Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury.

RATIONALE: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection. OBJECTIVES: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury. METHODS: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage. CONCLUSIONS: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention

Tuberculosis incidence correlates with sunshine : an ecological 28-year time series study

Birmingham is the largest UK city after London, and central Birmingham has an annual tuberculosis incidence of 80 per 100,000. We examined seasonality and sunlight as drivers of tuberculosis incidence. Hours of sunshine are seasonal, sunshine exposure is necessary for the production of vitamin D by the body and vitamin D plays a role in the host response to tuberculosis. Methods: We performed an ecological study that examined tuberculosis incidence in Birmingham from Dec 1981 to Nov 2009, using publicly-available data from statutory tuberculosis notifications, and related this to the seasons and hours of sunshine (UK Meteorological Office data) using unmeasured component models. Results: There were 9,739 tuberculosis cases over the study period. There was strong evidence for seasonality, with notifications being 24.1% higher in summer than winter (p<0.001). Winter dips in sunshine correlated with peaks in tuberculosis incidence six months later (4.7% increase in incidence for each 100 hours decrease in sunshine, p<0.001). Discussion and Conclusion: A potential mechanism for these associations includes decreased vitamin D levels with consequent impaired host defence arising from reduced sunshine exposure in winter. This is the longest time series of any published study and our use of statutory notifications means this data is essentially complete. We cannot, however, exclude the possibility that another factor closely correlated with the seasons, other than sunshine, is responsible. Furthermore, exposure to sunlight depends not only on total hours of sunshine but also on multiple individual factors. Our results should therefore be considered hypothesis-generating. Confirmation of a potential causal relationship between winter vitamin D deficiency and summer peaks in tuberculosis incidence would require a randomized-controlled trial of the effect of vitamin D supplementation on future tuberculosis incidence

Assessment of arterial stiffness, oxidative stress and inflammation in acute kidney injury

Background: It is well know that arterial stiffness, oxidative stress and inflammation are features of chronic kidney disease. The arterial changes have a multitude of potential interconnected causes including endothelial dysfunction, oxidative stress, inflammation, atherosclerosis and vascular calcification. There is evidence that arterial stiffness becomes progressively worse as CKD progresses. The contribution of the biochemical changes of uremic toxicity to arterial stiffness is less clear. The aim of this study is to elucidate the vascular changes in acute kidney injury. We hypothesise that arterial stiffness will be increased during acute kidney injury and this will return to normal after kidney function recovers

Seabird species vary in behavioural response to drone census

This is the final version of the article. Available from the publisher via the DOI in this record.Unmanned aerial vehicles (UAVs) provide an opportunity to rapidly census wildlife in remote areas while removing some of the hazards. However, wildlife may respond negatively to the UAVs, thereby skewing counts. We surveyed four species of Arctic cliff-nesting seabirds (glaucous gull Larus hyperboreus, Iceland gull Larus glaucoides, common murre Uria aalge and thick-billed murre Uria lomvia) using a UAV and compared censusing techniques to ground photography. An average of 8.5% of murres flew off in response to the UAV, but >99% of those birds were non-breeders. We were unable to detect any impact of the UAV on breeding success of murres, except at a site where aerial predators were abundant and several birds lost their eggs to predators following UAV flights. Furthermore, we found little evidence for habituation by murres to the UAV. Most gulls flew off in response to the UAV, but returned to the nest within five minutes. Counts of gull nests and adults were similar between UAV and ground photography, however the UAV detected up to 52.4% more chicks because chicks were camouflaged and invisible to ground observers. UAVs provide a less hazardous and potentially more accurate method for surveying wildlife. We provide some simple recommendations for their use.We thank T. Leonard and the Seabird Ecological Reserves Advisory Committee for permission to work at Witless Bay, the Canadian Wildlife Service for permits to work at Newfoundland and Nunavut and the Government of Nunavut for permits to work in Nunavut. Newfoundland and Labrador Murre Fund, Bird Studies Canada and the Molson Foundation directly funded the work. An NSERC Discovery Grant, the Canada Research Chair in Arctic Ecology and Polar Continental Shelf Project also helped fund the project. We thank T. Burke, G. Sorenson, T. Lazarus and M. Guigueno for their help and J. Nakoolak for keeping us safe from bear

