IL-33 induction and signaling are controlled by glutaredoxin-1 in mouse macrophages

<div><p>Interleukin (IL)-33 is an interleukin-1 like cytokine that enhances Th2 responses and mediates mucosal immunity and allergic inflammation but the mechanism regulating endogenous IL-33 production are still under investigation. In macrophages, lipopolysaccharide (LPS) administration resulted in marked induction of IL-33 mRNA that was blunted in macrophages from glutaredoxin-1 (Glrx) knockout mice and in RAW264.7 macrophages with Glrx knockdown by siRNA. Glutaredoxin-1 is a small cytosolic thioltransferase that controls a reversible protein thiol modification, S-glutationylation (protein-GSH adducts), thereby regulating redox signaling. In this study, we examined the mechanism of Glrx regulation of endogenous IL-33 induction in macrophages. Glrx knockdown resulted in impaired de-glutathionylation of TRAF6, which is required for TRAF6 activation, and inhibited downstream IKKβ and NF-κB activation. Inhibitors of NF-κB suppressed IL-33 induction and chromatin IP sequencing data analysis confirmed that IL-33 is an NF-κB-responsive gene. Since TRAF6-NF-κB activation is also essential for IL-33 signaling through its receptor, ST2L, we next tested the involvement of Glrx in exogenous IL-33 responses in RAW264.7 cells. Recombinant IL-33 (rIL-33) administration induced IL-33 mRNA expression in RAW264.7 macrophages, and this was inhibited by Glrx knockdown. Interestingly, rIL-33-induced IL-33 protein was identified as the 20 kDa cleaved form whereas LPS-induced IL-33 protein was identified as full-length IL-33, which may be less active than the cleaved form. In a clinically-relevant mouse model of asthma, intra-tracheal cockroach antigen treatment induced Glrx protein in wild type mouse lungs but Glrx induction was attenuated in IL-33 knockout mouse lungs, suggesting that IL-33 may regulate Glrx induction <i>in vivo</i> in response to allergen challenge. In summary, our data reveal a novel mechanism by which Glrx controls both LPS- and IL-33-mediated NF-κB activation leading to IL-33 production, and paracrine IL-33 can induce Glrx to further regulate inflammatory reactions.</p></div

Nuclear dependence coefficient α(A,qT)\alpha(A,q_T) for the Drell-Yan and J/ψ\psi production

Define the nuclear dependence coefficient $\alpha(A,q_T)$ in terms of ratio of transverse momentum spectrum in hadron-nucleus and in hadron-nucleon collisions: $\frac{d\sigma^{hA}}{dq_T^2}/ \frac{d\sigma^{hN}}{dq_T^2}\equiv A^{\alpha(A,q_T)}$. We argue that in small $q_T$ region, the $\alpha(A,q_T)$ for the Drell-Yan and J/$\psi$ production is given by a universal function:\ $a+b q_T^2$, where parameters a and b are completely determined by either calculable quantities or independently measurable physical observables. We demonstrate that this universal function $\alpha(A,q_T)$ is insensitive to the A for normal nuclear targets. For a color deconfined nuclear medium, the $\alpha(A,q_T)$ becomes strongly dependent on the A. We also show that our $\alpha(A,q_T)$ for the Drell-Yan process is naturally linked to perturbatively calculated $\alpha(A,q_T)$ at large $q_T$ without any free parameters, and the $\alpha(A,q_T)$ is consistent with E772 data for all $q_T$.Comment: latex, 28 pages, 10 figures, updated two figures, and add more discussion

Automorphic Equivalence within Gapped Phases of Quantum Lattice Systems

Gapped ground states of quantum spin systems have been referred to in the physics literature as being `in the same phase' if there exists a family of Hamiltonians H(s), with finite range interactions depending continuously on $s \in [0,1]$, such that for each $s$, H(s) has a non-vanishing gap above its ground state and with the two initial states being the ground states of H(0) and H(1), respectively. In this work, we give precise conditions under which any two gapped ground states of a given quantum spin system that 'belong to the same phase' are automorphically equivalent and show that this equivalence can be implemented as a flow generated by an $s$-dependent interaction which decays faster than any power law (in fact, almost exponentially). The flow is constructed using Hastings' 'quasi-adiabatic evolution' technique, of which we give a proof extended to infinite-dimensional Hilbert spaces. In addition, we derive a general result about the locality properties of the effect of perturbations of the dynamics for quantum systems with a quasi-local structure and prove that the flow, which we call the {\em spectral flow}, connecting the gapped ground states in the same phase, satisfies a Lieb-Robinson bound. As a result, we obtain that, in the thermodynamic limit, the spectral flow converges to a co-cycle of automorphisms of the algebra of quasi-local observables of the infinite spin system. This proves that the ground state phase structure is preserved along the curve of models $H(s), 0\leq s\leq 1$.Comment: Updated acknowledgments and new email address of S

