The 1963 Composition Revolution Will Not Be Televised, Computed, or Demonstrated by Any Other Means of Technology

ERIC Educational Resources Information Center

Rice, Jeff

2005-01-01

This article challenges the rebirth narrative traditionally attributed to Composition Studies and the date 1963. By revisiting specific media-oriented moments excluded from that narrative, the article discovers important moments ignored by Composition Studies regarding technological innovation and rhetorical production. The article argues that the…

Mathematical analysis of a multiple strain, multi-locus-allele system for antigenically variable infectious diseases revisited.

PubMed

Cherif, Alhaji

2015-09-01

Many important pathogens such as HIV/AIDS, influenza, malaria, dengue and meningitis generally exist in phenotypically distinct serotypes that compete for hosts. Models used to study these diseases appear as meta-population systems. Herein, we revisit one of the multiple strain models that have been used to investigate the dynamics of infectious diseases with co-circulating serotypes or strains, and provide analytical results underlying the numerical investigations. In particular, we establish the necessary conditions for the local asymptotic stability of the steady states and for the existence of oscillatory behaviors via Hopf bifurcation. In addition, we show that the existence of discrete antigenic forms among pathogens can either fully or partially self-organize, where (i) strains exhibit no strain structures and coexist or (ii) antigenic variants sort into non-overlapping or minimally overlapping clusters that either undergo the principle of competitive exclusion exhibiting discrete strain structures, or co-exist cyclically. Copyright © 2015. Published by Elsevier Inc.

Binary Star Orbits. 3. Revisiting the Remarkable Case of Tweedledum and Tweedledee

DTIC Science & Technology

2010-06-11

Observation Date 0.00 0.05 0.10 0.15 0.20 S ep ar at io n D iff er en ce FIN 332 Aa,Ab Unresolved Aa,Ab bB,aBdevlosernU bB,aB 233 NIF 1960 1970 1980 1990...2000 2010 Observation Date 0 50 100 150 200 P os iti on A ng le D iff er en ce FIN 332 Aa,Ab Unresolved Aa,Ab bB,aBdevlosernU bB,aB 233 NIF Figure

CHEK2*1100DELC Variant and Breast Cancer Risk

DTIC Science & Technology

2006-10-01

AD_________________ Award Number: DAMD17-03-1-0774 TITLE: CHEK2 *1100DELC Variant and Breast...01-10-2006 2. REPORT TYPE Final 3. DATES COVERED (From - To) 15 Sep 03 – 14 Sep 06 4. TITLE AND SUBTITLE CHEK2 *1100DELC...SUPPLEMENTARY NOTES 14. ABSTRACT: We propose to examine the association between the CHEK2 *1100delC gene variant and breast cancer among BRCA1/2

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

PubMed

Ceppi, Francesco; Gagné, Vincent; Douyon, Laurance; Quintin, Camille J; Colombini, Antonella; Parasole, Rosanna; Buldini, Barbara; Basso, Giuseppe; Conter, Valentino; Cazzaniga, Giovanni; Krajinovic, Maja

2018-01-01

We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

Revisiting Comparative Education in Latin America: Traditions, Uses, and Perspectives

ERIC Educational Resources Information Center

Acosta, Felicitas; Ruiz, Guillermo Ramón

2018-01-01

Comparative education is a field with a tradition that dates back to the beginning of the nineteenth century. The field has come a long way since the times when travellers sought educational experiences that could be applied in their places of origin; it has expanded across the world, though the rhythm of knowledge production varies significantly…

Shock Treatment: Using Immersive Digital Realism to Restage and Re-examine Milgram’s ‘Obedience to Authority’ Research

PubMed Central

Haslam, S. Alexander; Reicher, Stephen D.; Millard, Kathryn

2015-01-01

Attempts to revisit Milgram’s ‘Obedience to Authority’ (OtA) paradigm present serious ethical challenges. In recent years new paradigms have been developed to circumvent these challenges but none involve using Milgram’s own procedures and asking naïve participants to deliver the maximum level of shock. This was achieved in the present research by using Immersive Digital Realism (IDR) to revisit the OtA paradigm. IDR is a dramatic method that involves a director collaborating with professional actors to develop characters, the strategic withholding of contextual information, and immersion in a real-world environment. 14 actors took part in an IDR study in which they were assigned to conditions that restaged Milgrams’s New Baseline (‘Coronary’) condition and four other variants. Post-experimental interviews also assessed participants’ identification with Experimenter and Learner. Participants’ behaviour closely resembled that observed in Milgram’s original research. In particular, this was evidenced by (a) all being willing to administer shocks greater than 150 volts, (b) near-universal refusal to continue after being told by the Experimenter that “you have no other choice, you must continue” (Milgram’s fourth prod and the one most resembling an order), and (c) a strong correlation between the maximum level of shock that participants administered and the mean maximum shock delivered in the corresponding variant in Milgram’s own research. Consistent with an engaged follower account, relative identification with the Experimenter (vs. the Learner) was also a good predictor of the maximum shock that participants administered. PMID:25730318

75 FR 29768 - Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-27

... Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products... Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products'' dated January 2002 (2002 guidance), and the...CJD) by Blood and Blood Products''' dated August 2006 (2006 draft guidance). DATES: Submit electronic...

Whole-Exome Sequencing in Familial Parkinson Disease

PubMed Central

Farlow, Janice L.; Robak, Laurie A.; Hetrick, Kurt; Bowling, Kevin; Boerwinkle, Eric; Coban-Akdemir, Zeynep H.; Gambin, Tomasz; Gibbs, Richard A.; Gu, Shen; Jain, Preti; Jankovic, Joseph; Jhangiani, Shalini; Kaw, Kaveeta; Lai, Dongbing; Lin, Hai; Ling, Hua; Liu, Yunlong; Lupski, James R.; Muzny, Donna; Porter, Paula; Pugh, Elizabeth; White, Janson; Doheny, Kimberly; Myers, Richard M.; Shulman, Joshua M.; Foroud, Tatiana

2016-01-01

IMPORTANCE Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD. PMID:26595808

The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants.

PubMed

Fadista, João; Manning, Alisa K; Florez, Jose C; Groop, Leif

2016-08-01

Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 × 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity.

The Community College Effect Revisited: The Long-Term Impact of Community College Entry on B.A. Attainment.

ERIC Educational Resources Information Center

Crook, David B.; Lavin, David E.

To date, much of the research on the community college's effect on baccalaureate degree (B.A.) attainment has been based on the assumption that the educational attainment process occurs in the same way at two- and four-year institutions. However, the distinctive mission and clientele of community colleges create a different environment than that…

Historical photographs revisited: A case study for dating and characterizing recent loss of coral cover on the inshore Great Barrier Reef.

PubMed

Clark, Tara R; Leonard, Nicole D; Zhao, Jian-Xin; Brodie, Jon; McCook, Laurence J; Wachenfeld, David R; Duc Nguyen, Ai; Markham, Hannah L; Pandolfi, John M

2016-01-27

Long-term data with high-precision chronology are essential to elucidate past ecological changes on coral reefs beyond the period of modern-day monitoring programs. In 2012 we revisited two inshore reefs within the central Great Barrier Reef, where a series of historical photographs document a loss of hard coral cover between c.1890-1994 AD. Here we use an integrated approach that includes high-precision U-Th dating specifically tailored for determining the age of extremely young corals to provide a robust, objective characterisation of ecological transition. The timing of mortality for most of the dead in situ corals sampled from the historical photograph locations was found to coincide with major flood events in 1990-1991 at Bramston Reef and 1970 and 2008 at Stone Island. Evidence of some recovery was found at Bramston Reef with living coral genera similar to what was described in c.1890 present in 2012. In contrast, very little sign of coral re-establishment was found at Stone Island suggesting delayed recovery. These results provide a valuable reference point for managers to continue monitoring the recovery (or lack thereof) of coral communities at these reefs.

The Computational Complexity of the Kakuro Puzzle, Revisited

NASA Astrophysics Data System (ADS)

Ruepp, Oliver; Holzer, Markus

We present a new proof of NP-completeness for the problem of solving instances of the Japanese pencil puzzle Kakuro (also known as Cross-Sum). While the NP-completeness of Kakuro puzzles has been shown before [T. Seta. The complexity of CROSS SUM. IPSJ SIG Notes, AL-84:51-58, 2002], there are still two interesting aspects to our proof: we show NP-completeness for a new variant of Kakuro that has not been investigated before and thus improves the aforementioned result. Moreover some parts of the proof have been generated automatically, using an interesting technique involving SAT solvers.

Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases

DOE PAGES

Smedley, Damian; Kohler, Sebastian; Czeschik, Johanna Christina; ...

2014-07-30

Here, whole-exome sequencing (WES) has opened up previously unheard of possibilities for identifying novel disease genes in Mendelian disorders, only about half of which have been elucidated to date. However, interpretation of WES data remains challenging. As a result, we analyze protein–protein association (PPA) networks to identify candidate genes in the vicinity of genes previously implicated in a disease. The analysis, using a random-walk with restart (RWR) method, is adapted to the setting of WES by developing a composite variant-gene relevance score based on the rarity, location and predicted pathogenicity of variants and the RWR evaluation of genes harboring themore » variants. Benchmarking using known disease variants from 88 disease-gene families reveals that the correct gene is ranked among the top 10 candidates in ≥50% of cases, a figure which we confirmed using a prospective study of disease genes identified in 2012 and PPA data produced before that date. In conclusion, we implement our method in a freely available Web server, ExomeWalker, that displays a ranked list of candidates together with information on PPAs, frequency and predicted pathogenicity of the variants to allow quick and effective searches for candidates that are likely to reward closer investigation.« less

Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smedley, Damian; Kohler, Sebastian; Czeschik, Johanna Christina

Here, whole-exome sequencing (WES) has opened up previously unheard of possibilities for identifying novel disease genes in Mendelian disorders, only about half of which have been elucidated to date. However, interpretation of WES data remains challenging. As a result, we analyze protein–protein association (PPA) networks to identify candidate genes in the vicinity of genes previously implicated in a disease. The analysis, using a random-walk with restart (RWR) method, is adapted to the setting of WES by developing a composite variant-gene relevance score based on the rarity, location and predicted pathogenicity of variants and the RWR evaluation of genes harboring themore » variants. Benchmarking using known disease variants from 88 disease-gene families reveals that the correct gene is ranked among the top 10 candidates in ≥50% of cases, a figure which we confirmed using a prospective study of disease genes identified in 2012 and PPA data produced before that date. In conclusion, we implement our method in a freely available Web server, ExomeWalker, that displays a ranked list of candidates together with information on PPAs, frequency and predicted pathogenicity of the variants to allow quick and effective searches for candidates that are likely to reward closer investigation.« less

Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane.

PubMed

Corominas, Jordi; Colijn, Johanna M; Geerlings, Maartje J; Pauper, Marc; Bakker, Bjorn; Amin, Najaf; Lores Motta, Laura; Kersten, Eveline; Garanto, Alejandro; Verlouw, Joost A M; van Rooij, Jeroen G J; Kraaij, Robert; de Jong, Paulus T V M; Hofman, Albert; Vingerling, Johannes R; Schick, Tina; Fauser, Sascha; de Jong, Eiko K; van Duijn, Cornelia M; Hoyng, Carel B; Klaver, Caroline C W; den Hollander, Anneke I

2018-04-26

Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Genome-wide case-control association study of WES data. One thousand one hundred twenty-five AMD patients and 1361 control participants. A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. Genetic variants associated with AMD. We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07×10 -5 ). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane. This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Pathogenic Germline Variants in 10,389 Adult Cancers.

PubMed

Huang, Kuan-Lin; Mashl, R Jay; Wu, Yige; Ritter, Deborah I; Wang, Jiayin; Oh, Clara; Paczkowska, Marta; Reynolds, Sheila; Wyczalkowski, Matthew A; Oak, Ninad; Scott, Adam D; Krassowski, Michal; Cherniack, Andrew D; Houlahan, Kathleen E; Jayasinghe, Reyka; Wang, Liang-Bo; Zhou, Daniel Cui; Liu, Di; Cao, Song; Kim, Young Won; Koire, Amanda; McMichael, Joshua F; Hucthagowder, Vishwanathan; Kim, Tae-Beom; Hahn, Abigail; Wang, Chen; McLellan, Michael D; Al-Mulla, Fahd; Johnson, Kimberly J; Lichtarge, Olivier; Boutros, Paul C; Raphael, Benjamin; Lazar, Alexander J; Zhang, Wei; Wendl, Michael C; Govindan, Ramaswamy; Jain, Sanjay; Wheeler, David; Kulkarni, Shashikant; Dipersio, John F; Reimand, Jüri; Meric-Bernstam, Funda; Chen, Ken; Shmulevich, Ilya; Plon, Sharon E; Chen, Feng; Ding, Li

2018-04-05

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Revisiting Resident Assistant Burnout: Functions of Gender, Community Composition, Choice to Continue Employment, and Job Satisfaction

ERIC Educational Resources Information Center

Stoner, James C.

2017-01-01

Research on resident assistant burnout peaked in the 1980s, and there has been little scholarship since. Much of the original literature is dated, and some contains unresolved conflicts in the findings. Also, there is a glaring gap in the literature, specifically in how burnout relates to both RA job satisfaction and position departure. This study…

Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs

PubMed Central

Anderson, Heidi; Davison, Stephen; Hughes, Angela M.; Bouirmane, Julia; Lindqvist, Johan; Lytle, Katherine M.; Ganesan, Balasubramanian; Ottka, Claudia; Ruotanen, Päivi; Forman, Oliver P.; Fretwell, Neale; Cole, Cynthia A.; Lohi, Hannes

2018-01-01

Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com), an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare. PMID:29708978

Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs.

PubMed

Donner, Jonas; Anderson, Heidi; Davison, Stephen; Hughes, Angela M; Bouirmane, Julia; Lindqvist, Johan; Lytle, Katherine M; Ganesan, Balasubramanian; Ottka, Claudia; Ruotanen, Päivi; Kaukonen, Maria; Forman, Oliver P; Fretwell, Neale; Cole, Cynthia A; Lohi, Hannes

2018-04-01

Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com), an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare.

What drives health care expenditure?--Baumol's model of 'unbalanced growth' revisited.

PubMed

Hartwig, Jochen

2008-05-01

The share of health care expenditure in GDP rises rapidly in virtually all OECD countries, causing increasing concern among politicians and the general public. Yet, economists have to date failed to reach an agreement on what the main determinants of this development are. This paper revisits Baumol's [Baumol, W.J., 1967. Macroeconomics of unbalanced growth: the anatomy of urban crisis. American Economic Review 57 (3), 415-426] model of 'unbalanced growth', showing that the latter offers a ready explanation for the observed inexorable rise in health care expenditure. The main implication of Baumol's model in this context is that health care expenditure is driven by wage increases in excess of productivity growth. This hypothesis is tested empirically using data from a panel of 19 OECD countries. Our tests yield robust evidence in favor of Baumol's theory.

A clinical and molecular characterisation of CRB1-associated maculopathy.

PubMed

Khan, Kamron N; Robson, Anthony; Mahroo, Omar A R; Arno, Gavin; Inglehearn, Chris F; Armengol, Monica; Waseem, Naushin; Holder, Graham E; Carss, Keren J; Raymond, Lucy F; Webster, Andrew R; Moore, Anthony T; McKibbin, Martin; van Genderen, Maria M; Poulter, James A; Michaelides, Michel

2018-05-01

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Taï chimpanzees anticipate revisiting high-valued fruit trees from further distances.

PubMed

Ban, Simone D; Boesch, Christophe; Janmaat, Karline R L

2014-11-01

The use of spatio-temporal memory has been argued to increase food-finding efficiency in rainforest primates. However, the exact content of this memory is poorly known to date. This study investigated what specific information from previous feeding visits chimpanzees (Pan troglodytes verus), in Taï National Park, Côte d'Ivoire, take into account when they revisit the same feeding trees. By following five adult females for many consecutive days, we tested from what distance the females directed their travels towards previously visited feeding trees and how previous feeding experiences and fruit tree properties influenced this distance. To exclude the influence of sensory cues, the females' approach distance was measured from their last significant change in travel direction until the moment they entered the tree's maximum detection field. We found that chimpanzees travelled longer distances to trees at which they had previously made food grunts and had rejected fewer fruits compared to other trees. In addition, the results suggest that the chimpanzees were able to anticipate the amount of fruit that they would find in the trees. Overall, our findings are consistent with the hypothesis that chimpanzees act upon a retrieved memory of their last feeding experiences long before they revisit feeding trees, which would indicate a daily use of long-term prospective memory. Further, the results are consistent with the possibility that positive emotional experiences help to trigger prospective memory retrieval in forest areas that are further away and have fewer cues associated with revisited feeding trees.

Germline mutations in PALB2 in African-American breast cancer cases.

PubMed

Ding, Yuan Chun; Steele, Linda; Chu, Li-Hao; Kelley, Karen; Davis, Helen; John, Esther M; Tomlinson, Gail E; Neuhausen, Susan L

2011-02-01

Breast cancer incidence is lower in African Americans than in Caucasian Americans. However, African-American women have higher breast cancer mortality rates and tend to be diagnosed with earlier-onset disease. Identifying factors correlated to the racial/ethnic variation in the epidemiology of breast cancer may provide better understanding of the more aggressive disease at diagnosis. Truncating germline mutations in PALB2 have been identified in approximately 1% of early-onset and/or familial breast cancer cases. To date, PALB2 mutation testing has not been performed in African-American breast cancer cases. We screened for germline mutations in PALB2 in 139 African-American breast cases by denaturing high-performance liquid chromatography and direct sequencing. Twelve variants were identified in these cases and none caused truncation of the protein. Three missense variants, including two rare variants (P8L and T300I) and one common variant (P210L), were predicted to be pathogenic, and were located in a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding. We investigated and found no significant association between the P210L variant and breast cancer risk in a small case-control study of African-American women. This study adds to the literature that PALB2 mutations, although rare, appear to play a role in breast cancer in all populations investigated to date.

Nuclear transfer to prevent mitochondrial DNA disorders: revisiting the debate on reproductive cloning.

PubMed

Bredenoord, A L; Dondorp, W; Pennings, G; De Wert, G

2011-02-01

Preclinical experiments are currently performed to examine the feasibility of several types of nuclear transfer to prevent mitochondrial DNA (mtDNA) disorders. Whereas the two most promising types of nuclear transfer to prevent mtDNA disorders, spindle transfer and pronuclear transfer, do not amount to reproductive cloning, one theoretical variant, blastomere transfer does. This seems the most challenging both technically and ethically. It is prohibited by many jurisdictions and also the scientific community seems to avoid it. Nevertheless, this paper examines the moral acceptability of blastomere transfer as a method to prevent mtDNA disorders. The reason for doing so is that most objections against reproductive cloning refer to reproductive adult cloning, while blastomere transfer would amount to reproductive embryo cloning. After clarifying this conceptual difference, this paper examines whether the main non-safety objections brought forward against reproductive cloning also apply in the context of blastomere transfer. The conclusion is that if this variant were to become safe and effective, dismissing it because it would involve reproductive cloning is unjustified. Nevertheless, as it may lead to more complex ethical appraisals than the other variants, researchers should initially focus on the development of the other types of nuclear transfer to prevent mtDNA disorders. Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Molecular characterization of canine parvovirus strains in Argentina: Detection of the pathogenic variant CPV2c in vaccinated dogs.

PubMed

Calderon, Marina Gallo; Mattion, Nora; Bucafusco, Danilo; Fogel, Fernando; Remorini, Patricia; La Torre, Jose

2009-08-01

PCR amplification with sequence-specific primers was used to detect canine parvovirus (CPV) DNA in 38 rectal swabs from Argentine domestic dogs with symptoms compatible with parvovirus disease. Twenty-seven out of 38 samples analyzed were CPV positive. The classical CPV2 strain was not detected in any of the samples, but nine samples were identified as CPV2a variant and 18 samples as CPV2b variant. Further sequence analysis revealed a mutation at amino acid 426 of the VP2 gene (Asp426Glu), characteristic of the CPV2c variant, in 14 out of 18 of the samples identified initially by PCR as CPV2b. The appearance of CPV2c variant in Argentina might be dated at least to the year 2003. Three different pathogenic CPV variants circulating currently in the Argentine domestic dog population were identified, with CPV2c being the only variant affecting vaccinated and unvaccinated dogs during the year 2008.

Comparison between Mean Forces and Swarms-of-Trajectories String Methods.

PubMed

Maragliano, Luca; Roux, Benoît; Vanden-Eijnden, Eric

2014-02-11

The original formulation of the string method in collective variable space is compared with a recent variant called string method with swarms-of-trajectories. The assumptions made in the original method are revisited and the significance of the minimum free energy path (MFEP) is discussed in the context of reactive events. These assumptions are compared to those made in the string method with swarms-of-trajectories, and shown to be equivalent in a certain regime: in particular an expression for the path identified by the swarms-of-trajectories method is given and shown to be closely related to the MFEP. Finally, the algorithmic aspects of both methods are compared.

Historical photographs revisited: A case study for dating and characterizing recent loss of coral cover on the inshore Great Barrier Reef

PubMed Central

Clark, Tara R.; Leonard, Nicole D.; Zhao, Jian-xin; Brodie, Jon; McCook, Laurence J.; Wachenfeld, David R.; Duc Nguyen, Ai; Markham, Hannah L.; Pandolfi, John M.

2016-01-01

Long-term data with high-precision chronology are essential to elucidate past ecological changes on coral reefs beyond the period of modern-day monitoring programs. In 2012 we revisited two inshore reefs within the central Great Barrier Reef, where a series of historical photographs document a loss of hard coral cover between c.1890–1994 AD. Here we use an integrated approach that includes high-precision U-Th dating specifically tailored for determining the age of extremely young corals to provide a robust, objective characterisation of ecological transition. The timing of mortality for most of the dead in situ corals sampled from the historical photograph locations was found to coincide with major flood events in 1990–1991 at Bramston Reef and 1970 and 2008 at Stone Island. Evidence of some recovery was found at Bramston Reef with living coral genera similar to what was described in c.1890 present in 2012. In contrast, very little sign of coral re-establishment was found at Stone Island suggesting delayed recovery. These results provide a valuable reference point for managers to continue monitoring the recovery (or lack thereof) of coral communities at these reefs. PMID:26813703

No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes.

PubMed

Johnson, Emma C; Border, Richard; Melroy-Greif, Whitney E; de Leeuw, Christiaan A; Ehringer, Marissa A; Keller, Matthew C

2017-11-15

A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not. The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia. As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes. The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

77 FR 34390 - Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures To...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-11

... by Blood and Blood Products,'' Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...CJD) by Blood and Blood Products'' dated May 2010 (2010 CJD/vCJD guidance). When finalized, the... Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products' '' dated April 2012. The draft...

76 FR 66620 - Airworthiness Directives; Bombardier, Inc. Model CL-215-1A10, CL-215-6B11 (CL-215T Variant), and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-27

... effective date of this AD: Perform an in situ eddy current inspection for cracks on the forward lug of the...-6B11 (CL-415 Variant) airplanes). Thereafter, repeat the in situ eddy current inspection at intervals not to exceed 165 land landings. (2) If no crack is found: Repeat the in situ eddy current inspection...

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

PubMed Central

Huckins, L M; Hatzikotoulas, K; Southam, L; Thornton, L M; Steinberg, J; Aguilera-McKay, F; Treasure, J; Schmidt, U; Gunasinghe, C; Romero, A; Curtis, C; Rhodes, D; Moens, J; Kalsi, G; Dempster, D; Leung, R; Keohane, A; Burghardt, R; Ehrlich, S; Hebebrand, J; Hinney, A; Ludolph, A; Walton, E; Deloukas, P; Hofman, A; Palotie, A; Palta, P; van Rooij, F J A; Stirrups, K; Adan, R; Boni, C; Cone, R; Dedoussis, G; van Furth, E; Gonidakis, F; Gorwood, P; Hudson, J; Kaprio, J; Kas, M; Keski-Rahonen, A; Kiezebrink, K; Knudsen, G-P; Slof-Op 't Landt, M C T; Maj, M; Monteleone, A M; Monteleone, P; Raevuori, A H; Reichborn-Kjennerud, T; Tozzi, F; Tsitsika, A; van Elburg, A; Adan, R A H; Alfredsson, L; Ando, T; Andreassen, O A; Aschauer, H; Baker, J H; Barrett, J C; Bencko, V; Bergen, A W; Berrettini, W H; Birgegard, A; Boni, C; Boraska Perica, V; Brandt, H; Breen, G; Bulik, C M; Carlberg, L; Cassina, M; Cichon, S; Clementi, M; Cohen-Woods, S; Coleman, J; Cone, R D; Courtet, P; Crawford, S; Crow, S; Crowley, J; Danner, U N; Davis, O S P; de Zwaan, M; Dedoussis, G; Degortes, D; DeSocio, J E; Dick, D M; Dikeos, D; Dina, C; Ding, B; Dmitrzak-Weglarz, M; Docampo, E; Duncan, L; Egberts, K; Ehrlich, S; Escaramís, G; Esko, T; Espeseth, T; Estivill, X; Favaro, A; Fernández-Aranda, F; Fichter, M M; Finan, C; Fischer, K; Floyd, J A B; Foretova, L; Forzan, M; Franklin, C S; Gallinger, S; Gambaro, G; Gaspar, H A; Giegling, I; Gonidakis, F; Gorwood, P; Gratacos, M; Guillaume, S; Guo, Y; Hakonarson, H; Halmi, K A; Hatzikotoulas, K; Hauser, J; Hebebrand, J; Helder, S; Herms, S; Herpertz-Dahlmann, B; Herzog, W; Hilliard, C E; Hinney, A; Hübel, C; Huckins, L M; Hudson, J I; Huemer, J; Inoko, H; Janout, V; Jiménez-Murcia, S; Johnson, C; Julià, A; Juréus, A; Kalsi, G; Kaminska, D; Kaplan, A S; Kaprio, J; Karhunen, L; Karwautz, A; Kas, M J H; Kaye, W; Kennedy, J L; Keski-Rahkonen, A; Kiezebrink, K; Klareskog, L; Klump, K L; Knudsen, G P S; Koeleman, B P C; Koubek, D; La Via, M C; Landén, M; Le Hellard, S; Levitan, R D; Li, D; Lichtenstein, P; Lilenfeld, L; Lissowska, J; Lundervold, A; Magistretti, P; Maj, M; Mannik, K; Marsal, S; Martin, N; Mattingsdal, M; McDevitt, S; McGuffin, P; Merl, E; Metspalu, A; Meulenbelt, I; Micali, N; Mitchell, J; Mitchell, K; Monteleone, P; Monteleone, A M; Mortensen, P; Munn-Chernoff, M A; Navratilova, M; Nilsson, I; Norring, C; Ntalla, I; Ophoff, R A; O'Toole, J K; Palotie, A; Pante, J; Papezova, H; Pinto, D; Rabionet, R; Raevuori, A; Rajewski, A; Ramoz, N; Rayner, N W; Reichborn-Kjennerud, T; Ripatti, S; Roberts, M; Rotondo, A; Rujescu, D; Rybakowski, F; Santonastaso, P; Scherag, A; Scherer, S W; Schmidt, U; Schork, N J; Schosser, A; Slachtova, L; Sladek, R; Slagboom, P E; Slof-Op 't Landt, M C T; Slopien, A; Soranzo, N; Southam, L; Steen, V M; Strengman, E; Strober, M; Sullivan, P F; Szatkiewicz, J P; Szeszenia-Dabrowska, N; Tachmazidou, I; Tenconi, E; Thornton, L M; Tortorella, A; Tozzi, F; Treasure, J; Tsitsika, A; Tziouvas, K; van Elburg, A A; van Furth, E F; Wagner, G; Walton, E; Watson, H; Wichmann, H-E; Widen, E; Woodside, D B; Yanovski, J; Yao, S; Yilmaz, Z; Zeggini, E; Zerwas, S; Zipfel, S; Collier, D A; Sullivan, P F; Breen, G; Bulik, C M; Zeggini, E

2018-01-01

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes. PMID:29155802

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

PubMed

Huckins, L M; Hatzikotoulas, K; Southam, L; Thornton, L M; Steinberg, J; Aguilera-McKay, F; Treasure, J; Schmidt, U; Gunasinghe, C; Romero, A; Curtis, C; Rhodes, D; Moens, J; Kalsi, G; Dempster, D; Leung, R; Keohane, A; Burghardt, R; Ehrlich, S; Hebebrand, J; Hinney, A; Ludolph, A; Walton, E; Deloukas, P; Hofman, A; Palotie, A; Palta, P; van Rooij, F J A; Stirrups, K; Adan, R; Boni, C; Cone, R; Dedoussis, G; van Furth, E; Gonidakis, F; Gorwood, P; Hudson, J; Kaprio, J; Kas, M; Keski-Rahonen, A; Kiezebrink, K; Knudsen, G-P; Slof-Op 't Landt, M C T; Maj, M; Monteleone, A M; Monteleone, P; Raevuori, A H; Reichborn-Kjennerud, T; Tozzi, F; Tsitsika, A; van Elburg, A; Collier, D A; Sullivan, P F; Breen, G; Bulik, C M; Zeggini, E

2018-05-01

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6 ), and rs7700147, an intergenic variant (P=2.93 × 10 -5 ). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Revisiting DLB Diagnosis: A Consideration of Prodromal DLB and of the Diagnostic Overlap With Alzheimer Disease.

PubMed

McKeith, Ian; Taylor, John-Paul; Thomas, Alan; Donaghy, Paul; Kane, Joseph

2016-09-01

Efforts to clinically diagnose cases having dementia with Lewy bodies (DLB) identify those with a characteristic clinical syndrome (probable DLB) at the expense of missing an equal, if not greater, number of cases who have atypical presentations thought to be associated with coexisting Alzheimer pathologies. This article argues that further efforts should now be made to characterize this atypical group that constitutes cases previously identified postmortem as the Lewy body variant of Alzheimer disease (AD) or as AD with Lewy bodies. Since such fine distinction is unlikely to be achieved on clinical grounds alone, this new diagnostic category will require robust biomarker validation. Turning to a consideration of early/prodromal diagnosis of both typical and atypical DLB cases, it is suggested that there will be at least 3 prototypical forms-a mild cognitive impairment variant, associated with early visuoperceptual and attentional deficits; a delirium onset DLB with provoked or spontaneous delirium as the presenting features; and a psychiatric disorder DLB with its primary presentation as a late-onset affective disorder or psychosis. © The Author(s) 2016.

Towards Identifying Protective B-Cell Epitopes: The PspA Story.

PubMed

Khan, Naeem; Jan, Arif T

2017-01-01

Pneumococcal surface protein A (PspA) is one of the most abundant cell surface protein of Streptococcus pneumoniae ( S. pneumoniae ). PspA variants are structurally and serologically diverse and help evade complement-mediated phagocytosis of S. pneumoniae , which is essential for its survival in the host. PspA is currently been screened for employment in the generation of more effective (serotype independent) vaccine to overcome the limitations of polysaccharide based vaccines, providing serotype specific immune responses. The cross-protection eliciting regions of PspA localize to the α-helical and proline rich regions. Recent data indicate significant variation in the ability of antibodies induced against the recombinant PspA variants to recognize distinct S. pneumoniae strains. Hence, screening for the identification of the topographical repertoire of B-cell epitopes that elicit cross-protective immune response seems essential in the engineering of a superior PspA-based vaccine. Herein, we revisit epitope identification in PspA and the utility of hybridoma technology in directing the identification of protective epitope regions of PspA that can be used in vaccine research.

Photoconversion in orange and red fluorescent proteins

PubMed Central

Kremers, Gert-Jan; Hazelwood, Kristin L.; Murphy, Christopher S.; Davidson, Michael W.; Piston, David W.

2009-01-01

We report that photoconversion is fairly common among orange and red fluorescent proteins, as a screen of 12 variants yielded 8 that exhibit photoconversion. Specifically, three red fluorescent proteins can be switched into a green state, and two orange variants can be photoconverted to the far red. The orange highlighters are ideal for dual-probe highlighter applications, and they exhibit the most red-shifted excitation of all fluorescent protein described to date. PMID:19363494

Apolipoprotein L1 and kidney disease in African Americans

PubMed Central

Friedman, David J.; Pollak, Martin R.

2016-01-01

Genetic variants in the Apolipoprotein L1 (APOL1) gene cause high rates of kidney disease in African Americans. These variants, found only in individuals with recent African ancestry, confer enhanced innate immunity against African trypanosomes. Though they are among the most powerful disease-causing common variants discovered to date, we are just beginning to understand how they promote kidney injury. Since APOL1 is only present in a few primate species, much of our current knowledge has come from natural experiments in humans and in vitro studies while awaiting the development of transgenic animal models. Understanding more about the function of ApoL1 and how the high-risk variants behave differently from other ApoL1 molecules is a high priority in kidney disease research. PMID:26947522

Brachiomedian artery (arteria brachiomediana) revisited: a comprehensive review

PubMed Central

Kachlik, David; Konarik, Marek; Riedlova, Jitka; Baca, Vaclav

2016-01-01

This article reviews in detail the superficial brachiomedian artery (arteria brachiomediana superficialis), a very rare variant of the main arterial trunks of the upper limb. It branches either from the axillary artery or the brachial artery, descends superficially in the arm (similar to the course of the superficial brachial artery) and continues across the cubital fossa, runs superficially in the forearm, approaches the median nerve and enters the carpal canal to reach the hand. It usually terminates in the superficial palmar arch. The first drawing was published, in 1830, and the first description was published, in 1844. Altogether, to our knowledge, only 31 cases of a true, superficial brachiomedian artery have been reported (Some cases are incorrectly reported as superficial brachioradiomedian artery or superficial brachioulnomedian artery). Based on a meta-analysis of known, available studies, the incidence is 0.23% in Caucasians and 1.48% in Mongolians. Knowing whether or not this arterial variant is present is important in clinical medicine and relevant for: The catheterization via the radial or ulnar artery; harvesting the vascular pedicle for a forearm flap based on the radial, ulnar or superficial brachiomedian arteries; the possible collateral circulation in cases of the arterial closure; and the surgical management of carpal tunnel syndrome. Its presence can elevate the danger of an injury to the superficially located variant artery or of an accidental injection. PMID:27131025

Butyric acid – a well-known molecule revisited

PubMed Central

Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases. PMID:28702095

Butyric acid - a well-known molecule revisited.

PubMed

Borycka-Kiciak, Katarzyna; Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases.

LHD1, an allele of DTH8/Ghd8, controls late heading date in common wild rice (Oryza rufipogon).

PubMed

Dai, Xiaodong; Ding, Younian; Tan, Lubin; Fu, Yongcai; Liu, Fengxia; Zhu, Zuofeng; Sun, Xianyou; Sun, Xuewen; Gu, Ping; Cai, Hongwei; Sun, Chuanqing

2012-10-01

Flowering at suitable time is very important for plants to adapt to complicated environments and produce their seeds successfully for reproduction. In rice (Oryza rufipogon Griff.) photoperiod regulation is one of the important factors for controlling heading date. Common wild rice, the ancestor of cultivated rice, exhibits a late heading date and a more sensitive photoperiodic response than cultivated rice. Here, through map-based cloning, we identified a major quantitative trait loci (QTL) LHD1 (Late Heading Date 1), an allele of DTH8/Ghd8, which controls the late heading date of wild rice and encodes a putative HAP3/NF-YB/CBF-A subunit of the CCAAT-box-binding transcription factor. Sequence analysis revealed that several variants in the coding region of LHD1 were correlated with a late heading date, and a further complementary study successfully rescued the phenotype. These results suggest that a functional site for LHD1 could be among those variants present in the coding region. We also found that LHD1 could down-regulate the expression of several floral transition activators such as Ehd1, Hd3a and RFT1 under long-day conditions, but not under short-day conditions. This indicates that LHD1 may delay flowering by repressing the expression of Ehd1, Hd3a and RFT1 under long-day conditions. © 2012 Institute of Botany, Chinese Academy of Sciences.

APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease

PubMed Central

Ma, Lijun; Langefeld, Carl D.; Comeau, Mary E.; Bonomo, Jason A.; Rocco, Michael V.; Burkart, John M.; Divers, Jasmin; Palmer, Nicholette D.; Hicks, Pamela J.; Bowden, Donald W.; Lea, Janice P.; Krisher, Jenna O.; Clay, Margo J.; Freedman, Barry I.

2016-01-01

Relative to European Americans, evidence supports that African Americans with end-stage renal disease (ESRD) survive longer on dialysis. Renal-risk variants in the apolipoprotein L1 gene (APOL1), associated with non-diabetic nephropathy and less subclinical atherosclerosis, may contribute to dialysis outcomes. Here, APOL1 renal-risk variants were assessed for association with dialytic survival in 450 diabetic and 275 non-diabetic African American hemodialysis patients from Wake Forest and Emory School of Medicine outpatient facilities. Outcomes were provided by the ESRD Network 6-Southeastern Kidney Council Standardized Information Management System. Dates of death, receipt of a kidney transplant, and loss to follow-up were recorded. Outcomes were censored at the date of transplantation or through July 1, 2015. Multivariable Cox proportional hazards models were computed separately in patients with non-diabetic and diabetic ESRD, adjusting for the covariates age, gender, comorbidities, ancestry, and presence of an arteriovenous fistula or graft at dialysis initiation. In non-diabetic ESRD, patients with two (vs. zero/one) APOL1 renal-risk variants had significantly longer dialysis survival (hazard ratio 0.57); a pattern not observed in patients with diabetes-associated ESRD (hazard ratio 1.29). Thus, two APOL1 renal-risk variants are associated with longer dialysis survival in African Americans without diabetes, potentially relating to presence of renal-limited disease or less atherosclerosis. PMID:27157696

From days to hours: reporting clinically actionable variants from whole genome sequencing.

PubMed

Middha, Sumit; Baheti, Saurabh; Hart, Steven N; Kocher, Jean-Pierre A

2014-01-01

As the cost of whole genome sequencing (WGS) decreases, clinical laboratories will be looking at broadly adopting this technology to screen for variants of clinical significance. To fully leverage this technology in a clinical setting, results need to be reported quickly, as the turnaround rate could potentially impact patient care. The latest sequencers can sequence a whole human genome in about 24 hours. However, depending on the computing infrastructure available, the processing of data can take several days, with the majority of computing time devoted to aligning reads to genomics regions that are to date not clinically interpretable. In an attempt to accelerate the reporting of clinically actionable variants, we have investigated the utility of a multi-step alignment algorithm focused on aligning reads and calling variants in genomic regions of clinical relevance prior to processing the remaining reads on the whole genome. This iterative workflow significantly accelerates the reporting of clinically actionable variants with no loss of accuracy when compared to genotypes obtained with the OMNI SNP platform or to variants detected with a standard workflow that combines Novoalign and GATK.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

PubMed

Flannick, Jason; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M; Agarwala, Vineeta; Gaulton, Kyle J; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J; Rivas, Manuel A; Perry, John R B; Sim, Xueling; Blackwell, Thomas W; Robertson, Neil R; Rayner, N William; Cingolani, Pablo; Locke, Adam E; Tajes, Juan Fernandez; Highland, Heather M; Dupuis, Josee; Chines, Peter S; Lindgren, Cecilia M; Hartl, Christopher; Jackson, Anne U; Chen, Han; Huyghe, Jeroen R; van de Bunt, Martijn; Pearson, Richard D; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M; Gamazon, Eric R; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A; Below, Jennifer E; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L; Pasko, Dorota; Parker, Stephen C J; Varga, Tibor V; Green, Todd; Beer, Nicola L; Day-Williams, Aaron G; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F; Han, Bok-Ghee; Jenkinson, Christopher P; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C Y; Palmer, Nicholette D; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D; Neale, Benjamin M; Purcell, Shaun; Butterworth, Adam S; Howson, Joanna M M; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K L; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H T; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E; Rybin, Dennis; Farook, Vidya S; Fowler, Sharon P; Freedman, Barry I; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K; Puppala, Sobha; Scott, William R; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C; Mangino, Massimo; Bonnycastle, Lori L; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L; Herder, Christian; Groves, Christopher J; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A; Doney, Alex S F; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H; Stirrups, Kathleen; Wood, Andrew R; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N A; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M; Syvänen, Ann-Christine; Bergman, Richard N; Bharadwaj, Dwaipayan; Bottinger, Erwin P; Cho, Yoon Shin; Chandak, Giriraj R; Chan, Juliana Cn; Chia, Kee Seng; Daly, Mark J; Ebrahim, Shah B; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A; Lehman, Donna M; Jia, Weiping; Ma, Ronald C W; Pollin, Toni I; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J F; Small, Kerrin S; Ried, Janina S; DeFronzo, Ralph A; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R; Gloyn, Anna L; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D; Hattersley, Andrew T; Bowden, Donald W; Collins, Francis S; Atzmon, Gil; Chambers, John C; Spector, Timothy D; Laakso, Markku; Strom, Tim M; Bell, Graeme I; Blangero, John; Duggirala, Ravindranath; Tai, E Shyong; McVean, Gilean; Hanis, Craig L; Wilson, James G; Seielstad, Mark; Frayling, Timothy M; Meigs, James B; Cox, Nancy J; Sladek, Rob; Lander, Eric S; Gabriel, Stacey; Mohlke, Karen L; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J; Morris, Andrew P; Kang, Hyun Min; Altshuler, David; Burtt, Noël P; Florez, Jose C; Boehnke, Michael; McCarthy, Mark I

2017-12-19

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

PubMed Central

Jason, Flannick; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M.; Agarwala, Vineeta; Gaulton, Kyle J.; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J.; Rivas, Manuel A.; Perry, John R. B.; Sim, Xueling; Blackwell, Thomas W.; Robertson, Neil R.; Rayner, N William; Cingolani, Pablo; Locke, Adam E.; Tajes, Juan Fernandez; Highland, Heather M.; Dupuis, Josee; Chines, Peter S.; Lindgren, Cecilia M.; Hartl, Christopher; Jackson, Anne U.; Chen, Han; Huyghe, Jeroen R.; van de Bunt, Martijn; Pearson, Richard D.; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M.; Gamazon, Eric R.; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A.; Below, Jennifer E.; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L.; Pasko, Dorota; Parker, Stephen C. J.; Varga, Tibor V.; Green, Todd; Beer, Nicola L.; Day-Williams, Aaron G.; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J.; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P.; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F.; Han, Bok-Ghee; Jenkinson, Christopher P.; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C. Y.; Palmer, Nicholette D.; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E.; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D.; Neale, Benjamin M.; Purcell, Shaun; Butterworth, Adam S.; Howson, Joanna M. M.; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K. L.; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H. T.; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E.; Rybin, Dennis; Farook, Vidya S.; Fowler, Sharon P.; Freedman, Barry I.; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J.; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K.; Puppala, Sobha; Scott, William R.; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A.; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C.; Mangino, Massimo; Bonnycastle, Lori L.; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L.; Herder, Christian; Groves, Christopher J.; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A.; Doney, Alex S. F.; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J.; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E.; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H.; Stirrups, Kathleen; Wood, Andrew R.; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O.; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P.; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B.; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N. A.; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M.; Syvänen, Ann-Christine; Bergman, Richard N.; Bharadwaj, Dwaipayan; Bottinger, Erwin P.; Cho, Yoon Shin; Chandak, Giriraj R.; Chan, Juliana CN; Chia, Kee Seng; Daly, Mark J.; Ebrahim, Shah B.; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A.; Lehman, Donna M.; Jia, Weiping; Ma, Ronald C. W.; Pollin, Toni I.; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J. F.; Small, Kerrin S.; Ried, Janina S.; DeFronzo, Ralph A.; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J.; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W.; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R.; Gloyn, Anna L.; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D.; Hattersley, Andrew T.; Bowden, Donald W.; Collins, Francis S.; Atzmon, Gil; Chambers, John C.; Spector, Timothy D.; Laakso, Markku; Strom, Tim M.; Bell, Graeme I.; Blangero, John; Duggirala, Ravindranath; Tai, E. Shyong; McVean, Gilean; Hanis, Craig L.; Wilson, James G.; Seielstad, Mark; Frayling, Timothy M.; Meigs, James B.; Cox, Nancy J.; Sladek, Rob; Lander, Eric S.; Gabriel, Stacey; Mohlke, Karen L.; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J.; Morris, Andrew P.; Kang, Hyun Min; Altshuler, David; Burtt, Noël P.; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark I.

2017-01-01

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D. PMID:29257133

Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.

PubMed

Cesani, Martina; Lorioli, Laura; Grossi, Serena; Amico, Giulia; Fumagalli, Francesca; Spiga, Ivana; Filocamo, Mirella; Biffi, Alessandra

2016-01-01

Metachromatic leukodystrophy is a neurodegenerative disorder characterized by progressive demyelination. The disease is caused by variants in the ARSA gene, which codes for the lysosomal enzyme arylsulfatase A, or, more rarely, in the PSAP gene, which codes for the activator protein saposin B. In this Mutation Update, an extensive review of all the ARSA- and PSAP-causative variants published in the literature to date, accounting for a total of 200 ARSA and 10 PSAP allele types, is presented. The detailed ARSA and PSAP variant lists are freely available on the Leiden Online Variation Database (LOVD) platform at http://www.LOVD.nl/ARSA and http://www.LOVD.nl/PSAP, respectively. © 2015 WILEY PERIODICALS, INC.

Preparing for and responding to recent incursions of raccoon rabies variant into Canada.

PubMed

Stevenson, B; Goltz, J; Massé, A

2016-06-02

By the late 2000s, Canada had successfully eliminated the incursion of racoon rabies from the south and remained free of this rabies variant from approximately 2009 to 2014. However, new incursions of raccoon rabies variant have recently been detected in three Canadian provinces: Ontario, Quebec and New Brunswick. Actions to address previous and current incursions of this rabies variant include enhanced surveillance programs, a point infection control strategy to respond to cases, a trap-vaccine-release program and oral rabies vaccination campaigns in targeted areas to prevent further cases and spread. It is hard to predict when and where new incursions will appear because of the ecological adaptability of raccoons and the significant risk associated with inadvertent translocation events by vehicles, trains and ships and raccoon movements across bridges. To date, no cases of raccoon rabies variant have been detected in domestic animals in Canada. However, until racoon rabies can be pushed back from the Canadian border, it is important to remain prepared for the reappearance of this disease.

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation.

PubMed

Kapplinger, Jamie D; Pundi, Krishna N; Larson, Nicholas B; Callis, Thomas E; Tester, David J; Bikker, Hennie; Wilde, Arthur A M; Ackerman, Michael J

2018-02-01

Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation. © 2018 American Heart Association, Inc.

Spectroscopic and Redox Studies of Valence-Delocalized [Fe2S2]+ Centers in Thioredoxin-Like Ferredoxins

PubMed Central

Subramanian, Sowmya; Duin, Evert C.; Fawcett, Sarah E. J.; Armstrong, Fraser A.; Meyer, Jacques; Johnson, Michael K.

2015-01-01

Reduced forms of the C56S and C60S variants of the thioredoxin-like Clostridium pasteurianum [Fe2S2] ferredoxin (CpFd) provide the only known examples of valence-delocalized [Fe2S2]+ clusters, which constitute a fundamental building block of all higher nuclearity Fe-S clusters. In this work, we have revisited earlier work on the CpFd variants and carried out redox and spectroscopic studies on the [Fe2S2]2+,+ centers in wild-type and equivalent variants of the highly homologous and structurally characterized Aquifex aeolicus ferredoxin 4 (AaeFd4) using EPR, UV-visible-NIR absorption, CD and variable-temperature MCD, and protein-film electrochemistry. The results indicate that the [Fe2S2]+ centers in the equivalent AaeFd4 and CpFd variants reversibly interconvert between similar valence-localized S = 1/2 and valence-delocalized S = 9/2 forms as a function of pH, with pKa values in the range 8.3-9.0, due to protonation of the coordinated serinate residue. However, freezing high-pH samples results in partial or full conversion from valence-delocalized S = 9/2 to valence-localized S = 1/2 [Fe2S2]+ clusters. MCD saturation magnetization data for valence-delocalized S = 9/2 [Fe2S2]+ centers facilitated determination of transition polarizations and thereby assignments of low-energy MCD bands associated with the Fe−Fe interaction. The assignments provide experimental assessment of the double exchange parameter, B, for valence-delocalized [Fe2S2]+ centers and demonstrate that variable-temperature MCD spectroscopy provides a means of detecting and investigating the properties of valence-delocalized S = 9/2 [Fe2S2]+ fragments in higher nuclearity Fe-S clusters. The origin of valence delocalization in thioredoxin-like ferredoxin Cys-to-Ser variants and Fe-S clusters in general is discussed in light of these results. PMID:25790339

A large outbreak of acute gastroenteritis in Shippensburg, Pennsylvania, 1972 revisited: evidence for common source exposure to a recombinant GII.Pg/GII.3 norovirus.

PubMed

Johnson, J A; Parra, G I; Levenson, E A; Green, K Y

2017-06-01

Historical outbreaks can be an important source of information in the understanding of norovirus evolution and epidemiology. Here, we revisit an outbreak of undiagnosed gastroenteritis that occurred in Shippensburg, Pennsylvania in 1972. Nearly 5000 people fell ill over the course of 10 days. Symptoms included diarrhea, vomiting, stomach cramps, and fever, lasting for a median of 24 h. Using current techniques, including next-generation sequencing of full-length viral genomic amplicons, we identified an unusual norovirus recombinant (GII.Pg/GII.3) in nine of 15 available stool samples from the outbreak. This particular recombinant virus has not been reported in recent decades, although GII.3 and GII.Pg genotypes have been detected individually in current epidemic strains. The consensus nucleotide sequences were nearly identical among the four viral genomes analysed, although each strain had three to seven positions in the genome with heterogenous non-synonymous nucleotide subpopulations. Two of these resulting amino acid polymorphisms were conserved in frequency among all four cases, consistent with common source exposure and successful transmission of a mixed viral population. Continued investigation of variant nucleotide populations and recombination events among ancestral norovirus strains such as the Shippensburg virus may provide unique insight into the origin of contemporary strains.

Revisiting sweat chloride test results based on recent guidelines for diagnosis of cystic fibrosis.

PubMed

Pagaduan, Jayson V; Ali, Mahesheema; Dowlin, Michael; Suo, Liye; Ward, Tabitha; Ruiz, Fadel; Devaraj, Sridevi

2018-03-01

Recent sweat chloride guidelines published by the Cystic Fibrosis Foundation changed the intermediate sweat chloride concentration range from 40-59 mmol/L to 30-59 mmol/L for age > 6 months. We wanted to know how this new guideline would impact detection of cystic fibrosis among patients who previously had sweat tests done at Texas Children's Hospital. We revisited sweat chloride test results (n = 3012) in the last 5 years at Texas Children's Hospital based on the new guidelines on diagnosis of cystic fibrosis from the Cystic Fibrosis Foundation. We identified 125 patients that would be reclassified in the intermediate sweat chloride value with the new guidelines that were classified as "unlikely to have CF" in the previous guidelines. 8 (32%) patients with CFTR gene testing were positive for CFTR gene mutation(s). 4 (50%) of these patients were identified to have 2 CFTR mutations. One had variant combination that was reported to cause CF but all were diagnosed with CFTR-related metabolic syndrome. Our findings concur with the new CF diagnosis guidelines that changing the intermediate cut-off to 30-59 mmol/L sweat chloride concentration in combination with CFTR genetic analysis enhances the probability of identifying individuals that have risk of developing CF or have CF and enables for earlier therapeutic intervention.

Detection of the pandemic norovirus variant GII.4 Sydney 2012 in Rio Branco, state of Acre, northern Brazil

PubMed Central

da Silva, Luciana Damascena; Rodrigues, Evandro Leite; de Lucena, Maria Silvia Sousa; de Lima, Ian Carlos Gomes; Oliveira, Darleise de Sousa; Soares, Luana Silva; Mascarenhas, Joana D'Arc Pereira; Linhares, Alexandre da Costa; Gabbay, Yvone Benchimol

2013-01-01

Noroviruses (NoVs) are important cause of gastroenteritis in humans worldwide. Genotype GII.4 is responsible for the majority of outbreaks reported to date. This study describes, for the first time in Brazil, the circulation of NoV GII.4 variant Sydney 2012 in faecal samples collected from children aged less than or equal to eight years in Rio Branco, state of Acre, northern Brazil, during July-September 2012. PMID:24141954

Genomic Characterization of Brain Metastasis in Non-Small Cell Lung Cancer Patients

DTIC Science & Technology

2014-01-01

patients from our pilot set, we identified genomic variants (SNVs and CNVs to date) that are enriched in metastatic tumors. Aligned reads were used for...patient, illustrating variants that are detected at low VAF frequency in the primary tumor but greatly enriched in the metastatic lesion, or that are...more than one of the 9 samples, several of them, including PIK3CA E545K (not detectable at 25X read depth in patient 1 primary tumor, but present at

Whole genome sequences of a male and female supercentenarian, ages greater than 114 years.

PubMed

Sebastiani, Paola; Riva, Alberto; Montano, Monty; Pham, Phillip; Torkamani, Ali; Scherba, Eugene; Benson, Gary; Milton, Jacqueline N; Baldwin, Clinton T; Andersen, Stacy; Schork, Nicholas J; Steinberg, Martin H; Perls, Thomas T

2011-01-01

Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging.

Whole Genome Sequences of a Male and Female Supercentenarian, Ages Greater than 114 Years

PubMed Central

Sebastiani, Paola; Riva, Alberto; Montano, Monty; Pham, Phillip; Torkamani, Ali; Scherba, Eugene; Benson, Gary; Milton, Jacqueline N.; Baldwin, Clinton T.; Andersen, Stacy; Schork, Nicholas J.; Steinberg, Martin H.; Perls, Thomas T.

2012-01-01

Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals’ DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging. PMID:22303384

Hepatitis C Virus Induces Regulatory T Cells by Naturally Occurring Viral Variants to Suppress T Cell Responses

PubMed Central

Cusick, Matthew F.; Schiller, Jennifer J.; Gill, Joan C.; Eckels, David D.

2011-01-01

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3358-375 in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3358-375-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence. PMID:21197453

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.

PubMed

Leslie, Elizabeth J; Liu, Huan; Carlson, Jenna C; Shaffer, John R; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A; Jain, Deepti; Laurie, Cathy C; Doheny, Kimberly F; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R; Neiswanger, Katherine; Standley, Jennifer; Czeizel, Andrew E; Deleyiannis, Frederic; Christensen, Kaare; Munger, Ronald G; Lie, Rolv T; Wilcox, Allen; Romitti, Paul A; Field, L Leigh; Padilla, Carmencita D; Cutiongco-de la Paz, Eva Maria C; Lidral, Andrew C; Valencia-Ramirez, Luz Consuelo; Lopez-Palacio, Ana Maria; Valencia, Dora Rivera; Arcos-Burgos, Mauricio; Castilla, Eduardo E; Mereb, Juan C; Poletta, Fernando A; Orioli, Iêda M; Carvalho, Flavia M; Hecht, Jacqueline T; Blanton, Susan H; Buxó, Carmen J; Butali, Azeez; Mossey, Peter A; Adeyemo, Wasiu L; James, Olutayo; Braimah, Ramat O; Aregbesola, Babatunde S; Eshete, Mekonen A; Deribew, Milliard; Koruyucu, Mine; Seymen, Figen; Ma, Lian; de Salamanca, Javier Enríquez; Weinberg, Seth M; Moreno, Lina; Cornell, Robert A; Murray, Jeffrey C; Marazita, Mary L

2016-04-07

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease.

