Inhibition of TNF receptor p55 by a domain antibody attenuates the initial phase of acid-induced lung injury in mice

Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator36 induced lung injury. In the current study we explored the efficacy of this antibody in mouse models of acid-induced lung injury, to investigate the longer consequences of treatment. Methods: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting ‘dummy’ dAb, 1 or 4 hours before acid instillation. Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase. Conclusions: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 hours. Together with our previous data, the current study lends support towards the clinical targeting of p55 for patients with, or at risk of ARDS

Embodying masculinity in female dominated research settings: A male reflection of ‘doing research’ in massage parlours

This paper reflects on the male experience of conducting fieldwork in massage parlours; off-street settings where women exchange sexual services in predominantly heterosexual monetary transactions. It examines debates surrounding the desirability of gender incongruence between researchers and their informants. By acknowledging the complex interplay of gender and relations in the field, experiences of power are presented as variable and dynamic rather than fixed. Honest and detailed accounts of interactions with sex workers are used to show the complexities of embodying masculinity in clandestine and feminized spaces. The perceived benefits and limitations of gender incongruence are presented. The need to consciously manage and comprehensively reflect upon the impact of gender, and the complex array of power dynamics in the field is discussed

Evolution of Stress-Regulated Gene Expression in Duplicate Genes of Arabidopsis thaliana

Due to the selection pressure imposed by highly variable environmental conditions, stress sensing and regulatory response mechanisms in plants are expected to evolve rapidly. One potential source of innovation in plant stress response mechanisms is gene duplication. In this study, we examined the evolution of stress-regulated gene expression among duplicated genes in the model plant Arabidopsis thaliana. Key to this analysis was reconstructing the putative ancestral stress regulation pattern. By comparing the expression patterns of duplicated genes with the patterns of their ancestors, duplicated genes likely lost and gained stress responses at a rapid rate initially, but the rate is close to zero when the synonymous substitution rate (a proxy for time) is >∼0.8. When considering duplicated gene pairs, we found that partitioning of putative ancestral stress responses occurred more frequently compared to cases of parallel retention and loss. Furthermore, the pattern of stress response partitioning was extremely asymmetric. An analysis of putative cis-acting DNA regulatory elements in the promoters of the duplicated stress-regulated genes indicated that the asymmetric partitioning of ancestral stress responses are likely due, at least in part, to differential loss of DNA regulatory elements; the duplicated genes losing most of their stress responses were those that had lost more of the putative cis-acting elements. Finally, duplicate genes that lost most or all of the ancestral responses are more likely to have gained responses to other stresses. Therefore, the retention of duplicates that inherit few or no functions seems to be coupled to neofunctionalization. Taken together, our findings provide new insight into the patterns of evolutionary changes in gene stress responses after duplication and lay the foundation for testing the adaptive significance of stress regulatory changes under highly variable biotic and abiotic environments

Boreal forest floor greenhouse gas emissions across a Pleurozium schreberi-dominated, wildfire-disturbed chronosequence

The boreal forest is a globally critical biome for carbon cycling. Its forests are shaped by wildfire events that affect ecosystem properties and climate feedbacks including greenhouse gas (GHG) emissions. Improved understanding of boreal forest floor processes is needed to predict the impacts of anticipated increases in fire frequency, severity, and extent. In this study, we examined relationships between time since last wildfire (TSF), forest floor soil properties, and GHG emissions (CO2, CH4, N2O) along a Pleurozium schreberi-dominated chronosequence in mid- to late succession located in northern Sweden. Over three growing seasons in 2012–2014, GHG flux measurements were made in situ and samples were collected for laboratory analyses. We predicted that P. schreberi-covered forest floor GHG fluxes would be related to distinct trends in the soil properties and microbial community along the wildfire chronosequence. Although we found no overall effect of TSF on GHG emissions, there was evidence that soil C/N, one of the few properties to show a trend with time, was inversely linked to ecosystem respiration. We also found that local microclimatic conditions and site-dependent properties were better predictors of GHG fluxes than TSF. This shows that site-dependent co-variables (that is, forest floor climate and plant-soil properties) need to be considered as well as TSF to predict GHG emissions as wildfires become more frequent, extensive and severe

Body Size Evolution in Extant Oryzomyini Rodents: Cope's Rule or Miniaturization?

