An account of the operations of the British Army and of the state and sentiments of the people of Portugal and Spain : during the campaigns of the years 1808 & 1809 : in a series of letters

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

Oxysterols protect bovine endometrial cells against pore‐forming toxins from pathogenic bacteria

Many species of pathogenic bacteria secrete toxins that form pores in mammalian cell membranes. These membrane pores enable the delivery of virulence factors into cells, result in the leakage of molecules that bacteria can use as nutrients, and facilitate pathogen invasion. Inflammatory responses to bacteria are regulated by the side-chain-hydroxycholesterols 27-hydroxycholesterol and 25-hydroxycholesterol, but their effect on the intrinsic protection of cells against pore-forming toxins is unclear. Here, we tested the hypothesis that 27-hydroxycholesterol and 25-hydroxycholesterol help protect cells against pore-forming toxins. We treated bovine endometrial epithelial and stromal cells with 27-hydroxycholesterol or 25-hydroxycholesterol, and then challenged the cells with pyolysin, which is a cholesterol-dependent cytolysin from Trueperella pyogenes that targets these endometrial cells. We found that treatment with 27-hydroxycholesterol or 25-hydroxycholesterol protected both epithelial and stomal cells against pore formation and the damage caused by pyolysin. The oxysterols limited pyolysin-induced leakage of potassium and lactate dehydrogenase from cells, and reduced cytoskeletal changes and cytolysis. This oxysterol cytoprotection against pyolysin was partially dependent on reducing cytolysin-accessible cholesterol in the cell membrane and on activating liver X receptors. Treatment with 27-hydroxycholesterol also protected the endometrial cells against Staphylococcus aureus α hemolysin. Using mass spectrometry, we found 27-hydroxycholesterol and 25-hydroxycholesterol in uterine and follicular fluid. Furthermore, epithelial cells released additional 25-hydroxycholesterol in response to pyolysin. In conclusion, both 27-hydroxycholesterol and 25-hydroxycholesterol increased the intrinsic protection of bovine endometrial cells against pore-forming toxins. Our findings imply that side-chain-hydroxycholesterols may help defend the endometrium against pathogenic bacteria

SipA activation of caspase-3 is a decisive mediator of host cell survival at early stages of Salmonella enterica serovar Typhimurium infection

Salmonella invasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or other Salmonella pathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in an ex vivo intestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag for in vivo tracking of individual effectors

Propionic acid promotes the virulent phenotype of Crohn's disease-associated adherent-invasive Escherichia coli

Propionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn’s disease-associated adherent-invasive Escherichia coli (AIEC) through a murine model, in which intestinal PA levels are increased to mimic the human intestine, leads to the recovery of AIEC with significantly increased virulence. Similar phenotypic changes are observed outside the murine model when AIEC is grown in culture with PA as the sole carbon source; such PA exposure also results in AIEC that persists at 20-fold higher levels in vivo. RNA sequencing identifies an upregulation of genes involved in biofilm formation, stress response, metabolism, membrane integrity, and alternative carbon source utilization. PA exposure also increases virulence in a number of E. coli isolates from Crohn’s disease patients. Removal of PA is sufficient to reverse these phenotypic changes. Our data indicate that exposure to PA results in AIEC resistance and increased virulence in its presence

Whatever the Weather: Ambient Temperature Does Not Influence the Proportion of Males Born in New Zealand

BACKGROUND: The proportion of male births has been shown to be over 50% in temperate climates around the world. Given that fluctuations in ambient temperature have previously been shown to affect sex allocation in humans, we examined the hypothesis that ambient temperature predicts fluctuations in the proportion of male births in New Zealand. METHODOLOGY/PRINCIPAL FINDINGS: We tested three main hypotheses using time series analyses. Firstly, we used historical annual data in New Zealand spanning 1876-2009 to test for a positive effect of ambient temperature on the proportion of male births. The proportion of males born ranged by 3.17%, from 0.504 to 0.520, but no significant relationship was observed between male birth rates and mean annual temperature in the concurrent or previous years. Secondly, we examined whether changes in annual ambient temperature were negatively related to the proportion of male stillbirths from 1929-2009 and whether the proportion of male stillbirths negatively affected the proportion of male live births. We found no evidence that fewer male stillbirths occurred during warmer concurrent or previous years, though a declining trend in the proportion of male stillbirths was observed throughout the data. Thirdly, we tested whether seasonal ambient temperatures, or deviations from those seasonal patterns, were positively related to the proportion of male births using monthly data from 1980-2009. Patterns of male and female births are seasonal, but very similar throughout the year, resulting in a non-seasonal proportion of male births. However, no cross correlations between proportion of male births and lags of temperature were significant. CONCLUSIONS: Results showed, across all hypotheses under examination, that ambient temperatures were not related to the proportion of male births or the proportion of male stillbirths in New Zealand. While there is evidence that temperature may influence human sex allocation elsewhere, such effects of temperature are not universal

Propionic Acid Promotes the Virulent Phenotype of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli

The short chain fatty acid propionic acid is a bacterium-derived human intestinal antimicrobial and immune modulator used widely in Western food production and agriculture. Here, Ormsby et al. demonstrate that exposure to propionic acid induces virulence-associated phenotypic changes in Crohn's disease-associated adherent-invasive Escherichia coli (AIEC)

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

Constraints on the cosmic expansion history from GWTC-3

We use 47 gravitational-wave sources from the Third LIGO-Virgo-KAGRA Gravitational-Wave Transient Catalog (GWTC-3) to estimate the Hubble parameter $H(z)$, including its current value, the Hubble constant $H_0$. Each gravitational-wave (GW) signal provides the luminosity distance to the source and we estimate the corresponding redshift using two methods: the redshifted masses and a galaxy catalog. Using the binary black hole (BBH) redshifted masses, we simultaneously infer the source mass distribution and $H(z)$. The source mass distribution displays a peak around $34\, {\rm M_\odot}$, followed by a drop-off. Assuming this mass scale does not evolve with redshift results in a $H(z)$ measurement, yielding $H_0=68^{+12}_{-7} {\rm km\,s^{-1}\,Mpc^{-1}}$ ($68\%$ credible interval) when combined with the $H_0$ measurement from GW170817 and its electromagnetic counterpart. This represents an improvement of 17% with respect to the $H_0$ estimate from GWTC-1. The second method associates each GW event with its probable host galaxy in the catalog GLADE+, statistically marginalizing over the redshifts of each event's potential hosts. Assuming a fixed BBH population, we estimate a value of $H_0=68^{+8}_{-6} {\rm km\,s^{-1}\,Mpc^{-1}}$ with the galaxy catalog method, an improvement of 42% with respect to our GWTC-1 result and 20% with respect to recent $H_0$ studies using GWTC-2 events. However, we show that this result is strongly impacted by assumptions about the BBH source mass distribution; the only event which is not strongly impacted by such assumptions (and is thus informative about $H_0$) is the well-localized event GW190814