized that quantitative surface expression of one important chemokine receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3) is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis.

Robust analysis of semiparametric renewal process models.

A rate model is proposed for a modulated renewal process comprising a single long sequence, where the covariate process may not capture the dependencies in the sequence as in standard intensity models. We consider partial likelihood-based inferences under a semiparametric multiplicative rate model, which has been widely studied in the context of independent and identical data. Under an intensity model, gap times in a single long sequence may be used naively in the partial likelihood with variance estimation utilizing the observed information matrix. Under a rate model, the gap times cannot be treated as independent and studying the partial likelihood is much more challenging. We employ a mixing condition in the application of limit theory for stationary sequences to obtain consistency and asymptotic normality. The estimator's variance is quite complicated owing to the unknown gap times dependence structure. We adapt block bootstrapping and cluster variance estimators to the partial likelihood. Simulation studies and an analysis of a semiparametric extension of a popular model for neural spike train data demonstrate the practical utility of the rate approach in comparison with the intensity approach.

Independent Component Analysis Involving Autocorrelated Sources With an Application to Functional Magnetic Resonance Imaging.

Independent component analysis (ICA) is an effective data-driven method for blind source separation. It has been successfully applied to separate source signals of interest from their mixtures. Most existing ICA procedures are carried out by relying solely on the estimation of the marginal density functions, either parametrically or nonparametrically. In many applications, correlation structures within each source also play an important role besides the marginal distributions. One important example is functional magnetic resonance imaging (fMRI) analysis where the brain-function-related signals are temporally correlated. In this article, we consider a novel approach to ICA that fully exploits the correlation structures within the source signals. Specifically, we propose to estimate the spectral density functions of the source signals instead of their marginal density functions. This is made possible by virtue of the intrinsic relationship between the (unobserved) sources and the (observed) mixed signals. Our methodology is described and implemented using spectral density functions from frequently used time series models such as autoregressive moving average (ARMA) processes. The time series parameters and the mixing matrix are estimated via maximizing the Whittle likelihood function. We illustrate the performance of the proposed method through extensive simulation studies and a real fMRI application. The numerical results indicate that our approach outperforms several popular methods including the most widely used fastICA algorithm. This article has supplementary material online.

The prevalence of neck pain in migraine.

OBJECTIVE: To determine the prevalence of neck pain at the time of migraine treatment relative to the prevalence of nausea, a defining associated symptom of migraine. METHODS: This is a prospective, observational cross-sectional study of 113 migraineurs, ranging in attack frequency from episodic to chronic migraine. Subjects were examined by headache medicine specialists to confirm the diagnosis of migraine and exclude both cervicogenic headache and fibromyalgia. Details of all migraines were recorded over the course of at least 1 month and until 6 qualifying migraines had been treated. For each attack, subjects recorded the presence or absence of nausea as well as the intensity of headache and neck pain (graded as none, mild, moderate, or severe). RESULTS: Subjects recorded 2411 headache days, 786 of which were migraines. The majority of migraines were treated in the moderate pain stage. Regardless of the intensity of headache pain at time of treatment, neck pain was a more frequent accompaniment of migraine than was nausea (P< .0001). Prevalence of neck pain correlated with chronicity of headache as attacks moved from episodic to chronic daily headache. CONCLUSIONS: In this representative cross-section of migraineurs, neck pain was more commonly associated with migraine than was nausea, a defining characteristic of the disorder. Awareness of neck pain as a common associated feature of migraine may improve diagnostic accuracy and have a beneficial impact on time to treatment.

Application of functional ANOVA models for hazard regression to the Hisayama data.

A methodology for modeling covariate effects on the time-to-event data is developed. The covariates are allowed to be time dependent and their effects are modeled using polynomial splines in order to account for possibly non-linear effects. The methodology is applied to examine the effects on the incidence brain infarction based on a cohort study in Hisayama, Japan. The results indicate that at least two non-linear effects are significant (body mass index and systolic blood pressure) and there is a time-varying drug effect. The resulting significant risk factors are assessed by the proposed method that is more flexible and hence less biased than the traditional procedures where linear effects are imposed. These results are extremely important to the local medical investigation. In particular, more insight has been gained by examining the non-linear effects.

The origin of DNA replication and Fieller's problem.

The paper considers the statistical problem of estimating the origin of DNA replication within the human ribosomal DNA (rDNA) locus and the issue of assessing the standard error of the estimate. Based on mapping the cumulative replication index (CRI), two different modelling schemes are suggested and investigated. The statistical problem of constructing a confidence interval for the origin of DNA replication is related to Fieller's problem of obtaining a confidence interval for the ratio of two normal means. Standard normal theory, the delta and bootstrap methods are used to estimate the standard error of the estimate of the origin of DNA replication, as well as the variation of the replication rate.