The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways

Summary The interleukin 17 (IL-17) cytokine and receptor family is central to antimicrobial resistance and inflammation in the lung. Mice lacking IL-17A, IL-17F, or the IL-17RA subunit were compared with wild-type mice for susceptibility to airway inflammation in models of infection and allergy. Signaling through IL-17RA was required for efficient microbial clearance and prevention of allergy; in the absence of IL-17RA, signaling through IL-17RC on epithelial cells, predominantly by IL-17F, significantly exacerbated lower airway Aspergillus or Pseudomonas infection and allergic airway inflammation. In contrast, following infection with the upper respiratory pathogen Staphylococcus aureus , the IL-17F/IL-17RC axis mediated protection. Thus, IL-17A and IL-17F exert distinct biological effects during pulmonary infection; the IL-17F/IL-17RC signaling axis has the potential to significantly worsen pathogen-associated inflammation of the lower respiratory tract in particular, and should be investigated further as a therapeutic target for treating pathological inflammation in the lung

An updated checklist of the European Butterflies (Lepidoptera, Papilionoidea)

This paper presents an updated checklist of the butterflies of Europe, together with their original name combinations, and their occurrence status in each European country. According to this checklist, 496 species of the superfamily Papilionoidea occur in Europe. Changes in comparison with the last version (2.6.2) of Fauna Europaea are discussed. Compared to that version, 16 species are new additions, either due to cryptic species most of which have been discovered by molecular methods (13 cases) or due to discoveries of Asian species on the eastern border of the European territory in the Ural mountains (three cases). On the other hand, nine species had to be removed from the list, because they either do not occur in Europe or lost their species status due to new evidence. In addition, three species names had to be changed and 30 species changed their combination due to new evidence on phylogenetic relationships. Furthermore, minor corrections were applied to some authors¿ names and years of publication. Finally, the name Polyommatus ottomanus Lefèbvre, 1831, which is threatened by its senior synonym Lycaena legeri Freyer, 1830, is declared a nomen protectum, thereby conserving its name in the current combination Lycaena ottomana.VL was supported by grant N 14-14-00541 from the Russian Science Foundation to the Zoological Institute of the Russian Academy of Sciences and ZF by grant 14- 36098G from the Czech Science Foundation

Improved Unsteady RANS Models Applied to Jet Transverse to a Pipe Flow

An unsteady RANS model is developed in order to simulate the complex situations involving both free and bounded flows. This model tuned to catch coherent flow structures is developed both in the k-ε and k-l approaches. The full 3D geometry of a round jet exiting from a reservoir into a pipe has been computed. Periodic conditions are applied in order to compare with an experiments consisting of eight jets exiting in a cross pipe flow. Improvement has been obtained with this URANS turbulence model compared to RANS and good agreement compared with experiments has been obtained. Unsteady phenomena are reproduced by the model and provide more insight into the physical properties of the flow and of the transport of a passive scalar

Mixing in Circular and Non-circular Jets in Crossflow

Coherent structures and mixing in the flow field of a jet in crossflow have been studied using computational (large eddy simulation) and experimental (particle image velocimetry and laser-induced fluorescence) techniques. The mean scalar fields and turbulence statistics as determined by both are compared for circular, elliptic, and square nozzles. For the latter configurations, effects of orientation are considered. The computations reveal that the distribution of a passive scalar in a cross-sectional plane can be single- or double-peaked, depending on the nozzle shape and orientation. A proper orthogonal decomposition of the transverse velocity indicates that coherent structures may be responsible for this phenomenon. Nozzles which have a single-peaked distribution have stronger modes in transverse direction. The global mixing performance is superior for these nozzle types. This is the case for the blunt square nozzle and for the elliptic nozzle with high aspect ratio. It is further demonstrated that the flow field contains large regions in which a passive scalar is transported up the mean gradient (counter-gradient transport) which implies failure of the gradient diffusion hypothesis

Absence of COVID-19-associated changes in plasma coagulation proteins and pulmonary thrombosis in the ferret model

BACKGROUND: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection. OBJECTIVES: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis. MATERIAL AND METHODS: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed. RESULTS: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation. CONCLUSIONS: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited

Statistical analysis of the velocity field in a mechanical precessing jet flow

An experimental investigation of a precessing jet issuing from a mechanically rotating nozzle directed at an angle of α=45° relative to the axis of rotation is reported. Both conventional and conditional statistics of the velocity field of the jet were measured using a combined hot-wire and cold-wire (to identify any reverse flow) probe. Three distinct values (≈0.005, 0.01, and 0.02) of the precession Strouhal number Stp (≡ rotation frequency × nozzle diameter / jet exit bulk velocity) were used to assess the effect of varying Stp. The measurements reveal that the Strouhal number in general has significant influence on the entire mixing field generated by a precessing jet. The occurrence of precession at all the Strouhal numbers of investigation produces a central recirculation zone at x ≤ 7d, where x is a distance measured from the rotating nozzle exit. A critical Strouhal number, i.e., Stp,cr ≈0.008 for the present case, is identified: at Stp ≥ Stp,cr the core jet converges to the axis of rotation while at Stp ≥ Stp,cr it does not. The characteristics of the turbulent flow in the near and intermediate regions are quite different and depend upon the magnitude of Stp. The near-field region, x/d ≤ 10-15, is dominated by a regime of global precession of the entire jet. As a result, the large-scale entrainment of the ambient fluid is substantially enhanced while the fine-scale turbulent mixing is suppressed. Under the supercritical regime (i.e., Stp ≥ Stp,cr), the jet in the far field resembles some features of the nonprecessing counterpart. Nevertheless, significant differences still retain in the statistical properties. © 2005 American Institute of Physics.J. Mi and G. J. Natha

A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis

Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative l-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR–mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases

Conserved ancestral tropical niche but different continental histories explain the latitudinal diversity gradient in brush-footed butterflies.

The global increase in species richness toward the tropics across continents and taxonomic groups, referred to as the latitudinal diversity gradient, stimulated the formulation of many hypotheses to explain the underlying mechanisms of this pattern. We evaluate several of these hypotheses to explain spatial diversity patterns in a butterfly family, the Nymphalidae, by assessing the contributions of speciation, extinction, and dispersal, and also the extent to which these processes differ among regions at the same latitude. We generate a time-calibrated phylogeny containing 2,866 nymphalid species (~45% of extant diversity). Neither speciation nor extinction rate variations consistently explain the latitudinal diversity gradient among regions because temporal diversification dynamics differ greatly across longitude. The Neotropical diversity results from low extinction rates, not high speciation rates, and biotic interchanges with other regions are rare. Southeast Asia is also characterized by a low speciation rate but, unlike the Neotropics, is the main source of dispersal events through time. Our results suggest that global climate change throughout the Cenozoic, combined with tropical niche conservatism, played a major role in generating the modern latitudinal diversity gradient of nymphalid butterflies

Chikungunya Virus Neutralization Antigens and Direct Cell-to-Cell Transmission Are Revealed by Human Antibody-Escape Mutants

Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop “groove” as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis

Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans