Trained Immunity or Tolerance: Opposing Functional Programs Induced in Human Monocytes After Engagement of Various Pattern Recognition Receptors

Upon priming with Candida albicans or with the fungal cell wall component β-glucan, monocytes respond with an increased cytokine production upon restimulation, a phenomenon termed trained immunity. In contrast, the prestimulation of monocytes with lipopolysaccharide has long been known to induce tolerance. Because the vast majority of commensal microorganisms belong to bacterial or viral phyla, we sought to systematically investigate the functional reprogramming of monocytes induced by the stimulation of pattern recognition receptors (PRRs) with various bacterial or viral ligands. Monocytes were functionally programmed for either enhanced (training) or decreased (tolerance) cytokine production, depending on the type and concentration of ligand they encountered. The functional reprogramming of monocytes was also associated with cell shape, granulocity, and cell surface marker modifications. The training effect required p38- and Jun N-terminal protein kinase (JNK)-mediated mitogen-activated protein kinase (MAPK) signaling, with specific signaling patterns directing the functional fate of the cell. The long-term effects on the function of monocytes were mediated by epigenetic events, with both histone methylation and acetylation inhibitors blocking the training effects. In conclusion, our experiments identify the ability of monocytes to acquire adaptive characteristics after prior activation with a wide variety of ligands. Trained immunity and tolerance are two distinct and opposing functional programs induced by the specific microbial ligands engaging the monocytes

Geospatial analysis and living urban geometry

This essay outlines how to incorporate morphological rules within the exigencies of our technological age. We propose using the current evolution of GIS (Geographical Information Systems) technologies beyond their original representational domain, towards predictive and dynamic spatial models that help in constructing the new discipline of "urban seeding". We condemn the high-rise tower block as an unsuitable typology for a living city, and propose to re-establish human-scale urban fabric that resembles the traditional city. Pedestrian presence, density, and movement all reveal that open space between modernist buildings is not urban at all, but neither is the open space found in today's sprawling suburbs. True urban space contains and encourages pedestrian interactions, and has to be designed and built according to specific rules. The opposition between traditional self-organized versus modernist planned cities challenges the very core of the urban planning discipline. Planning has to be re-framed from being a tool creating a fixed future to become a visionary adaptive tool of dynamic states in evolution

Single-hole properties in the tt-JJ and strong-coupling models

We report numerical results for the single-hole properties in the $t$-$J$ model and the strong-coupling approximation to the Hubbard model in two dimensions. Using the hopping basis with over $10^6$ states we discuss (for an infinite system) the bandwidth, the leading Fourier coefficients in the dispersion, the band masses, and the spin-spin correlations near the hole. We compare our results with those obtained by other methods. The band minimum is found to be at ($\pi/2,\pi/2$) for the $t$-$J$ model for $0.1 \leq t/J \leq 10$, and for the strong-coupling model for $1 \leq t/J \leq 10$. The bandwidth in both models is approximately $2J$ at large $t/J$, in rough agreement with loop-expansion results but in disagreement with other results. The strong-coupling bandwidth for t/J\agt6 can be obtained from the $t$-$J$ model by treating the three-site terms in first-order perturbation theory. The dispersion along the magnetic zone face is flat, giving a large parallel/perpendicular band mass ratio.Comment: 1 RevTeX file with epsf directives to include 8 .eps figures 8 figure files encoded using uufile

Exact Hypersurface-Homogeneous Solutions in Cosmology and Astrophysics

A framework is introduced which explains the existence and similarities of most exact solutions of the Einstein equations with a wide range of sources for the class of hypersurface-homogeneous spacetimes which admit a Hamiltonian formulation. This class includes the spatially homogeneous cosmological models and the astrophysically interesting static spherically symmetric models as well as the stationary cylindrically symmetric models. The framework involves methods for finding and exploiting hidden symmetries and invariant submanifolds of the Hamiltonian formulation of the field equations. It unifies, simplifies and extends most known work on hypersurface-homogeneous exact solutions. It is shown that the same framework is also relevant to gravitational theories with a similar structure, like Brans-Dicke or higher-dimensional theories.Comment: 41 pages, REVTEX/LaTeX 2.09 file (don't use LaTeX2e !!!) Accepted for publication in Phys. Rev.

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Association of Nonobstructive Chronic Bronchitis with Respiratory Health Outcomes in Adults

Importance: Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain. Objective: To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers. Design, Setting, and Participants: This prospective cohort study included 22325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of &lt;0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018. Exposures: Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years. Main Outcomes and Measures: Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis. Results: Among 22325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11082 ever smokers with 99869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11243 never smokers with 120004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes. Conclusions and Relevance: The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Particle-yield modification in jet-like azimuthal di-hadron correlations in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The yield of charged particles associated with high-$p_{\rm T}$ trigger particles ($8 < p_{\rm T} < 15$ GeV/$c$) is measured with the ALICE detector in Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV relative to proton-proton collisions at the same energy. The conditional per-trigger yields are extracted from the narrow jet-like correlation peaks in azimuthal di-hadron correlations. In the 5% most central collisions, we observe that the yield of associated charged particles with transverse momenta $p_{\rm T}> 3$ GeV/$c$ on the away-side drops to about 60% of that observed in pp collisions, while on the near-side a moderate enhancement of 20-30% is found.Comment: 15 pages, 2 captioned figures, 1 table, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/350

The delta-function-kicked rotor: Momentum diffusion and the quantum-classical boundary

We investigate the quantum-classical transition in the delta-kicked rotor and the attainment of the classical limit in terms of measurement-induced state-localization. It is possible to study the transition by fixing the environmentally induced disturbance at a sufficiently small value, and examining the dynamics as the system is made more macroscopic. When the system action is relatively small, the dynamics is quantum mechanical and when the system action is sufficiently large there is a transition to classical behavior. The dynamics of the rotor in the region of transition, characterized by the late-time momentum diffusion coefficient, can be strikingly different from both the purely quantum and classical results. Remarkably, the early time diffusive behavior of the quantum system, even when different from its classical counterpart, is stabilized by the continuous measurement process. This shows that such measurements can succeed in extracting essentially quantum effects. The transition regime studied in this paper is accessible in ongoing experiments.Comment: 8 pages, 4 figures, revtex4 (revised version contains much more introductory material

Comprehensive lung injury pathology induced by mTOR inhibitors

Molecular Targets in Oncology[Abstract] Interstitial lung disease is a rare side effect of temsirolimus treatment in renal cancer patients. Pulmonary fibrosis is characterised by the accumulation of extracellular matrix collagen, fibroblast proliferation and migration, and loss of alveolar gas exchange units. Previous studies of pulmonary fibrosis have mainly focused on the fibro-proliferative process in the lungs. However, the molecular mechanism by which sirolimus promotes lung fibrosis remains elusive. Here, we propose an overall cascade hypothesis of interstitial lung diseases that represents a common, partly underlying synergism among them as well as the lung pathogenesis side effects of mammalian target of rapamycin inhibitors