THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion

Short intense ion pulses for materials and warm dense matter research

We have commenced experiments with intense short pulses of ion beams on the Neutralized Drift Compression Experiment-II at Lawrence Berkeley National Laboratory, by generating beam spots size with radius r < 1 mm within 2 ns FWHM and approximately 10^10 ions/pulse. To enable the short pulse durations and mm-scale focal spot radii, the 1.2 MeV Li+ ion beam is neutralized in a 1.6-meter drift compression section located after the last accelerator magnet. An 8-Tesla short focal length solenoid compresses the beam in the presence of the large volume plasma near the end of this section before the target. The scientific topics to be explored are warm dense matter, the dynamics of radiation damage in materials, and intense beam and beam-plasma physics including selected topics of relevance to the development of heavy-ion drivers for inertial fusion energy. Here we describe the accelerator commissioning and time-resolved ionoluminescence measurements of yttrium aluminium perovskite using the fully integrated accelerator and neutralized drift compression components.Comment: 7 pages, 9 figure

Brazilian urban population genetic structure reveals a high degree of admixture

Advances in genotyping technologies have contributed to a better understanding of human population genetic structure and improved the analysis of association studies. To analyze patterns of human genetic variation in Brazil, we used SNP data from 1129 individuals - 138 from the urban population of Sao Paulo, Brazil, and 991 from 11 populations of the HapMap Project. Principal components analysis was performed on the SNPs common to these populations, to identify the composition and the number of SNPs needed to capture the genetic variation of them. Both admixture and local ancestry inference were performed in individuals of the Brazilian sample. Individuals from the Brazilian sample fell between Europeans, Mexicans, and Africans. Brazilians are suggested to have the highest internal genetic variation of sampled populations. Our results indicate, as expected, that the Brazilian sample analyzed descend from Amerindians, African, and/or European ancestors, but intermarriage between individuals of different ethnic origin had an important role in generating the broad genetic variation observed in the present-day population. The data support the notion that the Brazilian population, due to its high degree of admixture, can provide a valuable resource for strategies aiming at using admixture as a tool for mapping complex traits in humans. European Journal of Human Genetics (2012) 20, 111-116; doi:10.1038/ejhg.2011.144; published online 24 August 2011CNPq (Brazil) [150653/2008-5]FAPESP [2007/58150-7]Hospital Samaritano, Sao Paul

Examining how response tokens function in a qualitative research interview

The general aim of this study was to describe some of the discursive practices for managing qualitative research interviews. The specific aim was to examine the form, function, and location of response tokens in a qualitative research interview. A conversation analysis (cf., Sacks, 1992) of 266 lines of transcribed talk from New Zealand Interview 2 (van den Berg, Wetherell, & Houtkoop-Steenstra, 2003) on race relations in New Zealand during the 1980s was completed. First, response tokens were identified in the transcript using Gardner’s taxonomy (Gardner, 2001). Second, the frequency was calculated for different classes of response tokens. Third, how the interviewer and the interviewee used response tokens to maintain or change speakership, maintain or change topic, and formulate answers were examined. Response tokens are a pervasive feature in qualitative research interviews accounting for 11.47% of all words spoken. The interviewer produced 60.7% and the respondent produced 39.3% of these. Continuers (e.g., Mm mhm), news-markers (e.g., Right), and acknowledgement tokens signalling hesitancy (e.g., Uhm), delicateness (e.g. Mm) and certainty (e.g., Yes) were oriented to points of grammatical completion in the talk and located at transition relevant places. Their function was therefore consistent with Gardner’s taxonomy. Response tokens were oriented to speakership enabling a speaker to hold the floor but allowing a recipient to signal continuing listenership or project an upcoming speaker’s bid. Response tokens shape the trajectory of a qualitative research interview by being oriented to the immediately prior turn. Response tokens manage multi-turn answers by marking mutual understanding as an ongoing accomplishment and by dealing with insertion sequences that divert talk away from the research question. Thus, they shape the overall structure of a qualitative research interview by helping to organise and design turns and speakership. These findings display how interviews are socially constructed and culturally informed events