Measuring the Meltdown: Drivers of Global Amphibian Extinction and Decline

Habitat loss, climate change, over-exploitation, disease and other factors have been hypothesised in the global decline of amphibian biodiversity. However, the relative importance of and synergies among different drivers are still poorly understood. We present the largest global analysis of roughly 45% of known amphibians (2,583 species) to quantify the influences of life history, climate, human density and habitat loss on declines and extinction risk. Multi-model Bayesian inference reveals that large amphibian species with small geographic range and pronounced seasonality in temperature and precipitation are most likely to be Red-Listed by IUCN. Elevated habitat loss and human densities are also correlated with high threat risk. Range size, habitat loss and more extreme seasonality in precipitation contributed to decline risk in the 2,454 species that declined between 1980 and 2004, compared to species that were stable (n = 1,545) or had increased (n = 28). These empirical results show that amphibian species with restricted ranges should be urgently targeted for conservation

Elevated nerve growth factor and neurotrophin-3 levels in cerebrospinal fluid of children with hydrocephalus

BACKGROUND: Elevated intracranial pressure (ICP) resulting from impaired drainage of cerebrospinal fluid (CSF) causes hydrocephalus with damage to the central nervous system. Clinical symptoms of elevated intracranial pressure (ICP) in infants may be difficult to diagnose, leading to delayed treatment by shunt placement. Until now, no biochemical marker of elevated ICP has been available for clinical diagnosis and monitoring. In experimental animal models, nerve growth factor (NGF) and neurotrophin-3 (NT-3) have been shown to be produced by glial cells as an adaptive response to hypoxia. We investigated whether concentrations of NGF and NT-3 are increased in the CSF of children with hydrocephalus. METHODS: NGF was determined in CSF samples collected from 42 hydrocephalic children on 65 occasions (taps or shunt placement surgery). CSF samples obtained by lumbar puncture from 22 children with suspected, but unconfirmed bacterial infection served as controls. Analysis was performed using ELISA techniques. RESULTS: NGF concentrations in hydrocephalic children were over 50-fold increased compared to controls (median 225 vs 4 pg/mL, p < 0.0001). NT-3 was detectable (> 1 pg/mL) in 14/31 hydrocephalus samples at 2–51 pg/mL but in none of 11 control samples (p = 0.007). CONCLUSION: NGF and NT-3 concentrations are increased in children with hydrocephalus. This may represent an adaptive response of the brain to elevated ICP

Tet2 disruption leads to enhanced self-renewal and altered differentiation of fetal liver hematopoietic stem cells

Somatic mutation of ten-eleven translocation 2 (TET2) gene is frequently found in human myeloid malignancies. Recent reports showed that loss of Tet2 led to pleiotropic hematopoietic abnormalities including increased competitive repopulating capacity of bone marrow (BM) HSCs and myeloid transformation. However, precise impact of Tet2 loss on the function of fetal liver (FL) HSCs has not been examined. Here we show that disruption of Tet2 results in the expansion of Lin−Sca-1+c-Kit+ (LSK) cells in FL. Furthermore, Tet2 loss led to enhanced self-renewal and long-term repopulating capacity of FL-HSCs in in vivo serial transplantation assay. Disruption of Tet2 in FL also led to altered differentiation of mature blood cells, expansion of common myeloid progenitors and increased resistance for hematopoietic progenitor cells (HPCs) to differentiation stimuli in vitro. These results demonstrate that Tet2 plays a critical role in homeostasis of HSCs and HPCs not only in the BM, but also in FL

Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells

BACKGROUND: Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. METHODS: Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model. RESULTS: All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib - treatment. CONCLUSIONS: Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline