Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2

Crumbs family proteins are apical transmembrane proteins with ancient roles in cell polarity. Mouse Crumbs2 mutants arrest at midgestation with abnormal neural plate morphology and a deficit of mesoderm caused by defects in gastrulation. We identified an ENU-induced mutation, wsnp, that phenocopies the Crumbs2 null phenotype. We show that wsnp is a null allele of Protein O-glucosyltransferase 1 (Poglut1), which encodes an enzyme previously shown to add O-glucose to EGF repeats in the extracellular domain of Drosophila and mammalian Notch, but the role of POGLUT1 in mammalian gastrulation has not been investigated. As predicted, we find that POGLUT1 is essential for Notch signaling in the early mouse embryo. However, the loss of mouse POGLUT1 causes an earlier and more dramatic phenotype than does the loss of activity of the Notch pathway, indicating that POGLUT1 has additional biologically relevant substrates. Using mass spectrometry, we show that POGLUT1 modifies EGF repeats in the extracellular domain of full-length mouse CRUMBS2. CRUMBS2 that lacks the O-glucose modification fails to be enriched on the apical plasma membrane and instead accumulates in the endoplasmic reticulum. The data demonstrate that CRUMBS2 is the target of POGLUT1 for the gastrulation epithelial-to-mesenchymal transitions (EMT) and that all activity of CRUMBS2 depends on modification by POGLUT1. Mutations in human POGLUT1 cause Dowling-Degos Disease, POGLUT1 is overexpressed in a variety of tumor cells, and mutations in the EGF repeats of human CRUMBS proteins are associated with human congenital nephrosis, retinitis pigmentosa and retinal degeneration, suggesting that O-glucosylation of CRUMBS proteins has broad roles in human health

Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics

© 2019 Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons

Environmental stress in the Gulf of Mexico and its potential impact on public health

© 2015 Elsevier Inc. The Deepwater Horizon (DWH) oil spill in the Gulf of Mexico was the largest maritime oil spill in history resulting in the accumulation of genotoxic substances in the air, soil, and water. This has potential far-reaching health impacts on cleanup field workers and on the populations living in the contaminated coastal areas. We have employed portable airborne particulate matter samplers (SKC Biosampler Impinger) and a genetically engineered bacterial reporter system (umu-ChromoTest from EBPI) to determine levels of genotoxicity of air samples collected from highly contaminated areas of coastal Louisiana including Grand Isle, Port Fourchon, and Elmer\u27s Island in the spring, summer and fall of 2011, 2012, 2013 and 2014. Air samples collected from a non-contaminated area, Sea Rim State Park, Texas, served as a control for background airborne genotoxic particles. In comparison to controls, air samples from the contaminated areas demonstrated highly significant increases in genotoxicity with the highest values registered during the month of July in 2011, 2013, and 2014, in all three locations. This seasonal trend was disrupted in 2012, when the highest genotoxicity values were detected in October, which correlated with hurricane Isaac landfall in late August of 2012, about five weeks before a routine collection of fall air samples. Our data demonstrate: (i) high levels of air genotoxicity in the monitored areas over last four years post DWH oil spill; (ii) airborne particulate genotoxicity peaks in summers and correlates with high temperatures and high humidity; and (iii) this seasonal trend was disrupted by the hurricane Isaac landfall, which further supports the concept of a continuous negative impact of the oil spill in this region

Automatic Classification of Autistic Child Vocalisations: A Novel Database and Results

Humanoid robots have in recent years shown great promise for supporting the educational needs of children on the autism spectrum. To further improve the efficacy of such interactions, user-adaptation strategies based on the individual needs of a child are required. In this regard, the proposed study assesses the suitability of a range of speech-based classification approaches for automatic detection of autism severity according to the com- monly used Social Responsiveness Scale ™ second edition (SRS- 2). Autism is characterised by socialisation limitations including child language and communication ability. When compared to neurotypical children of the same age these can be a strong indi- cation of severity. This study introduces a novel dataset of 803 utterances recorded from 14 autistic children aged between 4 – 10 years, during Wizard-of-Oz interactions with a humanoid robot. Our results demonstrate the suitability of support vector machines (SVMs) which use acoustic feature sets from multiple Interspeech C OM P AR E challenges. We also evaluate deep spec- trum features, extracted via an image classification convolutional neural network (CNN) from the spectrogram of autistic speech instances. At best, by using SVMs on the acoustic feature sets, we achieved a UAR of 73.7 % for the proposed 3-class task