Long-Range Forces of QCD

We consider the scattering of two color dipoles (e.g., heavy quarkonium states) at low energy - a QCD analog of Van der Waals interaction. Even though the couplings of the dipoles to the gluon field can be described in perturbation theory, which leads to the potential proportional to (N_c^2-1)/R^{7}, at large distances R the interaction becomes totally non-perturbative. Low-energy QCD theorems are used to evaluate the leading long-distance contribution \sim (N_f^2-1)/(11N_c - 2N_f)^2 R^{-5/2} exp(-2 \mu R) (\mu is the Goldstone boson mass), which is shown to arise from the correlated two-boson exchange. The sum rule which relates the overall strength of the interaction to the energy density of QCD vacuum is derived. Surprisingly, we find that when the size of the dipoles shrinks to zero (the heavy quark limit in the case of quarkonia), the non-perturbative part of the interaction vanishes more slowly than the perturbative part as a consequence of scale anomaly. As an application, we evaluate elastic \pi J/\psi and \pi J/\psi \to \pi \psi' cross sections.Comment: 16pages, 9 eps figures; discussion extended, 2 new references added, to appear in Phys.Rev.

Formation of dense partonic matter in relativistic nucleus-nucleus collisions at RHIC: Experimental evaluation by the PHENIX collaboration

Extensive experimental data from high-energy nucleus-nucleus collisions were recorded using the PHENIX detector at the Relativistic Heavy Ion Collider (RHIC). The comprehensive set of measurements from the first three years of RHIC operation includes charged particle multiplicities, transverse energy, yield ratios and spectra of identified hadrons in a wide range of transverse momenta (p_T), elliptic flow, two-particle correlations, non-statistical fluctuations, and suppression of particle production at high p_T. The results are examined with an emphasis on implications for the formation of a new state of dense matter. We find that the state of matter created at RHIC cannot be described in terms of ordinary color neutral hadrons.Comment: 510 authors, 127 pages text, 56 figures, 1 tables, LaTeX. Submitted to Nuclear Physics A as a regular article; v3 has minor changes in response to referee comments. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Experimental and Theoretical Challenges in the Search for the Quark Gluon Plasma: The STAR Collaboration's Critical Assessment of the Evidence from RHIC Collisions

We review the most important experimental results from the first three years of nucleus-nucleus collision studies at RHIC, with emphasis on results from the STAR experiment, and we assess their interpretation and comparison to theory. The theory-experiment comparison suggests that central Au+Au collisions at RHIC produce dense, rapidly thermalizing matter characterized by: (1) initial energy densities above the critical values predicted by lattice QCD for establishment of a Quark-Gluon Plasma (QGP); (2) nearly ideal fluid flow, marked by constituent interactions of very short mean free path, established most probably at a stage preceding hadron formation; and (3) opacity to jets. Many of the observations are consistent with models incorporating QGP formation in the early collision stages, and have not found ready explanation in a hadronic framework. However, the measurements themselves do not yet establish unequivocal evidence for a transition to this new form of matter. The theoretical treatment of the collision evolution, despite impressive successes, invokes a suite of distinct models, degrees of freedom and assumptions of as yet unknown quantitative consequence. We pose a set of important open questions, and suggest additional measurements, at least some of which should be addressed in order to establish a compelling basis to conclude definitively that thermalized, deconfined quark-gluon matter has been produced at RHIC.Comment: 101 pages, 37 figures; revised version to Nucl. Phys.

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin’s role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

J/psi Production as a Function of Charged Particle Multiplicity in pp Collisions at sqrt{s} = 7 TeV

The ALICE collaboration reports the measurement of the inclusive J/psi yield as a function of charged particle pseudorapidity density dN_{ch}/deta in pp collisions at sqrt{s} = 7 TeV at the LHC. J/psi particles are detected for p_t > 0, in the rapidity interval |y| < 0.9 via decay into e+e-, and in the interval 2.5 < y < 4.0 via decay into mu+mu- pairs. An approximately linear increase of the J/psi yields normalized to their event average (dN_{J/psi}/dy)/ with (dN_{ch}/deta)/ is observed in both rapidity ranges, where dN_{ch}/deta is measured within |eta| < 1 and p_t > 0. In the highest multiplicity interval with = 24.1, corresponding to four times the minimum bias multiplicity density, an enhancement relative to the minimum bias J/psi yield by a factor of about 5 at 2.5 < y < 4 (8 at |y| < 0.9) is observed.Comment: Submitted to Phys. Lett.