Perfusion of the interventricular septum during ventilation with positive end-expiratory pressure (PEEP)

Objective: To determine whether regional hypoperfusion of the interventricular septum occurs during ventilation with positive end-expiratory pressure. Design: Animal study. Animals: Anesthetized, closed chest dogs (n = 8). Interventions: Induction of experimental adult respiratory distress syndrome (ARDS) and then ventilation with 10,15, and 20 cm H2O of positive end-expiratory pressure. Measurements and Main Results: Cardiac output and regional interventricular septum blood flow 'were assessed at control, at induction of experimental ARDS, and at each level of positive end-expiratory pressure. Ventilation with 20 cm H2O of positive end-expiratory pressure decreased cardiac output (-32% vs. control, p <.05), and did not change absolute, but increased relative (to cardiac output) interventricular septum blood flow. During experimental ARDS and ventilation at 20 cm H2O end-expiratory pressure, there was a redistribution of flow toward the right ventricular free wall (+93%, p < .001) and the right ventricular part of the interventricular septum (+68%, p < .01), while flow to the left ventricular interventricular septum and to the left ventricular free wall remained unchanged. Locally hypoperfused interventricular septum areas or findings indicative of interventricular septum ischemia were not observed during positive end-expiratory pressure. Conclusions: The decrease in cardiac output during positive end-expiratory pressure is not caused by impaired interventricular septum blood supply. The preferential perfusion of the right ventricular interventricular septum indicates increased local right ventricular interventricular septum oxygen-demand and suggests that during positive end-expiratory pressure, this part of the interventricular septum functionally dissociates from the left ventricular interventricular septum and the left ventricular free wall to support the stressed right ventricle

Dichotomous Hamiltonians with Unbounded Entries and Solutions of Riccati Equations

An operator Riccati equation from systems theory is considered in the case that all entries of the associated Hamiltonian are unbounded. Using a certain dichotomy property of the Hamiltonian and its symmetry with respect to two different indefinite inner products, we prove the existence of nonnegative and nonpositive solutions of the Riccati equation. Moreover, conditions for the boundedness and uniqueness of these solutions are established.Comment: 31 pages, 3 figures; proof of uniqueness of solutions added; to appear in Journal of Evolution Equation

A Combination of the Immunotherapeutic Drug Anti-Programmed Death 1 with Lenalidomide Enhances Specific T Cell Immune Responses against Acute Myeloid Leukemia Cells

Immune checkpoint inhibitors can block inhibitory molecules on the surface of T cells, switching them from an exhausted to an active state. One of these inhibitory immune checkpoints, programmed cell death protein 1 (PD-1) is expressed on T cell subpopulations in acute myeloid leukemia (AML). PD-1 expression has been shown to increase with AML progression following allo-haematopoeitic stem cell transplantation, and therapy with hypomethylating agents. We have previously shown that anti-PD-1 can enhance the response of leukemia-associated antigen (LAA)-specific T cells against AML cells as well as leukemic stem and leukemic progenitor cells (LSC/LPCs) ex vivo. In concurrence, blocking of PD-1 with antibodies such as nivolumab has been shown to enhance response rates post-chemotherapy and stem cell transplant. The immune modulating drug lenalidomide has been shown to promote anti-tumour immunity including anti-inflammatory, anti-proliferative, pro-apoptotic and anti-angiogenicity. The effects of lenalidomide are distinct from chemotherapy, hypomethylating agents or kinase inhibitors, making lenalidomide an attractive agent for use in AML and in combination with existing active agents. To determine whether anti-PD-1 (nivolumab) and lenalidomide alone or in combination could enhance LAA-specific T cell immune responses, we used colony-forming immune and ELISpot assays. Combinations of immunother-apeutic approaches are believed to increase antigen-specific immune responses against leukemic cells including LPC/LSCs. In this study we used a combination of LAA-peptides with the immune checkpoint inhibitor anti-PD-1 and lenalidomide to enhance the killing of LSC/LPCs ex vivo. Our data offer a novel insight into how we could improve AML patient responses to treatment in future clinical studies

