51 research outputs found
β-Catenin Signaling Drives Differentiation and Proinflammatory Function of IRF8-Dependent Dendritic Cells.
β-Catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for β-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express β-catenin, and DCs from mice with CD11c-specific constitutive β-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8α(+), plasmacytoid, and CD103(+)CD11b(-) DCs. β-Catenin-stabilized CD8α(+) DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological β-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC β-catenin displayed abnormally high Th1 and CD8(+) T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for β-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection
Theory of High-Force DNA Stretching and Overstretching
Single molecule experiments on single- and double stranded DNA have sparked a
renewed interest in the force-extension of polymers. The extensible Freely
Jointed Chain (FJC) model is frequently invoked to explain the observed
behavior of single-stranded DNA. We demonstrate that this model does not
satisfactorily describe recent high-force stretching data. We instead propose a
model (the Discrete Persistent Chain, or ``DPC'') that borrows features from
both the FJC and the Wormlike Chain, and show that it resembles the data more
closely. We find that most of the high-force behavior previously attributed to
stretch elasticity is really a feature of the corrected entropic elasticity;
the true stretch compliance of single-stranded DNA is several times smaller
than that found by previous authors. Next we elaborate our model to allow
coexistence of two conformational states of DNA, each with its own stretch and
bend elastic constants. Our model is computationally simple, and gives an
excellent fit through the entire overstretching transition of nicked,
double-stranded DNA. The fit gives the first values for the elastic constants
of the stretched state. In particular we find the effective bend stiffness for
DNA in this state to be about 10 nm*kbt, a value quite different from either
B-form or single-stranded DNAComment: 33 pages, 11 figures. High-quality figures available upon reques
Quantum state engineering assisted by entanglement
We suggest a general scheme for quantum state engineering based on
conditional measurements carried out on entangled twin-beam of radiation.
Realistic detection schemes such as {\sc on/off} photodetection, homodyne
detection and joint measurement of two-mode quadratures are analyzed in
details. Imperfections of the apparatuses, such as nonunit quantum efficiency
and finite resolution, are taken into account. We show that conditional {\sc
on/off} photodetection provides a reliable scheme to verify nonclassicality,
whereas conditional homodyning represents a tunable and robust source of
squeezed light. We also describe optical teleportation as a conditional
measurement, and evaluate the degrading effects of finite amount of
entanglement, decoherence due to losses, and nonunit quantum efficiency.Comment: Some pics with low resolution. Originals at http://www.qubit.i
Mesoscopic models for DNA stretching under force: new results and comparison to experiments
Single molecule experiments on B-DNA stretching have revealed one or two
structural transitions, when increasing the external force. They are
characterized by a sudden increase of DNA contour length and a decrease of the
bending rigidity. It has been proposed that the first transition, at forces of
60--80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA,
while the second one, at stronger forces, is a strand peeling resulting in
single stranded DNAs (ssDNA), similar to thermal denaturation. But due to
experimental conditions these two transitions can overlap, for instance for
poly(dA-dT). We derive analytical formula using a coupled discrete worm like
chain-Ising model. Our model takes into account bending rigidity, discreteness
of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit
of zero force, this model simplifies into a coupled model already developed by
us for studying thermal DNA melting, establishing a connexion with previous
fitting parameter values for denaturation profiles. We find that: (i) ssDNA is
fitted, using an analytical formula, over a nanoNewton range with only three
free parameters, the contour length, the bending modulus and the monomer size;
(ii) a surprisingly good fit on this force range is possible only by choosing a
monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase
length; (iii) mesoscopic models are not able to fit B to ssDNA (or S to ss)
transitions; (iv) an analytical formula for fitting B to S transitions is
derived in the strong force approximation and for long DNAs, which is in
excellent agreement with exact transfer matrix calculations; (v) this formula
fits perfectly well poly(dG-dC) and -DNA force-extension curves with
consistent parameter values; (vi) a coherent picture, where S to ssDNA
transitions are much more sensitive to base-pair sequence than the B to S one,
emerges.Comment: 14 pages, 9 figure
Force unfolding kinetics of RNA using optical tweezers. II. Modeling experiments
By exerting mechanical force it is possible to unfold/refold RNA molecules
one at a time. In a small range of forces, an RNA molecule can hop between the
folded and the unfolded state with force-dependent kinetic rates. Here, we
introduce a mesoscopic model to analyze the hopping kinetics of RNA hairpins in
an optical tweezers setup. The model includes different elements of the
experimental setup (beads, handles and RNA sequence) and limitations of the
instrument (time lag of the force-feedback mechanism and finite bandwidth of
data acquisition). We investigated the influence of the instrument on the
measured hopping rates. Results from the model are in good agreement with the
experiments reported in the companion article (1). The comparison between
theory and experiments allowed us to infer the values of the intrinsic
molecular rates of the RNA hairpin alone and to search for the optimal
experimental conditions to do the measurements. We conclude that long handles
and soft laser traps represent the best conditions to extract rate estimates
that are closest to the intrinsic molecular rates. The methodology and
rationale presented here can be applied to other experimental setups and other
molecules.Comment: PDF file, 32 pages including 9 figures plus supplementary materia
SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling
Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19
The ICE hypothesis stands: How the dogma of late Cenozoic tectonic uplift can no longer be sustained in the light of data and physical laws
International audienceIn this reply, we address the issues raised by the comment of Chalmers et al. (2010) regarding our ICE hypothesis for the evolution of western Scandinavia. We reject their conjectures as based, uncritically and without consideration of physical mechanisms, on the long-standing dogma of late Cenozoic tectonic uplift. Our hypothesis, in contrast, honours well-documented physical laws and the present wealth of actual data constraints (as opposed to dogma-biased inferences). After careful consideration of the points raised by Chalmers et al. (2010) we maintain our simple explanation for the evolution of Scandinavian topography, as it honours well-documented actual data constraints, such as crustal structure (including its spatio-temporal variability), thermal history in the eastern North Sea, global and regional climatic change (including eustacy) and sedimentation in the adjacent basins. The inevitable conclusion is that, although more data constraints are desirable, the current best fit hypothesis, is that the Scandinavian topography is of Caledonide origin, and has been shaped by fluvial and glacial buzzsaw and periglacial processes, and most recently (last few Myr) been re-invigorated by extensive glacial erosion in the fjords and on the shelf
- …