PubMed

Ma, Lijun; Langefeld, Carl D; Comeau, Mary E; Bonomo, Jason A; Rocco, Michael V; Burkart, John M; Divers, Jasmin; Palmer, Nicholette D; Hicks, Pamela J; Bowden, Donald W; Lea, Janice P; Krisher, Jenna O; Clay, Margo J; Freedman, Barry I

2016-08-01

Relative to European Americans, evidence supports that African Americans with end-stage renal disease (ESRD) survive longer on dialysis. Renal-risk variants in the apolipoprotein L1 gene (APOL1), associated with nondiabetic nephropathy and less subclinical atherosclerosis, may contribute to dialysis outcomes. Here, APOL1 renal-risk variants were assessed for association with dialytic survival in 450 diabetic and 275 nondiabetic African American hemodialysis patients from Wake Forest and Emory School of Medicine outpatient facilities. Outcomes were provided by the ESRD Network 6-Southeastern Kidney Council Standardized Information Management System. Dates of death, receipt of a kidney transplant, and loss to follow-up were recorded. Outcomes were censored at the date of transplantation or through 1 July 2015. Multivariable Cox proportional hazards models were computed separately in patients with nondiabetic and diabetic ESRD, adjusting for the covariates age, gender, comorbidities, ancestry, and presence of an arteriovenous fistula or graft at dialysis initiation. In nondiabetic ESRD, patients with 2 (vs. 0/1) APOL1 renal-risk variants had significantly longer dialysis survival (hazard ratio 0.57), a pattern not observed in patients with diabetes-associated ESRD (hazard ratio 1.29). Thus, 2 APOL1 renal-risk variants are associated with longer dialysis survival in African Americans without diabetes, potentially relating to presence of renal-limited disease or less atherosclerosis. Copyright © 2016 International Society of Nephrology. All rights reserved.

Implant-based oral rehabilitation of a variant model of type I dentinal dysplasia: A rare case report

PubMed Central

Nettem, Sowmya; Nettemu, Sunil Kumar; Basha, K.; Venkatachalapathi, S

2014-01-01

Dentin dysplasia is an exceptionally rare, autosomal-dominant, hereditary condition, primarily characterized by defective dentin formation affecting both the deciduous and permanent dentitions. The etiology remains imprecise to date, in spite of the numerous hypotheses put forward and the constant updates on this condition. This case report of type I dentin dysplasia exhibits radiographic findings that are unique and diverse from the classical findings of various subtypes of this disease reported to date. This article also depicts the implant-based oral rehabilitation of the young patient diagnosed with this variant model of dentin dysplasia type I. Early diagnosis and implementation of this preventive and curative therapy is vital for avoiding premature exfoliation of deciduous and permanent dentition and the associated residual ridge resorption, thereby overcoming functional and esthetic deficits and ensuring protection of the remaining dentition from further harm. PMID:25225567

Original antigenic sin responses to influenza viruses.

PubMed

Kim, Jin Hyang; Skountzou, Ioanna; Compans, Richard; Jacob, Joshy

2009-09-01

Most immune responses follow Burnet's rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of "original antigenic sin" stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the "original Ag" rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.

Identifying genetic loci affecting antidepressant drug response in depression using drug–gene interaction models

PubMed Central

Noordam, Raymond; Avery, Christy L; Visser, Loes E; Stricker, Bruno H

2016-01-01

Antidepressants are often only moderately successful in decreasing the severity of depressive symptoms. In part, antidepressant treatment response in patients with depression is genetically determined. However, although a large number of studies have been conducted aiming to identify genetic variants associated with antidepressant drug response in depression, only a few variants have been repeatedly identified. Within the present review, we will discuss the methodological challenges and limitations of the studies that have been conducted on this topic to date (e.g., ‘treated-only design’, statistical power) and we will discuss how specifically drug–gene interaction models can be used to be better able to identify genetic variants associated with antidepressant drug response in depression. PMID:27248517

Effects of 22 Novel CYP2D6 Variants Found in the Chinese Population on the Bufuralol and Dextromethorphan Metabolisms In Vitro.

PubMed

Cai, Jie; Dai, Da-Peng; Geng, Pei-Wu; Wang, Shuang-Hu; Wang, Hao; Zhan, Yun-Yun; Huang, Xiang-Xin; Hu, Guo-Xin; Cai, Jian-Ping

2016-03-01

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that metabolizes a large number of therapeutic drugs. To date, more than 100 CYP2D6 allelic variants have been reported. Among these variants, we recently identified 22 novel variants in the Chinese population. The aim of this study was to functionally characterize the enzymatic activity of these variants in vitro. A baculovirus-mediated expression system was used to express wild-type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) at high levels. Then, the insect microsomes containing expressed CYP2D6 proteins were incubated with bufuralol or dextromethorphan at 37°C for 20 or 25 min., respectively. After termination, the metabolites were extracted and used for the detection with high-performance liquid chromatography. Among the 24 CYP2D6 variants tested, two variants (CYP2D6.92 and CYP2D6.96) were found to be catalytically inactive. The remaining 22 variants exhibited significantly decreased intrinsic clearance values for bufuralol 1'-hydroxylation and 20 variants showed significantly lower intrinsic clearance values for dextromethorphan O-demethylation than those of the wild-type CYP2D6.1. Our in vitro results suggest that most of the variants exhibit significantly reduced catalytic activities compared with the wild-type, and these data provide valuable information for personalized medicine in Chinese and other Asian populations. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Report of a Novel SHOX Missense Variant in a Boy With Short Stature and His Mother With Leri–Weill Dyschondrosteosis

PubMed Central

Lucchetti, Laura; Prontera, Paolo; Mencarelli, Amedea; Sallicandro, Ester; Mencarelli, Annalisa; Cofini, Marta; Leonardi, Alberto; Stangoni, Gabriela; Penta, Laura; Esposito, Susanna

2018-01-01

Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2–22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri–Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80–90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10–20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated SHOX allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone. PMID:29692759

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.

PubMed

Shim, Ye Jee; Kim, Jung Eun; Hwang, Su-Kyeong; Choi, Bong Seok; Choi, Byung Ho; Cho, Eun-Mi; Jang, Kyoung Mi; Ko, Cheol Woo

2015-01-01

To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells. © 2015 S. Karger AG, Basel.

Searching for missing heritability: Designing rare variant association studies

PubMed Central

Zuk, Or; Schaffner, Stephen F.; Samocha, Kaitlin; Do, Ron; Hechter, Eliana; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.; Sunyaev, Shamil R.; Lander, Eric S.

2014-01-01

Genetic studies have revealed thousands of loci predisposing to hundreds of human diseases and traits, revealing important biological pathways and defining novel therapeutic hypotheses. However, the genes discovered to date typically explain less than half of the apparent heritability. Because efforts have largely focused on common genetic variants, one hypothesis is that much of the missing heritability is due to rare genetic variants. Studies of common variants are typically referred to as genomewide association studies, whereas studies of rare variants are often simply called sequencing studies. Because they are actually closely related, we use the terms common variant association study (CVAS) and rare variant association study (RVAS). In this paper, we outline the similarities and differences between RVAS and CVAS and describe a conceptual framework for the design of RVAS. We apply the framework to address key questions about the sample sizes needed to detect association, the relative merits of testing disruptive alleles vs. missense alleles, frequency thresholds for filtering alleles, the value of predictors of the functional impact of missense alleles, the potential utility of isolated populations, the value of gene-set analysis, and the utility of de novo mutations. The optimal design depends critically on the selection coefficient against deleterious alleles and thus varies across genes. The analysis shows that common variant and rare variant studies require similarly large sample collections. In particular, a well-powered RVAS should involve discovery sets with at least 25,000 cases, together with a substantial replication set. PMID:24443550

The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants

PubMed Central

Heckman, Michael G.; Elbaz, Alexis; Soto-Ortolaza, Alexandra I.; Serie, Daniel J.; Aasly, Jan O.; Annesi, Grazia; Auburger, Georg; Bacon, Justin A.; Boczarska-Jedynak, Magdalena; Bozi, Maria; Brighina, Laura; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Destée, Alain; Ferrarese, Carlo; Ferraris, Alessandro; Fiske, Brian; Gispert, Suzana; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Ioannidis, John P. A.; Jasinska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lin, Chin-Hsien; Lohmann, Katja; Loriot, Marie-Anne; Lynch, Timothy; Mellick, George D.; Mutez, Eugénie; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Vassilatis, Demetrios K.; Vilariño-Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Xiromerisiou, Georgia; Maraganore, Demetrius M.; Farrer, Matthew J.; Ross, Owen A.

2013-01-01

The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. PMID:23962496

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

PubMed Central

Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

2017-01-01

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6) and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta‐Analysis

PubMed Central

Dujic, T; Zhou, K; Yee, SW; van Leeuwen, N; de Keyser, CE; Javorský, M; Goswami, S; Zaharenko, L; Hougaard Christensen, MM; Out, M; Tavendale, R; Kubo, M; Hedderson, MM; van der Heijden, AA; Klimčáková, L; Pirags, V; Kooy, A; Brøsen, K; Klovins, J; Semiz, S; Tkáč, I; Stricker, BH; Palmer, CNA; 't Hart, LM; Giacomini, KM

2017-01-01

Therapeutic response to metformin, a first‐line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large‐scale meta‐analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2‐K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D. PMID:27859023

The Role of Constitutional Copy Number Variants in Breast Cancer

PubMed Central

Walker, Logan C.; Wiggins, George A.R.; Pearson, John F.

2015-01-01

Constitutional copy number variants (CNVs) include inherited and de novo deviations from a diploid state at a defined genomic region. These variants contribute significantly to genetic variation and disease in humans, including breast cancer susceptibility. Identification of genetic risk factors for breast cancer in recent years has been dominated by the use of genome-wide technologies, such as single nucleotide polymorphism (SNP)-arrays, with a significant focus on single nucleotide variants. To date, these large datasets have been underutilised for generating genome-wide CNV profiles despite offering a massive resource for assessing the contribution of these structural variants to breast cancer risk. Technical challenges remain in determining the location and distribution of CNVs across the human genome due to the accuracy of computational prediction algorithms and resolution of the array data. Moreover, better methods are required for interpreting the functional effect of newly discovered CNVs. In this review, we explore current and future application of SNP array technology to assess rare and common CNVs in association with breast cancer risk in humans. PMID:27600231

Preparing for and responding to recent incursions of raccoon rabies variant into Canada

PubMed Central

Stevenson, B; Goltz, J; Massé, A

2016-01-01

By the late 2000s, Canada had successfully eliminated the incursion of racoon rabies from the south and remained free of this rabies variant from approximately 2009 to 2014. However, new incursions of raccoon rabies variant have recently been detected in three Canadian provinces: Ontario, Quebec and New Brunswick. Actions to address previous and current incursions of this rabies variant include enhanced surveillance programs, a point infection control strategy to respond to cases, a trap-vaccine-release program and oral rabies vaccination campaigns in targeted areas to prevent further cases and spread. It is hard to predict when and where new incursions will appear because of the ecological adaptability of raccoons and the significant risk associated with inadvertent translocation events by vehicles, trains and ships and raccoon movements across bridges. To date, no cases of raccoon rabies variant have been detected in domestic animals in Canada. However, until racoon rabies can be pushed back from the Canadian border, it is important to remain prepared for the reappearance of this disease. PMID:29770016

Gamma-aminobutyric acid A receptor, α-2 (GABRA2) variants as individual markers for alcoholism: a meta-analysis.

PubMed

Zintzaras, Elias

2012-08-01

The available evidence from the genetic association studies (GAS) published to date on the association between variants in the GABRA2 gene and alcoholism has produced inconclusive results. To interpret these results, a meticulous meta-analysis of all available studies was carried out. The PubMed database and the HuGE Navigator were searched for published GAS-related variants in the GABRA2 gene with susceptibility to alcoholism. Then, the GAS were synthesized to decrease the uncertainty of estimated genetic risk effects. The risk effects were estimated on the basis of the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR(G)), a model-free approach. Cumulative and recursive cumulative meta-analyses (CMA) were also carried out to investigate the trend and stability of effect sizes as evidence accumulates. Fourteen variants investigated in eight studies were analyzed. Significant associations were derived for four variants either for the allele contrast or for the OR(G). In particular, the variants rs279858 and rs279845 showed marginal significance for OR(G): OR(G)=1.27 (1.01-1.60) and OR(G)=1.49 (1.02-2.19), respectively. Also, the variants rs567926 and rs279844 showed significance for the allele contrast: OR=1.24 (1.06-1.46) and OR=1.23 (1.08-1.43), respectively; the ORG produced similar results. The variant rs279858 produced a large heterogeneity between studies. CMA showed a trend of an association only for the variant rs567926. Recursive CMA indicated that more evidence is needed to conclude on the status of significance of all variants. There is evidence that variants in the GABRA2 gene are associated with alcoholism. However, the present findings should be interpreted with caution.

Convergence between biological, behavioural and genetic determinants of obesity.

PubMed

Ghosh, Sujoy; Bouchard, Claude

2017-12-01

Multiple biological, behavioural and genetic determinants or correlates of obesity have been identified to date. Genome-wide association studies (GWAS) have contributed to the identification of more than 100 obesity-associated genetic variants, but their roles in causal processes leading to obesity remain largely unknown. Most variants are likely to have tissue-specific regulatory roles through joint contributions to biological pathways and networks, through changes in gene expression that influence quantitative traits, or through the regulation of the epigenome. The recent availability of large-scale functional genomics resources provides an opportunity to re-examine obesity GWAS data to begin elucidating the function of genetic variants. Interrogation of knockout mouse phenotype resources provides a further avenue to test for evidence of convergence between genetic variation and biological or behavioural determinants of obesity.

PPP-RTK by means of S-system theory: revisiting the undifferenced, uncombined network model and a case study

NASA Astrophysics Data System (ADS)

Zhang, Baocheng; Yuan, Yunbin

2017-04-01

A synthesis of two prevailing Global Navigation Satellite System (GNSS) positioning technologies, namely the precise point positioning (PPP) and the network-based real-time kinematic (NRTK), results in the emergence of the PPP-RTK. This new concept preferably integrates the typical advantage of PPP (e.g. flexibility) and that of NRTK (e.g. efficiency), such that it enables single-receiver users to achieve high positioning accuracy with reasonable timeliness through integer ambiguity resolution (IAR). The realization of PPP-RTK needs to accomplish two sequential tasks. The first task is to determine a class of corrections including, necessarily, the satellite orbits, the satellite clocks and the satellite phase (and code, in case of more than two frequencies) biases at the network level. With these corrections, the second task, then, is capable of solving for the ambiguity-fixed, absolute position(s) at the user level. In this contribution, we revisit three variants (geometry-free, geometry-fixed, and geometry- and satellite-clock-fixed) of undifferenced, uncombined PPP-RTK network model and discuss their implications for practical use. We carry out a case study using multi-day, dual-frequency GPS data from the Crustal Movement Observation Network of China (CMONOC), aiming to assess the (static and kinematic) positioning performance (in terms of time-to-first-fix and accuracy) that is achievable by PPP-RTK users across China.

Re-visiting the tympanic membrane vicinity as core body temperature measurement site

PubMed Central

Gan, Chee Wee; Liang, Wenyu

2017-01-01

Core body temperature (CBT) is an important and commonly used indicator of human health and endurance performance. A rise in baseline CBT can be attributed to an onset of flu, infection or even thermoregulatory failure when it becomes excessive. Sites which have been used for measurement of CBT include the pulmonary artery, the esophagus, the rectum and the tympanic membrane. Among them, the tympanic membrane is an attractive measurement site for CBT due to its unobtrusive nature and ease of measurement facilitated, especially when continuous CBT measurements are needed for monitoring such as during military, occupational and sporting settings. However, to-date, there are still polarizing views on the suitability of tympanic membrane as a CBT site. This paper will revisit a number of key unresolved issues in the literature and also presents, for the first time, a benchmark of the middle ear temperature against temperature measurements from other sites. Results from experiments carried out on human and primate subjects will be presented to draw a fresh set of insights against the backdrop of hypotheses and controversies. PMID:28414722

Re-visiting the tympanic membrane vicinity as core body temperature measurement site.

PubMed

Yeoh, Wui Keat; Lee, Jason Kai Wei; Lim, Hsueh Yee; Gan, Chee Wee; Liang, Wenyu; Tan, Kok Kiong

2017-01-01

Core body temperature (CBT) is an important and commonly used indicator of human health and endurance performance. A rise in baseline CBT can be attributed to an onset of flu, infection or even thermoregulatory failure when it becomes excessive. Sites which have been used for measurement of CBT include the pulmonary artery, the esophagus, the rectum and the tympanic membrane. Among them, the tympanic membrane is an attractive measurement site for CBT due to its unobtrusive nature and ease of measurement facilitated, especially when continuous CBT measurements are needed for monitoring such as during military, occupational and sporting settings. However, to-date, there are still polarizing views on the suitability of tympanic membrane as a CBT site. This paper will revisit a number of key unresolved issues in the literature and also presents, for the first time, a benchmark of the middle ear temperature against temperature measurements from other sites. Results from experiments carried out on human and primate subjects will be presented to draw a fresh set of insights against the backdrop of hypotheses and controversies.

Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population.

PubMed

Maeda, Akiko; Yoshida, Akiko; Kawai, Kanako; Arai, Yuki; Akiba, Ryutaro; Inaba, Akira; Takagi, Seiji; Fujiki, Ryoji; Hirami, Yasuhiko; Kurimoto, Yasuo; Ohara, Osamu; Takahashi, Masayo

2018-05-21

Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy caused by different genetic variants. More than 60 causative genes have been identified to date. The establishment of cost-effective molecular diagnostic tests with high sensitivity and specificity can be beneficial for patients and clinicians. Here, we developed a clinical diagnostic test for RP in the Japanese population. Evaluation of diagnostic technology, Prospective, Clinical and experimental study. A panel of 39 genes reported to cause RP in Japanese patients was established. Next generation sequence (NGS) technology was applied for the analyses of 94 probands with RP and RP-related diseases. After interpretation of detected genetic variants, molecular diagnosis based on a study of the genetic variants and a clinical phenotype was made by a multidisciplinary team including clinicians, researchers and genetic counselors. NGS analyses found 14,343 variants from 94 probands. Among them, 189 variants in 83 probands (88.3% of all cases) were selected as pathogenic variants and 64 probands (68.1%) have variants which can cause diseases. After the deliberation of these 64 cases, molecular diagnosis was made in 43 probands (45.7%). The final molecular diagnostic rate with the current system combining supplemental Sanger sequencing was 47.9% (45 of 94 cases). The RP panel provides the significant advantage of detecting genetic variants with a high molecular diagnostic rate. This type of race-specific high-throughput genotyping allows us to conduct a cost-effective and clinically useful genetic diagnostic test.

Contribution of AMACR and Phytanic Acid to Prostate Cancer Risk Among African Americans in North Carolina

DTIC Science & Technology

2009-05-01

ABOVE ADDRESS. 1. REPORT DATE 1 May 2009 2 . REPORT TYPE Final 3. DATES COVERED 15 Jan 2006 – 14 Apr 2009 4. TITLE AND SUBTITLE 5a. CONTRACT...North Carolina. 2 . The total of 518 subjects is slightly short of our goal. However, we exceeded our recruitment goals for control subjects, and...data we have collected will have the greatest possible impact in the fight against PCa. Task 2 . To identify sequence variant/mutation spectrum of

Nonsense variant in COL7A1 causes recessive dystrophic epidermolysis bullosa in Central Asian Shepherd dogs.

PubMed

Niskanen, Julia; Dillard, Kati; Arumilli, Meharji; Salmela, Elina; Anttila, Marjukka; Lohi, Hannes; Hytönen, Marjo K

2017-01-01

A rare hereditary mechanobullous disorder called epidermolysis bullosa (EB) causes blistering in the skin and the mucosal membranes. To date, nineteen EB-related genes have been discovered in human and other species. We describe here a novel EB variant in dogs. Two newborn littermates of Central Asian Shepherd dogs with severe signs of skin blistering were brought to a veterinary clinic and euthanized due to poor prognosis. In post-mortem examination, the puppies were shown to have findings in the skin and the mucosal membranes characteristic of EB. A whole-genome sequencing of one of the affected puppies was performed to identify the genetic cause. The resequencing data were filtered under a recessive model against variants from 31 other dog genomes, revealing a homozygous case-specific nonsense variant in one of the known EB-causing genes, COL7A1 (c.4579C>T, p.R1527*). The variant results in a premature stop codon and likely absence of the functional protein in the basement membrane of the skin in the affected dogs. This was confirmed by immunohistochemistry using a COL7A1 antibody. Additional screening of the variant indicated full penetrance and breed specificity at ~28% carrier frequency. In summary, this study reveals a novel COL7A1 variant causing recessive dystrophic EB and provides a genetic test for the eradication of the disease from the breed.

Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age.

PubMed

Hauth, Lothar; Kerstens, Jeroen; Yperzeele, Laetitia; Eyskens, François; Parizel, Paul M; Willekens, Barbara

2018-01-01

A 16-year-old male presented with episodic headaches and a brain magnetic resonance imaging (MRI) that showed multifocal punctate to patchy white matter lesions. The diagnosis of Fabry disease (FD) was suggested upon the finding of significantly reduced plasma alpha-galactosidase A activity (0.62 µmol/L or 13% of normal; normal range ≥ 1.65 μmol/L) and genetic investigation confirmed the presence of a hemizygous missense variant in the galactosidase alpha (GLA) gene (p.A143T). Baseline assessment of other systemic involvement showed only a discrete proteinuria. FD is a rare lysosomal storage disorder. Genetic screening studies have revealed over 600 variants in the GLA gene. The p.A143T variant is a genetic variant of unknown significance, with its associated phenotype ranging from classical FD to healthy unaffected patients. Some authors, however, deem this variant non-pathogenic. We describe the case of a 16-year-old male with multifocal white matter lesions on brain MRI, who was diagnosed with FD and carried this genetic variant. The causative p.A143T mutation can be associated with a more severe subclinical phenotype than has been reported to date. Furthermore, a diagnosis of FD should be considered when finding asymptomatic cerebral white matter lesions in a young patient.

Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.

PubMed

Oatts, Julius T; Duncan, Jacque L; Hoyt, Creig S; Slavotinek, Anne M; Moore, Anthony T

2017-12-01

Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome characterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy. To date, nystagmus, cortical visual impairment, impairment of central vision, optic nerve hypoplasia, and optic atrophy have been described in this condition. This article describes the retinal findings in a patient with biallelic deleterious sequence variants in BRAT1. Case report of a child with biallelic sequence variants in the BRAT1 gene. This patient had developmental delay, microcephaly, nystagmus, and esotropia, and full-field electroretinography (ERG) revealed an inner retinal dystrophy. She was found on exome sequencing to have compound heterozygous sequence variants in the BRAT1 gene: one maternally inherited frameshift variant (c.294dupA, predicting p.Leu99Thrfs*92), which has previously been reported, and one paternally inherited novel missense variant (c.803G>A, p.Arg268His), which is likely to affect protein function. Biallelic sequence variants in BRAT1 have been reported to cause a variety of ocular and systemic manifestations, but to our knowledge, this is the first report of inner retinal dysfunction manifest as selective loss of full-field ERG scotopic and photopic b-wave amplitudes.

Revisit rates and associated costs after an emergency department encounter: a multistate analysis.

PubMed

Duseja, Reena; Bardach, Naomi S; Lin, Grace A; Yazdany, Jinoos; Dean, Mitzi L; Clay, Theodore H; Boscardin, W John; Dudley, R Adams

2015-06-02

Return visits to the emergency department (ED) or hospital after an index ED visit strain the health system, but information about rates and determinants of revisits is limited. To describe revisit rates, variation in revisit rates by diagnosis and state, and associated costs. Observational study using the Healthcare Cost and Utilization Project databases. 6 U.S. states. Adults with ED visits between 2006 and 2010. Revisit rates and costs. Within 3 days of an index ED visit, 8.2% of patients had a revisit; 32% of those revisits occurred at a different institution. Revisit rates varied by diagnosis, with skin infections having the highest rate (23.1% [95% CI, 22.3% to 23.9%]). Revisit rates also varied by state. For skin infections, Florida had higher risk-adjusted revisit rates (24.8% [CI, 23.5% to 26.2%]) than Nebraska (10.6% [CI, 9.2% to 12.1%]). In Florida, the only state with complete cost data, total revisit costs for the 19.8% of patients with a revisit within 30 days were 118% of total index ED visit costs for all patients (including those with and without a revisit). Whether a revisit reflects inadequate access to primary care, a planned revisit, the patient's nonadherence to ED recommendations, or poor-quality care at the initial ED visit remains unknown. Revisits after an index ED encounter are more frequent than previously reported, in part because many occur outside the index institution. Among ED patients in Florida, more resources are spent on revisits than on index ED visits. Agency for Healthcare Research and Quality.

Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls.

PubMed

Buckley, Alexandra R; Standish, Kristopher A; Bhutani, Kunal; Ideker, Trey; Lasken, Roger S; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J

2017-06-12

Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.

PubMed

Bowles, Neil E; Jou, Chuanchau J; Arrington, Cammon B; Kennedy, Brett J; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L; Etheridge, Susan P; Saarel, Elizabeth V; Bleyl, Steven B; Yost, H Joseph; Yandell, Mark; Leppert, Mark F; Tristani-Firouzi, Martin; Gruber, Peter J

2015-12-01

Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. © 2015 Wiley Periodicals, Inc.

Exome Analysis of a Family with Wolff–Parkinson–White Syndrome Identifies a Novel Disease Locus

PubMed Central

Bowles, Neil E.; Jou, Chuanchau J.; Arrington, Cammon B.; Kennedy, Brett J.; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L.; Etheridge, Susan P.; Saarel, Elizabeth V.; Bleyl, Steven B.; Yost, H. Joseph; Yandell, Mark; Leppert, Mark F.; Tristani-Firouzi, Martin; Gruber, Peter J.

2016-01-01

Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

Revisiting the human polypeptide GalNAc-T1 and T13 paralogs

PubMed Central

Festari, María Florencia; Trajtenberg, Felipe; Berois, Nora; Pantano, Sergio; Revoredo, Leslie; Kong, Yun; Solari-Saquieres, Patricia; Narimatsu, Yoshiki; Freire, Teresa; Bay, Sylvie; Robello, Carlos; Bénard, Jean; Gerken, Thomas A; Clausen, Henrik; Osinaga, Eduardo

2017-01-01

Polypeptide GalNAc-transferases (GalNAc-Ts) constitute a family of 20 human glycosyltransferases (comprising 9 subfamilies), which initiate mucin-type O-glycosylation. The O-glycoproteome is thought to be differentially regulated via the different substrate specificities and expression patterns of each GalNAc-T isoforms. Here, we present a comprehensive in vitro analysis of the peptide substrate specificity of GalNAc-T13, showing that it essentially overlaps with the ubiquitous expressed GalNAc-T1 isoform found in the same subfamily as T13. We have also identified and partially characterized nine splice variants of GalNAc-T13, which add further complexity to the GalNAc-T family. Two variants with changes in their lectin domains were characterized by in vitro glycosylation assays, and one (Δ39Ex9) was inactive while the second one (Ex10b) had essentially unaltered activity. We used reverse transcription-polymerase chain reaction analysis of human neuroblastoma cell lines, normal brain and a small panel of neuroblastoma tumors to demonstrate that several splice variants (Ex10b, ΔEx9, ΔEx2-7 and ΔEx6/8-39bpEx9) were highly expressed in tumor cell lines compared with normal brain, although the functional implications remain to be unveiled. In summary, the GalNAc-T13 isoform is predicted to function similarly to GalNAc-T1 against peptide substrates in vivo, in contrast to a prior report, but is unique by being selectively expressed in the brain. PMID:27913570

[Pleomorphic rhabdomyosarcoma of the larynx--a case report and literature review].

PubMed

Prgomet, Drago; Males, Josip; Manojlović, Spomenka; Bumber, Zeljko

2006-06-01

Rhabdomyosarcoma is a very rare malignant tumor of the larynx which can present in a number of histologic variants. The pleomorphic variant of the tumor has been described in 16 patients to date. Being a rarity, rhabdomyosarcoma is as a rule managed according to the principle of treatment for malignant mesenchymal tumors of the head and neck, and includes radical surgery with postoperative radiotherapy and/or chemotherapy. A case is presented of a pleomorphic rhabdomyosarcoma of the vocal cord. Successfully treated by endoscopic CO2 laser cordectomy with adjuvant chemotherapy and 6-year uneventful follow up.

Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series.

PubMed

Goodspeed, Kimberly; Newsom, Cassandra; Morris, Mary Ann; Powell, Craig; Evans, Patricia; Golla, Sailaja

2018-03-01

Pitt-Hopkins syndrome (PTHS) is a rare, genetic disorder caused by a molecular variant of TCF4 which is involved in embryologic neuronal differentiation. PTHS is characterized by syndromic facies, psychomotor delay, and intellectual disability. Other associated features include early-onset myopia, seizures, constipation, and hyperventilation-apneic spells. Many also meet criteria for autism spectrum disorder. Here the authors present a series of 23 PTHS patients with molecularly confirmed TCF4 variants and describe 3 unique individuals. The first carries a small deletion but does not exhibit the typical facial features nor the typical pattern of developmental delay. The second exhibits typical facial features, but has attained more advanced motor and verbal skills than other reported cases to date. The third displays typical features of PTHS, however inherited a large chromosomal duplication involving TCF4 from his unaffected father with somatic mosaicism. To the authors' knowledge, this is the first chromosomal duplication case reported to date.

Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

PubMed Central

Hudson, Gavin; Gomez-Duran, Aurora; Wilson, Ian J.; Chinnery, Patrick F.

2014-01-01

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the “missing heritability” of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases. PMID:24852434

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

PubMed

Owen, David; Töpf, Ana; Preethish-Kumar, Veeramani; Lorenzoni, Paulo José; Vroling, Bas; Scola, Rosana Herminia; Dias-Tosta, Elza; Geraldo, Argemiro; Polavarapu, Kiran; Nashi, Saraswati; Cox, Daniel; Evangelista, Teresinha; Dawson, John; Thompson, Rachel; Senderek, Jan; Laurie, Steven; Beltran, Sergi; Gut, Marta; Gut, Ivo; Nalini, Atchayaram; Lochmüller, Hanns

2018-04-28

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS. © 2018 Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vardoyan, G.; Rao, Nageswara S; Towlsey, D.

In recent years, the computer networking community has seen a steady growth in bandwidth-delay products (BDPs). Several TCP variants were created to combat the shortcomings of legacy TCP when it comes to operation in high-BDP environments. These variants, among which are CUBIC, STCP, and H-TCP, have been extensively studied in some empirical contexts, and some analytical models exist for CUBIC and STCP. However, since these studies have been conducted, BDPs have risen even more, and new bulk data transfer tools have emerged that utilize multiple parallel TCP streams. In view of these new developments, it is imperative to revisit themore » question: Which congestion control algorithms are best adapted to current networking environments? In order to help resolve this question, we contribute the following: (i) using first principles, we develop a general throughput-prediction framework that takes into account buffer sizes and maximum window constraints; (ii) we validate the models using measurements and achieve low prediction errors; (iii) we note differences in TCP dynamics between two experimental configurations and find one of them to be significantly more deterministic than the other; we also find that CUBIC and H-TCP outperform STCP, especially when multiple streams are used; and (iv) we present preliminary results for modelling multiple TCP streams for CUBIC and STCP.« less

Use of natural products for oral hygiene maintenance: revisiting traditional medicine.

PubMed

Gupta, Pankaj; Shetty, Heeresh

2018-03-27

The use of traditional means of oral hygiene maintenance has a long-recorded history, with widespread usage in rural areas of Africa, South America and the Indian subcontinent till date. Though dental healthcare professionals and the general population, especially in the urban areas can have the temptation of out-rightly rejecting them as ineffective, the usage of these natural products is based on time-tested scientific principles. The present article provides an overview of the major traditional practices of oral hygiene maintenance and how they compare against the modern-day armamentarium of oral hygiene maintenance.

The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries

PubMed Central

Sanchez, Gonzalo M.; Burridge, Alwyn L.

2010-01-01

Dating from the seventeenth century b.c. the Edwin Smith papyrus is a unique treatise containing the oldest known descriptions of signs and symptoms of injuries of the spinal column and spinal cord. Based on a recent “medically based translation” of the Smith papyrus, its enclosed treasures in diagnostic, prognostic and therapeutic reasoning are revisited. Although patient demographics, diagnostic techniques and therapeutic options considerably changed over time, the documented rationale on spinal injuries can still be regarded as the state-of-the-art reasoning for modern clinical practice. PMID:20697750

Investigation of established genetic risk variants for glioma in prediagnostic samples from a population-based nested case-control study.

PubMed

Wibom, Carl; Späth, Florentin; Dahlin, Anna M; Langseth, Hilde; Hovig, Eivind; Rajaraman, Preetha; Johannesen, Tom Børge; Andersson, Ulrika; Melin, Beatrice

2015-05-01

Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included. To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research. We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study. Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis. Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. ©2015 American Association for Cancer Research.

Structural optimization under overhang constraints imposed by additive manufacturing technologies

NASA Astrophysics Data System (ADS)

Allaire, G.; Dapogny, C.; Estevez, R.; Faure, A.; Michailidis, G.

2017-12-01

This article addresses one of the major constraints imposed by additive manufacturing processes on shape optimization problems - that of overhangs, i.e. large regions hanging over void without sufficient support from the lower structure. After revisiting the 'classical' geometric criteria used in the literature, based on the angle between the structural boundary and the build direction, we propose a new mechanical constraint functional, which mimics the layer by layer construction process featured by additive manufacturing technologies, and thereby appeals to the physical origin of the difficulties caused by overhangs. This constraint, as well as some variants, is precisely defined; their shape derivatives are computed in the sense of Hadamard's method, and numerical strategies are extensively discussed, in two and three space dimensions, to efficiently deal with the appearance of overhang features in the course of shape optimization processes.

Cavβ2 transcription start site variants modulate calcium handling in newborn rat cardiomyocytes.

PubMed

Moreno, Cristian; Hermosilla, Tamara; Morales, Danna; Encina, Matías; Torres-Díaz, Leandro; Díaz, Pablo; Sarmiento, Daniela; Simon, Felipe; Varela, Diego

2015-12-01

In the heart, the main pathway for calcium influx is mediated by L-type calcium channels, a multi-subunit complex composed of the pore-forming subunit CaV1.2 and the auxiliary subunits CaVα2δ1 and CaVβ2. To date, five distinct CaVβ2 transcriptional start site (TSS) variants (CaVβ2a-e) varying only in the composition and length of the N-terminal domain have been described, each of them granting distinct biophysical properties to the L-type current. However, the physiological role of these variants in Ca(2+) handling in the native tissue has not been explored. Our results show that four of these variants are present in neonatal rat cardiomyocytes. The contribution of those CaVβ2 TSS variants on endogenous L-type current and Ca(2+) handling was explored by adenoviral-mediated overexpression of each CaVβ2 variant in cultured newborn rat cardiomyocytes. As expected, all CaVβ2 TSS variants increased L-type current density and produced distinctive changes on L-type calcium channel (LTCC) current activation and inactivation kinetics. The characteristics of the induced calcium transients were dependent on the TSS variant overexpressed. Moreover, the amplitude of the calcium transients varied depending on the subunit involved, being higher in cardiomyocytes transduced with CaVβ2a and smaller in CaVβ2d. Interestingly, the contribution of Ca(2+) influx and Ca(2+) release on total calcium transients, as well as the sarcoplasmic calcium content, was found to be TSS-variant-dependent. Remarkably, determination of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) messenger RNA (mRNA) abundance and cell size change indicates that CaVβ2 TSS variants modulate the cardiomyocyte hypertrophic state. In summary, we demonstrate that expression of individual CaVβ2 TSS variants regulates calcium handling in cardiomyocytes and, consequently, has significant repercussion in the development of hypertrophy.

Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment

PubMed Central

Santos, Regie Lyn P.; El-Shanti, Hatem; Sikandar, Shaheen; Lee, Kwanghyuk; Bhatti, Attya; Yan, Kai; Chahrour, Maria H.; McArthur, Nathan; Pham, Thanh L.; Mahasneh, Amjad Abdullah; Ahmad, Wasim

2010-01-01

To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212–2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3–4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment. PMID:16389551

A benchmark study of scoring methods for non-coding mutations.

PubMed

Drubay, Damien; Gautheret, Daniel; Michiels, Stefan

2018-05-15

Detailed knowledge of coding sequences has led to different candidate models for pathogenic variant prioritization. Several deleteriousness scores have been proposed for the non-coding part of the genome, but no large-scale comparison has been realized to date to assess their performance. We compared the leading scoring tools (CADD, FATHMM-MKL, Funseq2 and GWAVA) and some recent competitors (DANN, SNP and SOM scores) for their ability to discriminate assumed pathogenic variants from assumed benign variants (using the ClinVar, COSMIC and 1000 genomes project databases). Using the ClinVar benchmark, CADD was the best tool for detecting the pathogenic variants that are mainly located in protein coding gene regions. Using the COSMIC benchmark, FATHMM-MKL, GWAVA and SOMliver outperformed the other tools for pathogenic variants that are typically located in lincRNAs, pseudogenes and other parts of the non-coding genome. However, all tools had low precision, which could potentially be improved by future non-coding genome feature discoveries. These results may have been influenced by the presence of potential benign variants in the COSMIC database. The development of a gold standard as consistent as ClinVar for these regions will be necessary to confirm our tool ranking. The Snakemake, C++ and R codes are freely available from https://github.com/Oncostat/BenchmarkNCVTools and supported on Linux. damien.drubay@gustaveroussy.fr or stefan.michiels@gustaveroussy.fr. Supplementary data are available at Bioinformatics online.

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

PubMed

El-Hattab, Ayman W; Wang, Julia; Dai, Hongzheng; Almannai, Mohammed; Staufner, Christian; Alfadhel, Majid; Gambello, Michael J; Prasun, Pankaj; Raza, Saleem; Lyons, Hernando J; Afqi, Manal; Saleh, Mohammed A M; Faqeih, Eissa A; Alzaidan, Hamad I; Alshenqiti, Abduljabbar; Flore, Leigh Anne; Hertecant, Jozef; Sacharow, Stephanie; Barbouth, Deborah S; Murayama, Kei; Shah, Amit A; Lin, Henry C; Wong, Lee-Jun C

2018-04-01

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis. © 2017 Wiley Periodicals, Inc.

Sex differences in mate preferences revisited: do people know what they initially desire in a romantic partner?

PubMed

Eastwick, Paul W; Finkel, Eli J

2008-02-01

In paradigms in which participants state their ideal romantic-partner preferences or examine vignettes and photographs, men value physical attractiveness more than women do, and women value earning prospects more than men do. Yet it remains unclear if these preferences remain sex differentiated in predicting desire for real-life potential partners (i.e., individuals whom one has actually met). In the present study, the authors explored this possibility using speed dating and longitudinal follow-up procedures. Replicating previous research, participants exhibited traditional sex differences when stating the importance of physical attractiveness and earning prospects in an ideal partner and ideal speed date. However, data revealed no sex differences in the associations between participants' romantic interest in real-life potential partners (met during and outside of speed dating) and the attractiveness and earning prospects of those partners. Furthermore, participants' ideal preferences, assessed before the speed-dating event, failed to predict what inspired their actual desire at the event. Results are discussed within the context of R. E. Nisbett and T. D. Wilson's (1977) seminal article: Even regarding such a consequential aspect of mental life as romantic-partner preferences, people may lack introspective awareness of what influences their judgments and behavior. (c) 2008 APA, all rights reserved

Dandy-Walker variant associated with bipolar affective disorder

PubMed Central

Lingeswaran, Anand; Barathi, Deepak; Sharma, Gyaneswahr

2009-01-01

The Dandy-Walker malformation is a congenital brain malformation, typically involving the fourth ventricle and the cerebellum. To date, the Dandy-Walker syndrome has not been described in association with bipolar disorder type I mania, and therefore we briefly report the case of a Dandy-Walker variant associated with acute mania. A 10-year-old boy was brought by his mother to the outpatient clinic of the Department of Psychiatry of a tertiary care hospital, with symptoms of mania. The MRI brain of the patient showed a posterior fossa cystic lesion, a giant cisterna magna communicating with the fourth ventricle and mild hypoplasia of the cerebellar vermis, with the rest of the structures being normal and no signs of hydrocephalus. These findings showed that the patient had a Dandy-Walker variant. He responded partially to valproate and olanzepine, which controlled the acute manic symptoms in the ward. PMID:21887198

Molecular epidemiology of rabies virus in Poland.

PubMed

Orłowska, Anna; Żmudziński, Jan Franciszek

2014-08-01

The paper describes a phylogenetic study of 58 Polish isolates of rabies virus collected between 1992 and 2010. Sequences of the nucleoprotein (N) and glycoprotein (G) genes approximately 600 bp long were compared with reference sequences (GenBank) of European rabies viruses from neighbouring countries. The study confirmed a very high level of homology (94.4-100 %) of the Polish rabies virus strains irrespective of the date of isolation. Two variants of rabies virus: NEE (Northeastern Europe variant) and CE (Central Europe variant), depending on the geographical place of isolation, were circulating in Poland from 1992 to 2010. The Polish rabies virus isolates showed high similarity to European RABV strains, especially those collected in Ukraine and Romania. They were clearly different from vaccine strains SAD B19 and SAD Bern, which have been used for oral vaccination of foxes against rabies in Poland since 1993.

Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

PubMed Central

Cardno, Alastair G.

2014-01-01

There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant. PMID:24567502

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

PubMed Central

Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

2016-01-01

AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far. PMID:26173967

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.

PubMed

Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

2016-03-01

AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE): A Next-Generation Sequencing Study.

PubMed

Stevens, Todd M; Morlote, Diana; Swensen, Jeff; Ellis, Michelle; Harada, Shuko; Spencer, Sharon; Prieto-Granada, Carlos N; Folpe, Andrew L; Gatalica, Zoran

2018-05-07

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a malignant biphasic neoplasm of the thyroid or neck with propensity for late metastasis. Unlike synovial sarcoma, its main morphologic mimic, SETTLE lacks synovial sarcoma-associated translocations. A single case of SETTLE has shown a KRAS mutation but to date no comprehensive next generation sequencing studies of this rare neoplasm have been undertaken. Herein, we subjected 5 well defined cases of SETTLE to direct sequence analysis of 592 genes and fusion gene analysis of 52 genes frequently rearranged in human cancers. We identified one case with two pathogenic variants in the KMT2D gene, one being in an intron splice site (c.674-1A>G) and the other being a frameshift variant (p.M2829fs). This same case also had a pathogenic nonsense variant in the KMT2C gene (p.R1237*). A second case of SETTLE carried a pathogenic NRAS missense variant, Q61R. No other molecular alterations, microsatellite instability, gene fusions or amplifications were identified.

Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

PubMed

Bustamante, M Leonor; Herrera, Luisa; Gaspar, Pablo A; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

2017-10-01

Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. © 2017 Wiley Periodicals, Inc.

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.

PubMed

de Haas, Sanne; Delmar, Paul; Bansal, Aruna T; Moisse, Matthieu; Miles, David W; Leighl, Natasha; Escudier, Bernard; Van Cutsem, Eric; Carmeliet, Peter; Scherer, Stefan J; Pallaud, Celine; Lambrechts, Diether

2014-10-01

Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.

Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes.

PubMed

Karyadi, Danielle M; Geybels, Milan S; Karlins, Eric; Decker, Brennan; McIntosh, Laura; Hutchinson, Amy; Kolb, Suzanne; McDonnell, Shannon K; Hicks, Belynda; Middha, Sumit; FitzGerald, Liesel M; DeRycke, Melissa S; Yeager, Meredith; Schaid, Daniel J; Chanock, Stephen J; Thibodeau, Stephen N; Berndt, Sonja I; Stanford, Janet L; Ostrander, Elaine A

2017-01-03

Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.

Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.

PubMed

Beyer, Ulrike; Brand, Frank; Martens, Helge; Weder, Julia; Christians, Arne; Elyan, Natalie; Hentschel, Bettina; Westphal, Manfred; Schackert, Gabriele; Pietsch, Torsten; Hong, Bujung; Krauss, Joachim K; Samii, Amir; Raab, Peter; Das, Anibh; Dumitru, Claudia A; Sandalcioglu, I Erol; Hakenberg, Oliver W; Erbersdobler, Andreas; Lehmann, Ulrich; Reifenberger, Guido; Weller, Michael; Reijns, Martin A M; Preller, Matthias; Wiese, Bettina; Hartmann, Christian; Weber, Ruthild G

2017-12-01

In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequencing, we identified novel ADAR and RNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutations ADAR,c.577C>G;p.(P193A) and RNASEH2B,c.529G>A;p.(A177T) in the germline of familial glioma patients as well as in test and validation cohorts of glioblastomas and prostate carcinomas versus ethnicity-matched controls, whereby rare RNASEH2B variants were significantly more frequent in familial glioma patients. Tumors with ADAR or RNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carrying ADAR or RNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced by ADAR and RNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the AGS genes ADAR and RNASEH2B and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis, consistent with a genetic basis underlying inflammation-driven malignant transformation in glioma and prostate carcinoma development.

Cigarette brand variant portfolio strategy and the use of colour in a darkening market.

PubMed

Greenland, Steven J

2015-03-01

To evaluate cigarette branding strategies used to segment a market with some of the toughest tobacco controls. To document brand variant and packaging portfolios and assess the role played by colour before plain packaging, as well as consider the threat that recently implemented legislation poses for tobacco manufacturers. Brand variant and packaging details were extracted from manufacturer ingredient reports, as well as a retail audit of Australian supermarkets. Details were also collected for other product categories to provide perspective on cigarette portfolios. Secondary and primary data sources were analysed to evaluate variant and packaging portfolio strategy. In Australia, 12 leading cigarette brands supported 120 brand variants. Of these 61 had names with a specific colour and a further 26 had names with colour connotation. There were 338 corresponding packaging configurations, with most variants available in the primary cigarette distribution channel in four pack size options. Tobacco companies microsegment Australian consumers with highly differentiated product offerings and a family branding strategy that helps ameliorate the effects of marketing restrictions. To date, tobacco controls have had little negative impact upon variant and packaging portfolios, which have continued to expand. Colour has become a key visual signifier differentiating one variant from the next, and colour names are used to extend brand lines. However, the role of colour, as a heuristic to simplify consumer decision-making processes, becomes largely redundant with plain packaging. Plain packaging's impact upon manufacturers' branding strategies is therefore likely to be significant. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

PubMed

Maver, Ales; Lavtar, Polona; Ristić, Smiljana; Stopinšek, Sanja; Simčič, Saša; Hočevar, Keli; Sepčić, Juraj; Drulović, Jelena; Pekmezović, Tatjana; Novaković, Ivana; Alenka, Hodžić; Rudolf, Gorazd; Šega, Saša; Starčević-Čizmarević, Nada; Palandačić, Anja; Zamolo, Gordana; Kapović, Miljenko; Likar, Tina; Peterlin, Borut

2017-06-16

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

PubMed

Loley, Christina; Alver, Maris; Assimes, Themistocles L; Bjonnes, Andrew; Goel, Anuj; Gustafsson, Stefan; Hernesniemi, Jussi; Hopewell, Jemma C; Kanoni, Stavroula; Kleber, Marcus E; Lau, King Wai; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Nelson, Christopher P; Nikpay, Majid; Qu, Liming; Salfati, Elias; Scholz, Markus; Tukiainen, Taru; Willenborg, Christina; Won, Hong-Hee; Zeng, Lingyao; Zhang, Weihua; Anand, Sonia S; Beutner, Frank; Bottinger, Erwin P; Clarke, Robert; Dedoussis, George; Do, Ron; Esko, Tõnu; Eskola, Markku; Farrall, Martin; Gauguier, Dominique; Giedraitis, Vilmantas; Granger, Christopher B; Hall, Alistair S; Hamsten, Anders; Hazen, Stanley L; Huang, Jie; Kähönen, Mika; Kyriakou, Theodosios; Laaksonen, Reijo; Lind, Lars; Lindgren, Cecilia; Magnusson, Patrik K E; Marouli, Eirini; Mihailov, Evelin; Morris, Andrew P; Nikus, Kjell; Pedersen, Nancy; Rallidis, Loukianos; Salomaa, Veikko; Shah, Svati H; Stewart, Alexandre F R; Thompson, John R; Zalloua, Pierre A; Chambers, John C; Collins, Rory; Ingelsson, Erik; Iribarren, Carlos; Karhunen, Pekka J; Kooner, Jaspal S; Lehtimäki, Terho; Loos, Ruth J F; März, Winfried; McPherson, Ruth; Metspalu, Andres; Reilly, Muredach P; Ripatti, Samuli; Sanghera, Dharambir K; Thiery, Joachim; Watkins, Hugh; Deloukas, Panos; Kathiresan, Sekar; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; König, Inke R

2016-10-12

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alternations in CNS Development

DTIC Science & Technology

2009-10-01

2004. MECP2 structural and 3’-UTR variants in schizophrenia , autism and other psychiatric diseases: a possible association with autism. Am J Med...inhibition, thus potentially enabling enhancement of remyelination. Role: PI Award letter dated 12/11/06 Noble (PI) Cure Autism Now Foundation 02/05

Using the Neandertal genome to study the evolution of small insertions and deletions in modern humans.

PubMed

Chintalapati, Manjusha; Dannemann, Michael; Prüfer, Kay

2017-08-04

Small insertions and deletions occur in humans at a lower rate compared to nucleotide changes, but evolve under more constraint than nucleotide changes. While the evolution of insertions and deletions have been investigated using ape outgroups, the now available genome of a Neandertal can shed light on the evolution of indels in more recent times. We used the Neandertal genome together with several primate outgroup genomes to differentiate between human insertion/deletion changes that likely occurred before the split from Neandertals and those that likely arose later. Changes that pre-date the split from Neandertals show a smaller proportion of deletions than those that occurred later. The presence of a Neandertal-shared allele in Europeans or Asians but the absence in Africans was used to detect putatively introgressed indels in Europeans and Asians. A larger proportion of these variants reside in intergenic regions compared to other modern human variants, and some variants are linked to SNPs that have been associated with traits in modern humans. Our results are in agreement with earlier results that suggested that deletions evolve under more constraint than insertions. When considering Neandertal introgressed variants, we find some evidence that negative selection affected these variants more than other variants segregating in modern humans. Among introgressed variants we also identify indels that may influence the phenotype of their carriers. In particular an introgressed deletion associated with a decrease in the time to menarche may constitute an example of a former Neandertal-specific trait contributing to modern human phenotypic diversity.

Allelic Variation in Developmental Genes and Effects on Winter Wheat Heading Date in the U.S. Great Plains

PubMed Central

Brown-Guedira, Gina; Haley, Scott D.; McMaster, Gregory S.; Reid, Scott D.; Smith, Jared; Byrne, Patrick F.

2016-01-01

Heading date in wheat (Triticum aestivum L.) and other small grain cereals is affected by the vernalization and photoperiod pathways. The reduced-height loci also have an effect on growth and development. Heading date, which occurs just prior to anthesis, was evaluated in a population of 299 hard winter wheat entries representative of the U.S. Great Plains region, grown in nine environments during 2011–2012 and 2012–2013. The germplasm was evaluated for candidate genes at vernalization (Vrn-A1, Vrn-B1, and Vrn-D1), photoperiod (Ppd-A1, Ppd-B1 and Ppd-D1), and reduced-height (Rht-B1 and Rht-D1) loci using polymerase chain reaction (PCR) and Kompetitive Allele Specific PCR (KASP) assays. Our objectives were to determine allelic variants known to affect flowering time, assess the effect of allelic variants on heading date, and investigate changes in the geographic and temporal distribution of alleles and haplotypes. Our analyses enhanced understanding of the roles developmental genes have on the timing of heading date in wheat under varying environmental conditions, which could be used by breeding programs to improve breeding strategies under current and future climate scenarios. The significant main effects and two-way interactions between the candidate genes explained an average of 44% of variability in heading date at each environment. Among the loci we evaluated, most of the variation in heading date was explained by Ppd-D1, Ppd-B1, and their interaction. The prevalence of the photoperiod sensitive alleles Ppd-A1b, Ppd-B1b, and Ppd-D1b has gradually decreased in U.S. Great Plains germplasm over the past century. There is also geographic variation for photoperiod sensitive and reduced-height alleles, with germplasm from breeding programs in the northern Great Plains having greater incidences of the photoperiod sensitive alleles and lower incidence of the semi-dwarf alleles than germplasm from breeding programs in the central or southern plains. PMID:27058239

Critical comparison of several order-book models for stock-market fluctuations

NASA Astrophysics Data System (ADS)

Slanina, F.

2008-01-01

Far-from-equilibrium models of interacting particles in one dimension are used as a basis for modelling the stock-market fluctuations. Particle types and their positions are interpreted as buy and sel orders placed on a price axis in the order book. We revisit some modifications of well-known models, starting with the Bak-Paczuski-Shubik model. We look at the four decades old Stigler model and investigate its variants. One of them is the simplified version of the Genoa artificial market. The list of studied models is completed by the models of Maslov and Daniels et al. Generically, in all cases we compare the return distribution, absolute return autocorrelation and the value of the Hurst exponent. It turns out that none of the models reproduces satisfactorily all the empirical data, but the most promising candidates for further development are the Genoa artificial market and the Maslov model with moderate order evaporation.

Fast secant methods for the iterative solution of large nonsymmetric linear systems

NASA Technical Reports Server (NTRS)

Deuflhard, Peter; Freund, Roland; Walter, Artur

1990-01-01

A family of secant methods based on general rank-1 updates was revisited in view of the construction of iterative solvers for large non-Hermitian linear systems. As it turns out, both Broyden's good and bad update techniques play a special role, but should be associated with two different line search principles. For Broyden's bad update technique, a minimum residual principle is natural, thus making it theoretically comparable with a series of well known algorithms like GMRES. Broyden's good update technique, however, is shown to be naturally linked with a minimum next correction principle, which asymptotically mimics a minimum error principle. The two minimization principles differ significantly for sufficiently large system dimension. Numerical experiments on discretized partial differential equations of convection diffusion type in 2-D with integral layers give a first impression of the possible power of the derived good Broyden variant.

Nemesis revisited: tuberculosis infection in a New York City men's shelter.

PubMed Central

Paul, E A; Lebowitz, S M; Moore, R E; Hoven, C W; Bennett, B A; Chen, A

1993-01-01

In November 1990, a screening was conducted to determine the point prevalence of tuberculosis infection in a volunteer sample of homeless men (n = 161) living in a congregate shelter in New York City. Of those for whom we have results (n = 134), 79% were positive for tuberculosis. The mean length of shelter stay from date of shelter entry was 31.8 months and was significantly associated with the tuberculosis infection rate. The findings suggest that crowded living conditions and the presence of a stable resident pool in crowded congregate shelters may be associated with transmission of tuberculosis infection. Images p1744-a PMID:8259807

Revisiting the Roles of Culture and Culture-Independent Detection Tests for Campylobacter.

