Cloning of a Carcinoembryonic Antigen Gene Family Member Expressed in Leukocytes of Chronic Myeloid Leukemia Patients and Bone Marrow

The carcinoembryonic antigen (CEA) gene family belongs to the immunoglobulin superfamily and can be subdivided into the CEA and pregnancy-specific glycoprotein subgroups. The basic structure of the encoded proteins consists of, in addition to a leader, one IgV-like and 2, 3, or 6 IgC-like domains. These domains are followed by varying COOH-terminal regions responsible for secretion, transmembrane anchoring, or insertion into the membrane by a glycosyl phosphatidylinositol tail. Here we report on the characterization of CGM6, a new member of the CEA gene subgroup, by complementary DNA cloning. The deduced coding region comprises 349 amino acids and consists of a leader, one IgV-like, two IgC-like domains, and a hydrophobic region, which is replaced by a glycosyl phosphatidylinositol moiety in the mature protein. CGM6 transcripts were only found thus far in leukocytes of chronic myeloid leukemia patients, in normal bone marrow, and in marginal amounts in normal granulocytes. The CGM6 gene product might, therefore, represent a myeloid marker. Analyses of CGM6 protein-expressing HeLa transfectants with monoclonal antibodies strongly indicate that the CGM6 gene codes for the CEA family member NCA-95

Temperature is a poor proxy for synergistic climate forcing of plankton evolution

This is the author accepted manuscript. The final version is available from The Royal Society via the DOI in this record.Abundance data available in Figshare via the link in this record.Changes in biodiversity at all levels from molecules to ecosystems are often linked to climate change, which is widely represented univariately by temperature. A global environmental driving mechanism of biodiversity dynamics is thus implied by the strong correlation between temperature proxies and diversity patterns in a wide variety of fauna and flora. Yet climate consists of many interacting variables. Species likely respond to the entire climate system as opposed to its individual facets. Here, we examine ecological and morphological traits of 12,629 individuals of two species of planktonic foraminifera with similar ecologies but contrasting evolutionary outcomes. Our results show that morphological and ecological changes are correlated to the interactions between multiple environmental factors. Models including interactions between climate variables explain at least twice as much variation in size, shape and abundance changes as models assuming that climate parameters operate independently. No dominant climatic driver can be identified: temperature alone explains remarkably little variation through our highly resolved temporal sequences, implying that a multivariate approach is required to understand evolutionary response to abiotic forcing. Our results caution against the use of a ‘silver bullet’ environmental parameter to represent global climate while studying evolutionary responses to abiotic change, and show that more comprehensive reconstruction of paleobiological dynamics requires multiple biotic and abiotic dimensions.NERC Advanced Research Fellowship NE/J018163/1Royal Society Wolfson Research Merit Awar

Interleukin‐12p70-dependent interferon‐γ production is crucial for resistance in African trypanosomiasis

African trypanosomiasis encompasses diseases caused by pathogenic trypanosomes, infecting both humans and animals. In the present article, we dissected the possible role of members of the interleukin ( IL)-12 family during infection with Trypanosoma brucei brucei and Trypanosoma evansi in mice. IL-12p35(-/-) , IL-12p40(-/-) , and IL-12p35(-/-)/p40(-/-) mice were susceptible to both pathogens, as was demonstrated by the increased mortality among these mice, compared with wild-type C57BL/6 mice. The different IL-12p70(-/-) mouse strains showed similar mortality kinetics, suggesting that IL-12p70 - but not the IL-12p80 homodimer or IL-23 plays a crucial role in survival. Although there were similar plasma levels of immunoglobulin (Ig) M and IgG2a in IL-12-deficient mice and wild-type mice, interferon (IFN) - g production, especially during early infection, was severely impaired in all IL-12p70(-/-) mouse strains, demonstrating an IL-12p70 - dependent mechanism for IFN-gamma production. Because IFN-gamma receptor-deficient mice (IFN-gamma R-/(-)) were also highly susceptible to both Trypanosoma species, IL-12p70 - dependent IFN-gamma production seems to be the important mechanism involved in resistance against both pathogens

Electronic Excitations in Complex Molecular Environments: Many-Body Green's Functions Theory in VOTCA-XTP

Many-body Green's functions theory within the GW approximation and the Bethe-Salpeter Equation (BSE) is implemented in the open-source VOTCA-XTP software, aiming at the calculation of electronically excited states in complex molecular environments. Based on Gaussian-type atomic orbitals and making use of resolution of identify techniques, the code is designed specifically for non-periodic systems. Application to the small molecule reference set successfully validates the methodology and its implementation for a variety of excitation types covering an energy range from 2-8 eV in single molecules. Further, embedding each GW-BSE calculation into an atomistically resolved surrounding, typically obtained from Molecular Dynamics, accounts for effects originating from local fields and polarization. Using aqueous DNA as a prototypical system, different levels of electrostatic coupling between the regions in this GW-BSE/MM setup are demonstrated. Particular attention is paid to charge-transfer (CT) excitations in adenine base pairs. It is found that their energy is extremely sensitive to the specific environment and to polarization effects. The calculated redshift of the CT excitation energy compared to a nucelobase dimer treated in vacuum is of the order of 1 eV, which matches expectations from experimental data. Predicted lowest CT energies are below that of a single nucleobase excitation, indicating the possibility of an initial (fast) decay of such an UV excited state into a bi-nucleobase CT exciton. The results show that VOTCA-XTP's GW-BSE/MM is a powerful tool to study a wide range of types of electronic excitations in complex molecular environments

Can existing usability techniques prevent tomorrow's usability problems?

