3,444 research outputs found
Deciphering interplay between Salmonella invasion effectors
Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction
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Natural selection on individual variation in tolerance of gastrointestinal nematode infection
This is the final version of the article. Available from the publisher via the DOI in this record.Hosts may mitigate the impact of parasites by two broad strategies: resistance, which limits parasite burden, and tolerance, which limits the fitness or health cost of increasing parasite burden. The degree and causes of variation in both resistance and tolerance are expected to influence host-parasite evolutionary and epidemiological dynamics and inform disease management, yet very little empirical work has addressed tolerance in wild vertebrates. Here, we applied random regression models to longitudinal data from an unmanaged population of Soay sheep to estimate individual tolerance, defined as the rate of decline in body weight with increasing burden of highly prevalent gastrointestinal nematode parasites. On average, individuals lost weight as parasite burden increased, but whereas some lost weight slowly as burden increased (exhibiting high tolerance), other individuals lost weight significantly more rapidly (exhibiting low tolerance). We then investigated associations between tolerance and fitness using selection gradients that accounted for selection on correlated traits, including body weight. We found evidence for positive phenotypic selection on tolerance: on average, individuals who lost weight more slowly with increasing parasite burden had higher lifetime breeding success. This variation did not have an additive genetic basis. These results reveal that selection on tolerance operates under natural conditions. They also support theoretical predictions for the erosion of additive genetic variance of traits under strong directional selection and fixation of genes conferring tolerance. Our findings provide the first evidence of selection on individual tolerance of infection in animals and suggest practical applications in animal and human disease management in the face of highly prevalent parasites.This study was funded by Natural Environment Research Council (http://www.nerc.ac.uk/) Standard Grant no. NE/G004854/1 and European Research
Council (http://erc.europa.eu/) Large Grant no. 250098 to JMP. ADH is supported by European Research Council grant no. R/120448-11-1 to V. Lummaa; DHN is
supported by Biotechnology and Biological Sciences Research Council (http://www.bbsrc.ac.uk/) David Phillips Fellowship no. BB/H021686/1; AJW is supported by
BBSRC David Phillips Fellowship no. BB/G022976/1; ALG is supported by Princeton University and the Research and Policy for Infectious Disease Dynamics
(RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center of the National
Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Deformation of Codimension-2 Surface and Horizon Thermodynamics
The deformation equation of a spacelike submanifold with an arbitrary
codimension is given by a general construction without using local frames. In
the case of codimension-1, this equation reduces to the evolution equation of
the extrinsic curvature of a spacelike hypersurface. In the more interesting
case of codimension-2, after selecting a local null frame, this deformation
equation reduces to the well known (cross) focusing equations. We show how the
thermodynamics of trapping horizons is related to these deformation equations
in two different formalisms: with and without introducing quasilocal energy. In
the formalism with the quasilocal energy, the Hawking mass in four dimension is
generalized to higher dimension, and it is found that the deformation of this
energy inside a marginal surface can be also decomposed into the contributions
from matter fields and gravitational radiation as in the four dimension. In the
formalism without the quasilocal energy, we generalize the definition of slowly
evolving future outer trapping horizons proposed by Booth to past trapping
horizons. The dynamics of the trapping horizons in FLRW universe is given as an
example. Especially, the slowly evolving past trapping horizon in the FLRW
universe has close relation to the scenario of slow-roll inflation. Up to the
second order of the slowly evolving parameter in this generalization, the
temperature (surface gravity) associated with the slowly evolving trapping
horizon in the FLRW universe is essentially the same as the one defined by
using the quasilocal energy.Comment: Latex, 61 pages, no figures; v2, type errors corrected; v3,
references and comments are added, English is improved, to appear in JHE
Local structure study of the orbital order/disorder transition in LaMnO3
We use a combination of neutron and X-ray total scattering measurements
together with pair distribution function (PDF) analysis to characterise the
variation in local structure across the orbital order--disorder transition in
LaMnO. Our experimental data are inconsistent with a conventional
order--disorder description of the transition, and reflect instead the
existence of a discontinuous change in local structure between ordered and
disordered states. Within the orbital-ordered regime, the neutron and X-ray
PDFs are best described by a local structure model with the same local orbital
arrangements as those observed in the average (long-range) crystal structure.
We show that a variety of meaningfully-different local orbital arrangement
models can give fits of comparable quality to the experimental PDFs collected
within the disordered regime; nevertheless, our data show a subtle but
consistent preference for the anisotropic Potts model proposed in \emph{Phys
Rev.\ B} {\bf 79}, 174106 (2009). The key implications of this model are
electronic and magnetic isotropy together with the loss of local inversion
symmetry at the Mn site. We conclude with a critical assessment of the
interpretation of PDF measurements when characterising local symmetry breaking
in functional materials.Comment: 14 pages, 8 figures, 3 table
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A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.
PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease
Macrophage subsets exhibit distinct E. coli-LPS tolerisable cytokines associated with the negative regulators, IRAK-M and Tollip
<div><p>Macrophages (Mϕs) play a central role in mucosal immunity by pathogen sensing and instruction of adaptive immune responses. Prior challenge to endotoxin can render Mφs refractory to secondary exposure, suppressing the inflammatory response. Previous studies demonstrated a differential subset-specific sensitivity to endotoxin tolerance (ET), mediated by LPS from the oral pathogen, <i>Porphyromonas gingivalis</i> (PG). The aim of this study was to investigate ET mechanisms associated with Mφ subsets responding to entropathogenic <i>E</i>. <i>coli</i> K12-LPS. M1- and M2-like Mφs were generated <i>in vitro</i> from the THP-1 cell line by differentiation with PMA and Vitamin D<sub>3</sub>, respectively. This study investigated ET mechanisms induced in M1 and M2 Mφ subsets, by measuring modulation of expression by RT-PCR, secretion of cytokines by sandwich ELISA, LPS receptor, TLR4, as well as endogenous TLR inhibitors, IRAK-M and Tollip by Western blotting. In contrast to PG-LPS tolerisation, <i>E</i>. <i>coli</i> K12-LPS induced ET failed to exhibit a subset-specific response with respect to the pro-inflammatory cytokine, TNFα, whereas exhibited a differential response for IL-10 and IL-6. TNFα expression and secretion was significantly suppressed in both M1- and M2-like Mφs. IL-10 and IL-6, on the other hand, were suppressed in M1s and refractory to suppression in M2s. ET suppressed TLR4 mRNA, but not TLR4 protein, yet induced differential augmentation of the negative regulatory molecules, Tollip in M1 and IRAK-M in M2 Mφs. In conclusion, <i>E</i>. <i>coli</i> K12-LPS differentially tolerises Mφ subsets at the level of anti-inflammatory cytokines, associated with a subset-specific divergence in negative regulators and independent of TLR4 down-regulation.</p></div
Precision Astrometry of a Sample of Speckle Binaries and Multiples with the Adaptive Optics Facilities at the Hale and Keck II Telescopes
Using the adaptive optics facilities at the 200-in Hale and 10-m Keck II, we
observed in the near infrared a sample of 12 binary and multiple stars and one
open cluster. We used the near diffraction limited images of these systems to
measure the relative separations and position angles between their components.
In this paper, we investigate and correct for the influence of the differential
chromatic refraction and chip distortions on our relative astrometric
measurements. Over one night, we achieve an astrometric precision typically
well below 1 miliarcsecond and occasionally as small as 40 microarcseconds.
Such a precision is in principle sufficient to astrometrically detect planetary
mass objects around the components of nearby binary and multiple stars. Since
we have not had sufficiently large data sets for the observed sample of stars
to detect planets, we provide the limits to planetary mass objects based on the
obtained astrometric precision.Comment: 18 pages, 8 figures, 9 tables, to appear in MNRA
Examining the role of positive and negative intergroup contact and anti-immigrant prejudice in Brexit
This study examined the interplay of anti-immigrant prejudice and intergroup contact experience on voting intentions within Britain’s 2016 referendum on its membership within the European Union. In the days before the referendum we asked more than 400 British people how they planned to vote. We measured a number of demographic factors expected to predict voting intentions as well as individuals’ prejudice toward, and intergroup contact experience (positive and negative) with EU immigrants. Anti-immigrant prejudice was a strong correlate of support for Brexit. Negative intergroup contact experience was associated with higher anti-immigrant prejudice and, in turn, increased support for ‘Leave’. Positive intergroup contact, on the other hand, seemed to play a reparative role, predicting lower prejudice and increasing support for ‘Remain’
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