Exploring human-nature relationships in academic literature on the nitrogen cycle

The nitrogen (N) cycle is a familiar concept. As is the much simplified, often diagrammatic, representation commonly used to illustrate the scale, importance and interconnectedness of this global cycle that links air, water, rocks and living beings. However, in this representation, humans are often presented as a seemingly minor entity or not explicitly shown at all. This can obscure the idea that humanity is both a direct beneficiary of the nitrogen cycle (through food and resources) and an increasingly significant influence on its function. This study sought to understand how diverse Human-Nature relationships (HNR) are expressed in recent academic literature on the nitrogen cycle. A sample of peer-reviewed literature, containing explicit and inferred examples of HNR and the nitrogen cycle, was analysed using two approaches: 1) network analysis, identifying and illustrating all quantifiable links made between components of the nitrogen cycle, and 2) content analysis to understand how different kinds of terminology were being used to describe relationships between components in the cycle. The network analysis revealed diverse links between ‘human’ and ‘non-human nature’. The content analysis found some explicit use of relational terms, most commonly ‘depend*’. Both approaches highlighted strongly reciprocal links within the ‘human’ realm and the explicit centrality in which this is held across the corpus. We demonstrate the utility of combining quantitative and qualitative analysis to understand nuanced relationships in the nitrogen cycle and explore the utility this has to increase the acknowledgement and appreciation of HNR in science communication and science-policy interface work

ITAM Signaling by Vav Family Rho Guanine Nucleotide Exchange Factors Regulates Interstitial Transit Rates of Neutrophils In Vivo

In response to infection, neutrophils are quickly recruited from the blood into inflamed tissues. The interstitial migration of neutrophils is crucial for the efficient capture and control of rapidly proliferating microbes before microbial growth can overwhelm the host's defenses. However, the molecular mechanisms that regulate interstitial migration are incompletely understood.Here, we use two-photon microscopy (2PM) to study discrete steps of neutrophil responses during subcutaneous infection with bacteria. Our study demonstrates that signals emanating from ITAM-containing receptors mediated by Vav family Rho GEFs control the velocity, but not the directionality, of neutrophil migration towards sites of bacterial infection.Here we show that during neutrophil migration towards sites of bacterial infection, signals emanating from ITAM-containing receptors specifically control interstitial neutrophil velocity

Effect of Adenosine Agonists on the Proliferation and Differentiation of Chick Embryo Fibroblasts in Three Dimensional Reconstituted Tissue Constructs

Previous studies indicate that organ fibroblasts play an important role in wound healing, collagen production, remodeling processes and pathogenesis of progressive heart, lung, renal and hepatic fibrotic diseases. Several studies suggest a possible inhibitory role for adenosine in the regulation of fibroblast proliferation. The effect of adenosine A2 agonists on proliferation and differentiation of chick embryo skin/muscle fibroblasts was studied in collagen-based 3-dimensional tissue constructs and also in plated monolayer cells. Materials and Methods: Chick embryo primary fibroblasts were plated in separate groups and were synchronized by growth arrest before stimulation by different doses of adenosine, and A2 receptor agonists, CV1808, NECA and an A2 receptor antagonist, CGS15943, and control, in the presence of serum or serum free medium. The cell counts for each treatment of monolayer fibroblasts were compared to determine fibroblast proliferation. Western blot analysis, immunostaining and myofibroblast size measurements were conducted to measure the effect of adenosine on the fibroblast differentiation into myofibroblasts. Cell proliferation was also gauged with DNA assays in the 3-D constructs. Results: Adenosine agonists at low doses significantly reduced fibroblast proliferation in monolayer and 3-D cell culture in the presence of 5% Fetal Calf Serum (FCS) demonstrating a potential antifibrotic activity possibly by activation of the A2B receptor. Western blot analysis and immunostaining of cells revealed no significant inhibition of the expression of a-smooth muscle actin on a per cell basis by adenosine agonists. Cell size measurements indicated increased numbers of smaller fibroblasts suggesting that adenosine may inhibit the conversion of fibroblasts to myofibroblasts. Conclusion: This study suggests that agents that increase tissue cAMP levels may be of beneficial therapeutic value in organ tissue fibrosis

Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice

Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C–γ2 (PLC-γ2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-γ2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav

Manifest:Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis

PURPOSE: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi).METHODS: MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks.RESULTS: Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of &lt; 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with &gt; 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks.CONCLUSION: The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.</p

Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov. Plain language summary Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF

Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients

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