At the macroevolutionary level, one of the first and most important hypotheses that proposes an evolutionary tendency in the evolution of body sizes is “Cope's rule". This rule has considerable empirical support in the fossil record and predicts that the size of species within a lineage increases over evolutionary time. Nevertheless, there is also a large amount of evidence indicating the opposite pattern of miniaturization over evolutionary time. A recent analysis using a single phylogenetic tree approach and a Bayesian based model of evolution found no evidence for Cope's rule in extant mammal species. Here we utilize a likelihood-based phylogenetic method, to test the evolutionary trend in body size, which considers phylogenetic uncertainty, to discern between Cope's rule and miniaturization, using extant Oryzomyini rodents as a study model. We evaluated body size trends using two principal predictions: (a) phylogenetically related species are more similar in their body size, than expected by chance; (b) body size increased (Cope's rule)/decreased (miniaturization) over time. Consequently the distribution of forces and/or constraints that affect the tendency are homogenous and generate this directional process from a small/large sized ancestor. Results showed that body size in the Oryzomyini tribe evolved according to phylogenetic relationships, with a positive trend, from a small sized ancestor. Our results support that the high diversity and specialization currently observed in the Oryzomyini tribe is a consequence of the evolutionary trend of increased body size, following and supporting Cope's rule

Complex body size trends in the evolution of sloths (Xenarthra: Pilosa)

Background Extant sloths present an evolutionary conundrum in that the two living genera are superficially similar (small-bodied, folivorous, arboreal) but diverged from one another approximately 30 million years ago and are phylogenetically separated by a radiation of medium to massive, mainly ground-dwelling, taxa. Indeed, the species in the two living genera are among the smallest, and perhaps most unusual, of the 50+ known sloth species, and must have independently and convergently evolved small size and arboreality. In order to accurately reconstruct sloth evolution, it is critical to incorporate their extinct diversity in analyses. Here, we used a dataset of 57 species of living and fossil sloths to examine changes in body mass mean and variance through their evolution, employing a general time-variable model that allows for analysis of evolutionary trends in continuous characters within clades lacking fully-resolved phylogenies, such as sloths. Results Our analyses supported eight models, all of which partition sloths into multiple subgroups, suggesting distinct modes of body size evolution among the major sloth lineages. Model-averaged parameter values supported trended walks in most clades, with estimated rates of body mass change ranging as high as 126 kg/million years for the giant ground sloth clades Megatheriidae and Nothrotheriidae. Inclusion of living sloth species in the analyses weakened reconstructed rates for their respective groups, with estimated rates for Megalonychidae (large to giant ground sloths and the extant two-toed sloth) were four times higher when the extant genus Choloepus was excluded. Conclusions Analyses based on extant taxa alone have the potential to oversimplify or misidentify macroevolutionary patterns. This study demonstrates the impact that integration of data from the fossil record can have on reconstructions of character evolution and establishes that body size evolution in sloths was complex, but dominated by trended walks towards the enormous sizes exhibited in some recently extinct forms

The mammalian centrosome and its functional significance

Primarily known for its role as major microtubule organizing center, the centrosome is increasingly being recognized for its functional significance in key cell cycle regulating events. We are now at the beginning of understanding the centrosome’s functional complexities and its major impact on directing complex interactions and signal transduction cascades important for cell cycle regulation. The centrosome orchestrates entry into mitosis, anaphase onset, cytokinesis, G1/S transition, and monitors DNA damage. Recently, the centrosome has also been recognized as major docking station where regulatory complexes accumulate including kinases and phosphatases as well as numerous other cell cycle regulators that utilize the centrosome as platform to coordinate multiple cell cycle-specific functions. Vesicles that are translocated along microtubules to and away from centrosomes may also carry enzymes or substrates that use centrosomes as main docking station. The centrosome’s role in various diseases has been recognized and a wealth of data has been accumulated linking dysfunctional centrosomes to cancer, Alstrom syndrome, various neurological disorders, and others. Centrosome abnormalities and dysfunctions have been associated with several types of infertility. The present review highlights the centrosome’s significant roles in cell cycle events in somatic and reproductive cells and discusses centrosome abnormalities and implications in disease

PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis

Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS