Background
Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between ...patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.
Method
The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG‐subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE‐FAB and IgE‐BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?).
Results
All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed.
Conclusions
It is recommended to explore the use of allergen‐specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE‐FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Pyrin is a cytosolic immune sensor that nucleates an inflammasome in response to inhibition of RhoA by bacterial virulence factors, triggering the release of inflammatory cytokines, including IL-1β. ...Gain-of-function mutations in the MEFV gene encoding Pyrin cause autoinflammatory disorders, such as familial Mediterranean fever (FMF) and Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). To precisely define the role of Pyrin in pathogen detection in human immune cells, we compared initiation and regulation of the Pyrin inflammasome response in monocyte-derived macrophages (hMDM). Unlike human monocytes and murine macrophages, we determined that hMDM failed to activate Pyrin in response to known Pyrin activators Clostridioides difficile (C. difficile) toxins A or B (TcdA or TcdB), as well as the bile acid analogue BAA-473. The Pyrin inflammasome response was enabled in hMDM by prolonged priming with either LPS or type I or II interferons and required an increase in Pyrin expression. Notably, FMF mutations lifted the requirement for prolonged priming for Pyrin activation in hMDM, enabling Pyrin activation in the absence of additional inflammatory signals. Unexpectedly, in the absence of a Pyrin response, we found that TcdB activated the NLRP3 inflammasome in hMDM. These data demonstrate that regulation of Pyrin activation in hMDM diverges from monocytes and highlights its dysregulation in FMF.
Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that ...occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.
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•Macrophages adopt a transient metabolic state in response to TLR4 activation•MyD88 and TRIF synergistically facilitate signaling-driven changes in metabolism•Increases in glycolysis and ATP-citrate lyase activity foster histone acetylation•ATP-citrate lyase governs gene induction of a distinct LPS responsive gene set
TLR4 activation by LPS induces defined transcriptional cascades. Lauterbach et al. provide evidence that TLR activation induces a transient metabolic state that supports the transcriptional response. Mechanistically, they show that concerted increases in glycolytic flux and ATP-citrate lyase activity foster histone acetylation.
We analyse unsteady cavity dynamics, cavitation patterns and instability mechanisms governing partial cavitation in the flow past a sharp convergent–divergent wedge. Reproducing a recent reference ...experiment by numerical simulation, the investigated flow regime is characterised by large-scale cloud cavitation. In agreement with the experiments, we find that cloud shedding is dominated by the periodic occurrence of condensation shocks, propagating through the two-phase medium. The physical model is based on the homogeneous mixture approach, the assumption of thermodynamic equilibrium, and a closed-form barotropic equation of state. Compressibility of water and water vapour is taken into account. We deliberately suppress effects of molecular viscosity, in order to demonstrate that inertial effects dominate the flow evolution. We qualify the flow predictions, and validate the numerical approach by comparison with experiments. In agreement with the experiments, the vapour volume fraction within the partial cavity reaches values
${>}80\,\%$
for its spanwise average. Very good agreement is further obtained for the shedding Strouhal number, the cavity growth and collapse velocities, and for typical coherent flow structures. In accordance with the experiments, the simulations reproduce a condensation shock forming at the trailing part of the partial cavity. It is demonstrated that it satisfies locally Rankine–Hugoniot jump relations. Estimation of the shock propagation Mach number shows that the flow is supersonic. With a magnitude of only a few kPa, the pressure rise across the shock is much lower than for typical cavity collapse events. It is thus far too weak to cause cavitation erosion directly. However, by affecting the dynamics of the cavity, the flow aggressiveness can be significantly altered. Our results indicate that, in addition to classically observed re-entrant jets, condensation shocks feed an intrinsic instability mechanism of partial cavitation.
Mediated photon-photon interactions are realized in a superconducting coplanar waveguide cavity coupled to a superconducting charge qubit. These nonresonant interactions blockade the transmission of ...photons through the cavity. This so-called dispersive photon blockade is characterized by measuring the total transmitted power while varying the energy spectrum of the photons incident on the cavity. A staircase with four distinct steps is observed and can be understood in an analogy with electron transport and the Coulomb blockade in quantum dots. This work differs from previous efforts in that the cavity-qubit excitations retain a photonic nature rather than a hybridization of qubit and photon and provides the needed tolerance to disorder for future condensed matter experiments.
