The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Neural correlates of peer evaluation in irritable adolescents: Linking anticipation to receipt of social feedback.

Elevated irritability during adolescence predicts mental health issues in adulthood. Social interactions commonly elicit symptoms of irritability. Prior research has traditionally examined neural activity during the anticipation of, and immediate reaction to, social feedback separately in irritable adolescents. However, studies suggest that irritable adolescents demonstrate altered brain activation when anticipating feedback, and these alterations may have downstream effects on the neural activity when actually presented with feedback. Thus, the goal of this study was to characterize the influence of irritability on the relationship between brain function during anticipation and receipt of social feedback. We leveraged the Virtual School task to mimic social interactions using dynamic stimuli. Parallel region of interest (ROI) analyses tested effects of anticipatory bilateral amygdala (or dorsal anterior cingulate cortex; dACC) activation on the dACC (or bilateral amygdala) activation during receipt of peer feedback. Parallel exploratory whole-brain analyses were conducted to identify the effects of anticipatory bilateral amygdala or dACC activation on other regions during receipt of peer feedback. In ROI analyses, more vs. less irritable adolescents showed distinct relationships between anticipatory bilateral amygdala activation and dACC activation when receiving predictably mean feedback. Across both whole-brain analyses, anticipatory bilateral amygdala and dACC activation were separately associated with activation in socioemotional regions of the brain during subsequent feedback. These relationships were modulated by irritability, and the valence and predictability of the feedback. This suggests that irritable adolescents may engage in altered emotion processing and regulation strategies, depending on the valence and predictability of social feedback.

Gastrointestinal tuberculosis: a diagnosis not to miss.

Gastrointestinal tuberculosis is not rare but may present to the clinician in a variety of ways, leading to confusion with several other diseases. It is crucial to send tissue samples for culture.

Proteolytic processing of h1-like histones in chromatin: a physiologically and developmentally regulated event in Tetrahymena micronuclei.

Micronuclei isolated from growing cells of Tetrahymena thermophila contain three H1-like polypeptides alpha, beta, and gamma. Micronuclei isolated from young conjugating cells (3-7 h) also contain a larger molecular weight polypeptide, X, which is being actively synthesized and deposited into these nuclei (Allis, C. D., and J. C. Wiggins, 1984, Dev. Biol., 101:282-294). Pulse-chase experiments (with growing and conjugating cells) suggested that X is a precursor to alpha and that alpha is further processed to gamma and a previously undescribed and relatively minor species, delta. These precursor-product relationships were supported by cross-reactivity with polyclonal antibodies raised against alpha and peptide mapping. While beta consistently became labeled under chase conditions (both in growing and mating cells), it was not clear whether it is part of the vivo processing event(s) which interrelates X, alpha, gamma, and delta. Beta was not recognized by alpha antibodies. Despite this uncertainty, these results suggest that proteolytic processing serves to generate significant changes in the complement of H1-like histones present in this nucleus.

Chronic Spinal Cord Injury Reduces Gastrin-Releasing Peptide in the Spinal Ejaculation Generator in Male Rats.

Spinal cord injury (SCI) causes sexual dysfunction, including anejaculation in men. Likewise, chronic mid-thoracic contusion injury impairs ejaculatory reflexes in male rats. Ejaculation is controlled by a spinal ejaculation generator (SEG) comprised of a population of lumbar spinothalamic (LSt) neurons. LSt neurons co-express four neuropeptides, including gastrin-releasing peptide (GRP) and galanin and control ejaculation via release of these peptides in lumbar and sacral autonomic and motor nuclei. Here, we tested the hypothesis that contusion injury causes a disruption of the neuropeptides that are expressed in LSt cell bodies and axon terminals, thereby causing ejaculatory dysfunction. Male Sprague Dawley rats received contusion or sham surgery at spinal levels T6-7. Five to six weeks later, animals were perfused and spinal cords were immunoprocessed for galanin and GRP. Results showed that numbers of cells immunoreactive for galanin were not altered by SCI, suggesting that LSt cells are not ablated by SCI. In contrast, GRP immunoreactivity was decreased in LSt cells following SCI, evidenced by fewer GRP and galanin/GRP dual labeled cells. However, SCI did not affect efferent connections of LSt, cells as axon terminals containing galanin or GRP in contact with autonomic cells were not reduced following SCI. Finally, no changes in testosterone plasma levels or androgen receptor expression were noted after SCI. In conclusion, chronic contusion injury decreased immunoreactivity for GRP in LSt cell soma, but did not affect LSt neurons per se or LSt connections within the SEG. Since GRP is essential for triggering ejaculation, such loss may contribute to ejaculatory dysfunction following SCI.

Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate.

Glomerular epithelial protein 1 (GLEPP1) is a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte. The GLEPP1 gene (PTPRO:) was disrupted at an exon coding for the NH(2)-terminal region by gene targeting in embryonic stem cells. Heterozygote mating produced the expected genotypic ratio of 1:2:1, indicating that the Ptpro(-/-) genotype does not lead to embryonic or neonatal lethality. Kidney and glomerular structure was normal at the gross and light microscopic levels. Scanning and transmission electron microscopy showed that Ptpro(-/-) mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podocyte and that there were blunting and widening of the minor (foot) processes in association with altered distribution of the podocyte intermediate cytoskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular nephrin content and reduced glomerular filtration rate in Ptpro(-/-) mice. There was no detectable increase in the urine albumin excretion of Ptpro(-/-) mice. After removal of one or more kidneys, Ptpro(-/-) mice had higher blood pressure than did their wild-type littermates. These data support the conclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Effect on membrane potential and electrical activity of adding sodium to sodium-depleted cardiac purkinje fibers.

Canine cardiac Purkinje fibers exposed to Na-free solutions containing 128 mM TEA and 16 mM Ca show resting potentials in the range -50 to -90 mV; if the concentration of Na in the perfusate is raised from 0 to 4 to 24 mM, hyperpolarization follows. If the initial resting potential is low, the hyperpolarization tends to be greater; the average increase in the presence of 8 mM Na is 14 mV. Such hyperpolarization is not induced by adding Na to K-free solutions, is not seen in cooled fibers, or in fibers exposed to 10(-3) M ouabain, nor is it induced by adding Li and thus may result from electrogenic sodium extrusion. Fibers exposed to Na-free solutions are often spontaneously active; if they are quiescent they often show repetitive activity during depolarizing pulses. Such spontaneous or repetitive activity is suppressed by the addition of Na. This suppression may or may not be related to the hyperpolarization.

The St. Jude Medical cardiac valve in infants and children: role of anticoagulant therapy.

The experience at the University of Colorado with the St. Jude Medical cardiac valve was reviewed to determine the feasibility of placing this prosthesis in children and the role of anticoagulation. A St. Jude Medical cardiac valve was placed in 33 patients ranging in age from 2.5 months to 17 years. Seven patients were less than 1 year of age. Nineteen valves were placed in the aortic position in patients aged 5 months to 17 years (mean 9.5 years). Five patients had valve replacement only, 13 had concomitant aortoventriculoplasty and 1 a Manouguian procedure. Indications for anulus enlarging procedures were recurrent subaortic stenosis or inability to place an adult-sized valve in the native aortic anulus, or both. There were no early or late deaths. Fourteen valves were placed in the mitral position. They were anular positioned in 6 patients aged 6 months to 16 years and supraanular positioned in 8 patients aged 2.5 months to 2 years. There were no deaths with the anular positioned replacements and seven deaths (two early and five late) with the supraanular positioned replacements. Four of the five late deaths were associated with marked pre- and postoperative left ventricular dysfunction. The follow-up time was 784 patient-months in 31 long-term survivors. Anticoagulation was achieved with warfarin, usually in combination with sulfinpyrazone, dipyridamole or aspirin. There were four episodes of thromboembolism, three occurring in patients with suboptimal anticoagulation, and one in a patient lost to follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Histone positions within the nucleosome using platinum labeling and the scanning transmission electron microscope.