PubMed

Couturier, Marc Roger

2016-05-01

Culture-independent detection tests (CIDTs) for Campylobacter have become an area of intense controversy and confusion among laboratorians in the field of clinical microbiology. To date, the true analytical and clinical performance of stool antigen CIDTs versus truly optimized culture conditions is unknown. In this issue of the Journal of Clinical Microbiology, Fitzgerald and colleagues (C. Fitzgerald et al., J Clin Microbiol 54:1209-1215, 2016, http://dx.doi.org/10.1128/JCM.01925-15) report comprehensive performance data for four Campylobacter stool antigen CIDTs versus culture and molecular diagnostics. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.

PubMed

Rao, Shitao; Leung, Cherry She Ting; Lam, Macro Hb; Wing, Yun Kwok; Waye, Mary Miu Yee; Tsui, Stephen Kwok Wing

2017-03-01

To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. Copyright © 2016 Elsevier B.V. All rights reserved.

Neutralizing monoclonal antibodies recognize antigenic variants among isolates of infectious hematopoietic necrosis virus

USGS Publications Warehouse

Winton, J.R.; Arakawa, C.N.; Lannan, C.N.; Fryer, J.L.

1988-01-01

eutralizing monoclonal antibodies were developed against strains of infectious hematopoietic necrosis virus (IHNV) from steelhead trout Salmo gairdneri in the Deschutes River of Oregon, chinook salmon Oncorhynchus tshawytscha in the Sacramento River of California, and rainbow trout Salmo gairdneri reared in the Hagerman Valley of Idaho, USA. These antibodies were tested for neutralization of 12 IHNV isolates obtained from salmonids in Japan, Alaska, Washington, Oregon, California, and Idaho. The antibodies recognized antigenic variants among the isolates and could be used to separate the viruses into 4 groups. The members of each group tended to be related by geographic area rather than by source host species, virulence, or date of isolation.

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.

PubMed

Lorenzo, Melissa; Stolte-Dijkstra, Irene; van Rheenen, Patrick; Smith, Ronald Garth; Scheers, Tom; Walia, Jagdeep S

2018-06-01

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. © 2018 Wiley Periodicals, Inc.

Changing expressions: a hypothesis for the origin of the vascular plant life cycle.

PubMed

Kenrick, Paul

2018-02-05

Plant life cycles underwent fundamental changes during the initial colonization of the land in the Early Palaeozoic, shaping the direction of evolution. Fossils reveal unanticipated diversity, including new variants of meiotic cell division and leafless gametophytes with mycorrhizal-like symbioses, rhizoids, vascular tissues and stomata. Exceptional fossils from the 407-Ma Rhynie chert (Scotland) play a key role in unlocking this diversity. These fossils are reviewed against progress in our understanding of the plant tree of life and recent advances in developmental genetics. Combining data from different sources sheds light on a switch in life cycle that gave rise to the vascular plants. One crucial step was the establishment of a free-living sporophyte from one that was an obligate matrotroph borne on the gametophyte. It is proposed that this difficult evolutionary transition was achieved through expansion of gene expression primarily from the gametophyte to the sporophyte, establishing a now extinct life cycle variant that was more isomorphic than heteromorphic. These changes also linked for the first time in one developmental system rhizoids, vascular tissues and stomata, putting in place the critical components that regulate transpiration and forming a physiological platform of primary importance to the diversification of vascular plants.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. © 2017 The Author(s).

The Neandertal type site revisited: Interdisciplinary investigations of skeletal remains from the Neander Valley, Germany

PubMed Central

Schmitz, Ralf W.; Serre, David; Bonani, Georges; Feine, Susanne; Hillgruber, Felix; Krainitzki, Heike; Pääbo, Svante; Smith, Fred H.

2002-01-01

The 1856 discovery of the Neandertal type specimen (Neandertal 1) in western Germany marked the beginning of human paleontology and initiated the longest-standing debate in the discipline: the role of Neandertals in human evolutionary history. We report excavations of cave sediments that were removed from the Feldhofer caves in 1856. These deposits have yielded over 60 human skeletal fragments, along with a large series of Paleolithic artifacts and faunal material. Our analysis of this material represents the first interdisciplinary analysis of Neandertal remains incorporating genetic, direct dating, and morphological dimensions simultaneously. Three of these skeletal fragments fit directly on Neandertal 1, whereas several others have distinctively Neandertal features. At least three individuals are represented in the skeletal sample. Radiocarbon dates for Neandertal 1, from which a mtDNA sequence was determined in 1997, and a second individual indicate an age of ≈40,000 yr for both. mtDNA analysis on the same second individual yields a sequence that clusters with other published Neandertal sequences. PMID:12232049

Comparison of Tasseled Cap-based Landsat data structures for use in forest disturbance detection.

Treesearch

Sean P. Healey; Warren B. Cohen; Yang Zhiqiang; Olga N. Krankina

2005-01-01

Landsat satellite data has become ubiquitous in regional-scale forest disturbance detection. The Tasseled Cap (TC) transformation for Landsat data has been used in several disturbance-mapping projects because of its ability to highlight relevant vegetation changes. We used an automated composite analysis procedure to test four multi-date variants of the TC...

Combining Protein and Strain Engineering for the Production of Glyco-Engineered Horseradish Peroxidase C1A in Pichia pastoris

PubMed Central

Capone, Simona; Ćorajević, Lejla; Bonifert, Günther; Murth, Patrick; Maresch, Daniel; Altmann, Friedrich; Herwig, Christoph; Spadiut, Oliver

2015-01-01

Horseradish peroxidase (HRP), conjugated to antibodies and lectins, is widely used in medical diagnostics. Since recombinant production of the enzyme is difficult, HRP isolated from plant is used for these applications. Production in the yeast Pichia pastoris (P. pastoris), the most promising recombinant production platform to date, causes hyperglycosylation of HRP, which in turn complicates conjugation to antibodies and lectins. In this study we combined protein and strain engineering to obtain an active and stable HRP variant with reduced surface glycosylation. We combined four mutations, each being beneficial for either catalytic activity or thermal stability, and expressed this enzyme variant as well as the unmutated wildtype enzyme in both a P. pastoris benchmark strain and a strain where the native α-1,6-mannosyltransferase (OCH1) was knocked out. Considering productivity in the bioreactor as well as enzyme activity and thermal stability, the mutated HRP variant produced in the P. pastoris benchmark strain turned out to be interesting for medical diagnostics. This variant shows considerable catalytic activity and thermal stability and is less glycosylated, which might allow more controlled and efficient conjugation to antibodies and lectins. PMID:26404235

The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

PubMed

Hervás, Amaia; Toma, Claudio; Romarís, Patricia; Ribasés, Marta; Salgado, Marta; Bayes, Mònica; Balmaña, Noemí; Cormand, Bru; Maristany, Marta; Guijarro, Silvina; Arranz, María J

2014-08-01

Autism spectrum disorders (ASD) are highly inherited developmental syndromes, resulting from a complex interaction between environmental and genetic factors. To date, only a limited number of genetic variants have been discovered with respect to autism, and their contribution to the development of the disorder has not been clearly determined. Investigation of specific autistic symptomatology may improve the chances of identifying related genes and may help to better understand these disorders. We investigated the contribution of 80 genetic variants in 15 serotonin genes to ASD phenotypes [intelligence quotation (IQ), intellectual disability (ID) and language onset delay (LD)] in a cohort of 141 children and young adults (121 male patients and 20 female patients, average age 14.5±5.1 years). Two polymorphisms in the HTR2B gene, rs10194776 and rs16827801, were associated with IQ (P=0.0004 and 0.003, respectively), ID (P=0.02 and 0.03) and LD (P=0.04 and 0.004). Nominal associations were also detected between the ASD phenotypes investigated and 5-HT2A, 5-HT4 and 5-HT6 genetic variants. Our study provides evidence of the contribution of serotonergic variants to IQ, ID and LD in ASD patients.

Quantitative trait nucleotide analysis using Bayesian model selection.

PubMed

Blangero, John; Goring, Harald H H; Kent, Jack W; Williams, Jeff T; Peterson, Charles P; Almasy, Laura; Dyer, Thomas D

2005-10-01

Although much attention has been given to statistical genetic methods for the initial localization and fine mapping of quantitative trait loci (QTLs), little methodological work has been done to date on the problem of statistically identifying the most likely functional polymorphisms using sequence data. In this paper we provide a general statistical genetic framework, called Bayesian quantitative trait nucleotide (BQTN) analysis, for assessing the likely functional status of genetic variants. The approach requires the initial enumeration of all genetic variants in a set of resequenced individuals. These polymorphisms are then typed in a large number of individuals (potentially in families), and marker variation is related to quantitative phenotypic variation using Bayesian model selection and averaging. For each sequence variant a posterior probability of effect is obtained and can be used to prioritize additional molecular functional experiments. An example of this quantitative nucleotide analysis is provided using the GAW12 simulated data. The results show that the BQTN method may be useful for choosing the most likely functional variants within a gene (or set of genes). We also include instructions on how to use our computer program, SOLAR, for association analysis and BQTN analysis.

Genotyping of Canine parvovirus in western Mexico.

PubMed

Pedroza-Roldán, César; Páez-Magallan, Varinia; Charles-Niño, Claudia; Elizondo-Quiroga, Darwin; De Cervantes-Mireles, Raúl Leonel; López-Amezcua, Mario Alberto

2015-01-01

Canine parvovirus (CPV) is one of the most common infectious agents related to high morbidity rates in dogs. In addition, the virus is associated with severe gastroenteritis, diarrhea, and vomiting, resulting in high death rates, especially in puppies and nonvaccinated dogs. To date, there are 3 variants of the virus (CPV-2a, CPV-2b, and CPV-2c) circulating worldwide. In Mexico, reports describing the viral variants circulating in dog populations are lacking. In response to this deficiency, a total of 41 fecal samples of suspected dogs were collected from October 2013 through April 2014 in the Veterinary Hospital of the University of Guadalajara in western Mexico. From these, 24 samples resulted positive by polymerase chain reaction, and the viral variant was determined by restriction fragment length polymorphism. Five positive diagnosed samples were selected for partial sequencing of the vp2 gene and codon analysis. The results demonstrated that the current dominant viral variant in Mexico is CPV-2c. The current study describes the genotyping of CPV strains, providing valuable evidence of the dominant frequency of this virus in a dog population from western Mexico. © 2014 The Author(s).

Microstructure and physicochemical properties reveal differences between high moisture buffalo and bovine Mozzarella cheeses.

PubMed

Nguyen, Hanh T H; Ong, Lydia; Lopez, Christelle; Kentish, Sandra E; Gras, Sally L

2017-12-01

Mozzarella cheese is a classical dairy product but most research to date has focused on low moisture products. In this study, the microstructure and physicochemical properties of both laboratory and commercially produced high moisture buffalo Mozzarella cheeses were investigated and compared to high moisture bovine products. Buffalo and bovine Mozzarella cheeses were found to significantly differ in their microstructure, chemical composition, organic acid and proteolytic profiles but had similar hardness and meltability. The buffalo cheeses exhibited a significantly higher ratio of fat to protein and a microstructure containing larger fat patches and a less dense protein network. Liquid chromatography mass spectrometry detected the presence of only β-casein variant A2 and a single β-lactoglobulin variant in buffalo products compared to the presence of both β-casein variants A1 and A2 and β-lactoglobulin variants A and B in bovine cheese. These differences arise from the different milk composition and processing conditions. The differences in microstructure and physicochemical properties observed here offer a new approach to identify the sources of milk used in commercial cheese products. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetics and epigenetics of obesity.

PubMed

Herrera, Blanca M; Keildson, Sarah; Lindgren, Cecilia M

2011-05-01

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

42 CFR 488.30 - Revisit user fee for revisit surveys.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., or substantiated complaint survey and that is designed to evaluate the extent to which previously... 42 Public Health 5 2012-10-01 2012-10-01 false Revisit user fee for revisit surveys. 488.30... SERVICES (CONTINUED) STANDARDS AND CERTIFICATION SURVEY, CERTIFICATION, AND ENFORCEMENT PROCEDURES General...

42 CFR 488.30 - Revisit user fee for revisit surveys.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., or substantiated complaint survey and that is designed to evaluate the extent to which previously... 42 Public Health 5 2013-10-01 2013-10-01 false Revisit user fee for revisit surveys. 488.30... SERVICES (CONTINUED) STANDARDS AND CERTIFICATION SURVEY, CERTIFICATION, AND ENFORCEMENT PROCEDURES General...

42 CFR 488.30 - Revisit user fee for revisit surveys.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., or substantiated complaint survey and that is designed to evaluate the extent to which previously... 42 Public Health 5 2014-10-01 2014-10-01 false Revisit user fee for revisit surveys. 488.30... SERVICES (CONTINUED) STANDARDS AND CERTIFICATION SURVEY, CERTIFICATION, AND ENFORCEMENT PROCEDURES General...

42 CFR 488.30 - Revisit user fee for revisit surveys.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., or substantiated complaint survey and that is designed to evaluate the extent to which previously... 42 Public Health 5 2011-10-01 2011-10-01 false Revisit user fee for revisit surveys. 488.30... SERVICES (CONTINUED) STANDARDS AND CERTIFICATION SURVEY, CERTIFICATION, AND ENFORCEMENT PROCEDURES General...

42 CFR 488.30 - Revisit user fee for revisit surveys.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., or substantiated complaint survey and that is designed to evaluate the extent to which previously... 42 Public Health 5 2010-10-01 2010-10-01 false Revisit user fee for revisit surveys. 488.30... SERVICES (CONTINUED) STANDARDS AND CERTIFICATION SURVEY, CERTIFICATION, AND ENFORCEMENT PROCEDURES General...

Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation

PubMed Central

Gregory, L. C.; Humayun, K. N.; Turton, J. P. G.; McCabe, M. J.; Rhodes, S. J.

2015-01-01

Background: LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. Objective/Hypothesis: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. Method: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. Results: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. Conclusion: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life. PMID:25871839

Genome-Wide Association of Heroin Dependence in Han Chinese.

PubMed

Kalsi, Gursharan; Euesden, Jack; Coleman, Jonathan R I; Ducci, Francesca; Aliev, Fazil; Newhouse, Stephen J; Liu, Xiehe; Ma, Xiaohong; Wang, Yingcheng; Collier, David A; Asherson, Philip; Li, Tao; Breen, Gerome

2016-01-01

Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.

Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility

PubMed Central

FitzGerald, Liesel M.; Kumar, Akash; Boyle, Evan A.; Zhang, Yuzheng; McIntosh, Laura M.; Kolb, Suzanne; Stott-Miller, Marni; Smith, Tiffany; Karyadi, Danielle M.; Ostrander, Elaine A.; Hsu, Li; Shendure, Jay; Stanford, Janet L.

2013-01-01

Background Rare, inherited mutations account for 5%–10% of all prostate cancer (PCa) cases. However, to date, few causative mutations have been identified. Methods To identify rare mutations for PCa, we performed whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 PCa cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident PCa cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated PCa risk in the population-based study (rs41441651: OR = 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR = 2.5; 95% CI, 1.16–5.46; P = 0.019). Conclusions Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact Results implicate BTNL2 as a novel PCa susceptibility gene. PMID:23833122

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.

PubMed

Shahzad, Mohsin; Yousaf, Sairah; Waryah, Yar M; Gul, Hadia; Kausar, Tasleem; Tariq, Nabeela; Mahmood, Umair; Ali, Muhammad; Khan, Muzammil A; Waryah, Ali M; Shaikh, Rehan S; Riazuddin, Saima; Ahmed, Zubair M

2017-03-07

Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56% (95% CI: 46.52-65.24%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

PubMed Central

Loley, Christina; Alver, Maris; Assimes, Themistocles L.; Bjonnes, Andrew; Goel, Anuj; Gustafsson, Stefan; Hernesniemi, Jussi; Hopewell, Jemma C.; Kanoni, Stavroula; Kleber, Marcus E.; Lau, King Wai; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Nelson, Christopher P.; Nikpay, Majid; Qu, Liming; Salfati, Elias; Scholz, Markus; Tukiainen, Taru; Willenborg, Christina; Won, Hong-Hee; Zeng, Lingyao; Zhang, Weihua; Anand, Sonia S.; Beutner, Frank; Bottinger, Erwin P.; Clarke, Robert; Dedoussis, George; Do, Ron; Esko, Tõnu; Eskola, Markku; Farrall, Martin; Gauguier, Dominique; Giedraitis, Vilmantas; Granger, Christopher B.; Hall, Alistair S.; Hamsten, Anders; Hazen, Stanley L.; Huang, Jie; Kähönen, Mika; Kyriakou, Theodosios; Laaksonen, Reijo; Lind, Lars; Lindgren, Cecilia; Magnusson, Patrik K. E.; Marouli, Eirini; Mihailov, Evelin; Morris, Andrew P.; Nikus, Kjell; Pedersen, Nancy; Rallidis, Loukianos; Salomaa, Veikko; Shah, Svati H.; Stewart, Alexandre F. R.; Thompson, John R.; Zalloua, Pierre A.; Chambers, John C.; Collins, Rory; Ingelsson, Erik; Iribarren, Carlos; Karhunen, Pekka J.; Kooner, Jaspal S.; Lehtimäki, Terho; Loos, Ruth J. F.; März, Winfried; McPherson, Ruth; Metspalu, Andres; Reilly, Muredach P.; Ripatti, Samuli; Sanghera, Dharambir K.; Thiery, Joachim; Watkins, Hugh; Deloukas, Panos; Kathiresan, Sekar; Samani, Nilesh J.; Schunkert, Heribert; Erdmann, Jeanette; König, Inke R.

2016-01-01

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD. PMID:27731410

Upregulation of the splice variant MUC4/Y in the pancreatic cancer cell line MIA PaCa-2 potentiates proliferation and suppresses apoptosis: new insight into the presence of the transcript variant of MUC4.

PubMed

Xie, Kunling; Zhi, Xiaofei; Tang, Jie; Zhu, Yi; Zhang, Jingjing; Li, Zheng; Tao, Jinqiu; Xu, Zekuan

2014-05-01

MUC4/Y, the transcript variant 4 of MUC4, lacks exon 2 as compared with the transcript variant 1 of MUC4. To date, direct evidence for the function of MU4/Y remains to be reported. Previous studies based their hypotheses regarding the function of MUC4/Y on the characteristic structure domains of this variant. The aim of the present study was to investigate the specific function of MUC4/Y. The pancreatic cancer cell line MIA PaCa-2 with low MUC4/Y expression was used to establish a stable cell model of MUC4/Y upregulation using a lentivirus vector system. Results showed that MUC4/Y anchored on the cytomembrane and affected cell morphology and cell cycle. Functional analyses indicated that MUC4/Y upregulation slightly potentiated cell proliferation and significantly suppressed apoptosis both in vivo and in vitro. Further studies revealed that the JNK and AKT signalling pathways were activated. Meanwhile, MUC4/Y upregulation elicited minimal effect on the phosphorylation level of HER2, a membrane partner of MUC4. These results suggest that MUC4/Y promotes tumour progression through its anti-apoptotic and weak mitogenic effect on MIA PaCa-2 cells.

Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians.

PubMed

Benzinou, Michael; Walley, Andrew; Lobbens, Stephan; Charles, Marie-Aline; Jouret, Béatrice; Fumeron, Frédéric; Balkau, Beverley; Meyre, David; Froguel, Philippe

2006-10-01

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity.

Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells.

PubMed

Böhringer, Judith; Santer, René; Schumacher, Neele; Gieseke, Friederike; Cornils, Kerstin; Pechan, Maria; Kustermann-Kuhn, Birgit; Handgretinger, Rupert; Schöls, Ludger; Harzer, Klaus; Krägeloh-Mann, Ingeborg; Müller, Ingo

2017-11-01

Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T > C, c.195delC, c.229G > C, c.545C > G, c.674A > G, c.852T > A, and c.1274A > G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSA -/- cell system, the seven ARSA mutants showed ARSA activity of less than 10% when compared with wild type, which is evidence for the pathogenicity of all seven variants. In conclusion, the system of ARSA -/- -immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants. © 2017 Wiley Periodicals, Inc.

The evolutionary dynamics of canid and mongoose rabies virus in Southern Africa.

PubMed

Davis, P L; Rambaut, A; Bourhy, H; Holmes, E C

2007-01-01

Two variants of rabies virus (RABV) currently circulate in southern Africa: canid RABV, mainly associated with dogs, jackals, and bat-eared foxes, and mongoose RABV. To investigate the evolutionary dynamics of these variants, we performed coalescent-based analyses of the G-L inter-genic region, allowing for rate variation among viral lineages through the use of a relaxed molecular clock. This revealed that mongoose RABV is evolving more slowly than canid RABV, with mean evolutionary rates of 0.826 and 1.676 x 10(-3) nucleotide substitutions per site, per year, respectively. Additionally, mongoose RABV exhibits older genetic diversity than canid RABV, with common ancestors dating to 73 and 30 years, respectively, and while mongoose RABV has experienced exponential population growth over its evolutionary history in Africa, populations of canid RABV have maintained a constant size. Hence, despite circulating in the same geographic region, these two variants of RABV exhibit striking differences in evolutionary dynamics which are likely to reflect differences in their underlying ecology.

Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.

PubMed

Lin, Pengfei; Zhang, Dong; Xu, Guangrun; Yan, Chuanzhu

2018-04-01

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant, clinically heterogeneous neurodegenerative disorders. SCA18 is a rare autosomal dominant sensory/motor neuropathy with ataxia (OMIM#607458) associated with a single missense variant c.514 A>G in the interferon related developmental regulator 1 (IFRD1) gene previously reported in a five-generation American family of Irish origin. However, to date, there have been no other reports of the IFRD1 mutation to confirm its role in SCA. Here, we report a Han Chinese family with SCA18; the family members presented with a slowly progressing gait ataxia, pyramidal tract signs, and peripheral neuropathy. We identified a missense variant (c.514 A>G, p.I172V) in IFRD1 gene in the family using targeted next-generation sequencing and Sanger direct sequencing with specific primers. Our results suggest that the IFRD1 gene may be the causative allele for SCA18.

Modeling and Validation of the Ecological Behavior of Wild-Type Listeria monocytogenes and Stress-Resistant Variants.

PubMed

Metselaar, Karin I; Abee, Tjakko; Zwietering, Marcel H; den Besten, Heidy M W

2016-09-01

Listeria monocytogenes exhibits a heterogeneous response upon stress exposure which can be partially attributed to the presence of stable stress-resistant variants. This study aimed to evaluate the impact of the presence of stress-resistant variants of Listeria monocytogenes and their corresponding trade-offs on population composition under different environmental conditions. A set of stress robustness and growth parameters of the wild type (WT) and an rpsU deletion variant was obtained and used to model their growth behavior under combined mild stress conditions and to model their kinetics under single- and mixed-strain conditions in a simulated food chain. Growth predictions for the WT and the rpsU deletion variant matched the experimental data generally well, although some deviations from the predictions were observed. The data highlighted the influence of the environmental conditions on the ratio between the WT and variant. Prediction of performance in the simulated food chain proved to be challenging. The trend of faster growth and lower stress robustness for the WT than for the rpsU variant in the different steps of the chain was confirmed, but especially for the inactivation steps and the time needed to resume growth after an inactivation step, the experimental data deviated from the model predictions. This report provides insights into the conditions which can select for stress-resistant variants in industrial settings and discusses their potential persistence in food processing environments. Listeria monocytogenes exhibits a heterogeneous stress response which can partially be attributed to the presence of genetic variants. These stress-resistant variants survive better under severe conditions but have, on the other hand, a reduced growth rate. To date, the ecological behavior and potential impact of the presence of stress-resistant variants is not fully understood. In this study, we quantitatively assessed growth and inactivation behavior of wild-type L. monocytogenes and its stress-resistant variants. Predictions were validated under different conditions, as well as along a model food chain. This work illustrates the effects of environmental factors on population dynamics of L. monocytogenes and is a first step in evaluating the impact of population diversity on food safety. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

How do we know about Earth's history? Constructing the story of Earth's geologic history by collecting and interpreting evidence based scenarios.

NASA Astrophysics Data System (ADS)

Ruthford, Steven; DeBari, Susan; Linneman, Scott; Boriss, Miguel; Chesbrough, John; Holmes, Randall; Thibault, Allison

2013-04-01

Beginning in 2003, faculty from Western Washington University, Skagit Valley Community College, local public school teachers, and area tribal college members created an innovative, inquiry based undergraduate geology curriculum. The curriculum, titled "Energy and Matter in Earth's Systems," was supported through various grants and partnerships, including Math and Science Partnership and Noyce Teacher Scholarship grants from the National Science Foundation. During 2011, the authors wrote a geologic time unit for the curriculum. The unit is titled, "How Do We Know About Earth's History?" and has students actively investigate the concepts related to geologic time and methods for determining age. Starting with reflection and assessment of personal misconceptions called "Initial Ideas," students organize a series of events into a timeline. The unit then focuses on the concepts of relative dating, biostratigraphy, and historical attempts at absolute dating, including uniformitarianism, catastrophism, Halley and Joly's Salinity hypothesis, and Kelvin's Heat Loss model. With limited lecture and text, students then dive into current understandings of the age of the Earth, which include radioactive decay rates and radiometric dating. Finally, using their newfound understanding, students investigate a number of real world scenarios and create a timeline of events related to the geologic history of the Earth. The unit concludes with activities that reinforce the Earth's absolute age and direct students to summarize what they have learned by reorganizing the timeline from the "Initial Ideas" and sharing with the class. This presentation will include the lesson materials and findings from one activity titled, "The Earth's Story." The activity is located midway through the unit and begins with reflection on the question, "What are the major events in the Earth's history and when did they happen?" Students are directed to revisit the timeline of events from the "Initial Ideas" activity at the beginning of the unit. After the review and reflection, students collect and interpret six evidence based scenarios dealing with the absolute ages of various rocks, including moon and meteorite samples, microfossil data, banded iron formations, plant and animal fossils, tectonic movement, extinction events, and human migration. The scenarios are dated and allow students to have a more complete view of geologic time. Using this more complete view, students are prompted to revisit and reorganize the timeline from the "Initial Ideas." By the end of the lesson, students will demonstrate a more complete understanding of the age of the Earth, the geologic time scale, and the role of biotic factors in Earth's systems.

WHATIF: an open-source desktop application for extraction and management of the incidental findings from next-generation sequencing variant data

PubMed Central

Ye, Zhan; Kadolph, Christopher; Strenn, Robert; Wall, Daniel; McPherson, Elizabeth; Lin, Simon

2015-01-01

Background Identification and evaluation of incidental findings in patients following whole exome (WGS) or whole genome sequencing (WGS) is challenging for both practicing physicians and researchers. The American College of Medical Genetics and Genomics (ACMG) recently recommended a list of reportable incidental genetic findings. However, no informatics tools are currently available to support evaluation of incidental findings in next-generation sequencing data. Methods The Wisconsin Hierarchical Analysis Tool for Incidental Findings (WHATIF), was developed as a stand-alone Windows-based desktop executable, to support the interactive analysis of incidental findings in the context of the ACMG recommendations. WHATIF integrates the European Bioinformatics Institute Variant Effect Predictor (VEP) tool for biological interpretation and the National Center for Biotechnology Information ClinVar tool for clinical interpretation. Results An open-source desktop program was created to annotate incidental findings and present the results with a user-friendly interface. Further, a meaningful index (WHATIF Index) was devised for each gene to facilitate ranking of the relative importance of the variants and estimate the potential workload associated with further evaluation of the variants. Our WHATIF application is available at: http://tinyurl.com/WHATIF-SOFTWARE Conclusions The WHATIF application offers a user-friendly interface and allows users to investigate the extracted variant information efficiently and intuitively while always accessing the up to date information on variants via application programming interfaces (API) connections. WHATIF’s highly flexible design and straightforward implementation aids users in customizing the source code to meet their own special needs. PMID:25890833

Phylodynamic and Genetic Diversity of Canine Parvovirus Type 2c in Taiwan

PubMed Central

Chiang, Shu-Yun; Wu, Hung-Yi; Lin, Jih-Hui; Chiou, Ming-Tang; Lin, Chao-Nan

2017-01-01

Canine parvovirus type 2c (CPV-2c) emerged in 2000 and is known for causing a more severe disease than other CPV-2 variants in puppies. In 2015, the emerging CPV-2c variant was isolated in Taiwan and it subsequently became the predominant variant. To trace the evolution of Taiwanese CPV-2c, we compared complete VP2 genes of CPV-2c from Taiwan and sequences obtained from GenBank. The evolutionary rate of CPV-2c was estimated to be 4.586 × 10−4 substitutions per site per year (95% highest posterior density (HPD) was 3.284–6.076 × 10−4). The time to the most recent common ancestor (TMRCA) dated to 1990 (95% HPD: 1984–1996) and 2011 (95% HPD: 2010–2013) for the CPV-2c variant and Taiwanese isolates, respectively. The CPV-2c variant isolated from Taiwan was clustered with CPV-2c from China. This phylogenetic clade began to branch off in approximately 2010 (95% HPD was 3.823–6.497). Notably, two unique mutations of Taiwanese CPV-2c were found, Q383R and P410L. In summary, this is the first report on the genome evolution of CPV-2c in Taiwan, revealing that this CPV-2c variant shares a common evolutionary origin with strains from China. The demographic history inferred by the Bayesian skyline plot showed that the effective population of CPV-2c increased until 2006 and then slowly declined until 2011. PMID:29236084

Revisiting nucleosynthesis in globular clusters. The case of NGC 2808 and the role of He and K

NASA Astrophysics Data System (ADS)

Prantzos, N.; Charbonnel, C.; Iliadis, C.

2017-12-01

Context. Motivated by recent reports concerning the observation of limited enrichment in He but excess K in stars of globular clusters, we revisit the H-burning conditions that lead to the chemical properties of multiple stellar populations in these systems. Aims: In particular, we are interested in correlations of He and K with other elements, such as O, Na, Al, Mg and Si, reported in stars of NGC 2808. Methods: We performed calculations of nucleosynthesis at constant temperature and density, exploring the temperature range of 25 to 200 × 106 K (25 to 200 MK), using a detailed nuclear reaction network and the most up-to-date nuclear reaction rates. Results: We find that Mg is the most sensitive "thermometer" of hydrostatic H-burning conditions, pointing to a temperature range of 70-80 MK for NGC 2808, while He is a lesser - but not negligible - constraint. Potassium can be produced at the levels reported for NGC 2808 at temperatures >180 MK and Si at T > 80 MK. However, in the former temperature range Al and Na are totally destroyed and no correlation can be obtained, in contrast to the reported observations. None of the putative polluter sources proposed so far seem to satisfy the ensemble of nucleosynthesis constraints.

The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-Analysis Revisited: Evidence of Genetic Moderation

PubMed Central

Karg, Katja; Burmeister, Margit; Shedden, Kerby; Sen, Srijan

2013-01-01

Context The initial report of an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression is perhaps the best-known and most cited finding in psychiatric genetics. Two recent meta-analyses explored the studies seeking to replicate this initial report and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have explored the relationship between 5-HTTLPR, stress and depression. Objective We sought to perform a meta-analysis including all relevant studies assessing whether 5-HTTLPR moderates the relationship between stress and depression. Data Sources We identified relevant articles from previous meta-analyses and reviews and a PubMed database search. Study Selection We excluded two studies presenting data that were included in other, larger, studies already included in our meta-analysis to avoid duplicate counting of subjects. Data Extraction In order to perform a more inclusive meta-analysis, we used the Liptak-Stouffer Z-score method to combine findings of primary studies at the significance test level rather than raw data level. Results We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (p<0.0001). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafo studies p=0.16; Risch studies p=0.11). This suggests that the difference in results between previous meta-analyses and ours was not due to the difference in meta-analytic technique but instead to the expanded set of studies included in this analysis. Conclusions Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that 5-HTTLPR moderates the relationship between stress and depression in the studies published to date. PMID:21199959

Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.

PubMed

Clissold, Rhian L; Clarke, Helen C; Spasic-Boskovic, Olivera; Brugger, Kim; Abbs, Stephen; Bingham, Coralie; Shaw-Smith, Charles

2017-07-12

Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease. A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient's renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards. In an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

Discovery of a new mechanism for regulation of plant triacylglycerol metabolism: The peanut diacylglycerol acyltransferase-1 gene family transcriptome is highly enriched in alternative splicing variants

USDA-ARS?s Scientific Manuscript database

Triacylglycerols (TAGs) are the most important energy storage form in oilseed crops. Diacylglycerol acyltransferase (DGAT) catalyzes the rate-limiting step of the Kennedy pathway of TAG biosynthesis. To date, little is known about the regulation of DGAT activity in peanut (Arachis hypogaea), an agr...

Assessment of Cognitive Function in Breast Cancer and Lymphoma Patients Receiving Chemotherapy | Division of Cancer Prevention

Cancer.gov

Cognitive impairments in cancer patients represent an important clinical problem. Studies to date estimating prevalence of difficulties in memory, executive function, and attention deficits have been limited by small sample sizes and many have lacked healthy control groups. More information is needed on promising biomarkers and allelic variants that may help to determine the

Ocular findings in a case of trisomy 18 with variant of Dandy-Walker syndrome.

PubMed

Lim, Fong-Fong; Ng, Yan-Yan; Hu, Jui-Ming; Chen, Suh-Jen; Su, Pen-Hua; Chen, Jia-Yuh

2010-10-01

Trisomy 18 is the second most common chromosomal syndrome and has multiple dysmorphic features. However, ocular findings in trisomy 18 are rarely reported. Retinal folds are the most common ocular finding described to date, although retinal hypopigmentation, dysplasia, and areas of hemorrhage and gliosis are also found in trisomy 18. Dandy-Walker syndrome is a brain malformation that has been reported in association with numerous chromosomal abnormalities, although it has rarely been reported in association with trisomy 18. Here, we present a case of trisomy 18 with ocular pathology and variant of Dandy-Walker syndrome, a combination that has not previously been reported. Copyright © 2010 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.

Alcohol & drug abuse: Revisiting employee assistance programs and substance use problems in the workplace: key issues and a research agenda.

PubMed

Merrick, Elizabeth S Levy; Volpe-Vartanian, Joanna; Horgan, Constance M; McCann, Bernard

2007-10-01

This column describes employee assistance program (EAPs) and identifies key issues for contemporary EAPs. These programs began as occupational alcohol programs and have evolved into more comprehensive resources. To better understand contemporary EAPs, the authors suggest a research agenda that includes descriptive studies to provide an up-to-date picture of services; investigations of how contemporary EAPs address substance use problems, including management consultation for early identification; further study of EAPs' effects on outcomes, such as productivity and work group outcomes; examination of the relationship between EAPs and other workplace resources; further examination of influences on EAP utilization; and development and testing of EAP performance measures.

Revisiting Employee Assistance Programs and Substance Use Problems in the Workplace: Key Issues and a Research Agenda

PubMed Central

Levy Merrick, Elizabeth S.; Volpe-Vartanian, Joanna; Horgan, Constance M.; McCann, Bernard

2012-01-01

This column describes employee assistance program (EAPs) and identifies key issues for contemporary EAPs. These programs began as occupational alcohol programs and have evolved into more comprehensive resources. To better understand contemporary EAPs, the authors suggest a research agenda at includes descriptive studies to provide an up-to-date picture of services; investigations of how contemporary EAPs address substance use problems, including management consultation for early identification; further study of EAPs’ effects on outcomes, such as productivity and work group outcomes; examination of the relationship between EAPs and other workplace resources; further examination of influences on EAP utilization; and development and testing of EAP performance measures. PMID:17914000

Low Temperature Refrigeration as an Alternative Anti-Pest Treatment of Dates

NASA Astrophysics Data System (ADS)

Lallouche, Ahmed; Kolodyaznaya, Valentina; Boulkrane, Mohamed Said; Baranenko, Denis

2017-11-01

Large amounts of dates are produced and consumed around the world each year. Apomyelois ceratoniae causes main losses during storage and export of date fruit. Fumigation is the most widely used treatment to prevent postharvest losses. However, this treatment negatively affects the biological value of dates, environmental and economic parameters of production. Widespread fumigation agent methyl bromide is toxic to a human body and contributes to the destruction of the ozone layer. The aim of the current work was to find a new method based on the use of low temperature refrigeration to reduce the pest and insect infestation preserving the nutritive value of dates during cold storage at the same time. A. ceratoniae mortality under different temperatures and dates respiration rate, sugar, organic acids, pectic substances content and sensorial characteristics were studied. The results indicate that at -18 °C the A. ceratonie larva dies within 2 h, the eggs and larvae - within 24 h respectively. Thus, it is clearly shown that there is no need in using chemicals or irradiation to prevent dates pests. Physicochemical and organoleptic proprieties of dates were satisfactory during 360 d at -18 °C and during 180 d at +4 °C. The low temperature refrigeration and storage at -18 °C is recommended for dates to prevent pests and quality losses. It is apparently advantageous for environment and climate if compared with other anti-pest treatment variants.

Mesyatsy "knizhnye" i "nebesnye": ikh sootnoshenie na stranitsakh letopisej %t "Literary" and "heavenly" months: their correlations in Russian chronicles

NASA Astrophysics Data System (ADS)

Zhuravel', A. V.

The overwhelming majority of Old-Russian dates are Julian, and this fact seems to prove that the Julian calendar gained a foothold after the baptism of Rus'. However, there are also about 10 lunar datings (mainly from the XV c.) in Russian chronicles. This fact corresponds to the words of Kirik (the Novgorod mathematician of the XII c.) who distinguished "heavenly" months from "literary" ones. The research shows that Kirik's words are true for the entire Medieval period of Russian history: the Julian calendar was really the "literary" one and people continued to count days by the Moon in their day-to-day life. Thus, lunar dating came up in Russian chronicles again and again. That is why attempts of recalculation into the Julian manner generated many mistakes (variant readings). If we take into account these "traces", we can reconstruct the initial lunar dating and determine more precisely the course of historical events.

Setting the Revisit Interval in Primary Care

PubMed Central

Schwartz, Lisa M; Woloshin, Steven; Wasson, John H; Renfrew, Roger A; Welch, H Gilbert

1999-01-01

OBJECTIVE Although longitudinal care constitutes the bulk of primary care, physicians receive little guidance on the fundamental question of how to time follow-up visits. We sought to identify important predictors of the revisit interval and to describe the variability in how physicians set these intervals when caring for patients with common medical conditions. DESIGN Cross-sectional survey of physicians performed at the end of office visits for consecutive patients with hypertension, angina, diabetes, or musculoskeletal pain. PARTICIPANTS/SETTING One hundred sixty-four patients under the care of 11 primary care physicians in the Dartmouth Primary Care Cooperative Research Network. MEASUREMENTS The main outcome measures were the variability in mean revisit intervals across physicians and the proportion of explained variance by potential determinants of revisit intervals. We assessed the relation between the revisit interval (dependent variable) and three groups of independent variables, patient characteristics (e.g., age, physician perception of patient health), identification of individual physician, and physician characterization of the visit (e.g., routine visit, visit requiring a change in management, or visit occurring on a “hectic” day), using multiple regression that accounted for the natural grouping of patients within physician. MAIN RESULTS Revisit intervals ranged from 1 week to over 1 year. The most common intervals were 12 and 16 weeks. Physicians’ perception of fair-poor health status and visits involving a change in management were most strongly related to shorter revisit intervals. In multivariate analyses, patient characteristics explained about 18% of the variance in revisit intervals, and adding identification of the individual provider doubled the explained variance to about 40%. Physician characterization of the visit increased explained variance to 57%. The average revisit interval adjusted for patient characteristics for each of the 11 physicians varied from 4 to 20 weeks. Although all physicians lengthened revisit intervals for routine visits and shortened them when changing management, the relative ranking of mean revisit intervals for each physician changed little for different visit characterizations—some physicians were consistently long and others were consistently short. CONCLUSION Physicians vary widely in their recommendations for office revisits. Patient factors accounted for only a small part of this variation. Although physicians responded to visits in predictable ways, each physician appeared to have a unique set point for the length of the revisits interval. PMID:10203635

[Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder].

PubMed

Ortega-Rojas, Jenny; Arboleda-Bustos, Carlos E; Morales, Luis; Benítez, Bruno A; Beltrán, Diana; Izquierdo, Álvaro; Arboleda, Humberto; Vásquez, Rafael

Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.

PubMed

Vilboux, Thierry; Kayser, Michael; Introne, Wendy; Suwannarat, Pim; Bernardini, Isa; Fischer, Roxanne; O'Brien, Kevin; Kleta, Robert; Huizing, Marjan; Gahl, William A

2009-12-01

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

PubMed Central

Vilboux, Thierry; Kayser, Michael; Introne, Wendy; Suwannarat, Pim; Bernardini, Isa; Fischer, Roxanne; O’Brien, Kevin; Kleta, Robert; Huizing, Marjan; Gahl, William A.

2009-01-01

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene, HGD, that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8 and 13. We assessed the potential effect of all missense variations on protein function, using 5 bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT and SNAP). We also analyzed the potential effect of splice site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease. PMID:19862842

Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib.

PubMed

Ou, Sai-Hong Ignatius; Klempner, Samuel J; Greenbowe, Joel R; Azada, Michele; Schrock, Alexa B; Ali, Siraj M; Ross, Jeffrey S; Stephens, Philip J; Miller, Vincent A

2014-12-01

Huntingtin-interacting protein 1 (HIP1) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC). To date, two variants of HIP1-ALK (H21; A20) and (H28; A20) have been identified in NSCLC. However, the response of patients with NSCLC harboring HIP1-ALK to ALK inhibitors and potential resistance mechanisms to such remain unknown. Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively) located in the hydrophobic regulatory spine (R-spine) of the ALK kinase in both the cases as identified by a comprehensive next-generation sequencing-based assay performed on biopsies of new liver metastases that developed during alectinib treatment.

Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature.

PubMed

Li, Niu; Chang, Guoying; Xu, Yufei; Ding, Yu; Li, Guoqiang; Yu, Tingting; Yao, Ruen; Li, Juan; Shen, Yiping; Wang, Xiumin; Wang, Jian

2017-12-01

Biallelic mutations in the GPD1 gene cause a rare autosomal recessive inherited disease known as transient infantile hypertriglyceridemia (OMIM #614480). To date, only five pathogenic variants have been reported in 15 patients from three studies. The clinical symptoms of the affected individuals present a certain degree of heterogeneity. Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature. Targeted next-generation sequencing revealed a novel compound heterozygous variant in GPD1 gene (c.220-2A>G and c.820G>A; p.Ala274Thr). In vitro studies demonstrated that the Ala274Thr variant induced a decrease in GPD1 protein expression. Further in vitro investigation of the splicing pattern in a minigene construct in HEK293 cells showed that the c.220-2A>G variant generated an altered transcript with one cryptic splice site in exon 3, resulting in the loss of 69 bases in exon 3 (c.220_288del, p.74_96del). This is the first report involving an Asian who harbored GPD1 mutations. Our work not only expands the mutant spectrum of the GPD1 gene but also provides new insights on its resulting phenotype. © 2017 Wiley Periodicals, Inc.

Common variants of the vitamin D binding protein gene and adverse health outcomes.

PubMed

Malik, Suneil; Fu, Lei; Juras, David James; Karmali, Mohamed; Wong, Betty Y L; Gozdzik, Agnes; Cole, David E C

2013-01-01

The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene - rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys - change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged.

Circular revisit orbits design for responsive mission over a single target

NASA Astrophysics Data System (ADS)

Li, Taibo; Xiang, Junhua; Wang, Zhaokui; Zhang, Yulin

2016-10-01

The responsive orbits play a key role in addressing the mission of Operationally Responsive Space (ORS) because of their capabilities. These capabilities are usually focused on supporting specific targets as opposed to providing global coverage. One subtype of responsive orbits is repeat coverage orbit which is nearly circular in most remote sensing applications. This paper deals with a special kind of repeating ground track orbit, referred to as circular revisit orbit. Different from traditional repeat coverage orbits, a satellite on circular revisit orbit can visit a target site at both the ascending and descending stages in one revisit cycle. This typology of trajectory allows a halving of the traditional revisit time and does a favor to get useful information for responsive applications. However the previous reported numerical methods in some references often cost lots of computation or fail to obtain such orbits. To overcome this difficulty, an analytical method to determine the existence conditions of the solutions to revisit orbits is presented in this paper. To this end, the mathematical model of circular revisit orbit is established under the central gravity model and the J2 perturbation. A constraint function of the circular revisit orbit is introduced, and the monotonicity of that function has been studied. The existent conditions and the number of such orbits are naturally worked out. Taking the launch cost into consideration, optimal design model of circular revisit orbit is established to achieve a best orbit which visits a target twice a day in the morning and in the afternoon respectively for several days. The result shows that it is effective to apply circular revisit orbits in responsive application such as reconnoiter of natural disaster.

Predictors and Outcomes of Revisits in Older Adults Discharged from the Emergency Department.

PubMed

de Gelder, Jelle; Lucke, Jacinta A; de Groot, Bas; Fogteloo, Anne J; Anten, Sander; Heringhaus, Christian; Dekkers, Olaf M; Blauw, Gerard J; Mooijaart, Simon P

2018-04-01

To study predictors of emergency department (ED) revisits and the association between ED revisits and 90-day functional decline or mortality. Multicenter cohort study. One academic and two regional Dutch hospitals. Older adults discharged from the ED (N=1,093). At baseline, data on demographic characteristics, illness severity, and geriatric parameters (cognition, functional capacity) were collected. All participants were prospectively followed for an unplanned revisit within 30 days and for functional decline and mortality 90 days after the initial visit. The median age was 79 (interquartile range 74-84), and 114 participants (10.4%) had an ED revisit within 30 days of discharge. Age (hazard ratio (HR)=0.96, 95% confidence interval (CI)=0.92-0.99), male sex (HR=1.61, 95% CI=1.05-2.45), polypharmacy (HR=2.06, 95% CI=1.34-3.16), and cognitive impairment (HR=1.71, 95% CI=1.02-2.88) were independent predictors of a 30-day ED revisit. The area under the receiver operating characteristic curve to predict an ED revisit was 0.65 (95% CI=0.60-0.70). In a propensity score-matched analysis, individuals with an ED revisit were at higher risk (odds ratio=1.99 95% CI=1.06-3.71) of functional decline or mortality. Age, male sex, polypharmacy, and cognitive impairment were independent predictors of a 30-day ED revisit, but no useful clinical prediction model could be developed. However, an early ED revisit is a strong new predictor of adverse outcomes in older adults. © 2018 The Authors. The Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

PubMed Central

Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire; Ucurum, Zöhre; Schlessinger, Avner; Fotiadis, Dimitrios

2018-01-01

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures (Tms) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting Tms indicated stabilization of AdiC variants upon ligand binding, in which Tms and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family. PMID:29558430

On the Structural Plasticity of the Human Genome: Chromosomal Inversions Revisited

PubMed Central

Alves, Joao M; Lopes, Alexandra M; Chikhi, Lounès; Amorim, António

2012-01-01

With the aid of novel and powerful molecular biology techniques, recent years have witnessed a dramatic increase in the number of studies reporting the involvement of complex structural variants in several genomic disorders. In fact, with the discovery of Copy Number Variants (CNVs) and other forms of unbalanced structural variation, much attention has been directed to the detection and characterization of such rearrangements, as well as the identification of the mechanisms involved in their formation. However, it has long been appreciated that chromosomes can undergo other forms of structural changes - balanced rearrangements - that do not involve quantitative variation of genetic material. Indeed, a particular subtype of balanced rearrangement – inversions – was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome. PMID:23730202

A new function for the yeast trehalose-6P synthase (Tps1) protein, as key pro-survival factor during growth, chronological ageing, and apoptotic stress.

PubMed

Petitjean, Marjorie; Teste, Marie-Ange; Léger-Silvestre, Isabelle; François, Jean M; Parrou, Jean-Luc

2017-01-01

Looking back to our recent work that challenged the paradigm of trehalose in stress resistance in yeast, our objective was to revisit the role of this disaccharide in chronological life span (CLS), and in the control of apoptosis. Using a catalytically dead variant of the trehalose-6-phosphate synthase (Tps1) protein, (the first enzyme in the trehalose biosynthetic pathway), and by manipulating intracellular trehalose independently of this pathway, we demonstrated that trehalose has no role in CLS or in the inhibition of acetic acid or H 2 0 2 -triggered cell death. We showed instead that, in the absence of any apoptotic stimulus, the Tps1 protein itself was necessary in preventing massive, spontaneous commitment of yeast cells to apoptosis during growth. Without Tps1p, the life span was shortened and cells were sensitized to acetic acid (AA) and H 2 0 2 , whereas the overexpression of the inactive variant of Tps1p almost abolished AA-triggered apoptosis. Genetic interaction analysis of TPS1 and genes such as YCA1, NUC1 and AIF1 indicated that these key executioners of cell death partially relayed tps1Δ-triggered signaling. Our results suggested that the pro-survival role of Tps1p could be connected with its ability to preserve ATP levels in yeast cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters.

PubMed

Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire; Ucurum, Zöhre; Schlessinger, Avner; Fotiadis, Dimitrios

2018-03-20

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures ( T m s) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting T m s indicated stabilization of AdiC variants upon ligand binding, in which T m s and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family.

Enhanced Multistatic Active Sonar via Innovative Signal Processing

DTIC Science & Technology

2015-09-30

3. DATES COVERED (From - To) Oct. 01, 2014-Sept. 30, 2015 4. TITLE AND SUBTITLE Enhanced Multistatic Active Sonar via Innovative Signal...active sonar (CAS) in the presence of strong direct blast is studied for the Doppler-tolerant linear frequency modulation waveform. A receiver design...beamformer variants is examined. 15. SUBJECT TERMS Pulsed active sonar (PAS), continuous active sonar (CAS), strong delay and Doppler-spread direct blast

An exome-wide analysis of low frequency and rare variants in relation to risk of breast cancer in African American Women: the AMBER Consortium

PubMed Central

Haddad, Stephen A.; Ruiz-Narváez, Edward A.; Haiman, Christopher A.; Sucheston-Campbell, Lara E.; Bensen, Jeannette T.; Zhu, Qianqian; Liu, Song; Yao, Song; Bandera, Elisa V.; Rosenberg, Lynn; Olshan, Andrew F.; Ambrosone, Christine B.; Palmer, Julie R.; Lunetta, Kathryn L.

2016-01-01

A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER−), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2×10–6), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2×10–6), were significantly associated with ER− breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors—thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs. PMID:27267999

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

PubMed Central

Ilkovski, Biljana; Pagnamenta, Alistair T.; O'Grady, Gina L.; Kinoshita, Taroh; Howard, Malcolm F.; Lek, Monkol; Thomas, Brett; Turner, Anne; Christodoulou, John; Sillence, David; Knight, Samantha J.L.; Popitsch, Niko; Keays, David A.; Anzilotti, Consuelo; Goriely, Anne; Waddell, Leigh B.; Brilot, Fabienne; North, Kathryn N.; Kanzawa, Noriyuki; Macarthur, Daniel G.; Taylor, Jenny C.; Kini, Usha; Murakami, Yoshiko; Clarke, Nigel F.

2015-01-01

Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20–50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5′-UTR regions despite their typically low coverage in exome data. PMID:26293662

blaNDM-21, a new variant of blaNDM in an Escherichia coli clinical isolate carrying blaCTX-M-55 and rmtB.

PubMed

Liu, Lu; Feng, Yu; McNally, Alan; Zong, Zhiyong

2018-06-14

New Delhi MBL (NDM) is a type of carbapenemase; 20 variants of NDM have been identified to date. We have found a new variant of NDM, NDM-21, and describe it here. A carbapenem-resistant Escherichia coli was subjected to WGS using an Illumina X10 sequencer to identify the antimicrobial resistance genes and its ST. The gene encoding the new variant of NDM was cloned into E. coli DH5α, with blaNDM-5 being cloned as the control. Transformants were tested for susceptibility to carbapenems. Mating was performed to obtain the plasmid carrying the new blaNDM gene and the complete plasmid sequence was obtained using long-read MinION sequencing. The E. coli isolate belonged to ST617 and phylogenetic group A. It had a gene encoding NDM-21, a new NDM variant. NDM-21 differs from NDM-5 by a Gly-to-Ser amino acid substitution at position 69 (G69S). NDM-21 retains the same activity against carbapenems as NDM-5. blaNDM-21 is carried by a 46.1 kb IncX3 plasmid, which is self-transmissible, and is located in a complex genetic context as blaNDM-5. The isolate also carried blaCTX-M-55, which encodes an ESBL conferring resistance to aztreonam (which completed its resistance to all clinically available β-lactams), and rmtB, which mediates high-level resistance to aminoglycosides, on an IncFII plasmid. A new NDM variant has been identified and blaNDM-21 has evolved from blaNDM-5 on an IncX3 plasmid.

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies.

PubMed

Ilkovski, Biljana; Pagnamenta, Alistair T; O'Grady, Gina L; Kinoshita, Taroh; Howard, Malcolm F; Lek, Monkol; Thomas, Brett; Turner, Anne; Christodoulou, John; Sillence, David; Knight, Samantha J L; Popitsch, Niko; Keays, David A; Anzilotti, Consuelo; Goriely, Anne; Waddell, Leigh B; Brilot, Fabienne; North, Kathryn N; Kanzawa, Noriyuki; Macarthur, Daniel G; Taylor, Jenny C; Kini, Usha; Murakami, Yoshiko; Clarke, Nigel F

2015-11-01

Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data. © The Author 2015. Published by Oxford University Press.

Genetic Traits in the Liver Anatomy Between Parents and Children: An Analysis of Liver Transplant Recipients and Living Donors.

PubMed

Jeong, M J; Hwang, S; Song, G W; Jung, D H; Ha, T Y; Park, G C; Alshahrani, A A; Kirchner, V A; Beduschi, T; Lee, S G

2016-01-01

To date, no significant similarities in the anatomy of the hepatic vasculature have been observed between blood-related individuals. However, we have frequently encountered anatomic similarities between parents and their children; thus, we performed an analysis of the genetic traits in the anatomy of the liver. The study cohort was 330 adult cases of living-donor liver transplantation (LDLT), in which the donor-recipient relationship was child to parent. The subjects underwent LDLT from January 2013 to December 2014. Preoperative dynamic computerized tomographic scans were used to classify the anatomy of the hepatic vasculature. Portal vein (PV) anatomy was classified as typical and 2 variant types. PV anatomy combinations in donor and recipient were typical in 232 subjects, variant in 16, and typical-variant in 82. The PV concordance rate was 75.2%, and the contingency coefficient was 0.130 (P = .017). Hepatic artery (HA) anatomy was classified as typical and 4 variant types. HA anatomy combinations in donor and recipient were typical in 167 subjects, variant in 33, and typical-variant in 130. The HA concordance rate was 60.6%, and the contingency coefficient was 0.058 (P = .294). The sizable inferior right hepatic vein in donor and recipient was present in 44 subjects, absent in 160, and discordant in 126; its concordance rate was 61.8% and contingency coefficient 0.133 (P = .014). There may be a shared but weak genetic trait between parents and children regarding the anatomy of the PV and inferior hepatic vein. This information may be helpful when LDLT is performed between 1st-degree relatives. Copyright © 2016 Elsevier Inc. All rights reserved.

TATES: Efficient Multivariate Genotype-Phenotype Analysis for Genome-Wide Association Studies

PubMed Central

van der Sluis, Sophie; Posthuma, Danielle; Dolan, Conor V.

2013-01-01

To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype–phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype–phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5–9 times higher than the power of univariate tests based on composite scores and 1.5–2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype–phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor. PMID:23359524

High molecular weight FGF2: the biology of a nuclear growth factor

PubMed Central

Chlebova, K.; Bryja, V.; Dvorak, P.; Kozubik, A.; Wilcox, W. R.

