Intra- and interspecies interactions between prion proteins and effects of mutations and polymorphisms

Recently, crystallization of the prion protein in a dimeric form was reported. Here we show that native soluble homogenous FLAG-tagged prion proteins from hamster, man and cattle expressed in the baculovirus system are predominantly dimeric. The PrP/PrP interaction was confirmed in Semliki Forest virus-RNA transfected BHK cells co-expressing FLAG- and oligohistidine-tagged human PrP. The yeast two-hybrid system identified the octarepeat region and the C-terminal structured domain (aa90-aa230) of PrP as PrP/PrP interaction domains. Additional octarepeats identified in patients suffering from fCJD reduced (wtPrP versus PrP+90R) and completely abolished (PrP+90R versus PrP+90R) the PrP/PrP interaction in the yeast two-hybrid system. In contrast, the Met/Val polymorphism (aa129), the GSS mutation Pro102Leu and the FFI mutation Asp178Asn did not affect PrP/PrP interactions. Proof of interactions between human or sheep and bovine PrP, and sheep and human PrP, as well as lack of interactions between human or bovine PrP and hamster PrP suggest that interspecies PrP interaction studies in the yeast two-hybrid system may serve as a rapid pre-assay to investigate species barriers in prion diseases

Optimization of over-summer snow storage at midlatitudes and low elevation

Climate change, including warmer winter temperatures, a shortened snowfall season, and more rain-on-snow events, threatens nordic skiing as a sport. In response, oversummer snow storage, attempted primarily using woodchips as a cover material, has been successfully employed as a climate change adaptation strategy by high-elevation and/or high-latitude ski centers in Europe and Canada. Such storage has never been attempted at a site that is both low elevation and midlatitude, and few studies have quantified storage losses repeatedly through the summer. Such data, along with tests of different cover strategies, are prerequisites to optimizing snow storage strategies. Here, we assess the rate at which the volume of two woodchip-covered snow piles (each ∼ 200 m3), emplaced during spring 2018 in Craftsbury, Vermont (45° N and 360 m a.s.l.), changed. We used these data to develop an optimized snow storage strategy. In 2019, we tested that strategy on a much larger, 9300 m3 pile. In 2018, we continually logged air-to-snow temperature gradients under different cover layers including rigid foam, open-cell foam, and woodchips both with and without an underlying insulating blanket and an overlying reflective cover. We also measured ground temperatures to a meter depth adjacent to the snow piles and used a snow tube to measure snow density. During both years, we monitored volume change over the melt season using terrestrial laser scanning every 10- 14 d from spring to fall. In 2018, snow volume loss ranged from 0.29 to 2.81 m3 d-1, with the highest rates in midsummer and lowest rates in the fall; mean rates of volumetric change were 1.24 and 1.50 m3 d-1, 0.55 % to 0.72 % of initial pile volume per day. Snow density did increase over time, but most volume loss was the result of melting. Wet woodchips underlain by an insulating blanket and covered with a reflective sheet were the most effective cover combination for minimizing melt, likely because the aluminized surface reflected incoming short-wave radiation while the wet woodchips provided significant thermal mass, allowing much of the energy absorbed during the day to be lost by long-wave emission at night. The importance of the pile surface-area-tovolume ratio is demonstrated by 4-fold lower rates of volumetric change for the 9300 m3 pile emplaced in 2019; it lost \u3c 0:16 % of its initial volume per day between April and October, retaining ∼ 60 % of the initial snow volume over summer. Together, these data demonstrate the feasibility of oversummer snow storage at midlatitudes and low elevations and suggest efficient cover strategies