Biodiversity Loss and the Taxonomic Bottleneck: Emerging Biodiversity Science

Human domination of the Earth has resulted in dramatic changes to global and local patterns of biodiversity. Biodiversity is critical to human sustainability because it drives the ecosystem services that provide the core of our life-support system. As we, the human species, are the primary factor leading to the decline in biodiversity, we need detailed information about the biodiversity and species composition of specific locations in order to understand how different species contribute to ecosystem services and how humans can sustainably conserve and manage biodiversity. Taxonomy and ecology, two fundamental sciences that generate the knowledge about biodiversity, are associated with a number of limitations that prevent them from providing the information needed to fully understand the relevance of biodiversity in its entirety for human sustainability: (1) biodiversity conservation strategies that tend to be overly focused on research and policy on a global scale with little impact on local biodiversity; (2) the small knowledge base of extant global biodiversity; (3) a lack of much-needed site-specific data on the species composition of communities in human-dominated landscapes, which hinders ecosystem management and biodiversity conservation; (4) biodiversity studies with a lack of taxonomic precision; (5) a lack of taxonomic expertise and trained taxonomists; (6) a taxonomic bottleneck in biodiversity inventory and assessment; and (7) neglect of taxonomic resources and a lack of taxonomic service infrastructure for biodiversity science. These limitations are directly related to contemporary trends in research, conservation strategies, environmental stewardship, environmental education, sustainable development, and local site-specific conservation. Today’s biological knowledge is built on the known global biodiversity, which represents barely 20% of what is currently extant (commonly accepted estimate of 10 million species) on planet Earth. Much remains unexplored and unknown, particularly in hotspots regions of Africa, South Eastern Asia, and South and Central America, including many developing or underdeveloped countries, where localized biodiversity is scarcely studied or described. ‘‘Backyard biodiversity’’, defined as local biodiversity near human habitation, refers to the natural resources and capital for ecosystem services at the grassroots level, which urgently needs to be explored, documented, and conserved as it is the backbone of sustainable economic development in these countries. Beginning with early identification and documentation of local flora and fauna, taxonomy has documented global biodiversity and natural history based on the collection of ‘‘backyard biodiversity’’ specimens worldwide. However, this branch of science suffered a continuous decline in the latter half of the twentieth century, and has now reached a point of potential demise. At present there are very few professional taxonomists and trained local parataxonomists worldwide, while the need for, and demands on, taxonomic services by conservation and resource management communities are rapidly increasing. Systematic collections, the material basis of biodiversity information, have been neglected and abandoned, particularly at institutions of higher learning. Considering the rapid increase in the human population and urbanization, human sustainability requires new conceptual and practical approaches to refocusing and energizing the study of the biodiversity that is the core of natural resources for sustainable development and biotic capital for sustaining our life-support system. In this paper we aim to document and extrapolate the essence of biodiversity, discuss the state and nature of taxonomic demise, the trends of recent biodiversity studies, and suggest reasonable approaches to a biodiversity science to facilitate the expansion of global biodiversity knowledge and to create useful data on backyard biodiversity worldwide towards human sustainability

Hard Photodisintegration of a Proton Pair

We present a study of high energy photodisintegration of proton-pairs through the gamma + 3He -> p+p+n channel. Photon energies from 0.8 to 4.7 GeV were used in kinematics corresponding to a proton pair with high relative momentum and a neutron nearly at rest. The s-11 scaling of the cross section, as predicted by the constituent counting rule for two nucleon photodisintegration, was observed for the first time. The onset of the scaling is at a higher energy and the cross section is significantly lower than for deuteron (pn pair) photodisintegration. For photon energies below the scaling region, the scaled cross section was found to present a strong energy-dependent structure not observed in deuteron photodisintegration.Comment: 7 pages, 3 figures, for submission to Phys. Lett.

GI Bleeding in the Elderly

Purpose: To determine the risk factors contributing to and etiologies of gastrointestinal bleeding in an elderly patient population seen by Southwest Gastroenterology (SWGA) providers. Methods: This study reviews charts of patients with GI bleeding from documented sources between 1/1999 and 3/2006. The cases are gathered retrospectively from the clinical records of SWGA, a 12-person private, single specialty gastroenterology group serving community hospitals. Etiology and risk factors for GI hemorrhages are recorded in an elderly population, defined as patients age 55 and older. Results: GI hemorrhages are identified in 105 patients. The majority (83, 79%) of hemorrhages are upper GI bleeds (UGIB) comparing to 22 (21%) lower GI bleeds (LGIB). In the UGIB group, the most common etiology of bleed is gastric ulcer (29%). We also found 72% of UGIB patients on prescribed anticoagulation medications, including anti-platelet agents or non-steroidal anti-inflammatory drugs (NSAIDs). 20% of these patients are also positive for H. Pylori. Thirty patients in the UGIB group smoke or consume alcohol heavily (consuming more than 3 drinks per day for men and two drinks per day for women) while 2 patients smoke or consume alcohol in the LGIB group. Previous bleeds are common in both groups with 39 (41%) in UGIB and 9 (47%) in LGIB. Co-morbidity is the most common risk factor with 20 (91%) in LGIB and 73 (88%) in UGIB. In the peptic ulcer disease (PUD) bleeds, the majority (77%) are taking NSAIDs, while in the non-PUD bleeds, only 38% are currently on NSAIDs. Overall, there are 2 mortalities resulting from cardiovascular complications of GI bleeding. Conclusion: The etiologies of GI bleeds in this population are comparable to other studies in the literature. The ratio of UGIB to LGIB in this elderly population is also similar to that reported in the literature. The risk factors shown to be most correlated to bleeding are co-morbidities, previous episodes of bleeding, anticoagulation, NSAID use, smoking and alcohol use. NSAID use is significant in PUD bleed patients. This study reinforces that increased knowledge of etiology, incidence and contributing factors of GI bleeding are necessary for physicians to efficiently treat GI bleeds in the elderly population

