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POGZ truncating alleles cause syndromic intellectual disability
Janson White1,
Christine R. Beck1,
Tamar Harel1,
Jennifer E. Posey1,
Shalini N. Jhangiani2,
Sha Tang3,
Kelly D. Farwell3,
Zöe Powis3,
Nancy J. Mendelsohn4,
Janice A. Baker4,
Lynda Pollack5,
Kati J. Mason5,
Klaas J. Wierenga6,
Daniel K. Arrington6,
Melissa Hall6,
Apostolos Psychogios7,
Laura Fairbrother7,
Magdalena Walkiewicz1,8,
Richard E. Person1,8,
Zhiyv Niu1,8,
Jing Zhang1,8,
Jill A. Rosenfeld1,8,
Donna M. Muzny2,
Christine Eng1,8,
Arthur L. Beaudet1,10,
James R. Lupski1,2,9,10,
Eric Boerwinkle2,11,
Richard A. Gibbs1,2,
Yaping Yang1,
Fan Xia1,8 &
V. Reid Sutton1
Genome Medicine volume 8, Article number: 3 (2016) Cite this article
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Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.
Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.
We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.
While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.
Neurodevelopmental disorders (NDDs) reflect a molecularly and phenotypically heterogeneous classification encompassing intellectual disability (ID), microcephaly, and neurobehavioral traits such as autism spectrum disorder (ASD) [1]. Collectively, these traits are quite common, with ASD having a prevalence of ~1 % and ID occurring in ~2–3 % of the population. The delineation of various NDDs is not discrete, as more than one phenotype is often present in an individual. Whole exome sequencing (WES) has revealed that mutations in the same gene may be associated with a broad spectrum of neurobehavioral and neurodevelopmental phenotypes [2, 3].
The clinical and genetic heterogeneity of ASD and other neurobehavioral traits represents a challenge for both molecular diagnoses and new gene discovery [4]. ASD is characterized by impairment in social interaction as well as restricted and stereotyped patterns of interest and activities, and is often accompanied by ID and language delay. Recent advances in personal genome analysis and the assembly of large cohorts for study have begun to identify potentially pathogenic variants in individuals with ASD; however, the majority of ASD loci have yet to be identified and may include gene-regulatory mechanisms such as epigenetic modifications and noncoding RNAs [1]. There is emerging evidence for shared genomic underpinnings and genetic etiologies of neuropsychiatric disorders, including ASD, schizophrenia and ID, as evidenced by both WES studies [5] and the mirror trait manifestations of some copy number variants (CNVs) [6].
The over-representation of de novo mutations in affected individuals illustrates the strong genetic basis for NDDs [5, 7, 8]. The prevalence of de novo CNVs has been extensively explored during the past decade, with a large proportion of ASD cases containing these events [9–12]. Moreover, cognitive phenotypes have been tied to CNV in population cohorts [6, 13]. However, despite the known molecular etiology for ~20–30 % of cases, the genetic etiology in the majority of individuals with ASD is presently unable to be identified.
Genomic approaches to diagnosis include array comparative genomic hybridization (aCGH), whole genome sequencing (WGS) and WES. These approaches have identified the genetic etiology of many diverse Mendelian diseases [14]. Recently, large-scale WES studies have been conducted on a number of NDD cohorts [15–20]. These studies have identified many likely pathogenic single nucleotide variants, resulting in the generation of candidate gene lists for neurodevelopmental traits. However, the large number of individuals in cohort publications precludes the reporting of detailed clinical information for each case and often diagnostically relevant dysmorphology is not recognized until a cohort of individuals with a shared genetic etiology is assembled.
Premature truncating mutations in pogo transposable element with zinc finger domain, or POGZ (MIM#614787), have been implicated by WES in three ASD cohort studies [16–18], cohorts examining developmental delay (DD) and ID [15, 16] and one schizophrenia cohort [20]. Additionally, a recently published case report details a missense POGZ mutation present in an individual with microcephaly, ASD, ID, and other clinical features [21]. The recurrent identification of POGZ in these studies has robustly implicated POGZ in diverse NDDs, yet no thorough clinical analysis for POGZ variant-associated phenotypic features has been published to date.
Although relatively little is known about the function of POGZ, a recent study detailed the interaction of the zinc finger domain of POGZ with HP1α and the resultant activation of Aurora B kinase [22]. Therefore, POGZ likely plays a role in mitotic progression through heterochromatin formation and chromosomal segregation, and may also influence gene expression. These functions of POGZ are consistent with the presence of deleterious variants in patients with microcephaly and other neurodevelopmental phenotypes [1].
We have identified five POGZ disrupting mutations in patients with diverse clinical assessments. These individuals have variable NDDs with shared features comprising ID, global DD, behavioral abnormalities, microcephaly, short stature, strabismus, and shared facial characteristics. Together with eight pathogenic mutations from the literature, we describe the spectrum of phenotypes in individuals with deleterious mutations in POGZ. Ascertainment of patients with a shared molecular diagnosis and subsequent phenotypic characterization delineates the clinical presentation common to individuals with POGZ mutations. This genotype-driven approach may be especially relevant for the variable presentations of NDDs, and can be used to further clinically characterize candidate genes identified in diverse cohort studies.
This study conforms to the Helsinki Declaration and was performed with approval by the Baylor College of Medicine institutional review board, protocol number H-29697, for all sequencing conducted at the Baylor College of Medicine Human Sequencing Center. Written informed consent was obtained from the parents/legal guardians of the patients for publication of this research and any accompanying images. Exome sequence analysis across all sequencing centers followed the guidelines and process for classifying sequencing variants developed by the American College of Medical Genetics and Genomics [23]. Trio-based sequencing allowed for the prioritization of de novo loss-of-function mutations in four patients. An average of 2.5 de novo mutations were identified in each proband, of which POGZ was the only truncating allele. Additionally, variants in POGZ were selected for confirmation and co-segregation with the phenotype because loss-of-function mutations in this gene have been found in large cohorts of individuals with neuropsychiatric phenotypes. All identified variants in POGZ have been deposited into ClinVar under accession numbers SCV000256903, SCV000256904, SCV000256905, SCV000256906, and SCV000256907 in agreement with institutional review board approval and patient consent.
DNA from patient 1 and her mother was subjected to WES at the BCM Human Genome Sequencing Center through the Baylor-Hopkins Center for Mendelian Genomics initiative. Exome sequencing and analysis were performed according to previously described methods [24]. Potential de novo mutations were identified in silico by subtracting variants observed in the mother from those observed in patient 1. Candidate variants were filtered against exome data in publicly available databases, including the 1000 Genomes Project, the National Heart, Lung, and Blood Institute Exome Sequencing Project (ESP), the Atherosclerosis Risk in Communities Study (ARIC) database (http://www2.cscc.unc.edu/aric), and our in-house-generated database of approximately 5000 exomes.
Patients 2 and 3 were identified through diagnostic WES at the Baylor-Miraca Medical Genetics Laboratory. Sequencing and data analysis were conducted as previously described [25]. Briefly, the average coverage for ~20,000 targeted genes (42 Mb of targeted regions, including untranslated exons) was greater than 100×, and more than 95 % of the target bases were covered by at least 20 reads [26].
Patients 4 and 5 were identified via diagnostic exome sequencing at Ambry Genetics (Aliso Viejo, CA, USA). Sequencing and data analysis at Ambry Genetics were conducted as previously described [27]. The mean coverage across the parent–proband trio of patient 4 and patient 5 was greater than 90× with >91 % of the targeted bases covered at >20× .
PCR amplification and Sanger sequencing to verify all candidate mutations were done according to standard procedures and candidate variants were annotated using the POGZ RefSeq transcript NM_015100.3. Parental samples, when available, were also tested via standard Sanger sequencing.
Characteristic clinical findings are summarized in Table 1.
Table 1 Phenotypic and molecular data
Patient 1 is a 15-year-old female who initially presented in infancy with global DD. She walked at 17 months and her first words were at 18 months. She had a developmental assessment done at 5 years 8 months of age, at which time her motor skills were at age level with a performance IQ of 70, overall IQ of 50, and full scale IQ of 56. Behavioral abnormalities were apparent before 2 years of age, and as she developed, her psychiatric symptoms became more pronounced and included aggressive behavior, self-injury and property destruction that necessitated multiple inpatient psychiatric admissions. Other medical issues included a disturbed sleep cycle that responded to melatonin, mild obstructive sleep apnea, early-onset obesity, and mild myopia. On physical examination at 15 years, her weight was 80.7 kg (97th percentile), height was 152 cm (6th percentile), and head circumference was 52.1 cm (−2 standard deviations). Her body mass index was 34.9 kg/m2 (99th percentile). Facial characteristics include brachycephaly, a long and flat malar region, broad and depressed nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth and pointed chin. She had generalized hypotonia with a mildly wide-based and waddling gait. Brain magnetic resonance imaging (MRI), electroencephalogram, and audiology were normal. She was initially suspected to have Smith-Magenis syndrome due to sleep disturbance and global DD but high-density aCGH for chromosome 17p11.2 was normal. Molecular testing revealed a novel missense variant in RAI1 (NM_030665.3,c.4103A>G, p.S1212G) [28]. This variant was predicted to be benign and polymorphic by PolyPhen-2 and MutationTaster, and is poorly conserved in mammalian evolution. However, the variant was inherited from her father who had a history of learning disability and a personality disorder, and is shared with her sister who had clinical features suggestive of Smith-Magenis syndrome [28]. Thus, we could not conclusively rule out that this missense variant in RAI1 is contributing to the phenotype present in patient 1, but her more severe developmental disability compared with her father and sister warranted further work-up. Additional diagnostic evaluation was noncontributory and included chromosome analysis, fluorescent in situ hybridization (FISH) for 22q11.2 deletion, MECP2 sequencing, fragile X testing, lead levels, thyroid function studies, plasma amino acids and urine organic acids. Due to the equivocal interpretation of the RAI1 variant, research exome sequencing was undertaken.
