Identification and characterisation of enteroaggregative Escherichia coli subtypes associated with human disease

Enteroaggregative E. coli (EAEC) are a major cause of diarrhoea worldwide. Due to their heterogeneity and carriage in healthy individuals, identification of diagnostic virulence markers for pathogenic strains has been difficult. In this study, we have determined phenotypic and genotypic differences between EAEC strains of sequence types (STs) epidemiologically associated with asymptomatic carriage (ST31) and diarrhoeal disease (ST40). ST40 strains demonstrated significantly enhanced intestinal adherence, biofilm formation, and pro-inflammatory interleukin-8 secretion compared with ST31 isolates. This was independent of whether strains were derived from diarrhoea patients or healthy controls. Whole genome sequencing revealed differences in putative virulence genes encoding aggregative adherence fimbriae, E. coli common pilus, flagellin and EAEC heat-stable enterotoxin 1. Our results indicate that ST40 strains have a higher intrinsic potential of human pathogenesis due to a specific combination of virulence-related factors which promote host cell colonization and inflammation. These findings may contribute to the development of genotypic and/or phenotypic markers for EAEC strains of high virulence

Development of a novel human intestinal model to elucidate the effect of anaerobic commensals on Escherichia coli infection

The gut microbiota plays a crucial role in protecting against enteric infection. However, the underlying mechanisms are largely unknown due to a lack of suitable experimental models. Whilst most gut commensals are anaerobic, intestinal epithelial cells require oxygen for survival. In addition, most intestinal cell lines do not produce mucus which provides a habitat for the microbiota. Here, we have developed a microaerobic, mucus-producing vertical diffusion chamber (VDC) model and determined the influence of Limosilactobacillus reuteri and Ruminococcus gnavus on enteropathogenic E. coli (EPEC) infection. Optimization of the culture medium enabled bacterial growth in the presence of mucus-producing T84/LS174T cells. While L. reuteri diminished EPEC growth and adhesion to T84/LS174T and mucus-deficient T84 epithelia, R. gnavus only demonstrated a protective effect in the presence of LS174T cells. Reduced EPEC adherence was not associated with altered type III secretion pore formation. In addition, co-culture with L. reuteri and R. gnavus dampened EPEC-induced interleukin-8 secretion. The microaerobic mucin-producing VDC system will facilitate investigations into the mechanisms underpinning colonization resistance and aid the development of microbiota-based anti-infection strategies

An observational study of ear-tagged calf mortality (1 to 100 days) on Irish dairy farms and associations between biosecurity practices and calf mortality on farms participating in a Johne's disease control program

Postnatal mortality among replacement stock has a detrimental effect on the social, economic, and environmental sustainability of dairy production. Calf mortality rates vary between countries and show differences in temporal trends; most, however, are characterized by high levels of between-farm variability. Explaining this variation can be difficult because herd-level information on management practices relevant to calf health is often not available. The Irish Johne's Control Programme (IJCP) contains a substantial on-farm monitoring program called the Veterinary Risk Assessment and Management Plan (VRAMP). Although this risk assessment is largely focused on factors relevant to the transmission of paratuberculosis, many of its principles are good practice biocontainment policies that are also advocated for the protection of calf health. The objectives of this study were (1) to quantify mortality in ear-tagged Irish dairy calves between 2016 and 2020 using both survival and risk approaches, (2) to determine risk factors for 100-d cumulative mortality hazard in ear-tagged Irish dairy calves between 2016 and 2020, (3) to determine whether 100-d cumulative mortality hazard was higher in ear-tagged calves within herds registered in the IJCP versus those that were not registered in the IJCP and whether there were differences between these cohorts over time, and (4) within IJCP herds, to determine whether VRAMP score or changes in VRAMP score were associated with 100-d cumulative mortality hazard. Excluding perinatal mortality, the overall 100-d cumulative mortality hazard was 4.1%. Calf mortality was consistently underestimated using risk approaches that did not account for calf censoring. Cox proportional hazards models showed that cumulative mortality hazard was greater in male calves; particularly, calves born to Jersey breed dams and those with a beef breed sire. Mortality hazard increased with increasing herd size, was highest in calves born in herds that contract-reared heifers, and lowest in those born in mixed dairy-beef enterprises. Mortality hazard decreased over time with the mortality hazard in 2020 being 0.83 times that of 2016. Mortality hazard was higher in IJCP-registered herds than nonregistered herds (hazard ratio 1.06, 95% CI 1.01–1.12), likely reflecting differences in herds that enrolled in the national program. However, we detected a significant interaction between IJCP status (enrolled vs. not enrolled) and year (hazard ratio 0.96, 95% CI 0.92–1.00), indicating that the decrease in mortality hazard between 2016 and 2020 was greater in IJCP herds versus non-IJCP herds. Finally, increasing VRAMP scores (indicating higher risk for paratuberculosis transmission) were positively associated with increased calf mortality hazard. Postnatal calf mortality rates in Irish dairy herds declined between 2016 and 2020. Our study suggests that implementation of recommended biocontainment practices to control paratuberculosis in IJCP herds was associated with a reduction in calf mortality hazard