All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. ...Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis.
Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1.
Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical modification of the selenocysteine (Sec) in TrxR1 by electrophiles leads to rapid inhibition of thioredoxin disulfide reductase activity, often combined with induction of NADPH oxidase activity of the derivatized enzyme, thereby affecting many downstream redox pathways. The notion of TrxR1 as a regulator of Nrf2 is supported by many publications on effects in human cells of selenium deficiency, oxidative stress or electrophile exposure, as well as the phenotypes of genetic mouse models.
Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes.
An interesting aspect of 2D materials is the change of their electronic structure with the reduction of thickness. Molybdenum and tungsten‐based transition metal dichalcogenides form an important ...family of 2D materials, whose members show a thickness‐dependent bandgap and strong light–matter interaction. In this work, the experimental determination of the complex refractive index of 1‐, 2‐, 3‐layer thick MoS2, MoSe2, WS2, and WSe2 in the range from 400 to 850 nm of the electromagnetic spectrum is reported by using microreflectance spectroscopy and combined with calculations based on the Fresnel equations. It is further provided a comparison with the bulk refractive index values reported in the literature and a discussion of the difference/similarity between our work and the monolayer refractive index available from the literature, finding that the results from different techniques are in good agreement.
Mo‐ and W‐based transition metal dichalcogenides form an important family of layered materials with a strong dependency of the bandgap energy on the thickness. In this work, the experimental determination of the complex refractive index of 1‐, 2‐, 3‐layer thick MoS2, MoSe2, WS2, and WSe2 in the range from 400 to 850 nm of the electromagnetic spectrum is reported.
Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative ...damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.
Cognitive impairments are currently regarded as important determinants of functional domains and are promising treatment goals in schizophrenia. Nevertheless, the exact nature of the interdependent ...relationship between neurocognition and social cognition as well as the relative contribution of each of these factors to adequate functioning remains unclear. The purpose of this article is to systematically review the findings and methodology of studies that have investigated social cognition as a mediator variable between neurocognitive performance and functional outcome in schizophrenia. Moreover, we carried out a study to evaluate this mediation hypothesis by the means of structural equation modeling in a large sample of 148 schizophrenia patients. The review comprised 15 studies. All but one study provided evidence for the mediating role of social cognition both in cross-sectional and in longitudinal designs. Other variables like motivation and social competence additionally mediated the relationship between social cognition and functional outcome. The mean effect size of the indirect effect was 0.20. However, social cognitive domains were differentially effective mediators. On average, 25% of the variance in functional outcome could be explained in the mediation model. The results of our own statistical analysis are in line with these conclusions: Social cognition mediated a significant indirect relationship between neurocognition and functional outcome. These results suggest that research should focus on differential mediation pathways. Future studies should also consider the interaction with other prognostic factors, additional mediators, and moderators in order to increase the predictive power and to target those factors relevant for optimizing therapy effects.
ABSTRACT We report the discovery of SMSS J160540.18−144323.1, a new ultra metal-poor halo star discovered with the SkyMapper telescope. We measure $\left\rm {Fe}/\rm {H}\right= -6.2 \pm 0.2$ (1D ...LTE), the lowest ever detected abundance of iron in a star. The star is strongly carbon-enhanced, $\left\rm {C}/\rm {Fe}\right = 3.9 \pm 0.2$, while other abundances are compatible with an α-enhanced solar-like pattern with $\left\rm {Ca}/\rm {Fe}\right = 0.4 \pm 0.2$, $\left\rm {Mg}/\rm {Fe}\right = 0.6 \pm 0.2$, $\left\rm {Ti}/\rm {Fe}\right = 0.8 \pm 0.2$, and no significant s- or r-process enrichment, $\left\rm {Sr}/\rm {Fe}\right \lt 0.2$ and $\left\rm {Ba}/\rm {Fe}\right \lt 1.0$ (3σ limits). Population III stars exploding as fallback supernovae may explain both the strong carbon enhancement and the apparent lack of enhancement of odd-Z and neutron-capture element abundances. Grids of supernova models computed for metal-free progenitor stars yield good matches for stars of about $10\, \rm M_\odot$ imparting a low kinetic energy on the supernova ejecta, while models for stars more massive than roughly $20\, \rm M_\odot$ are incompatible with the observed abundance pattern.
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