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Summary of genomic variants.

Summary of single nucleotide variants.

Summary of somatic and de novo germline events.

Supplemental Figures S1-S7, Supplemental Tables S1-S7. Methods and Figures S1-S8; Tables S1-S7. SF1: Heterozygous TP53 deletion in the germline and tumor of patient 1 and expression timelines of DSE. SF2: Mutational signatures in pGBM samples. SF3: Deletions at immune-modulatory loci and their effect on gene expression. SF4: Dynamics of germlines SVs during tumor evolution. SF5: Copy number assays using TaqMan probes confirm the deletion at the ATRX locus. SF6: Genetic heterogeneity at the ATRX locus. SF7: Distribution of allelic frequencies and clonal sizes in pGBM samples. ST1: Calgary pediatric GBM cohort. ST2: Therapeutic approach taken for each pediatric GBM patient in the Calgary cohort. ST3: Toronto pediatric GBM cohort used for WGS with linked reads and bulk RNA-seq. ST4: Features of each sample analyzed by whole-genome sequencing with linked reads. ST5: Genes mutated in diagnostic pGBM samples in more than one patient. ST6: Genes mutated in follow-up resections in more than one patient. ST7: Results of the fits of the first incomplete moment and the negative binomial like distribution to the samples.

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.Significance:This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11’s role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina’s Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

South Africa's evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs.Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent.This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871).20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

A significant number of students reside in high stress, high risk, and under-resourced communities in the USA. Social and cultural factors are often reported to contribute to low educational outcomes in distressed communities. However, students attending under-resourced schools demonstrate a great deal of positive traits that are conducive to high academic achievement. For those students from challenging backgrounds, a constellation of traits contributes to academic success. Grouped together, they come under the term resilience. How is resilience impacted by values education? What specific components of Sathya Sai Education in Human Values (SSEHV) are most effective in helping students become better students? What role does a conceptual theory play in replicating the effects of SSEHV? After providing evidence for a sound theoretical framework, we seek to answer these questions using an illustrative form of a knowledge case study.

Resilience and the application of the Sathya Sai Education in Human Values Program (SSEHV) to the phenomenological variant of ecological systems theory (PVEST) were discussed at length in Chap. 5. In this chapter, we examine the concept of mindfulness as a type of silent sitting and provide practical tools and resources for creatively integrating mindfulness into Grades K–12 and college classrooms. The purpose of this chapter is to provide specific techniques to help hone students’ attention and focus and to model creative use of activities to increase opportunities for mindfulness in the classroom.

The NeuroDevNet Autism Spectrum Disorder Demonstration Project interfaces at many levels with the network's research themes and priorities. Our interdisciplinary team aims to improve understanding of genetic factors underlying vulnerability to autism spectrum disorders (ASDs) to develop better diagnostic strategies and, ultimately, to pinpoint molecular pathways relevant to developing biologically based treatments. Linking our existing longitudinal ASD cohorts with both genetics and neuroimaging studies will provide, for the first time, integrated data on how the genetic variation influences brain and behavioral development in ASD. Importantly, as our science progresses and we translate this information to the health care system, we will also educate policy makers, media, and business, so an informed society is prepared to capitalize on new genomic advances and effectively integrate these into health services for the broader community. We believe that this research has the potential to transform assessment and care for individuals with ASD.

Undergraduate psychology students at a mid-Atlantic HBCU were assessed on their knowledge of synaptic transmission, the multi-step process of brain cell communication. Comparison of final grades revealed that the use of the flipped classroom format along with learning techniques, self-explanation and practice testing increased the final course grade over previous semesters. Multiple sessions of practice testing integrated the use of mobile technology to make grading easier. Self-explanation required that students use online videos to explain the process in their own words. These techniques increased time studying the course material and led to higher exam grades. Thus, the use of effective learning techniques, embedded within STEM courses may play a significant role in increasing retention in STEM disciplines among African Americans.Keywords: STEM, education, flipped classroom, academic performance, HBCUIntroductionIn a required course, Physiological Psychology, undergraduate psychology students at a midAtlantic historically Black college and university (HBCU) were assessed on their knowledge of synaptic transmission, the multi-step physiological process of brain cell communication. The students were asked to describe the neural network communication process in terms of the anatomy of the nerve cell, ion transfer across the cell membrane, and how ionic changes would register on an oscilloscope graph. These topics comprised the majority of the midterm exam and were a major component of the cumulative final exam.All students enrolled in the course were Psychology majors and most were seniors. During discussions held during the introductory lecture, many students routinely expressed a dislike for biological science. Students commented that courses with a focus on math or biology content are more challenging. One reason for this view may be the fact that required courses within the Psychology curriculum, such as Qualitative Methods, Experimental Psychology, and Anatomy and Physiology are spread out, if taken in the recommended sequence, across six semesters. In addition, earlier math/sciences courses in General Education are ordinarily taken during freshmen or sophomore years. Therefore, it is often difficult for students to see the relationships and similarities between the subject matter of each course.Addressing the myriad and varied reasons behind the lower numbers of college students, particularly minority students, who attain degrees in science, technology, engineering, and mathematics (STEM) disciplines are necessary in order to reverse current trends. As of 2008, less than 10% of all bachelor's degrees are awarded to African American and Hispanic students (National Science Foundation, 2010; Palmer, Maramba, & Dancy, 2011). Nonetheless, according to U.S. Census Bureau data, 2020 population projections indicate that minority populations will comprise nearly 40% (66 million people) of the American workforce (Toosie, 2012). Reducing attrition rates in STEM majors and increasing enrollment and graduation rates is vital for increasing the number of future workers and for ensuring that the STEM workforce is diverse and inclusive (National Science Foundation, 2010; Palmer, Maramba, & Dancy, 2011; Soldner et al., 2012). Therefore, the factors influencing these students to drop out of college or to switch to nonSTEM majors must be assessed (Palmer, Maramba, & Dancy, 2011).At the university in which this study was conducted, psychology professors who teach courses with more biology or math content commonly report lower average class grades than other courses in the department. The activities communicated in this report were undertaken by a newly hired instructor in response to consistently lower average course grades (approximately 68%). Low averages were recorded for 3 consecutive semesters in the course Psychology 412, Physiological Psychology. A grade of C (70%) is considered passing and is necessary to meet graduation requirements. …

The middle and late 1930s were years of severe change for the USSR. Stalin, in an effort to destroy any effective political opposition, completed his great purge. The Soviets, seeking to avoid an international conflagration, attempted to build collective security as a bulwark against their avowed ideological enemies, the Nazis. As a consequence of these domestic and international developments and the Party's reaction to them, the historical profession experienced profound changes as well. The State,which had formerly demanded that historians write Marxist history based upon class-struggle and socio-economic analyses exclusively, now ordered historians to produce more traditional and nationalistic interpretations of the past within the context of Marxism.

International audience; We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.