"Cognitive Penetrability" - Ch 3 of Seemings and Epistemic Justification

In this chapter I introduce the thesis that perceptual appearances are cognitively penetrable and analyse cases made against phenomenal conservatism hinging on this thesis. In particular, I focus on objections coming from the externalist reliabilist camp and the internalist inferentialist camp. I conclude that cognitive penetrability doesn’t yield lethal or substantive difficulties for phenomenal conservatism

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

BACKGROUND: Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+) T cell responses to a malaria antigen induced by a live vaccine. METHODOLOGY AND FINDINGS: Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+) T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes

A VERITAS/Breakthrough Listen Search for Optical Technosignatures

The Breakthrough Listen Initiative is conducting a program using multiple telescopes around the world to search for "technosignatures": artificial transmitters of extraterrestrial origin from beyond our solar system. The VERITAS Collaboration joined this program in 2018, and provides the capability to search for one particular technosignature: optical pulses of a few nanoseconds duration detectable over interstellar distances. We report here on the analysis and results of dedicated VERITAS observations of Breakthrough Listen targets conducted in 2019 and 2020 and of archival VERITAS data collected since 2012. Thirty hours of dedicated observations of 136 targets and 249 archival observations of 140 targets were analyzed and did not reveal any signals consistent with a technosignature. The results are used to place limits on the fraction of stars hosting transmitting civilizations. We also discuss the minimum-pulse sensitivity of our observations and present VERITAS observations of CALIOP: a space-based pulsed laser onboard the CALIPSO satellite. The detection of these pulses with VERITAS, using the analysis techniques developed for our technosignature search, allows a test of our analysis efficiency and serves as an important proof-of-principle.Comment: 15 pages, 7 figure

VERITAS discovery of very high energy gamma-ray emission from S3 1227+25 and multiwavelength observations

We report the detection of very high energy gamma-ray emission from the blazar S3 1227+25 (VER J1230+253) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS). VERITAS observations of the source were triggered by the detection of a hard-spectrum GeV flare on May 15, 2015 with the Fermi-Large Area Telescope (LAT). A combined five-hour VERITAS exposure on May 16th and May 18th resulted in a strong 13$\sigma$ detection with a differential photon spectral index, $\Gamma$ = 3.8 $\pm$ 0.4, and a flux level at 9% of the Crab Nebula above 120 GeV. This also triggered target of opportunity observations with Swift, optical photometry, polarimetry and radio measurements, also presented in this work, in addition to the VERITAS and Fermi-LAT data. A temporal analysis of the gamma-ray flux during this period finds evidence of a shortest variability timescale of $\tau_{obs}$ = 6.2 $\pm$ 0.9 hours, indicating emission from compact regions within the jet, and the combined gamma-ray spectrum shows no strong evidence of a spectral cut-off. An investigation into correlations between the multiwavelength observations found evidence of optical and gamma-ray correlations, suggesting a single-zone model of emission. Finally, the multiwavelength spectral energy distribution is well described by a simple one-zone leptonic synchrotron self-Compton radiation model.Comment: 18 pages, 6 figures. Accepted for publication in the Astrophysical Journal (ApJ

CANDELS: The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey - The Hubble Space Telescope Observations, Imaging Data Products and Mosaics

This paper describes the Hubble Space Telescope imaging data products and data reduction procedures for the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). This survey is designed to document the evolution of galaxies and black holes at $z\sim1.5-8$, and to study Type Ia SNe beyond $z>1.5$. Five premier multi-wavelength sky regions are selected, each with extensive multiwavelength observations. The primary CANDELS data consist of imaging obtained in the Wide Field Camera 3 / infrared channel (WFC3/IR) and UVIS channel, along with the Advanced Camera for Surveys (ACS). The CANDELS/Deep survey covers \sim125 square arcminutes within GOODS-N and GOODS-S, while the remainder consists of the CANDELS/Wide survey, achieving a total of \sim800 square arcminutes across GOODS and three additional fields (EGS, COSMOS, and UDS). We summarize the observational aspects of the survey as motivated by the scientific goals and present a detailed description of the data reduction procedures and products from the survey. Our data reduction methods utilize the most up to date calibration files and image combination procedures. We have paid special attention to correcting a range of instrumental effects, including CTE degradation for ACS, removal of electronic bias-striping present in ACS data after SM4, and persistence effects and other artifacts in WFC3/IR. For each field, we release mosaics for individual epochs and eventual mosaics containing data from all epochs combined, to facilitate photometric variability studies and the deepest possible photometry. A more detailed overview of the science goals and observational design of the survey are presented in a companion paper.Comment: 39 pages, 25 figure

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Sloan Digital Sky Survey IV: Mapping the Milky Way, Nearby Galaxies, and the Distant Universe

We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median $z\sim 0.03$). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between $z\sim 0.6$ and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July