Patient 2 is a 31-month-old female with microcephaly, short stature, global DD, non-ocular visual impairment, failure to thrive and multiple congenital abnormalities, including diaphragmatic hernia and a duplicated renal collecting system. Initial echocardiogram showed a patent ductus arteriosus and a patent foramen ovale or atrial septal defect, which resolved without surgical intervention. Physical examination revealed brachycephaly, sparse hair, low-set and posteriorly rotated ears, long malar region, hypertelorism with downslanting palpebral fissures, a flat nasal bridge, with a broad and depressed nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth, pointed chin, and a short neck with mild webbing. A full psychological and developmental assessment was performed at two years of age. According to the Mullen Scales of Early Learning her visual reception was within the 20th percentile, fine motor was within the 20th percentile, receptive language was within the 20th percentile, and expressive language was within the 20th percentile. According to the Vineland adaptive behavior scales her communication skills were below the first percentile, daily living skills were below the first percentile, socialization was within the first percentile, motor skills were below the first percentile, and adaptive behavior were below the first percentile. Collectively, the results of her formal assessment indicate significant delays across all areas with relative weakness in expressive language skills. Brain MRI showed nonspecific delayed myelination and diffuse T2 hyperintensity. Skeletal anomalies included multiple Wormian bones and mild hypoplasia of the cervical vertebral bodies. Previous work-up included chromosome analysis and aCGH which were normal as well as very long chain fatty acids. A clinical concern for Pallister-Killian was entertained at birth due to facial features and congenital diaphragmatic hernia.
Patient 3 is a 3-year 10-month-old male with global DD, complex partial seizures and behavioral abnormalities concerning for ASD. He first presented at two months of age due to poor weight gain and poor suck and latch. At 34 months of age, DAYC-2 formal developmental assessment was administered and he scored a General Developmental Index of 67, interpreted as significantly below age-level across all areas. His full scale IQ at 34 months was 71 (third percentile), verbal comprehension was 85 (14th percentile) and non-verbal abilities were 64 (first percentile). Physical examination revealed strabismus, bifid uvula, a wide space between the central incisors, brachydactyly, large thumbs, broad feet, and large toes. Ophthalmology exam at 12 months of age detected hyperopia and astigmatism. Family history was significant for seizures on the maternal side. He has complex partial seizures localizing to the left frontoparietal area. He was initially treated with phenobarbital but switched to levetiracetam and was well-controlled. Due to concern that this drug was contributing to his behavioral issues, the patient was switched to oxcarbazepine. He developed tic-like movements after the second dose and it was stopped. Topiramate was added and he did start having new seizures while he was on both topiramate and levetiracetam but controlled with higher doses of topiramate. Levetiracetam was eventually weaned and the irritability has improved. Previous work-up was unrevealing and included chromosome analysis, aCGH, metabolic testing, Angelman methylation studies and CREBBP and EP300 testing for Rubinstein-Taybi syndrome I and II.
Patient 4 is a 5-year-old female with microcephaly, short stature, global DD, and a history of low muscle tone. Additional medical concerns included feeding difficulties, severe gastroesophageal reflux disease, sensorineural hearing loss, exotropia, and obstructive sleep apnea. Facial characteristics included brachycephaly, a sloping broad forehead, posteriorly rotated ears, upslanting palpebral fissures, long and flat malar region, broad and depressed nasal tip, short philtrum, downturned corners of the mouth, high palate, pointed chin, and relative prognathia. Ophthalmology exam showed exotropia, anisometropia, optic nerve hypoplasia, and rod-cone retinal dystrophy. Brain MRI showed optic nerve hypoplasia with no other structural abnormalities. Skeletal survey was normal other than significant brachycephaly. At age 27 months she underwent a developmental assessment. According to both the Clinical and Auditory Milestones Scale and Cognitive adaptive test she scored at a basal level of 6 months, indicating severe delays across all areas of development with most significant delays to her acquisition of speech and language. Previous molecular testing included aCGH, which revealed a paternally inherited 125-kb copy number gain within chromosome 12q24.12; she had a normal chromosome analysis, an unrevealing targeted microcephaly gene panel, and normal thyroid function studies, plasma amino acids, urine organic acids, and urine mucopolysaccharides.
Patient 5 is a 4-year 7-month-old female with microcephaly, cleft palate, global DD, hypotonia and ASD. She presented at birth with cleft palate, micrognathia and a duplicated renal collecting system. Facial and physical characteristics included broad forehead, brachycephaly, broad and depressed nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth, pointed chin, and small hands with relative brachydactyly. Upon her initial clinical presentation additional features were noted, including auditory neuropathy, immune deficiency, and left duplicated renal collecting system. Ophthalmology exam showed exotropia, astigmatism and small optic nerves. Brain MRI revealed Dandy-Walker variant, decreased white matter, and enlarged third and fourth ventricles. Her original exome report identified compound heterozygous variants of unknown clinical significance in STIL, associated with primary microcephaly. Additionally, microarray revealed a paternally inherited Xq21.1 duplication. Previous normal testing included chromosome analysis, FISH for 22q11 deletion, methylation studies for Prader Willi and Angelman syndromes, and ROR2 sequencing. Other testing, all normal, included urine organic acids, serum amino acids, acylcarnitine, and very long chain fatty acids.
Phenotypic spectrum
The clinical description of the individuals in this study overlaps with the descriptions of previously reported patients [15–20]. All five subjects had global DD and/or ID. Behavioral abnormalities ranged from self-injurious behavior to high-functioning ASD. Additional common features included microcephaly (3/5), stature below the tenth percentile (4/5), hypotonia (4/5), strabismus (4/5), vision abnormalities (5/5), sensorineural hearing loss (3/5), and gastrointestinal manifestations including poor feeding, gastroesophageal reflux, and/or constipation (4/5). Recurrent facial and physical characteristics included hypotonic facies with an open mouth, brachycephaly (4/5), long and flat malar region (4/5), posteriorly rotated ears (2/5), broad nasal tip (5/5), flat nasal bridge (3/5), short philtrum (5/5), thin vermillion border (4/5), downturned corners of the mouth (4/5), high arched palate (3/5), and pointed chin (4/5). An overview of clinical features is presented in Table 1. Pictures of the five patients are shown in Fig. 1.
Photographs of patients displaying common facial features. Shared facial dysmorphology among affected individuals includes brachycephaly, long and flat malar region, broad and depressed nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth and pointed chin
Genomic analyses
To date, seven de novo mutations leading to premature termination of POGZ have been identified in cohorts of individuals with diverse NDDs, including ASD (N = 3), ID (N = 6), DD (N = 2), or schizophrenia (N = 1) [15–20]. The truncating variants result in termination of the protein prior to or within the C-terminal DDE and/or coiled-coil domains. Additionally, a de novo missense mutation in the CENP-B like DNA binding domain of POGZ was also reported in a child with ASD, ID and dysmorphic features (Fig. 2) [21].
Locations and chromatograms of variants identified. a The functional protein domains of POGZ. Functional protein domains include zinc-finger domains (orange and yellow), a predicted proline-rich domain (red), CENP-B like DNA binding domain (green), DDE transposase domain (blue) and a coiled-coil domain (purple). The seven truncating mutations and one deleterious missense previously reported are indicated by stars above the predicted domains. b Truncating mutations identified in the current study are indicated at their respective locations on the protein with arrows, and the chromatograms displaying each mutation are presented below the details of the individual nucleotide and amino acid changes
