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"Allen, Amy"
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Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations
Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.
The main cell types involved in autism spectrum disorders through elevated protein synthesis are not well identified. Here, the authors show that overexpression of translation initiation factor eIF4E in microglia results in autism-like behaviour in male, but not female, mice.
Journal Article
Justification and emancipation : the critical theory of Rainer Forst
\"A collection of essays on the work of German political theorist Rainer Forst, covering subjects such as justice, toleration, and the critique of power from within a normative theory of justice and law\"-- Provided by publisher.
Book
Justification and Emancipation
This work is both an introduction to and a critical appraisal of
the work of Rainer Forst, one of the most important political
theorists in Germany today. Structured for classroom use, this
collection of original essays engages with Forst's extant corpus in
ways that are both appreciative and critical.
Forst is an original, prolific, and widely known member of the
\"fourth generation\" of Frankfurt School theorists. His significant
contributions include a Rawlsian-Habermasian conception of justice
that takes seriously the dissent of citizens and moral agents; an
original interpretation and analysis of the concept of toleration;
and, most recently, a generative idea of \"noumenal power,\" to which
every human being has a claim by virtue of their equal standing
within the moral community of all rational beings. Opening with an
essay by Forst on the normative conception of progress and closing
with a reply to his critics, this volume is both a primer on and a
window into the latest contributions to the tradition of critical
theory.
In addition to the editors, the contributors include John
Christman, Mattias Iser, Catherine Lu, John P. McCormick, Sarah
Clark Miller, and Melissa Yates.
eBook
Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma
Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.
Journal Article
General paediatrics outpatient consultation fees, bulk billing rates and service use patterns in Australia
To determine: 1) the mean, median and range of fees for initial and subsequent private outpatient consultations with a general paediatrician in Australia; 2) any variation in fees and bulk billing rates between states/territories; and 3) volume of outpatient general paediatric specialist consultations relative to child population.
Analysis of Medicare claims data from the years 2011 and 2014 for initial consultations (items 110 and 132), subsequent consultations (items 116 and 133), and autism or pervasive developmental disorder (PDD) initial consultation (item 135) with a general paediatrician.
Fees for initial and subsequent general paediatric outpatient consultations varied within, and between, states and territories. Fees increased slightly from 2011 to 2014, after accounting for inflation. The volume of consultations relative to child population varied markedly across states and territories, as did bulk billing rates. Use of item codes for patients with multiple morbidities (132 and 133) increased significantly from 2011 to 2014. Autism/PDD consultation service use (item 135) and fees remained relatively stable.
There was variation in service use, fees and bulk billing within, and between, states and territories, and across time and consultation types.
Future studies should assess the impact of such variation on access to paediatric services and the relationship, if any, to variation in state investment in public paediatric outpatient services.
Journal Article
Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling
Specific and effective treatments for autism spectrum disorder (ASD) are lacking due to a poor understanding of disease mechanisms. Here we test the idea that similarities between diverse ASD mouse models are caused by deficits in common molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome (
Fmr1
knockout), cortical dysplasia focal epilepsy syndrome (
Cntnap2
knockout),
PTEN
hamartoma tumor syndrome (
Pten
haploinsufficiency), ANKS1B syndrome (
Anks1b
haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the
ANKS1B
model displays altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the pathogenesis of this disorder.
Journal Article
Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice
Pten germline haploinsufficient (Pten+/−) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical–subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/− mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal “hard-wired” connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/− mice and their wild-type littermates from weaning under either standard (4–5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9–10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/− mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/− mice and partially rescued increased repetitive behavior in Pten+/− males. We found that Pten+/− mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/− mice, possibly through normalizing the excitatory synaptic protein abundance.
Journal Article
Advance care planning imperative: High-quality patient-centred goals of care
Advance care planning (ACP) discussions aim to ensure goal-concordant care for patients with serious illness, throughout treatment and especially at the end of life. But recent literature has forced the field of palliative care to wrestle with the definition and impact of ACP. Are ACP discussions worthwhile? Is there a difference between ACP discussions early in a patient’s illness versus discussions occurring later when a concrete medical care decision must be made? Here, we identify elements needed to answer these questions and describe how a multisite initiative will elucidate the value of discussing and documenting what matters most to patients.
Journal Article
Differential Effects of Dopamine Receptor D1-Type and D2-Type Antagonists and Phase of the Estrous Cycle on Social Learning of Food Preferences, Feeding, and Social Interactions in Mice
The neurobiological bases of social learning, by which an animal can ‘exploit the expertise of others’ and avoid the disadvantages of individual learning, are only partially understood. We examined the involvement of the dopaminergic system in social learning by administering a dopamine D1-type receptor antagonist, SCH23390 (0.01, 0.05, and 0.1 mg/kg), or a D2-type receptor antagonist, raclopride (0.1, 0.3, and 0.6 mg/kg), to adult female mice prior to socially learning a food preference. We found that while SCH23390 dose-dependently inhibited social learning without affecting feeding behavior or the ability of mice to discriminate between differently flavored diets, raclopride had the opposite effects, inhibiting feeding but leaving social learning unaffected. We showed that food odor, alone or in a social context, was insufficient to induce a food preference, proving the specifically social nature of this paradigm. The estrous cycle also affected social learning, with mice in proestrus expressing the socially acquired food preference longer than estrous and diestrous mice. This suggests gonadal hormone involvement, which is consistent with known estrogenic regulation of female social behavior and estrogen receptor involvement in social learning. Furthermore, a detailed ethological analysis of the social interactions during which social learning occurs showed raclopride- and estrous phase-induced changes in agonistic behavior, which were not directly related to effects on social learning. Overall, these results suggest a differential involvement of the D1-type and D2-type receptors in the regulation of social learning, feeding, and agonistic behaviors that are likely mediated by different underlying states.
Journal Article