Summary
Airway and intestinal epithelial layers represent first‐line physical barriers, playing a key role in mucosal immunity. Barrier dysfunction, characterized by alterations such as disruption of ...cell–cell apical junctions and aberrant epithelial responses, probably constitutes early and key events for chronic immune responses to environmental antigens in the skin and in the gut. For instance, barrier dysfunction drives Th2 responses in atopic disorders or eosinophilic esophagitis. Such epithelial impairment is also a salient feature of allergic asthma and growing evidence indicates that barrier alterations probably play a driving role in this disease. IgA has been identified as the most abundant immunoglobulin in mucosa, where it acts as an active barrier through immune exclusion of inhaled or ingested antigens or pathogens. Historically, it has been thought to represent the serum factor underlying reaginic activity before IgE was discovered. Despite several studies about regulation and major functions of IgA at mucosal surfaces, its role in allergy remains largely unclear. This review aims at summarizing findings about epithelial functions and IgA biology that are relevant to allergy, and to integrate the emerging concepts and the recent developments in mucosal immunology, and how these could translate to clinical observations in allergy.
Selective gene silencing is key to development. It is generally accepted that H3K27me3-enriched heterochromatin maintains transcriptional repression established during early development and regulates ...cell fate. Conversely, H3K9me3-enriched heterochromatin prevents differentiation but constitutes protection against transposable elements. We exploited the fungus Podospora anserina, a valuable alternative to higher eukaryote models, to question the biological relevance and functional interplay of these two distinct heterochromatin conformations.
We established genome-wide patterns of H3K27me3 and H3K9me3 modifications, and found these marks mutually exclusive within gene-rich regions but not within repeats. We generated the corresponding histone methyltransferase null mutants and showed an interdependence of H3K9me3 and H3K27me3 marks. Indeed, removal of the PaKmt6 EZH2-like enzyme resulted not only in loss of H3K27me3 but also in significant H3K9me3 reduction. Similarly, removal of PaKmt1 SU(VAR)3-9-like enzyme caused loss of H3K9me3 and substantial decrease of H3K27me3. Removal of the H3K9me binding protein PaHP1 provided further support to the notion that each type of heterochromatin requires the presence of the other. We also established that P. anserina developmental programs require H3K27me3-mediated silencing, since loss of the PaKmt6 EZH2-like enzyme caused severe defects in most aspects of the life cycle including growth, differentiation processes and sexual reproduction, whereas loss of the PaKmt1 SU(VAR)3-9-like enzyme resulted only in marginal defects, similar to loss of PaHP1.
Our findings support a conserved function of the PRC2 complex in fungal development. However, we uncovered an intriguing evolutionary fluidity in the repressive histone deposition machinery, which challenges canonical definitions of constitutive and facultative heterochromatin.
The future regimes of operation of the LHC will require improved control of β* measurements to successfully level the luminosities in the interaction points. The method of k modulation has been ...widely used in other machines to measure lattice beta functions. In the LHC, k modulation of the closest quadrupoles to the interaction point (IP) is the most accurate method to measure β* at the IP. This paper highlights the challenge of high precision tune measurements (down to 10−5 ) for the correct determination of β* in the high luminosity LHC. Furthermore it presents a new analytical method for the calculation of β* using k modulation.
Collimation simulations for the FCC-ee Abramov, A.; Broggi, G.; Bruce, R. ...
Journal of instrumentation,
02/2024, Letnik:
19, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
The collimation system of the Future Circular Collider,
operating with leptons (FCC-ee), must protect not only the
experiments against backgrounds, but also the machine itself from
beam ...losses. With a 17.8 MJ stored energy of the electron and
positron beams, they are highly destructive, and beam losses risk to
cause damage or a quench of superconducting elements. Accurate
collimation simulation tools and models are needed to design the
collimation system and optimize the collimation performance,
including magnetic tracking, synchrotron radiation and optics
tapering, as well as particle-matter interactions. As no existing
code was found that incorporated all these features, a new
simulation software tool has been developed. The tool is based on an
interface between a particle tracking engine, pyAT or Xtrack, and a
Monte-Carlo particle-matter interaction engine for collimator
scattering, BDSIM, which is based on Geant4. Results from a
simulation of edge scattering from a beam halo collimator in the
FCC-ee are presented to demonstrate the capabilities of the tool.
Diagnostics of nonlinear beam dynamics has become more important for the LHC as it advances into increasingly challenging regimes of operation, as well as for the High Luminosity LHC where machine ...nonlinearities will have a significantly larger impact. Limitations of traditional excitation methods at top energy, in particular due to machine protection, have pushed the development of safe alternative methods using ac dipoles to characterize the nonlinear content of the LHC. One of the methods that has been proposed is the dynamic aperture under forced oscillation of ac dipoles. This new observable has the potential to help characterize relative changes in the nonlinear content of the machine, improve the understanding of the nonlinear models by comparing to simulations, validate nonlinear optics corrections, and give a qualitative lower bound estimate on the free dynamic aperture. This paper presents the first experimental demonstration of forced dynamic aperture measurements under forced oscillations performed using the LHC ac dipoles, and discusses the benefits of forced dynamic aperture measurements in circular colliders.