We identified five patients with heterozygous truncating mutations in POGZ. Four of the five variants were confirmed to be de novo in the affected individual; the father of patient 1 was unavailable for analysis but his mother did not harbor the POGZ variant. Extensive testing for each of these individuals was negative, with the exception of a paternally inherited missense variant in RAI1 in patient 1 of uncertain clinical significance [28] and compound heterozygous variants of uncertain clinical significance in STIL in patient 5. We identified heterozygous truncating variants in POGZ in all five individuals by WES; these five variants were validated by Sanger sequencing (Fig. 2). Publicly available databases, including ARIC and the Exome Aggregation Consortium (ExAC; version 0.3; Cambridge, MA, USA; http://exac.broadinstitute.org) confirmed that the identified variants are unique to our patients. Table 2 provides a molecular description of variants identified in these five patients and eight previously identified cases. Indels resulting in frameshift mutations were present in three of five patients and two of five contained nonsense mutations (one transition and one transversion). Three of the five variants occur in the final exon of POGZ and can potentially escape nonsense-mediated decay. However, the two patients with variants predicted to be subject to degradation by nonsense-mediated decay do not have distinguishing phenotypic features from the three terminal exon-containing patients. All five truncating mutations are predicted to result in the loss of greater than 402 amino acids at the C-terminus of POGZ. Loss of this region of the protein is predicted by conceptual translation to result in deletion of the CENP-B like DNA binding domain, the DDE domain and the coiled-coil domain. Thus, the mutations present in each of the five individuals in this study likely result in loss of function. The assertion that heterozygous loss of function mutations in POGZ cause diverse NDDs is further supported by the presence of two CNVs encompassing POGZ coding regions in the DECIPHER database [29]. The two individuals with small deletions of POGZ are phenotypically described as having DD and additional significant developmental and morphological phenotypes.
Table 2 Molecular data for all individuals with variants in POGZ
Large cohort studies have associated truncating mutations in POGZ with behavioral abnormalities, ID, and DD [16–21]. The identification of numerous candidate genes in these studies highlights their value. However, to thoroughly describe the clinically relevant phenotypes associated with mutation in a given gene, targeted analyses of a molecularly defined cohort are required. Here, we utilized a genotype-first approach to identify shared facial and physical characteristics as well as the spectrum of individual phenotypes resulting from deleterious mutations in POGZ.
We identified five patients with novel truncating mutations in POGZ, likely resulting in loss-of-function alleles. The description of the five individuals and a review of eight patients from the literature indicate that individuals with mutations in POGZ are likely to have global DD, microcephaly, ID, strabismus and variable hearing loss. Comparison of facial and physical characteristics in our five subjects has revealed shared facial features, including brachycephaly, long and flat malar region, broad nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth and pointed chin (Fig. 1). Patients also present with highly variable neurobehavioral phenotypes, ranging from ASD to severe aggressive behaviors similar to what is seen in individuals with Smith-Magenis syndrome (Table 1).
It is possible that patient 1 and patient 2 may have a blended phenotype; patient 1 has a paternally inherited missense mutation in RAI1, which is associated with Smith-Magenis syndrome. In addition to the characteristic features, patient 2 also presented with congenital abnormalities, including diaphragmatic hernia, a renal tract anomaly, and heart defects. Other than the de novo POGZ mutation, we did not identify additional molecular events that would account for her phenotype. Therefore, although it is possible that POGZ truncating mutations could lead to clinical phenotypes including mild congenital abnormalities, an additional unidentified cause in patient 2 could potentially be responsible for her uncharacteristic presentations. Together, our data and a literature review indicate that damaging variants in POGZ result in a broad range of features distinguished by global DD, ID, neurobehavioral abnormalities (most often ASD), short stature, hypotonia, strabismus, characteristic facial features, including brachycephaly, long and flat malar region, broad nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth, and pointed chin, and variable hearing loss.
POGZ has not been extensively characterized; the protein product contains eight canonical C2H2-like zinc finger domains that are implicated in protein–protein interactions and have the potential for DNA interactions [30]. The C-terminus of the protein contains a B-like centromere binding domain and a DDE domain (Fig. 2). Interestingly, POGZ interacts with HP1α via the zinc finger domain; this activates Aurora B kinase, indicating a potential role for POGZ in mitotic progression and neuronal differentiation [22]. Similar to POGZ, many genes encoding proteins required for proper centrosomal function or chromosome segregation are mutated in patients with microcephaly, demonstrating a common theme of aberrant neuronal proliferation and migration [1, 31].
POGZ is expressed in developing cortical projection neurons which have been implicated in a network convergence of neurodevelopmental risk genes [32]. HP1α also strongly interacts with NIPBL, which is mutated in individuals with Cornelia de Lange syndrome. The overlapping molecular networks of POGZ and NIPBL may indicate common mechanisms of transcriptional dysregulation with deleterious mutation of these genes [24].
Although NDDs are typically a clinical diagnosis, molecular genetic testing, including both aCGH and WES, is capable of more precisely defining syndromes and disorders with highly variable phenotypes [33]. With the expanding number of single-gene candidates for NDDs and the variability of these phenotypes, WES was crucial in defining the cohort of five patients presented here. The increasing emergence of candidate genes for various disorders necessitates genotype-driven approaches for describing associated phenotypic spectrums. Furthermore, with a better understanding of the clinical presentations of patients with deleterious POGZ mutations, more molecular diagnoses may be forthcoming.
We report the detailed phenotypic features associated with loss of function variants in POGZ. These include a broad range of features distinguished by global DD, microcephaly, ID, neurobehavioral abnormalities (including ASD), short stature, hypotonia, strabismus and variable hearing loss. We also describe characteristic facial features of this disorder that include brachycephaly, long and flat malar region, broad nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth, and pointed chin. Identification of POGZ variants and subsequent description of characteristic clinical presentations demonstrate the utility of human reverse genetics in an era of personal genome analyses and clinical genomics.
aCGH:
Array comparative genomic hybridization
ASD:
CNV:
Copy number variant
Developmental delay
Fluorescent in situ hybridization
NDD:
WES:
Whole-exome sequencing
WGS:
Whole-genome sequencing.
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Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511(7509):344–7.
Deciphering Decelopmnetal Disorders Study. Largescale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8.
We thank the patients and families for their contribution to this study. This work was supported by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number HG006542 to the Baylor-Hopkins Center for Mendelian Genomics; the Smith-Magenis Syndrome Research Foundation (SMSRF); the National Institute of Neurological Disorders and Stroke (NINDS) NS058529, National Institute of General Medical Sciences Grant Number T32GM008307, the National Institute of Child Health and Development (NICHD) HD024064 Intellectual and Developmental Disabilities Research Center (IDDRC). C.R.B. is an HHMI fellow of the Damon Runyon Cancer Research Foundation (DRG 2155-13). T.H. and J.E.P. supported by the Medical Genetics Research Fellowship Program NIH/NIGMS NIH T32 GM07526. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C).
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA
Janson White, Christine R. Beck, Tamar Harel, Jennifer E. Posey, Magdalena Walkiewicz, Richard E. Person, Zhiyv Niu, Jing Zhang, Jill A. Rosenfeld, Christine Eng, Arthur L. Beaudet, James R. Lupski, Richard A. Gibbs, Yaping Yang, Fan Xia & V. Reid Sutton
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
Shalini N. Jhangiani, Donna M. Muzny, James R. Lupski, Eric Boerwinkle & Richard A. Gibbs
Ambry Genetics, Aliso Viejo, CA, 92656, USA
Sha Tang, Kelly D. Farwell & Zöe Powis
Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55102, USA
Nancy J. Mendelsohn & Janice A. Baker
Arnold Palmer Medical Center, Division of Genetics, Orlando, FL, 32806, USA
Lynda Pollack & Kati J. Mason
University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Klaas J. Wierenga, Daniel K. Arrington & Melissa Hall
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37212, USA
Apostolos Psychogios & Laura Fairbrother
Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA
Magdalena Walkiewicz, Richard E. Person, Zhiyv Niu, Jing Zhang, Jill A. Rosenfeld, Christine Eng & Fan Xia
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
James R. Lupski
Texas Children's Hospital, Houston, TX, 77030, USA
Arthur L. Beaudet & James R. Lupski
University of Texas Health Science Center, Houston, TX, USA
Eric Boerwinkle
Janson White
Christine R. Beck
Tamar Harel
Jennifer E. Posey
Shalini N. Jhangiani
Sha Tang
Kelly D. Farwell
Zöe Powis
Nancy J. Mendelsohn
Janice A. Baker
Lynda Pollack
Kati J. Mason
Klaas J. Wierenga
Daniel K. Arrington
Melissa Hall
Apostolos Psychogios
Laura Fairbrother
Magdalena Walkiewicz
Richard E. Person
Zhiyv Niu
Jill A. Rosenfeld
Donna M. Muzny
Christine Eng
Arthur L. Beaudet
Richard A. Gibbs
Yaping Yang
Fan Xia
V. Reid Sutton
Correspondence to V. Reid Sutton.
J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., is a member of the Scientific Advisory Board of Baylor Miraca Genetics Laboratories, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in the Baylor Miraca Genetics Laboratory (BMGL; http://www.bmgl.com/BMGL/Default.aspx). S.T., K.F.H., and Z.P. are employed by and receive a salary from Ambry Genetics. Exome sequencing is among the commercially available tests available at Ambry Genetics. The remaining authors declare that they have no competing interests.
J.W. and C.R.B. analyzed the data and wrote the manuscript. T.H. and V.R.S. organized phenotype assessment and supervised the study. J.E.P., S.N.J., C.E., A.L.B., J.R.L., D.M.M., E.B., R.A.G., Y.Y., and F.X. generated and advised on data analysis. S.T., K.D.F., Z.P., N.J.M., J.A.B., L.P., K.M., K.J.W., D.K.A., M.H., A.P., L.F., M.W., R.E.P., Z.N., J.Z., and J.A.R. identified and collected patients. All authors have read and approved the final manuscript.
Janson White and Christine R. Beck contributed equally to this work.
White, J., Beck, C.R., Harel, T. et al. POGZ truncating alleles cause syndromic intellectual disability. Genome Med 8, 3 (2016). https://doi.org/10.1186/s13073-015-0253-0
Microcephaly
Zinc Finger Domain


