Children with autism have a significantly lower quality of life compared with their neurotypical peers. While multiple studies have quantified the impact of autism on health-related quality of life ...(HRQoL) through standardized surveys such as the PedsQL, none have specifically investigated the impact of
syndromic
autism. Here we evaluate HRQoL in children diagnosed with three genetic disorders that strongly predispose to syndromic autism: Phelan-McDermid syndrome (PMD), Rett syndrome (RTT), and
SYNGAP1
-related intellectual disability (
SYNGAP1
-ID). We find the most severely impacted dimension is physical functioning. Strikingly, syndromic autism results in worse quality of life than other chronic disorders including idiopathic autism. This study demonstrates the utility of caregiver surveys in prioritizing phenotypes, which may be targeted as clinical endpoints for genetically defined ASDs.
Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain ...function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
► We review the current status of TeV gamma-ray astronomy. ► A description of the current instruments is given. ► The current source catalog is discussed. ► We summarize plans for the future, ...including upgrades and new instrumentation.
The field of TeV gamma-ray astronomy has produced many exciting results over the last decade. Both the source catalogue, and the range of astrophysical questions which can be addressed, continue to expand. This article presents a topical review of the field, with a focus on the observational results of the imaging atmospheric Cherenkov telescope arrays. The results encompass pulsars and their nebulae, supernova remnants, gamma-ray binary systems, star forming regions and starburst and active galaxies.
Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting ...mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.
Summary
Objective
The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss‐of‐function mutations in SHANK3 have intellectual ...disability, autism, and variably, epilepsy.2‐5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations.
Methods
A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss‐of‐function mutation in SHANK3 identified through whole‐exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist.
Results
There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure.
Significance
All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.
In this issue of Neuron, Lennox et al. (2020) report the largest cohort of patients to date with DDX3X syndrome, discovering unique genotype-phenotype relationships that inform molecular ...pathogenesis. They then uncover unique roles of DDX3X in cortical neuron development and ribonucleoprotein granule formation.
In this issue of Neuron, Lennox et al. (2020) report the largest cohort of patients to date with DDX3X syndrome, discovering unique genotype-phenotype relationships that inform molecular pathogenesis. They then uncover unique roles of DDX3X in cortical neuron development and ribonucleoprotein granule formation.
A more effective treatment of bacteremia requires a diagnostic platform that is both sensitive, accurate and rapid. Currently, clinical laboratory techniques require growth of bacteria prior to ...diagnosis, take days to complete, and leave empiric therapy and broad spectrum antibiotics as the only option at the onset of treatment. In order to bypass this growth requirement, we engineered a system that purifies bacteria from blood to improve performance in a bacteriophage-based luminescence assay. To perform the purification, we used acoustophoresis in plastic microfluidic chips, enabling future development into a low cost point-of-care system. Acoustophoresis achieves differential separation on the basis of size differences between bacteria and blood cells. We show isolation of three known pathogen species, including members of both Gram-negative and positive-bacteria from blood, and show isolation at clinically relevant concentrations. Using the device as a preparation step prior to the bacteriophage-based luminescence assay, we demonstrate a 33-fold improvement in limit of detection, compared with the unpurified sample, achieving a limit of detection of 6 bacteria.
The ability to control the mechanical properties of cell culture environments is known to influence cell morphology, motility, invasion and differentiation. The present work shows that it is possible ...to control the mechanical properties of collagen gels by manipulating gelation conditions near the sol gel transition. This manipulation is accomplished by performing gelation in two stages at different temperatures. The mechanical properties of the gel are found to be strongly dependent on the duration and temperature of the first stage. In the second stage the system is quickly depleted of free collagen which self assembles into a highly branched network characteristic of gelation at the higher temperature (37 °C). An important aspect of the present work is the use of advanced rheometric techniques to assess the transition point between viscoelastic liquid and viscoelastic solid behaviour which occurs upon establishment of a sample spanning network at the gel point. The gel time at the stage I temperature is found to indicate the minimum time that the gelling collagen sample must spend under stage I conditions before the two stage gelation procedure generates an enhancement of mechanical properties. Further, the Fractional Maxwell Model is found to provide an excellent description of the time-dependent mechanical properties of the mature collagen gels.
It is shown herein that it is possible to control the mechanical and microstructural properties of collagen gels by manipulating temperature in the vicinity of the sol-gel transition; the Fractional Maxwell Model is also shown to accurately describe the rheological behaviour of such gels.
Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas ...duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage. To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability. Interestingly, we discovered that several kinases in the MEK/ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Mechanistically, we show that ERK2 binds Shank3 and phosphorylates it at three residues to promote its poly-ubiquitination-dependent degradation. Altogether, our findings uncover a druggable pathway as a potential therapeutic target for disorders with reduced SHANK3 dosage, provide a rich resource for studying Shank3 regulation, and demonstrate the feasibility of this approach for identifying regulators of dosage-sensitive genes.
Abstract Dental tissue infection and disease result in acute and chronic activation of the innate immune response, which is mediated by molecular and cellular signaling. Different cell types within ...the dentin-pulp complex are able to detect invading bacteria at all stages of the infection. Indeed, at relatively early disease stages, odontoblasts will respond to bacterial components, and as the disease progresses, core pulpal cells including fibroblasts, stems cells, endothelial cells, and immune cells will become involved. Pattern recognition receptors, such as Toll-like receptors expressed on these cell types, are responsible for detecting bacterial components, and their ligand binding leads to the activation of the nuclear factor-kappa B and p38 mitogen-activated protein (MAP) kinase intracellular signaling cascades. Subsequent nuclear translocation of the transcription factor subunits from these pathways will lead to proinflammatory mediator expression, including increases in cytokines and chemokines, which trigger host cellular defense mechanisms. The complex molecular signaling will result in the recruitment of immune system cells targeted at combating the invading microbes; however, the trafficking and antibacterial activity of these cells can lead to collateral tissue damage. Recent evidence suggests that if inflammation is resolved relatively low levels of proinflammatory mediators may promote tissue repair, whereas if chronic inflammation ensues repair mechanisms become inhibited. Thus, the effects of mediators are temporal context dependent. Although containment and removal of the infection are keys to enable dental tissue repair, it is feasible that the development of anti-inflammatory and immunomodulatory approaches, based on molecular, epigenetic, and photobiomodulatory technologies, may also be beneficial for future endodontic treatments.
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