2011-01-01

Fibroblast growth factor 2 (FGF2) is one of the most studied growth factors to date. Most attention has been dedicated to the smallest, 18kDa FGF2 variant that is released by cells and acts through activation of cell-surface FGF-receptor tyrosine kinases. There are, however, several higher molecular weight (HMW) variants of FGF2 that rarely leave their producing cells, are retained in the nucleus and act independently of FGF-receptors (FGFR). Despite significant evidence documenting the expression and intracellular trafficking of HMW FGF2, many important questions remain about the physiological roles and mechanisms of action of HMW FGF2. In this review, we summarize the current knowledge about the biology of HMW FGF2, its role in disease and areas for future investigation. PMID:18850066

Current state-of-art of STR sequencing in forensic genetics.

PubMed

Alonso, Antonio; Barrio, Pedro A; Müller, Petra; Köcher, Steffi; Berger, Burkhard; Martin, Pablo; Bodner, Martin; Willuweit, Sascha; Parson, Walther; Roewer, Lutz; Budowle, Bruce

2018-05-11

The current state of validation and implementation strategies of MPS technology for the analysis of STR markers for forensic genetics use is described, covering the topics of the current catalogue of commercial MPS-STR panels, leading MPS-platforms, and MPS-STR data analysis tools. In addition, the developmental and internal validation studies carried out to date to evaluate reliability, sensitivity, mixture analysis, concordance, and the ability to analyze challenged samples are summarized. The results of various MPS-STR population studies that showed a large number of new STR sequence variants that increase the power of discrimination in several forensically-relevant loci are also presented. Finally, various initiatives developed by several international projects and standardization (or guidelines) groups to facilitate application of MPS technology for STR marker analyses are discussed in regard to promoting a standard STR sequence nomenclature, performing population studies to detect sequence variants, and developing a universal system to translate sequence variants into a simple STR nomenclature (numbers and letters) compatible with national STR databases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Medicinal cannabis (Bedrolite) substitution therapy in inpatients with a psychotic disorder and a comorbid cannabis use disorder: A case series.

PubMed

Schipper, Regi; Dekker, Mathilde; de Haan, Lieuwe; van den Brink, Wim

2018-03-01

Cannabis use disorders are frequently comorbid in patients with a psychotic disorder and are associated with worse outcomes. To date there are no proven effective strategies to achieve cannabis abstinence in this population. An alternative for abstinence might be harm reduction, i.e. replacing the use of street cannabis with high tetrahydrocannabinol and low cannabidiol levels by medicinal cannabis variants with relatively low tetrahydrocannabinol and relatively high cannabidiol levels, thereby reducing the psychosis inducing effects of cannabis and enhancing the antipsychotic effects of cannabis. Here we present the data of a case series with seven inpatients diagnosed with a psychotic disorder and a treatment-resistant cannabis use disorder who received substitution therapy with a low tetrahydrocannabinol medicinal cannabis variant (Bedrolite). The results suggest that the low tetrahydrocannabinol medicinal cannabis variant Bedrolite is not effective in the treatment of inpatients with a psychotic disorder and comorbid cannabis use disorder. Bedrolite is thus not very likely to become an effective harm reduction strategy in these patients.

Reference genotype and exome data from an Australian Aboriginal population for health-based research

PubMed Central

Tang, Dave; Anderson, Denise; Francis, Richard W.; Syn, Genevieve; Jamieson, Sarra E.; Lassmann, Timo; Blackwell, Jenefer M.

2016-01-01

Genetic analyses, including genome-wide association studies and whole exome sequencing (WES), provide powerful tools for the analysis of complex and rare genetic diseases. To date there are no reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 72 Aboriginal individuals to a depth of 20X coverage in ∼80% of the sequenced nucleotides. We determined 320,976 single nucleotide variants (SNVs) and 47,313 insertions/deletions using the Genome Analysis Toolkit. We had previously genotyped a subset of the Aboriginal individuals (70/72) using the Illumina Omni2.5 BeadChip platform and found ~99% concordance at overlapping sites, which suggests high quality genotyping. Finally, we compared our SNVs to six publicly available variant databases, such as dbSNP and the Exome Sequencing Project, and 70,115 of our SNVs did not overlap any of the single nucleotide polymorphic sites in all the databases. Our data set provides a useful reference point for genomic studies on Aboriginal Australians. PMID:27070114

Reference genotype and exome data from an Australian Aboriginal population for health-based research.

PubMed

Tang, Dave; Anderson, Denise; Francis, Richard W; Syn, Genevieve; Jamieson, Sarra E; Lassmann, Timo; Blackwell, Jenefer M

2016-04-12

Genetic analyses, including genome-wide association studies and whole exome sequencing (WES), provide powerful tools for the analysis of complex and rare genetic diseases. To date there are no reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 72 Aboriginal individuals to a depth of 20X coverage in ∼80% of the sequenced nucleotides. We determined 320,976 single nucleotide variants (SNVs) and 47,313 insertions/deletions using the Genome Analysis Toolkit. We had previously genotyped a subset of the Aboriginal individuals (70/72) using the Illumina Omni2.5 BeadChip platform and found ~99% concordance at overlapping sites, which suggests high quality genotyping. Finally, we compared our SNVs to six publicly available variant databases, such as dbSNP and the Exome Sequencing Project, and 70,115 of our SNVs did not overlap any of the single nucleotide polymorphic sites in all the databases. Our data set provides a useful reference point for genomic studies on Aboriginal Australians.

Using SHRIMP zircon dating to unravel tectonothermal events in arc environments. The early Palaeozoic arc of NW Iberia revisited

USGS Publications Warehouse

Abati, J.; Castineiras, P.G.; Arenas, R.; Fernandez-Suarez, J.; Barreiro, J.G.; Wooden, J.L.

2007-01-01

Dating of zircon cores and rims from granulites developed in a shear zone provides insights into the complex relationship between magmatism and metamorphism in the deep roots of arc environments. The granulites belong to the uppermost allochthonous terrane of the NW Iberian Massif, which forms part of a Cambro-Ordovician magmatic arc developed in the peri-Gondwanan realm. The obtained zircon ages confirm that voluminous calc-alkaline magmatism peaked around 500Ma and was shortly followed by granulite facies metamorphism accompanied by deformation at c. 480Ma, giving a time framework for crustal heating, regional metamorphism, deformation and partial melting, the main processes that control the tectonothermal evolution of arc systems. Traces of this arc can be discontinuously followed in different massifs throughout the European Variscan Belt, and we propose that the uppermost allochthonous units of the NW Iberian Massif, together with the related terranes in Europe, constitute an independent and coherent terrane that drifted away from northern Gondwana prior to the Variscan collisional orogenesis. ?? 2007 Blackwell Publishing Ltd.

Eocene Loranthaceae pollen pushes back divergence ages for major splits in the family.

PubMed

Grímsson, Friðgeir; Kapli, Paschalia; Hofmann, Christa-Charlotte; Zetter, Reinhard; Grimm, Guido W

2017-01-01

We revisit the palaeopalynological record of Loranthaceae, using pollen ornamentation to discriminate lineages and to test molecular dating estimates for the diversification of major lineages. Fossil Loranthaceae pollen from the Eocene and Oligocene are analysed and documented using scanning-electron microscopy. These fossils were associated with molecular-defined clades and used as minimum age constraints for Bayesian node dating using different topological scenarios. The fossil Loranthaceae pollen document the presence of at least one extant root-parasitic lineage (Nuytsieae) and two currently aerial parasitic lineages (Psittacanthinae and Loranthinae) by the end of the Eocene in the Northern Hemisphere. Phases of increased lineage diversification (late Eocene, middle Miocene) coincide with global warm phases. With the generation of molecular data becoming easier and less expensive every day, neontological research should re-focus on conserved morphologies that can be traced through the fossil record. The pollen, representing the male gametophytic generation of plants and often a taxonomic indicator, can be such a tracer. Analogously, palaeontological research should put more effort into diagnosing Cenozoic fossils with the aim of including them into modern systematic frameworks.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

PubMed Central

Ferreira, Manuel A. R.; Matheson, Melanie C.; Tang, Clara S.; Granell, Raquel; Ang, Wei; Hui, Jennie; Kiefer, Amy K.; Duffy, David L.; Baltic, Svetlana; Danoy, Patrick; Bui, Minh; Price, Loren; Sly, Peter D.; Eriksson, Nicholas; Madden, Pamela A.; Abramson, Michael J.; Holt, Patrick G.; Heath, Andrew C.; Hunter, Michael; Musk, Bill; Robertson, Colin F.; Le Souëf, Peter; Montgomery, Grant W.; Henderson, A. John; Tung, Joyce Y.; Dharmage, Shyamali C.; Brown, Matthew A.; James, Alan; Thompson, Philip J.; Pennell, Craig; Martin, Nicholas G.; Evans, David M.; Hinds, David A.; Hopper, John L.

2014-01-01

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency. PMID:24388013

ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A>G and c.5461-10T>C cause Stargardt disease due to defective splicing.

PubMed

Jonsson, Frida; Westin, Ida Maria; Österman, Lennart; Sandgren, Ola; Burstedt, Marie; Holmberg, Monica; Golovleva, Irina

2018-02-20

Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP-binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing. The splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE-19, using a minigene system containing variants c.4773+3A>G and c.5461-10T>C. We showed that both ABCA4 variants, c.4773+3A>G and c.5461-10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type. Two intronic variants c.4773+3A>G and c.5461-10T>C, both predicted to affect splicing, are indeed disease-causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable. © 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Canary: an atomic pipeline for clinical amplicon assays.

PubMed

Doig, Kenneth D; Ellul, Jason; Fellowes, Andrew; Thompson, Ella R; Ryland, Georgina; Blombery, Piers; Papenfuss, Anthony T; Fox, Stephen B

2017-12-15

High throughput sequencing requires bioinformatics pipelines to process large volumes of data into meaningful variants that can be translated into a clinical report. These pipelines often suffer from a number of shortcomings: they lack robustness and have many components written in multiple languages, each with a variety of resource requirements. Pipeline components must be linked together with a workflow system to achieve the processing of FASTQ files through to a VCF file of variants. Crafting these pipelines requires considerable bioinformatics and IT skills beyond the reach of many clinical laboratories. Here we present Canary, a single program that can be run on a laptop, which takes FASTQ files from amplicon assays through to an annotated VCF file ready for clinical analysis. Canary can be installed and run with a single command using Docker containerization or run as a single JAR file on a wide range of platforms. Although it is a single utility, Canary performs all the functions present in more complex and unwieldy pipelines. All variants identified by Canary are 3' shifted and represented in their most parsimonious form to provide a consistent nomenclature, irrespective of sequencing variation. Further, proximate in-phase variants are represented as a single HGVS 'delins' variant. This allows for correct nomenclature and consequences to be ascribed to complex multi-nucleotide polymorphisms (MNPs), which are otherwise difficult to represent and interpret. Variants can also be annotated with hundreds of attributes sourced from MyVariant.info to give up to date details on pathogenicity, population statistics and in-silico predictors. Canary has been used at the Peter MacCallum Cancer Centre in Melbourne for the last 2 years for the processing of clinical sequencing data. By encapsulating clinical features in a single, easily installed executable, Canary makes sequencing more accessible to all pathology laboratories. Canary is available for download as source or a Docker image at https://github.com/PapenfussLab/Canary under a GPL-3.0 License.

Association of emergency department albuterol dispensing with pediatric asthma revisits and readmissions.

PubMed

Hall, A Brad; Novotny, April; Bhisitkul, Donna M; Melton, James; Regan, Tim; Leckie, Maureen

2017-06-01

Although pediatric asthma continues to be a highly studied disease, data to suggest clear strategies to decrease asthma related revisits or readmissions is lacking. The purpose of our study was to assess the effect of emergency department (ED) direct dispensing of beta-agonist metered dose inhalers on pediatric asthma ED revisit and readmission rates. We conducted a retrospective cohort study of pediatric patients discharged from the pediatric ED with a diagnosis of asthma. Our primary outcome measured the rate of asthma revisits to the ED or admissions to the hospital within 28 days. Logistic regression analysis was used to assess ED beta-agonist MDI dispensing and revisit and/or readmission as the outcome. A total of 853 patients met eligibility for inclusion in the study, with 657 enrolled in the Baseline group and 196 enrolled in the ED-MDI group. The Baseline group experienced a revisit and readmission rate of 7.0% (46/657) versus 2.6% (5/196) in the ED-MDI group, (p = 0.026). ED direct dispensing of MDIs was found to be independently associated with a decreased risk of revisit or readmission (odds ratio 0.37; 95% confidence interval 0.14-0.95). In our study, ED direct dispensing of beta-agonist MDIs resulted in a reduction in 28-day revisit and readmission to the hospital. Further studies should be performed to evaluate the economic impact of reducing these revisits and readmissions against the costs of maintaining a dispensing program. Our findings may support modification of asthma programs to include dispensing MDIs from the emergency department.

SNIF-ACT: A Cognitive Model of User Navigation on the World Wide Web

DTIC Science & Technology

2007-01-03

opinions of others on a particular topic or problems. Obviously, our model was not able to answer these questions directly, and more research is... Research Center 3333 Coyote Hill Rd Palo Alto, CA 94304, USA Manuscript submitted to Human-Computer Interaction Date: Jan 03, 2007...models. Rational analysis is a variant form of an approach called methodological adaptationism that has also shaped research programs in behavioral

First Report of the Ug99 race group of wheat stem rust, Puccinia graminis f. sp. tritici, in Egypt

USDA-ARS?s Scientific Manuscript database

Since the first detection of Ug99 (or race TTKSK) of Puccinia graminis f.sp. tritici (Pgt) in Uganda in 1998 (Pretorius et al. 2000), it has been a priority to track further spread to other wheat growing areas. To date, variants in the Ug99 race group have been detected in 12 countries, i.e., Uganda...

Tempered mlo broad-spectrum resistance to barley powdery mildew in an Ethiopian landrace

PubMed Central

Ge, Xintian; Deng, Weiwei; Lee, Zheng Zhou; Lopez-Ruiz, Francisco J.; Schweizer, Patrick; Ellwood, Simon R.

2016-01-01

Recessive mutations in the Mlo gene confer broad spectrum resistance in barley (Hordeum vulgare) to powdery mildew (Blumeria graminis f. sp. hordei), a widespread and damaging disease. However, all alleles discovered to date also display deleterious pleiotropic effects, including the naturally occurring mlo-11 mutant which is widely deployed in Europe. Recessive resistance was discovered in Eth295, an Ethiopian landrace, which was developmentally controlled and quantitative without spontaneous cell wall appositions or extensive necrosis and loss of photosynthetic tissue. This resistance is determined by two copies of the mlo-11 repeat units, that occur upstream to the wild-type Mlo gene, compared to 11–12 in commonly grown cultivars and was designated mlo-11 (cnv2). mlo-11 repeat unit copy number-dependent DNA methylation corresponded with cytological and macroscopic phenotypic differences between copy number variants. Sequence data indicated mlo-11 (cnv2) formed via recombination between progenitor mlo-11 repeat units and the 3′ end of an adjacent stowaway MITE containing region. mlo-11 (cnv2) is the only example of a moderated mlo variant discovered to date and may have arisen by natural selection against the deleterious effects of the progenitor mlo-11 repeat unit configuration. PMID:27404990

The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?

PubMed

Vitrano, Angela; Calvaruso, Giuseppina; Lai, Eliana; Colletta, Grazia; Quota, Alessandra; Gerardi, Calogera; Concetta Rigoli, Luciana; Pitrolo, Lorella; Cuccia, Liana; Gagliardotto, Francesco; Filosa, Aldo; Caruso, Vincenzo; Argento, Crocetta; Campisi, Saveria; Rizzo, Michele; Prossomariti, Luciano; Fidone, Carmelo; Fustaneo, Maria; Di Maggio, Rosario; Maggio, Aurelio

2017-01-01

In the last few decades, the life expectancy of regularly transfused β-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with β-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6-17·5] before 1965 to 2·8 (95% CI 0·8-9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions. © 2016 John Wiley & Sons Ltd.

Molecular dynamics simulations revealed structural differences among WRKY domain-DNA interaction in barley (Hordeum vulgare).

PubMed

Pandey, Bharati; Grover, Abhinav; Sharma, Pradeep

2018-02-12

The WRKY transcription factors are a class of DNA-binding proteins involved in diverse plant processes play critical roles in response to abiotic and biotic stresses. Genome-wide divergence analysis of WRKY gene family in Hordeum vulgare provided a framework for molecular evolution and functional roles. So far, the crystal structure of WRKY from barley has not been resolved; moreover, knowledge of the three-dimensional structure of WRKY domain is pre-requisites for exploring the protein-DNA recognition mechanisms. Homology modelling based approach was used to generate structures for WRKY DNA binding domain (DBD) and its variants using AtWRKY1 as a template. Finally, the stability and conformational changes of the generated model in unbound and bound form was examined through atomistic molecular dynamics (MD) simulations for 100 ns time period. In this study, we investigated the comparative binding pattern of WRKY domain and its variants with W-box cis-regulatory element using molecular docking and dynamics (MD) simulations assays. The atomic insight into WRKY domain exhibited significant variation in the intermolecular hydrogen bonding pattern, leading to the structural anomalies in the variant type and differences in the DNA-binding specificities. Based on the MD analysis, residual contribution and interaction contour, wild-type WRKY (HvWRKY46) were found to interact with DNA through highly conserved heptapeptide in the pre- and post-MD simulated complexes, whereas heptapeptide interaction with DNA was missing in variants (I and II) in post-MD complexes. Consequently, through principal component analysis, wild-type WRKY was also found to be more stable by obscuring a reduced conformational space than the variant I (HvWRKY34). Lastly, high binding free energy for wild-type and variant II allowed us to conclude that wild-type WRKY-DNA complex was more stable relative to variants I. The results of our study revealed complete dynamic and structural information about WRKY domain-DNA interactions. However, no structure base information reported to date for WRKY variants and their mechanism of interaction with DNA. Our findings highlighted the importance of selecting a sequence to generate newer transgenic plants that would be increasingly tolerance to stress conditions.

Factors Associated With Length of Stay and 30-Day Revisits in Pediatric Acute Pancreatitis.

PubMed

Gay, Anna C; Barreto, Nicolas; Schrager, Sheree M; Russell, Christopher J

2018-05-30

Identify factors associated with length of stay (LOS) and 30-day hospital revisit for patients hospitalized with acute pancreatitis (AP). Multicenter, retrospective cohort study using the Pediatric Health Information System database. Multilevel linear and logistic regression was used to identify factors independently associated with the primary outcome variables of LOS and 30-day hospital revisit in children aged 1-18 years discharged with a primary discharge diagnosis of AP from participating hospitals between 2008 and 2013. For the 7693 discharges, median LOS was 4 days (interquartile range 3-7 days) and 30-day revisit rate 17.6% (n = 1356). Discharges were primarily female (55%), Caucasian (46%), and six years old or older (85%). On multilevel regression, factors independently associated with both longer LOS and higher revisit odds included malignant and gastrointestinal complex chronic conditions and total parenteral nutrition (TPN) use while hospitalized. Male gender was associated with both lower LOS (aLOS = -0.6 days, 95% CI = -0.8, -0.4) and decreased revisit odds (aOR 0.85; 95% CI = 0.74, 0.97). Hispanic ethnicity was associated with increased LOS (aLOS = +0.8 days, 95% CI = +0.5, +1.1) but no change in revisit odds. Certain demographic and clinical factors, including gender, ethnicity, and type of complex chronic condition, were independently associated with LOS and risk of 30-day hospital revisit for pediatric AP. Children with malignant and gastrointestinal complex chronic conditions who require TPN are at highest risk for both longer LOS and hospital revisit when admitted with AP. These patient populations may benefit from intensive care coordination when hospitalized for AP.

Common variants of the vitamin D binding protein gene and adverse health outcomes

PubMed Central

Malik, Suneil; Fu, Lei; Juras, David James; Karmali, Mohamed; Wong, Betty Y. L.; Gozdzik, Agnes

2013-01-01

The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene – rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys – change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged. PMID:23427793

Development of a genotyping microarray for Usher syndrome.

PubMed

Cremers, Frans P M; Kimberling, William J; Külm, Maigi; de Brouwer, Arjan P; van Wijk, Erwin; te Brinke, Heleen; Cremers, Cor W R J; Hoefsloot, Lies H; Banfi, Sandro; Simonelli, Francesca; Fleischhauer, Johannes C; Berger, Wolfgang; Kelley, Phil M; Haralambous, Elene; Bitner-Glindzicz, Maria; Webster, Andrew R; Saihan, Zubin; De Baere, Elfride; Leroy, Bart P; Silvestri, Giuliana; McKay, Gareth J; Koenekoop, Robert K; Millan, Jose M; Rosenberg, Thomas; Joensuu, Tarja; Sankila, Eeva-Marja; Weil, Dominique; Weston, Mike D; Wissinger, Bernd; Kremer, Hannie

2007-02-01

Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype.

PubMed

Boulling, Arnaud; Masson, Emmanuelle; Zou, Wen-Bin; Paliwal, Sumit; Wu, Hao; Issarapu, Prachand; Bhaskar, Seema; Génin, Emmanuelle; Cooper, David N; Li, Zhao-Shen; Chandak, Giriraj R; Liao, Zhuan; Chen, Jian-Min; Férec, Claude

2017-08-01

The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis-driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Third, employing a novel cis-regulatory module (CRM)-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L CRM located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype. © 2017 Wiley Periodicals, Inc.

Development of a genotyping microarray for Usher syndrome

PubMed Central

Cremers, Frans P M; Kimberling, William J; Külm, Maigi; de Brouwer, Arjan P; van Wijk, Erwin; te Brinke, Heleen; Cremers, Cor W R J; Hoefsloot, Lies H; Banfi, Sandro; Simonelli, Francesca; Fleischhauer, Johannes C; Berger, Wolfgang; Kelley, Phil M; Haralambous, Elene; Bitner‐Glindzicz, Maria; Webster, Andrew R; Saihan, Zubin; De Baere, Elfride; Leroy, Bart P; Silvestri, Giuliana; McKay, Gareth J; Koenekoop, Robert K; Millan, Jose M; Rosenberg, Thomas; Joensuu, Tarja; Sankila, Eeva‐Marja; Weil, Dominique; Weston, Mike D; Wissinger, Bernd; Kremer, Hannie

2007-01-01

Background Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein‐coding exons. Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele‐specific oligonucleotides corresponding to all 298 Usher syndrome‐associated sequence variants known to date, 76 of which are novel, were arrayed. Results Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. Conclusion The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first‐pass screening tool. PMID:16963483

The Effects of Korean Medical Service Quality and Satisfaction on Revisit Intention of the United Arab Emirates Government Sponsored Patients.

PubMed

Lee, Seoyoung; Kim, Eun-Kyung

2017-06-01

The purpose of this study was to investigate medical service quality, satisfaction and to examine factors influencing hospital revisit intention of the United Arab Emirates government sponsored patients in Korea. A total of 152 UAE government sponsored patients who visited Korean hospitals participated in the questionnaire survey from August to November 2016. Stepwise multiple regression was used to identify the factors that affected the revisit intention of the participants. The mean scores of medical service quality, satisfaction, and revisit intention were 5.72 out of 7, 88.88 out of 100, 4.59 out of 5, respectively. Medical service quality and satisfaction, Medical service quality and revisit intention, satisfaction and revisit intention were positively correlated. Medical service of physician, visiting routes and responsiveness of medical service quality explained about 23.8% of revisit intention. There are needs for physicians to communicate with patients while ensuring sufficient consultation time based on excellent medical skills and nurses to respond immediately for the patients' needs through an empathic encounter in order to improve medical service quality and patient satisfaction so that to increase the revisit intention of the United Arab Emirates government sponsored patients. Further, it is necessary for the hospitals to have support plans for providing country specialized services in consideration of the UAE culture to ensure that physicians' and nurses' competencies are not undervalued by non-medical service elements such as interpreters and meals. Copyright © 2017. Published by Elsevier B.V.

A Novel de novo CDH1 Germline Variant Aids in the Classification of C-terminal E-cadherin Alterations Predicted to Escape Nonsense-Mediated mRNA Decay.

PubMed

Krempely, Kate; Karam, Rachid

2018-05-24

Most truncating CDH1 pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer and lobular breast cancer. However, transcripts containing carboxyl-terminal (C-terminal) premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay (NMD) pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing due to a personal history of invasive lobular breast cancer diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c.2506G>T (p.E836*), in the last exon of the gene. Subsequent parental testing for the alteration was negative and additional short tandem repeat analysis confirmed the familial relationships and the de novo occurrence in the proband. Based on the de novo occurrence, clinical history, and rarity in general population databases, this alteration was classified as a likely pathogenic variant. This is the most C-terminal pathogenic alteration reported to date. Additionally, this alteration contributed to the classification of six other upstream CDH1 C-terminal truncating variants as pathogenic or likely pathogenic. Identifying the most distal pathogenic alteration provides evidence to classify other C-terminal truncating variants as either pathogenic or benign, a fundamental step to offering pre-symptomatic screening and prophylactic procedures to the appropriate patients. Cold Spring Harbor Laboratory Press.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

PubMed

Legge, S E; Hamshere, M L; Ripke, S; Pardinas, A F; Goldstein, J I; Rees, E; Richards, A L; Leonenko, G; Jorskog, L F; Chambert, K D; Collier, D A; Genovese, G; Giegling, I; Holmans, P; Jonasdottir, A; Kirov, G; McCarroll, S A; MacCabe, J H; Mantripragada, K; Moran, J L; Neale, B M; Stefansson, H; Rujescu, D; Daly, M J; Sullivan, P F; Owen, M J; O'Donovan, M C; Walters, J T R

2017-10-01

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10 -8 ), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

PubMed Central

Legge, S E; Hamshere, M L; Ripke, S; Pardinas, A F; Goldstein, J I; Rees, E; Richards, A L; Leonenko, G; Jorskog, L F; Goldstein, Jacqueline I; Jarskog, L Fredrik; Hilliard, Chris; Alfirevic, Ana; Duncan, Laramie; Fourches, Denis; Huang, Hailiang; Lek, Monkol; Neale, Benjamin M; Ripke, Stephan; Shianna, Kevin; Szatkiewicz, Jin P; Tropsha, Alexander; van den Oord, Edwin JCG; Cascorbi, Ingolf; Dettling, Michael; Gazit, Ephraim; Goff, Donald C; Holden, Arthur L; Kelly, Deanna L; Malhotra, Anil K; Nielsen, Jimmi; Pirmohamed, Munir; Rujescu, Dan; Werge, Thomas; Levy, Deborah L; Josiassen, Richard C; Kennedy, James L; Lieberman, Jeffrey A; Daly, Mark J; Sullivan, Patrick F; Chambert, K D; Collier, D A; Genovese, G; Giegling, I; Holmans, P; Jonasdottir, A; Kirov, G; McCarroll, S A; MacCabe, J H; Mantripragada, K; Moran, J L; Neale, B M; Stefansson, H; Rujescu, D; Daly, M J; Sullivan, P F; Owen, M J; O'Donovan, M C; Walters, J T R

2017-01-01

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect. PMID:27400856

Danish Gulf War Veterans Revisited: No Evidence of Increased Sickness Absence or Reduced Labor Market Outcome After Deployment to the Persian Gulf.

PubMed

Nissen, Lars Ravnborg; Stoltenberg, Christian; Nielsen, Anni B Sternhagen; Vedtofte, Mia S; Marott, Jacob L; Gyntelberg, Finn; Guldager, Bernadette

2016-11-01

To examine the assumption that postdeployment incidence of sickness and other absence from work are higher among Gulf War Veterans compared with nonveterans. A prospective registry study including a cohort of 721 Danish Gulf War Veterans and a control cohort of 3,629 nonveterans selected from the general Danish population. Outcome measures were up to 23 years postdeployment incidence of (1) long-term sickness absence and (2) long-term all types of absence from work. Long term with regard to sickness and other absence was defined as exceeding 8 weeks. The association between outcomes and information on deployment history was studied using time-to-event analysis. The index date was the return date from the last deployment to the Gulf. The follow-up period was the time from index date until April 27, 2014. As the main finding, no difference was found between veterans and nonveterans in the incidence rate of long-term sickness absence. After an initial short period (3 months) with elevated incidence rate of long-term absence from work among veterans, there was no difference between the cohorts. Among Danish Gulf War Veterans, no postdeployment increased risk of long-term sickness absence or long-term absence from work was found as compared with nonveterans. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

14 CFR 1214.205 - Revisit and/or retrieval services.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Revisit and/or retrieval services. 1214.205... Reimbursement for Shuttle Services Provided to Civil U.S. Government Users and Foreign Users Who Have Made Substantial Investment in the STS Program § 1214.205 Revisit and/or retrieval services. These services will be...

Changing choices: disabled and chronically ill people's experiences of reconsidering choices.

PubMed

Baxter, Kate

2013-06-01

To increase understanding of disabled and chronically ill people's experiences of revisiting choices by considering events that prompted people to reconsider choices; what factors motivated them to act upon these events and what factors affected their experiences of revisiting choices. A sub-sample of 20 disabled and chronically ill people who took part in a qualitative, longitudinal study exploring choice-making in the context of changing circumstances. Each person was interviewed three times. Analysis focussed on choices that people had been prompted to revisit. Most choices were about health or social care and were revisited within a year due to: changes in health or social circumstances; poorer than expected outcomes; and external interventions. People were motivated to make changes by a desire to maintain independence and control, but perceived short-term costs of decision-making could act as a deterrent. Experiences of revisiting choices were affected by help from other people and emotional strength. Making and revisiting choices is complex; people need support to engage with the continual cycle of choice-making. People who instigate revisions of their own accord may be particularly vulnerable to lack of support.

Delayed Diagnoses in Children with Constipation: Multicenter Retrospective Cohort Study.

PubMed

Freedman, Stephen B; Rodean, Jonathan; Hall, Matthew; Alpern, Elizabeth R; Aronson, Paul L; Simon, Harold K; Shah, Samir S; Marin, Jennifer R; Cohen, Eyal; Morse, Rustin B; Katsogridakis, Yiannis; Berry, Jay G; Neuman, Mark I

2017-07-01

The use of abdominal radiographs contributes to increased healthcare costs, radiation exposure, and potentially to misdiagnoses. We evaluated the association between abdominal radiograph performance and emergency department (ED) revisits with important alternate diagnosis among children with constipation. Retrospective cohort study of children aged <18 years diagnosed with constipation at one of 23 EDs from 2004 to 2015. The primary exposure was abdominal radiograph performance. The primary outcome was a 3-day ED revisit with a clinically important alternate diagnosis. RAND/University of California, Los Angeles methodology was used to define whether the revisit was related to the index visit and due to a clinically important condition other than constipation. Regression analysis was performed to identify exposures independently related to the primary outcome. A total of 65.7% (185 439/282 225) of children with constipation had an index ED visit abdominal radiograph performed. Three-day revisits occurred in 3.7% (10 566/282 225) of children, and 0.28% (784/282 225) returned with a clinically important alternate related diagnosis. Appendicitis was the most common such revisit, accounting for 34.1% of all 3-day clinically important related revisits. Children who had an abdominal radiograph performed were more likely to have a 3-day revisit with a clinically important alternate related diagnosis (0.33% vs 0.17%; difference 0.17%; 95% CI 0.13-0.20). Following adjustment for covariates, abdominal radiograph performance was associated with a 3-day revisit with a clinically important alternate diagnosis (aOR: 1.39; 95% CI 1.15-1.67). Additional characteristics associated with the primary outcome included narcotic (aOR: 2.63) and antiemetic (aOR: 2.35) administration and underlying comorbidities (aOR: 2.52). Among children diagnosed with constipation, abdominal radiograph performance is associated with an increased risk of a revisit with a clinically important alternate related diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic basis of arrhythmogenic cardiomyopathy.

PubMed

Karmouch, Jennifer; Protonotarios, Alexandros; Syrris, Petros

2018-05-01

To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM. Use of next-generation sequencing methods has resulted in the identification of novel causative variants and genes for ACM. The involvement of filamin C in ACM demonstrates the genetic overlap between ACM and other types of cardiomyopathy. Putative pathogenic variants have been detected in cadherin 2 gene, a protein involved in cell adhesion. Large genomic rearrangements in desmosome genes have been systematically investigated in a cohort of ACM patients. Recent studies have identified novel causes of ACM providing new insights into the genetic spectrum of the disease and highlighting an overlapping phenotype between ACM and dilated cardiomyopathy. Next-generation sequencing is a useful tool for research and genetic diagnostic screening but interpretation of identified sequence variants requires caution and should be performed in specialized centres.

Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions.

PubMed

Hill, W D; Davies, G; Harris, S E; Hagenaars, S P; Liewald, D C; Penke, L; Gale, C R; Deary, I J

2016-12-13

Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium (n=53 949) and UK Biobank (n=36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

A Phylogenetic Analysis of 34 Chloroplast Genomes Elucidates the Relationships between Wild and Domestic Species within the Genus Citrus

PubMed Central

Carbonell-Caballero, Jose; Alonso, Roberto; Ibañez, Victoria; Terol, Javier; Talon, Manuel; Dopazo, Joaquin

2015-01-01

Citrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here, we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels (insertions and deletions), and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analyzed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus but also provides original insights into other elusive evolutionary processes, such as chloroplast inheritance, heteroplasmy, and gene selection. PMID:25873589

Detection of Emerging Vaccine-Related Polioviruses by Deep Sequencing.

PubMed

Sahoo, Malaya K; Holubar, Marisa; Huang, ChunHong; Mohamed-Hadley, Alisha; Liu, Yuanyuan; Waggoner, Jesse J; Troy, Stephanie B; Garcia-Garcia, Lourdes; Ferreyra-Reyes, Leticia; Maldonado, Yvonne; Pinsky, Benjamin A

2017-07-01

Oral poliovirus vaccine can mutate to regain neurovirulence. To date, evaluation of these mutations has been performed primarily on culture-enriched isolates by using conventional Sanger sequencing. We therefore developed a culture-independent, deep-sequencing method targeting the 5' untranslated region (UTR) and P1 genomic region to characterize vaccine-related poliovirus variants. Error analysis of the deep-sequencing method demonstrated reliable detection of poliovirus mutations at levels of <1%, depending on read depth. Sequencing of viral nucleic acids from the stool of vaccinated, asymptomatic children and their close contacts collected during a prospective cohort study in Veracruz, Mexico, revealed no vaccine-derived polioviruses. This was expected given that the longest duration between sequenced sample collection and the end of the most recent national immunization week was 66 days. However, we identified many low-level variants (<5%) distributed across the 5' UTR and P1 genomic region in all three Sabin serotypes, as well as vaccine-related viruses with multiple canonical mutations associated with phenotypic reversion present at high levels (>90%). These results suggest that monitoring emerging vaccine-related poliovirus variants by deep sequencing may aid in the poliovirus endgame and efforts to ensure global polio eradication. Copyright © 2017 Sahoo et al.

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

PubMed Central

Perry, John R.B.; Hsu, Yi-Hsiang; Chasman, Daniel I.; Johnson, Andrew D.; Elks, Cathy; Albrecht, Eva; Andrulis, Irene L.; Beesley, Jonathan; Berenson, Gerald S.; Bergmann, Sven; Bojesen, Stig E.; Bolla, Manjeet K.; Brown, Judith; Buring, Julie E.; Campbell, Harry; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J.; Cox, Angela; Czene, Kamila; D'adamo, Adamo Pio; Davies, Gail; Deary, Ian J.; Dennis, Joe; Easton, Douglas F.; Engelhardt, Ellen G.; Eriksson, Johan G.; Esko, Tõnu; Fasching, Peter A.; Figueroa, Jonine D.; Flyger, Henrik; Fraser, Abigail; Garcia-Closas, Montse; Gasparini, Paolo; Gieger, Christian; Giles, Graham; Guenel, Pascal; Hägg, Sara; Hall, Per; Hayward, Caroline; Hopper, John; Ingelsson, Erik; Kardia, Sharon L.R.; Kasiman, Katherine; Knight, Julia A.; Lahti, Jari; Lawlor, Debbie A.; Magnusson, Patrik K.E.; Margolin, Sara; Marsh, Julie A.; Metspalu, Andres; Olson, Janet E.; Pennell, Craig E.; Polasek, Ozren; Rahman, Iffat; Ridker, Paul M.; Robino, Antonietta; Rudan, Igor; Rudolph, Anja; Salumets, Andres; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Smith, Erin N.; Smith, Jennifer A.; Southey, Melissa; Stöckl, Doris; Swerdlow, Anthony J.; Thompson, Deborah J.; Truong, Therese; Ulivi, Sheila; Waldenberger, Melanie; Wang, Qin; Wild, Sarah; Wilson, James F; Wright, Alan F.; Zgaga, Lina; Ong, Ken K.; Murabito, Joanne M.; Karasik, David; Murray, Anna

2014-01-01

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility. PMID:24357391

Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

PubMed Central

Hill, W D; Davies, G; Harris, S E; Hagenaars, S P; Davies, Gail; Deary, Ian J; Debette, Stephanie; Verbaas, Carla I; Bressler, Jan; Schuur, Maaike; Smith, Albert V; Bis, Joshua C; Bennett, David A; Ikram, M Arfan; Launer, Lenore J; Fitzpatrick, Annette L; Seshadri, Sudha; van Duijn, Cornelia M; Mosley Jr, Thomas H; Liewald, D C; Penke, L; Gale, C R; Deary, I J

2016-01-01

Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium (n=53 949) and UK Biobank (n=36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions. PMID:27959336

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity.

PubMed

Revelas, Mary; Thalamuthu, Anbupalam; Oldmeadow, Christopher; Evans, Tiffany-Jane; Armstrong, Nicola J; Kwok, John B; Brodaty, Henry; Schofield, Peter R; Scott, Rodney J; Sachdev, Perminder S; Attia, John R; Mather, Karen A

2018-06-08

Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls. Copyright © 2018. Published by Elsevier B.V.

Emergence as an outbreak of the HIV-1 CRF19_cpx variant in treatment-naïve patients in southern Spain.

PubMed

González-Domenech, Carmen M; Viciana, Isabel; Delaye, Luis; Mayorga, María Luisa; Palacios, Rosario; de la Torre, Javier; Jarilla, Francisco; Castaño, Manuel; Del Arco, Alfonso; Clavijo, Encarnación; Santos, Jesús

2018-01-01

CRF19_cpx is a complex circulating recombination form (CRF) of HIV-1. We describe the characteristics of an outbreak of the CRF19_cpx variant among treatment-naïve patients in southern Spain. The study was undertaken at the Virgen de la Victoria Hospital, a reference centre for the analysis of HIV-1 genotype in Malaga (Spain). Subtyping was performed through REGA v3.0 and the relationship of our CRF19_cpx sequences, among themselves and regarding other reference sequences from the same variant, was defined by phylogenetic analysis. We used PhyML program to perform a reconstruction of the phylogeny by Maximum Likelihood method as well as further confirmation of the transmission clusters by Bayesian inference. Additionally, we collected demographic, clinical and immunovirological data. Between 2011 and 2016, we detected 57 treatment-naïve patients with the CRF19_cpx variant. Of these, 55 conformed a very well-defined transmission cluster, phylogenetically close to CRF19_cpx sequences from the United Kingdom. The origin of this subtype in Malaga was dated between 2007 and 2010. Over 50% of the patients presented the non-nucleoside reverse transcriptase inhibitor G190A resistance mutation. This variant was mostly represented by young adult Spanish men who had sex with men. Almost half of them were recent seroconverters, though a similar percentage was diagnosed at a late state of HIV infection. Five cases of AIDS and one non-AIDS defined death occurred during follow-up. The majority of patients treated with first-line combination antiretroviral therapy (ART) responded. We report the largest HIV-1 CRF19_cpx cohort of treatment-naïve patients outside Cuba, almost all emerging as an outbreak in the South of Spain. Half the cases had the G190A resistance mutation. Unlike previous studies, the variant from Malaga seems less pathogenic, with few AIDS events and an excellent response to ART.

Whole-Exome Sequencing to Identify Rare Variants and Gene Networks that Increase Susceptibility to Scleroderma in African Americans.

PubMed

Gourh, Pravitt; Remmers, Elaine F; Boyden, Steven E; Alexander, Theresa; Morgan, Nadia D; Shah, Ami A; Mayes, Maureen D; Doumatey, Ayo; Bentley, Amy R; Shriner, Daniel; Domsic, Robyn T; Medsger, Thomas A; Steen, Virginia D; Ramos, Paula S; Silver, Richard M; Korman, Benjamin; Varga, John; Schiopu, Elena; Khanna, Dinesh; Hsu, Vivien; Gordon, Jessica K; Saketkoo, Lesley Ann; Gladue, Heather; Kron, Brynn; Criswell, Lindsey A; Derk, Chris T; Bridges, S Louis; Shanmugam, Victoria K; Kolstad, Kathleen D; Chung, Lorinda; Jan, Reem; Bernstein, Elana J; Goldberg, Avram; Trojanowski, Marcin; Kafaja, Suzanne; Maksimowicz-McKinnon, Kathleen M; Mullikin, James C; Adeyemo, Adebowale; Rotimi, Charles; Boin, Francesco; Kastner, Daniel L; Wigley, Fredrick M

2018-05-06

Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway increasing SSc susceptibility. Our goal was to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African Americans (AA). SSc patients of AA ancestry were enrolled from 23 academic centers across the United States under the Genome Research in African American Scleroderma Patients (GRASP) consortium. Unrelated AA individuals without serological evidence of autoimmunity enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the two WES studies in EA SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity pathway analysis in 379 patients and 411 controls. Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds with about equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EAs, and none remained significant including ATP8B4 (P U nCorr =0.98). However, we confirm the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (P C orr =1.95×10 -4 ). This is the largest genetic study in AAs with SSc to date, corroborating the role of functional variants aggregating in a fibrotic pathway and increasing SSc susceptibility. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations.

PubMed

Huang, Linda; Fernandes, Helen; Zia, Hamid; Tavassoli, Peyman; Rennert, Hanna; Pisapia, David; Imielinski, Marcin; Sboner, Andrea; Rubin, Mark A; Kluk, Michael; Elemento, Olivier

2017-05-01

This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu ), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations. PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically. At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB's interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API. An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology. The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

PubMed Central

Rochette, Claire; Jullien, Nicolas; Saveanu, Alexandru; Caldagues, Emmanuelle; Bergada, Ignacio; Braslavsky, Debora; Pfeifer, Marija; Reynaud, Rachel; Herman, Jean-Paul; Barlier, Anne; Brue, Thierry; Enjalbert, Alain; Castinetti, Frederic

2015-01-01

LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients’ phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations. PMID:25955177

Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

PubMed

Cox, Liza L; Cox, Timothy C; Moreno Uribe, Lina M; Zhu, Ying; Richter, Chika T; Nidey, Nichole; Standley, Jennifer M; Deng, Mei; Blue, Elizabeth; Chong, Jessica X; Yang, Yueqin; Carstens, Russ P; Anand, Deepti; Lachke, Salil A; Smith, Joshua D; Dorschner, Michael O; Bedell, Bruce; Kirk, Edwin; Hing, Anne V; Venselaar, Hanka; Valencia-Ramirez, Luz C; Bamshad, Michael J; Glass, Ian A; Cooper, Jonathan A; Haan, Eric; Nickerson, Deborah A; van Bokhoven, Hans; Zhou, Huiqing; Krahn, Katy N; Buckley, Michael F; Murray, Jeffrey C; Lidral, Andrew C; Roscioli, Tony

2018-06-07

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P. Copyright © 2018 American Society of Human Genetics. All rights reserved.

Recurrent emergence of structural variants of LTR retrotransposon CsRn1 evolving novel expression strategy and their selective expansion in a carcinogenic liver fluke, Clonorchis sinensis.

PubMed

Kim, Seon-Hee; Kong, Yoon; Bae, Young-An

2017-06-01

Autonomous retrotransposons, in which replication and transcription are coupled, encode the essential gag and pol genes as a fusion or separate overlapping form(s) that are expressed in single transcripts regulated by a common upstream promoter. The element-specific expression strategies have driven development of relevant translational recoding mechanisms including ribosomal frameshifting to satisfy the protein stoichiometry critical for the assembly of infectious virus-like particles. Retrotransposons with different recoding strategies exhibit a mosaic distribution pattern across the diverse families of reverse transcribing elements, even though their respective distributions are substantially skewed towards certain family groups. However, only a few investigations to date have focused on the emergence of retrotransposons evolving novel expression strategy and causal genetic drivers of the structural variants. In this study, the bulk of genomic and transcribed sequences of a Ty3/gypsy-like CsRn1 retrotransposon in Clonorchis sinensis were analyzed for the comprehensive examination of its expression strategy. Our results demonstrated that structural variants with single open reading frame (ORF) have recurrently emerged from precedential CsRn1 copies encoding overlapping gag-pol ORFs by a single-nucleotide insertion in an upstream region of gag stop codon. In the parasite genome, some of the newly evolved variants appeared to undergo proliferative burst as active master lineages together with their ancestral copies. The genetic event was similarly observed in Opisthorchis viverrini, the closest neighbor of C. sinensis, whereas the resulting structural variants might have failed to overcome purifying selection and comprised minor remnant copies in the Opisthorchis genome. Copyright © 2017 Elsevier B.V. All rights reserved.

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

PubMed

Arno, Gavin; Agrawal, Smriti A; Eblimit, Aiden; Bellingham, James; Xu, Mingchu; Wang, Feng; Chakarova, Christina; Parfitt, David A; Lane, Amelia; Burgoyne, Thomas; Hull, Sarah; Carss, Keren J; Fiorentino, Alessia; Hayes, Matthew J; Munro, Peter M; Nicols, Ralph; Pontikos, Nikolas; Holder, Graham E; Asomugha, Chinwe; Raymond, F Lucy; Moore, Anthony T; Plagnol, Vincent; Michaelides, Michel; Hardcastle, Alison J; Li, Yumei; Cukras, Catherine; Webster, Andrew R; Cheetham, Michael E; Chen, Rui

2016-12-01

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

PubMed

Bansagi, Boglarka; Antoniadi, Thalia; Burton-Jones, Sarah; Murphy, Sinead M; McHugh, John; Alexander, Michael; Wells, Richard; Davies, Joanna; Hilton-Jones, David; Lochmüller, Hanns; Chinnery, Patrick; Horvath, Rita

2015-08-01

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

Skeletal idiopathic osteosclerosis helps to perform personal identification of unknown decedents: A novel contribution from anatomical variants through CT scan.

PubMed

De Angelis, D; Gibelli, D; Palazzo, E; Sconfienza, L; Obertova, Z; Cattaneo, C

2016-07-01

Personal identification consists of the comparison of ante-mortem information from a missing person with post-mortem data obtained from an unidentified corpse. Such procedure is based on the assessment of individualizing features which may help in providing a conclusive identification between ante-mortem and post-mortem material. Anatomical variants may provide important clues to correctly identify human remains. Areas of idiopathic osteosclerosis (IO), or dense bone islands (DBIs) characterized by radiopaque areas of dense, trabeculated, non-inflamed vital bone represent one of these, potentially individualizing, anatomical features. This study presents a case where the finding of DBI was crucial for a positive identification through CT-scan. A decomposed body was found in an apartment in June 2014 in advanced decomposition and no dental records were available to perform a comparison for positive identification. Genetic tests were not applicable because of the lack of relatives in a direct line. The analysis of the only ante-mortem documentation, a CT-scan to the deceased dating back to August 2009, showed the presence of three DBIs within the trabecular bone of the proximal portion of the right femur. The same bony district was removed from the corpse during the autopsy and analysed by CT-scan, which verified the presence of the same features. Forensic practitioners should therefore be aware of the great importance of anatomical bone variants, such as dense bone islands for identification purposes, and the importance of advanced radiological technique for addressing the individualizing potential of such variants. We propose that anatomical variants of the human skeleton should be considered as being "primary identification characteristics" similar to dental status, fingerprints and DNA. Copyright © 2016 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

Directed evolution of a monomeric, bright and photostable version of Clavularia cyan fluorescent protein: structural characterization and applications in fluorescence imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al, Hui-wang; Henderson, J. Nathan; Remington, S. James

The arsenal of engineered variants of the GFP [green FP (fluorescent protein)] from Aequorea jellyfish provides researchers with a powerful set of tools for use in biochemical and cell biology research. The recent discovery of diverse FPs in Anthozoa coral species has provided protein engineers with an abundance of alternative progenitor FPs from which improved variants that complement or supersede existing Aequorea GFP variants could be derived. Here, we report the engineering of the first monomeric version of the tetrameric CFP (cyan FP) cFP484 from Clavularia coral. Starting from a designed synthetic gene library with mammalian codon preferences, we identifiedmore » dimeric cFP484 variants with fluorescent brightness significantly greater than the wild-type protein. Following incorporation of dimer-breaking mutations and extensive directed evolution with selection for blue-shifted emission, high fluorescent brightness and photostability, we arrived at an optimized variant that we have named mTFP1 [monomeric TFP1 (teal FP 1)]. The new mTFP1 is one of the brightest and most photostable FPs reported to date. In addition, the fluorescence is insensitive to physiologically relevant pH changes and the fluorescence lifetime decay is best fitted as a single exponential. The 1.19 {angstrom} crystal structure (1 {angstrom}=0.1 nm) of mTFP1 confirms the monomeric structure and reveals an unusually distorted chromophore conformation. As we experimentally demonstrate, the high quantum yield of mTFP1 (0.85) makes it particularly suitable as a replacement for ECFP (enhanced CFP) or Cerulean as a FRET (fluorescence resonance energy transfer) donor to either a yellow or orange FP acceptor.« less

The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations

PubMed Central

Huang, Linda; Fernandes, Helen; Zia, Hamid; Tavassoli, Peyman; Rennert, Hanna; Pisapia, David; Imielinski, Marcin; Sboner, Andrea; Rubin, Mark A; Kluk, Michael

2017-01-01

Objective: This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations. Materials and Methods: PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically. Results: At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB’s interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API. Discussion: An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology. Conclusion: The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API. PMID:27789569

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

PubMed

Ferreira, Manuel A R; Matheson, Melanie C; Tang, Clara S; Granell, Raquel; Ang, Wei; Hui, Jennie; Kiefer, Amy K; Duffy, David L; Baltic, Svetlana; Danoy, Patrick; Bui, Minh; Price, Loren; Sly, Peter D; Eriksson, Nicholas; Madden, Pamela A; Abramson, Michael J; Holt, Patrick G; Heath, Andrew C; Hunter, Michael; Musk, Bill; Robertson, Colin F; Le Souëf, Peter; Montgomery, Grant W; Henderson, A John; Tung, Joyce Y; Dharmage, Shyamali C; Brown, Matthew A; James, Alan; Thompson, Philip J; Pennell, Craig; Martin, Nicholas G; Evans, David M; Hinds, David A; Hopper, John L

2014-06-01

To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

The Y-Chromosome Tree Bursts into Leaf: 13,000 High-Confidence SNPs Covering the Majority of Known Clades

PubMed Central

Hallast, Pille; Batini, Chiara; Zadik, Daniel; Maisano Delser, Pierpaolo; Wetton, Jon H.; Arroyo-Pardo, Eduardo; Cavalleri, Gianpiero L.; de Knijff, Peter; Destro Bisol, Giovanni; Dupuy, Berit Myhre; Eriksen, Heidi A.; Jorde, Lynn B.; King, Turi E.; Larmuseau, Maarten H.; López de Munain, Adolfo; López-Parra, Ana M.; Loutradis, Aphrodite; Milasin, Jelena; Novelletto, Andrea; Pamjav, Horolma; Sajantila, Antti; Schempp, Werner; Sears, Matt; Tolun, Aslıhan; Tyler-Smith, Chris; Van Geystelen, Anneleen; Watkins, Scott; Winney, Bruce; Jobling, Mark A.

2015-01-01

Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51×, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes. PMID:25468874

Pharmacogenomics of Breast Cancer Therapy: An Update

PubMed Central

Westbrook, Kelly

2013-01-01

Clinical and histopathologic characteristics of breast cancer have long played an important role in treatment decision-making. Well-recognized prognostic factors include tumor size, node status, presence or absence of metastases, tumor grade, and hormone receptor expression. High tumor grade, presence of hormone receptors, and HER2-positivity are a few predictive markers of response to chemotherapy, endocrine manipulations, and anti-HER2 agents, respectively. However, there is much heterogeneity of outcomes in patients with similar clinical and pathologic features despite equivalent treatment regimens. Some of the difference in response to specific therapies can be attributed to somatic tumor characteristics, such as degree of estrogen receptor expression and HER2 status. In recent years, there has been great interest in evaluating the role that pharmacogenetics/pharmacogenomics, or variations in germline DNA, play in alteration of drug metabolism and activity, thus leading to disparate outcomes among patients with similar tumor characteristics. The utility of these variations in treatment decision-making remains debated. Here we review the data available to date on genomic variants that may influence response to drugs commonly used to treat breast cancer. While none of the variants reported to date have demonstrated clinical utility, ongoing prospective studies and increasing understanding of pharmacogenetics will allow us to better predict risk of toxicity or likelihood of response to specific treatments and to provide a more personalized therapy. PMID:23500718

Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice

PubMed Central

Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M.; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A.; Mead, Simon; Brandner, Sebastian; Hill, Andrew F.; Collinge, John

2008-01-01

Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD. PMID:18316717

General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

DOE PAGES

Brinkmann-Chen, Sabine; Flock, Tilman; Cahn, Jackson K. B.; ...

2013-06-17

To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymesmore » having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. As a result, high-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch.« less

Eocene Loranthaceae pollen pushes back divergence ages for major splits in the family

PubMed Central

Kapli, Paschalia; Hofmann, Christa-Charlotte

2017-01-01

Background We revisit the palaeopalynological record of Loranthaceae, using pollen ornamentation to discriminate lineages and to test molecular dating estimates for the diversification of major lineages. Methods Fossil Loranthaceae pollen from the Eocene and Oligocene are analysed and documented using scanning-electron microscopy. These fossils were associated with molecular-defined clades and used as minimum age constraints for Bayesian node dating using different topological scenarios. Results The fossil Loranthaceae pollen document the presence of at least one extant root-parasitic lineage (Nuytsieae) and two currently aerial parasitic lineages (Psittacanthinae and Loranthinae) by the end of the Eocene in the Northern Hemisphere. Phases of increased lineage diversification (late Eocene, middle Miocene) coincide with global warm phases. Discussion With the generation of molecular data becoming easier and less expensive every day, neontological research should re-focus on conserved morphologies that can be traced through the fossil record. The pollen, representing the male gametophytic generation of plants and often a taxonomic indicator, can be such a tracer. Analogously, palaeontological research should put more effort into diagnosing Cenozoic fossils with the aim of including them into modern systematic frameworks. PMID:28607837

Update on genetics of essential tremor.

PubMed

Jiménez-Jiménez, F J; Alonso-Navarro, H; García-Martín, E; Lorenzo-Betancor, O; Pastor, P; Agúndez, J A G

2013-12-01

Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case-control association studies, and exome sequencing in familial ET. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases.