Materials characterization of cermet anodes tested in a pilot cell

Cermet anodes were evaluated as nonconsumable substitutes for carbon anodes using a pilot-scale reduction cell at the Reynolds Manufacturing Technology Laboratory. After pilot cell testing, tile anodes were subjected to extensive materials characterization and physical properties measurements at the Pacific Northwest Laboratory. Significant changes in the composition of the cermet anodes were observed including the growth of a reaction layer and penetration of electrolyte deep into the cermet matrix. Fracture strength and toughness were measured as a function of temperature and the ductile-brittle transition wasreduced by 500C following pilot cell testing. These results imply difficulties with anode material and control of operating conditions in the pilot cell, and suggest that additional development work be performed before the cermet anodes are used in commercial reduction cells. The results also highlight specific fabrication and operational considerations that should be addressed in future testing

An Electron Fixed Target Experiment to Search for a New Vector Boson A' Decaying to e+e-

We describe an experiment to search for a new vector boson A' with weak coupling alpha' > 6 x 10^{-8} alpha to electrons (alpha=e^2/4pi) in the mass range 65 MeV < m_A' < 550 MeV. New vector bosons with such small couplings arise naturally from a small kinetic mixing of the "dark photon" A' with the photon -- one of the very few ways in which new forces can couple to the Standard Model -- and have received considerable attention as an explanation of various dark matter related anomalies. A' bosons are produced by radiation off an electron beam, and could appear as narrow resonances with small production cross-section in the trident e+e- spectrum. We summarize the experimental approach described in a proposal submitted to Jefferson Laboratory's PAC35, PR-10-009. This experiment, the A' Experiment (APEX), uses the electron beam of the Continuous Electron Beam Accelerator Facility at Jefferson Laboratory (CEBAF) at energies of ~1-4 GeV incident on 0.5-10% radiation length Tungsten wire mesh targets, and measures the resulting e+e- pairs to search for the A' using the High Resolution Spectrometer and the septum magnet in Hall A. With a ~1 month run, APEX will achieve very good sensitivity because the statistics of e+e- pairs will be ~10,000 times larger in the explored mass range than any previous search for the A' boson. These statistics and the excellent mass resolution of the spectrometers allow sensitivity to alpha'/alpha one to three orders of magnitude below current limits, in a region of parameter space of great theoretical and phenomenological interest. Similar experiments could also be performed at other facilities, such as the Mainz Microtron.Comment: 19 pages, 12 figures, 2 table

Radiographers supporting radiologists in the interpretation of screening mammography: a viable strategy to meet the shortage in the number of radiologists.

BackgroundAn alternative approach to the traditional model of radiologists interpreting screening mammography is necessary due to the shortage of radiologists to interpret screening mammograms in many countries.MethodsWe evaluated the performance of 15 Mexican radiographers, also known as radiologic technologists, in the interpretation of screening mammography after a 6 months training period in a screening setting. Fifteen radiographers received 6 months standardized training with radiologists in the interpretation of screening mammography using the Breast Imaging Reporting and Data System (BI-RADS) system. A challenging test set of 110 cases developed by the Breast Cancer Surveillance Consortium was used to evaluate their performance. We estimated sensitivity, specificity, false positive rates, likelihood ratio of a positive test (LR+) and the area under the subject-specific Receiver Operating Characteristic (ROC) curve (AUC) for diagnostic accuracy. A mathematical model simulating the consequences in costs and performance of two hypothetical scenarios compared to the status quo in which a radiologist reads all screening mammograms was also performed.ResultsRadiographer's sensitivity was comparable to the sensitivity scores achieved by U.S. radiologists who took the test but their false-positive rate was higher. Median sensitivity was 73.3 % (Interquartile range, IQR: 46.7-86.7 %) and the median false positive rate was 49.5 % (IQR: 34.7-57.9 %). The median LR+ was 1.4 (IQR: 1.3-1.7 %) and the median AUC was 0.6 (IQR: 0.6-0.7). A scenario in which a radiographer reads all mammograms first, and a radiologist reads only those that were difficult for the radiographer, was more cost-effective than a scenario in which either the radiographer or radiologist reads all mammograms.ConclusionsGiven the comparable sensitivity achieved by Mexican radiographers and U.S. radiologists on a test set, screening mammography interpretation by radiographers appears to be a possible adjunct to radiologists in countries with shortages of radiologists. Further studies are required to assess the effectiveness of different training programs in order to obtain acceptable screening accuracy, as well as the best approaches for the use of non-physician readers to interpret screening mammography