Two weeks ago I noticed this enormous insect at the entrance of Fafa, then this week he hung out around the fern at the yellow triangle door. Finally looked up to find it was a Praying Mantis, mantis means prophet in Greek. Here's some info I've compiled about our visitor while he stayed for a time.
If you know anything about the praying mantis, it will come as no shock that this insect is the paramount spiritual symbol of stillness and patience. The praying mantis takes its time in all that it does. It takes care to pay diligent attention to its surroundings, and moving through life at its own pace. It serves as a reminder for humans to slow down in our chaotic, fast-paced lives.
The praying mantis also teaches us how to still our bodies and go within our own mind. By doing this, we can connect with ourselves, drawing up greater physical, mental, emotional, and spiritual power. This stillness and concentration is a form of meditation, a practice that the mantis places much importance in.
Wisdom emerges when we are still and quiet, sensing and feeling rather than thinking critically. It comes with experience, age, and being, rather than traditional schooling. It cannot be obtained through arrogance.
The praying mantis meaning has a variety of traits: temperance, quietness, awareness, calmness, clairvoyance, patience, mindfulness and innovation. These insects are well known for their pre-strike pose, which is a popular symbol of balance and patience in and of itself.
In fact, the Chinese honor the praying mantis for its elegant, mindful, and contemplative movements. By reminding ourselves to have patience with ourselves in our own movement, we, like the mantis, can grow in our wisdom. They remind us to have patience in acquiring the things we want and to remain balanced throughout the duration of the wait.
If a praying mantis strikes too soon, its prey gets away. Because of this, it has evolved to be patient: so patient, in fact, that it will not budge unless it is 100% positive that it is the correct thing to do. This acts as a direct message to us, reminding us to contemplate our movements just as carefully and precisely.
When our timing is off, we may generate an unnecessary (and unpleasant) struggle or blow an opportunity entirely. Through stillness, awareness, and balance, we can hear and recognize the perfect moment. We must listen to the voice that speaks to us with openness, not fear. If we have patience, the right moment will come, and we will succeed.
Man is a unity of body and spirit which makes him utterly distinct from the rest of creation. "Man is not merely an evolution but rather a revolution," muses G.K. Chesterton.
Technically speaking, however, the moonrise for the September 2017 and October 2017 full Moons are very close this year. For several days after both full Moons, the Moon rises a shorter-than-usual time after sunset, creating more light during harvest time. During both months, the Moon will hang large after sunset, casting its beautiful light on our fields of grain.
Today is the 10th anniversary of Pope Benedict's remarkable, generous and important motu proprio Summorum Pontificum, which liberalized the traditional Mass and introduced a new generation to the Church's treasury of sacred music and liturgy.
There is an old saying, lex orandi, lex credendi, lex vivendi, which essentially means how you pray leads to what you believe and then ultimately how you live.
Love is the highest frequency & the most powerful force in the universe. Love transcends time & space. Love really is all that matters!
Find that thing that is not passing.
The Feast of the Epiphany on Lights brings you "Fire" Created By Sophia Ann Elizabeth. Enjoy!
On the 12th Day of Christmas my True Love gave to me, Twelve drummers drumming stands for Twelve articles of the Apostles' Creed.