PubMed

Anaya, Juan-Manuel; Kim-Howard, Xana; Prahalad, Sampath; Cherñavsky, Alejandra; Cañas, Carlos; Rojas-Villarraga, Adriana; Bohnsack, John; Jonsson, Roland; Bolstad, Anne Isine; Brun, Johan G; Cobb, Beth; Moser, Kathy L; James, Judith A; Harley, John B; Nath, Swapan K

2012-02-01

Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated 'predisposing' variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren's syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele 'A' is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (p(meta)=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis. Copyright © 2011 Elsevier B.V. All rights reserved.

Gluino coannihilation revisited

DOE PAGES

Ellis, John; Luo, Feng; Olive, Keith A.

2015-09-21

In this study, some variants of the MSSM feature a strip in parameter space where the lightest neutralino χ is identified as the lightest supersymmetric particle (LSP), the gluino g ~ is the next-to-lightest supersymmetric particle (NLSP) and is nearly degenerate with χ, and the relic cold dark matter density is brought into the range allowed by astrophysics and cosmology by coannihilation with the gluino NLSP. We calculate the relic density along this gluino coannihilation strip in the MSSM, including the effects of gluino-gluino bound states and initial-state Sommerfeld enhancement, and taking into account the decoupling of the gluino andmore » LSP densities that occurs for large values of the squark mass m q ~. We find that bound-state effects can increase the maximum m χ for which the relic cold dark matter density lies within the range favoured by astrophysics and cosmology by as much as ~50% if m q ~/m g ~=1.1 , and that the LSP may weigh up to ~8 TeV for a wide range of m q ~/m g ~≲100 .« less

Traveling waves and their tails in locally resonant granular systems

DOE PAGES

Xu, H.; Kevrekidis, P. G.; Stefanov, A.

2015-04-22

In the present study, we revisit the theme of wave propagation in locally resonant granular crystal systems, also referred to as mass-in-mass systems. We use three distinct approaches to identify relevant traveling waves. In addition, the first consists of a direct solution of the traveling wave problem. The second one consists of the solution of the Fourier tranformed variant of the problem, or, more precisely, of its convolution reformulation (upon an inverse Fourier transform) in real space. Finally, our third approach will restrict considerations to a finite domain, utilizing the notion of Fourier series for important technical reasons, namely themore » avoidance of resonances, which will be discussed in detail. All three approaches can be utilized in either the displacement or the strain formulation. Typical resulting computations in finite domains result in the solitary waves bearing symmetric non-vanishing tails at both ends of the computational domain. Importantly, however, a countably infinite set of anti-resonance conditions is identified for which solutions with genuinely rapidly decaying tails arise.« less

Granular Superconductors and Gravity

NASA Technical Reports Server (NTRS)

Noever, David; Koczor, Ron

1999-01-01

As a Bose condensate, superconductors provide novel conditions for revisiting previously proposed couplings between electromagnetism and gravity. Strong variations in Cooper pair density, large conductivity and low magnetic permeability define superconductive and degenerate condensates without the traditional density limits imposed by the Fermi energy (approx. 10(exp -6) g cu cm). Recent experiments have reported anomalous weight loss for a test mass suspended above a rotating Type II, YBCO superconductor, with a relatively high percentage change (0.05-2.1%) independent of the test mass' chemical composition and diamagnetic properties. A variation of 5 parts per 104 was reported above a stationary (non-rotating) superconductor. In experiments using a sensitive gravimeter, bulk YBCO superconductors were stably levitated in a DC magnetic field and exposed without levitation to low-field strength AC magnetic fields. Changes in observed gravity signals were measured to be less than 2 parts in 108 of the normal gravitational acceleration. Given the high sensitivity of the test, future work will examine variants on the basic magnetic behavior of granular superconductors, with particular focus on quantifying their proposed importance to gravity.

Immunohistochemical Patterns in the Interfollicular Caucasian Scalps: Influences of Age, Gender, and Alopecia

PubMed Central

Piérard-Franchimont, Claudine; Loussouarn, Geneviève; Panhard, Ségolène; Saint Léger, Didier; Mellul, Myriam; Piérard, Gérald E.

2013-01-01

Skin ageing and gender influences on the scalp have been seldom studied. We revisited the changes in the interfollicular scalp. The study was performed on a population of 650 volunteers (300 women and 350 men) for over 7 years. Three age groups were selected in both genders, namely, subjects aged 20–35, 50–60, and 60–70 years. The hair status was further considered according to nonalopecic and alopecic patterns and severity (discrete, moderate, and severe). Biopsies from the parietal area were processed for immunohistochemistry. Stromal cells were distinguished according to the presence of vimentin, Factor XIIIa, CD117, and versican. Blood and lymphatic vessels were highlighted by Ulex europaeus agglutinin-1 and human podoplanin immunoreactivities, respectively. Actinic elastosis was identified by the lysozyme coating of elastic fibres. The epidermis was explored using the CD44 variant 3 and Ki67 immunolabellings. Biplot analyses were performed. Immunohistochemistry revealed a prominent gender effect in young adults. Both Factor XIIIa+ dermal dendrocytes and the microvasculature size decreased with scalp ageing. Alopecia changes mimicked stress-induced premature senescence. PMID:24455724

Polymorphisms for ghrelin with consequences on satiety and metabolic alterations.

PubMed

Perret, Jason; De Vriese, Carine; Delporte, Christine

2014-07-01

To understand the current trend of ghrelin genetic variations on the control of satiety, eating behaviours, obesity, and metabolic alterations, and its development over the last 18 months. Several polymorphisms of the ghrelin gene, its receptor gene and ghrelin's acylating enzyme, ghrelin O-acyl transferase, have been identified and studied over the last decade in relation to control of satiety, obesity, eating behaviours, metabolic syndrome, glucose homeostasis, and type 2 diabetes. However, the effects described are either small or nonsignificant and often subjected to contradictory conclusions between studies. In the last 18 months, several of these areas of investigations have been revisited under more controlled conditions or have been subjected to meta-analysis. The effects of ghrelin gene polymorphism, is a complex area of investigation, due to ghrelin's interplay with a host of various factors part of an integrative network. However, taken together, results suggest that there are no or nonsignificant effects of the common genetic variants. A better understanding of the network, probably by a systems biology type approach, will be necessary to assign the exact role played by gene polymorphism of the component of the ghrelin axis.

Potentially malignant disorders of the oral cavity: a clinical study.

PubMed

Shukla, Anirudh

2014-01-01

Oral cancers in India, unlike in the West are the most common cancers encountered, be it a primary or a tertiary referral practice. This makes the study and management of these cancers an important issue especially for the otolaryngologist. It is well known that the most common variant of oral cancers is the squamous cell carcinoma. Also the etiology is well established; with tobacco use in both smoking and smokeless forms, alcohol, betel nut and recently the Human Papilloma virus infection being implicated. Certain conditions which definitely increase the probability of getting oral cancers are known and this study aims in revisiting these aspects of pre-malignancy. The progression from a pre-cancerous lesion/condition to frank cancer is well established across many studies and many specialties. Also timely recognizing these pre-cancerous conditions and administration of proper treatment will greatly help in reducing the morbidity and mortality from subsequent much advanced and dangerous oral cancer. Keeping these facts in mind this study was planned to study the established pre-cancerous lesions which are known to progress to oral cancers.

Revisiting Folk Moral Realism.

PubMed

Pölzler, Thomas

2017-01-01

Moral realists believe that there are objective moral truths. According to one of the most prominent arguments in favour of this view, ordinary people experience morality as realist-seeming, and we have therefore prima facie reason to believe that realism is true. Some proponents of this argument have claimed that the hypothesis that ordinary people experience morality as realist-seeming is supported by psychological research on folk metaethics. While most recent research has been thought to contradict this claim, four prominent earlier studies (by Goodwin and Darley, Wainryb et al., Nichols, and Nichols and Folds-Bennett) indeed seem to suggest a tendency towards realism. My aim in this paper is to provide a detailed internal critique of these four studies. I argue that, once interpreted properly, all of them turn out in line with recent research. They suggest that most ordinary people experience morality as "pluralist-" rather than realist-seeming, i.e., that ordinary people have the intuition that realism is true with regard to some moral issues, but variants of anti-realism are true with regard to others. This result means that moral realism may be less well justified than commonly assumed.

Characterization methodology for lead zirconate titanate thin films with interdigitated electrode structures

NASA Astrophysics Data System (ADS)

Nigon, R.; Raeder, T. M.; Muralt, P.

2017-05-01

The accurate evaluation of ferroelectric thin films operated with interdigitated electrodes is quite a complex task. In this article, we show how to correct the electric field and the capacitance in order to obtain identical polarization and CV loops for all geometrical variants. The simplest model is compared with corrections derived from Schwartz-Christoffel transformations, and with finite element simulations. The correction procedure is experimentally verified, giving almost identical curves for a variety of gaps and electrode widths. It is shown that the measured polarization change corresponds to the average polarization change in the center plane between the electrode fingers, thus at the position where the electric field is most homogeneous with respect to the direction and size. The question of maximal achievable polarization in the various possible textures, and compositional types of polycrystalline lead zirconate titanate thin films is revisited. In the best case, a soft (110) textured thin film with the morphotropic phase boundary composition should yield a value of 0.95Ps, and in the worst case, a rhombohedral (100) textured thin film should deliver a polarization of 0.74Ps.

Traveling waves and their tails in locally resonant granular systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, H.; Kevrekidis, P. G.; Stefanov, A.

In the present study, we revisit the theme of wave propagation in locally resonant granular crystal systems, also referred to as mass-in-mass systems. We use three distinct approaches to identify relevant traveling waves. In addition, the first consists of a direct solution of the traveling wave problem. The second one consists of the solution of the Fourier tranformed variant of the problem, or, more precisely, of its convolution reformulation (upon an inverse Fourier transform) in real space. Finally, our third approach will restrict considerations to a finite domain, utilizing the notion of Fourier series for important technical reasons, namely themore » avoidance of resonances, which will be discussed in detail. All three approaches can be utilized in either the displacement or the strain formulation. Typical resulting computations in finite domains result in the solitary waves bearing symmetric non-vanishing tails at both ends of the computational domain. Importantly, however, a countably infinite set of anti-resonance conditions is identified for which solutions with genuinely rapidly decaying tails arise.« less

Characteristics of revisits of children at risk for serious infections in pediatric emergency care.

PubMed

de Vos-Kerkhof, Evelien; Geurts, Dorien H F; Steyerberg, Ewout W; Lakhanpaul, Monica; Moll, Henriette A; Oostenbrink, Rianne

2018-04-01

In this study, we aimed to identify characteristics of (unscheduled) revisits and its optimal time frame after Emergency Department (ED) discharge. Children with fever, dyspnea, or vomiting/diarrhea (1 month-16 years) who attended the ED of Erasmus MC-Sophia, Rotterdam (2010-2013), the Netherlands, were prospectively included. Three days after ED discharge, we applied standardized telephonic questionnaires on disease course and revisits. Multivariable logistic regression analysis was used to identify independent characteristics of revisits. Young age, parental concern, and alarming signs and symptoms (chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea) were associated with revisits (n = 527) in children at risk for serious infections discharged from the ED (n = 1765). Children revisited the ED within a median of 2 days (IQR 1.0-3.0), but this was proven to be shorter in children with vomiting/diarrhea (1.0 day (IQR 1.0-2.0)) compared to children with fever or dyspnea (2.0 (IQR 1.0-3.0)). Young age, parental concern, and alarming signs and symptoms (chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea) were associated with emergency health care revisits in children with fever, dyspnea, and vomiting/diarrhea. These characteristics could help to define targeted review of children during post-discharge period. We observed a disease specific and differential timing of control revisits after ED discharge. What is Known • Fever, dyspnea, and vomiting/diarrhea are major causes of emergency care attendance in children. • As uncertainty remains on uneventful recovery, patients at risk need to be identified on order to improve safety netting after discharge from the ED. What is New • In children with fever, dyspnea, and vomiting/diarrhea, young age, parental concern and chest wall retractions, ill appearance, clinical signs of dehydration, and tachypnea help to define targeted review of children during the post-discharge period. • A revisit after ED discharge is disease-specific and seems to be shorter for children with vomiting/diarrhea than others.

Takotsubo cardiomyopathy associated with cardiac arrest following cardiac surgery: new variants of an unusual syndrome.

PubMed

Vernick, William J; Hargrove, W Clark; Augoustides, John G; Horak, Jiri

2010-11-01

Takotsubo cardiomyopathy is increasingly being recognized in the perioperative period. To date, there have been only three previous cases involving cardiac surgery reported and this represents the fourth case. The precise mechanism remains elusive, and there is no definitive management strategy. It appears that the syndromes course in cardiac surgical patients is self-limited. This syndrome must now be considered in the differential diagnosis of postcardiotomy cardiac failure. © 2010 Wiley Periodicals, Inc.

An Immunotherapeutic Approach to the Treatment and Prevention of Breast Cancer, Based on Epidermal Growth Factor Receptor Variant, Type III

DTIC Science & Technology

1999-05-01

H. (1996). Pulmonary metastases neutralization and tumor rejection by in vivo administration of B glucan and bispecific antibody. Int. J. Cancer 65...AD GRANT NUMBER DAMD17-96-1-6016 Title: An Immunotherapeutic Approach to the Treatment and Prevention of Breast Cancer , Based on Epidermal Growth...Leave blank) 2. REPORT DATE May 1999 4. TITLE AND SUBTITLE An Immunotherapeutic Approach to the Treatment and Prevention of Breast Cancer

High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer

DTIC Science & Technology

2016-12-01

AWARD NUMBER: W81XWH-13-1-0371 TITLE: High-Throughput Sequencing of Germline and Tumor From Men with Early- Onset Metastatic Prostate Cancer...DATES COVERED 30 Sep 2013 - 29 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER High-Throughput Sequencing of Germline and Tumor From Men with...presenting with metastatic prostate cancer at a young age (before age 60 years). Whole exome sequencing identified a panel of germline variants that have

Which Eye Tracker is Right for Your Research Performance Evaluation of Several Cost Variant Eye Trackers

DTIC Science & Technology

2016-09-19

REPORT TYPE 3. DATES COVERED (From - To) 21-10-16 Conference Proceedings 10/2015 – 03/2016 4. TITLE AND SUBTITLE Which eye tracker is right for...Force Research Laboratory 711th Human Performance Wing Airman Systems Directorate Warfighter Interface Division Applied Neuroscience Branch Wright...88ABW-2016-1334; Human Factors and Ergonomics Society 2016 Annual Meeting 19 – 23 Sept 2016 14. Though not often mentioned, the price point of many

Identification of Novel, Inherited Genetic Markers for Aggressive PCa in European and African Americans Using Whole Genome Sequencing

DTIC Science & Technology

2013-09-01

DATES COVERED (From - To) 22 August 2012 – 21 August 2013 4. TITLE AND SUBTITLE Identification of Novel, Inherited Genetic Markers for Aggressive... Inherited markers of aggressive PCa could be used for screening and diagnosis of aggressive PCa at an early stage while reducing over-diagnosis and...treatment for others. The overall hypothesis is that inherited sequence variants in the genome are associated with a lethal (aggressive) form of PCa but not

A practical method of predicting client revisit intention in a hospital setting.

PubMed

Lee, Kyun Jick

2005-01-01

Data mining (DM) models are an alternative to traditional statistical methods for examining whether higher customer satisfaction leads to higher revisit intention. This study used a total of 906 outpatients' satisfaction data collected from a nationwide survey interviews conducted by professional interviewers on a face-to-face basis in South Korea, 1998. Analyses showed that the relationship between overall satisfaction with hospital services and outpatients' revisit intention, along with word-of-mouth recommendation as intermediate variables, developed into a nonlinear relationship. The five strongest predictors of revisit intention were overall satisfaction, intention to recommend to others, awareness of hospital promotion, satisfaction with physician's kindness, and satisfaction with treatment level.

K-Ca and Rb-Sr Dating of Lunar Granite 14321 Revisited

NASA Technical Reports Server (NTRS)

Simon, Justin I.; Shih, C.-Y.; Nyquist, L. E.

2011-01-01

K-Ca and Rb-Sr age determinations were made for a bulk feldspar-rich portion of an Apollo rock fragment of the pristine lunar granite clast (14321,1062), an acid-leached split of the sample, and the leachate. K-Ca and Rb-Sr data were also obtained for a whole rock sample of Apollo ferroan anorthosite (FAN, 15415). The recent detection [1] of widespread intermediate composition plagioclase indicates that the generation of a diversity of evolved lunar magmas maybe more common and therefore more important to our understanding of crust formation than previously believed. Our new data strengthen the K-Ca and Rb-Sr internal isochrons of the well-studied Apollo sample 14321 [2], which along with a renewed effort to study evolved lunar magmas will provide an improved understanding of the petrogenetic history of evolved rocks on the Moon.

The male bisexuality debate revisited: some bisexual men have bisexual arousal patterns.

PubMed

Rosenthal, A M; Sylva, David; Safron, Adam; Bailey, J Michael

2012-02-01

Self-identified bisexual men report high sexual arousal to both male and female stimuli, but no study to date has compellingly demonstrated that such men have a bisexual pattern of genital arousal. We examined sexual arousal patterns among bisexual men recruited using stringent criteria designed to exclude those who were less likely to have sexual interest in both sexes. Furthermore, we included a bisexual stimulus depicting a man engaged in sex simultaneously with another man and a woman. On average, the bisexual men showed a bisexual arousal pattern, with respect to both self-reported and genital arousal. Additionally, the bisexual men were more aroused by the bisexual stimulus compared with the homosexual and heterosexual men. Some bisexual-identified men have bisexual genital arousal patterns, although it remains unclear how common they are.

[Causes of 72-hour return visits to hospital emergency departments].

PubMed

Jiménez-Puente, Alberto; Del Río-Mata, José; Arjona-Huertas, José Luis; Mora-Ordóñez, Begoña; Nieto-de Haro, Lourdes; Lara-Blanquer, Antonio; Martínez-Reina, Alfonso; Martínez Del Campo, Miguel

2015-10-01

The return-visit rate has been suggested as a measure of emergency department quality of care. We aimed to identify the reasons for emergency revisits and the percentage of returns related to problems with quality of care in the previous visit. Cross-sectional observational study of clinical records for a random sample of unscheduled returns within 72 hours of discharge from the emergency departments of 3 hospitals attending a population of nearly 3 million in the Spanish province of Malaga. The records were reviewed by 2 data collectors, who assigned a reason for revisits according to a standardized classification. A sample of 1075 emergency revisits were reviewed; 895 met the inclusion criteria. The most common reasons for revisits were the persistence or progression of disease (48.8%), an unrelated new problem (9.3%), and referral from a hospital that did not have the required specialized service (8.6%). Reasons attributable to the patient accounted for 14.5% of the revisits; 15.2% were attributable to health care staff errors, 9.2% to system organization, and 61.1% to the disease process. Most emergency department revisits are related to the progression of the disease that led to the first visit. Only a small percentage can be linked to diagnostic or treatment errors in the previous visit.

A comparative approach to recombinantly produce the plant enzyme horseradish peroxidase in Escherichia coli.

PubMed

Gundinger, Thomas; Spadiut, Oliver

2017-04-20

Horseradish peroxidase (HRP) is used in various biotechnological and medical applications. Since its isolation from plant provides several disadvantages, the bacterium Escherichia coli was tested as recombinant expression host in former studies. However, neither production from refolded inclusion bodies nor active enzyme expression in the periplasm exceeded final titres of 10mg per litre cultivation broth. Thus, the traditional way of production of HRP from plant still prevails. In this study, we revisited the recombinant production of HRP in E. coli and investigated and compared both strategies, (a) the production of HRP as inclusion bodies (IBs) and subsequent refolding and (b) the production of active HRP in the periplasm. In fact, we were able to produce HRP in E. coli either way. We obtained a refolding yield of 10% from IBs giving a final titre of 100mgL -1 cultivation broth, and were able to produce 48mg active HRP per litre cultivation broth in the periplasm. In terms of biochemical properties, soluble HRP showed a highly reduced catalytic activity and stability which probably results from the fusion partner DsbA used in this study. Refolded HRP showed similar substrate affinity, an 11-fold reduced catalytic efficiency and 2-fold reduced thermal stability compared to plant HRP. In conclusion, we developed a toolbox for HRP engineering and production. We propose to engineer HRP by directed evolution or semi-rational protein design, express HRP in the periplasm of E. coli allowing straight forward screening for improved variants, and finally produce these variants as IB in high amounts, which are then refolded. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Antibody repertoire development in fetal and neonatal piglets. XVII. IgG subclass transcription revisited with emphasis on new IgG3.

PubMed

Butler, John E; Wertz, Nancy

2006-10-15

Fetal piglets offer an in vivo model for determining whether Ag-independent IgG subclass transcription proceeds in a manner that differs from subclass transcription in pigs exposed to environmental Ags and TLR ligands. Our data from approximately 12,000 Cgamma clones from > 60 piglets provide the first report on the relative usage of all known porcine Cgamma genes in fetal and young pigs. Studies revealed that among the six Cgamma genes, allelic variants of IgG1 comprised 50-80% of the repertoire, and IgG2 alleles comprised < 10% in nearly all tissues. However, relative transcription of allelic variants of IgG1 randomly deviate from the 1:1 ratio expected in heterozygotes. Most surprising was the finding that IgG3 accounted for half of all Cgamma transcripts in the ileal Peyer's patches (IPPs) and mesenteric lymph nodes but on average only approximately 5% of the clones from the thymus, tonsil, spleen, peripheral blood, and bone marrow of newborns. Lymphoid tissues from late term fetuses revealed a similar expression pattern. Except for IgG3 in the IPPs and mesenteric lymph nodes, no stochastic pattern of Cgamma expression during development was seen in animals from mid-gestation through 5 mo. The age and tissue dependence of IgG3 transcription paralleled the developmental persistence of the IPP, and its near disappearance corresponds to the diversification of the preimmune VDJ repertoire in young piglets. We hypothesize that long-hinged porcine IgG3 may be important in preadaptive responses to T cell-independent Ags similar to those described for its murine namesake.

Novel Variations of FANCA Gene Provokes Fanconi Anemia: Molecular Diagnosis in a Special Chinese Family.

PubMed

Li, Niu; Song, Aiyun; Ding, Lixia; Zhu, Hua; Li, Guoqiang; Miao, Yan; Wang, Jian; Li, Benshang; Chen, Jing

2018-07-01

Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ∼1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA.

Comparative Metabolite Profiling of Triterpenoid Saponins and Flavonoids in Flower Color Mutations of Primula veris L.

PubMed Central

Apel, Lysanne; Kammerer, Dietmar R.; Stintzing, Florian C.; Spring, Otmar

2017-01-01

Primula veris L. is an important medicinal plant with documented use for the treatment of gout, headache and migraine reaching back to the Middle Ages. Triterpenoid saponins from roots and flowers are used in up-to-date phytotherapeutic treatment of bronchitis and colds due to their expectorant and secretolytic effects. In addition to the wild type plants with yellow petals, a red variant and an intermediate orange form of Primula veris L. have recently been found in a natural habitat. The secondary metabolite profiles of roots, leaves and flowers of these rare variants were investigated and compared with the wild type metabolome. Two flavonoids, six flavonoid glycosides, four novel methylated flavonoid glycosides, five anthocyanins and three triterpenoid saponins were identified in alcoholic extracts from the petals, leaves and roots of the three variants by high performance liquid chromatography (HPLC)-diode array detection (DAD)/mass spectrometry (MSn) analyses. Anthocyanins were detected in the petals of the red and orange variety, but not in the wild type. No other effects on the metabolite profiles of the three varieties have been observed. The possibility is discussed that a regulatory step of the anthocyanin biosynthetic pathway may have been affected by mutation thus triggering color polymorphism in the petals. PMID:28098796

Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity

PubMed Central

Cork, David M.W.; Darby, Steven; Ryan-Munden, Claudia A.; Nakjang, Sirintra; Mendes Côrtes, Leticia; Treumann, Achim; Gaughan, Luke

2017-01-01

Abstract The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity. Inactivation of this site causes AR to accumulate on chromatin and inactivates its transcriptional function as a consequence of inability to bind to p300. Additionally, mutation at lysine 311 affects cellular transcriptome altering the expression of genes involved in chromatin organization, signaling, adhesion, motility, development and metabolism. Even though this site is present in clinically relevant AR-variants it can only be ubiquitinated in cells when AR retains LBD suggesting a role for AR C-terminus in E2/E3 substrate recognition. We report that as a consequence AR variants lacking the LBD cannot be ubiquitinated in the cellular environment and their protein turnover must be regulated via an alternate pathway. PMID:27903893

Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies.

PubMed

Basile, Kevin J; Johnson, Matthew E; Xia, Qianghua; Grant, Struan F A

2014-01-01

Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.

Myxoid atypical fibroxanthoma: a previously undescribed variant.

PubMed

Patton, A; Page, R; Googe, P B; King, R

2009-11-01

Atypical fibroxanthomas (AFX) are dermal-based cutaneous tumors typically found in sun-damaged skin of the elderly. Histologic variants include spindle cell, clear cell, osteoid, osteoclastic, chondroid, pigmented, and granular cell. To date, myxoid change in AFX, has not been described. Four cases were retrieved from the consultation and surgical pathology files of Knoxville Dermatopathology Laboratory, Knoxville, Tennessee during a 4-year period. The clinical and histologic findings were reviewed and Alcian blue/periodic acid-Schiff (PAS) stain and panel of immunohistochemical stains was obtained. All 4 lesions occurred as solitary lesions in elderly males on the head and neck (2 cases) and upper extremity (2 cases). Histologically all tumors demonstrated a well-circumscribed, cellular lesion centered in the dermis and composed of a mix of atypical pleomorphic and spindle cells in a prominent myxomatous background. A junctional component was absent and the tumors did not arise from the epidermis or adnexal structures. Subcutaneous involvement was absent in all cases. Tumor cells were negative for melanocytic and epithelial markers. Positive staining was noted with CD10 (3/4 cases) and vimentin (4/4 cases). Myxoid change in AFX is rare and previously undescribed in the English literature. Myxoid change may be a prominent finding in benign and malignant cutaneous tumors and awareness of this variant of AFX will avoid misdiagnosis.

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

PubMed

Sporn, Zachary A; Hines, Justin K

2015-01-01

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

PubMed

Leonenko, Ganna; Richards, Alexander L; Walters, James T; Pocklington, Andrew; Chambert, Kimberly; Al Eissa, Mariam M; Sharp, Sally I; O'Brien, Niamh L; Curtis, David; Bass, Nicholas J; McQuillin, Andrew; Hultman, Christina; Moran, Jennifer L; McCarroll, Steven A; Sklar, Pamela; Neale, Benjamin M; Holmans, Peter A; Owen, Michael J; Sullivan, Patrick F; O'Donovan, Michael C

2017-10-01

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies. © 2017 Wiley Periodicals, Inc.

Rare variation facilitates inferences of fine-scale population structure in humans.

PubMed

O'Connor, Timothy D; Fu, Wenqing; Mychaleckyj, Josyf C; Logsdon, Benjamin; Auer, Paul; Carlson, Christopher S; Leal, Suzanne M; Smith, Joshua D; Rieder, Mark J; Bamshad, Michael J; Nickerson, Deborah A; Akey, Joshua M

2015-03-01

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.

PubMed

Le Saux, Olivier; Beck, Konstanze; Sachsinger, Christine; Treiber, Carina; Göring, Harald H H; Curry, Katie; Johnson, Eric W; Bercovitch, Lionel; Marais, Anna-Susan; Terry, Sharon F; Viljoen, Denis L; Boyd, Charles D

2002-10-01

Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.

CACNA1C risk variant affects facial emotion recognition in healthy individuals.

PubMed

Nieratschker, Vanessa; Brückmann, Christof; Plewnia, Christian

2015-11-27

Recognition and correct interpretation of facial emotion is essential for social interaction and communication. Previous studies have shown that impairments in this cognitive domain are common features of several psychiatric disorders. Recent association studies identified CACNA1C as one of the most promising genetic risk factors for psychiatric disorders and previous evidence suggests that the most replicated risk variant in CACNA1C (rs1006737) is affecting emotion recognition and processing. However, studies investigating the influence of rs1006737 on this intermediate phenotype in healthy subjects at the behavioral level are largely missing to date. Here, we applied the "Reading the Mind in the Eyes" test, a facial emotion recognition paradigm in a cohort of 92 healthy individuals to address this question. Whereas accuracy was not affected by genotype, CACNA1C rs1006737 risk-allele carries (AA/AG) showed significantly slower mean response times compared to individuals homozygous for the G-allele, indicating that healthy risk-allele carriers require more information to correctly identify a facial emotion. Our study is the first to provide evidence for an impairing behavioral effect of the CACNA1C risk variant rs1006737 on facial emotion recognition in healthy individuals and adds to the growing number of studies pointing towards CACNA1C as affecting intermediate phenotypes of psychiatric disorders.

Virus-encoded miRNAs in Ebola virus disease.

PubMed

Duy, Janice; Honko, Anna N; Altamura, Louis A; Bixler, Sandra L; Wollen-Roberts, Suzanne; Wauquier, Nadia; O'Hearn, Aileen; Mucker, Eric M; Johnson, Joshua C; Shamblin, Joshua D; Zelko, Justine; Botto, Miriam A; Bangura, James; Coomber, Moinya; Pitt, M Louise; Gonzalez, Jean-Paul; Schoepp, Randal J; Goff, Arthur J; Minogue, Timothy D

2018-04-24

Ebola virus (EBOV) is a negative-strand RNA virus that replicates in the cytoplasm and causes an often-fatal hemorrhagic fever. EBOV, like other viruses, can reportedly encode its own microRNAs (miRNAs) to subvert host immune defenses. miRNAs are short noncoding RNAs that can regulate gene expression by hybridizing to multiple mRNAs, and viral miRNAs can enhance viral replication and infectivity by regulating host or viral genes. To date, only one EBOV miRNA has been examined in human infection. Here, we assayed mouse, rhesus macaque, cynomolgus macaque, and human samples infected with three EBOV variants for twelve computationally predicted viral miRNAs using RT-qPCR. Ten miRNAs aligned to EBOV variants and were detectable in the four species during disease with several viral miRNAs showing presymptomatic amplification in animal models. miRNA abundances in both the mouse and nonhuman primate models mirrored the human cohort, with miR-1-5p, miR-1-3p, and miR-T3-3p consistently at the highest levels. These striking similarities in the most abundant miRNAs during infection with different EBOV variants and hosts indicate that these miRNAs are potential valuable diagnostic markers and key effectors of EBOV pathogenesis.

Dipeptidyl peptidase (DP) 6 and DP10: novel brain proteins implicated in human health and disease.

PubMed

McNicholas, Kym; Chen, Tong; Abbott, Catherine A

2009-01-01

Dipeptidyl peptidase (DP) 6 and DP10 are non-enzyme members of the dipeptidyl peptidase IV family, which includes fibroblast activation protein, DP8, and DP9. DP6 and DP10 proteins have been shown to be critical components of voltage-gated potassium (Kv) channels important in determining cellular excitability. The aim of this paper was to review the research to date on DP6 and DP10 structure, expression, and functions. To date, the protein region responsible for modulating Kv4 channels has not been conclusively identified and the significance of the splice variants has not been resolved. Resolution of these issues will improve our overall knowledge of DP6 and DP10 and lead to a better understanding of their role in diseases, such as asthma and Alzheimer's disease.

[Molecular epidemiological analysis of HIV-1 variants circulating in Russia in 1987-2015].

PubMed

Lapovok, I A; Lopatukhin, A E; Kireev, D E; Kazennova, E V; Lebedev, A V; Bobkova, M R; Kolomeets, A N; Turbina, G I; Shipulin, G A; Ladnaya, N N; Pokrovsky, V V

To simultaneously analyze HIV-1 samples from all Russian regions to characterize the epidemiology of HIV infection in the country as a whole. The most extensive study was conducted to examine nucleotide sequences of the pol gene of HIV-1 samples isolated from HIV-positive persons in different regions of Russia, with the diagnosis date being fixed during 1987-2015. The nucleotide sequences of the HIV-1 genome were analyzed using computer programs and on-line applications to identify a virus subtype and new recombinant forms. The nucleotide sequences of the pol gene were analyzed in 1697 HIV-1 samples and the findings were that the genetic variant subtype A1 (IDU-A) was dominant throughout the entire territory of Russia (in more than 80% of all infection cases). Other virus variants circulating in Russia were analyzed; the phenomenon of the higher distribution of the recombinant form CRF63/02A in Siberia, which had been previously described in the literature, was also confirmed. Four new recombinant forms generated by the virus subtype A1 (IDU-A) and B and two AG recombinant forms were found. There was a larger genetic distance between the viruses of IDU-A variant circulating among the injecting drug users and those infected through heterosexual contact, as well as a change in the viruses of subtype G that caused the outbreak in the south of the country over time in 1988-1989. The findings demonstrate continuous HIV-1 genetic variability and recombination over time in Russia, as well as increased genetic diversity with higher HIV infection rates in the population.

Optimal Patrol to Detect Attacks at Dispersed Heterogeneous Locations

DTIC Science & Technology

2013-12-01

path with one revisit SPR2 Shortest path with two revisits SPR3 Shortest path with three revisits TSP Traveling salesman problem UAV Unmanned aerial...path patrol pattern. Finding the shortest-path patrol pattern is an example of solving a traveling salesman problem , as described in Section 16.5 of...use of patrol paths based on the traveling salesman prob- lem (TSP), where patrollers follow the shortest Hamiltonian cycle in a graph in order to

Evidence of Intercontinental Spread and Uncommon Variants of Low-Pathogenicity Avian Influenza Viruses in Ducks Overwintering in Guatemala.

PubMed

Gonzalez-Reiche, Ana S; Nelson, Martha I; Angel, Mathew; Müller, Maria L; Ortiz, Lucia; Dutta, Jayeeta; van Bakel, Harm; Cordon-Rosales, Celia; Perez, Daniel R

2017-01-01

Over a hundred species of aquatic birds overwinter in Central America's wetlands, providing opportunities for the transmission of influenza A viruses (IAVs). To date, limited IAV surveillance in Central America hinders our understanding of the evolution and ecology of IAVs in migratory hosts within the Western Hemisphere. To address this gap, we sequenced the genomes of 68 virus isolates obtained from ducks overwintering along Guatemala's Pacific Coast during 2010 to 2013. High genetic diversity was observed, including 9 hemagglutinin (HA) subtypes, 7 neuraminidase (NA) subtypes, and multiple avian IAV lineages that have been detected at low levels (<1%) in North America. An unusually large number of viruses with the rare H14 subtype were identified ( n = 14) over two consecutive seasons, the highest number of H14 viruses ever reported in a single location, providing evidence for a possible H14 source population located outside routinely sampled regions of North America. Viruses from Guatemala were positioned within minor clades divergent from the main North American lineage on phylogenies inferred for the H3, H4, N2, N8, PA, NP, and NS segments. A time-scaled phylogeny indicates that a Eurasian virus PA segment introduced into the Americas in the early 2000s disseminated to Guatemala during ~2007.1 to 2010.4 (95% highest posterior density [HPD]). Overall, the diversity detected in Guatemala in overwintering ducks highlights the potential role of Central America in the evolution of diverse IAV lineages in the Americas, including divergent variants rarely detected in the United States, and the importance of increasing IAV surveillance throughout Central America. IMPORTANCE Recent outbreaks of highly pathogenic H7N3, H5Nx, and H7N8 avian influenza viruses in North America were introduced by migratory birds, underscoring the importance of understanding how wild birds contribute to the dissemination and evolution of IAVs in nature. At least four of the main IAV duck host species in North America migrate through or overwinter within a narrow strip of Central America, providing opportunities for diverse IAV lineages to mix and exchange gene segments. By obtaining whole-genome sequences of 68 IAV isolates collected from migratory waterfowl in Guatemala (2010 to 2013), the largest data set available from Central America to date, we detected extensive viral diversity, including gene variants rarely found in North America and gene segments of Eurasian origin. Our findings highlight the need for increased IAV surveillance across the geographical span of bird migration flyways, including Neotropical regions that have been vastly undersampled to date.

New constraints on kinetic isotope effects during CO2(aq) hydration and hydroxylation: Revisiting theoretical and experimental data

NASA Astrophysics Data System (ADS)

Sade, Ziv; Halevy, Itay

2017-10-01

CO2 (de)hydration (i.e., CO2 hydration/HCO3- dehydration) and (de)hydroxylation (i.e., CO2 hydroxylation/HCO3- dehydroxylation) are key reactions in the dissolved inorganic carbon (DIC) system. Kinetic isotope effects (KIEs) during these reactions are likely to be expressed in the DIC and recorded in carbonate minerals formed during CO2 degassing or dissolution of gaseous CO2. Thus, a better understanding of KIEs during CO2 (de)hydration and (de)hydroxylation would improve interpretations of disequilibrium compositions in carbonate minerals. To date, the literature lacks direct experimental constraints on most of the oxygen KIEs associated with these reactions. In addition, theoretical estimates describe oxygen KIEs during separate individual reactions. The KIEs of the related reverse reactions were neither derived directly nor calculated from a link to the equilibrium fractionation. Consequently, KIE estimates of experimental and theoretical studies have been difficult to compare. Here we revisit experimental and theoretical data to provide new constraints on oxygen KIEs during CO2 (de)hydration and (de)hydroxylation. For this purpose, we provide a clearer definition of the KIEs and relate them both to isotopic rate constants and equilibrium fractionations. Such relations are well founded in studies of single isotope source/sink reactions, but they have not been established for reactions that involve dual isotopic sources/sinks, such as CO2 (de)hydration and (de)hydroxylation. We apply the new quantitative constraints on the KIEs to investigate fractionations during simultaneous CaCO3 precipitation and HCO3- dehydration far from equilibrium.

Molecular Epidemiological Analysis of Dengue Fever in Bolivia from 1998 to 2008

PubMed Central

Roca, Yelin; Baronti, Cécile; Revollo, Roberto Jimmy; Cook, Shelley; Loayza, Roxana; Ninove, Laetitia; Fernandez, Roberto Torrez; Flores, Jorge Vargas; Herve, Jean-Pierre; de Lamballerie, Xavier

2012-01-01

Dengue fever was first recognized in Bolivia in 1931. However, very limited information was available to date regarding the genetic characterization and epidemiology of Bolivian dengue virus strains. Here, we performed genetic characterization of the full-length envelope gene of 64 Bolivian isolates from 1998 to 2008 and investigated their origin and evolution to determine whether strains circulated simultaneously or alternatively, and whether or not multiple introductions of distinct viral variants had occurred during the period studied. We determined that, during the last decade, closely related viruses circulated during several consecutive years (5, 6, and 6 years for DENV-1, DENV-2, and DENV-3, respectively) and the co-circulation of two or even three serotypes was observed. Emergence of new variants (distinct from those identified during the previous episodes) was identified in the case of DENV-1 (2007 outbreak) and DENV-2 (2001 outbreak). In all cases, it is likely that the viruses originated from neighboring countries. PMID:19505253

Minimal shortening of leukocyte telomere length across age groups in a cross-sectional study for carriers of a longevity-associated FOXO3 allele.

PubMed

Davy, Philip M C; Willcox, D Craig; Shimabukuro, Michio; Donlon, Timothy A; Torigoe, Trevor; Suzuki, Makoto; Higa, Moritake; Masuzaki, Hiroaki; Sata, Masataka; Chen, Randi; Murkofsky, Rachel; Morris, Brian J; Lim, Eunjung; Allsopp, Richard C; Willcox, Bradley J

2018-04-21

FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a cross-sectional study comprising of samples from 121 healthy Okinawan-Japanese donors aged 21-95 years. We found that telomere length for carriers of the longevity associated allele of FOXO3 single nucleotide polymorphism rs2802292 displayed no significant correlation with age, an effect that was most pronounced in older (>50) participants. This is the first validated longevity gene variant identified to date showing an association with negligible loss of telomere length with age in humans in a cross sectional study. Reduced telomere attrition may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype studied.

An analysis of the sequence of the BAD gene among patients with maturity-onset diabetes of the young (MODY).

PubMed

Antosik, Karolina; Gnyś, Piotr; Jarosz-Chobot, Przemysława; Myśliwiec, Małgorzata; Szadkowska, Agnieszka; Małecki, Maciej; Młynarski, Wojciech; Borowiec, Maciej

2017-01-01

Monogenic diabetes is a rare disease caused by single gene mutations. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognised in the paediatric population. To date, 13 genes have been related to MODY development. The aim of the study was to analyse the sequence of the BCL2-associated agonist of cell death (BAD) gene in patients with clinical suspicion of GCK-MODY, but who were negative for glucokinase (GCK) gene mutations. A group of 122 diabetic patients were recruited from the "Polish Registry for Paediatric and Adolescent Diabetes - nationwide genetic screening for monogenic diabetes" project. The molecular testing was performed by Sanger sequencing. A total of 10 sequence variants of the BAD gene were identified in 122 analysed diabetic patients. Among the analysed patients suspected of MODY, one possible pathogenic variant was identified in one patient; however, further confirmation is required for a certain identification.

Environmental Stability of Seed Carbohydrate Profiles in Soybeans Containing Different Alleles of the Raffinose Synthase 2 (RS2) Gene.

PubMed

Bilyeu, Kristin D; Wiebold, William J

2016-02-10

Soybean [Glycine max (L.) Merr.] is important for the high protein meal used for livestock feed formulations. Carbohydrates contribute positively or negatively to the potential metabolizable energy in soybean meal. The positive carbohydrate present in soybean meal consists primarily of sucrose, whereas the negative carbohydrate components are the raffinose family of oligosaccharides (RFOs), raffinose and stachyose. Increasing sucrose and decreasing raffinose and stachyose are critical targets to improve soybean. In three recently characterized lines, variant alleles of the soybean raffinose synthase 2 (RS2) gene were associated with increased sucrose and decreased RFOs. The objective of this research was to compare the environmental stability of seed carbohydrates in soybean lines containing wild-type or variant alleles of RS2 utilizing a field location study and a date of planting study. The results define the carbohydrate variation in distinct regional and temporal environments using soybean lines with different alleles of the RS2 gene.

Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.

PubMed

Carlson, Christopher S; Matise, Tara C; North, Kari E; Haiman, Christopher A; Fesinmeyer, Megan D; Buyske, Steven; Schumacher, Fredrick R; Peters, Ulrike; Franceschini, Nora; Ritchie, Marylyn D; Duggan, David J; Spencer, Kylee L; Dumitrescu, Logan; Eaton, Charles B; Thomas, Fridtjof; Young, Alicia; Carty, Cara; Heiss, Gerardo; Le Marchand, Loic; Crawford, Dana C; Hindorff, Lucia A; Kooperberg, Charles L

2013-09-01

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study.

PubMed

Papadimitriou, Ioannis D; Lucia, Alejandro; Pitsiladis, Yannis P; Pushkarev, Vladimir P; Dyatlov, Dmitry A; Orekhov, Evgeniy F; Artioli, Guilherme G; Guilherme, João Paulo L F; Lancha, Antonio H; Ginevičienė, Valentina; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa, Carlos A; Kouvatsi, Anastasia; Massidda, Myosotis; Calò, Carla Maria; Garton, Fleur; Houweling, Peter J; Wang, Guan; Austin, Krista; Druzhevskaya, Anastasiya M; Astratenkova, Irina V; Ahmetov, Ildus I; Bishop, David J; North, Kathryn N; Eynon, Nir

2016-04-13

To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. To examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin sprinters from 10 different countries. Sprinters were genotyped for ACTN3 R577X and ACE ID variants. On average, male Caucasian sprinters with the ACTN3 577RR or the ACE DD genotype had faster best 200-m sprint time than their 577XX (21.19 ± 0.53 s vs. 21.86 ± 0.54 s, p = 0.016) and ACE II (21.33 ± 0.56 vs. 21.93 ± 0.67 sec, p = 0.004) counterparts and only one case of ACE II, and no cases of ACTN3 577XX, had a faster 200-m time than the 2012 London Olympics qualifying (vs. 12 qualified sprinters with 577RR or 577RX genotype). Caucasian sprinters with the ACE DD genotype had faster best 400-m sprint time than their ACE II counterparts (46.94 ± 1.19 s vs. 48.50 ± 1.07 s, p = 0.003). Using genetic models we found that the ACTN3 577R allele and ACE D allele dominant model account for 0.92 % and 1.48 % of sprint time variance, respectively. Despite sprint performance relying on many gene variants and environment, the % sprint time variance explained by ACE and ACTN3 is substantial at the elite level and might be the difference between a world record and only making the final.

Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study

PubMed Central

Carlson, Christopher S.; Matise, Tara C.; North, Kari E.; Haiman, Christopher A.; Fesinmeyer, Megan D.; Buyske, Steven; Schumacher, Fredrick R.; Peters, Ulrike; Franceschini, Nora; Ritchie, Marylyn D.; Duggan, David J.; Spencer, Kylee L.; Dumitrescu, Logan; Eaton, Charles B.; Thomas, Fridtjof; Young, Alicia; Carty, Cara; Heiss, Gerardo; Le Marchand, Loic; Crawford, Dana C.; Hindorff, Lucia A.; Kooperberg, Charles L.

2013-01-01

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging. PMID:24068893

Characterization of the genetic variation present in CYP3A4 in three South African populations.

PubMed

Drögemöller, Britt; Plummer, Marieth; Korkie, Lundi; Agenbag, Gloudi; Dunaiski, Anke; Niehaus, Dana; Koen, Liezl; Gebhardt, Stefan; Schneider, Nicol; Olckers, Antonel; Wright, Galen; Warnich, Louise

2013-01-01

The CYP3A4 enzyme is the most abundant human cytochrome P450 (CYP) and is regarded as the most important enzyme involved in drug metabolism. Inter-individual and inter-population variability in gene expression and enzyme activity are thought to be influenced, in part, by genetic variation. Although Southern African individuals have been shown to exhibit the highest levels of genetic diversity, they have been under-represented in pharmacogenetic research to date. Therefore, the aim of this study was to identify genetic variation within CYP3A4 in three South African population groups comprising of 29 Khoisan, 65 Xhosa and 65 Mixed Ancestry (MA) individuals. To identify known and novel CYP3A4 variants, 15 individuals were randomly selected from each of the population groups for bi-directional Sanger sequencing of ~600 bp of the 5'-upstream region and all thirteen exons including flanking intronic regions. Genetic variants detected were genotyped in the rest of the cohort. In total, 24 SNPs were detected, including CYP3A4(*)12, CYP3A4(*)15, and the reportedly functional CYP3A4(*)1B promoter polymorphism, as well as two novel non-synonymous variants. These putatively functional variants, p.R162W and p.Q200H, were present in two of the three populations and all three populations, respectively, and in silico analysis predicted that the former would damage the protein product. Furthermore, the three populations were shown to exhibit distinct genetic profiles. These results confirm that South African populations show unique patterns of variation in the genes encoding xenobiotic metabolizing enzymes. This research suggests that population-specific genetic profiles for CYP3A4 and other drug metabolizing genes would be essential to make full use of pharmacogenetics in Southern Africa. Further investigation is needed to determine if the identified genetic variants influence CYP3A4 metabolism phenotype in these populations.

Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging.

PubMed

Ridge, Perry G; Maxwell, Taylor J; Corcoran, Christopher D; Norton, Maria C; Tschanz, Joann T; O'Brien, Elizabeth; Kerber, Richard A; Cawthon, Richard M; Munger, Ronald G; Kauwe, John S K

2012-01-01

Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.

Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging

PubMed Central

Ridge, Perry G.; Maxwell, Taylor J.; Corcoran, Christopher D.; Norton, Maria C.; Tschanz, JoAnn T.; O’Brien, Elizabeth; Kerber, Richard A.; Cawthon, Richard M.; Munger, Ronald G.; Kauwe, John S. K.

2012-01-01

Background Alzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. Methodology/Principal Findings We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Conclusions/Significance Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary. PMID:23028804

Revised paleoenvironmental analysis of the Holocene portion of the Barbados sea-level record: Cobbler's Reef revisited

NASA Astrophysics Data System (ADS)

Toscano, Marguerite A.

2016-06-01

Sample elevations corrected for tectonic uplift and assessed relative to local modeled sea levels provide a new perspective on paleoenvironmental history at Cobbler's Reef, Barbados. Previously, 14C-dated surface samples of fragmented Acropora palmata plotted above paleo sea level based on their present (uplifted) elevations, suggesting supratidal rubble deposited during a period of extreme storms (4500-3000 cal BP), precipitating reef demise. At several sites, however, A. palmata persisted, existing until ~370 cal BP. Uplift-corrected A. palmata sample elevations lie below the western Atlantic sea-level curve, and ~2 m below ICE-6G-modeled paleo sea level, under slow rates of sea-level rise, negating the possibility that Cobbler's Reef is a supratidal storm ridge. Most sites show limited age ranges from corals likely damaged/killed on the reef crest, not the mixed ages of rubble ridges, strongly suggesting the reef framework died off in stages over 6500 yr. Reef crest death assemblages invoke multiple paleohistoric causes, from ubiquitous hurricanes to anthropogenic impacts. Comparison of death assemblage ages to dated regional paleotempestological sequences, proxy-based paleotemperatures, recorded hurricanes, tsunamis, European settlement, deforestation, and resulting turbidity, reveals many possible factors inimical to the survival of A. palmata along Cobbler's Reef.

What matters to infrequent customers: a pragmatic approach to understanding perceived value and intention to revisit trendy coffee café.

PubMed

Ting, Hiram; Thurasamy, Ramayah

2016-01-01

Notwithstanding the rise of trendy coffee café, little is done to investigate revisit intention towards the café in the context of developing markets. In particular, there is a lack of study which provides theoretical and practical explanation to the perceptions and behaviours of infrequent customers. Hence, the study aims to look into the subject matter by using the theory of reasoned action and social exchange theory as the underpinning basis. The framework proposed by Pine and Gilmore (Strat Leadersh 28:18-23, 2000), which asserts the importance of product quality, service quality and experience quality in a progressive manner, is used to decompose perceived value in the model so as to determine their effects on intention to revisit the café. Given the importance to gain practical insights into revisit intention of infrequent customers, pragmatism stance is assumed. Explanatory sequential mixed-method design is thus adopted whereby qualitative approach is used to confirm and complement quantitative findings. Self-administered questionnaire-based survey is first administered before personal interview is carried out at various cafés. Partial least squares structural equation modelling and content analysis are appropriated successively. In the quantitative findings, although product quality, service quality and experience quality are found to have positive effect on perceived value and revisit intention towards trendy coffee café, experience quality is found to have the greater effect than the others among the infrequent customers. The qualitative findings not only confirm their importance, but most importantly explain the favourable impressions they have at trendy coffee café based on their last in-store experience. While product and service quality might not necessary stimulate them to revisit trendy coffee café, experience quality driven by purposes of visit would likely affect their intention to revisit. As retaining customers is of utmost importance to businesses, and infrequent customers more than often make up the majority of the customers, the study provides meaningful and practical understanding of revisit intention.

New Model for Agglutinitic Glass Formation from LSCC Data

NASA Technical Reports Server (NTRS)

Pieters, C. M.; Taylor, L. A.

2003-01-01

Since the return of the first lunar samples it has been well known that glass-welded aggregates (agglutinates) accumulate in lunar soil as the result of multiple processes, many of which are driven by micrometeorite impacts. The proportion of agglutinates increases with increasing exposure to the space environment, and for an individual soil the proportion of agglutinates also increases with decreasing particle size. Detailed chemical and petrographic analyses of a suite of mare soils and their agglutinate constituents prepared by the Lunar Soil Characterization Consortium appeared to confirm the "Fusion of the Finest Fraction" model for agglutinate formation (or F3) proposed by Papike et al. However, recent LSCC data for highland soils are not consistent with the F3 model and alternate models for agglutinate formation must be revisited. Instead, we suggest differential melting of soil species may be more consistent with the full range of soil data to date.

The meaning of the EPSRC principles of robotics

NASA Astrophysics Data System (ADS)

Bryson, Joanna J.

2017-04-01

In revisiting the Principles of Robotics (as we do in this special issue), it is important to carefully consider their full meaning - their history, the intentions behind them, and their actual societal impact to date. Here I address first the meaning of the document as a whole, then of its constituent parts. Further, I describe the nature of policy, and use the Principles as a case study to discuss how government and academia can interact in constructing policy. I defend the Principles and their main themes: that commercially manufactured robots should not be responsible parties under the law, and that users should not be deceived about robots' capacities or moral status. This perspective allows for the incorporation of robots immediately into UK society and law - the objective of the Principles. The Principles were not designed for every conceivable robot, but rather serve in part as design specifications for robots to be incorporated as legal products into British society.

REVISITING THE CHLORINE ABUNDANCE IN DIFFUSE INTERSTELLAR CLOUDS FROM MEASUREMENTS WITH THE COPERNICUS SATELLITE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moomey, Daniel; Federman, S. R.; Sheffer, Y., E-mail: steven.federman@utoledo.edu, E-mail: ysheffer@astro.umd.edu

2012-01-10

We reanalyzed interstellar Cl I and Cl II spectra acquired with the Copernicus satellite. The directions for this study come from those of Crenny and Federman and sample the transition from atomic to molecular-rich clouds where the unique chemistry leading to molecules containing chlorine is initiated. Our profile syntheses relied on up-to-date laboratory oscillator strengths and component structures derived from published high-resolution measurements of K I absorption that were supplemented with Ca II and Na I D results. We obtain self-consistent results for the Cl I lines at 1088, 1097, and 1347 A from which precise column densities are derived.more » The improved set of results reveals clearer correspondences with H{sub 2} and total hydrogen column densities. These linear relationships arise from rapid conversion of Cl{sup +} to Cl{sup 0} in regions where H{sub 2} is present.« less

From dental science to clinical practice: Knowledge translation and evidence-based dentistry principles.

PubMed

Afrashtehfar, Kelvin I; Assery, Mansour K

2017-07-01

It has been claimed that in order to decrease the gap between what we know and what we do, research findings must be translated from knowledge to action. Such practices better enable dentists to make evidence-based decisions instead of personal ideas and judgments. To this end, this literature review aims to revisit the concepts of knowledge translation and evidence-based dentistry (EBD) and depict their role and influence within dental education. It addresses some possible strategies to facilitate knowledge translation (KT), encourage dental students to use EBD principles, and to encourage dental educators to create an environment in which students become self-directed learners. It concludes with a call to develop up-to-date and efficient online platforms that could grant dentists better access to EBD sources in order to more efficiently translate research evidence into the clinic.

A Two Dimensional Prediction of Solar Cycle 25

NASA Astrophysics Data System (ADS)

Munoz-Jaramillo, A.; Martens, P. C.

2017-12-01

To this date solar cycle most cycle predictions have focused on the forecast of solar cycle amplitude and cycle bell-curve shape. However, recent intriguing observational results suggest that all solar cycles follow the same longitudinal path regardless of their amplitude, and have a very similar decay once they reach a sufficient level of maturity. Cast in the light of our current understanding, these results suggest that the toroidal fields inside the Sun are subject to a very high turbulent diffusivity (of the order of magnitude of mixing-length estimates), and their equatorward propagation is driven by a steady meridional flow. Assuming this is the case, we will revisit the relationship between the polar fields at minimum and the amplitude of the next cycle and deliver a new generation of polar-field based predictions that include the depth of the minimum, as well as the latitude and time of the first active regions of solar cycle 25.

Ancient genomes revisit the ancestry of domestic and Przewalski's horses.