Product usability is a product quality that ensures efficient and effective products which satisfy users. In spite of the many usability techniques that are available many users still experience usability problems when using electronic products. In this paper we present two studies that explore the (mis)match between the types of uncertainty addressed by existing usability techniques and the types of uncertainty in the product development process that can eventually result in usability problems. To explore this (mis)match, two studies are presented. The first study is to discover which usability techniques are used in practice to retrieve usability information to address the different types of uncertainty. The second study is a case study in product development practice which explores the types of uncertainty that causes the usability problems of a specific product. The overall contribution of this paper is that it offers greater insight into how usability techniques (do not) address uncertainty in the product development process

IL-13 Signals Independent of IL-4 Receptor-Alpha Chain to Drive Ovalbumin-Induced Dermatitis

Atopic dermatitis (AD) is an allergic skin condition that can result from intrinsic genetic factors or repetitive occupational damage. Disruption of the skin barrier leads to sensitization to allergens followed by local inflammation (Leung et al., 2004, Pigatto et al., 1992). Strong evidence has shown that the T helper-2 (Th2) cytokine, IL-13, is the dominant disease-causing factor in the pathogenesis of AD in mice (Nieuwenhuizen et al., 2009, Sivaprasad et al., 2010, Tazawa et al., 2004). Hence, it is possible that patients with AD would benefit from treatments specifically targeting IL-13 signaling pathways. However, current treatment strategies are limited to broader therapies, such as emollients, topical glucocorticoids, and calcineurin inhibitors (Beck et al., 2014, De Benedetto et al., 2012, Gittler et al., 2012). A recent study by Beck et al. (2014), which used the monoclonal antibody dupilumab to block IL-4 receptor-alpha (IL-4Rα) signaling, showed promise in targeting specific immunological pathways. Until recently, IL-13 was thought to signal only through the IL-4Rα/IL-13Rα1 complex; however, recent data suggest that IL-13 may also signal via IL-13Rα2, previously known as a decoy receptor. In AD, the signaling pathway of IL-13 remains to be defined. In this study we addressed this problem by using a combination of IL-4Rα–deficient mice that lacked or overexpressed IL-13 to determine if IL-13 can signal independently of the IL-4Rα chain to mediate AD. Our results may have potential implications for therapeutic strategies, such as using IL-4Rα–antagonists to treat the disease.National Research Foundation (South Africa

Aeronautic Instruments. Section II : Altitude Instruments

This report is Section two of a series of reports on aeronautic instruments (Technical Report nos. 125 to 132, inclusive). This section discusses briefly barometric altitude determinations, and describes in detail the principal types of altimeters and barographs used in aeronautics during the recent war. This is followed by a discussion of performance requirements for such instruments and an account of the methods of testing developed by the Bureau of Standards. The report concludes with a brief account of the results of recent investigations. For accurate measurements of altitude, reference must also be made to thermometer readings of atmospheric temperature, since the altitude is not fixed by atmospheric pressure alone. This matter is discussed in connection with barometric altitude determination

Understanding different types of recreational runners and how they use running-related technology

This study aims to help professionals in the field of running and running-related technology (i.e., sports watches and smartphone applications) to address the needs of runners. It investigates the various runner types—in terms of their attitudes, interests, and opinions (AIOs) with regard to running—and studies how they differ in the technology they use. Data used in this study were drawn from the standardized online Eindhoven Running Survey 2016 (ERS2016). In total, 3723 participants completed the questionnaire. Principal component analysis and cluster analysis were used to identify the different running types, and crosstabs obtained insights into the use of technology between different typologies. Based on the AIOs, four distinct runner types were identified: casual individual, social competitive, individual competitive, and devoted runners. Subsequently, we related the types to their use of sports watches and apps. Our results show a difference in the kinds of technology used by different runner types. Differentiation between types of runners can be useful for health professionals, policymakers involved in public health, engineers, and trainers or coaches to adapt their services to specific segments, in order to make use of the full potential of running-related systems to support runners to stay active and injury-free and contribute to a healthy lifestyle.</p

Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape

Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria

The Dynamics of Diachronous Extinction Associated with Climatic Deterioration near the Neogene/Quaternary Boundary

This is the final version. Available on open access from Wiley via the DOI in this recordTo predict extinction we must understand the processes leading to terminal population decline. Once a critical threshold of population size is reached, small environmental perturbations can push a species over the cliff-edge to extinction, so the main drivers of extinction are the factors that cause the initial reduction in population size. Most studies of population decline leading up to extinction focus on modern species in a human-dominated world. The drivers of population decline leading to non-human mediated extinctions are less well known but changes in climate are arguably the most widely invoked mechanism. Here, we report data on >16,000 individuals of the planktonic foraminifer Globoconella puncticulata from six sites in the Atlantic Ocean along a 83 degree-long latitudinal transect, over a 600,000-year interval leading up to the species’ global extinction during the late Pliocene-earliest Pleistocene intensification of Northern Hemisphere glaciation. We show changes in geographic range, abundance and body size. We find that populations do not follow a North-to-South sequence in extinction as Earth cooled and developed large ice sheets in the high latitudes of the Northern Hemisphere. Instead, our results suggest that (1) populations are differentially adapted to local environmental conditions such as nutrient availability, (2) population dynamics in core populations differ from those at the edge of their range, and (3) individual population responses to external pressures are essential to understanding the drivers of global extinction. Our study demonstrates the potential to transform our understanding of extinction dynamics through spatially replicated sampling of the highly-resolved marine microfossil record