IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders ...are associated with significant childhood morbidity and mortality. OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly. DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children’s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase–AKT (serine/threonine kinase)–mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders. RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size. CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.
BACKGROUNDOutcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4-associated (ABCA4-associated) retinopathy. We aimed to quantify ellipsoid zone ...(EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4-associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age.METHODSWe analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4-associated retinopathy from a prospective natural history study with a median IQR follow-up of 4.2 years 3.1, 5.1. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30° × 15°) were segmented using a deep learning (DL) approach. For genotype-phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm2) as the dependent variable.RESULTSPatients exhibited an average (square-root-transformed) EZ-loss progression rate of 95% CI 0.09 mm/y 0.06, 0.11. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss. The average distance from the EZ-loss boundary to normalization of ONL thickness (to ±2 z score units) was 3.20° 2.53, 3.87. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20° 0.91, 1.48 for the IS and 0.60° 0.49, 0.72 for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss.CONCLUSIONPatients with ABCA4-associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss. DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants.TRIAL REGISTRATIONClinicalTrials.gov identifier: NCT01736293.FUNDINGNational Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.
To systematically assess the ability to detect change and retest reliability for a panel of visual function assessments in ABCA4 retinopathy.
Prospective natural history study (NCT01736293).
Patients ...with at least 1 documented pathogenic ABCA4 variant and a clinical phenotype consistent with ABCA4 retinopathy were recruited from a tertiary referral center. Participants underwent longitudinal, multifaceted functional testing, including measures of function at fixation (best-corrected visual acuity, low-vision Cambridge Color Test), macular function (microperimetry), and retina-wide function (full-field electroretinography ERG). Two- and 5-year ability to detect change was determined based on the η2 statistic.
A total of 134 eyes from 67 participants with a mean follow-up of 3.65 years were included. In the 2-year interval, the microperimetry-derived perilesional sensitivity (η2 of 0.73 0.53, 0.83; –1.79 dB/y –2.2, –1.37) and mean sensitivity (η2 of 0.62 0.38, 0.76; –1.28 dB/y –1.67, –0.89) showed most change over time, but could only be recorded in 71.6% of the participants. In the 5-year interval, the dark-adapted ERG a- and b-wave amplitude showed marked change over time as well (eg, DA 30 a-wave amplitude with an η2 of 0.54 0.34, 0.68; –0.02 log10(µV)/y –0.02, –0.01). The genotype explained a large fraction of variability in the ERG-based age of disease initiation (adjusted R2 of 0.73)
Microperimetry-based clinical outcome assessments were most sensitive to change but could only be acquired in a subset of participants. Across a 5-year interval, the ERG DA 30 a-wave amplitude was sensitive to disease progression, potentially allowing for more inclusive clinical trial designs encompassing the whole ABCA4 retinopathy spectrum.
Exploring political skill and deception Clements, Jeffrey A; Boyle, Randy; Proudfoot, Jeffrey G
International journal of sociology and social policy,
04/2016, Letnik:
36, Številka:
3/4
Journal Article
Recenzirano
Purpose
– The purpose of this paper is to explore and develop a model which examines the effects of political skill on an individual’s intent to deceive.
Design/methodology/approach
– Data were ...obtained through a survey research design (n=273). The sample consisted of college students. A covariance-based structural equation modeling approach was used to analyze the data.
Findings
– Individual’s with high levels of political skill had more deception confidence and less deception guilt. Increased deception confidence was shown to be positively related to perceptions of deception success which is turn is positively associated with deception intent. The factors duping delight and deception guilt were also found to be related to deception intent.
Research limitations/implications
– This research furthers deception research by using a strong behavioral framework to determine the motivational influences on an individual’s politically motivated intent to deceive. In doing so, this research identifies factors which contribute to the general understanding of politically motivated deception intent. However, caution must be applied when making external generalizations outside of the sample of college students.
Practical implications
– There are practical applications to this research as well. In general those who are highly politically skilled seem to have a stronger intention to deceive. At best, these findings can begin to contribute to the understanding of who we can trust and who we should be wary of. At worst, these findings can help us know who we should turn to when we need to deceive and manipulate others without them catching on. Perhaps this is why we love the rock-star politicians on the side of the isle but loathe the rock-star politicians on the other side of the isle. If we are able to assess the level of political skill in our friends, co-workers, bosses, politicians, etc., we may be keener in picking up on the signals of deception.
Social implications
– One final area of future research which can build on the concepts presented in this study is the area of social and political power at the macro level. Though the focus of this study is the individual, it is possible that political skill and deceptive communications play an important part of power relationships in wide range of stable institutional systems. Future research should examine to what extent an individual’s political skill and deception abilities can influence society at large.
Originality/value
– This research extends research on political skill as it explores the effect of political skill in a new context. This research identifies an important facet of why some individuals are better able than others to successfully deceive and may help explain some of the variability in the inability to consistently detect deception efforts.
Standard two-dimensional ultrasound has been used to aid prenatal visualization and detection of anomalies for the past 60 years. Three-dimensional ultrasound, introduced in the 1980s, provides the ...additional capability of examining the in utero environment from a variety of different angles. Use of this technology in conjunction with standard two-dimensional ultrasound can lead to a more thorough evaluation of structural defects and a greater patient understanding of genetic conditions.
The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active ...enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
We report on a 20-month-old male, diagnosed prenatally with de novo mosaic ring chromosome 18 and low level monosomy 18, who also exhibited an inherited and apparently balanced translocation between ...chromosomes 3 and 6. We believe this to be the first reported case of prenatally diagnosed mosaic ring chromosome 18 and monosomy 18 in which the child was carried to term. Ring chromosomes are associated with an abnormal phenotype that is dependent on the amount of material that is deleted from the p and q arms. This child has a 22.5 Mb deletion of 18q and a 2.8 Mb deletion of 18p as a result of ring formation. Although the large deletion has resulted in some developmental delays and health problems, the child is making more developmental progress than was anticipated prenatally. We present his clinical course and the genetic counseling challenges associated with this case.
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