Nico Rosberg revealed he doesn't miss Formula 1, and that he is no daredevil meaning the sport sometimes scared him.
The German driver shocked the world of motorsport when he announced his retirement from racing just five days after beating Mercedes team-mate Lewis Hamilton to the 2016 World Championship.
Now, in an interview with German TV station ZDF, the 33-year-old confirmed he has no regrets over his retirement.
"I have to confess, there are moments when I'm watching and I think, 'It's good I'm not in that car'.
"In Baku for example – when they race through the streets of a city at a speed of 360kph, millimetres away from a wall.
Rosberg said his choice to walk away in 2016 was the "best decision", but at the time he wasn't so sure.
"Back then, when I decided to leave the sport, I had no idea what it would feel like in two or three months or a year," he added.
"It was a complete stop – something fundamental in my life was suddenly gone.
"Luckily I had my family and other passions. I quickly found a new way for me. It was the best decision.
The post Formula 1 scared Nico Rosberg at times appeared first on PlanetF1.


text:
https://episodes.castos.com/5e475406b6db92-07042111/XRL024-Aditya-Vishwanath.mp3
Learning complex STEM concepts like physics or chemistry off a chalkboard is no easy task, because it removes a key factor from the equation – presence. Inspirit VR's Aditya Vishwanath explains how giving that presence back ignites a learner's innate curiosity.
Julie: Hello, my name is Julie Smithson, and I am your XR for Learning podcast host. I look forward to bringing you insight into changing the way that we learn and teach using XR technologies to explore, enhance, and individualize learning for everyone. Today my guest is Aditya Vishwanath. Aditya is a PhD candidate in Learning Sciences and Technology Design and a Knight-Hennessy Scholar at Stanford University. He's the co-founder of Inspirit, a company that develops virtual reality learning content. And his research focuses on developing technologies that support universal access to immersive learning content. Welcome to the show.
Aditya: Thank you. I'm so excited to be doing this.
Julie: That's great. And we've had a couple of conversations about education, and the courses that need to be implemented into classes, and that sort of thing. Why don't you tell me a little bit about Inspirit, where you started from, and where you guys are today?
Aditya: Inspirit was actually a research project that I started out with a friend and now co-founder of mine — her name is Amrita — and the two of us were both researchers in a lab at Georgia Tech in Atlanta. And we really stumbled upon this opportunity to explore and study what it would take to bring immersive VR to a few public schools in the city of Atlanta. And it was really just a phenomenal experience for the two of us, because what we thought was going to be just a few weeks of a project — where we were playing the roles of research assistance — exploded into what is Inspirit today. Our mission — and my research too, at Stanford — is really trying to be that bridge between the best of academic research and what we know about virtual reality and education, and then cutting edge technologies that can be used in industry and go straight into classrooms and learning environments. Inspirit was founded with that goal of accelerating the pace at which we could bring research findings of VR and education into schools, into universities, into learning environments around the world.
Julie: It's definitely a big concern now, the speed of education. And not just how much we're learning, because I feel like every day it's like a firehose of things to learn. Now it's a matter of how did the education systems keep up with the demands of change that's taking place, both through innovation and changes within a company? It sounds like that's something that Inspirit is trying to address?
Aditya: STEM education is what we do at Inspirit. And fundamentally, somewhere down the road, STEM education stopped becoming a hands-on interactive learning experience. And this was largely due to the needs of supporting larger and larger classrooms, more and more students, both in an online and an offline learning environment. And suddenly that personalization, that hands-on, that immersive interactive aspect to science and STEM education was completely lost. But a lot of the science learning today happens in a very passive way, with a video lecture or somebody giving you a passive lecture with a set of PowerPoint slides. And very rarely, are you interacting or actively solving a problem outside of a science lab. So our goal with Inspirit really was to bring back that hands-on piece and that interactive piece in a self-based, in a comfortable, and in an immersive environment using the power of virtual reality, both offline in schools and universities, and also online, if you're learning anything from anywhere in the world.
Julie: I'm looking at the curriculum that you offer, and very science focused. And I've done my own personal research over the last little bit, just on the critical thinking skills that science offers. And I think this is one of those hidden gems that is a part of science that we never really tackled before, trying to analyze all of this through technology. But can you speak a little bit more to that, about the critical thinking skills and the skill bases that are taught within these courses that revolve around science? But there's a deeper meaning in there for future skillsets.
Aditya: So, I mean, we have a lot of academic evidence that shows that when done right, immersive virtual reality can hugely and greatly promote deeper, critical thinking and problem solving skills and learners. And what we mean by that is, critical thinking — the way I like to think about this — is really just the ability for a student or a learner to be asking people questions. They are no longer asking surface level, high level, introductory, basic questions, but just by virtue of being immersed in this space — that is pedagogically thought out and that is designed in a very thoughtful way — can hugely change the way in which they ask questions. Now they're engaging multiple bodies of knowledge, they're actively pushing back at the information that they're receiving, and they're actively analyzing and engaging with it in a more immersive manner. So we notice very often in our pilot projects that the students tend to move their questions from "what" to "why" and "how". "*How* does the mitochondria generate the energy that is required to power the cell? *Why* is the DNA helix shaped the way it is? *Why* does something happen in this way?" And it's no longer "what", "What is a mitochondria?" But it's "Why is it the way it is?" And it's really fascinating that just simply immersing yourself for a very short amount of time — our simulations on the Inspirit platform are also designed to be extremely short experiences — just with 46 minutes of VR can dramatically transform the way in which students engage with the material.
Julie: I've had so many different conversations — even in over the last week — about curiosity, and how the next generation is not curious right now. Even my own kids, I'm having a little bit of a hard time trying to inspire their curiosity.
Aditya: Right.
Julie: You're telling me that within 46 minutes already, students are changing that question of "What is this?" to "Why is this?" or "How is this the way it is?" That's huge. Why do you think that? [chuckles] I'm gonna ask *you* a "why" question.
Aditya: [chuckles] Yeah, so that's a great question. And that's really what I am researching right now at Stanford, and what we're trying to answer with Inspirit. The way I like to think about it is, the most powerful thing that virtual reality is able to afford is this phenomenon of presence. This is a term that was borrowed from the social psychology space. I mean, presence is really just that ability for a tool or technology to make you believe that you are somewhere else. The fact that you can embody the shoes of another being, another space, another character, another experience is something that was just truly never possible before with any other technology. And we have evidence that when you experience something very visceral or something very powerful in a different space that you feel present in, so this could be something like the Great Wall of China — what a lot of these field trips in VR tend to do — or taking you inside the human body into a microscopic cell, or transporting you to the surface of the moon. And we have all of these modules on our Inspirit platform. We're able to demonstrate that when you experience the topic or the process of learning in these new spaces, when you are situated and you feel present in these spaces, the conscious part of your brain knows that this is not real, I mean, it's an animated world, really. And so the front part of your brain — the cortex — knows that this is not a real experience, but the real part of your brain, the part that's usually designed for your fight or flight response, the part that is your survival instinct is essentially subconsciously fooling your body into believing that you are learning in this new environment, in a very hands-on engaging way. And this tends to activate more receptors in your brain, as well as more physiological indicators for being in a different place. So, for example, a very popular VR experience — that you may have also experienced — that we do a lot in our VR lab at Stanford is the "walk the plank" VR simulation, where you have a user walk a plank on top of a 50 story building. And they know it's an animated world, but everyone's going to start sweating, your palms are going to get sweaty at the very least, and that's what presence is. You believe consciously that this is not ideal world, but subconsciously, unconsciously, your brain fools your body into believing you are somewhere else. And this leads to deeper retention in the long term, the deeper sense of behavior change in many cases that we're also able to measure persists after the experience is over.
Julie: So interesting. The formula of being immersed allows you to become more curious about your environment, because you need to have more answers, I guess, in front of you. It's kind of that unfolding answer there. But I think it's so critical right now to where we are in education. And the fact that students don't have that same curiosity of why things happen or how did things happen. Google provides most answers to kids, and the calculator provides the answers to mathematical equations. The approach that you've taken, obviously, with sciences, which– sciences are so important, so underrated and everybody knows that. And I think it's fantastic that you've done that. Do you have a more favorite course than another, yourself? Like, are you more interested in physics, or the biology side, or chemistry, yourself?
Aditya: Personally, I have always grown up being super fascinated by physics, and I think our physics simulations on the Inspirit platform are really super interesting. And there's another point that I also want to touch on that you just mentioned, about the curiosity piece that seems to be largely missing in our schools today. And you're absolutely right. I mean, there is– I read the statistic just a few months ago, and it just really blew my mind. More than 50 percent — that's half the number of students — who start a STEM course — whether at the college level or at the school level, whether online or offline — do not complete the course. There are very high attrition rates, very high dropout rates, especially at the community college level, at later stages of high school. And these dropout rates severely affect underserved and marginalized communities much more than others. And a huge reason for why this happens is because of that lack of solidifying the fundamental topics. It's because of the lack of connecting these seemingly distant topics to reality, to your everyday life. It's building that critical thinking, that confidence, that self-efficacy,y and that belief that "I can do this and I want to know more about this." And we have so much evidence about how VR can promote this, with just very short 10 minute long simulations. And that's really the biggest thing that we're trying to address with our platform. Coming back to the physics topic, we have one simulation in our platform, which is this physics playground like experience, where you're dropped into this world, this park where you have the ability to manipulate and move around various objects and learn virtually all of Newton's laws of motion by throwing a ball, by throwing something down a ramp, by rolling objects on the floor. And then we give the user, the student, the control to manipulate and change parameters in this world so they can do things that would not be possible in the real world, like change friction of a surface, change the mass or the weight of a ball, and then throw it and see the free body diagram of that ball as it flies through the air. And then we also let them change things like gravity. So now you can experience throwing the same ball on the surface of the moon, and understand that physical intuition for the laws and the equations of motion, before you get back into your class and start solving the math equations. So we have evidence that shows that when you just spent 10 minutes building that intuition for "What happens, does the ball go higher or lower? Does something move faster or slower when I change X, or when I change Y?" Just building that for 10 minutes in the virtual world, followed by deep assessments and an active math equation that you would anyways be doing in the classroom. That combination is what needs to the self-efficacy of this critical thinking, this confidence amends deeper, deeper interest and engagement with science.
Julie: I just want to go back to what you're saying. So throwing this ball in just a– in a virtual environment under Earth's circumstances, shall we call it. Regular circumstances. And then being able to take that same person and immerse them into being on the moon and trying to throw a ball there. That is something that's never been able to be done before. We've never been able to do that. I didn't get to do that in high school. So I can only imagine the potential of curiosity and query of "why" and "how does this work," and "let's try this again," and adjusting levels, and adjusting positions and things like that. And all of a sudden the whole experience becomes a laboratory experience of trying different things and teaches us to be curious, to critically think about the ramifications of one thing happening over the other. And again, another skillset that I don't believe is taught well enough in the schools these days.
Julie: So your program, Inspirit, who are you directly working with right now? Like I know you mentioned, you're from Stanford University. Are there any schools that are implementing your programs into their schooling at this time?
Aditya: Yes. So we work across the United States and also internationally with private schools, charter schools, public schools, and also low-income public title 1 schools around the country. And our goal really is to work very closely with the teacher and with the classroom to understand how we can meaningfully integrate this technology in their environment. Virtual reality is really a buzzword that is being thrown around everywhere today, to explain anything and everything from something that's a snazzy, glamorous looking headset. Many people are trying to sell VR for its novelty or they're trying to sell VR as the silver bullet that will solve all education problems. But really, as a company, our work in VR is just half the battle. The other half of the entire picture is really understanding curriculum, understanding learning outcomes, understanding the background of the students and the teachers and the school. The context is so relevant and so important to meaningfully bring this into a school or a university. So we work both at the K-12 and the higher ed and early undergraduate education levels. And we partner directly with schools and institutions and teachers and classrooms. And we also go through other distribution partners, like a publishing company or another ed-tech distributor, so that we can then, through them, access a larger audience of users. But however we get to the classroom, it's very important for us to be aligned with standards, with curriculum. So we build in assessments into our modules and our simulations, and our assessments and our testing is designed to be customizable. So a teacher can also edit it or change it to to customize a lab — whether it's a physics chemistry or biology lab — to her syllabus or her curriculum or her everyday lesson plan. We also build activities and other worksheets to be done outside of VR, that a teacher can use to better integrate VR into the classroom, because VR is not the only thing someone's doing in the school or at home. They are doing a bunch of different things and it's very important to understand context and how VR fits there. And then the last thing we do on the hardware side is really trying to be as agnostic to hardware as possible, so we can be compatible both on high-end VR headsets, but we have also built out a non-immersive 2D platform that works at a PC, a Mac or a Windows machine, so that many students can directly get started with working in virtual labs today at home, as well as in the school. And really being close to the teacher and responding to the needs is so important. I mean, to give you a very quick example, because we did so many pilot studies over the last six months, we decided to include a social VR, collaborative VR experience as part of our platform. This was never on the cards for us, and we would have totally missed out on the signal. But we were able to recognize this as a very important feature only because we spent so much time in the schools and the classrooms. And so our platform actually also comes in with a social component, where students can meet each other in a lab and together solve these virtual activities in the virtual space, even if there were many, many miles away from each other.
Julie: That's so important, is to build that collaboration piece.
Aditya: Mm-mm.
Julie: I'm a big advocator of collaboration, and started XRcollaboration.com with our partners. And I think this is one thing that's so relevant to having a good education about how things are going to work in the future. And nobody can do anything alone. So having that collaboration piece, where the students are able to go and discuss problems together and figure out how to solve them, it's a key component to platforms these days, to be able to have that meetup and have that communication piece, so it's not just one sided.
Aditya: Absolutely.
Julie: Then the teachers can also observe the feedback of the social interactivity, and who's contributing more than another, or what type of contributions are they contributing, and maybe the courses ain't aligned right or something like that. So there's a whole bunch of different purposes for that observation.
Julie: That's great. I love that you're supporting teachers. I think some of the key components that you just spoke about, too. Right now teachers are struggling more than ever to try and figure out how to teach their course with relevancy and also introduce technology, not on a full time basis, but as an aid to teach a message or a lesson. And sounds like you have done a really good job of trying to implement this and become that support for the education system that's taking on your program into their classes. So congratulations on that.
Aditya: Oh, thank you. We're only getting started, and I'm super excited for what lies ahead.
Julie: Do you have a roadmap of other courses that you're going to integrate, or are you going to stick with the science focus and then just broaden out into biology and physics and chemistry?
Aditya: Actually, our platform goes live by the end of July. And by by going live, I mean, we're building an entire teacher dashboard, a student dashboard, the entire classroom management tools, along with these labs and these simulations. Right now, we're launching with almost every introductory topic in physics, chemistry and biology. But we want to be a STEM education platform. And so we're very keen on jumping into math and anatomy and other lab-based, as well as other simulation based experiences across all of STEM education.
Julie: So if I was a teacher or somebody from the education system, what kind of piece of advice would you give any of our listeners right now, with regards to learning and teaching using XR technologies?
Aditya: Oh, that's a tough one. I think the biggest piece of advice I will give teachers is to definitely not to be afraid to give it a shot, to try it out for once. It is a challenging technology. It is a new technology. It is a very novel technology. And I think teachers already know these things. It's really the people like me, the engineers, the developers of these tools that need to know these better. But integrating these technologies into your lesson plan, into your everyday curriculum and aligning these with existing assessments, with existing testing is what is going to sustain long-term use. Adopting VR or XR just for the novelty or for the wow factor that it brings to the table will add value in the short term, but in the long term it's going to only be another device that collects dust on the shelf. So it's incredibly important from the get-go that you think about even the practicalities of things like having a classroom management tool, aligning this with curriculum and with standards. Which I think teachers already tried to advocate for, and we do our best to support them right from the very beginning.
Julie: Can you tell everybody where to find yourself, and how they can get a hold of you and where they can find it Inspirit VR?
Aditya: So our website is inspiritvr.com. And you can always get in touch with me at aditya@inspirit.com. I'm also available on Twitter, and social media is also another great way to get in touch with me. But I'm always happy to talk to people who are interested in working with us and learning more about virtual reality and education.
Julie: Well, thank you so much for joining us. Thank you again, Aditya.
Aditya: Thank you so much. My pleasure.
Julie: And thanks to all of our listeners. You can check out this podcast at xrforlearning.io. My name is Julie Smithson. Thanks, everyone. Take care.
Looking for more insights on XR and the future of learning? Subscribe to our podcast on iTunes, Google Play, or Spotify. You can also follow us on Twitter @XRLearningPod and connect with Julie on LinkedIn.
Inspirit VRStanford UniversitySTEMVR
Gearing Up for the 2020 Educators in VR Summit, with Daniel Dyboski-Bryant and Lorelle VanFossen
Teaching Soft Skills with Science in VR Labs, with Labster CEO Michael Jensen

