Professional Manual for the Parent Reaction to Autism Diagnosis Scales (PRADS-2) with Guidance for Tailoring Parent Supports

The Parent Reaction to Autism Diagnosis Scales (PRADS-2) is a 60-item survey, which provides 15 scale scores to measure a parent’s specific areas of strengths and difficulties in raising their child with autism. The measure allows researchers to obtain objective data on parent responses, and it allows service providers to tailor specific supports for parents. This peer-reviewed professional manual describes our research, statistical development, and validation of the scales, and then describes the steps for applications in service work, specifying how our measure may be used accurately, ethically, and compassionately, for the benefit of parents and families. The manual includes the informed consent form, the survey, scoring sheet, profile graph form, guide for tailoring services, a tailored worksheet, steps for follow-up interviewing, and a complete illustration for an example parent.https://digitalcommons.humboldt.edu/textbooks/1011/thumbnail.jp

The complete and fully assembled genome sequence of Aeromonas salmonicida subsp. pectinolytica and its comparative analysis with other Aeromonas species: investigation of the mobilome in environmental and pathogenic strains.

Due to the predominant usage of short-read sequencing to date, most bacterial genome sequences reported in the last years remain at the draft level. This precludes certain types of analyses, such as the in-depth analysis of genome plasticity. Here we report the finalized genome sequence of the environmental strain Aeromonas salmonicida subsp. pectinolytica 34mel, for which only a draft genome with 253 contigs is currently available. Successful completion of the transposon-rich genome critically depended on the PacBio long read sequencing technology. Using finalized genome sequences of A. salmonicida subsp. pectinolytica and other Aeromonads, we report the detailed analysis of the transposon composition of these bacterial species. Mobilome evolution is exemplified by a complex transposon, which has shifted from pathogenicity-related to environmental-related gene content in A. salmonicida subsp. pectinolytica 34mel. Obtaining the complete, circular genome of A. salmonicida subsp. pectinolytica allowed us to perform an in-depth analysis of its mobilome. We demonstrate the mobilome-dependent evolution of this strain's genetic profile from pathogenic to environmental

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC(50) of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 A revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy

A therapeutic non-self-reactive SARS-CoV-2 antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC(50) value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy

National identity predicts public health support during a global pandemic

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = −0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.publishedVersio

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function