Can heterogeneity in ventilation be good?

Selection of the optimal positive end-expiratory pressure (PEEP) to avoid ventilator-induced lung injury in patients under mechanical ventilation is still a matter of debate. Many methods are available, but none is considered the gold standard. In the previous issue of Critical Care, Zhao and colleagues applied a method based on electrical impedance tomography to help select the PEEP that minimized ventilation inhomogeneities. Though promising when alveolar collapse and overdistension are present, this method might be misleading in patients with normal lungs

[spatial Analysis Of Counting Data With Excess Zeros Applied To The Study Of Dengue Incidence In Campinas, São Paulo State, Brazil].

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Stand dynamics modulate water cycling and mortality risk in droughted tropical forest

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Transpiration from the Amazon rainforest generates an essential water source at a global and local scale. However, changes in rainforest function with climate change can disrupt this process, causing significant reductions in precipitation across Amazonia, and potentially at a global scale. We report the only study of forest transpiration following a long-term (>10 year) experimental drought treatment in Amazonian forest. After 15 years of receiving half the normal rainfall, drought-related tree mortality caused total forest transpiration to decrease by 30%. However, the surviving droughted trees maintained or increased transpiration because of reduced competition for water and increased light availability, which is consistent with increased growth rates. Consequently, the amount of water supplied as rainfall reaching the soil and directly recycled as transpiration increased to 100%. This value was 25% greater than for adjacent nondroughted forest. If these drought conditions were accompanied by a modest increase in temperature (e.g., 1.5°C), water demand would exceed supply, making the forest more prone to increased tree mortality.This work is a product of UK NERC grant NE/J011002/1 to PM and MM, CNPQ grant 457914/2013-0/MCTI/CNPq/FNDCT/LBA/ESECAFLOR to ACLD, an ARC grant FT110100457 to PM and a UK NERC independent fellowship grant NE/N014022/1 to LR. It was previously supported by NERC NER/A/S/2002/00487, NERC GR3/11706, EU FP5-Carbonsink and EU FP7-Amazalert to PM. RP acknowledges support of MINECO (Spain), grant CGL2014-5583-JIN

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Deep Inelastic Scattering in Conformal QCD

We consider the Regge limit of a CFT correlation function of two vector and two scalar operators, as appropriate to study small-x deep inelastic scattering in N=4 SYM or in QCD assuming approximate conformal symmetry. After clarifying the nature of the Regge limit for a CFT correlator, we use its conformal partial wave expansion to obtain an impact parameter representation encoding the exchange of a spin j Reggeon for any value of the coupling constant. The CFT impact parameter space is the three-dimensional hyperbolic space H3, which is the impact parameter space for high energy scattering in the dual AdS space. We determine the small-x structure functions associated to the exchange of a Reggeon. We discuss unitarization from the point of view of scattering in AdS and comment on the validity of the eikonal approximation. We then focus on the weak coupling limit of the theory where the amplitude is dominated by the exchange of the BFKL pomeron. Conformal invariance fixes the form of the vector impact factor and its decomposition in transverse spin 0 and spin 2 components. Our formalism reproduces exactly the general results predict by the Regge theory, both for a scalar target and for gamma*-gamma* scattering. We compute current impact factors for the specific examples of N=4 SYM and QCD, obtaining very simple results. In the case of the R-current of N=4 SYM, we show that the transverse spin 2 component vanishes. We conjecture that the impact factors of all chiral primary operators of N=4 SYM only have components with 0 transverse spin.Comment: 44+16 pages, 7 figures. Some correction

Correlation function of null polygonal Wilson loops with local operators

We consider the correlator of a light-like polygonal Wilson loop with n cusps with a local operator (like the dilaton or the chiral primary scalar) in planar N =4 super Yang-Mills theory. As a consequence of conformal symmetry, the main part of such correlator is a function F of 3n-11 conformal ratios. The first non-trivial case is n=4 when F depends on just one conformal ratio \zeta. This makes the corresponding correlator one of the simplest non-trivial observables that one would like to compute for generic values of the `t Hooft coupling \lambda. We compute F(\zeta,\lambda) at leading order in both the strong coupling regime (using semiclassical AdS5 x S5 string theory) and the weak coupling regime (using perturbative gauge theory). Some results are also obtained for polygonal Wilson loops with more than four edges. Furthermore, we also discuss a connection to the relation between a correlator of local operators at null-separated positions and cusped Wilson loop suggested in arXiv:1007.3243.Comment: 36 pages, 2 figure

The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming.