An approach to studying the organization of macromolecular complexes using heavy-atom labeling has been developed and applied to the problem of determining the positions of the histone proteins within the nucleosome. The approach is based on the capability of the scanning transmission electron microscope to image heavy atoms. Nucleosomes containing histones labeled with heavy atoms were prepared by lysine modification of selected histones with methyl (methylthio)acetimidate, followed by reconstitution of the modified histones into nucleosomes, and reaction of the reconstituted nucleosomes with chloroglycyl-1-methioninatoplatinum (II). Micrographs of the platinum-labeled nucleosomes were obtained using the scanning transmission electron microscope, and analyzed using both computer and manual techniques. The results of the analysis were 24 A resolution maps of the distribution of high electron scattering density picture elements (representative of platinum atoms) indicating the position of each histone. The significance of those results and the general applicability of the platinum-labeling techniques are discussed. Finally, a description of the histone positions within the nucleosomes is presented and discussed in relation to the current literature on nucleosome structure.

Distribution of mass within native thick filaments of vertebrate skeletal muscle.

The distribution of mass within the vertebrate skeletal thick filament has been determined by scanning transmission electron microscopy. Thick and thin filaments from fresh rabbit muscle were mixed with tobacco mosaic virus (TMV), fixed with formaldehyde, dried onto thin carbon films and viewed in a computer-linked microscope. Electron scattering data from both TMV and thick filaments were analysed with reference to the long axis of the particles so that the distribution of mass within the particles could be determined. While TMV appeared to be a uniform rod at the resolution employed (4.3 nm), the thick filament was clearly differentiated along its length. M-line remnants at the centre of the filament were flanked by regions of low mass per unit length, corresponding to the bare zone of the filament, and then by the more massive cross-bridge regions. The mass per unit length was approximately constant through most of the cross-bridge zone and declined at the filament tips, in a manner consistent with a constant number of myosin molecules per 14.3 nm interval (crown) throughout the cross-bridge zone. Fourier analysis of the data failed to detect the expected 43 nm periodicity of C-protein. The total mass of the thick filament was 184 Mdalton (s.e.m., 1.6 X 10(6); n = 70). The mass of adhering M-line proteins was highly variable but, on average, was about 4 Mdalton. The total mass of the filament and the mass distribution in the cross-bridge zone are consistent with three myosin molecules per crown.

Ductile thermoset polymers via controlling network flexibility.

We report the design and synthesis of a polymer structure from a cross-linkable epoxy-ionic liquid system which behaves like a hard and brittle epoxy thermoset, perfectly ductile thermoplastic and an elastomer, all depending on controllable network compositions.

L-Dopa inhibits prolactin secretion in proestrous rats.

Female rats received an ip injection of L-dopa on the afternoon of proestrus. L-Dopa reduced serum prolactin concentrations within 1 h, whether administered just prior to, or during, the normal surge in serum hormone level. This inhibition lasted for 2-3 h, after which serum prolactin concentrations rose substantially. Pretreatment of proestrous rats with MK-486, a peripheral inhibitor of aromatic-L-amino acid decarboxylase, did not block the effect of L-dopa on serum prolactin levels. In fact, MK-486 pretreatment appeared to prolong the effectiveness of L-dopa. Pretreatment with RO4-4602 at a dose sufficient to block central decarboxylase activity, however, did prevent dopa from inhibiting the proestrous surge in serum prolactin. These data are consistent with a role for dopamine in the control of prolactin secretion and suggest that the mechanism of action of L-dopa apparently does not require peripheral decarboxylation.

Photometric assays for FcRI-dependent binding, phagocytosis, and antibody-dependent cellular cytotoxicity mediated by monomeric IgG gamma 2a in murine peritoneal macrophages.