An extreme proto-cluster of luminous dusty starbursts in the early Universe

We report the identification of an extreme proto-cluster of galaxies in the early Universe whose core (nicknamed Distant Red Core, DRC) is formed by at least ten dusty star-forming galaxies (DSFGs), confirmed to lie at $z_{\rm spec} = 4.002$ via detection of [CI](1-0), $^{12}$CO(6-5), $^{12}$CO(4-3), $^{12}$CO(2-1) and ${\rm H_2O} (2_{11} - 2_{02})$ emission lines, detected using ALMA and ATCA. The spectroscopically-confirmed components of the proto-cluster are distributed over a ${\rm 260\, kpc \times 310\, kpc}$ region and have a collective obscured star-formation rate (SFR) of $\sim 6500 \, M_\odot \, {\rm yr}^{-1}$, considerably higher than has been seen before in any proto-cluster of galaxies or over-densities of DSFGs at $z \gtrsim 4$. Most of the star formation is taking place in luminous DSFGs since no Ly$\alpha$ emitters are detected in the proto-cluster core, apart from a Ly$\alpha$ blob located next to one of the DRC dusty components and extending over $60\,{\rm kpc}$. The total obscured SFR of the proto-cluster could rise to ${\rm SFR} \sim 14,400 \, M_\odot \, {\rm yr}^{-1}$ if all the members of an over-density of bright DSFGs discovered around DRC in a wide-field LABOCA 870-$\mu$m image are part of the same structure. The total halo mass of DRC could be as high as $\sim 4.4 \times 10^{13}\,M_\odot$ and could be the progenitor of a Coma-like cluster at $z = 0$. The relatively short gas-depletion times of the DRC components suggest either the presence of a mechanism able to trigger extreme star formation simultaneously in galaxies spread over a few hundred kpc or the presence of gas flows from the cosmic web able to sustain star formation over several hundred million years.Comment: Submitted to ApJ. Minor updates added, including a change of the source name. Comments welcom

Vitamin D related genes in lung development and asthma pathogenesis

Background: Poor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility. We hypothesized that vitamin D pathway genes are developmentally active in the fetal lung and that these developmental genes would be associated with asthma susceptibility and regulation in asthma. Methods: Vitamin D pathway genes were derived from PubMed and Gene Ontology surveys. Principal component analysis was used to identify characteristic lung development genes. Results: Vitamin D regulated genes were markedly over-represented in normal human (odds ratio OR 2.15, 95% confidence interval CI: 1.69-2.74) and mouse (OR 2.68, 95% CI: 2.12-3.39) developing lung transcriptomes. 38 vitamin D pathway genes were in both developing lung transcriptomes with >63% of genes more highly expressed in the later than earlier stages of development. In immortalized B-cells derived from 95 asthmatics and their unaffected siblings, 12 of the 38 (31.6%) vitamin D pathway lung development genes were significantly differentially expressed (OR 3.00, 95% CI: 1.43-6.21), whereas 11 (29%) genes were significantly differentially expressed in 43 control versus vitamin D treated immortalized B-cells from Childhood Asthma Management Program subjects (OR 2.62, 95% CI: 1.22-5.50). 4 genes, LAMP3, PIP5K1B, SCARB2 and TXNIP were identified in both groups; each displays significant biologic plausibility for a role in asthma. Conclusions: Our findings demonstrate a significant association between early lung development and asthma–related phenotypes for vitamin D pathway genes, supporting a genomic mechanistic basis for the epidemiologic observations relating maternal vitamin D intake and childhood asthma susceptibility

Antimicrobial Microwebs of DNA–Histone Inspired from Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs) are decondensed chromatin networks released by neutrophils that can trap and kill pathogens but can also paradoxically promote biofilms. The mechanism of NET functions remains ambiguous, at least in part, due to their complex and variable compositions. To unravel the antimicrobial performance of NETs, a minimalistic NET‐like synthetic structure, termed “microwebs,” is produced by the sonochemical complexation of DNA and histone. The prepared microwebs have structural similarity to NETs at the nanometer to micrometer dimensions but with well‐defined molecular compositions. Microwebs prepared with different DNA to histone ratios show that microwebs trap pathogenic Escherichia coli in a manner similar to NETs when the zeta potential of the microwebs is positive. The DNA nanofiber networks and the bactericidal histone constituting the microwebs inhibit the growth of E. coli. Moreover, microwebs work synergistically with colistin sulfate, a common and a last‐resort antibiotic, by targeting the cell envelope of pathogenic bacteria. The synthesis of microwebs enables mechanistic studies not possible with NETs, and it opens new possibilities for constructing biomimetic bacterial microenvironments to better understand and predict physiological pathogen responses.Microwebs with bacteria trapping and killing functions are designed to mimic neutrophil extracellular traps—an immune defense weapon to fight against invading pathogens. The composition–structure–function relationship of the synthetic structure is discussed, and the collaborative action between microwebs and antibiotics allows better elimination of pathogenic bacteria, Escherichia coli.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/1/adma201807436-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/2/adma201807436_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/3/adma201807436.pd