Infection of host cells by Toxoplasma gondii is an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex secreted on the parasite surface that functions to promote infection competency. MIC1 and MIC4 are known to bind terminal sialic acid residues and galactose residues, respectively and to induce IL-12 production from splenocytes. Here we show that rMIC1- and rMIC4-stimulated dendritic cells and macrophages produce proinflammatory cytokines, and they do so by engaging TLR2 and TLR4. This process depends on sugar recognition, since point mutations in the carbohydrate-recognition domains (CRD) of rMIC1 and rMIC4 inhibit innate immune cells activation. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to MICs. Following in vitro infection, parasites lacking MIC1 or MIC4, as well as expressing MIC proteins with point mutations in their CRD, failed to induce wild-type (WT) levels of IL-12 secretion by innate immune cells. However, only MIC1 was shown to impact systemic levels of IL-12 and IFN-γ in vivo. Together, our data show that MIC1 and MIC4 interact physically with TLR2 and TLR4 N-glycans to trigger IL-12 responses, and MIC1 is playing a significant role in vivo by altering T. gondii infection competency and murine pathogenesis

Is the proteome of bronchoalveolar lavage extracellular vesicles a marker of advanced lung cancer?

Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years´ follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.R.M. is supported by Fundação para a Ciência e a Tecnologia (CEEC position, 2019–2025 investigator). This article is a result of the projects (iNOVA4Health—UID/Multi/04462/2013), supported by Lisboa Portugal Regional Operational Programme (Lisboa2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work is also funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT—Portuguese Foundation for Science and Technology under the projects number PTDC/BTM-TEC/30087/2017 and PTDC/BTM-TEC/30088/2017. This work was supported by the Wellcome Trust/DBT India Alliance Margdarshi Fellowship (grant number IA/M/15/1/502023) awarded to A.P. B.C.-S., M.C.S.C. and C.B. are supported by the Champalimaud Foundation and the EMBO Installation Grant 3921

Temporal allocation of foraging effort in female Australian fur seals (Arctocephalus pusillus doriferus)

Across an individual\u27s life, foraging decisions will be affected by multiple intrinsic and extrinsic drivers that act at differing timescales. This study aimed to assess how female Australian fur seals allocated foraging effort and the behavioural changes used to achieve this at three temporal scales: within a day, across a foraging trip and across the final six months of the lactation period. Foraging effort peaked during daylight hours (57% of time diving) with lulls in activity just prior to and after daylight. Dive duration reduced across the day (196 s to 168 s) but this was compensated for by an increase in the vertical travel rate (1500–1600 m•h−1) and a reduction in postdive duration (111–90 s). This suggests physiological constraints (digestive costs) or prey availability may be limiting mean dive durations as a day progresses. During short trips (<2.9 d), effort remained steady at 55% of time diving, whereas, on long trips (>2.9 d) effort increased up to 2–3 d and then decreased. Dive duration decreased at the same rate in short and long trips, respectively, before stabilising (long trips) between 4–5 d. Suggesting that the same processes (digestive costs or prey availability) working at the daily scale may also be present across a trip. Across the lactation period, foraging effort, dive duration and vertical travel rate increased until August, before beginning to decrease. This suggests that as the nutritional demands of the suckling pup and developing foetus increase, female effort increases to accommodate this, providing insight into the potential constraints of maternal investment in this specie