Abstract Operation of the Large Hadron Collider (LHC) requires strong octupolar magnetic fields to suppress coherent beam instabilities. The amplitude detuning that is generated by these octupolar ...magnetic fields brings the tune of individual particles close to harmful resonances, which are mostly driven by the octupolar fields themselves. In 2023, new optics were deployed in the LHC at injection with optimized betatronic phase advances to minimize the resonances from the octupolar fields without affecting the amplitude detuning. This paper reports on the optics design, commissioning, and lifetime measurements performed to validate the optics.
Nonlinear magnetic errors in low-
β
insertions can have a significant impact on the beam-dynamics of a collider, such as the CERN Large Hadron Collider (LHC) and its luminosity upgrade (HL-LHC). ...Indeed, correction of sextupole and octupole magnetic errors in LHC experimental insertions has yielded clear operational benefits in recent years. Numerous studies predict, however, that even correction of nonlinearitites up to dodecapole order will be required to ensure successful exploitation of the HL-LHC. It was envisaged during HL-LHC design that compensation of high-order errors would be based upon correction of specific resonances, as determined from magnetic measurements during construction. Experience at the LHC demonstrated that beam-based measurement and correction of the sextupole and octupole errors was an essential complement to this strategy. As such, significant interest also exists regarding the practicality of beam-based observables of multipoles up to dodecapole order. Based on experience during the LHC’s second operational run, the viability of beam-based observables relevant to dodecapole order errors in the experimental insertions of the HL-LHC are assessed and discussed in detail in this paper.
Actin polymerization is essential for cell locomotion and is thought to generate the force responsible for cellular protrusions. The Arp2/3 complex is required to stimulate actin assembly at the ...leading edge in response to signalling. The bacteria Listeria and Shigella bypass the signalling pathway and harness the Arp2/3 complex to induce actin assembly and to propel themselves in living cells. However, the Arp2/3 complex alone is insufficient to promote movement. Here we have used pure components of the actin cytoskeleton to reconstitute sustained movement in Listeria and Shigella in vitro. Actin-based propulsion is driven by the free energy released by ATP hydrolysis linked to actin polymerization, and does not require myosin. In addition to actin and activated Arp2/3 complex, actin depolymerizing factor (ADF, or cofilin) and capping protein are also required for motility as they maintain a high steady-state level of G-actin, which controls the rate of unidirectional growth of actin filaments at the surface of the bacterium. The movement is more effective when profilin, α-actinin and VASP (for Listeria) are also included. These results have implications for our understanding of the mechanism of actin-based motility in cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since 2015 the LHC has been operating at 6.5 TeV. In 2016 the β -functions at the interaction points of ATLAS and CMS were squeezed to 0.4 m. This is below the design β*=0.55m at 7 TeV, and has been ...instrumental to surpass the design luminosity of 1034cm−2s−1 . Achieving a lower than nominal β* has been possible thanks to the extraordinary performance of the LHC, in which the control of the optics has played a fundamental role. Even though the β -beating for the virgin machine was above 100%, corrections reduced the rms β -beating below 1% at the two main experiments and below 2% rms around the ring. This guarantees a safe operation as well as providing equal amount of luminosity for the two experiments. In this article we describe the recent improvements to the measurement, correction algorithms and technical equipment which allowed this unprecedented control of the optics for a high-energy hadron collider.
To propel itself in infected cells, the pathogen Shigella flexneri subverts the Cdc42-controlled machinery responsible for actin assembly during filopodia formation. Using a combination of bacterial ...motility assays in platelet extracts with Escherichia coli expressing the Shigella IcsA protein and in vitro analysis of reconstituted systems from purified proteins, we show here that the bacterial protein IcsA binds N-WASP and activates it in a Cdc42-like fashion. Dramatic stimulation of actin assembly is linked to the formation of a ternary IcsA-N-WASP-Arp2/3 complex, which nucleates actin polymerization. The Arp2/3 complex is essential in initiation of actin assembly and Shigella movement, as previously observed for Listeria monocytogenes. Activation of N-WASP by IcsA unmasks two domains acting together in insertional actin polymerization. The isolated COOH-terminal domain of N-WASP containing a verprolin-homology region, a confilin-homology sequence, and an acidic terminal segment (VCA) interacts with G-actin in a unique profilin-like functional fashion. Hence, when N-WASP is activated, its COOH-terminal domain feeds barbed end growth of filaments and lowers the critical concentration at the bacterial surface. On the other hand, the NH2-terminal domain of N-WASP interacts with F-actin, mediating the attachment of the actin tail to the bacterium surface. VASP is not involved in Shigella movement, and the function of profilin does not require its binding to proline-rich regions.
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