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Patrick J Short, Jeremy F McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, Daniel H Geschwind, Caroline F Wright, Helen V Firth, David R FitzPatrick, Jeffrey C Barrett, Matthew E Hurles
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders...
March 21, 2018: Nature
Tang-Wei Chuang, Shou-Chien Chen, Kow-Tong Chen
AIMS: The aim of this study was to explore the recent advances in diagnosis and treatment of gastroesophageal reflux disease (GERD). METHODS: Previous studies were searched using the terms "gastroesophageal reflux disease" and "diagnosis" or "treatment" in Medline and Pubmed. Articles that were not published in the English language, manuscripts without an abstract, reviews, meta-analysis, and opinion articles were excluded from the review...
July 2017: Acta Gastro-enterologica Belgica
Lauren Mullen, Kim Boerrigter, Nicholas Ferriero, Jeff Rosalsky, Abigail van Buren Barrett, Patrick J Murray, Andrew D Steen
Proteins constitute a particularly bioavailable subset of organic carbon and nitrogen in aquatic environments but must be hydrolyzed by extracellular enzymes prior to being metabolized by microorganisms. Activities of extracellular peptidases (protein-degrading enzymes) have frequently been assayed in freshwater systems, but such studies have been limited to substrates for a single enzyme [leucyl aminopeptidase (Leu-AP)] out of more than 300 biochemically recognized peptidases. Here, we report kinetic measurements of extracellular hydrolysis of five substrates in 28 freshwater bodies in the Delaware Water Gap National Recreation Area in the Pocono Mountains (PA, United States) and near Knoxville (TN, United States), between 2013 and 2016...
2018: Frontiers in Microbiology
Vanessa V Sarathy, Mellodee White, Li Li, Jaclyn A Kaiser, Gerald A Campbell, Gregg N Milligan, Nigel Bourne, Alan D T Barrett
The mosquito-borne disease dengue is caused by four serologically- and genetically-related viruses, termed DENV-1 to DENV-4. Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/β/γ receptors). Recently, our group established lethal AG129 mouse infection models of DENV-1, DENV-3, and DENV-4 using human isolates. Here we compare a non-lethal, disseminated model of DENV-3 infection using strain D83-144 to that of the lethal outcome following infection by strain C0360/94...
March 20, 2018: Scientific Reports
Kelly M Goedert, Peii Chen, Anne L Foundas, A M Barrett
Spatial neglect commonly follows right hemisphere stroke. It is defined as impaired contralesional stimulus detection, response, or action, causing functional disability. While prism adaptation treatment is highly promising to promote functional recovery of spatial neglect, not all individuals respond. Consistent with a primary effect of prism adaptation on spatial movements, we previously demonstrated that functional improvement after prism adaptation treatment is linked to frontal lobe lesions. However, that study was a treatment-only study with no randomised control group...
March 20, 2018: Neuropsychological Rehabilitation
Alpesh A Patel, Shah-Nawaz M Dodwad, Barrett S Boody, Surabhi Bhatt, Jason W Savage, Wellington K Hsu, Nan E Rothrock
STUDY DESIGN: Prospective, cohort study. OBJECTIVE: Demonstrate validity of PROMIS physical function, pain interference, and pain behavior computer adaptive tests (CATs) in surgically treated lumbar stenosis patients. SUMMARY OF BACKGROUND DATA: There has been increasing attention given to patient reported outcomes associated with spinal interventions. Historical patient outcome measures have inadequate validation, demonstrate floor/ceiling effects, and infrequently used due to time constraints...
March 19, 2018: Spine
Mary H Hayden, Erika Barrett, Guyah Bernard, Eunice N Toko, Maurice Agawo, Amanda M Okello, Jayleen K L Gunn, Kacey C Ernst
Increasing the active participation of professional women in vector control (VC) activities may help promote greater gender equity in the workplace and reduce the burden of vector-borne diseases. This stakeholder survey examined the current roles and perspective of professionals employed in the VC sector in Kenya, Indonesia, India, and other countries. The largest barriers that women face in pursuing leadership roles in the VC sector include lack of awareness of career opportunities, limitations based on cultural norms, and the belief that VC is men's work...
March 19, 2018: American Journal of Tropical Medicine and Hygiene
Gregory Sharp, Barrett A Lee
Much of the research on ethnoracial diversity in nonmetropolitan America consists of case studies describing how the arrival of Hispanics has transformed a particular community. To complement this work, we examine the dimensions and sources of diversity for a sample of 10,000 nonmetro places. Two dimensions of diversity-magnitude and structure-are identified, and hypotheses about their changes and correlates are drawn from the spatial assimilation and locational persistence perspectives and relevant scholarship...
September 2017: Rural Sociology
Suzanne Scheele, Jennifer A Geiger, Amy E DeRocher, Ryan Choi, Tess R Smith, Matthew A Hulverson, Rama Subba Rao Vidadala, Lynn K Barrett, Dustin J Maly, Ethan A Merritt, Kayode K Ojo, Wesley C Van Voorhis, Marilyn Parsons
In Toxoplasma gondii , calcium-dependent protein kinase 1 (CDPK1) is an essential protein kinase required for invasion of host cells. We have developed several hundred CDPK1 inhibitors, many of which block invasion. Inhibitors with similar IC50 s were tested in thermal shift assays for their ability to stabilize CDPK1 in cell lysates, in intact cells, or in purified form. Compounds that inhibited parasite growth stabilized CDPK1 in all assays. In contrast, two compounds that showed poor growth inhibition stabilized CDPK1 in lysates but not in cells...