Mouse peritoneal macrophages possess distinct Fc receptors (FcR) for binding the various murine IgG isotypes. FcRI binds monomeric IgG gamma 2a, but not monomeric IgG gamma 2b or IgG gamma 1 with high affinity at 4 degrees C and is sensitive to trypsin degradation. We have assessed the functional consequences of the cytophilic binding at 4 degrees C of monomeric IgG gamma 2a to FcRI of mouse peritoneal macrophages using newly developed photometric microassays for quantification of binding, phagocytosis, and antibody dependent cellular cytotoxicity (ADCC) of post-opsonized sheep red blood cell (SRBC) targets. Dose-dependent binding specificity of monomeric IgG gamma 2a, but not IgG gamma 2b or IgG gamma 1 to FcRI of oil-elicited mouse peritoneal macrophages at 4 degrees C for 2 h was confirmed to display typical saturation kinetics both by the photometric assay and by a cellular enzyme-linked immunosorbent assay (CELISA). Binding of monomeric IgG gamma 2a to macrophage FcRI promoted highly efficient phagocytosis of opsonized SRBC in that most cells that were bound were also rapidly internalized by the phagocytic process during a 1 h incubation at 37 degrees C. Upregulation of FcRI-dependent binding and phagocytosis occurred during 24-48 h in vitro culture of macrophages as shown both by the photometric assays and CELISA. Trypsin treatment of macrophages abrogated FcRI-dependent binding and phagocytosis by monomeric IgG gamma 2a, but had little effect on FcRII-dependent functions. Cytophilic binding of monomeric IgG gamma 2a to FcRI failed to trigger ADCC activation. Thus functional characterization of macrophage FcRI-dependent effector functions confirmed the fidelity of binding specificity of monomeric IgG gamma 2a to a trypsin degradable receptor which mediates highly efficient phagocytosis but fails to initiate the signal for ADCC activation. It appears that passively bound immune monomeric IgG gamma 2a could provide an efficient mechanism by macrophages in vivo for FcRI-dependent immune clearance of soluble or particulate cellular antigens without elicitation of potentially harmful cytolytic factors associated with ADCC activation.

Cardiotonic agents. 1. Novel 8-aryl-substituted imidazo[1,2-a]- and -[1,5-a]pyridines and imidazo[1,5-a]pyridinones as potential positive inotropic agents.

Several 8-arylimidazo[1,2-a]pyridines, 8-arylimidazo[1,5-a]pyridines, and 8-arylimidazo[1,5-a]pyridinones were prepared and tested in vitro for potential cardiac inotropic and electrophysiological activity. Selected analogues were further tested in vivo in canine hemodynamic and cardiac electrophysiology models. Compounds having an imidazole substituent consistently showed activity. A pharmacophoric relationship between heterocycle-phenyl-imidazole and positive inotropic activity was noted. The significance of this relationship is discussed.

Cardiotonic agents. 7. Prodrug derivatives of 4-ethyl-1,3-dihydro- 5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H-imidazol-2-one.

The cardiotonic agent 4-ethyl-1,3-dihydro-5-4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one (1) was found to have low bioavailability when administered orally to rats and dogs. A series of N-acyl derivatives, an underutilized prodrug of acidic NH compounds, has been synthesized and tested for their ability to improve the oral bioavailability of 1. Reaction of the monosodium salt of 1 with various anhydrides afforded the N-1 monoacylimidazolones with surprisingly high regioselectivity. In addition to the prodrugs, acylation of 1 with propionic or phenylacetic anhydride led to the novel 3H-pyrrolo[1,2-c]imidazole-3,5(2H)-diones 6. The prodrugs showed a significant increase in the partition coefficients with a minor decrease in the aqueous solubility. The benzoyl derivative 4b exhibited the highest stability in both pH 1.5 and 7.4 buffer solutions. Further evaluation of 4b showed rapid conversion to 1 in canine plasma (t1/2 = 38 min), and human plasma (t1/2 = 10 min). Oral studies indicated that the bioavailability of 4b was increased to greater than 75% (compared to less than 20% for 1), and hemodynamic studies demonstrated that the selective inotropic profile of 1 was retained.