Activation of mitogen-activated protein kinases during natural freezing and thawing in the wood frog

The responses of mitogen-activated protein kinase (MAPK) family members, including ERK (extracellular signal-regulated kinase), JNK (c-Jun NH2- terminal kinase), and p38, in the metabolic responses to whole animal freezing (up to 24 h frozen at -2.5°C) and thawing (up to 4 h at 5°C after a 12 h freeze) were examined in four organs (liver, kidney, heart, brain) of the freeze-tolerant wood frog Rana sylvatica. Levels of the active phosphorylated form of p38 increased within 20 min as an early response to freezing in liver and kidney but rose later (after 12 h) in heart. Both JNK and p38 were activated during thawing in liver, kidney and heart with temporally-distinct patterns in each organ. The only MAPK response to freeze/thaw in frog brain was a transient elevation of p38 after 90 min thawing. ERK activity did not respond to freeze/thaw in any organ. The levels of c-Fos increased during freezing in kidney and brain whereas c-Jun was unaffected by freeze/thaw. Organ-specific responses by MAPKs, particularly p38, suggest that these may have roles in regulating metabolic or gene expression responses that may be adaptive in dealing with freezing stress or metabolic recovery during thawing

The effect of prolonged anoxia on enzyme activities in oysters (Crassostrea virginica) at different seasons

The effect of prolonged anoxia (96 h under a N2 atmosphere) during either winter (November) or summer (July) was investigated by measuring the maximal activities of 20 metabolic enzymes in gill, mantle, hepatopancreas, and phasic and catch adductor muscles of the oyster, Crassostrea virginica. The enzymes analyzed are involved in carbohydrate and amino acid metabolism, the pentose phosphate shunt, anaplerotic reactions of the TCA cycle, and phosphagen/adenylate metabolism. The data demonstrate that oyster metabolism is influenced by both long-term seasonal change and by shorter-term environmental insult (anoxia). Seasonal changes were concentrated among enzymes involved in glycogen metabolism whereas the prominent response to anoxia was suppression of PK activity. Anoxia exposure induced tissue- specific changes in enzyme activities suggesting a substantial metabolic reorganization involving both coarse controls on enzyme amount and reversible covalent modification. In addition, the effects of anoxia on enzymes of intermediary metabolism were seasonally dependent and more widespread in the winter. These results demonstrate the interaction of two environmental variables (season, anoxia) and suggest the importance of season as a modifying factor in the anoxic response

The Impact of Epigenetics on Cardiovascular Disease

Mortality and morbidity from cardiovascular diseases (CVDs) represents a huge burden to society. It is recognized that environmental factors and individual lifestyles play important roles in disease susceptibility, but the link between these external risk factors and our genetics has been unclear. However, the discovery of sequence-independent heritable DNA changes (epigenetics) have helped us to explain the link between genes and the environment. Multiple diverse epigenetic processes, including DNA methylation, histone modification, and the expression of non-coding RNA molecules affect the expression of genes that produce important changes in cellular differentiation and function, influencing the health and adaptability of the organism. CVDs such as congenital heart disease, cardiomyopathy, heart failure, cardiac fibrosis, hypertension, and atherosclerosis are now being viewed as much more complex and dynamic disorders. The role of epigenetics in these and other CVDs is currently under intense scrutiny, and we can expect important insights to emerge, including novel biomarkers and new approaches to enable precision medicine. This review summarizes the recent advances in our understanding of the role of epigenetics in CVD.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Echocardiographic Image Quality Deteriorates with Age in Children and Young Adults with Duchenne Muscular Dystrophy

BackgroundAdvances in medical care for patients with Duchenne muscular dystrophy (DMD) have resulted in improved survival and an increased prevalence of cardiomyopathy. Serial echocardiographic surveillance is recommended to detect early cardiac dysfunction and initiate medical therapy. Clinical anecdote suggests that echocardiographic quality diminishes over time, impeding accurate assessment of left ventricular systolic function. Furthermore, evidence-based guidelines for the use of cardiac imaging in DMD, including cardiac magnetic resonance imaging (CMR), are limited. The objective of our single-center, retrospective study was to quantify the deterioration in echocardiographic image quality with increasing patient age and identify an age at which CMR should be considered.MethodsWe retrospectively reviewed and graded the image quality of serial echocardiograms obtained in young patients with DMD. The quality of 16 left ventricular segments in two echocardiographic views was visually graded using a binary scoring system. An endocardial border delineation percentage (EBDP) score was calculated by dividing the number of segments with adequate endocardial delineation in each imaging window by the total number of segments present in that window and multiplying by 100. Linear regression analysis was performed to model the relationship between the EBDP scores and patient age.ResultsFifty-five echocardiograms from 13 patients (mean age 11.6 years, range 3.6–19.9) were systematically reviewed. By 13 years of age, 50% of the echocardiograms were classified as suboptimal with ≥30% of segments inadequately visualized, and by 15 years of age, 78% of studies were suboptimal. Linear regression analysis revealed a negative correlation between patient age and EBDP score (r = −2.49, 95% confidence intervals −4.73, −0.25; p = 0.032), with the score decreasing by 2.5% for each 1 year increase in age.ConclusionEchocardiographic image quality declines with increasing age in DMD. Alternate imaging modalities may play a role in cases of poor echocardiographic image quality

Mitogen-activated protein kinases and anoxia tolerance in turtles

The response of two vertebrate mitogen-activated protein kinase (MAPK) family members, the extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), to anoxia exposure in vivo was examined in organs (liver, heart, kidney, brain, spleen) of the anoxia-tolerant adult turtle, Trachemys scripta elegans. ERKs activities rose during anoxia only in spleen (a 2.8-fold increase). JNK activity showed a significant increase only in liver (4-fold increase) after 5 hr of anoxic submergence but declined thereafter. Levels of the transcription factor c-Fos were strongly suppressed in liver, heart, and kidney of anoxia-exposed turtles, whereas levels increased 2-fold in anoxic brain. The effect of anoxia on c-Myc was organ-specific and variable with 2- and 1.5-fold increases in protein expression in kidney and brain, respectively, and a 60% decrease in anoxic spleen. These results for an anoxia-tolerant animal suggest the potential importance of the MAPKs and of the immediate-early genes (c-fos, c-myc) in mediating adaptive responses to oxygen deprivation. (C) 2000 Wiley-Liss, Inc

Whole-Heart Assessment of Turbulent Kinetic Energy in the Repaired Tetralogy of Fallot

Approximately 10% of congenital heart diseases (CHDs) include Tetralogy of Fallot (TOF). Fortunately, due to advanced surgical techniques, most patients survive until adulthood. However, these patients require frequent monitoring for postoperative complications leading to heart hemodynamic alterations. Turbulent kinetic energy (TKE), as derived from 4D-flow magnetic resonance imaging (4D-flow MRI), has been used to characterize abnormal heart hemodynamics in CHD. Hence, this study aimed to assess the difference in TKE between patients with repaired TOF (rTOF) and healthy volunteers. A total of 35 subjects, 17 rTOF patients and 18 controls, underwent standard-of-care cardiac MRI and research 4D-flow MRI using a clinical 3T scanner. Heart chambers and great vessels were segmented using 3D angiograms derived from 4D-flow MRI. The TKE was quantified within segmented volumes. TKE was compared to standard cardiac MRI metrics. Controls demonstrated higher TKE in the left atria and left ventricle. However, patients demonstrated higher TKE in the right atria, right ventricle (p &lt; 0.05), and pulmonary artery. Lastly, no correlation was observed between TKE and standard clinical measurements. TKE can be a key indicator of the abnormal hemodynamics present in patients with rTOF and can assist future interventions and help monitor long-term outcomes