After approximately 130 years since their discovery as rare granulocytes that circulate in blood, basophils are just now gaining respect as significant contributors in the pathogenesis underlying ...allergic inflammation and disease. While long known for secreting preformed and newly synthesized mediators and for selectively infiltrating tissue during immunoglobulin E (IgE)‐mediated inflammation, their role has largely been viewed as redundant to that of tissue mast cells in functioning as effector cells. This line of thought has persisted even though it has been known in humans for approximately 20 years that basophils additionally produce relatively large quantities of cytokines, e.g. interleukin‐4 (IL‐4)/IL‐13, that are central for the manifestations of allergic disease. Studies using novel IL‐4 reporter mice have significantly added to the in vivo importance of basophils as IL‐4 producing cells, with recent findings indicating that these cells also function as antigen‐presenting cells essential in initiating T‐helper 2 responses. If confirmed and translated to humans, these provocative findings will give new meaning to the role basophils have in allergic disease, and in immunology overall.
The energetic economy of running benefits from tendon and other tissues that store and return elastic energy, thus saving muscles from costly mechanical work. The classic "Spring-mass" computational ...model successfully explains the forces, displacements and mechanical power of running, as the outcome of dynamical interactions between the body center of mass and a purely elastic spring for the leg. However, the Spring-mass model does not include active muscles and cannot explain the metabolic energy cost of running, whether on level ground or on a slope. Here we add explicit actuation and dissipation to the Spring-mass model, and show how they explain substantial active (and thus costly) work during human running, and much of the associated energetic cost. Dissipation is modeled as modest energy losses (5% of total mechanical energy for running at 3 m s-1) from hysteresis and foot-ground collisions, that must be restored by active work each step. Even with substantial elastic energy return (59% of positive work, comparable to empirical observations), the active work could account for most of the metabolic cost of human running (about 68%, assuming human-like muscle efficiency). We also introduce a previously unappreciated energetic cost for rapid production of force, that helps explain the relatively smooth ground reaction forces of running, and why muscles might also actively perform negative work. With both work and rapid force costs, the model reproduces the energetics of human running at a range of speeds on level ground and on slopes. Although elastic return is key to energy savings, there are still losses that require restorative muscle work, which can cost substantial energy during running.
The use of satellites to monitor the color of the ocean requires effective removal of the atmospheric signal. This can be performed by extrapolating the aerosol optical properties to the visible from ...the near-infra-red (NIR) spectral region assuming that seawater is totally absorbent in this latter part of the spectrum, the so-called black pixel assumption. While this assumption is verified for most phytoplankton dominated waters, it is invalid in turbid waters. Consequently, for the past ten years, several algorithms have been developed on alternative assumptions. Studies comparing these algorithms are of great interest for further improvement in water leaving radiance (Lw(λ)) retrievals from satellite images explaining the focus of the present research. Four published atmospheric correction algorithms for MODIS-Aqua are compared: (1) the standard NIR algorithm of NASA, (2) the NIR similarity spectrum algorithm, (3) the NIR-SWIR algorithm and (4) an Artificial Neural Network algorithm. The MODIS-Aqua estimated normalized Lw(λ) are validated with AERONET-Ocean Color data and cruise measurements presenting moderately to highly turbid waters. Based on a match-up exercise, the former three algorithms show the best results in the green region of the spectrum (relative error, RE, between 11 and 20%) and the largest errors in the blue and red region of the spectrum (RE exceeding 30%). In contrast, the Artificial Neural Network algorithm performs better in the red band (RE of 22%). The latter tends to overestimate the normalized Lw(λ) at all wavelengths while the NIR similarity spectrum algorithm tends to underestimate it. Retrievals of aerosol products, such as the Ångström coefficient, α(531,869), and the optical thickness, τ(869), present RE above 44% and 72%, respectively.
The performance of the algorithms is also investigated as a function of water types. For water masses mainly dominated by phytoplankton, the standard NIR algorithm performs better. In contrast, for water masses mainly dominated by detrital and mineral material, the neural network-based algorithm shows the best results. The largest errors are encountered above water masses dominated by high phytoplankton and CDOM concentrations. This work conducted to a number of perspectives for improving the atmospheric correction algorithms.
► Four atmospheric correction algorithms for MODIS Aqua images are validated. ► A validation is also performed as a function of the water type. ► Overall, the standard NIR algorithm of the NASA performs the best. ► Large errors in water leaving reflectance retrievals are still observed. ► The performances of the algorithms are function of the water type.
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly evolved into a pandemic -the likes of which has not been experienced in 100 ...years. While novel vaccines show great efficacy, and therapeutics continue to be developed, the persistence of disease, with the concomitant threat of emergent variants, continues to impose massive health and socioeconomic issues worldwide. Studies show that in susceptible individuals, SARS-CoV-2 infection can rapidly progress toward lung injury and acute respiratory distress syndrome (ARDS), with evidence for an underlying dysregulated innate immune response or cytokine release syndrome (CRS). The mechanisms responsible for this CRS remain poorly understood, yet hyper-inflammatory features were also evident with predecessor viruses within the β-coronaviridae family, namely SARS-CoV-1 and the Middle East Respiratory Syndrome (MERS)-CoV. It is further known that the spike protein (S) of SARS-CoV-2 (as first reported for other β-coronaviruses) possesses a so-called
within the N-terminal domain of the S1 subunit (S1-NTD). This fold (or pocket) shows structural homology nearly identical to that of human galectin-3 (Gal-3). In this respect, we have recently shown that Gal-3, when associated with epithelial cells or anchored to a solid phase matrix, facilitates the activation of innate immune cells, including basophils, DC, and monocytes. A synthesis of these findings prompted us to test whether segments of the SARS-CoV-2 spike protein might also activate innate immune cells in a manner similar to that observed in our Gal-3 studies. Indeed, by immobilizing S components onto microtiter wells, we show that only the S1 subunit (with the NTD) activates human monocytes to produce a near identical pattern of cytokines as those reported in COVID-19-related CRS. In contrast, both the S1-CTD/RBD, which binds ACE2, and the S2 subunit (stalk), failed to mediate the same effect. Overall, these findings provide evidence that the SARS-CoV-2 spike protein can activate monocytes for cytokines central to COVID-19, thus providing insight into the innate immune mechanisms underlying the CRS and the potential for therapeutic interventions.
Background Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of ...response remain unknown. Objective We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow’s milk (CM) allergy. Methods We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG4 levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels. Results Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge ( P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG4 levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group. Conclusion OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.
Basophils from allergy to cancer Poto, Remo; Gambardella, Adriana Rosa; Marone, Gianni ...
Frontiers in immunology,
12/2022, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
Human basophils, first identified over 140 years ago, account for just 0.5-1% of circulating leukocytes. While this scarcity long hampered basophil studies, innovations during the past 30 years, ...beginning with their isolation and more recently in the development of mouse models, have markedly advanced our understanding of these cells. Although dissimilarities between human and mouse basophils persist, the overall findings highlight the growing importance of these cells in health and disease. Indeed, studies continue to support basophils as key participants in IgE-mediated reactions, where they infiltrate inflammatory lesions, release pro-inflammatory mediators (histamine, leukotriene C
: LTC
) and regulatory cytokines (IL-4, IL-13) central to the pathogenesis of allergic diseases. Studies now report basophils infiltrating various human cancers where they play diverse roles, either promoting or hampering tumorigenesis. Likewise, this activity bears remarkable similarity to the mounting evidence that basophils facilitate wound healing. In fact, both activities appear linked to the capacity of basophils to secrete IL-4/IL-13, with these cytokines polarizing macrophages toward the M2 phenotype. Basophils also secrete several angiogenic factors (vascular endothelial growth factor: VEGF-A, amphiregulin) consistent with these activities. In this review, we feature these newfound properties with the goal of unraveling the increasing importance of basophils in these diverse pathobiological processes.
Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of ...mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
Purpose
Prior reports on the location and sizes of brain metastases almost entirely focus on patients with primary breast and pulmonary cancer. This is the first study comparing multiple other types ...of cancer that metastasize to the brain.
Methods
This monocentric retrospective study includes 369 untreated patients with 3313 intraaxial brain metastases. Following semi-manual segmentation of metastases on post-contrast T1WI, cumulative spatial probability distribution maps of brain metastases were created for the whole group and for all primary tumors. Furthermore, mixed effects logistic regression model analysis was performed to determine if the primary tumor, patient age, and patient sex influence lesion location.
Results
The cerebellum as location of brain metastases was proportionally overrepresented. Breast and pulmonary cancer caused higher number of brain metastases to what would normally be expected. Multivariate analyses revealed a significant accumulation of brain metastases from skin cancer in a frontal and from breast and gastrointestinal cancer in a cerebellar location.
Conclusion
Distribution of brain metastases is very heterogeneous for the distinct primaries, possibly reflecting the diversity of mechanisms involved in brain metastases formation. In daily clinical practice distribution patters may be beneficial to predict the primary cancer site, if unknown.
Evidence for epithelial cell (EC)-derived cytokines (e.g., thymic stromal lymphopoietin TSLP) activating human basophils remains controversial. We therefore hypothesize that ECs can directly activate ...basophils via cell-to-cell interaction. Basophils in medium alone or with IL-3 ± anti-IgE were coincubated with TSLP, IL-33, or IL-25. Analogous experiments cocultured basophils (1-72 h) directly with EC lines. Supernatants were tested for mediators and cytokines. Abs targeting receptors were tested for neutralizing effects. Lactic acid (pH 3.9) treatment combined with passive sensitization tested the role of IgE. Overall, IL-33 augmented IL-13 secretion from basophils cotreated with IL-3, with minimal effects on histamine and IL-4. Conversely, basophils (but not mast cells) released histamine and marked levels of IL-4/IL-13 (10-fold) when cocultured with A549 EC and IL-3, without exogenous allergen or IgE cross-linking stimuli. The inability to detect IL-33 or TSLP, or to neutralize their activity, suggested a unique mode of basophil activation by A549 EC. Half-maximal rates for histamine (4 h) and IL-4 (5 h) secretion were slower than observed with standard IgE-dependent activation. Ig stripping combined with passive sensitization ± omalizumab showed a dependency for basophil-bound IgE, substantiated by a requirement for cell-to-cell contact, aggregation, and FcεRI-dependent signaling. A yet unidentified IgE-binding lectin associated with A549 EC is implicated after discovering that LacNAc suppressed basophil activation in cocultures. These findings point to a lectin-dependent activation of basophil requiring IgE but independent of allergen or secreted cytokine. Pending further investigation, we predict this unique mode of activation is linked to inflammatory conditions whereby IgE-dependent activation of basophils occurs despite the absence of any known allergen.
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