Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Acquiring a pet dog significantly reduces stress of primary carers for children with autism spectrum disorder: a prospective case control study

This study describes the impact of pet dogs on stress of primary carers of children with Autism Spectrum Disorder (ASD). Stress levels of 38 primary carers acquiring a dog and 24 controls not acquiring a dog were sampled at: Pre-intervention (17 weeks before acquiring a dog), post-intervention (3–10 weeks after acquisition) and follow-up (25–40 weeks after acquisition), using the Parenting Stress Index. Analysis revealed significant improvements in the intervention compared to the control group for Total Stress, Parental Distress and Difficult Child. A significant number of parents in the intervention group moved from clinically high to normal levels of Parental Distress. The results highlight the potential of pet dogs to reduce stress in primary carers of children with an ASD

The clinical and functional significance of c-Met in breast cancer: a review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.CMH-Y is funded by a Cancer Research UK Clinical Research Fellowship. JLJ is funded by the Breast Cancer Campaign Tissue Bank

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology

Use of machine learning to shorten observation-based screening and diagnosis of autism

The Autism Diagnostic Observation Schedule-Generic (ADOS) is one of the most widely used instruments for behavioral evaluation of autism spectrum disorders. It is composed of four modules, each tailored for a specific group of individuals based on their language and developmental level. On average, a module takes between 30 and 60 min to deliver. We used a series of machine-learning algorithms to study the complete set of scores from Module 1 of the ADOS available at the Autism Genetic Resource Exchange (AGRE) for 612 individuals with a classification of autism and 15 non-spectrum individuals from both AGRE and the Boston Autism Consortium (AC). Our analysis indicated that 8 of the 29 items contained in Module 1 of the ADOS were sufficient to classify autism with 100% accuracy. We further validated the accuracy of this eight-item classifier against complete sets of scores from two independent sources, a collection of 110 individuals with autism from AC and a collection of 336 individuals with autism from the Simons Foundation. In both cases, our classifier performed with nearly 100% sensitivity, correctly classifying all but two of the individuals from these two resources with a diagnosis of autism, and with 94% specificity on a collection of observed and simulated non-spectrum controls. The classifier contained several elements found in the ADOS algorithm, demonstrating high test validity, and also resulted in a quantitative score that measures classification confidence and extremeness of the phenotype. With incidence rates rising, the ability to classify autism effectively and quickly requires careful design of assessment and diagnostic tools. Given the brevity, accuracy and quantitative nature of the classifier, results from this study may prove valuable in the development of mobile tools for preliminary evaluation and clinical prioritization—in particular those focused on assessment of short home videos of children—that speed the pace of initial evaluation and broaden the reach to a significantly larger percentage of the population at risk

Surface Feature-Guided Mapping of Cerebral Metabolic Changes in Cognitively Normal and Mildly Impaired Elderly

Purpose: The aim of this study was to investigate the longitudinal positron emission tomography (PET) metabolic changes in the elderly. Procedures: Nineteen nondemented subjects (mean Mini-Mental Status Examination 29.4±0.7 SD) underwent two detailed neuropsychological evaluations and resting 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET scan (interval 21.7±3.7 months), baseline structural 3T magnetic resonance (MR) imaging, and apolipoprotein E4 genotyping. Cortical PET metabolic changes were analyzed in 3-D using the cortical pattern matching technique. Results: Baseline vs. follow-up whole-group comparison revealed significant metabolic decline bilaterally in the posterior temporal, parietal, and occipital lobes and the left lateral frontal cortex. The declining group demonstrated 10–15 % decline in bilateral posterior cingulate/precuneus, posterior temporal, parietal, and occipital cortices. The cognitively stable group showed 2.5–5% similarly distributed decline. ApoE4-positive individuals underwent 5–15 % metabolic decline in the posterior association cortices. Conclusions: Using 3-D surface-based MR-guided FDG-PET mapping, significant metaboli

Anatomical Global Spatial Normalization

Anatomical global spatial normalization (aGSN) is presented as a method to scale high-resolution brain images to control for variability in brain size without altering the mean size of other brain structures. Two types of mean preserving scaling methods were investigated, “shape preserving” and “shape standardizing”. aGSN was tested by examining 56 brain structures from an adult brain atlas of 40 individuals (LPBA40) before and after normalization, with detailed analyses of cerebral hemispheres, all gyri collectively, cerebellum, brainstem, and left and right caudate, putamen, and hippocampus. Mean sizes of brain structures as measured by volume, distance, and area were preserved and variance reduced for both types of scale factors. An interesting finding was that scale factors derived from each of the ten brain structures were also mean preserving. However, variance was best reduced using whole brain hemispheres as the reference structure, and this reduction was related to its high average correlation with other brain structures. The fractional reduction in variance of structure volumes was directly related to ρ2, the square of the reference-to-structure correlation coefficient. The average reduction in variance in volumes by aGSN with whole brain hemispheres as the reference structure was approximately 32%. An analytical method was provided to directly convert between conventional and aGSN scale factors to support adaptation of aGSN to popular spatial normalization software packages

Ezrin Ubiquitylation by the E3 Ubiquitin Ligase, WWP1, and Consequent Regulation of Hepatocyte Growth Factor Receptor Activity

The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF) stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY477 present in ezrin’s C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY477 motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression

Infant Brain Atlases from Neonates to 1- and 2-Year-Olds

Background: Studies for infants are usually hindered by the insufficient image contrast, especially for neonates. Prior knowledge, in the form of atlas, can provide additional guidance for the data processing such as spatial normalization, label propagation, and tissue segmentation. Although it is highly desired, there is currently no such infant atlas which caters for all these applications. The reason may be largely due to the dramatic early brain development, image processing difficulties, and the need of a large sample size. Methodology: To this end, after several years of subject recruitment and data acquisition, we have collected a unique longitudinal dataset, involving 95 normal infants (56 males and 39 females) with MRI scanned at 3 ages, i.e., neonate, 1-yearold, and 2-year-old. State-of-the-art MR image segmentation and registration techniques were employed, to construct which include the templates (grayscale average images), tissue probability maps (TPMs), and brain parcellation maps (i.e., meaningful anatomical regions of interest) for each age group. In addition, the longitudinal correspondences between agespecific atlases were also obtained. Experiments of typical infant applications validated that the proposed atlas outperformed other atlases and is hence very useful for infant-related studies. Conclusions: We expect that the proposed infant 0–1–2 brain atlases would be significantly conducive to structural and functional studies of the infant brains. These atlases are publicly available in our website