PubMed

Gaunitz, Charleen; Fages, Antoine; Hanghøj, Kristian; Albrechtsen, Anders; Khan, Naveed; Schubert, Mikkel; Seguin-Orlando, Andaine; Owens, Ivy J; Felkel, Sabine; Bignon-Lau, Olivier; de Barros Damgaard, Peter; Mittnik, Alissa; Mohaseb, Azadeh F; Davoudi, Hossein; Alquraishi, Saleh; Alfarhan, Ahmed H; Al-Rasheid, Khaled A S; Crubézy, Eric; Benecke, Norbert; Olsen, Sandra; Brown, Dorcas; Anthony, David; Massy, Ken; Pitulko, Vladimir; Kasparov, Aleksei; Brem, Gottfried; Hofreiter, Michael; Mukhtarova, Gulmira; Baimukhanov, Nurbol; Lõugas, Lembi; Onar, Vedat; Stockhammer, Philipp W; Krause, Johannes; Boldgiv, Bazartseren; Undrakhbold, Sainbileg; Erdenebaatar, Diimaajav; Lepetz, Sébastien; Mashkour, Marjan; Ludwig, Arne; Wallner, Barbara; Merz, Victor; Merz, Ilja; Zaibert, Viktor; Willerslev, Eske; Librado, Pablo; Outram, Alan K; Orlando, Ludovic

2018-04-06

The Eneolithic Botai culture of the Central Asian steppes provides the earliest archaeological evidence for horse husbandry, ~5500 years ago, but the exact nature of early horse domestication remains controversial. We generated 42 ancient-horse genomes, including 20 from Botai. Compared to 46 published ancient- and modern-horse genomes, our data indicate that Przewalski's horses are the feral descendants of horses herded at Botai and not truly wild horses. All domestic horses dated from ~4000 years ago to present only show ~2.7% of Botai-related ancestry. This indicates that a massive genomic turnover underpins the expansion of the horse stock that gave rise to modern domesticates, which coincides with large-scale human population expansions during the Early Bronze Age. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Aphasia and the Diagram Makers Revisited: an Update of Information Processing Models

PubMed Central

2006-01-01

Aphasic syndromes from diseases such as stroke and degenerative disorders are still common and disabling neurobehavioral disorders. Diagnosis, management and treatment of these communication disorders are often dependent upon understanding the neuropsychological mechanisms that underlie these disorders. Since the work of Broca it has been recognized that the human brain is organized in a modular fashion. Wernicke realized that the types of signs and symptoms displayed by aphasic patients reflect the degradation or disconnection of the modules that comprise this speech-language network. Thus, he was the first to propose a diagrammatic or information processing model of this modular language-speech network. Since he first published this model many new aphasic syndromes have been discovered and this has led to modifications of this model. This paper reviews some of the early (nineteenth century) models and then attempts to develop a more up-to-date and complete model. PMID:20396501

Big bang nucleosynthesis revisited via Trojan Horse method measurements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pizzone, R. G.; Spartá, R.; Spitaleri, C.

Nuclear reaction rates are among the most important input for understanding primordial nucleosynthesis and, therefore, for a quantitative description of the early universe. An up-to-date compilation of direct cross-sections of {sup 2}H(d, p){sup 3}H, {sup 2}H(d, n){sup 3}He, {sup 7}Li(p, α){sup 4}He, and {sup 3}He(d, p){sup 4}He reactions is given. These are among the most uncertain cross-sections used and input for big bang nucleosynthesis calculations. Their measurements through the Trojan Horse method are also reviewed and compared with direct data. The reaction rates and the corresponding recommended errors in this work were used as input for primordial nucleosynthesis calculations tomore » evaluate their impact on the {sup 2}H, {sup 3,4}He, and {sup 7}Li primordial abundances, which are then compared with observations.« less

Sentinel 2 products and data quality status

NASA Astrophysics Data System (ADS)

Clerc, Sebastien; Gascon, Ferran; Bouzinac, Catherine; Touli-Lebreton, Dimitra; Francesconi, Benjamin; Lafrance, Bruno; Louis, Jerome; Alhammoud, Bahjat; Massera, Stephane; Pflug, Bringfried; Viallefont, Francoise; Pessiot, Laetitia

2017-04-01

Since July 2015, Sentinel-2A provides high-quality multi-spectral images with 10 m spatial resolution. With the launch of Sentinel-2B scheduled for early March 2017, the mission will create a consistent time series with a revisit time of 5 days. The consistency of the time series is ensured by some specific performance requirements such as multi-temporal spatial co-registration and radiometric stability, routinely monitored by the Sentinel-2 Mission Performance Centre (S2MPC). The products also provide a rich set of metadata and auxiliary data to support higher-level processing. This presentation will focus on the current status of the Sentinel-2 L1C and L2A products, including dissemination and product format aspects. Up-to-date mission performance estimations will be presented. Finally we will provide an outlook on the future evolutions: commissioning tasks for Sentinel-2B, geometric refinement, product format and processing improvements.

SCPS-TP, TCP, and Rate-Based Protocol Evaluation. Revised

NASA Technical Reports Server (NTRS)

Tran, Diepchi T.; Lawas-Grodek, Frances J.; Dimond, Robert P.; Ivancic, William D.

2005-01-01

Tests were performed at Glenn Research Center to compare the performance of the Space Communications Protocol Standard Transport Protocol (SCPS TP, otherwise known as "TCP Tranquility") relative to other variants of TCP and to determine the implementation maturity level of these protocols, particularly for higher speeds. The testing was performed over reasonably high data rates of up to 100 Mbps with delays that are characteristic of near-planetary environments. The tests were run for a fixed packet size, but for variously errored environments. This report documents the testing performed to date.

The management of esophageal achalasia: from diagnosis to surgical treatment.

PubMed

Dobrowolsky, Adrian; Fisichella, P Marco

2014-03-01

The goal of this review is to illustrate our approach to patients with achalasia in terms of preoperative evaluation and surgical technique. Indications, patient selection and management are herein discussed. Specifically, we illustrate the pathogenetic theories and diagnostic algorithm with current up-to-date techniques to diagnose achalasia and its manometric variants. Finally, we focus on the therapeutic approaches available today: medical and surgical. A special emphasis is given on the surgical treatment of achalasia and we provide the reader with a detailed description of our pre and postoperative management.

The Tumor Suppressor Protein p53 and its Physiological Splicing Variant p53as in a Mouse Mammary Cancer Model

DTIC Science & Technology

1997-10-01

and Biomedical Laboratories. PI - Signature Date TABLE OF CONTENTS Report Documentation Page ii Foreword m Introduction 1-2 Experimental Methods...life studies of P53 or p53as in G1, S, and G2/ M was unsuccessful as reported last year. Long cell cycle times may be responsible for lack of separation...of S-phase 5 cells from G2/ M -phase cells by centrifugal elutriation. Attempts to synchronize cells by density arrest and/or serum starvation resulted

SRD5A1 Genetic Variation and Prostate Cancer Epidemiology

DTIC Science & Technology

2005-05-01

DATES COVERED (Leave blank) May 2005 Annual Summary (1 May 2004 - 30 Apr 2005) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS SRD5A1 Genetic Variation and...secondary structure of the luciferase+ SRD5A1 3’-UTR mRNA was so different from the native SRD5Al message, that the 3’-UTR variants should be tested...in the context of a native mRNA. A eukaryotic expression vector containing 850bp of the human SRD5A1 promoter was seamlessly cloned onto the 5’ end of

Kontekst stratygraficzny zastosowania różnych odmian metody termoluminescencyjnej w datowaniu lessów z terenu Polski południowo-wschodniej i Ukrainy północno-zachodniej

NASA Astrophysics Data System (ADS)

Kusiak, Jarosław

2008-01-01

Loess profiles contain a complex but usually incomplete sequence of deposits. In order to chronologically organize deposit layers accessible in different exposures it is necessary to use absolute dating methods. The 14C, TL and OSL methods are widely used for dating of the Upper Pleistocene deposits whereas to older Pleistocene deposits only luminescence methods are applied. Some attempts are made to use the OSL method for dating of the deposits older than the Upper Pleistocene. However, the OSL ages seem to be consistently lower than the TL ages, and also considerably underestimated with reference to stratigraphic interpretation. This fact indicates that the TL method should be used above all. The possibility of TL dating of loesses is connected with their aeolian origin. The obtained TL age should correspond to geological time when mineral grains constituting deposit were exposed to sunlight before deposition. Such exactly condition is met in case of loess deposits. There are many variants of thermoluminescence method because different measuring procedures can be used. Depending on the used procedure, the TL ages obtained for the same sample can be considerably different. The manner of equivalent dose determination is decisive for the obtained TL ages. The factors influencing the value of equivalent dose are presented in this paper. The equivalent dose is determined by comparison of thermoluminescence measured for a given sample with thermoluminescence of the same sample after irradiation in laboratory with known doses of ionizing radiation. The following criteria should be taken into account: size of mineral grains, relation between thermoluminescence and heating temperature, way of reduction of unstable thermoluminescence, and the results of plateau test. The variant of thermoluminescence method used in the TL Laboratory of the Department of Physical Geography and Palaeogeography, Maria Curie-Skłodowska University in Lublin is as follows. The dose rate is determined by gamma spectrometry. The equivalent dose is determined by the total-bleach technique for the 45-63 μm fraction. Blue light obtained using the BG-28 filter is applied. Samples are preheated at 160°C for 3 hours before measurement. Light sum is read as the maximum height of glow curve. The application of such measurement procedure allows reliable dating of climatic episodes recorded in loess deposits not only related to the last glacial but also in older ones.

Acknowledgment Tokens and Speakership Incipiency Revisited.

ERIC Educational Resources Information Center

Zimmerman, Don H.

1993-01-01

Drummond and Hopper's article in this issue, "Back Channels Revisited," is argued to have decontextualized Jefferson's acknowledgement token phenomenon. The need for careful coding protocols for research on conversational practices is discussed. (eight references) (LB)

High Resolution Rapid Revisits Insar Monitoring of Surface Deformation

NASA Astrophysics Data System (ADS)

Singhroy, V.; Li, J.; Charbonneau, F.

2014-12-01

Monitoring surface deformation on strategic energy and transportation corridors requires high resolution spatial and temporal InSAR images for mitigation and safety purposes. High resolution air photos, lidar and other satellite images are very useful in areas where the landslides can be fatal. Recently, radar interferometry (InSAR) techniques using more rapid revisit images from several radar satellites are increasingly being used in active deformation monitoring. The Canadian RADARSAT Constellation (RCM) is a three-satellite mission that will provide rapid revisits of four days interferometric (InSAR) capabilities that will be very useful for complex deformation monitoring. For instance, the monitoring of surface deformation due to permafrost activity, complex rock slide motion and steam assisted oil extraction will benefit from this new rapid revisit capability. This paper provide examples of how the high resolution (1-3 m) rapid revisit InSAR capabilities will improve our monitoring of surface deformation and provide insights in understanding triggering mechanisms. We analysed over a hundred high resolution InSAR images over a two year period on three geologically different sites with various configurations of topography, geomorphology, and geology conditions. We show from our analysis that the more frequent InSAR acquisitions are providing more information in understanding the rates of movement and failure process of permafrost triggered retrogressive thaw flows; the complex motion of an asymmetrical wedge failure of an active rock slide and the identification of over pressure zones related to oil extraction using steam injection. Keywords: High resolution, InSAR, rapid revisits, triggering mechanisms, oil extraction.

Embryonal tumors with abundant neuropil and true rosettes: 2 illustrative cases and a review of the literature.

PubMed

Manjila, Sunil; Ray, Abhishek; Hu, Yin; Cai, Dan X; Cohen, Mark L; Cohen, Alan R

2011-01-01

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently identified variant of primitive neuroectodermal tumor, with fewer than 50 cases reported in the literature to date. Histologically, this tumor has features of ependymoblastoma and neuroblastoma, demonstrating areas of fine fibrillary neuropil intermingled with ependymoblastic rosettes and zones of undifferentiated neuroepithelial cells. However, ETANTR is distinguished pathologically from other embryonal tumors by the striking abundance of neuropil. Clinically, ETANTRs have shown high malignant potential and poor clinical outcome despite aggressive treatment. The authors describe 2 illustrative surgical cases of ETANTR, one involving the longest reported survival in the literature to date. The other had a poor outcome despite high-dose adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue. The authors review the natural history and treatment strategies available for this unusual malignant pediatric brain tumor.

Predator-prey interactions, resource depression and patch revisitation

USGS Publications Warehouse

Erwin, R.M.

1989-01-01

Generalist predators may be confronted by different types of prey in different patches: sedentary and conspicuous, cryptic (with or without refugia), conspicuous and nonsocial, or conspicuous and social. I argue that, where encounter rates with prey are of most importance, patch revisitation should be a profitable tactic where prey have short 'recovery' times (conspicuous, nonsocial prey), or where anti-predator response (e.g. shoaling) may increase conspicuousness. Predictions are made for how temporal changes in prey encounter rates should affect revisit schedules and feeding rates for the 4 different prey types.

New insights into the history of the C-14010 lactase persistence variant in Eastern and Southern Africa.

PubMed

Macholdt, Enrico; Slatkin, Montgomery; Pakendorf, Brigitte; Stoneking, Mark

2015-04-01

Lactase persistence (LP), the ability to digest lactose into adulthood, is strongly associated with the cultural traits of pastoralism and milk-drinking among human populations, and several different genetic variants are known that confer LP. Recent studies of LP variants in Southern African populations, with a focus on Khoisan-speaking groups, found high frequencies of an LP variant (the C-14010 allele) that also occurs in Eastern Africa, and concluded that the C-14010 allele was brought to Southern Africa via a migration of pastoralists from Eastern Africa. However, this conclusion was based on indirect evidence; to date no study has jointly analyzed data on the C-14010 allele from both Southern African Khoisan-speaking groups and Eastern Africa. Here, we combine and analyze published data on the C-14010 allele in Southern and Eastern African populations, consisting of haplotypes with the C-14010 allele and four closely-linked short tandem repeat loci. Our results provide direct evidence for the previously-hypothesized Eastern African origin of the C-14010 allele in Southern African Khoisan-speaking groups. In addition, we find evidence for a separate introduction of the C-14010 allele into the Bantu-speaking Xhosa. The estimated selection intensity on the C-14010 allele in Eastern Africa is lower than that in Southern Africa, which suggests that in Eastern Africa the dietary changes conferring the fitness advantage associated with LP occurred some time after the origin of the C-14010 allele. Conversely, in Southern Africa the fitness advantage was present when the allele was introduced, as would be expected if pastoralism was introduced concomitantly. © 2014 Wiley Periodicals, Inc.

The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome.

PubMed

Cossins, Judith; Liu, Wei Wei; Belaya, Katsiaryna; Maxwell, Susan; Oldridge, Michael; Lester, Tracy; Robb, Stephanie; Beeson, David

2012-09-01

Congenital myasthenic syndromes (CMS) are a group of inherited diseases that affect synaptic transmission at the neuromuscular junction and result in fatiguable muscle weakness. A subgroup of CMS patients have a recessively inherited limb-girdle pattern of weakness caused by mutations in DOK7. DOK7 encodes DOK7, an adaptor protein that is expressed in the skeletal muscle and heart and that is essential for the development and maintenance of the neuromuscular junction. We have screened the DOK7 gene for mutations by polymerase chain reaction amplification and bi-directional sequencing of exonic and promoter regions and performed acetylcholine receptor (AChR) clustering assays and used exon trapping to determine the pathogenicity of detected variants. Approximately 18% of genetically diagnosed CMSs in the UK have mutations in DOK7, with mutations in this gene identified in more than 60 kinships to date. Thirty-four different pathogenic mutations were identified as well as 27 variants likely to be non-pathogenic. An exon 7 frameshift duplication c.1124_1127dupTGCC is commonly found in at least one allele. We analyse the effect of the common frameshift c.1124_1127dupTGCC and show that 10/11 suspected missense mutations have a deleterious effect on AChR clustering. We identify for the first time homozygous or compound heterozygous mutations that are localized 5' to exon 7. In addition, three silent variants in the N-terminal half of DOK7 are predicted to alter the splicing of the DOK7 RNA transcript. The DOK7 gene is highly polymorphic, and within these many variants, we define a spectrum of mutations that can underlie DOK7 CMS that will inform in managing this disorder.

Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia

PubMed Central

Makrythanasis, Periklis; Kato, Mitsuhiro; Zaki, Maha S.; Saitsu, Hirotomo; Nakamura, Kazuyuki; Santoni, Federico A.; Miyatake, Satoko; Nakashima, Mitsuko; Issa, Mahmoud Y.; Guipponi, Michel; Letourneau, Audrey; Logan, Clare V.; Roberts, Nicola; Parry, David A.; Johnson, Colin A.; Matsumoto, Naomichi; Hamamy, Hanan; Sheridan, Eamonn; Kinoshita, Taroh; Antonarakis, Stylianos E.; Murakami, Yoshiko

2016-01-01

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310∗) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability. PMID:26996948

Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia.

PubMed

Makrythanasis, Periklis; Kato, Mitsuhiro; Zaki, Maha S; Saitsu, Hirotomo; Nakamura, Kazuyuki; Santoni, Federico A; Miyatake, Satoko; Nakashima, Mitsuko; Issa, Mahmoud Y; Guipponi, Michel; Letourneau, Audrey; Logan, Clare V; Roberts, Nicola; Parry, David A; Johnson, Colin A; Matsumoto, Naomichi; Hamamy, Hanan; Sheridan, Eamonn; Kinoshita, Taroh; Antonarakis, Stylianos E; Murakami, Yoshiko

2016-04-07

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310(∗)) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Hemoglobin Le Lamentin in the province of Albacete, Spain: Discovery of 32 cases.

PubMed

Martínez-López, Rosalina; Ropero, Paloma; Ballesteros Gallar, Cristina; Romero Román, Carlos; de la Fuente-Gonzalo, Félix; M Nieto, Jorge; Navarro Casado, Laura; González, Fernando A

2017-03-01

Hemoglobin Le Lamentin (α20(B1)His→Gln) is a ubiquitous variant that has been previously described in a small number of isolated patients. We report the incidental observation of Hb Le Lamentin in a large population from the province of Albacete, in southeastern Spain. Our study investigates possible reasons for the elevated number of carriers of this variant and its implications for the management of diabetes in our region. The subjects are 32 diabetic patients whose hemoglobin displayed an unusual peak while they were being tested for glycated hemoglobin at the laboratory of the University General Hospital of Albacete over a 3-year period. Measurements were made by high performance liquid chromatography using a Variant™ II Turbo Kit-2.0, and subsequently the samples of the 32 patients with anomalous peaks were sent to the Hospital Clínico San Carlos (Madrid, Spain) for molecular characterization of any Hb variants. Molecular studies revealed 31 out of 32 patients heterozygous for Le Lamentin, and in one of them, Hb City of Hope was associated with Hb Le Lamentin. The remaining patient was homozygous for the Le Lamentin mutation. Additionally, most patients were native to the northeastern half of the province of Albacete and were unrelated. Our study describes the largest finding to date of hemoglobin Le Lamentin in a sample of patients. The fact that our region has been perpetually depopulated, with a population that has remained stable in small localities over the centuries, may have favored the survival of the mutation. Since the presence of this variant underestimates the true value of glycated hemoglobin measured by HPLC, it is necessary to systematically review chromatograms. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only

PubMed Central

Böhmer, Anne C.; Bowes, John; Nikolić, Miloš; Ishorst, Nina; Wyatt, Niki; Hammond, Nigel L.; Gölz, Lina; Thieme, Frederic; Barth, Sandra; Schuenke, Hannah; Klamt, Johanna; Spielmann, Malte; Aldhorae, Khalid; Rojas-Martinez, Augusto; Nöthen, Markus M.; Rada-Iglesias, Alvaro; Dixon, Michael J.; Knapp, Michael; Mangold, Elisabeth

2017-01-01

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation. PMID:28087736

Solid variant of aneurysmal bone cyst of the thoracic spine: a case report

PubMed Central

2011-01-01

Introduction The solid variant of aneurysmal bone cyst is rare, and only 13 cases involving the spine have been reported to date, including seven in the thoracic vertebrae. The diagnosis is difficult to secure radiographically before biopsy or surgery. Case report An 18-year-old Hispanic man presented to our facility with a one-year history of left chest pain without any significant neurological deficits. An MRI scan demonstrated a 6 cm diameter enhancing multi-cystic mass centered at the T6 vertebral body with involvement of the left proximal sixth rib and extension into the pleural cavity; the spinal cord was severely compressed with evidence of abnormal T2 signal changes. Our patient was taken to the operating room for a total spondylectomy of T6 with resection of the left sixth rib from a single-stage posterior-only approach. The vertebral column was reconstructed in a 360° manner with an expandable titanium cage and pedicle screw fixation. Histologically, the resected specimen showed predominant solid fibroblastic proliferation, with minor foci of reactive osteoid formation, an area of osteoclastic-like giant cells, and cyst-like areas filled with erythrocytes and focal hemorrhage, consistent with a predominantly solid variant of aneurysmal bone cyst. At 16 months after surgery, our patient remains neurologically intact with resolution of his chest and back pain. Conclusions Because of its rarity, location, and radical treatment approach, we considered this case worthy of reporting. The solid variant of aneurysmal bone cyst is difficult to diagnose radiologically before biopsy or surgery, and we hope to remind other physicians that it should be included in the differential diagnosis of any lytic expansile destructive lesion of the spine. PMID:21718507

Attenuated variants of Lesch-Nyhan disease

PubMed Central

Ceballos-Picot, Irene; Torres, Rosa J.; Visser, Jasper E.; Schretlen, David J.; Verdu, Alfonso; Laróvere, Laura E.; Chen, Chung-Jen; Cossu, Antonello; Wu, Chien-Hui; Sampat, Radhika; Chang, Shun-Jen; de Kremer, Raquel Dodelson; Nyhan, William; Harris, James C.; Reich, Stephen G.; Puig, Juan G.

2010-01-01

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency. PMID:20176575

QSAR models for prediction of chromatographic behavior of homologous Fab variants.

PubMed

Robinson, Julie R; Karkov, Hanne S; Woo, James A; Krogh, Berit O; Cramer, Steven M

2017-06-01

While quantitative structure activity relationship (QSAR) models have been employed successfully for the prediction of small model protein chromatographic behavior, there have been few reports to date on the use of this methodology for larger, more complex proteins. Recently our group generated focused libraries of antibody Fab fragment variants with different combinations of surface hydrophobicities and electrostatic potentials, and demonstrated that the unique selectivities of multimodal resins can be exploited to separate these Fab variants. In this work, results from linear salt gradient experiments with these Fabs were employed to develop QSAR models for six chromatographic systems, including multimodal (Capto MMC, Nuvia cPrime, and two novel ligand prototypes), hydrophobic interaction chromatography (HIC; Capto Phenyl), and cation exchange (CEX; CM Sepharose FF) resins. The models utilized newly developed "local descriptors" to quantify changes around point mutations in the Fab libraries as well as novel cluster descriptors recently introduced by our group. Subsequent rounds of feature selection and linearized machine learning algorithms were used to generate robust, well-validated models with high training set correlations (R 2  > 0.70) that were well suited for predicting elution salt concentrations in the various systems. The developed models then were used to predict the retention of a deamidated Fab and isotype variants, with varying success. The results represent the first successful utilization of QSAR for the prediction of chromatographic behavior of complex proteins such as Fab fragments in multimodal chromatographic systems. The framework presented here can be employed to facilitate process development for the purification of biological products from product-related impurities by in silico screening of resin alternatives. Biotechnol. Bioeng. 2017;114: 1231-1240. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

PubMed Central

Wijsman, Ellen M.; Nato, Alejandro Q.; Matsushita, Mark M.; Chapman, Kathy L.; Stanaway, Ian B.; Wolff, John; Oda, Kaori; Gabo, Virginia B.; Raskind, Wendy H.

2016-01-01

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID:27120335

Discovery of a new mechanism for regulation of plant triacylglycerol metabolism: The peanut diacylglycerol acyltransferase-1 gene family transcriptome is highly enriched in alternative splicing variants.

PubMed

Zheng, Ling; Shockey, Jay; Guo, Feng; Shi, Lingmin; Li, Xinguo; Shan, Lei; Wan, Shubo; Peng, Zhenying

2017-12-01

Triacylglycerols (TAGs) are the most important energy storage form in oilseed crops. Diacylglycerol acyltransferase (DGAT) catalyzes the rate-limiting step of the Kennedy pathway of TAG biosynthesis. To date, little is known about the regulation of DGAT activity in peanut (Arachis hypogaea), an agronomically important oilseed crop that is cultivated in many parts of the world. In this study, seven distinct forms of type 1 DGAT (AhDGAT1.1-AhDGAT1.7) were identified, cloned, and characterized. Comparisons of the nucleotide sequences and gene structures revealed many different splicing variants of AhDGAT1, some of which displayed different organ-specific expression patterns. A representative gene (AhDGAT1.1) was transformed into wild-type tobacco and was shown to increase seed fatty acid (FA) content by 14.7%-20.9%. All seven AhDGAT1s were expressed in TAG-deficient Saccharomyces cerevisiae strain H1246; the five longest AhDGAT1 variants generated high levels of acyltransferase activity and complemented the free fatty acid lethality phenotype in this strain. The alternative splicing that gives rise to AhDGAT1.2 and AhDGAT1.4 creates predicted protein C-terminal truncations. The proteins encoded by these two variants were not active and did not complement the fatty acid sensitivity in H1246. These results were verified by visualization of intracellular lipid droplets using Nile Red staining. Collectively, the results presented here represent the first comprehensive analysis of the peanut DGAT1 gene family, which, unlike in other published plant DGAT1 sequences, shows widespread alternative splicing that may affect the expression patterns and enzyme activities of some members of the gene family. Copyright © 2017. Published by Elsevier GmbH.

Pyruvate Kinase Deficiency in Sub-Saharan Africa: Identification of a Highly Frequent Missense Mutation (G829A;Glu277Lys) and Association with Malaria

PubMed Central

Machado, Patrícia; Manco, Licínio; Gomes, Cláudia; Mendes, Cristina; Fernandes, Natércia; Salomé, Graça; Sitoe, Luis; Chibute, Sérgio; Langa, José; Ribeiro, Letícia; Miranda, Juliana; Cano, Jorge; Pinto, João; Amorim, António; do Rosário, Virgílio E.; Arez, Ana Paula

2012-01-01

Background Pyruvate kinase (PK) deficiency, causing hemolytic anemia, has been associated to malaria protection and its prevalence in sub-Saharan Africa is not known so far. This work shows the results of a study undertaken to determine PK deficiency occurrence in some sub-Saharan African countries, as well as finding a prevalent PK variant underlying this deficiency. Materials and Methods Blood samples of individuals from four malaria endemic countries (Mozambique, Angola, Equatorial Guinea and Sao Tome and Principe) were analyzed in order to determine PK deficiency occurrence and detect any possible high frequent PK variant mutation. The association between this mutation and malaria was ascertained through association studies involving sample groups from individuals showing different malaria infection and outcome status. Results The percentage of individuals showing a reduced PK activity in Maputo was 4.1% and the missense mutation G829A (Glu277Lys) in the PKLR gene (only identified in three individuals worldwide to date) was identified in a high frequency. Heterozygous carrier frequency was between 6.7% and 2.6%. A significant association was not detected between either PK reduced activity or allele 829A frequency and malaria infection and outcome, although the variant was more frequent among individuals with uncomplicated malaria. Conclusions This was the first study on the occurrence of PK deficiency in several areas of Africa. A common PKLR mutation G829A (Glu277Lys) was identified. A global geographical co-distribution between malaria and high frequency of PK deficiency seems to occur suggesting that malaria may be a selective force raising the frequency of this 277Lys variant. PMID:23082140

Identification and functional activity of a staphylocoagulase type XI variant originating from staphylococcal food poisoning isolates.

PubMed

Suzuki, Y; Matsushita, S; Kubota, H; Kobayashi, M; Murauchi, K; Higuchi, Y; Kato, R; Hirai, A; Sadamasu, K

2016-09-01

Staphylocoagulase, an extracellular protein secreted by Staphylococcus aureus, has been used as an epidemiological marker. At least 12 serotypes and 24 genotypes subdivided on the basis of nucleotide sequence have been reported to date. In this study, we identified a novel staphylocoagulase nucleotide sequence, coa310, from staphylococcal food poisoning isolates that had the ability to coagulate plasma, but could not be typed using the conventional method. The protein encoded by coa310 contained the six fundamental conserved domains of staphylocoagulase. The full-length nucleotide sequence of coa310 shared the highest similarity (77·5%) with that of staphylocoagulase-type (SCT) XIa. The sequence of the D1 region, which would be responsible for the determination of SCT, shared the highest similarity (91·8%) with that of SCT XIa. These results suggest that coa310 is a novel variant of SCT XI. Moreover, we demonstrated that coa310 encodes a functioning coagulase, by confirming the coagulating activity of the recombinant protein expressed from coa310. This is the first study to directly demonstrate that Coa310, a putative SCT XI, has coagulating activity. These findings may be useful for the improvement of the staphylocoagulase-typing method, including serotyping and genotyping. This is the first study to identify a novel variant of staphylocoagulase type XI based on its nucleotide sequence and to demonstrate coagulating activity in the variant using a recombinant protein. Elucidation of the variety of staphylocoagulases will provide suggestions for further improvement of the staphylocoagulase-typing method and contribute to our understanding of the epidemiologic characterization of Staphylococcus aureus. © 2016 The Society for Applied Microbiology.

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

PubMed

Ng, Michael; Thakkar, Dipti; Southam, Lorraine; Werker, Paul; Ophoff, Roel; Becker, Kerstin; Nothnagel, Michael; Franke, Andre; Nürnberg, Peter; Espirito-Santo, Ana Isabel; Izadi, David; Hennies, Hans Christian; Nanchahal, Jagdeep; Zeggini, Eleftheria; Furniss, Dominic

2017-09-07

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10 -8 . As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Early Recurrence of a Solid Variant of Aneurysmal Bone Cyst in a Young Child After Resection: Technique and Literature Review and Two-year Follow-up After Corpectomy.

PubMed

Samir Barakat, Ahmed; Alsingaby, Hisham; Shousha, Mootaz; El Saghir, Hesham; Boehm, Heinrich

2018-05-15

Aneurysmal bone cysts (ABCs) are considered to be rare benign tumors that may affect long bones or the vertebral column. Their incidence varies and is reported to be 1.4% of all benign skeletal tumors. The solid-variant aneurysmal bone cyst (S-ABC) is even rarer and constitutes 3.5% to 7% of all vertebral ABCs. We report the case of an Enneking stage 3 S-ABC in a 5-year-old boy at C7 that showed rapid local recurrence after primary excision from posterior and dorsal stabilization requiring ventral corpectomy and posterior excision of the right lateral mass and right posterolateral fusion. Histologic examination disclosed an S-ABC. To our knowledge, this is the first case of S-ABC described in the literature that used both anterior and posterior approaches and complete corpectomy. Over a 2-year period, the patient showed no radiologic or clinical signs of local recurrence with excellent neurologic function. Solid-variant aneurysmal bone cysts are difficult to diagnose and treat, and careful clinical and radiologic assessment should be done to tailor an appropriate surgical plan to prevent recurrence and neurologic sequelae. To the best of our knowledge, there are to date no publications that studied the behavior of this subtype.

The Role of Genetics in IBS

PubMed Central

Saito, Yuri A.

2011-01-01

IBS is a common disorder that has been shown to aggregate in families, to affect multiple generations, but not in a manner consistent with a major Mendelian effect. Relatives of an individual with IBS are two to three times as likely to have IBS, with both genders being affected. The estimated genetic liability ranges between 1–20%, with heritability estimates ranging between 0–57%. Although the role of childhood events such as nasogastric tube placement, poor nutrition, abuse, and other stressors have been clearly associated with IBS, these factors have not been studied in families and are unlikely to completely explain the clustering of bowel dysfunction observed in family studies. Furthermore, the familial clustering of IBS does not appear to be explained by psychological traits, based on family studies as well as candidate gene studies of functional variants associated with other psychiatric disorders. To date, over a hundred genetic variants in over 60 genes from various pathways have been studied in a number of candidate gene studies with several positive associations reported. These findings suggest that there may be distinct, as well as shared, molecular underpinnings for IBS and its subtypes. Much new and confirmatory work remains to be performed to elucidate the role of specific genetic variants in IBS development, as well as the specific ways the genes and environment interact to result in IBS susceptibility. PMID:21333900

Pediatric constipation in the emergency department: evaluation, treatment, and outcomes.

PubMed

Freedman, Stephen B; Thull-Freedman, Jennifer; Rumantir, Maggie; Eltorki, Mohamed; Schuh, Suzanne

2014-09-01

Limited knowledge exists surrounding the pharmacologic management of pediatric constipation in the emergency department (ED) setting and the success of interventions. Our primary objective was to determine whether enema administration is associated with 7-day ED revisits for persistent symptoms. Secondary objectives focused on assessing other predictors of ED revisits. We conducted a retrospective cohort study of children <18 years old, diagnosed as having constipation (International Classification of Diseases-10 codes F98.1 nonorganic encopresis, K59.0 constipation) in a pediatric ED in Toronto, Canada, between November 2008 and October 2010. A total of 3592 visits were included; 6% (n = 225) were associated with a revisit. Children with revisits more frequently had vomiting (28% vs 17%, P = 0.001), more pain (5.7 ± 3.6 vs 4.6-3.6 of 10, P = 0.01), and underwent more blood tests (19% 05, 11%, 95% confidence interval [CI] of the difference 3%-14%] and diagnostic imaging (62% vs 47%, 95% CI of the difference 9%-22%). Children administered an enema were 1.54 times more likely to revisit the ED than those who did not receive an enema (8.6% vs 5.5%, 95% CI of the difference 1.1%-5.2%, P = 0.001). Type of enema administered varied by age (P < 0.001). Regression analysis identified the following independent predictors of revisits: diagnostic imaging (odds ratio [OR] 1.54, 95% CI 1.15-2.06), vomiting (OR 1.45, 95% CI 1.07-1.98), enema administration (OR 1.40, 95% CI 1.05-1.88), and significant medical history (OR 1.26, 95% CI 1.04-1.53). Enema administration and diagnostic imaging are associated with revisits in children diagnosed with constipation. Their role in the ED management of pediatric constipation requires further evaluation.

Correcting Spatial Variance of RCM for GEO SAR Imaging Based on Time-Frequency Scaling.

PubMed

Yu, Ze; Lin, Peng; Xiao, Peng; Kang, Lihong; Li, Chunsheng

2016-07-14

Compared with low-Earth orbit synthetic aperture radar (SAR), a geosynchronous (GEO) SAR can have a shorter revisit period and vaster coverage. However, relative motion between this SAR and targets is more complicated, which makes range cell migration (RCM) spatially variant along both range and azimuth. As a result, efficient and precise imaging becomes difficult. This paper analyzes and models spatial variance for GEO SAR in the time and frequency domains. A novel algorithm for GEO SAR imaging with a resolution of 2 m in both the ground cross-range and range directions is proposed, which is composed of five steps. The first is to eliminate linear azimuth variance through the first azimuth time scaling. The second is to achieve RCM correction and range compression. The third is to correct residual azimuth variance by the second azimuth time-frequency scaling. The fourth and final steps are to accomplish azimuth focusing and correct geometric distortion. The most important innovation of this algorithm is implementation of the time-frequency scaling to correct high-order azimuth variance. As demonstrated by simulation results, this algorithm can accomplish GEO SAR imaging with good and uniform imaging quality over the entire swath.

Correcting Spatial Variance of RCM for GEO SAR Imaging Based on Time-Frequency Scaling

PubMed Central

Yu, Ze; Lin, Peng; Xiao, Peng; Kang, Lihong; Li, Chunsheng

2016-01-01

Compared with low-Earth orbit synthetic aperture radar (SAR), a geosynchronous (GEO) SAR can have a shorter revisit period and vaster coverage. However, relative motion between this SAR and targets is more complicated, which makes range cell migration (RCM) spatially variant along both range and azimuth. As a result, efficient and precise imaging becomes difficult. This paper analyzes and models spatial variance for GEO SAR in the time and frequency domains. A novel algorithm for GEO SAR imaging with a resolution of 2 m in both the ground cross-range and range directions is proposed, which is composed of five steps. The first is to eliminate linear azimuth variance through the first azimuth time scaling. The second is to achieve RCM correction and range compression. The third is to correct residual azimuth variance by the second azimuth time-frequency scaling. The fourth and final steps are to accomplish azimuth focusing and correct geometric distortion. The most important innovation of this algorithm is implementation of the time-frequency scaling to correct high-order azimuth variance. As demonstrated by simulation results, this algorithm can accomplish GEO SAR imaging with good and uniform imaging quality over the entire swath. PMID:27428974

Two-component dark-bright solitons in three-dimensional atomic Bose-Einstein condensates.

PubMed

Wang, Wenlong; Kevrekidis, P G

2017-03-01

In the present work, we revisit two-component Bose-Einstein condensates in their fully three-dimensional (3D) form. Motivated by earlier studies of dark-bright solitons in the 1D case, we explore the stability of these structures in their fully 3D form in two variants. In one the dark soliton is planar and trapping a planar bright (disk) soliton. In the other case, a dark spherical shell soliton creates an effective potential in which a bright spherical shell of atoms is trapped in the second component. We identify these solutions as numerically exact states (up to a prescribed accuracy) and perform a Bogolyubov-de Gennes linearization analysis that illustrates that both structures can be dynamically stable in suitable intervals of sufficiently low chemical potentials. We corroborate this finding theoretically by analyzing the stability via degenerate perturbation theory near the linear limit of the system. When the solitary waves are found to be unstable, we explore their dynamical evolution via direct numerical simulations which, in turn, reveal wave forms that are more robust. Finally, using the SO(2) symmetry of the model, we produce multi-dark-bright planar or shell solitons involved in pairwise oscillatory motion.

[New etiological concepts in uveitis].

PubMed

Bodaghi, B

2005-05-01

Uveitis remains an important cause of visual impairment, particularly in young patients. Idiopathic forms of intraocular inflammation should no longer be regarded as a presumed clinical entity, and the ophthalmologist must reconsider the specific etiology of primary uveitis when the clinical examination does not yield a definitive diagnosis or when the course of the disease on corticosteroids remains atypical. Laboratory tests based on serum analysis have limited value and should not be considered as diagnostic proof in different clinical presentations. The diagnostic management of infectious uveitis has been greatly improved by the use of molecular techniques applied to ocular fluids and tissues. Polymerase chain reaction (PCR) technology is a powerful tool that should be proposed in atypical cases of uveitis or retinitis of unclear but potentially infectious origin. This strategy is a major step before using unconventional and new immunomodulatory agents such as anti-TNF-alpha molecules. Under strict experimental conditions including adequate testing to rule out a possible contamination, PCR and its variants have changed our practical approach to intraocular inflammatory disorders and have provided new details for the understanding of infectious uveitis. The concept of pathogen-induced intraocular inflammation can be revisited in the light of molecular data obtained after anterior chamber paracentesis or diagnostic vitrectomy.

Thyroid cancer following scalp irradiation: a reanalysis accounting for uncertainty in dosimetry.

PubMed

Schafer, D W; Lubin, J H; Ron, E; Stovall, M; Carroll, R J

2001-09-01

In the 1940s and 1950s, over 20,000 children in Israel were treated for tinea capitis (scalp ringworm) by irradiation to induce epilation. Follow-up studies showed that the radiation exposure was associated with the development of malignant thyroid neoplasms. Despite this clear evidence of an effect, the magnitude of the dose-response relationship is much less clear because of probable errors in individual estimates of dose to the thyroid gland. Such errors have the potential to bias dose-response estimation, a potential that was not widely appreciated at the time of the original analyses. We revisit this issue, describing in detail how errors in dosimetry might occur, and we develop a new dose-response model that takes the uncertainties of the dosimetry into account. Our model for the uncertainty in dosimetry is a complex and new variant of the classical multiplicative Berkson error model, having components of classical multiplicative measurement error as well as missing data. Analysis of the tinea capitis data suggests that measurement error in the dosimetry has only a negligible effect on dose-response estimation and inference as well as on the modifying effect of age at exposure.

Leishmaniasis: current challenges and prospects for elimination with special focus on the South Asian region.

PubMed

Karunaweera, Nadira D; Ferreira, Marcelo U

2018-04-01

SUMMARYLeishmania donovani, the most virulent species of Leishmania, is found in the South Asian region that harbours the majority of visceral leishmaniasis (VL) cases in the world. The traditionally accepted relationships between the causative species of Leishmania and the resultant disease phenotype have been challenged during recent years and have underscored the importance of revisiting the previously established taxonomy with revisions to its classification. The weak voice of the afflicted with decades of neglect by scientists and policy makers have led to the miserably inadequate and slow advancements in product development in the fields of diagnostics, chemotherapeutics and vector control that continue to hinder the effective management and control of this infection. Limitations notwithstanding, the regional drive for the elimination of VL initiated over a decade ago that focused on India, Nepal and Bangladesh, the three main afflicted countries in the Indian subcontinent is therefore, commendable, with the subsequent status reviews and restructuring of strategies possibly even more so. However, the renewed efforts would need to be combined with plans to combat new challenges in the South-Asian region that includes the emergence of atypical parasite variants, in order to realistically achieve the set goal of regional elimination of VL.

A multitemporal probabilistic error correction approach to SVM classification of alpine glacier exploiting sentinel-1 images (Conference Presentation)

NASA Astrophysics Data System (ADS)

Callegari, Mattia; Marin, Carlo; Notarnicola, Claudia; Carturan, Luca; Covi, Federico; Galos, Stephan; Seppi, Roberto

2016-10-01

In mountain regions and their forelands, glaciers are key source of melt water during the middle and late ablation season, when most of the winter snow has already melted. Furthermore, alpine glaciers are recognized as sensitive indicators of climatic fluctuations. Monitoring glacier extent changes and glacier surface characteristics (i.e. snow, firn and bare ice coverage) is therefore important for both hydrological applications and climate change studies. Satellite remote sensing data have been widely employed for glacier surface classification. Many approaches exploit optical data, such as from Landsat. Despite the intuitive visual interpretation of optical images and the demonstrated capability to discriminate glacial surface thanks to the combination of different bands, one of the main disadvantages of available high-resolution optical sensors is their dependence on cloud conditions and low revisit time frequency. Therefore, operational monitoring strategies relying only on optical data have serious limitations. Since SAR data are insensitive to clouds, they are potentially a valid alternative to optical data for glacier monitoring. Compared to past SAR missions, the new Sentinel-1 mission provides much higher revisit time frequency (two acquisitions each 12 days) over the entire European Alps, and this number will be doubled once the Sentinel1-b will be in orbit (April 2016). In this work we present a method for glacier surface classification by exploiting dual polarimetric Sentinel-1 data. The method consists of a supervised approach based on Support Vector Machine (SVM). In addition to the VV and VH signals, we tested the contribution of local incidence angle, extracted from a digital elevation model and orbital information, as auxiliary input feature in order to account for the topographic effects. By exploiting impossible temporal transition between different classes (e.g. if at a given date one pixel is classified as rock it cannot be classified as glacier ice in a following date) we here propose an innovative post classification correction based on SVM classification probabilities. Optical data, i.e. Landsat-8 and Sentinel-2, have been employed, when available, for training sample collection. Detailed field observations from two glaciers located in the Ortles-Cevedale massif (Eastern Italian Alps) have been employed for validation.

The "Mushroom Cloud" Demonstration Revisited

ERIC Educational Resources Information Center

Panzarasa, Guido; Sparnacci, Katia

2013-01-01

A revisitation of the classical "mushroom cloud" demonstration is described. Instead of aniline and benzoyl peroxide, the proposed reaction involves household chemicals such as alpha-pinene (turpentine oil) and trichloroisocyanuric acid ("Trichlor") giving an impressive demonstration of oxidation and combustion reactions that…

A genome-wide identification of the miRNAome in response to salinity stress in date palm (Phoenix dactylifera L.).

PubMed

Yaish, Mahmoud W; Sunkar, Ramanjulu; Zheng, Yun; Ji, Bo; Al-Yahyai, Rashid; Farooq, Sardar A

2015-01-01

Although date palm is relatively salt-tolerant, little is known about the underlying molecular mechanisms that contribute to its salt tolerance. Only recently, investigators have uncovered microRNA-mediated post-transcriptional gene regulation, which is critical for typical plant development and adaptation to stress conditions such as salinity. To identify conserved and novel miRNAs in date palm and to characterize miRNAs that could play a role in salt tolerance, we have generated sRNA libraries from the leaves and roots of NaCl-treated and untreated seedlings of date palm. Deep sequencing of these four sRNA libraries yielded approximately 251 million reads. The bioinformatics analysis has identified 153 homologs of conserved miRNAs, 89 miRNA variants, and 180 putative novel miRNAs in date palm. Expression profiles under salinity revealed differential regulation of some miRNAs in date palm. In leaves, 54 of the identified miRNAs were significantly affected and the majority (70%) of them were upregulated, whereas in roots, 25 of the identified miRNAs were significantly affected and 76% of them were upregulated by the salinity stress. The salt-responsiveness of some of these miRNAs was further validated using semi-quantitative PCR (qPCR). Some of the predicted targets for the identified miRNA include genes with known functions in plant salt tolerance, such as potassium channel AKT2-like proteins, vacuolar protein sorting-associated protein, calcium-dependent and mitogen-activated proteins. As one of the first cultivated trees in the world that can tolerate a wide range of abiotic stresses, date palm contains a large population of conserved and non-conserved miRNAs that function at the post-transcriptional level. This study provided insights into miRNA-mediated gene expression that are important for adaptation to salinity in date palms.

The microspace launcher: first step to the fully air-breathing space launcher

NASA Astrophysics Data System (ADS)

Falempin, F.; Bouchez, M.; Calabro, M.

2009-09-01

A possible application for the high-speed air-breathing propulsion is the fully or partially reusable space launcher. Indeed, by combining the high-speed air-breathing propulsion with a conventional rocket engine (combined cycle or combined propulsion system), it should be possible to improve the average installed specific impulse along the ascent trajectory and then make possible more performing launchers and, hopefully, a fully reusable one. During the last 15 years, a lot of system studies have been performed in France on that subject within the framework of different and consecutive programs. Nevertheless, these studies never clearly demonstrated that a space launcher could take advantage of using a combined propulsion system. During last years, the interest to air-breathing propulsion for space application has been revisited. During this review and taking into account technologies development activities already in progress in Europe, clear priorities have been identified regarding a minimum complementary research and technology program addressing specific needs of space launcher application. It was also clearly identified that there is the need to restart system studies taking advantage of recent progress made regarding knowledge, tools, and technology and focusing on more innovative airframe/propulsion system concepts enabling better trade-off between structural efficiency and propulsion system performance. In that field, a fully axisymmetric configuration has been considered for a microspace launcher (10 kg payload). The vehicle is based on a main stage powered by air-breathing propulsion, combined or not with liquid rocket mode. A "kick stage," powered by a solid rocket engine provides the final acceleration. A preliminary design has been performed for different variants: one using a separated booster and a purely air-breathing main stage, a second one using a booster and a main stage combining air-breathing and rocket mode, a third one without separated booster, the main stage ensuring the initial acceleration in liquid rocket mode and a complementary acceleration phase in rocket mode beyond the air-breathing propulsion system operation. Finally, the liquid rocket engine of this third variant can be replaced by a continuous detonation wave rocket engine. The paper describes the main guidelines for the design of these variants and provides their main characteristics. On this basis, the achievable performance, estimated by trajectory simulation, are detailed.

Revisiting Bioaccumulation Criteria

EPA Science Inventory

The objective of workgroup 5 was to revisit the B(ioaccumulation) criteria that are currently being used to identify POPs under the Stockholm Convention and PBTs under CEPA, TSCA, REACh and other programs. Despite the lack of a recognized definition for a B substance, we defined ...

Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding.

PubMed

Mundell, S J; Rabbolini, D; Gabrielli, S; Chen, Q; Aungraheeta, R; Hutchinson, J L; Kilo, T; Mackay, J; Ward, C M; Stevenson, W; Morel-Kopp, M-C

2018-01-01

Essentials Three dominant variants for the autosomal recessive bleeding disorder type-8 have been described. To date, there has been no phenotype/genotype correlation explaining their dominant transmission. Proline plays an important role in P2Y12R ligand binding and signaling defects. P2Y12R homodimer formation is critical for the receptor function and signaling. Background Although inherited platelet disorders are still underdiagnosed worldwide, advances in molecular techniques are improving disease diagnosis and patient management. Objective To identify and characterize the mechanism underlying the bleeding phenotype in a Caucasian family with an autosomal dominant P2RY12 variant. Methods Full blood counts, platelet aggregometry, flow cytometry and western blotting were performed before next-generation sequencing (NGS). Detailed molecular analysis of the identified variant of the P2Y12 receptor (P2Y12R) was subsequently performed in mammalian cells overexpressing receptor constructs. Results All three referred individuals had markedly impaired ADP-induced platelet aggregation with primary wave only, despite normal total and surface P2Y12R expression. By NGS, a single P2RY12:c.G794C substitution (p.R265P) was identified in all affected individuals, and this was confirmed by Sanger sequencing. Mammalian cell experiments with the R265P-P2Y12R variant showed normal receptor surface expression versus wild-type (WT) P2Y12R. Agonist-stimulated R265P-P2Y12R function (both signaling and surface receptor loss) was reduced versus WT P2Y12R. Critically, R265P-P2Y12R acted in a dominant negative manner, with agonist-stimulated WT P2Y12R activity being reduced by variant coexpression, suggesting dramatic loss of WT homodimers. Importantly, platelet P2RY12 cDNA cloning and sequencing in two affected individuals also revealed three-fold mutant mRNA overexpression, decreasing even further the likelihood of WT homodimer formation. R265 located within extracellular loop 3 (EL3) is one of four residues that are important for receptor functional integrity, maintaining the binding pocket conformation and allowing rotation following ligand binding. Conclusion This novel dominant negative variant confirms the important role of R265 in EL3 in the functional integrity of P2Y12R, and suggests that pathologic heterodimer formation may underlie this family bleeding phenotype. © 2017 International Society on Thrombosis and Haemostasis.

Revisiting Lake Hämelsee: reconstructing abrupt Lateglacial climate transitions using state- of-the-art palaeoclimatological proxies

NASA Astrophysics Data System (ADS)

Engels, Stefan; Hoek, Wim; Lane, Christine; Sachse, Dirk; Wagner-Cremer, Friederike

2015-04-01

Lake Hämelsee (Germany) is one of the northernmost sites in NW Europe that has varved sediments throughout large parts of its Lateglacial and Early Holocene sediment sequence. Previous research on this site has shown its potential, in terms of chronological resolution and palaeoecological reconstructions, for reconstructing the abrupt transitions into and out of the Younger Dryas, the last cold period of the last glacial. The site was revisited during a 1-week summer school for Early Stage Researchers (2013), within the INTIMATE Example training and research project, supported by EU Cost Action ES0907. Two overlapping sediment sequences were retrieved from the centre of the lake during the summer school. These sediments have since formed the basis for follow-up research projects, which have sparked the collaboration of around 30 researchers in 12 laboratories across Europe. A chronological framework for the core has been composed from a combination of varve counting, radiocarbon dating and tephrochronology. Tephrostratigraphic correlations allow direct correlation and precise comparison of the record to marine and ice core records from the North Atlantic region, and other terrestrial European archives. Furthermore, the core is has been subjected to multiple sedimentological (e.g. XRF, loss-on-ignition), geochemical (e.g. lipid biomarkers, GDGTs) and palaeoecological (e.g. pollen, chironomids) proxy-based reconstructions of past environmental and climatic conditions. The results provide important insights into the nature of the abrupt climate transitions of the Lateglacial and Early Holocene, both locally and on a continental scale. The INTIMATE Example participants: Illaria Baneschi, Achim Brauer, Christopher Bronk Ramsey, Renee de Bruijn, Siwan Davies, Aritina Haliuc, Katalin Hubay, Gwydion Jones, Meike Müller, Johanna Menges, Josef Merkt, Tom Peters, Francien Peterse, Anneke ter Schure, Kathrin Schuetrumpf, Richard Staff, Falko Turner, Valerie van den Bos.

The Evil of Banality: Arendt Revisited

ERIC Educational Resources Information Center

Minnich, Elizabeth

2014-01-01

"The banality of evil" (Arendt) remains controversial and useful. Ironically, the concept is now itself a banality. To revisit and extend it, we consider the "evil of banality", the profound dangers of cliched thoughtlessness. A distinction is proposed: "intensive" versus "extensive evils". The former takes…

Lakatos Revisited.

ERIC Educational Resources Information Center

Court, Deborah

1999-01-01

Revisits and reviews Imre Lakatos' ideas on "Falsification and the Methodology of Scientific Research Programmes." Suggests that Lakatos' framework offers an insightful way of looking at the relationship between theory and research that is relevant not only for evaluating research programs in theoretical physics, but in the social…

Emergent Dead Vegetation and Paired Cosmogenic Isotope Constraints on Ice Cap Activity, Baffin Island, Arctic Canada

NASA Astrophysics Data System (ADS)

Pendleton, S.; Miller, G. H.

2014-12-01

Recent summer warming has now raised the equilibrium line above almost all ice caps on Baffin Island, resulting in surface lowering and marginal recession everywhere. As cold-based ice recedes it frequently exposes in situ tundra plants that were living at the time ice expanded across the site. Radiocarbon dates for each plant records when cold summers dropped regional snowline below the site, killing the plants, and snowline remained below the site until the collection date. The kill dates also represent the last time that the climate was warm enough to expose the sampling location. Seventy-six vegetation samples collected in 2013 from the Penny Ice Cap region have been dated, with significant age populations at ~0.5, 1.8, 2.3, and 3.6 ka. The absence of ages around ~1, 2, 3, 4.5, and 5.5 ka suggest periods of either no snowline depression or stability. Sixteen vegetation samples returned ages of >45 ka (2 revisited sites from 2010, 14 new). It is postulated that these radiocarbon dead samples were last exposed during the last interglaciation (~120 ka), the last time climate was as warm as present. In addition to plant collections, bedrock exposures at the ice margins were sampled for 26Al/10Be cosmogenic nuclide dating. Seven samples from and around the Penny Ice cap have returned maximum exposure ages from ~ 0.6-0.9 ma and total histories of ~0.6-1.5 ma. In general, samples from the larger Penny Ice Cap exhibited lower amounts of exposure (~20% of total history) than those samples from smaller, localized ice caps (~55%). Radiocarbon dead sites north of the Penny Ice cap experienced significantly more exposure over their lifetimes than their counterparts east of the Penny Ice cap, suggesting significant differences in local and regional land ice fluctuations over the last 2 million years. Utilizing both the method of in situ moss and 26Al/10Be dating provides new insight into both the recent activity and long-term evolution of ice on Baffin Island. In particular these new data help to shed light on how late Holocene coolings affect both large and small ice bodies and how this behavior is represented in the longer-term burial/exposure record contained within the rock surface.

The Longevity Consortium: Harnessing diverse approaches to understand the genetic basis of human longevity and healthy aging. An introduction to a series of articles.

PubMed

Kahn, Arnold

2011-04-01

The Longevity Consortium is a multi-investigator, multi-institutional research group focused on identifying the genetic variants that regulate human lifespan and healthy aging. The text that follows is an introduction to a series of seven articles prepared by Consortium investigators that represent a profile of planned and ongoing research and up-to-date reviews of topics of major interest to biogerontologists and others scientists and clinicians interested in ageing research. Copyright © 2010 Elsevier B.V. All rights reserved.

Evidence of Intercontinental Spread and Uncommon Variants of Low-Pathogenicity Avian Influenza Viruses in Ducks Overwintering in Guatemala

PubMed Central

Gonzalez-Reiche, Ana S.; Nelson, Martha I.; Angel, Mathew; Müller, Maria L.; Ortiz, Lucia; Dutta, Jayeeta; van Bakel, Harm

2017-01-01

ABSTRACT Over a hundred species of aquatic birds overwinter in Central America’s wetlands, providing opportunities for the transmission of influenza A viruses (IAVs). To date, limited IAV surveillance in Central America hinders our understanding of the evolution and ecology of IAVs in migratory hosts within the Western Hemisphere. To address this gap, we sequenced the genomes of 68 virus isolates obtained from ducks overwintering along Guatemala’s Pacific Coast during 2010 to 2013. High genetic diversity was observed, including 9 hemagglutinin (HA) subtypes, 7 neuraminidase (NA) subtypes, and multiple avian IAV lineages that have been detected at low levels (<1%) in North America. An unusually large number of viruses with the rare H14 subtype were identified (n = 14) over two consecutive seasons, the highest number of H14 viruses ever reported in a single location, providing evidence for a possible H14 source population located outside routinely sampled regions of North America. Viruses from Guatemala were positioned within minor clades divergent from the main North American lineage on phylogenies inferred for the H3, H4, N2, N8, PA, NP, and NS segments. A time-scaled phylogeny indicates that a Eurasian virus PA segment introduced into the Americas in the early 2000s disseminated to Guatemala during ~2007.1 to 2010.4 (95% highest posterior density [HPD]). Overall, the diversity detected in Guatemala in overwintering ducks highlights the potential role of Central America in the evolution of diverse IAV lineages in the Americas, including divergent variants rarely detected in the United States, and the importance of increasing IAV surveillance throughout Central America. IMPORTANCE Recent outbreaks of highly pathogenic H7N3, H5Nx, and H7N8 avian influenza viruses in North America were introduced by migratory birds, underscoring the importance of understanding how wild birds contribute to the dissemination and evolution of IAVs in nature. At least four of the main IAV duck host species in North America migrate through or overwinter within a narrow strip of Central America, providing opportunities for diverse IAV lineages to mix and exchange gene segments. By obtaining whole-genome sequences of 68 IAV isolates collected from migratory waterfowl in Guatemala (2010 to 2013), the largest data set available from Central America to date, we detected extensive viral diversity, including gene variants rarely found in North America and gene segments of Eurasian origin. Our findings highlight the need for increased IAV surveillance across the geographical span of bird migration flyways, including Neotropical regions that have been vastly undersampled to date. PMID:28405632

Satellite-based monitoring of grassland: assessment of harvest dates and frequency using SAR

NASA Astrophysics Data System (ADS)

Siegmund, R.; Grant, K.; Wagner, M.; Hartmann, S.

2016-10-01

Grasslands are among the largest ecosystems worldwide and according to the FAO they contribute to the livelihoods of more than 800 million people. Harvest dates and frequency can be utilised for an improved estimation of grassland yields. In the presented project a highly automatised methodology for detecting harvest dates and frequency using SARamplitude data was developed based on an amplitude change detection techniques. This was achieved by evaluating spatial statistics over field boundaries provided by the European Integrated Administration and Control System (IACS) to identify changes between pre- and post-harvest acquisitions. The combination of this method with a grassland yield model will result in more reliable and regional-wide numbers of grassland yields. In our contribution we will focus on SAR-remote sensing for monitoring harvest frequencies, discuss the requirements concerning the acquisition system, present the technical approach and analyse the verified results. In terms of the acquisition system a high temporal acquisition rate is required, which is generally met by using SARsatellite constellations providing a revisit time of few days. COSMO-SkyMed data were utilised for the pilot study for developing and prototyping a monitoring system. Subsequently the approach was adapted to the use of the C-Band system Sentinel-1A becoming fully operational with the availability of Sentinal-1B. The study area is situated northeast of Munich, Germany, extending to an area of approx. 40km to 40km and covering major verification sites and in-situ data provided by research farms or continuously surveyed in-situ campaigns. An extended time series of SAR data was collected during the cultivation and vegetation cycles between March 2014 and March 2016. All data were processed and harmonised in a GIS database to be analysed and verified according to corresponding in-situ data.

Revisiting the block method for evaluating thermal conductivities of clay and granite

USDA-ARS?s Scientific Manuscript database

Determination of thermal conductivities of porous media using the contact method is revisited and revalidated with consideration of thermal contact resistance. Problems that limit the accuracy of determination of thermal conductivities of porous media are discussed. Thermal conductivities of granite...

Phenomenology of n - n ¯ oscillations revisited

DOE PAGES

Gardner, S.; Jafari, E.

2015-05-22

We revisit the phenomenology of n-n¯ oscillations in the presence of external magnetic fields, highlighting the role of spin. We show, contrary to long-held belief, that the n-n¯ transition rate need not be suppressed, opening new opportunities for its empirical study.

Magnetic Braking Revisited: Activities for the Undergraduate Laboratory

ERIC Educational Resources Information Center

Ireson, Gren; Twidle, John

2008-01-01

This paper revisits the demonstration of Lenz by dropping magnets down a non-magnetic tube. Recent publications are reviewed and ideas for undergraduate laboratory investigations are suggested. Finally, an example of matching theory to observation is presented. (Contains 4 tables, 5 figures and 3 footnotes.)

Phenomenology of n - n ¯ oscillations revisited

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gardner, S.; Jafari, E.

We revisit the phenomenology of n-n¯ oscillations in the presence of external magnetic fields, highlighting the role of spin. We show, contrary to long-held belief, that the n-n¯ transition rate need not be suppressed, opening new opportunities for its empirical study.

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia.

PubMed

Maxwell, Rochelle R; Cole, Peter D

2017-06-01

The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

Structural genomic variations and Parkinson's disease.

PubMed

Bandrés-Ciga, Sara; Ruz, Clara; Barrero, Francisco J; Escamilla-Sevilla, Francisco; Pelegrina, Javier; Vives, Francisco; Duran, Raquel

2017-10-01

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.

Adaptive algorithm of selecting optimal variant of errors detection system for digital means of automation facility of oil and gas complex

NASA Astrophysics Data System (ADS)

Poluyan, A. Y.; Fugarov, D. D.; Purchina, O. A.; Nesterchuk, V. V.; Smirnova, O. V.; Petrenkova, S. B.

2018-05-01

To date, the problems associated with the detection of errors in digital equipment (DE) systems for the automation of explosive objects of the oil and gas complex are extremely actual. Especially this problem is actual for facilities where a violation of the accuracy of the DE will inevitably lead to man-made disasters and essential material damage, at such facilities, the diagnostics of the accuracy of the DE operation is one of the main elements of the industrial safety management system. In the work, the solution of the problem of selecting the optimal variant of the errors detection system of errors detection by a validation criterion. Known methods for solving these problems have an exponential valuation of labor intensity. Thus, with a view to reduce time for solving the problem, a validation criterion is compiled as an adaptive bionic algorithm. Bionic algorithms (BA) have proven effective in solving optimization problems. The advantages of bionic search include adaptability, learning ability, parallelism, the ability to build hybrid systems based on combining. [1].

Indocyanine green videoangiography methodological variations: review.

PubMed

Simal-Julián, Juan A; Miranda-Lloret, Pablo; Evangelista-Zamora, Rocio; Sanromán-Álvarez, Pablo; Pérez de San Román, Laila; Pérez-Borredá, Pedro; Beltrán-Giner, Andrés; Botella-Asunción, Carlos

2015-01-01

Indocyanine green videoangiography (ICGVA) procedures have become widespread within the spectrum of microsurgical techniques for neurovascular pathologies. We have conducted a review to identify and assess the impact of all of the methodological variations of conventional ICGVA applied in the field of neurovascular pathology that have been published to date in the English literature. A total of 18 studies were included in this review, identifying four primary methodological variants compared to conventional ICGVA: techniques based on the transient occlusion, intra-arterial ICG administration via catheters, use of endoscope system with a filter to collect florescence of ICG, and quantitative fluorescence analysis. These variants offer some possibilities for resolving the limitations of the conventional technique (first, the vascular structure to be analyzed must be exposed and second, vascular filling with ICG follows an additive pattern) and allow qualitatively superior information to be obtained during surgery. Advantages and disadvantages of each procedure are discussed. More case studies with a greater number of patients are needed to compare the different procedures with their gold standard, in order to establish these results consistently.

[[Is it necessary to perform a central lymphodissection in highly differentiated iviicrocarcinoiva of thyroid gland?].

PubMed

Zavgorodniy, S N; Danilyuk, M B; Rylov, A I; Dolya, O S

2016-08-01

The rate of the highly differentiated thyroid microcarcinoma methastasizing in central (6th) group of cervical lymph nodes was studied. In the clinic in 2013 - 2015 yrs 62 patients were operated for primary thyroid microcarcinoma. In accordance to TNM (UICC, AJCC, 2009) classification, papillary cancer in stage TlaNOMO was diagnosed in 35 (56.5%) patients, T1aN1MO - in 22 (35.5%); follicular cancer stage T1aNOMO - in 2 (3.2%); papillary cancer, follicular variant in stage T1aN1 MO - in 2 (3.2%); follicu- lar cancer, papillary variant in stage T1aNOMO - in 1 (1.6%). In 8 (12.9%) patients intraorgan multifocal metastasizing into contralateral thyroid lobe was revealed. In accordance to morphological investigation date of the excised samples, in 24 (38.7%) patients the metastases into the 6th group lymph nodes were revealed. In 4 (16.7%) patients, to whom lateral cervical lymphodissection was done, metastases in 2 - 5th groups of lymph nodes on the thyroid affection side were revealed.

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

PubMed Central

Carmi, Shai; Hui, Ken Y.; Kochav, Ethan; Liu, Xinmin; Xue, James; Grady, Fillan; Guha, Saurav; Upadhyay, Kinnari; Ben-Avraham, Dan; Mukherjee, Semanti; Bowen, B. Monica; Thomas, Tinu; Vijai, Joseph; Cruts, Marc; Froyen, Guy; Lambrechts, Diether; Plaisance, Stéphane; Van Broeckhoven, Christine; Van Damme, Philip; Van Marck, Herwig; Barzilai, Nir; Darvasi, Ariel; Offit, Kenneth; Bressman, Susan; Ozelius, Laurie J.; Peter, Inga; Cho, Judy H.; Ostrer, Harry; Atzmon, Gil; Clark, Lorraine N.; Lencz, Todd; Pe’er, Itsik

2014-01-01

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum. PMID:25203624

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

PubMed Central

Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

2017-01-01

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

Gene and environment interaction: is the differential susceptibility hypothesis relevant for obesity?

PubMed Central

Dalle Molle, Roberta; Fatemi, Hajar; Dagher, Alain; Levitan, Robert D.; Silveira, Patricia P.; Dubé, Laurette

2017-01-01

The differential susceptibility model states that a given genetic variant is associated with an increased risk of pathology in negative environments but greater than average resilience in enriched ones. While this theory was first implemented in psychiatric-genetic research, it may also help us to unravel the complex ways that genes and environments interact to influence feeding behavior and obesity. We reviewed evidence on gene vs. environment interactions that influence obesity development, aiming to support the applicability of the differential susceptibility model for this condition, and propose that various environmental “layers” relevant for human development should be considered when bearing the differential susceptibility model in mind. Mother-child relationship, socioeconomic status and individual's response are important modifiers of BMI and food intake when interacting with gene variants, “for better and for worse”. While only a few studies to date have investigated obesity outcomes using this approach, we propose that the differential susceptibility hypothesis is in fact highly applicable to the study of genetic and environmental influences on feeding behavior and obesity risk. PMID:28024828

Study of the S427G polymorphism and of MYBL2 variants in patients with acute myeloid leukemia.

PubMed

Dolz, Sandra; García, Paloma; Llop, Marta; Fuster, Óscar; Luna, Irene; Ibáñez, Mariam; Gómez, Inés; López, María; Such, Esperanza; Cervera, José; Sanz, Miguel A; De Juan, Inmaculada; Palanca, Sarai; Murria, Rosa; Bolufer, Pascual; Barragán, Eva

2015-06-19

Dysregulation of MYBL2 has been associated to tumorigenesis and the S427G polymorphism could induce partial inactivation of MYBL2, associating it with cancer risk. It has previously been shown that MYBL2 was over-expressed in some acute myeloid leukemias (AML), portending poor prognosis. However, to date no studies have investigated the S427G or other genetic variants of MYBL2 in AML. This study analyzed the S427G in 197 AML patients and 179 controls and screened the MYBL2 sequence in patients. In contrast to other studies in solid tumors, the S427G was not associated with the incidence of AML. This study detected four unannotated genetic alterations, of which the Q67X could be involved in MYBL2 dysfunction. Eight polymorphisms were identified, among which the rs73116571, located in a splicing region, was associated with higher incidence in AML and weaker MYBL2 expression, suggesting pre-disposition to AML. Additional functional studies should be performed to verify these genetic variations as possible targets in AML.

Osteogenesis Imperfecta: A Review with Clinical Examples

PubMed Central

van Dijk, F.S.; Cobben, J.M.; Kariminejad, A.; Maugeri, A.; Nikkels, P.G.J.; van Rijn, R.R.; Pals, G.

2011-01-01

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the ‘Sillence classification’), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI. PMID:22570641

Variation in the ovine MYF5 gene and its effect on carcass lean meat yield in New Zealand Romney sheep.

PubMed

Wang, Jiqing; Zhou, Huitong; Forrest, Rachel H J; Hu, Jiang; Liu, Xiu; Li, Shaobin; Luo, Yuzhu; Hickford, Jon G H

2017-09-01

Myogenic factor 5 (MYF5) plays an important role in regulating skeletal muscle, but to date there have been no reports on whether the gene is variable and whether this variation is associated with meat yield in sheep. In this study, four variants (A to D) of ovine MYF5 containing two Single Nucleotide Polymorphisms (SNPs) and one basepair (bp) insertion/deletion were detected by Polymerase Chain Reaction - Single Stranded Conformational Polymorphism (PCR-SSCP) analysis. Breed differences in variant frequencies were observed. The effect of variation in ovine MYF5 on lean meat yield, predicted using VIAScan® technology, was investigated in 388 male NZ Romney lambs. Only genotypes AA and AB were found in these lambs. Lambs with genotype AA had a higher leg yield (P=0.044), loin yield (P=0.002) and total yield (P=0.012) than those with genotype AB. No association with shoulder yield was detected. These results suggest that ovine MYF5 may be a valuable genetic marker for improved lean meat yield. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

PubMed Central

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fred; Schildkraut, Joellen; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Olama, Ali Amin Al; Berndt, Sonja I; Giovannucci, Edward; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter; Goode, Ellen L.; Permuth, Jennifer; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma’en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

2016-01-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. PMID:27197191

Genetic and Environmental Factors Associated with Cannabis Involvement

PubMed Central

Bogdan, Ryan; Winstone, Jonathan MA; Agrawal, Arpana

2016-01-01

Approximately 50-70% of the variation in cannabis use and use disorders can be attributed to heritable factors. For cannabis use, the remaining variance can be parsed in to familial and person-specific environmental factors while for use disorders, only the latter contribute. While numerous candidate gene studies have identified the role of common variation influencing liability to cannabis involvement, replication has been elusive. To date, no genomewide association study has been sufficiently powered to identify significant loci. Despite this, studies adopting polygenic techniques and integrating genetic variation with neural phenotypes and measures of environmental risk, such as childhood adversity, are providing promising new leads. It is likely that the small effect sizes associated with variants related to cannabis involvement will only be robustly identified in substantially larger samples. Results of such large-scale efforts will provide valuable single variant targets for translational research in neurogenetic, pharmacogenetic and non-human animal models as well as polygenic risk indices that can be used to explore a host of other genetic hypotheses related to cannabis use and misuse. PMID:27642547

The Association Between Limited English Proficiency and Unplanned Emergency Department Revisit Within 72 Hours.

PubMed

Ngai, Ka Ming; Grudzen, Corita R; Lee, Roy; Tong, Vicky Y; Richardson, Lynne D; Fernandez, Alicia

2016-08-01

Language barriers are known to negatively affect many health outcomes among limited English proficiency patient populations, but little is known about the quality of care such patients receive in the emergency department (ED). This study seeks to determine whether limited English proficiency patients experience different quality of care than English-speaking patients in the ED, using unplanned revisit within 72 hours as a surrogate quality indicator. We conducted a retrospective cohort study in an urban adult ED in 2012, with a total of 41,772 patients and 56,821 ED visits. We compared 2,943 limited English proficiency patients with 38,829 English-speaking patients presenting to the ED after excluding patients with psychiatric complaints, altered mental status, and nonverbal states, and those with more than 4 ED visits in 12 months. Two main outcomes-the risk of inpatient admission from the ED and risk of unplanned ED revisit within 72 hours-were measured with odds ratios from generalized estimating equation multivariate models. Limited English proficiency patients were more likely than English speakers to be admitted (32.0% versus 27.2%; odds ratio [OR]=1.20; 95% confidence interval [CI] 1.11 to 1.30). This association became nonsignificant after adjustments (OR=1.04; 95% CI 0.95 to 1.15). Included in the analysis of ED revisit within 72 hours were 32,857 patients with 45,546 ED visits; 4.2% of all patients (n=1,380) had at least 1 unplanned revisit. Limited English proficiency patients were more likely than English speakers to have an unplanned revisit (5.0% versus 4.1%; OR=1.19; 95% CI 1.02 to 1.45). This association persisted (OR=1.24; 95% CI 1.02 to 1.53) after adjustment for potential confounders, including insurance status. We found no difference in hospital admission rates between limited English proficiency patients and English-speaking patients. Yet limited English proficiency patients were 24% more likely to have an unplanned ED revisit within 72 hours, with an absolute difference of 0.9%, suggesting challenges in ED quality of care. Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

The presence of nuclear families in prehistoric collective burials revisited: the bronze age burial of Montanissell Cave (Spain) in the light of aDNA.

PubMed

Simón, Marc; Jordana, Xavier; Armentano, Nuria; Santos, Cristina; Díaz, Nancy; Solórzano, Eduvigis; López, Joan B; González-Ruiz, Mercedes; Malgosa, Assumpció

2011-11-01

Ancient populations have commonly been thought to have lived in small groups where extreme endogamy was the norm. To contribute to this debate, a genetic analysis has been carried out on a collective burial with eight primary inhumations from Montanissell Cave in the Catalan pre-Pyrenees. Radiocarbon dating clearly placed the burial in the Bronze Age, around 3200 BP. The composition of the group-two adults (one male, one female), one young woman, and five children from both sexes-seemed to represent the structure of a typical nuclear family. The genetic evidence proves this assumption to be wrong. In fact, at least five out of the eight mitochondrial haplotypes were different, denying the possibility of a common maternal ancestor for all of them. Nevertheless, 50% of the inhumations shared haplogroup J, so the possibility of a maternal relationship cannot be ruled out. Actually, combining different analyses performed using ancient and living populations, the probability of having four related J individuals in Montanissell Cave would range from 0.9884 to 0.9999. Owing to the particularities of this singular collective burial (small number of bodies placed altogether in a hidden cave, the evidence of non-simultaneous interments, close dating and unusual grave goods), we suggest that it might represent a small group with a patrilocal mating system. Copyright © 2011 Wiley-Liss, Inc.

Revisiting the Role of Organizational Effectiveness in Educational Evaluation.

ERIC Educational Resources Information Center

Lotto, Linda S.

Organizational effectiveness ought to play a role in educational evaluation, and the development of alternative perspectives for viewing organizations could be a starting point for revisiting organizational evaluation in education. Five possible perspectives and criteria for evaluating organizations have been developed. If an organization is…

Colloquial Hebrew Imperatives Revisited

ERIC Educational Resources Information Center

Bolozky, Shmuel

2009-01-01

In revisiting Bolozky's [Bolozky, Shmuel, 1979. "On the new imperative in colloquial Hebrew." "Hebrew Annual Review" 3, 17-24] and Bat-El's [Bat-El, Outi, 2002. "True truncation in colloquial Hebrew imperatives." "Language" 78(4), 651-683] analyses of colloquial Hebrew imperatives, the article argues for restricting Imperative Truncation to the…

Transformation of Learning in Education and Training: Key Qualifications Revisited. CEDEFOP Reference Series.

ERIC Educational Resources Information Center

Kamarainen, Pekka, Ed.; Attwell, Graham, Ed.; Brown, Alan, Ed.

This book contains 15 papers examining European approaches to the theme of key qualifications. The following papers are included: "Key Qualifications Revisited: An Introduction" (Pekka Kamarainen); "Exploring Key Qualifications: Context, Theory, and Practice in Europe" (Pekka Kamarainen); "Rethinking Key Qualifications:…

The Importance of Being a Complement: CED Effects Revisited

ERIC Educational Resources Information Center

Jurka, Johannes

2010-01-01

This dissertation revisits subject island effects (Ross 1967, Chomsky 1973) cross-linguistically. Controlled acceptability judgment studies in German, English, Japanese and Serbian show that extraction out of specifiers is consistently degraded compared to extraction out of complements, indicating that the Condition on Extraction domains (CED,…

Revisiting separation properties of convex fuzzy sets

USDA-ARS?s Scientific Manuscript database

Separation of convex sets by hyperplanes has been extensively studied on crisp sets. In a seminal paper separability and convexity are investigated, however there is a flaw on the definition of degree of separation. We revisited separation on convex fuzzy sets that have level-wise (crisp) disjointne...

Moral Judgment Development across Cultures: Revisiting Kohlberg's Universality Claims

ERIC Educational Resources Information Center

Gibbs, John C.; Basinger, Karen S.; Grime, Rebecca L.; Snarey, John R.

2007-01-01

This article revisits Kohlberg's cognitive developmental claims that stages of moral judgment, facilitative processes of social perspective-taking, and moral values are commonly identifiable across cultures. Snarey [Snarey, J. (1985). "The cross-cultural universality of social-moral development: A critical review of Kohlbergian research."…

Co-expression networks reveal the tissue-specific regulation of transcription and splicing

PubMed Central

Saha, Ashis; Kim, Yungil; Gewirtz, Ariel D.H.; Jo, Brian; Gao, Chuan; McDowell, Ian C.; Engelhardt, Barbara E.

2017-01-01

Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues. PMID:29021288

A coupled in vitro/in vivo approach for engineering a heterologous type III PKS to enhance polyketide biosynthesis in Saccharomyces cerevisiae.

PubMed

Vickery, Christopher R; Cardenas, Javier; Bowman, Marianne E; Burkart, Michael D; Da Silva, Nancy A; Noel, Joseph P

2018-06-01

Polyketides are attractive compounds for uses ranging from biorenewable chemical precursors to high-value therapeutics. In many cases, synthesis in a heterologous host is required to produce these compounds in industrially relevant quantities. The type III polyketide synthase 2-pyrone synthase (2-PS) from Gerbera hybrida was used for the production of triacetic acid lactone (TAL) in Saccharomyces cerevisiae. Initial in vitro characterization of 2-PS led to the identification of active site variants with improved kinetic properties relative to wildtype. Further in vivo evaluation in S. cerevisiae suggested certain 2-PS mutations altered enzyme stability during fermentation. In vivo experiments also revealed beneficial cysteine to serine mutations that were not initially explored due to their distance from the active site of 2-PS, leading to the design of additional 2-PS enzymes. While these variants showed varying catalytic efficiencies in vitro, they exhibited up to 2.5-fold increases in TAL production when expressed in S. cerevisiae. Coupling of the 2-PS variant [C35S,C372S] to an engineered S. cerevisiae strain led to over 10 g/L TAL at 38% of theoretical yield following fed-batch fermentation, the highest reported to date. Our studies demonstrate the success of a coupled in vitro/in vivo approach to engineering enzymes and provide insight on cysteine-rich enzymes and design principles toward their use in non-native microbial hosts. © 2018 Wiley Periodicals, Inc.

Understanding the molecular basis of the high oxygen affinity variant human hemoglobin Coimbra.

PubMed

Jorge, S E; Bringas, M; Petruk, A A; Arrar, M; Marti, M A; Skaf, M S; Costa, F F; Capece, L; Sonati, M F; Estrin, D

2018-01-01

Human hemoglobin (Hb) Coimbra (βAsp99Glu) is one of the seven βAsp99 Hb variants described to date. All βAsp99 substitutions result in increased affinity for O 2 and decreased heme-heme cooperativity and their carriers are clinically characterized by erythrocytocis, caused by tissue hypoxia. Since βAsp99 plays an important role in the allosteric α1β2 interface and the mutation in Hb Coimbra only represents the insertion of a CH 2 group in this interface, the present study of Hb Coimbra is important for a better understanding of the global impact of small modifications in this allosteric interface. We carried out functional, kinetic and dynamic characterization of this hemoglobin, focusing on the interpretation of these results in the context of a growth of the position 99 side chain length in the α1β2 interface. Oxygen affinity was evaluated by measuring p50 values in distinct pHs (Bohr effect), and the heme-heme cooperativity was analyzed by determining the Hill coefficient (n), in addition to the effect of the allosteric effectors inositol hexaphosphate (IHP) and 2,3-bisphosphoglyceric acid (2,3-BPG). Computer simulations revealed a stabilization of the R state in the Coimbra variant with respect to the wild type, and consistently, the T-to-R quaternary transition was observed on the nanosecond time scale of classical molecular dynamics simulations. Copyright © 2017 Elsevier Inc. All rights reserved.

Ribosomal DNA Organization Before and After Magnification in Drosophila melanogaster

PubMed Central

Bianciardi, Alessio; Boschi, Manuela; Swanson, Ellen E.; Belloni, Massimo; Robbins, Leonard G.

2012-01-01

In all eukaryotes, the ribosomal RNA genes are stably inherited redundant elements. In Drosophila melanogaster, the presence of a Ybb− chromosome in males, or the maternal presence of the Ribosomal exchange (Rex) element, induces magnification: a heritable increase of rDNA copy number. To date, several alternative classes of mechanisms have been proposed for magnification: in situ replication or extra-chromosomal replication, either of which might act on short or extended strings of rDNA units, or unequal sister chromatid exchange. To eliminate some of these hypotheses, none of which has been clearly proven, we examined molecular-variant composition and compared genetic maps of the rDNA in the bb2 mutant and in some magnified bb+ alleles. The genetic markers used are molecular-length variants of IGS sequences and of R1 and R2 mobile elements present in many 28S sequences. Direct comparison of PCR products does not reveal any particularly intensified electrophoretic bands in magnified alleles compared to the nonmagnified bb2 allele. Hence, the increase of rDNA copy number is diluted among multiple variants. We can therefore reject mechanisms of magnification based on multiple rounds of replication of short strings. Moreover, we find no changes of marker order when pre- and postmagnification maps are compared. Thus, we can further restrict the possible mechanisms to two: replication in situ of an extended string of rDNA units or unequal exchange between sister chromatids. PMID:22505623

Rationally evolving tRNAPyl for efficient incorporation of noncanonical amino acids

PubMed Central

Fan, Chenguang; Xiong, Hai; Reynolds, Noah M.; Söll, Dieter

2015-01-01

Genetic encoding of noncanonical amino acids (ncAAs) into proteins is a powerful approach to study protein functions. Pyrrolysyl-tRNA synthetase (PylRS), a polyspecific aminoacyl-tRNA synthetase in wide use, has facilitated incorporation of a large number of different ncAAs into proteins to date. To make this process more efficient, we rationally evolved tRNAPyl to create tRNAPyl-opt with six nucleotide changes. This improved tRNA was tested as substrate for wild-type PylRS as well as three characterized PylRS variants (Nϵ-acetyllysyl-tRNA synthetase [AcKRS], 3-iodo-phenylalanyl-tRNA synthetase [IFRS], a broad specific PylRS variant [PylRS-AA]) to incorporate ncAAs at UAG codons in super-folder green fluorescence protein (sfGFP). tRNAPyl-opt facilitated a 5-fold increase in AcK incorporation into two positions of sfGFP simultaneously. In addition, AcK incorporation into two target proteins (Escherichia coli malate dehydrogenase and human histone H3) caused homogenous acetylation at multiple lysine residues in high yield. Using tRNAPyl-opt with PylRS and various PylRS variants facilitated efficient incorporation of six other ncAAs into sfGFP. Kinetic analyses revealed that the mutations in tRNAPyl-opt had no significant effect on the catalytic efficiency and substrate binding of PylRS enzymes. Thus tRNAPyl-opt should be an excellent replacement of wild-type tRNAPyl for future ncAA incorporation by PylRS enzymes. PMID:26250114

A ghrelin gene variant may predict crossover rate from restricting-type anorexia nervosa to other phenotypes of eating disorders: a retrospective survival analysis.

PubMed

Ando, Tetsuya; Komaki, Gen; Nishimura, Hiroki; Naruo, Tetsuro; Okabe, Kenjiro; Kawai, Keisuke; Takii, Masato; Oka, Takakazu; Kodama, Naoki; Nakamoto, Chiemi; Ishikawa, Toshio; Suzuki-Hotta, Mari; Minatozaki, Kazunori; Yamaguchi, Chikara; Nishizono-Maher, Aya; Kono, Masaki; Kajiwara, Sohei; Suematsu, Hiroyuki; Tomita, Yuichiro; Ebana, Shoichi; Okamoto, Yuri; Nagata, Katsutaro; Nakai, Yoshikatsu; Koide, Masanori; Kobayashi, Nobuyuki; Kurokawa, Nobuo; Nagata, Toshihiko; Kiriike, Nobuo; Takenaka, Yoshito; Nagamine, Kiyohide; Ookuma, Kazuyoshi; Murata, Shiho

2010-08-01

Patients with anorexia nervosa restricting type (AN-R) often develop bulimic symptoms and crossover to AN-binge eating/purging type (AN-BP), or to bulimia nervosa (BN). We have reported earlier that genetic variants of an orexigenic peptide ghrelin are associated with BN. Here, the relationship between a ghrelin gene variant and the rate of change from AN-R to other phenotypes of eating disorders (EDs) was investigated. Participants were 165 patients with ED, initially diagnosed as AN-R. The dates of their AN-R onset and changes in diagnosis to other subtypes of ED were investigated retrospectively. Ghrelin gene 3056 T-->C SNP (single nucleotide polymorphism) was genotyped. Probability and hazard ratios were analyzed using life table analysis and Cox's proportional hazard regression model, in which the starting point was the time of AN-R onset and the outcome events were the time of (i) onset of binge eating, that is, when patients changed to binge eating AN and BN and (ii) recovery of normal weight, that is, when patients changed to BN or remission. Patients with the TT genotype at 3056 T-->C had a higher probability and hazard ratio for recovery of normal weight. The ghrelin SNP was not related with the onset of binge eating. The 3056 T-->C SNP of the ghrelin gene is related to the probability and the rate of recovery of normal body weight from restricting-type AN.

Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families.

PubMed

Martin-Merida, Inmaculada; Aguilera-Garcia, Domingo; Jose, Patricia Fernandez-San; Blanco-Kelly, Fiona; Zurita, Olga; Almoguera, Berta; Garcia-Sandoval, Blanca; Avila-Fernandez, Almudena; Arteche, Ana; Minguez, Pablo; Carballo, Miguel; Corton, Marta; Ayuso, Carmen

2018-05-01

To provide a comprehensive overview of the molecular basis of autosomal dominant retinitis pigmentosa (adRP) in Spanish families. Thus, we established the molecular characterization rate, gene prevalence, and mutational spectrum in the largest European cohort reported to date. A total of 258 unrelated Spanish families with a clinical diagnosis of RP and suspected autosomal dominant inheritance were included. Clinical diagnosis was based on complete ophthalmologic examination and family history. Retrospective and prospective analysis of Spanish adRP families was carried out using a combined strategy consisting of classic genetic techniques and next-generation sequencing (NGS) for single-nucleotide variants and copy number variation (CNV) screening. Overall, 60% of our families were genetically solved. Interestingly, 3.1% of the cohort carried pathogenic CNVs. Disease-causing variants were found in an autosomal dominant gene in 55% of the families; however, X-linked and autosomal recessive forms were also identified in 3% and 2%, respectively. Four genes (RHO, PRPF31, RP1, and PRPH2) explained up to 62% of the solved families. Missense changes were most frequently found in adRP-associated genes; however, CNVs represented a relevant disease cause in PRPF31- and CRX-associated forms. Implementation of NGS technologies in the adRP study clearly increased the diagnostic yield compared with classic approaches. Our study outcome expands the spectrum of disease-causing variants, provides accurate data on mutation gene prevalence, and highlights the implication of CNVs as important contributors to adRP etiology.

Exome sequencing is an efficient tool for variant late-infantile neuronal ceroid lipofuscinosis molecular diagnosis.

PubMed

Patiño, Liliana Catherine; Battu, Rajani; Ortega-Recalde, Oscar; Nallathambi, Jeyabalan; Anandula, Venkata Ramana; Renukaradhya, Umashankar; Laissue, Paul

2014-01-01

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease.

Ostreid herpesvirus type 1 genomic diversity in wild populations of Pacific oyster Crassostrea gigas from Italian coasts.

PubMed

Burioli, E A V; Prearo, M; Riina, M V; Bona, M C; Fioravanti, M L; Arcangeli, G; Houssin, M

2016-06-01

Ostreid herpesvirus 1 (OsHV-1) is a significant pathogen affecting the young Pacific oyster Crassostrea gigas, worldwide. A new variant, OsHV-1 μVar, has been associated with recurrent mortality events in Europe since 2008. Epidemiological data collection is key for global risk assessment; however little is known about health status and genotypes present in European wild oyster beds. Most studies to date have involved only cultivated individuals during mortality events, and reported low genotype diversity. With this study, conducted along the Italian coasts, we investigated for the first time the presence of OsHV-1 in European natural oyster beds. Analysis of three genomic regions revealed the presence of at least nine different genotypes, including two variants close to the OsHV-1 reference, known since the early 1990s but with no European record reported since 2010, and highlights relevant genotype diversity in natural environment. Phylogenetic analysis distinguished two distinct clusters and geographical distribution of genotypes, with the exception of a variant very closely related to the μVar, which appeared the single genotype present in all the Adriatic sites. Interestingly, these wild symptom free populations could represent, in Europe, an accessible alternative to the import of OsHV-1-resistant oyster strains from the East Pacific, the native area of C. gigas, avoiding the high-risk of non-native marine species and new pathogen introductions. Copyright © 2016 Elsevier Inc. All rights reserved.

Facilitating Grade Acceleration: Revisiting the Wisdom of John Feldhusen

ERIC Educational Resources Information Center

Culross, Rita R.; Jolly, Jennifer L.; Winkler, Daniel

2013-01-01

This article revisits the 1986 Feldhusen, Proctor, and Black recommendations on grade skipping. These recommendations originally appeared as 12 guidelines. In this article, the guidelines are grouped into three general categories: how to screen accelerant candidates, how to engage with the adults in the acceleration process (e.g., teachers,…

Revisiting Individual Creativity Assessment: Triangulation in Subjective and Objective Assessment Methods

ERIC Educational Resources Information Center

Park, Namgyoo K.; Chun, Monica Youngshin; Lee, Jinju

2016-01-01

Compared to the significant development of creativity studies, individual creativity research has not reached a meaningful consensus regarding the most valid and reliable method for assessing individual creativity. This study revisited 2 of the most popular methods for assessing individual creativity: subjective and objective methods. This study…

Children's Social Play Sequence: Parten's Classic Theory Revisited

ERIC Educational Resources Information Center

Xu, Yaoying

2010-01-01

The purpose of this article is to revisit Parten's study on social play from cultural, environmental, social and economic aspects. Young children's social play is viewed as a critical means to foster and enhance language, cognitive, social and emotional development. Social play theory has been predominately viewed from developmental perspectives.…

Threshold Concepts and Student Engagement: Revisiting Pedagogical Content Knowledge

ERIC Educational Resources Information Center

Zepke, Nick

2013-01-01

This article revisits the notion that to facilitate quality learning requires teachers in higher education to have pedagogical content knowledge. It constructs pedagogical content knowledge as a teaching and learning space that brings content and pedagogy together. On the content knowledge side, it suggests that threshold concepts, akin to a…

DNA as Genetic Material: Revisiting Classic Experiments through a Simple, Practical Class

ERIC Educational Resources Information Center

Malago, Wilson, Jr.; Soares-Costa, Andrea; Henrique-Silva, Flavio

2009-01-01

In 1928, Frederick Griffith demonstrated a transmission process of genetic information by transforming "Pneumococcus". In 1944, Avery et al. demonstrated that Griffith's transforming principle was DNA. We revisited these classic experiments in a practical class for undergraduate students. Both experiments were reproduced in simple, adapted forms.…

Atmospheric Entry Heating of Micrometeorites Revisited: Higher Temperatures and Potential Biases

NASA Technical Reports Server (NTRS)

Love, S.; Alexander, C. M. OD.

2001-01-01

The atmospheric entry heating model of Love and Brownlee appears to have overestimated evaporation rates by as much as two orders of magnitude. Here we revisit the issue of atmospheric entry heating, using a revised prescription for evaporation rates. Additional information is contained in the original extended abstract.

The Rotating Morse-Pekeris Oscillator Revisited

ERIC Educational Resources Information Center

Zuniga, Jose; Bastida, Adolfo; Requena, Alberto

2008-01-01

The Morse-Pekeris oscillator model for the calculation of the vibration-rotation energy levels of diatomic molecules is revisited. This model is based on the realization of a second-order exponential expansion of the centrifugal term about the minimum of the vibrational Morse oscillator and the subsequent analytical resolution of the resulting…

Revisiting Constructivist Teaching Methods in Ontario Colleges Preparing for Accreditation

ERIC Educational Resources Information Center

Schultz, Rachel A.

2015-01-01

At the time of writing, the first community colleges in Ontario were preparing for transition to an accreditation model from an audit system. This paper revisits constructivist literature, arguing that a more pragmatic definition of constructivism effectively blends positivist and interactionist philosophies to achieve both student centred…

Revisiting Interpretation of Canonical Correlation Analysis: A Tutorial and Demonstration of Canonical Commonality Analysis

ERIC Educational Resources Information Center

Nimon, Kim; Henson, Robin K.; Gates, Michael S.

2010-01-01

In the face of multicollinearity, researchers face challenges interpreting canonical correlation analysis (CCA) results. Although standardized function and structure coefficients provide insight into the canonical variates produced, they fall short when researchers want to fully report canonical effects. This article revisits the interpretation of…

The Linguistic Repertoire Revisited

ERIC Educational Resources Information Center

Busch, Brigitta

2012-01-01

This article argues for the relevance of poststructuralist approaches to the notion of a linguistic repertoire and introduces the notion of language portraits as a basis for empirical study of the way in which speakers conceive and represent their heteroglossic repertoires. The first part of the article revisits Gumperz's notion of a linguistic…

Revisiting Professional Teacher Standards

ERIC Educational Resources Information Center

Watson, Amanda

2016-01-01

The Australian Society for Music Education's (ASME) involvement in the development of professional standards for music educators was a significant and active research time in the history of the Society. As ASME celebrates its golden jubilee, it is appropriate to revisit that history and consider the future prospects of subject-specific standards.…

Framing the Future: Revisiting the Place of Educational Expectations in Status Attainment

ERIC Educational Resources Information Center

Bozick, Robert; Alexander, Karl; Entwisle, Doris; Dauber, Susan; Kerr, Kerri

2010-01-01

This study revisits the Wisconsin model of status attainment from a life course developmental perspective. Fixed-effects regression analyses lend strong support to the Wisconsin framework's core proposition that academic performance and significant others' influence shape educational expectations. However, investigating the process of expectation…

Revisiting the Rhetorical Curriculum

ERIC Educational Resources Information Center

Rutten, Kris; Soetaert, Ronald

2012-01-01

The aim of the special strand on "Revisiting the rhetorical curriculum" is to explore the educational potential of a new rhetorical perspective, specifically in relation to different traditions within educational and rhetorical studies. This implies that we do not only look at education "in" rhetoric, but that we position education also "as" a…

The Best and the Rest: Revisiting the Norm of Normality of Individual Performance

ERIC Educational Resources Information Center

O'Boyle, Ernest, Jr.; Aguinis, Herman

2012-01-01

We revisit a long-held assumption in human resource management, organizational behavior, and industrial and organizational psychology that individual performance follows a Gaussian (normal) distribution. We conducted 5 studies involving 198 samples including 633,263 researchers, entertainers, politicians, and amateur and professional athletes.…

Commentary on "Distributed Revisiting: An Analytic for Retention of Coherent Science Learning"

ERIC Educational Resources Information Center

Hewitt, Jim

2015-01-01

The article, "Distributed Revisiting: An Analytic for Retention of Coherent Science Learning" is an interesting study that operates at the intersection of learning theory and learning analytics. The authors observe that the relationship between learning theory and research in the learning analytics field is constrained by several…

Genome-wide sequence variations between wild and cultivated tomato species revisited by whole genome sequence mapping.

PubMed

Sahu, Kamlesh Kumar; Chattopadhyay, Debasis

2017-06-02

Cultivated tomato (Solanum lycopersicum L.) is the second most important vegetable crop after potato and a member of thirteen interfertile species of Solanum genus. Domestication and continuous selection for desirable traits made cultivated tomato species susceptible to many stresses as compared to the wild species. In this study, we analyzed and compared the genomes of wild and cultivated tomato accessions to identify the genomic regions that encountered changes during domestication. Analysis was based on SNP and InDel mining of twentynine accessions of twelve wild tomato species and forty accessions of cultivated tomato. Percentage of common SNPs among the accessions within a species corresponded with the reproductive behavior of the species. SNP profiles of the wild tomato species within a phylogenetic subsection varied with their geographical distribution. Interestingly, the ratio of genic SNP to total SNPs increased with phylogenetic distance of the wild tomato species from the domesticated species, suggesting that variations in gene-coding region play a major role in speciation. We retrieved 2439 physical positions in 1594 genes including 32 resistance related genes where all the wild accessions possessed a common wild variant allele different from all the cultivated accessions studied. Tajima's D analysis predicted a very strong purifying selection associated with domestication in nearly 1% of its genome, half of which is contributed by chromosome 11. This genomic region with a low Tajima's D value hosts a variety of genes associated with important agronomic trait such as, fruit size, tiller number and wax deposition. Our analysis revealed a broad-spectrum genetic base in wild tomato species and erosion of that in cultivated tomato due to recurrent selection for agronomically important traits. Identification of the common wild variant alleles and the genomic regions undergoing purifying selection during cultivation would facilitate future breeding program by introgression from wild species.

Asexuality: an extreme variant of sexual desire disorder?

PubMed

Brotto, Lori A; Yule, Morag A; Gorzalka, Boris B

2015-03-01

Human asexuality is defined as a lack of sexual attraction to anyone or anything. Various theories have been proposed to explain how asexuality should best be classified, and some have maintained that asexuality is an extreme variant of hypoactive sexual desire disorder (HSDD)-a sexual dysfunction characterized by a lack of interest in sex and significant distress. To date, this has never been empirically examined. Using measures of sexual desire and behavior, sex-related distress, personality, and psychopathology, the aim of the current study was to compare individuals scoring above the cutoff for asexuality identification (AIS >40) (n = 192) to sexual individuals (n = 231). The sexual group was further divided into a control group (n = 122), a HSDD group (n = 50), and a group with symptoms of low desire that were nondistressing (n = 59). Analyses were controlled for age. Individuals in the AIS >40 group had a greater likelihood of never previously engaging in sexual intercourse, fantasies, or kissing and petting than all other groups and a lower likelihood of experiencing sex-related distress than those with HSDD. For women, those in the HSDD and AIS >40 groups had significantly lower desire than the subclinical HSDD and control groups. Men in the AIS >40 group had significantly lower desire than the other three groups. Symptoms of depression were highest among those with subclinical HSDD and HSDD, whereas there were no group differences on alexithymia or desirable responding. A binary logistic regression indicated that relationship status (long-term dating/married), sexual desire, sex-related distress, and lower alexithymia scores were the best predictors of group membership (HSDD vs. AIS >40). Taken together, these results challenge the speculation that asexuality should be classified as a sexual dysfunction of low desire. © 2014 International Society for Sexual Medicine.

Interim estimates of divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance (2010-2015) in Hangzhou, southeast of China.

PubMed

Li, Jun; Zhou, Yin-yan; Kou, Yu; Yu, Xin-fen; Zheng, Zhi-bei; Yang, Xu-hui; Wang, Hao-qiu

2015-11-01

In the post-pandemic period 2010-2015, seasonal influenza A(H3N2) virus predominated in Hangzhou, southeast of China, with an increased activity and semi-annual seasons. This study utilized HA virus gene segment sequences to analyze the divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance in Hangzhou. Virological and serological analyses of 124 representative A(H3N2) viruses from prospective studies of systematic surveillance samples were conducted to quantify the genetic and antigenic characteristics and their vaccine strain match. Bayesian phylogenetic inference showed that two separate subgroups 3C.3 and 3C.2 probably diverged from group 3C in early 2012 and then evolved into groups 3C.3a and 3C.2a, respectively, in the 2014/15 influenza season. Furthermore, high amino acid substitution rates of the HA1 subunit were found in A(H3N2) group 3C.2a variants, indicating that increased antigenic drift of A(H3N2) group 3C.2a virus is associated with a vaccine mismatch to the 2015/16 vaccine reference strain Switzerland/9715293/2013 (group 3C.3a). A portion of the group 3C.2a isolates are not covered by the current A(H3N2) vaccine strain. These findings offer insights into the emergence of group 3C.2a variants with epidemic potential in the imminent influenza seasons. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

PubMed

Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

2015-04-01

Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. © 2015 WILEY PERIODICALS, INC.

Mathematical models of radiation action on living cells: From the target theory to the modern approaches. A historical and critical review.

PubMed

Bodgi, Larry; Canet, Aurélien; Pujo-Menjouet, Laurent; Lesne, Annick; Victor, Jean-Marc; Foray, Nicolas

2016-04-07

Cell survival is conventionally defined as the capability of irradiated cells to produce colonies. It is quantified by the clonogenic assays that consist in determining the number of colonies resulting from a known number of irradiated cells. Several mathematical models were proposed to describe the survival curves, notably from the target theory. The Linear-Quadratic (LQ) model, which is to date the most frequently used model in radiobiology and radiotherapy, dominates all the other models by its robustness and simplicity. Its usefulness is particularly important because the ratio of the values of the adjustable parameters, α and β, on which it is based, predicts the occurrence of post-irradiation tissue reactions. However, the biological interpretation of these parameters is still unknown. Throughout this review, we revisit and discuss historically, mathematically and biologically, the different models of the radiation action by providing clues for resolving the enigma of the LQ model. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Future of Engineering Education--Revisited

ERIC Educational Resources Information Center

Wankat, Phillip C.; Bullard, Lisa G.

2016-01-01

This paper revisits the landmark CEE series, "The Future of Engineering Education," published in 2000 (available free in the CEE archives on the internet) to examine the predictions made in the original paper as well as the tools and approaches documented. Most of the advice offered in the original series remains current. Despite new…

Commentary: Revisiting "Guidelines for Using Technology to Prepare Social Studies Teachers"

ERIC Educational Resources Information Center

Hartshorne, Richard; Waring, Scott M.

2015-01-01

In Hicks, Lee, Berson, Bolick, and Diem (2014), the authors revisited and revised a series of principles focusing on the preparation of social studies teachers for using digital technologies in the classroom, originally presented in the inaugural issue of "Contemporary Issues in Technology and Teacher Education" (Mason et al., 2000).…

Applied Linguistics Redux: A Derridean Exploration of Alzheimer Lifehistories

ERIC Educational Resources Information Center

Ramanathan, Vaidehi

2008-01-01

Advocating a position of self-critique, whereby we revisit our old research sites to dis-assemble our prior thinking in relation to our current cognitions, this paper offers, among other things, a critical revisitation and Derridean interpretation of one of my previous long-term, ethnographic endeavours: my extended work with the memories and…

My First CMC Article Revisited: A Window on Spanish L2 Interlanguage

ERIC Educational Resources Information Center

Blake, Robert

2016-01-01

The computer-assisted language learning (CALL) field seems to change overnight with new technological affordances. Blake revisits his 2000 "LLT" article on computer-mediation communication (CMC) in order to reflect on how the field has examined this topic over the past decade or so. While the Interaction Hypothesis continues to guide…

Rigor Revisited: Scaffolding College Student Learning by Incorporating Their Lived Experiences

ERIC Educational Resources Information Center

Castillo-Montoya, Milagros

2018-01-01

This chapter explores how students' lived experiences contribute to the rigor of their thinking. Insights from research indicate faculty can enhance rigor by accounting for the many ways it may surface in the classroom. However, to see this type of rigor, we must revisit the way we conceptualize it for higher education.

Parentocracy Revisited: Still a Relevant Concept for Understanding Middle Class Educational Advantage?

ERIC Educational Resources Information Center

Barrett DeWiele, Corinne E.; Edgerton, Jason D.

2016-01-01

In this paper, we revisit Brown's ("Br J Soc Educ" 14: 65-85, 1990) concept of "parentocracy" which has been informatively applied in educational research in a number of studies in various countries internationally--but almost none in North America. We provide an expanded conceptualization of parentocracy and suggest that it…

Revisiting Learning in Higher Education--Framing Notions Redefined through an Ecological Perspective

ERIC Educational Resources Information Center

Damsa, Crina; Jornet, Alfredo

2016-01-01

This article employs an ecological perspective as a means of revisiting the notion of learning, with a particular focus on learning in higher education. Learning is reconceptualised as a process entailing mutually constitutive, epistemic, social and affective relations in which knowledge, identity and agency become collective achievements of whole…

Revisiting High School Conversions: What is Sustained After the Funding Goes?

ERIC Educational Resources Information Center

Wallach, Catherine A.

2009-01-01

School reformers hope that converting comprehensive high schools into collections of small schools will produce results similar to those realized in freestanding small schools. This comparative case study revisits two "conversions" as they complete the grant funding that supported the reform, in order to explore the extent to which…

Language Transmission Revisited: Family Type, Linguistic Environment and Language Attitudes

ERIC Educational Resources Information Center

Schupbach, Doris

2009-01-01

This article revisits factors in intergenerational language maintenance and shift within the family. It does so through an in-depth analysis of what 14 migrants to Australia from German-speaking Switzerland reported in written life stories and subsequent life story interviews. The participants represent four family types and a wide age range, and…

The Concept of Experience by John Dewey Revisited: Conceiving, Feeling and "Enliving"

ERIC Educational Resources Information Center

Hohr, Hansjorg

2013-01-01

"The concept of experience by John Dewey revisited: conceiving, feeling and 'enliving'." Dewey takes a few steps towards a differentiation of the concept of experience, such as the distinction between primary and secondary experience, or between ordinary (partial, raw, primitive) experience and complete, aesthetic experience. However, he does not…

Mentoring, Advocacy, and Leadership: Revisiting First-Year Student Advocate Award Recipients

ERIC Educational Resources Information Center

White, Michelle M.; Anttonen, Ralph G.

2007-01-01

This study revisited research on award-winning campus leaders who were effective change agents working on the behalf of first-year students (Anttonen & Chaskes, 2002). Participants were recipients of the "Outstanding First-Year Student Advocate Award" given annually by the National Resource Center for the First-Year Experience and Students in…

Teacher Communication Concerns Revisited: Calling into Question the Gnawing Pull towards Equilibrium

ERIC Educational Resources Information Center

Dannels, Deanna P.

2015-01-01

This study revisits the long-standing teacher communication concerns framework originating over three decades ago. Analysis of 10 years of contemporary GTA teacher communication concerns reveals a typology of 10 concerns, which taken together construct teaching as a process of negotiating relationships, managing identities, and focusing attention.…

Revisiting "Grutter" and "Gratz" in the Wake of "Fisher": Looking Back to Move Forward

ERIC Educational Resources Information Center

Ledesma, Maria C.

2013-01-01

This article revisits the University of Michigan's 2003 affirmative action cases, "Grutter v. Bollinger" and "Gratz v. Bollinger." Through the aid of critical textual analysis and critical race theory, the author looks back at the predominant narratives that framed the challenge to, and defense of, race-conscious affirmative…

Revisiting the Scale-Invariant, Two-Dimensional Linear Regression Method

ERIC Educational Resources Information Center

Patzer, A. Beate C.; Bauer, Hans; Chang, Christian; Bolte, Jan; Su¨lzle, Detlev

2018-01-01

The scale-invariant way to analyze two-dimensional experimental and theoretical data with statistical errors in both the independent and dependent variables is revisited by using what we call the triangular linear regression method. This is compared to the standard least-squares fit approach by applying it to typical simple sets of example data…

Revisiting the Age-Old Question: Does Money Matter in Education?

ERIC Educational Resources Information Center

Baker, Bruce D.

2012-01-01

This policy brief revisits the long and storied literature on whether money matters in providing a quality education. Increasingly, political rhetoric adheres to the unfounded certainty that money doesn't make a difference in education, and that reduced funding is unlikely to harm educational quality. Such proclamations have even been used to…

Revisiting Jack Goody to Rethink Determinisms in Literacy Studies

ERIC Educational Resources Information Center

Collin, Ross

2013-01-01

This article revisits Goody's arguments about literacy's influence on social arrangements, culture, cognition, economics, and other domains of existence. Whereas some of his arguments tend toward technological determinism (i.e., literacy causes change in the world), other of his arguments construe literacy as a force that shapes and is shaped by…

Revisiting Feminist Identity Development Theory, Research, and Practice

ERIC Educational Resources Information Center

Moradi, Bonnie; Subich, Linda Mezydlo; Phillips, Julia C.

2002-01-01

The model of feminist identity development proposed by Downing and Roush in 1985 is revisited as a potentially useful framework in counseling psychology theory, research, and practice. An examination of the historical context from which the model arose illustrates how it advanced theory in the psychology of women. A critical review of the extant…

A Feminist Revisit to the First-Year Curriculum.

ERIC Educational Resources Information Center

Bernstein, Anita

1996-01-01

A seminar at Chicago-Kent College of Law (Illinois) that reviews six first-year law school courses by focusing on feminist issues in course content and structure is described. The seminar functions as both a review and a shift in perspective. Courses revisited include civil procedure, contracts, criminal law, justice and the legal system,…

The Peter Effect Revisited: Reading Habits and Attitudes of College Students

ERIC Educational Resources Information Center

Applegate, Anthony J.; Applegate, Mary DeKonty; Mercantini, Martha A.; McGeehan, Catherine M.; Cobb, Jeanne B.; DeBoy, Joanne R.; Modla, Virginia B.; Lewinski, Kimberly E.