March 19, 2018: Antimicrobial Agents and Chemotherapy
Julie Kovářová, Andrew W Pountain, David Wildridge, Stefan Weidt, Frédéric Bringaud, Richard J S Burchmore, Fiona Achcar, Michael P Barrett
Transketolase (TKT) is part of the non-oxidative branch of the pentose phosphate pathway (PPP). Here we describe the impact of removing this enzyme from the pathogenic protozoan Leishmania mexicana. Whereas the deletion had no obvious effect on cultured promastigote forms of the parasite, the Δtkt cells were not infective to mice. Δtkt promastigotes were more susceptible to oxidative stress and various leishmanicidal drugs than wild-type, and metabolomics analysis revealed profound changes to metabolism in these cells...
March 19, 2018: PLoS Pathogens
Barrett A Lee, Michael J R Martin, Stephen A Matthews, Chad R Farrell
Background: Few studies have examined long-term changes in ethnoracial diversity for US states despite the potential social, economic, and political ramifications of such changes at the state level. Objective: We describe shifts in diversity magnitude and structure from 1980 through 2015 to determine if states are following a universal upward path. Methods: Decennial census data for 1980-2010 and American Community Survey data for 2015 are used to compute entropy index ( E ) and Simpson index ( S ) measures of diversity magnitude based on five panethnic populations...
December 2017: Demographic Research
Jing Dong, David M Levine, Matthew F Buas, Rui Zhang, Lynn Onstad, Rebecca C Fitzgerald, Douglas A Corley, Nicholas J Shaheen, Jesper Lagergren, Laura J Hardie, Brian J Reid, Prasad G Iyer, Harvey A Risch, Carlos Caldas, Isabel Caldas, Paul D Pharoah, Geoffrey Liu, Marilie D Gammon, Wong-Ho Chow, Leslie Bernstein, Nigel C Bird, Weimin Ye, Anna H Wu, Lesley A Anderson, Stuart MacGregor, David C Whiteman, Thomas L Vaughan, Aaron P Thrift
BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE...
March 15, 2018: Clinical Gastroenterology and Hepatology
Bing Liu, Chi Toan Le, Russell L Barrett, Daniel L Nickrent, Zhiduan Chen, Limin Lu, Romina Vidal-Russell
Coadaptation between mistletoes and birds captured the attention of Charles Darwin over 150 years ago, stimulating considerable scientific research. Here we used Loranthaceae, a speciose and ecologically important mistletoe family, to obtain new insights into the interrelationships among its hosts and dispersers. Phylogenetic analyses of Loranthaceae were based on a dataset of nuclear and chloroplast DNA sequences. Divergence time estimation, ancestral area reconstruction, and diversification rate analyses were employed to examine historical biogeography...
March 14, 2018: Molecular Phylogenetics and Evolution
Michael J R Martin, Stephen A Matthews, Barrett A Lee
Although increasing racial and ethnic diversity is a demographic trend with society-wide implications, it has advanced farther in some parts of the United States than others. Our research seeks to understand this unevenness at the local level. Drawing on 1980-2010 census data, we use an innovative spatial analytic approach to examine the spread or diffusion of diversity across counties in the 48 contiguous states. Three perspectives-locational persistence, spatial assimilation, and institutional hub-offer different expectations about the nature of the diffusion process...
October 2017: Spatial Demography
C Kern, K Kortüm, M Müller, A Kampik, S Priglinger, W J Mayer
Purpose: To compare two calculators for toric intraocular lens (IOL) calculation and to evaluate the prediction of refractive outcome. Methods: Sixty-four eyes of forty-five patients underwent cataract surgery followed by implantation of a toric intraocular lens (Zeiss Torbi 709 M) calculated by a standard industry calculator using front keratometry values. Prediction error, median absolute error, and refractive astigmatism error were evaluated for the standard calculator...
2018: Journal of Ophthalmology
Sanjay Tewari, George Renney, John Brewin, Kate Gardner, Fenella Kirkham, Baba Inusa, James E Barrett, Stephan Menzel, Swee Lay Thein, Malcolm Ward, David C Rees
Silent cerebral infarction is the commonest neurological abnormality in children with sickle cell anemia, affecting 30-40% 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS)...
March 15, 2018: Haematologica
Hetal Patel, Manikandan Periyasamy, Georgina P Sava, Alexander Bondke, Brian W Slafer, Sebastian H B Kroll, Marion Barbazanges, Richard Starkey, Silvia Ottaviani, Alison Harrod, Eric O Aboagye, Laki Buluwela, Matthew J Fuchter, Anthony G M Barrett, Charles Coombes, Simak Ali
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942...
March 15, 2018: Molecular Cancer Therapeutics
Julia E Gerson, Kathleen M Farmer, Natalie Henson, Diana L Castillo-Carranza, Mariana Carretero Murillo, Urmi Sengupta, Alan Barrett, Rakez Kayed
BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target...
March 15, 2018: Molecular Neurodegeneration
S Sanagapalli, A Emmanuel, R Leong, S Kerr, L Lovat, R Haidry, M Banks, D Graham, A Raeburn, N Zarate-Lopez, R Sweis
BACKGROUND: Esophageal dysmotility may predispose to Barrett's esophagus (BE). We hypothesized that high-resolution manometry (HRM) performed with additional physiologic challenge would better delineate dysmotility in BE. METHODS: Included patients had typical reflux symptoms and underwent endoscopy, HRM with single water swallows and adjunctive testing with solids and rapid drink challenge (RDC) before ambulatory pH-impedance monitoring. BE and endoscopy-negative reflux disease (ENRD) subjects were compared against functional heartburn patient-controls (FHC)...
March 15, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Vipan K Parihar, Mattia Maroso, Amber Syage, Barrett D Allen, Maria C Angulo, Ivan Soltesz, Charles L Limoli
Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars...
March 11, 2018: Experimental Neurology
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