Matrix Metalloprotease 9 Mediates Neutrophil Migration into the Airways in Response to Influenza Virus-Induced Toll-Like Receptor Signaling

The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88−/− airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes

The new political economy of higher education: between distributional conflicts and discursive stratification

The higher education sector has been undergoing a far-reaching institutional re-orientation during the past two decades. Many adjustments appear to have strengthened the role of competition in the governance of higher education, but the character of the sector?s emerging new political economy has frequently remained unclear. Serving as the introduction for the special issue, this article makes the case for a multidimensional strategy to probe higher education?s competitive transformation. In terms of conceptualizing the major empirical shifts, we argue for analyzing three core phenomena: varieties of academic capitalism, the discursive construction of inequality, and the transformation of hierarchies in competitive settings. With respect to theoretical tools, we emphasize the complementary contributions of institutional, class-oriented, and discourse analytical approaches. As this introduction elaborates and the contributions to the special issue demonstrate, critical dialog among different analytical traditions over the interpretation of change is crucial for improving established understandings. Arguably, it is essential for clarifying the respective roles of capitalist power and hierarchical rule in the construction of the sector?s new order

Oyster Reefs as Natural Breakwaters Mitigate Shoreline Loss and Facilitate Fisheries

Shorelines at the interface of marine, estuarine and terrestrial biomes are among the most degraded and threatened habitats in the coastal zone because of their sensitivity to sea level rise, storms and increased human utilization. Previous efforts to protect shorelines have largely involved constructing bulkheads and seawalls which can detrimentally affect nearshore habitats. Recently, efforts have shifted towards “living shoreline” approaches that include biogenic breakwater reefs. Our study experimentally tested the efficacy of breakwater reefs constructed of oyster shell for protecting eroding coastal shorelines and their effect on nearshore fish and shellfish communities. Along two different stretches of eroding shoreline, we created replicated pairs of subtidal breakwater reefs and established unaltered reference areas as controls. At both sites we measured shoreline and bathymetric change and quantified oyster recruitment, fish and mobile macro-invertebrate abundances. Breakwater reef treatments mitigated shoreline retreat by more than 40% at one site, but overall vegetation retreat and erosion rates were high across all treatments and at both sites. Oyster settlement and subsequent survival were observed at both sites, with mean adult densities reaching more than eighty oysters m−2 at one site. We found the corridor between intertidal marsh and oyster reef breakwaters supported higher abundances and different communities of fishes than control plots without oyster reef habitat. Among the fishes and mobile invertebrates that appeared to be strongly enhanced were several economically-important species. Blue crabs (Callinectes sapidus) were the most clearly enhanced (+297%) by the presence of breakwater reefs, while red drum (Sciaenops ocellatus) (+108%), spotted seatrout (Cynoscion nebulosus) (+88%) and flounder (Paralichthys sp.) (+79%) also benefited. Although the vertical relief of the breakwater reefs was reduced over the course of our study and this compromised the shoreline protection capacity, the observed habitat value demonstrates ecological justification for future, more robust shoreline protection projects

Galectin-9 binds IgM-BCR to regulate B cell signaling

The galectin family of secreted lectins have emerged as important regulators of immune cell function; however, their role in B-cell responses is poorly understood. Here we identify IgM-BCR as a ligand for galectin-9. Furthermore, we show enhanced BCR microcluster formation and signaling in galectin-9-deficient B cells. Notably, treatment with exogenous recombinant galectin-9 nearly completely abolishes BCR signaling. We investigated the molecular mechanism for galectin-9-mediated inhibition of BCR signaling using super-resolution imaging and single-particle tracking. We show that galectin-9 merges pre-existing nanoclusters of IgM-BCR, immobilizes IgM-BCR, and relocalizes IgM-BCR together with the inhibitory molecules CD45 and CD22. In resting naive cells, we use dual-color super-resolution imaging to demonstrate that galectin-9 mediates the close association of IgM and CD22, and propose that the loss of this association provides a mechanism for enhanced activation of galectin-9-deficient B cells.</p

Impact of baseline patient characteristics on dupilumab efficacy in type 2 asthma

Dupilumab treatment versus placebo improved exacerbation rate and lung function outcomes in patients with uncontrolled moderate-to-severe asthma and high type 2 biomarkers at baseline, regardless of baseline characteristics in the phase 3 QUEST study https://bit.ly/3yR7Ml

DUPILUMAB LEADS TO CLINICAL ASTHMA REMISSION INDICATIVE OF COMPREHENSIVE IMPROVEMENT IN PATIENTS WITH ASTHMA: RESULTS FROM THE LIBERTY ASTHMA QUEST AND TRAVERSE STUDIES

Introduction: Asthma treatment response is ascertained by improvement in several important outcomes: exacerbations, symptom control, and lung function. A recent consensus framework defined criteria for remission in severe asthma. This post hoc analysis assessed clinical asthma remission following dupilumab treatment in the phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies using a multicomponent endpoint. Method: Patients with uncontrolled, non-OCS dependent, moderate-to-severe asthma received add-on dupilumab 200 mg or 300 mg every 2 weeks (q2w) or matched placebo for 52 weeks in QUEST, followed by add-on dupilumab 300 mg q2w for up to 96 weeks in TRAVERSE (dupilumab/dupilumab and placebo/dupilumab groups, respectively). Clinical asthma remission (no exacerbations and 5-item Asthma Control Questionnaire [ACQ-5] total score <1.5 and improvement in pre-bronchodilator forced expiratory volume in 1 second [FEV1] ≥ 100 mL [TRAVERSE] or either improvement in pre-bronchodilator FEV1 ≥ 100 mL, or post-bronchodilator percent predicted FEV1 ≥ 80% and no OCS use [QUEST]) was assessed at QUEST Week 52 and TRAVERSE Week 48 in patients with baseline eosinophils ≥150 cells/μL or FeNO ≥ 25 ppb. Results: 1519 patients from QUEST (dupilumab: n = 992; placebo: n = 527) and 1,227 QUEST patients who enrolled in TRAVERSE (dupilumab/dupilumab: n = 804; placebo/dupilumab: n = 423) were included in this post hoc analysis. At Week 52 of QUEST, 31.7% (314) dupilumab-treated vs. 17.7% (93) placebo-treated patients achieved all four criteria, meeting the requirements for clinical remission. At Week 48 of TRAVERSE, 36.4% (293) and 29.6% (125) of dupilumab/dupilumab and placebo/dupilumab patients met all criteria for clinical remission. Conclusion: Approximately 32% of patients in QUEST with elevated type 2 biomarkers and uncontrolled, moderate-to-severe asthma achieved a multicomponent endpoint representing clinical asthma remission after 1 year of dupilumab treatment. This percentage increased to 36% after an additional 48 weeks of treatment in TRAVERSE