redpajama_set_name: RedPajamaCommonCrawl


The extended deck takes the 36 card basic deck and adds some or all of nine additional cards.
The Excuse has no suit and no rank. It is usually treated as a blank, inert card.
The Pawns are a new rank of card, between 9s and Crowns. There are four Pawns. Each one has three suits, with each suit appearing on two of the four Pawns.
The Courts introduce yet another rank of card, between Pawns and Crowns. Just as the Pawns, the Courts are four cards, each with three suits. The Court cards include the combinations of suits that don't appear on any basic deck card (like Moons and Wyrms) but none of the most common combinations (like Moons and Suns).


GOP legislators say questions about oversight remain.
The two highest-profile public officials on the U.S. Bank Stadium oversight commission stepped down Thursday amid growing legislative and public pressure over their use of two luxury suites to host friends, family and political allies at games and concerts.
Michele Kelm-Helgen, chairwoman of the Minnesota Sports Facilities Authority (MSFA), announced her resignation early in the day, saying the decision was her own. By early afternoon, Executive Director Ted Mondale resigned rather than face an impending vote to remove him.
The departures came as state legislators move to overhaul the MSFA's structure, claiming lax management and oversight by the pair. Gov. Mark Dayton, who had been supportive of the two, said their resignations would "enable the authority to move ahead and, hopefully, allow everyone to regain perspective" on the stadium.
The DFL governor praised Mondale and Kelm-Helgen for "commendable" and "exceptional" work and pledged to work with legislators on the future of the MSFA.
"Everybody's still kind of taking stock of what's occurred" in the past 24 hours, Dayton said.
Ted Mondale and Michele Kelm-Helgen responded after Minnesota Legislative Auditor James Nobles delivered a scathing report to the House and Senate State Government Finance committee on Feb. 7.
At a four-hour joint hearing on the release of Nobles' report last week, Mondale and Kelm-Helgen faced hours of blunt questions from Republicans who didn't buy their explanations.
Dayton said he didn't ask for either resignation. But supporting them grew politically difficult after a House committee voted 17-1 to support a bill to reshape the MSFA, with all but one DFL lawmaker joining Republicans in support.
Kelm-Helgen was appointed by Dayton, so he had the authority to remove her. Mondale, however, could have been fired by a vote of the four remaining MSFA commissioners — and a movement was afoot to do so.
Former state Supreme Court Chief Justice Kathleen Blatz, appointed in January to the MSFA, said she spoke with fellow board members Thursday and the plan was to vote to remove Mondale as soon as possible.
The other three commissioners have been in place for at least a year, and also used the suites themselves for friends and family. They are Tony Sertich, Bill McCarthy and Barbara Butts Williams.
Three Republican legislators were leading a push to retool the MSFA's composition. One of them, Rep. Sarah Anderson of Plymouth, argued a clean sweep was necessary. "I don't know why you would want to continue with an operation where there's a culture of not doing things right," Anderson said.
Their proposal would overhaul the structure of the MSFA, and eliminate the paid position Kelm-Helgen had been occupying. It would also slash the executive director's salary. The board would grow to seven members from five, and would be appointed by legislative leaders from both parties as well as the governor and the Minneapolis mayor.
Anderson also repeatedly said the suites were just the "tip of the iceberg" in terms of questionable management of the stadium. She charged that the board had illegally given Kelm-Helgen and Mondale authority to enter contracts above $200,000 without board approval.
The statement said Anderson falsely claimed the MSFA wasn't aware of changes made by Mondale and Kelm-Helgen. The votes are on the board's website and board members were briefed on all actions between monthly meetings, Hathaway wrote.
Nobles' 100-page report faulted Kelm-Helgen and Mondale's leadership of the MSFA, saying they had violated a core ethical principle by using public office for personal gain, by handing out free tickets, VIP parking, food and drink to friends and allies.


text:
Vital Preparatory Nursery School holds graduation ceremony
Jul 18, 2014, 10:53 AM | Article By: Njie Baldeh
Vital Preparatory Nursery and Lower Basic School Thursday held its 5th graduation ceremony at the school grounds in Kanifing.
In her welcoming speech, Sofi Gomez, headmistress of the school, said as head of the school, she was honored and privileged to preside over the graduation ceremony of Nursery Three to Grade one and the outgoing Grade six pupils of the institution, as the name implies, bidding them farewell to higher education level.
Madam Gomez added that Vital Nursery in the academic year 2012/2013 had an enrolment of 34 pupils in the three grades, namely nursery one, two and three.
The year 2013/2014, the nursery registered 49 pupils and the Lower Basic registered 81 pupils, she said, adding that this year the school registered 101 pupils in the Lower Basic, which shows that the school is growing gradually; nonetheless they need more pupils to meet the class target.
According to headmistress Gomez, the school has seen massive development thanks to the cooperation and dedication of hardworking staff.
To them she said a "big thank you" and to the ancillary staff she said "thank you" for the upkeep of the classes, toilets and school environment.
"In the area of development, we enjoin all and sundry to help in the development of the school through sponsorship as we desperately need some facilities like a room to house the computers, library or a resource room for the pupils and staff," she said.
The pupils of Grade six are the ambassadors who would sell the good name of the school by endeavouring to show dedication, discipline and hard work at all times as it is very vital in their new environment hence she hopes they would always maintain the momentum, she stated.
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text:
Home Vlerick Business School Digital Leadership
SchoolVlerick Business School
All dates January 14-18, 2019
LocationVlerick Campus Brussels, Brussel, BE
Price €6,295
CategoryTechnology, Leadership
Do you want to reassure your digital leadership and make a step forward transforming your organisation? If you are a future-driven executive this programme is for you!
Focus on transformational change strategies and the critical fusion of disruptive technologies and the business. What does digital transformation mean for your business? How do you start? Where do you invest? And where not? How do you compare with your peers or versus best practices?
Put yourself and your company on the front row of understanding today's digitised business environment and the impact that disruptive technologies have on the leadership in your company.
This world-class digital leadership programme is reserved for executives, middle managers and high potentials with an aspiration to lead digital projects within their organisations. Entrepreneurs can join the programme to gain inspiration on digital innovation to check their initiatives and vision against the realities of the digital world, and to develop their business plans with digital experiments.
The programme targets people passionate about "digital" and going beyond the obvious to achieve a competitive advantage.
All applicants are subject to a qualification process (review CV or LinkedIn profile). Candidates will be notified of the admission decision within one week of receipt of their application.
Participants that typically register include the following functions: Digital Project Manager, VP Customer Orientation & Transformation, CIO, Digital Transformation Executive, Marketing Director, CEO, Digital Architect, Business Unit Manager, Strategy Manager... and they come from a variety of sectors such as Pharmaceutical, Industrial Assembly, Automotive, Food and Beverage, Banking & Insurance, Fashion Retailer, Services, Consulting, Industrial Manufacturing...
Digital impacts the entire organisation, requiring leadership at multiple points across the enterprise. Together, we will shape the future of Digital in organisations. We'll discuss where we are heading, and – through action planning – we'll inspire and guide you in taking the lead in defining the next phase.
As a participant in this Digital Leadership programme, you are removed from the everyday concerns of the workplace so that you can focus on transformational change strategies and the critical fusion of disruptive technologies – such as social media, analytics, mobile and cloud – and the business. You will use the critical skills acquired in the programme to transform your role for greater responsibilities and increased leadership.
We promise you an intensive and highly interactive learning experience – based on best-practice frameworks and pragmatic tools, complemented by real-life case studies with actionable insights. You'll experience a blend of lectures, guest speakers, case studies, self-assessment, action learning and problem solving. And the peer networking creates a unique climate that complements the theory, frameworks and tools presented in this programme.
You will return to your organisation with a new understanding of today's digitised business environment and the impact that disruptive technologies have on the technology leadership in your organisation.
Course information from Vlerick Business School
Stijn Viaene
Professor & Partner
Stijn is passionate about what it means to successfully create a digital enterprise, capturing the value that comes with the use of novel technological advances such as big data, analytics, social media, mobile computing, and the cloud. The research for business initiatives he develops in collaboration with industry and public sector partners at Vlerick Business School, including the Centre for Excellence "BPM Network" (Business Process Management), and the Centre for Excellence "Enterprise Architecture Management" contribute to a significantly better practical and academic understanding of what it means to make optimal use of IT in a contemporary organizational context. Stijn loves teaching with cases. He has written teaching cases with, among others, FedEx ("Enterprise Business-IT engagement in an Empowered Business Environment"), ING ("Marketing's Business Transformation at ING Belgium Retail"), KLM ("CRM Excellence at KLM Royal Dutch Airlines"), Barco ("Corporate IT Transformation at Barco"), BNP Paribas Fortis ("Hello Bank! The Birth of a Mobile Bank"), and Solvay ("Leveraging Solvay Group Culture with a Third Generation Intranet"). Stijn can also be followed on twitter (@destivia).
Frank Goedertier
Within the school Frank Goedertier is responsible for the Vlerick Brand Management Centre and acts as Program Director of the Brand Management & Communication Programme. Over the past years he has executed customised teaching assignments and customised business research projects for companies such as Belfius, KPN Belgium/Base, AG Insurance, Agoria, Macintosh Retail Group, Sanoma, SD Worx, Velux, Optima, Tiense Suiker, Belgacom Proximus, General Motors, Barco etc.
Frank Goedertier has been Visiting Scholar at the Richard Ivey School of Business (London Ontario-Canada) and at Kellogg School of Management (Chicago-USA). Frank Goedertier has received awards for managerial flair and teamwork skills (Winner of the Vlerick Henkel Prize in 2001) and academic rigor in the execution of managerially relevant research (Winner of the Best Paper award at Said Business School (Oxford) - Academy of Marketing's Corporate Brand, Reputation and Corporate Identity SIG conference in 2011).
Frank's expertise lies in the areas of branding, marketing communication, consumer psychology and consumer behaviour in general. In his recent work he concentrates on developing theories to successfully engage in branding in the digital age and in developing simple marketing tactics to efficiently communicate in an information overload era.
Peter De Prins
Professor of Management Practice
Peter De Prins is Professor of Management Practice. He is recognised as a dynamic and interactive teacher. He focuses on the practical use of theoretical and academic models making use of group-participation and collaborative learning. He is also a sought after speaker on motivation, leadership, coaching and management.
As an entrepreneur Peter has travelled the world and worked with a wide range of nationalities. He has hands-on experience of people-management, executive coaching and leadership mainly in Europe and the USA.
His research focuses on the behavioural aspects of business coaches (he co-developed the Business Coach Behavioural Index) and the coaching aspects of leadership.
Miguel Meuleman
Miguel Meuleman studies how entrepreneurs and intrapreneurs successfully identify and exploit new opportunities. He looks at different aspects of the new venture creation process: opportunity identification techniques, business model generation, managing uncertainty and financing new ventures. Based on insights from practitioners and academics, he developed a website that lays out the process and principles behind new venture creation. As a member of the investment committee of the Ark Angel Fund, he evaluates new venture ideas on a daily basis and has experience with the obstacles in the new venture financing process.
Miguel Meuleman has recently also been involved in the launch of The Entrepreneurial Buyout Platform at Vlerick Business School. A new business can be established from scratch or acquired in some way or another through a buyout. In an entrepreneurial buyout an entrepreneurial individual or team pool their own money together with investor money to buy shares in the company from its current owners to create a new independent entity with the main goal to explore entrepreneurial initiative in order to increase efficiency and achieve growth. The Entrepreneurial Buyout Platform wants to promote acquisitions to individuals seeking entrepreneurial opportunities by creating awareness and developing and spreading state-of-the-art knowledge on the processes underlying successful entrepreneurial buyouts.
Vlerick Campus Brussels
21 Bolwerklaan
Disclaimer: When you click submit, we will send an email on your behalf to Vlerick Business School from which you are requesting information. The email will contain your contact information so a school representative will be able to get in touch with you.
April 15-16, 2020 2 days
Integrating Performance and Progress
The Explorer Mindset: New Frontiers in Executive Leadership
November 15, 2020 - March 25, 2021 10 days
Learning to Lead