2014-01-01

Certainly a primary goal of literacy education is the creation of avid, enthusiastic, and highly motivated readers. However, in this article revisiting the Peter Effect (Applegate & Applegate, 2004), researchers surveyed more than 1,000 college sophomores and found strikingly low levels of enthusiasm for reading. Only 46.6% of surveyed…

A Hydrostatic Paradox Revisited

ERIC Educational Resources Information Center

Ganci, Salvatore

2012-01-01

This paper revisits a well-known hydrostatic paradox, observed when turning upside down a glass partially filled with water and covered with a sheet of light material. The phenomenon is studied in its most general form by including the mass of the cover. A historical survey of this experiment shows that a common misunderstanding of the phenomenon…

Revisiting Individualism and Collectivism: A Multinational Examination of Pre-Service Teachers' Perceptions on Student Academic Performances

ERIC Educational Resources Information Center

Jiang, Heng

2016-01-01

This study explores how pre-service teachers in Singapore, Hong Kong, Taiwan, and the United States perceive educational diversity in relation to students' academic achievement by means of qualitative content analysis. It takes cultural psychological perspectives to revisit the attribute reasoning embedded in individualist and collectivist…

Sunday School Revisited: An Alternative to Christian Education of the Church Today?

ERIC Educational Resources Information Center

Song, Nam Soon

2013-01-01

This article attempts to demonstrate similarities between the socioeconomic, cultural, and religious contexts of 18th-century England and 21st-century Canada. Revisiting the Sunday School movement in 18th-century England provides insights for the development of renewed Sunday School models in the current Canadian context of transnational…

Revisiting the Trust Effect in Urban Elementary Schools

ERIC Educational Resources Information Center

Adams, Curt M.; Forsyth, Patrick B.

2013-01-01

More than a decade after Goddard, Tschannen-Moran, and Hoy (2001) found that collective faculty trust in clients predicts student achievement in urban elementary schools, we sought to identify a plausible link for this relationship. Our purpose in revisiting the trust effect was twofold: (1) to test the main effect of collective faculty trust on…

Nucleotide polymorphism affecting FLC expression underpins heading date variation in horticultural brassicas.

PubMed

Irwin, Judith A; Soumpourou, Eleni; Lister, Clare; Ligthart, Jan-Dick; Kennedy, Sue; Dean, Caroline

2016-09-01

Variation in flowering time and response to overwintering has been exploited to breed brassica vegetables that can be harvested year-round. Our knowledge of flowering time control now enables the investigation of the molecular basis of this important variation. Here, we show that a major determinant of heading date variation in Brassica oleracea is from variation in vernalization response through allelic variation at FLOWERING LOCUS C.C2 (BoFLC4). We characterize two alleles of BoFLC.C2 that are both functional and confer a requirement for vernalization, but they show distinct expression dynamics in response to cold. Complementation experiments in Arabidopsis thaliana revealed that the allelic variation results from cis polymorphism at BoFLC.C2, which quantitatively influences the degree of cold-induced epigenetic silencing. This results in one allelic variant conferring consistently later heading under both glasshouse and field conditions through reduced environmental sensitivity. Our results suggest that breeding of brassica varieties for commercially valuable variation in heading date has been achieved through the selection of cis polymorphism at FLC, similar to that underpinning natural variation in A. thaliana. This understanding will allow for the selection of alleles with distinct sensitivities to cold and robust heading dates under variable climatic conditions, and will facilitate the breeding of varieties more resistant to climate change. © 2016 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

An analytic algorithm for global coverage of the revisiting orbit and its application to the CFOSAT satellite

NASA Astrophysics Data System (ADS)

Xu, Ming; Huang, Li

2014-08-01

This paper addresses a new analytic algorithm for global coverage of the revisiting orbit and its application to the mission revisiting the Earth within long periods of time, such as Chinese-French Oceanic Satellite (abbr., CFOSAT). In the first, it is presented that the traditional design methodology of the revisiting orbit for some imaging satellites only on the single (ascending or descending) pass, and the repeating orbit is employed to perform the global coverage within short periods of time. However, the selection of the repeating orbit is essentially to yield the suboptimum from the rare measure of rational numbers of passes per day, which will lose lots of available revisiting orbits. Thus, an innovative design scheme is proposed to check both rational and irrational passes per day to acquire the relationship between the coverage percentage and the altitude. To improve the traditional imaging only on the single pass, the proposed algorithm is mapping every pass into its ascending and descending nodes on the specified latitude circle, and then is accumulating the projected width on the circle by the field of view of the satellite. The ergodic geometry of coverage percentage produced from the algorithm is affecting the final scheme, such as the optimal one owning the largest percentage, and the balance one possessing the less gradient in its vicinity, and is guiding to heuristic design for the station-keeping control strategies. The application of CFOSAT validates the feasibility of the algorithm.

Revisit, Subsequent Hospitalization, Recurrent Fall, and Death Within 6 Months After a Fall Among Elderly Emergency Department Patients.

PubMed

Sri-On, Jiraporn; Tirrell, Gregory P; Bean, Jonathan F; Lipsitz, Lewis A; Liu, Shan W

2017-10-01

We seek to describe the risk during 6 months and specific risk factors for recurrent falls, emergency department (ED) revisits, subsequent hospitalizations, and death within 6 months after a fall-related ED presentation. This was a secondary analysis of a retrospective cohort of elderly fall patients who presented to the ED from one urban teaching hospital. We included patients aged 65 years and older who had an ED fall visit in 2012. We examined the frequency and risk factors of adverse events (composite of recurrent falls, ED revisits, subsequent hospitalization, and death, selected a priori) at 6 months. Our study included 350 older adults. Adverse events steadily increased, from 7.7% at 7 days, 21.4% at 30 days, and 50.3% at 6 months. Within 6 months, 22.6% of patients had at least one recurrent fall, 42.6% revisited the ED, 31.1% had subsequent hospitalizations, and 2.6% died. In multivariable logistic regression analysis, psychological or sedative drug use predicted recurrent falls, ED revisits, subsequent hospitalizations, and adverse events. More than half of fall patients had an adverse event within 6 months of presenting to the ED after a fall. The risk during 6 months of these adverse events increased with psychological or sedative drug use. Larger future studies should confirm this association and investigate methods to minimize recurrent falls through management of such medications. Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Estrogen-Related Receptor Alpha Modulates Lactate Dehydrogenase Activity in Thyroid Tumors

PubMed Central

Mirebeau-Prunier, Delphine; Le Pennec, Soazig; Jacques, Caroline; Fontaine, Jean-Fred; Gueguen, Naig; Boutet-Bouzamondo, Nathalie; Donnart, Audrey; Malthièry, Yves; Savagner, Frédérique

2013-01-01

Metabolic modifications of tumor cells are hallmarks of cancer. They exhibit an altered metabolism that allows them to sustain higher proliferation rates in hostile environment outside the cell. In thyroid tumors, the expression of the estrogen-related receptor α (ERRα), a major factor of metabolic adaptation, is closely related to the oxidative metabolism and the proliferative status of the cells. To elucidate the role played by ERRα in the glycolytic adaptation of tumor cells, we focused on the regulation of lactate dehydrogenases A and B (LDHA, LDHB) and the LDHA/LDHB ratio. Our study included tissue samples from 10 classical and 10 oncocytic variants of follicular thyroid tumors and 10 normal thyroid tissues, as well as samples from three human thyroid tumor cell lines: FTC-133, XTC.UC1 and RO82W-1. We identified multiple cis-acting promoter elements for ERRα, in both the LDHA and LDHB genes. The interaction between ERRα and LDH promoters was confirmed by chromatin immunoprecipitation assays and in vitro analysis for LDHB. Using knock-in and knock-out cellular models, we found an inverse correlation between ERRα expression and LDH activity. This suggests that thyroid tumor cells may reprogram their metabolic pathways through the up-regulation of ERRα by a process distinct from that proposed by the recently revisited Warburg hypothesis. PMID:23516535

Languages Support Efficient Communication about the Environment: Words for Snow Revisited

PubMed Central

Carstensen, Alexandra

2016-01-01

The claim that Eskimo languages have words for different types of snow is well-known among the public, but has been greatly exaggerated through popularization and is therefore viewed with skepticism by many scholars of language. Despite the prominence of this claim, to our knowledge the line of reasoning behind it has not been tested broadly across languages. Here, we note that this reasoning is a special case of the more general view that language is shaped by the need for efficient communication, and we empirically test a variant of it against multiple sources of data, including library reference works, Twitter, and large digital collections of linguistic and meteorological data. Consistent with the hypothesis of efficient communication, we find that languages that use the same linguistic form for snow and ice tend to be spoken in warmer climates, and that this association appears to be mediated by lower communicative need to talk about snow and ice. Our results confirm that variation in semantic categories across languages may be traceable in part to local communicative needs. They suggest moreover that despite its awkward history, the topic of “words for snow” may play a useful role as an accessible instance of the principle that language supports efficient communication. PMID:27073981

Structural and biochemical studies on ATP binding and hydrolysis by the Escherichia coli RNA chaperone Hfq.

PubMed

Hämmerle, Hermann; Beich-Frandsen, Mads; Večerek, Branislav; Rajkowitsch, Lukas; Carugo, Oliviero; Djinović-Carugo, Kristina; Bläsi, Udo

2012-01-01

In Escherichia coli the RNA chaperone Hfq is involved in riboregulation by assisting base-pairing between small regulatory RNAs (sRNAs) and mRNA targets. Several structural and biochemical studies revealed RNA binding sites on either surface of the donut shaped Hfq-hexamer. Whereas sRNAs are believed to contact preferentially the YKH motifs present on the proximal site, poly(A)(15) and ADP were shown to bind to tripartite binding motifs (ARE) circularly positioned on the distal site. Hfq has been reported to bind and to hydrolyze ATP. Here, we present the crystal structure of a C-terminally truncated variant of E. coli Hfq (Hfq(65)) in complex with ATP, showing that it binds to the distal R-sites. In addition, we revisited the reported ATPase activity of full length Hfq purified to homogeneity. At variance with previous reports, no ATPase activity was observed for Hfq. In addition, FRET assays neither indicated an impact of ATP on annealing of two model oligoribonucleotides nor did the presence of ATP induce strand displacement. Moreover, ATP did not lead to destabilization of binary and ternary Hfq-RNA complexes, unless a vast stoichiometric excess of ATP was used. Taken together, these studies strongly suggest that ATP is dispensable for and does not interfere with Hfq-mediated RNA transactions.

Craniofacial Duplication: A Case Report

PubMed Central

Suryawanshi, Pradeep; Deshpande, Mandar; Verma, Nitin; Mahendrakar, Vivek; Mahendrakar, Sandhya

2013-01-01

A craniofacial duplication or diprosopus is an unusual variant of conjoined twinning. The reported incidence is one in 180,000-15 million births and 35 cases have been reported till date. The phenotype is wide, with the partial duplication of a few facial structures to complete dicephalus. A complete duplication is associated with a high incidence of anomalies in the central nervous system, cardiovascular system, gastrointestinal system and the respiratory system, whereas no major anomalies are found in the infants with a partial duplication. A term baby with the features of a craniofacial duplication has been described, with the proposed theories on embryogenesis and a brief review of the literature. PMID:24179933

Craniofacial duplication: a case report.

PubMed

Suryawanshi, Pradeep; Deshpande, Mandar; Verma, Nitin; Mahendrakar, Vivek; Mahendrakar, Sandhya

2013-09-01

A craniofacial duplication or diprosopus is an unusual variant of conjoined twinning. The reported incidence is one in 180,000-15 million births and 35 cases have been reported till date. The phenotype is wide, with the partial duplication of a few facial structures to complete dicephalus. A complete duplication is associated with a high incidence of anomalies in the central nervous system, cardiovascular system, gastrointestinal system and the respiratory system, whereas no major anomalies are found in the infants with a partial duplication. A term baby with the features of a craniofacial duplication has been described, with the proposed theories on embryogenesis and a brief review of the literature.

Genetics of Temporal Lobe Epilepsy: A Review

PubMed Central

Salzmann, Annick; Malafosse, Alain

2012-01-01

Temporal lobe epilepsy (TLE) is usually regarded as a polygenic and complex disorder. To understand its genetic component, numerous linkage analyses of familial forms and association studies of cases versus controls have been conducted since the middle of the nineties. The present paper lists genetic findings for TLE from the initial segregation analysis to the most recent results published in May 2011. To date, no genes have been clearly related to TLE despite many efforts to do so. However, it is vital to continue replication studies and collaborative attempts to find significant results and thus determine which gene variant combination plays a definitive role in the aetiology of TLE. PMID:22957248

Cutaneous Squamous Cell Carcinoma.

PubMed

Parekh, Vishwas; Seykora, John T

2017-09-01

Cutaneous squamous cell carcinoma (cSCC) is a malignant neoplasm of the skin characterized by an aberrant proliferation of keratinocytes. Cutaneous SCC is the second most common malignancy globally, and usually arises in the chronically sun-damaged skin of elderly white individuals. From a pathologist's perspective, it is important to differentiate cSCC from the benign and reactive squamoproliferative lesions and identify the high-risk features associated with aggressive tumor behavior. In this article, we provide an up-to-date overview of cSCC along with its precursor lesions and important histologic variants, with a particular emphasis on the histopathologic features and molecular pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

75 FR 60611 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-01

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model A300 C4...; Model A300 B4-601, B4- 603, B4-620, B4-622, B4-605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F...-- Dated-- A300 series airplanes......... A300-32A0447..... April 22, 2004. A300 B4-600, B4-600R, and F4...

The H2A.Z/H2B dimer is unstable compared to the dimer containing the major H2A isoform.

PubMed

Placek, Brandon J; Harrison, L Nicole; Villers, Brooke M; Gloss, Lisa M

2005-02-01

The nucleosome, the basic fundamental repeating unit of chromatin, contains two H2A/H2B dimers and an H3/H4 tetramer. Modulation of the structure and dynamics of the nucleosome is an important regulation mechanism of DNA-based chemistries in the eukaryotic cell, such as transcription and replication. One means of altering the properties of the nucleosome is by incorporation of histone variants. To provide insights into how histone variants may impact the thermodynamics of the nucleosome, the stability of the heterodimer between the H2A.Z variant and H2B was determined by urea-induced denaturation, monitored by far-UV circular dichroism, intrinsic Tyr fluorescence intensity, and anisotropy. In the absence of stabilizing agents, the H2A.Z/H2B dimer is only partially folded. The stabilizing cosolute, trimethylamine-N-oxide (TMAO) was used to promote folding of the unstable heterodimer. The equilibrium stability of the H2A.Z/H2B dimer is compared to that of the H2A/H2B dimer. The equilibrium folding of both histone dimers is highly reversible and best described by a two-state model, with no detectable equilibrium intermediates populated. The free energies of unfolding, in the absence of denaturant, of H2A.Z/H2B and H2A/H2B are 7.3 kcal mol(-1) and 15.5 kcal mol(-1), respectively, in 1 M TMAO. The H2A.Z/H2B dimer is the least stable histone fold characterized to date, while H2A/H2B appears to be the most stable. It is speculated that this difference in stability may contribute to the different biophysical properties of nucleosomes containing the major H2A and the H2A.Z variant.

Melanocortin-4 receptor pathway dysfunction in obesity: Patient stratification aimed at MC4R agonist treatment.

PubMed

Ayers, Kristin L; Glicksberg, Benjamin S; Garfield, Alastair S; Longerich, Simonne; White, Joseph A; Yang, Pengwei; Du, Lei; Chittenden, Thomas W; Gulcher, Jeffery R; Roy, Sophie; Fiedorek, Fred; Gottesdiener, Keith; Cohen, Sarah; North, Kari E; Schadt, Eric E; Li, Shuyu D; Chen, Rong; Van der Ploeg, Lex H T

2018-05-02

The hypothalamic melanocortin 4 receptor (MC4R)-pathway serves a critical role in regulating bodyweight. Loss of function (LoF) mutations in the MC4R pathway including mutations in the POMC (1), PCSK1, LEPR (2) or the MC4R genes (3) have been shown to be causative of early-onset severe obesity. Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1 and LEPR genes, we sought to estimate the number of US individuals with bi-allelic MC4R pathway LoF variants. We predict approximately 650 α-MSH/POMC, 8,500 PCSK1 and 3,600 LEPR homozygous and compound heterozygous individuals in the US, cumulatively enumerating over 12,800 MC4R pathway deficient obese patients. Very few of these have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC, PCSK1 N221D, and a novel PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity we tested associations between body-mass index (BMI) and LoF mutation-burden in the POMC, PCSK1 and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway predisposes to a higher BMI than non-carriers or heterozygous LoF carriers with a defect in only one gene. Our analysis represents a genetically-rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese sub-populations should be studied to understand MC4R agonist (e.g., setmelanotide) treatment responsiveness.

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans

PubMed Central

Verhoeven, Virginie J. M.; Hysi, Pirro G.; Wojciechowski, Robert; Singh, Pawan Kumar; Kumar, Ashok; Thinakaran, Gopal; Williams, Cathy

2015-01-01

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development. PMID:26313004

In search of causal variants: refining disease association signals using cross-population contrasts.

PubMed

Saccone, Nancy L; Saccone, Scott F; Goate, Alison M; Grucza, Richard A; Hinrichs, Anthony L; Rice, John P; Bierut, Laura J

2008-08-29

Genome-wide association (GWA) using large numbers of single nucleotide polymorphisms (SNPs) is now a powerful, state-of-the-art approach to mapping human disease genes. When a GWA study detects association between a SNP and the disease, this signal usually represents association with a set of several highly correlated SNPs in strong linkage disequilibrium. The challenge we address is to distinguish among these correlated loci to highlight potential functional variants and prioritize them for follow-up. We implemented a systematic method for testing association across diverse population samples having differing histories and LD patterns, using a logistic regression framework. The hypothesis is that important underlying biological mechanisms are shared across human populations, and we can filter correlated variants by testing for heterogeneity of genetic effects in different population samples. This approach formalizes the descriptive comparison of p-values that has typified similar cross-population fine-mapping studies to date. We applied this method to correlated SNPs in the cholinergic nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4, in a case-control study of cocaine dependence composed of 504 European-American and 583 African-American samples. Of the 10 SNPs genotyped in the r2 > or = 0.8 bin for rs16969968, three demonstrated significant cross-population heterogeneity and are filtered from priority follow-up; the remaining SNPs include rs16969968 (heterogeneity p = 0.75). Though the power to filter out rs16969968 is reduced due to the difference in allele frequency in the two groups, the results nevertheless focus attention on a smaller group of SNPs that includes the non-synonymous SNP rs16969968, which retains a similar effect size (odds ratio) across both population samples. Filtering out SNPs that demonstrate cross-population heterogeneity enriches for variants more likely to be important and causative. Our approach provides an important and effective tool to help interpret results from the many GWA studies now underway.

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States

PubMed Central

Miller, Marcus J.; Burrage, Lindsay C.; Gibson, James B.; Strenk, Meghan E.; Lose, Edward J.; Bick, David P.; Elsea, Sarah H.; Sutton, V. Reid; Sun, Qin; Graham, Brett H.; Craigen, William J.; Zhang, Victor Wei; Wong, Lee-Jun C.

2016-01-01

Very long chain acyl-coA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of fatty acid oxidation detected by newborn screening (NBS). Follow-up molecular analyses are often required to clarify VLCADD-suggestive NBS results, but to date the outcome of these studies are not well described for the general screen-positive population. In the following study, we report the molecular findings for 693 unrelated patients that sequentially received Sanger sequence analysis of ACADVL as a result of a positive NBS for VLCADD. Highlighting the variable molecular underpinnings of this disorder, we identified 94 different pathogenic ACADVL variants (40 novel), as well as 134 variants of unknown clinical significance (VUSs). Evidence for the pathogenicity of a subset of recurrent VUSs was provided using multiple in silico analyses. Surprisingly, the most frequent finding in our cohort was carrier status, 57% all individuals had a single pathogenic variant or VUS. This result was further supported by follow-up array and/or acylcarnitine analysis that failed to provide evidence of a second pathogenic allele. Notably, exon-targeted array analysis of 131 individuals screen positive for VLCADD failed to identify copy number changes in ACADVL thus suggesting this test has a low yield in the setting of NBS follow-up. While no genotype was common, the c.848T>C (p.V283A) pathogenic variant was clearly the most frequent; at least one copy was found in ∼10% of all individuals with a positive NBS. Clinical and biochemical data for seven unrelated patients homozygous for the p.V283A allele suggests that it results in a mild phenotype that responds well to standard treatment, but hypoglycemia can occur. Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder. PMID:26385305

Discovery of a Mammalian Splice Variant of Myostatin That Stimulates Myogenesis

PubMed Central

Jeanplong, Ferenc; Falconer, Shelley J.; Oldham, Jenny M.; Thomas, Mark; Gray, Tarra S.; Hennebry, Alex; Matthews, Kenneth G.; Kemp, Frederick C.; Patel, Ketan; Berry, Carole; Nicholas, Gina; McMahon, Christopher D.

2013-01-01

Myostatin plays a fundamental role in regulating the size of skeletal muscles. To date, only a single myostatin gene and no splice variants have been identified in mammals. Here we describe the splicing of a cryptic intron that removes the coding sequence for the receptor binding moiety of sheep myostatin. The deduced polypeptide sequence of the myostatin splice variant (MSV) contains a 256 amino acid N-terminal domain, which is common to myostatin, and a unique C-terminus of 65 amino acids. Western immunoblotting demonstrated that MSV mRNA is translated into protein, which is present in skeletal muscles. To determine the biological role of MSV, we developed an MSV over-expressing C2C12 myoblast line and showed that it proliferated faster than that of the control line in association with an increased abundance of the CDK2/Cyclin E complex in the nucleus. Recombinant protein made for the novel C-terminus of MSV also stimulated myoblast proliferation and bound to myostatin with high affinity as determined by surface plasmon resonance assay. Therefore, we postulated that MSV functions as a binding protein and antagonist of myostatin. Consistent with our postulate, myostatin protein was co-immunoprecipitated from skeletal muscle extracts with an MSV-specific antibody. MSV over-expression in C2C12 myoblasts blocked myostatin-induced Smad2/3-dependent signaling, thereby confirming that MSV antagonizes the canonical myostatin pathway. Furthermore, MSV over-expression increased the abundance of MyoD, Myogenin and MRF4 proteins (P<0.05), which indicates that MSV stimulates myogenesis through the induction of myogenic regulatory factors. To help elucidate a possible role in vivo, we observed that MSV protein was more abundant during early post-natal muscle development, while myostatin remained unchanged, which suggests that MSV may promote the growth of skeletal muscles. We conclude that MSV represents a unique example of intra-genic regulation in which a splice variant directly antagonizes the biological activity of the canonical gene product. PMID:24312578

White matter damage in primary progressive aphasias: a diffusion tensor tractography study.

PubMed

Galantucci, Sebastiano; Tartaglia, Maria Carmela; Wilson, Stephen M; Henry, Maya L; Filippi, Massimo; Agosta, Federica; Dronkers, Nina F; Henry, Roland G; Ogar, Jennifer M; Miller, Bruce L; Gorno-Tempini, Maria Luisa

2011-10-01

Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts' mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

PubMed Central

2010-01-01

Introduction Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. PMID:21194473

The role of ST2 and ST2 genetic variants in schistosomiasis.

PubMed

Long, Xin; Daya, Michelle; Zhao, Jianping; Rafaels, Nicholas; Liang, Huifang; Potee, Joseph; Campbell, Monica; Zhang, Bixiang; Araujo, Maria Ilma; Oliveira, Ricardo R; Mathias, Rasika A; Gao, Li; Ruczinski, Ingo; Georas, Steve N; Vercelli, Donata; Beaty, Terri H; Barnes, Kathleen C; Chen, Xiaoping; Chen, Qian

2017-11-01

Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant T h 2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. We investigated the role of ST2 (a receptor for the T h 2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Genome-Wide Association Study of Breast Cancer in the Japanese Population

PubMed Central

Low, Siew-Kee; Takahashi, Atsushi; Ashikawa, Kyota; Inazawa, Johji; Miki, Yoshio; Kubo, Michiaki; Nakamura, Yusuke; Katagiri, Toyomasa

2013-01-01

Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0×10−5) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10−12, OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10−11, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10−10, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer. PMID:24143190

Revisiting Insider-Outsider Research in Comparative and International Education. Bristol Papers in Education: Comparative and International Studies

ERIC Educational Resources Information Center

Crossley, Michael, Ed.; Arthur, Lore, Ed.; McNess, Elizabeth, Ed.

2016-01-01

This volume recognises how many researchers across the social sciences, and in comparative and international education in particular, see themselves as insiders or outsiders or, more pertinently, shifting combinations of both, in the research process. The book revisits and problematises these concepts in an era where the global mobility of…

Revisiting Evidence for Modularity and Functional Equivalence across Verbal and Spatial Domains in Memory

ERIC Educational Resources Information Center

Guerard, Katherine; Tremblay, Sebastien

2008-01-01

The authors revisited evidence in favor of modularity and of functional equivalence between the processing of verbal and spatial information in short-term memory. This was done by investigating the patterns of intrusions, omissions, transpositions, and fill-ins in verbal and spatial serial recall and order reconstruction tasks under control,…

Considerations of the Social, Individual, and Embodied: A Response to Comments on "Schema Theory Revisited"

ERIC Educational Resources Information Center

McVee, Mary B.; Gavelek, James R.; Dunsmore, Kailonnie L.

2007-01-01

This article presents the authors' response and clarifications to the comments of Margaret E. Gredler and of Karen A. Krasny, Mark Sadoski, and Allan Paivio on their article "Schema Theory Revisited." The authors first respond to Gredler's criticism contending that they "transmogrified" Harre's (1984) "ignominiously named...Vygotsky space" in…

Reading Researchers in Search of Common Ground: The Expert Study Revisited. 2nd Edition

ERIC Educational Resources Information Center

Flippo, Rona F., Ed.

2011-01-01

In "Reading Researchers in Search of Common Ground, Second Edition", Rona F. Flippo revisits her study, in which she set out to find common ground among experts in the much-fragmented field of reading research. The original edition, featuring contributions from participants in the study, commentary from additional distinguished literacy scholars…

Ambiguity Advantage Revisited: Two Meanings Are Better than One when Accessing Chinese Nouns

ERIC Educational Resources Information Center

Lin, Chien-Jer Charles; Ahrens, Kathleen

2010-01-01

This paper revisits the effect of lexical ambiguity in word recognition, which has been controversial as previous research reported advantage, disadvantage, and null effects. We discuss factors that were not consistently treated in previous research (e.g., the level of lexical ambiguity investigated, parts of speech of the experimental stimuli,…

Revisiting the Regenerative Possibilities of Ortiz

ERIC Educational Resources Information Center

Duques, Matthew

2004-01-01

The author of this article revisits Simon Ortiz's poem, "From Sand Creek," in which the latter can in so few words convey both the horrific tragedy of conquest and colonization, while at the same time find a space for possibility, a means for recovery that is never about forgetting but always occurs as a kind of recuperative remembering. Ortiz…

Revisiting Dialogues and Monologues

ERIC Educational Resources Information Center

Kvernbekk, Tone

2012-01-01

In educational discourse dialogue tends to be viewed as being (morally) superior to monologue. When we look at them as basic forms of communication, we find that dialogue is a two-way, one-to-one form and monologue is a one-way, one-to-many form. In this paper I revisit the alleged (moral) superiority of dialogue. First, I problematize certain…

New Orleans Revisited and Revised: Recommendations for the Field of Speech Communication.

ERIC Educational Resources Information Center

Roever, James E.; And Others

This collection of four papers is the result of an action caucus held in association with the Speech Communication Association's 1972 convention, focusing on developments in the speech communication field since the 1968 USOE/SAA New Orleans conference (ED 028 164). In the first paper, "New Orleans Revisited but Briefly," James E. Roever summarizes…

A Multi-Level Model of Moral Functioning Revisited

ERIC Educational Resources Information Center

Reed, Don Collins

2009-01-01

The model of moral functioning scaffolded in the 2008 "JME" Special Issue is here revisited in response to three papers criticising that volume. As guest editor of that Special Issue I have formulated the main body of this response, concerning the dynamic systems approach to moral development, the problem of moral relativism and the role of…

Literary Origins of the Term "School Psychologist" Revisited

ERIC Educational Resources Information Center

Fagan, Thomas K.

2005-01-01

Previous research on the literary origins of the term "school psychologist" is revisited, and conclusions are revised in light of new evidence. It appears that the origin of the term in the American literature occurred as early as 1898 in an article by Hugo Munsterberg, predating the usage by Wilhelm Stern in 1911. The early references to the…

Structuralism's Relevance in a Post-Structural Era: Re-Visiting Research on Multicultural Curricular Studies

ERIC Educational Resources Information Center

Shim, Jenna Min

2011-01-01

At the current historical juncture in which differences and inequalities are surfacing greater than ever in the world, societies, and schools, the main goal of this essay is to revisit the aspects of structuralism that can potentially contribute productively to understanding the invisible structures and forces that everyone carries (mostly…

Re-Visit to the School Nurse and Adolescents' Medicine Use

ERIC Educational Resources Information Center

Borup, Ina K.; Andersen, Anette; Holstein, Bjorn E.

2011-01-01

Objective: To examine if students who re-visit the school nurse use medicines differently than other students when exposed to aches and psychological problems. Methods: The study includes all 11-, 13- and 15-year-old students from a random sample of schools in Denmark, response rate 87 per cent, n = 5,205. The data collection followed the…

Where Are They Now? LJ Revisits a Decade's Worth of Graduates

ERIC Educational Resources Information Center

Kuzyk, Raya

2006-01-01

In this article, the author revisits 11 graduates who were profiled as part of LJ's annual Placements & Salaries issue. Armed with a library science degree from various institutions, they had just secured jobs in librarianship and were off to a good start forging their careers. Since then, they have worked at elementary school, college, and…

The Relationship between Undergraduate Attendance and Performance Revisited: Alignment of Student and Instructor Goals

ERIC Educational Resources Information Center

Westerman, James W.; Perez-Batres, Luis A.; Coffey, Betty S.; Pouder, Richard W.

2011-01-01

We revisit the relationship between attendance and performance in the undergraduate university setting and apply agency theory in the instructor-student context. Building on agency theory propositions in the educational setting advanced by Smith, Zsidisin, and Adams (2005), we propose that the student and instructor must align goals to promote the…

Educational Administration and the Management of Knowledge: 1980 Revisited

ERIC Educational Resources Information Center

Bates, Richard

2013-01-01

This paper revisits the thesis of a 1980 paper that suggested a new approach to educational administration based upon the New Sociology of Education. In particular it updates answers to the six key questions asked by that paper: what counts as knowledge; how is what counts as knowledge organised; how is what counts as knowledge transmitted; how is…

Revisiting the Metaphor of the Island: Challenging "World Culture" from an Island Misunderstood

ERIC Educational Resources Information Center

Rappleye, Jeremy

2015-01-01

This article revisits the newly "discovered" island that world culture theorists have repeatedly utilised to explain their theoretical stance, conceptual preferences and methodological approach. Yet, it seeks to (re)connect world culture with the real world by replacing their imagined atoll with a real one--the island-nation of Japan. In…

Revisiting "The Widget Effect": Teacher Evaluation Reforms and the Distribution of Teacher Effectiveness

ERIC Educational Resources Information Center

Kraft, Matthew A.; Gilmour, Allison F.

2017-01-01

In 2009, the New Teacher Project's "The Widget Effect" documented the failure of U.S. public school districts to recognize and act on differences in teacher effectiveness. We revisit these findings by compiling teacher performance ratings across 24 states that adopted major reforms to their teacher evaluation systems. In the vast…

Using destination image to predict visitors' intention to revisit three Hudson River Valley, New York, communities

Treesearch

Rudy M. Schuster; Laura Sullivan; Duarte Morais; Diane Kuehn

2009-01-01

This analysis explores the differences in Affective and Cognitive Destination Image among three Hudson River Valley (New York) tourism communities. Multiple regressions were used with six dimensions of visitors' images to predict future intention to revisit. Two of the three regression models were significant. The only significantly contributing independent...

Reflecting Back and Looking Forward: Revisiting "Teaching about Writing, Righting Misconceptions" Five Years on

ERIC Educational Resources Information Center

Wardle, Elizabeth; Downs, Doug

2013-01-01

In this Retrospective, we revisit our 2007 "College Composition and Communication" article in order to clarify our primary argument, address some questions and critiques that have arisen, and consider anew the value of composition courses that study writing. We review our core argument that engaging students with the research and ideas of writing…

Epistatic interaction between the monoamine oxidase A and serotonin transporter genes in anorexia nervosa.

PubMed

Urwin, Ruth Elizabeth; Nunn, Kenneth Patrick

2005-03-01

The serotonin (5-HT) and norepinephrine (NE) systems are likely involved in the aetiology of anorexia nervosa (AN) as sufferers are premorbidly anxious. Specifically, we hypothesize that genes encoding proteins, which clear 5-HT and NE from the synapse, are prime candidates for affecting susceptibility to AN. Supporting our hypothesis, we earlier showed that the NE transporter (NET) and monoamine oxidase A (MAOA) genes appear to contribute additively to increased risk of developing restricting AN (AN-R). With regard to the MAOA gene, a sequence variant that increases MAOA activity and has suggested association with the anxiety condition, panic disorder was preferentially transmitted from parents to affected children. Here we provide evidence in support of interaction between the MAOA and serotonin transporter (SERT) genes in 114 AN nuclear families (patient with AN plus biological parents). A SERT gene genotype with no apparent individual effect on risk and known to be associated with anxiety is preferentially transmitted to children with AN (chi2 trend=9.457, 1 df, P=0.0021) and AN-R alone (chi2 trend=7.477, 1 df, P=0.0063) when the 'more active' MAOA gene variant is also transmitted. The increased risk of developing the disorder is up to eight times greater than the risk imposed by the MAOA gene variant alone--an example of synergistic epistatic interaction. If independently replicated, our findings to date suggest that we may have identified three genes affecting susceptibility to AN, particularly AN-R: the MAOA, SERT, and NET genes.

DNM1 encephalopathy

PubMed Central

von Spiczak, Sarah; Helbig, Katherine L.; Shinde, Deepali N.; Huether, Robert; Pendziwiat, Manuela; Lourenço, Charles; Nunes, Mark E.; Sarco, Dean P.; Kaplan, Richard A.; Dlugos, Dennis J.; Kirsch, Heidi; Slavotinek, Anne; Cilio, Maria R.; Cervenka, Mackenzie C.; Cohen, Julie S.; McClellan, Rebecca; Fatemi, Ali; Yuen, Amy; Sagawa, Yoshimi; Littlejohn, Rebecca; McLean, Scott D.; Hernandez-Hernandez, Laura; Maher, Bridget; Møller, Rikke S.; Palmer, Elizabeth; Lawson, John A.; Campbell, Colleen A.; Joshi, Charuta N.; Kolbe, Diana L.; Hollingsworth, Georgie; Neubauer, Bernd A.; Muhle, Hiltrud; Stephani, Ulrich; Scheffer, Ingrid E.; Pena, Sérgio D.J.; Sisodiya, Sanjay M.

2017-01-01

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention. PMID:28667181

Co-expression networks reveal the tissue-specific regulation of transcription and splicing.

PubMed

Saha, Ashis; Kim, Yungil; Gewirtz, Ariel D H; Jo, Brian; Gao, Chuan; McDowell, Ian C; Engelhardt, Barbara E; Battle, Alexis

2017-11-01

Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues. © 2017 Saha et al.; Published by Cold Spring Harbor Laboratory Press.

Exome Sequencing Is an Efficient Tool for Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Molecular Diagnosis

PubMed Central

Ortega-Recalde, Oscar; Nallathambi, Jeyabalan; Anandula, Venkata Ramana; Renukaradhya, Umashankar; Laissue, Paul

2014-01-01

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease. PMID:25333361

Tendon and ligament injuries: the genetic component

PubMed Central

September, Alison V; Schwellnus, Martin P; Collins, Malcolm

2007-01-01

Tendons and ligaments within the upper and lower limbs are some of the more common sites of musculoskeletal injuries during physical activity. Several extrinsic and intrinsic factors have been shown to be associated with these injuries. More recently, studies have suggested that there is also, at least in part, a genetic component to the Achilles tendon, rotator cuff and anterior cruciate ligament injuries. However, specific genes have not been suggested to be associated with rotator cuff or anterior cruciate ligament injuries. Sequence variants of the tenascin C (TNC) gene, on the other hand, have been shown to be associated with Achilles tendinopathies and Achilles tendon ruptures, whereas a variant of the collagen V α 1 (COL5A1) gene has also been shown to be associated with Achilles tendinopathies. Both genes encode for important structural components of tendons and ligaments. The COL5A1 gene encodes for a component of type V collagen, which has an important role in regulating collagen fibre assembly and fibre diameters. The TNC gene, on the other hand, encodes for TNC, which regulates the tissue's response to mechanical load. To date, only variants in two genes have been shown to be associated with Achilles tendon injuries. In addition, although specific genes have not been identified, investigators have suggested that there is also a genetic component to both rotator cuff and anterior cruciate ligament injuries. In future, specific genotypes associated with increased risk of injury to specific tendons and ligaments can prevent these injuries by identifying individuals at higher risk. PMID:17261551

Genome-wide association study of age at menarche in African-American women

PubMed Central

Demerath, Ellen W.; Liu, Ching-Ti; Franceschini, Nora; Chen, Gary; Palmer, Julie R.; Smith, Erin N.; Chen, Christina T.L.; Ambrosone, Christine B.; Arnold, Alice M.; Bandera, Elisa V.; Berenson, Gerald S.; Bernstein, Leslie; Britton, Angela; Cappola, Anne R.; Carlson, Christopher S.; Chanock, Stephen J.; Chen, Wei; Chen, Zhao; Deming, Sandra L.; Elks, Cathy E.; Evans, Michelle K.; Gajdos, Zofia; Henderson, Brian E.; Hu, Jennifer J.; Ingles, Sue; John, Esther M.; Kerr, Kathleen F.; Kolonel, Laurence N.; Le Marchand, Loic; Lu, Xiaoning; Millikan, Robert C.; Musani, Solomon K.; Nock, Nora L.; North, Kari; Nyante, Sarah; Press, Michael F.; Rodriquez-Gil, Jorge L.; Ruiz-Narvaez, Edward A.; Schork, Nicholas J.; Srinivasan, Sathanur R.; Woods, Nancy F.; Zheng, Wei; Ziegler, Regina G.; Zonderman, Alan; Heiss, Gerardo; Gwen Windham, B.; Wellons, Melissa; Murray, Sarah S.; Nalls, Michael; Pastinen, Tomi; Rajkovic, Aleksandar; Hirschhorn, Joel; Adrienne Cupples, L.; Kooperberg, Charles; Murabito, Joanne M.; Haiman, Christopher A.

2013-01-01

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10−8 threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women. PMID:23599027

Paleoenvironmental evidence for first human colonization of the eastern Caribbean

NASA Astrophysics Data System (ADS)

Siegel, Peter E.; Jones, John G.; Pearsall, Deborah M.; Dunning, Nicholas P.; Farrell, Pat; Duncan, Neil A.; Curtis, Jason H.; Singh, Sushant K.

2015-12-01

Identifying and dating first human colonization of new places is challenging, especially when group sizes were small and material traces of their occupations were ephemeral. Generating reliable reconstructions of human colonization patterns from intact archaeological sites may be difficult to impossible given post-depositional taphonomic processes and in cases of island and coastal locations the inundation of landscapes resulting from post-Pleistocene sea-level rise. Paleoenvironmental reconstruction is proving to be a more reliable method of identifying small-scale human colonization events than archaeological data alone. We demonstrate the method through a sediment-coring project across the Lesser Antilles and southern Caribbean. Paleoenvironmental data were collected informing on the timing of multiple island-colonization events and land-use histories spanning the full range of human occupations in the Caribbean, from the initial forays into the islands through the arrival and eventual domination of the landscapes and indigenous people by Europeans. In some areas, our data complement archaeological, paleoecological, and historical findings from the Lesser Antilles and in others amplify understanding of colonization history. Here, we highlight data relating to the timing and process of initial colonization in the eastern Caribbean. In particular, paleoenvironmental data from Trinidad, Grenada, Martinique, and Marie-Galante (Guadeloupe) provide a basis for revisiting initial colonization models of the Caribbean. We conclude that archaeological programs addressing human occupations dating to the early to mid-Holocene, especially in dynamic coastal settings, should systematically incorporate paleoenvironmental investigations.

Mapping Irrigated Areas in the Tunisian Semi-Arid Context with Landsat Thermal and VNIR Data Imagery

NASA Astrophysics Data System (ADS)

Rivalland, Vincent; Drissi, Hsan; Simonneaux, Vincent; Tardy, Benjamin; Boulet, Gilles

2016-04-01

Our study area is the Merguellil semi-arid irrigated plain in Tunisia, where the water resource management is an important stake for governmental institutions, farmer communities and more generally for the environment. Indeed, groundwater abstraction for irrigation is the primary cause of aquifer depletion. Moreover, unregistered pumping practices are widespread and very difficult to survey by authorities. Thus, the identification of areas actually irrigated in the whole plain is of major interest. In order to map the irrigated areas, we tried out a methodology based on the use of Landsat 7 and 8 Land Surface Temperature (LST) data issued from atmospherically corrected thermal band using the LANDARTs Tool jointly with the NDVI vegetation indices obtained from visible ane near infrared (VNIR) bands. For each Landsat acquisition during the years 2012 to 2014, we computed a probability of irrigation based on the location of the pixel in the NDVI - LST space. Basically for a given NDVI value, the cooler the pixel the higher its probability to be irrigated is. For each date, pixels were classified in seven bins of irrigation probability ranges. Pixel probabilities for each date were then summed over the study period resulting in a probability map of irrigation. Comparison with ground data shows a consistent identification of irrigated plots and supports the potential operational interest of the method. However, results were hampered by the low Landsat LST data availability due to clouds and the inadequate revisit frequency of the sensor.

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

PubMed

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward L; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan K; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Buchanan, Daniel D; Casey, Graham; Conti, David V; Edlund, Christopher K; Gallinger, Steven; Haile, Robert W; Jenkins, Mark; Le Marchand, Loïc; Li, Li; Lindor, Noralene M; Schmit, Stephanie L; Thibodeau, Stephen N; Woods, Michael O; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

2016-09-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR. ©2016 American Association for Cancer Research.

Hybrid Ameloblastoma of the Maxilla: A Puzzling Pathology.

PubMed

Lakshmi, Chintamaneni Raja; Bhavana, Sujana Mulk; Nallamilli, Sai Madhavi; Prabhat, Meka Poorna Venkata; Sarat, Gummadapu; Anuradha, Chennupati

2016-07-01

Ameloblastomas are slow growing, locally invasive, benign odontogenic tumors of an epithelial origin, accounting for approximately 1% of all oral tumors. A 40-year-old man presented with a chief complaint of a swelling over the left side of his face of 4 years' duration. On examination, gross facial asymmetry was detected, and a well-defined swelling was noted intraorally involving the left maxilla medially from the mid palatal raphe and obliterating the buccal vestibule laterally. The swelling was non-tender and exhibited dual consistencies: firm in the palate and cystic in the vestibular region. Computed tomography revealed a multilocular radiolucency, which involved the left maxilla, encroached into the left maxillary sinus and the nasal complex, and caused bony erosion. Early diagnosis and treatment are the key tools in managing ameloblastomas, failure of which may lead to a significant deterioration of the prognosis and an increased recurrence rate. Uncommon variants of ameloblastomas have been gaining interest recently. To date, 25 cases of hybrid ameloblastomas have been documented in the scientific literature. We present an extremely rare hybrid type of the ameloblastoma with combined follicular, cystic, acanthomatous, and desmoplastic variants, which render it the first of its kind to have ever been reported.

Variant Carvajal syndrome with additional dental anomalies.

PubMed

Barber, Sophy; Day, Peter; Judge, Mary; Toole, Edell O'; Fayle, Stephen

2012-09-01

This paper aims to review the case of a girl who presented with a number of dental anomalies, in addition to unusual skin, nail and hair conditions. Tragically an undiagnosed cardiomyopathy caused unexpected sudden death. The case is discussed with reference to a number of dermatological and oral conditions which were considered as possible diagnoses. AW had been under long term dental care for prepubertal periodontitis, premature root resorption of primary teeth, soft tissue and dental anomalies, and angular cheilitis. Separately she had also been seen by several dermatologists with respect to palmar plantar keratosis, striae keratoderma, wiry hair and abnormal finger nails. Tragically the patient suffered a sudden unexpected death and the subsequent post mortem identified an undiagnosed dilated cardiomyopathy. The most likely diagnosis is that this case is a variant of Carvajal Syndrome with additional dental anomalies. To date we have been unable to identify mutations in the desoplakin gene. We aim to emphasise the importance of recognising these dental and dermatological signs when they present together as a potential risk factor for cardiac abnormalities. © 2012 The Authors. International Journal of Paediatric Dentistry © 2012 BSPD, IAPD and Blackwell Publishing Ltd.

BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures

PubMed Central

Medina-Gómez, Carolina; Chesi, Alessandra; Heppe, Denise H.M.; Zemel, Babette S.; Yin, Jia-Lian; Kalkwarf, Heidi J.; Hofman, Albert; Lappe, Joan M.; Kelly, Andrea; Kayser, Manfred; Oberfield, Sharon E.; Gilsanz, Vicente; Uitterlinden, André G.; Shepherd, John A.; Jaddoe, Vincent W.V.; Grant, Struan F.A.; Lao, Oscar; Rivadeneira, Fernando

2015-01-01

Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait. PMID:26226985

Characterization of Two Historic Smallpox Specimens from a Czech Museum

PubMed Central

Pajer, Petr; Dresler, Jiri; Kabíckova, Hana; Písa, Libor; Aganov, Pavel; Fucik, Karel; Elleder, Daniel; Hron, Tomas; Kuzelka, Vitezslav; Velemínsky, Petr; Klimentova, Jana; Fucikova, Alena; Pejchal, Jaroslav; Hrabakova, Rita; Dundr, Pavel; Stríbrny, Jan; Antwerpen, Markus H.; Meyer, Hermann

2017-01-01

Although smallpox has been known for centuries, the oldest available variola virus strains were isolated in the early 1940s. At that time, large regions of the world were already smallpox-free. Therefore, genetic information of these strains can represent only the very last fraction of a long evolutionary process. Based on the genomes of 48 strains, two clades are differentiated: Clade 1 includes variants of variola major, and clade 2 includes West African and variola minor (Alastrim) strains. Recently, the genome of an almost 400-year-old Lithuanian mummy was determined, which fell basal to all currently sequenced strains of variola virus on phylogenetic trees. Here, we determined two complete variola virus genomes from human tissues kept in a museum in Prague dating back 60 and 160 years, respectively. Moreover, mass spectrometry-based proteomic, chemical, and microscopic examinations were performed. The 60-year-old specimen was most likely an importation from India, a country with endemic smallpox at that time. The genome of the 160-year-old specimen is related to clade 2 West African and variola minor strains. This sequence likely represents a new endemic European variant of variola virus circulating in the midst of the 19th century in Europe. PMID:28749451

Exploration of large, rare copy number variants associated with psychiatric and neurodevelopmental disorders in individuals with anorexia nervosa.

PubMed

Yilmaz, Zeynep; Szatkiewicz, Jin P; Crowley, James J; Ancalade, NaEshia; Brandys, Marek K; van Elburg, Annemarie; de Kovel, Carolien G F; Adan, Roger A H; Hinney, Anke; Hebebrand, Johannes; Gratacos, Monica; Fernandez-Aranda, Fernando; Escaramis, Georgia; Gonzalez, Juan R; Estivill, Xavier; Zeggini, Eleftheria; Sullivan, Patrick F; Bulik, Cynthia M

2017-08-01

Anorexia nervosa (AN) is a serious and heritable psychiatric disorder. To date, studies of copy number variants (CNVs) have been limited and inconclusive because of small sample sizes. We conducted a case-only genome-wide CNV survey in 1983 female AN cases included in the Genetic Consortium for Anorexia Nervosa. Following stringent quality control procedures, we investigated whether pathogenic CNVs in regions previously implicated in psychiatric and neurodevelopmental disorders were present in AN cases. We observed two instances of the well-established pathogenic CNVs in AN cases. In addition, one case had a deletion in the 13q12 region, overlapping with a deletion reported previously in two AN cases. As a secondary aim, we also examined our sample for CNVs over 1 Mbp in size. Out of the 40 instances of such large CNVs that were not implicated previously for AN or neuropsychiatric phenotypes, two of them contained genes with previous neuropsychiatric associations, and only five of them had no associated reports in public CNV databases. Although ours is the largest study of its kind in AN, larger datasets are needed to comprehensively assess the role of CNVs in the etiology of AN.

Characterization of Two Historic Smallpox Specimens from a Czech Museum.

PubMed

Pajer, Petr; Dresler, Jiri; Kabíckova, Hana; Písa, Libor; Aganov, Pavel; Fucik, Karel; Elleder, Daniel; Hron, Tomas; Kuzelka, Vitezslav; Velemínsky, Petr; Klimentova, Jana; Fucikova, Alena; Pejchal, Jaroslav; Hrabakova, Rita; Benes, Vladimir; Rausch, Tobias; Dundr, Pavel; Pilin, Alexander; Cabala, Radomir; Hubalek, Martin; Stríbrny, Jan; Antwerpen, Markus H; Meyer, Hermann

2017-07-27

Although smallpox has been known for centuries, the oldest available variola virus strains were isolated in the early 1940s. At that time, large regions of the world were already smallpox-free. Therefore, genetic information of these strains can represent only the very last fraction of a long evolutionary process. Based on the genomes of 48 strains, two clades are differentiated: Clade 1 includes variants of variola major, and clade 2 includes West African and variola minor (Alastrim) strains. Recently, the genome of an almost 400-year-old Lithuanian mummy was determined, which fell basal to all currently sequenced strains of variola virus on phylogenetic trees. Here, we determined two complete variola virus genomes from human tissues kept in a museum in Prague dating back 60 and 160 years, respectively. Moreover, mass spectrometry-based proteomic, chemical, and microscopic examinations were performed. The 60-year-old specimen was most likely an importation from India, a country with endemic smallpox at that time. The genome of the 160-year-old specimen is related to clade 2 West African and variola minor strains. This sequence likely represents a new endemic European variant of variola virus circulating in the midst of the 19th century in Europe.

VARiD: a variation detection framework for color-space and letter-space platforms.

PubMed

Dalca, Adrian V; Rumble, Stephen M; Levy, Samuel; Brudno, Michael

2010-06-15

High-throughput sequencing (HTS) technologies are transforming the study of genomic variation. The various HTS technologies have different sequencing biases and error rates, and while most HTS technologies sequence the residues of the genome directly, generating base calls for each position, the Applied Biosystem's SOLiD platform generates dibase-coded (color space) sequences. While combining data from the various platforms should increase the accuracy of variation detection, to date there are only a few tools that can identify variants from color space data, and none that can analyze color space and regular (letter space) data together. We present VARiD--a probabilistic method for variation detection from both letter- and color-space reads simultaneously. VARiD is based on a hidden Markov model and uses the forward-backward algorithm to accurately identify heterozygous, homozygous and tri-allelic SNPs, as well as micro-indels. Our analysis shows that VARiD performs better than the AB SOLiD toolset at detecting variants from color-space data alone, and improves the calls dramatically when letter- and color-space reads are combined. The toolset is freely available at http://compbio.cs.utoronto.ca/varid.

Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

PubMed

Raz, Naftali; Daugherty, Ana M; Sethi, Sean K; Arshad, Muzamil; Haacke, E Mark

2017-08-01

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

PubMed Central

Malinge, Pauline; Magistrelli, Giovanni; Fischer, Nicolas; Sahin, Mehmet; Bergthaler, Andreas; Igonet, Sebastien; ter Meulen, Jan; Rigo, Dorothée; Meda, Paolo; Rabah, Nadia; Coutard, Bruno; Bowden, Thomas A.; Lambert, Paul-Henri; Siegrist, Claire-Anne; Pinschewer, Daniel D.

2015-01-01

Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein’s globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy. PMID:26587982

Lack of replication for the myosin-18B association with mathematical ability in independent cohorts

PubMed Central

Pettigrew, K A; Fajutrao Valles, S F; Moll, K; Northstone, K; Ring, S; Pennell, C; Wang, C; Leavett, R; Hayiou-Thomas, M E; Thompson, P; Simpson, N H; Fisher, S E; Whitehouse, A J O; Snowling, M J; Newbury, D F; Paracchini, S

2015-01-01

Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities. PMID:25778778

Occupational and genetic risk factors for osteoarthritis: A review

PubMed Central

Yucesoy, Berran; Charles, Luenda E.; Baker, Brent; Burchfiel, Cecil M.

2015-01-01

BACKGROUND Osteoarthritis (OA) is a multifactorial disease with strong genetic and occupational components. Although published studies have described several risk factors for OA, very few studies have investigated the occupational and genetic factors that contribute to this debilitating condition. OBJECTIVE To describe occupational and genetic factors that may contribute to the risk of developing (OA). METHODS A literature search was conducted in PubMed using the search terms osteoarthritis, occupation, work, and genetics. RESULTS Heavy physical work load was the most common occupational risk factor for OA in several anatomical locations. Other factors include kneeling and regular stair climbing, crawling, bending and whole body vibration, and repetitive movements. Numerous studies have also shown the influence of genetic variability in the pathogenesis of OA. Genetic variants of several groups of genes e.g., cartilage extracellular matrix structural genes and the genes related to bone density have been implicated in disease pathogenesis. CONCLUSION This review shows that occupational factors were extensively studied in knee OA unlike OA of other anatomical regions. Although genetic association studies performed to date identified a number of risk variants, some of these associations have not been consistently replicated across different studies and populations. Therefore, more research is needed. PMID:24004806

Instant Video Revisiting for Reflection: Extending the Learning of Children and Teachers.

ERIC Educational Resources Information Center

Hong, Seong B.; Broderick, Jane T.

This article discusses how instant video revisiting (IVR) promotes reflective thinking for both teachers and children. IVR was used as a daily classroom experience with both the children and the teachers throughout one semester in two preschool classrooms with children 2.5 to 5 years old. The teachers used a digital video camera to generate data…

The Postgraduate Premium: Revisiting Trends in Social Mobility and Educational Inequalities in Britain and America

ERIC Educational Resources Information Center

Lindley, Joanne; Machin, Stephen

2013-01-01

This report revisits the debate about why social mobility levels are relatively low in Great Britain and the United States of America compared to other countries. It focuses on three main areas within this debate: (1) the changing role of educational inequalities; (2) the expectation of ever higher levels of education as revealed in increasing…

Public Administration Education in a Continental European Legalistic Setting: The Hungarian Case

ERIC Educational Resources Information Center

Gellén, Márton

2014-01-01

The Trans-European Dialogue in 2013 was dedicated to the revisiting of the research undertaken by György Hajnal in 2003 (Hajnal, 2003) on public administration education in Europe. As part of the preparations to the conference, Hajnal also revisited his research after 10 years. The findings presented on the conference offer a theoretical framework…

Globalisation, the Singapore Developmental State and Education Policy: A Thesis Revisited

ERIC Educational Resources Information Center

Gopinathan, S.

2007-01-01

In this article I revisit and extend arguments made in 1996 and 1997 about the relationship between globalisation, the state and education policy. I was particularly concerned then to see how a small but strong state, Singapore, was responding in the education arena to globalisation. I also wished to draw attention to the literature on the high…

Service-Learning in Crisis Communication Education: Revisiting Coombs' Objectives for the Crisis Communication Course

ERIC Educational Resources Information Center

Maresh-Fuehrer, Michelle M.

2015-01-01

The purpose of this study was to revisit Coombs' suggestions for teaching the crisis communication course using service-learning as a framework. The author sought to assess the effectiveness of using this method in terms of the benefits to both students and the partnering organization and students' perceptions of whether they met the learning…