Prevalence and determinants of the use of self-tests by members of the public: a mixed methods study

Background Self-tests can be used by members of the public to diagnose conditions without involving a doctor, nurse or other health professional. As technologies to design and manufacture diagnostic tests have developed, a range of self-tests have become available to the public to buy over-the-counter and via the Internet. This study aims to describe how many people have used self-tests and identify factors associated with their use. Methods A postal questionnaire will elicit basic information, including sociodemographic characteristics, and whether the person has used or would use specified self-tests. Consent will be sought to recontact people who want to participate further in the study, and interviews and focus groups will be used to develop hypotheses about factors associated with self-test use. These hypotheses will be tested in a case-control study. An in-depth questionnaire will be developed incorporating the identified factors. This will be sent to: people who have used a self-test (cases); people who have not used a self-test but would use one in the future (controls); and people who have not used and would not use a self-test (controls). Logistic regression analysis will be used to establish which factors are associated with self-test use. Discussion Self-tests do have potential benefits, for example privacy and convenience, but also potential harms, for example delay seeking treatment after a true negative result when the symptoms are actually due to another condition. It is anticipated that the outcomes from this study will include recommendations about how to improve the appropriate use of self-tests and existing health services, as well as information to prepare health professionals for patients who have used self-tests

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

BackgroundGlobal gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.MethodsWe used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.ResultsThe SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.ConclusionFocusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids

Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - Prediction of combined effects by concentration addition

This is the post-print version of the final paper published in Aquatic Toxicology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2013 Elsevier B.V.Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment.European Commission and Natural Environment Research Council

Census politics in deeply divided societies

Population censuses in societies that are deeply divided along ethnic, religious or linguistic lines can be sensitive affairs – particularly where political settlements seek to maintain peace through the proportional sharing of power between groups. This brief sets out some key findings from a research project investigating the relationship between census politics and the design of political institutions in Bosnia and Herzegovina, Kenya, Lebanon and Northern Ireland

A near-infrared morphological comparison of high-redshift submm and radio galaxies: massive star-forming discs vs relaxed spheroids

We present deep, high-quality K-band images of complete subsamples of powerful radio and sub-mm galaxies at z=2. The data were obtained in the best available seeing at UKIRT and Gemini North, with integration times scaled to ensure that comparable rest-frame surface brightness levels are reached for all galaxies. We fit two-dimensional axi-symmetric galaxy models to determine galaxy morphologies at rest-frame optical wavelengths > 4000A, varying luminosity, axial ratio, half-light radius, and Sersic index. We find that, while some images show evidence of galaxy interactions, >95% of the rest-frame optical light in all galaxies is well-described by these simple models. We also find a clear difference in morphology between these two classes of galaxy; fits to the individual images and image stacks reveal that the radio galaxies are moderately large (=8.4+-1.1kpc; median r{1/2}=7.8), de Vaucouleurs spheroids ( = 4.07+-0.27; median n=3.87), while the sub-mm galaxies appear to be moderately compact (=3.4+-0.3kpc; median r{1/2}=3.1kpc) exponential discs (=1.44+-0.16; median n=1.08). We show that the z=2 radio galaxies display a well-defined Kormendy relation but that, while larger than other recently-studied high-z massive galaxy populations, they are still ~1.5 times smaller than their local counterparts. The scalelengths of the starlight in the sub-mm galaxies are comparable to those reported for the molecular gas. Their sizes are also similar to those of comparably massive quiescent galaxies at z>1.5. In terms of stellar mass surface density, the majority of the radio galaxies lie within the locus defined by local ellipticals. In contrast, while best modelled as discs, most of the sub-mm galaxies have higher stellar mass densities than local galaxies, and appear destined to evolve into present-day massive ellipticals.Comment: 24 pages, 9 figure