text:
package com.qubole.qds.sdk.java.client;

import com.qubole.qds.sdk.java.api.ClusterApi;
import com.qubole.qds.sdk.java.api.CommandApi;
import com.qubole.qds.sdk.java.api.DbTapApi;
import com.qubole.qds.sdk.java.api.HiveMetadataApi;
import com.qubole.qds.sdk.java.api.ReportApi;
import com.qubole.qds.sdk.java.api.SchedulerApi;
import com.qubole.qds.sdk.java.api.sparkjobserver.AppApi;
import com.qubole.qds.sdk.java.details.RequestDetails;
import com.qubole.qds.sdk.java.details.ForPage;
import javax.ws.rs.client.InvocationCallback;
import javax.ws.rs.core.GenericType;
import java.io.Closeable;
import java.util.concurrent.Future;

/**
 * client interface
 */
public interface QdsClient extends Closeable
{
    /**
     * Return cluster api factory
     *
     * @return cluster api factory
     */
    public ClusterApi cluster();

    /**
     * Return command api factory
     *
     * @return command api factory
     */
    public CommandApi command();

    /**
     * Return hive metadata api factory
     *
     * @return hive metadata factory
     */
    public HiveMetadataApi hiveMetadata();

    /**
     * Return DbTaps api factory
     *
     * @return DbTaps factory
     */
    public DbTapApi dbTaps();

    /**
     * Return report api factory
     *
     * @return report factory
     */
    public ReportApi report();

    /**
     * Return scheduler api factory
     *
     * @return scheduler factory
     */
    public SchedulerApi scheduler();

    /**
     * Return spark job server apps api factory
     *
     * @return spark job server apps api factory
     */
    public AppApi sparkJobServerApp();

    /**
     * Low-level request invoker. Not normally used directly. Use the api factories instead.
     *
     * @param forPage paging info or null
     * @param requestDetails request entity or null
     * @param responseType type of the response
     * @param additionalPaths additional path components
     * @return async result
     */
    public <T> Future<T> invokeRequest(ForPage forPage, RequestDetails requestDetails, Class<T> responseType, String... additionalPaths);

    /**
     * Low-level request invoker. Not normally used directly. Use the api factories instead.
     *
     * @param forPage paging info or null
     * @param requestDetails request entity or null
     * @param responseType type of the response
     * @param additionalPaths additional path components
     * @return async result
     */
    public <T> Future<T> invokeRequest(ForPage forPage, RequestDetails requestDetails, GenericType<T> responseType, String... additionalPaths);

    /**
     * Low-level request invoker. Not normally used directly. Use the api factories instead.
     *
     * @param forPage paging info or null
     * @param requestDetails request entity or null
     * @param callback response callback
     * @param additionalPaths additional path components
     * @return async result
     */
    public <T> Future<T> invokeRequest(ForPage forPage, RequestDetails requestDetails, InvocationCallback<T> callback, String... additionalPaths);

    @Override
    public void close();
}

redpajama_set_name: RedPajamaGithub


Andrew, you symbolize why this game of publishing is worth playing. I'm convinced the secret to success is two-fold. One, write more books and keep them coming out on a regular basis. Two, do everything you can to help other authors succeed, and they will help you get there as well.
To start with a thousand apologies for being such an age in writing to thank you for the book. I absolutely adore it. I read it once and straight away I read it again. I think it is absolutely stunning. You have a marvellous style and a beautiful delivery as it were. My feeling is that you have a lot of Proust about you.
I have reviewed of your application to become an Amazon Associate, and visited the website where you planned to advertise for Amazon.co.uk.
When selecting Amazon.co.uk Associates Programme participants, we try to determine why a customer would seek out the website in question, review the topic or content of the website, and subsequently follow a link to Amazon.co.uk.
The programme is not set up to simply advertise Amazon.co.uk and third party links within websites, or make mini Amazon websites.
Since your website does not appear to be finished, we are unable to view your content in its entirety.
We have decided that your site may not present a mutually beneficial business opportunity and because of this, we can not accept your application at this time.
We encourage you to resubmit your application after creating a unique site with original content.
Thank you for your interest in the Associates Programme.


text:
California, San Francisco Sue Trump Administration Over Sanctuary City GrantsThe state of California and city of San Francisco are suing the U.S. Department of Justice over President Donald Trump's sanctuary city restrictions on public safety grants.
California Senate OKs Statewide Immigrant Sanctuary BillCalifornia lawmakers gave initial approval to a measure that prevents law enforcement from cooperating with federal immigration officials.
Marin County Immigrant Families Are Planning For The WorstRumors of immigration raids has put a Marin County community on edge.
San Francisco Signs Immigrant Protection Memo With Mexican Consular GeneralThe Mexican Consul General and the San Francisco District Attorney signed a memo extending victim advocacy program for the undocumented.
Federal Lawsuit Claims Wells Fargo Illegally Denied Student Loans To ImmigrantsA federal lawsuit accuses banking giant Wells Fargo of illegally denying student loans to young immigrants who are protected from deportation and allowed to work and study in the U.S. under a program created by former President Barack Obama.
Bullet That Killed Kate Steinle In SF Pier Shooting Appears To Have RicochetedThe bullet that killed a young San Francisco woman may have ricocheted before striking her in the back while she was sightseeing with her father along the city's popular waterfront, a ballistic expert testified Wednesday.
Undocumented Immigrant Makes Court Appearance In Shooting Death Of Woman On San Francisco's WaterfrontAn undocumented immigrant suspected of fatally shooting a 32-year-old San Francisco woman in broad daylight at the San Francisco waterfront last month attended his preliminary hearing Tuesday.
Most New California Licenses Going To Undocumented ImmigrantsAfter a new law went into effect in January, more than half of all new driver's licenses issued in California this year have gone to people who are in the country illegally, the state said Friday.
Bay Area's Undocumented Immigrants Watching Closely As President Set To Unveil Amnesty PlanUndocumented immigrants in the San Francisco Bay Area will be watching closely as President Obama unveils his plan to let them stay.
San Jose Police Officer Accused Of Raping Undocumented Immigrant Faces New Sexual Assault AllegationsThere are new sexual assault allegations against a San Jose police officer accused of raping an undocumented immigrant while on duty.
DMV Opening New Outlets To Accommodate Undocumented Immigrants In CaliforniaThe DMV is opening new temporary outlets to accommodate an expected surge in demand from undocumented immigrants in California.
California DMV Expanding Hours To Meet Demand For Immigrants Seeking Driver's LicensesCalifornia's Department of Motor Vehicles is expanding office hours as it prepares to issue an expected 1.4 million licenses to people in the country illegally.
More SF Landlords Evicting Tenants Without Any Evidence, According To New Housing ReportA new report shows a rising trend of San Francisco landlords evicting tenants for alleged nuisances that include cooking late at night and parking a car outside of the lines.
Bay Area Schools Prepare For Influx Of New Immigrant Students From Central AmericaFor some of the children from Central America who crossed the border without their parents in the past few months, their new life means starting school in the Bay Area.
Santa Clara County Official Looks To Invite Undocumented Immigrant Children To Silicon ValleyWhile some Southwestern communities have seen protests against undocumented immigrant children being placed in their towns, Santa Clara County officials want to invite some of those children to come to the Silicon Valley.
5:00 PM5th Quarter
5:30 PMKPIX 5 News