Effect of 3D-scaffold formation on differentiation and survival in human neural progenitor cells

<p>Abstract</p> <p>Background</p> <p>3D-scaffolds have been shown to direct cell growth and differentiation in many different cell types, with the formation and functionalisation of the 3D-microenvironment being important in determining the fate of the embedded cells. Here we used a hydrogel-based scaffold to investigate the influences of matrix concentration and functionalisation with laminin on the formation of the scaffolds, and the effect of these scaffolds on human neural progenitor cells cultured within them.</p> <p>Methods</p> <p>In this study we used different concentrations of the hydrogel-based matrix PuraMatrix. In some experiments we functionalised the matrix with laminin I. The impact of concentration and treatment with laminin on the formation of the scaffold was examined with atomic force microscopy. Cells from a human fetal neural progenitor cell line were cultured in the different matrices, as well as in a 2D culture system, and were subsequently analysed with antibody stainings against neuronal markers. In parallel, the survival rate of the cells was determined by a live/dead assay.</p> <p>Results</p> <p>Atomic force microscopy measurements demonstrated that the matrices are formed by networks of isolated PuraMatrix fibres and aggregates of fibres. An increase of the hydrogel concentration led to a decrease in the mesh size of the scaffolds and functionalisation with laminin promoted aggregation of the fibres (bundle formation), which further reduces the density of isolated fibres. We showed that laminin-functionalisation is essential for human neural progenitor cells to build up 3D-growth patterns, and that proliferation of the cells is also affected by the concentration of matrix. In addition we found that 3D-cultures enhanced neuronal differentiation and the survival rate of the cells compared to 2D-cultures.</p> <p>Conclusions</p> <p>Taken together, we have demonstrated a direct influence of the 3D-scaffold formation on the survival and neuronal differentiation of human neural progenitor cells. These findings emphasize the importance of optimizing 3D-scaffolds protocols prior to <it>in vivo </it>engraftment of stem and progenitor cells in the context of regenerative medicine.</p

Comparing linear and non-linear models to estimate the appropriate cochlear implant electrode array length—are current methods precise enough?

Purpose In cochlear implantation with flexible lateral wall electrode arrays, a cochlear coverage (CC) range between 70% and 80% is considered ideal for optimal speech perception. To achieve this CC, the cochlear implant (CI) electrode array has to be chosen according to the individual cochlear duct length (CDL). Here, we mathematically analyzed the suitability of different flexible lateral wall electrode array lengths covering between 70% and 80% of the CDL. Methods In a retrospective cross-sectional study preoperative high-resolution computed tomography (HRCT) from patients undergoing cochlear implantation was investigated. The CDL was estimated using an otosurgical planning software and the CI electrode array lengths covering 70–80% of the CDL was calculated using (i) linear and (ii) non-linear models. Results The analysis of 120 HRCT data sets showed significantly different model-dependent CDL. Significant differences between the CC of 70% assessed from linear and non-linear models (mean difference: 2.5 mm, p < 0.001) and the CC of 80% assessed from linear and non-linear models (mean difference: 1.5 mm, p < 0.001) were found. In up to 25% of the patients none of the existing flexible lateral wall electrode arrays fit into this range. In 59 cases (49,2%) the models did not agree on the suitable electrode arrays. Conclusions The CC varies depending on the underlying CDL approximation, which critically influences electrode array choice. Based on the literature, we hypothesize that the non-linear method systematically overestimates the CC and may lead to rather too short electrode array choices. Future studies need to assess the accuracy of the individual mathematical models

Depletion of mammalian target of rapamycin (mTOR) via siRNA mediated knockdown leads to stabilization of β-catenin and elicits distinct features of cardiomyocyte hypertrophy

AbstractCardiac myocyte growth is under differential control of mammalian target of rapamycin (mTOR) and glycogen-synthase-kinase-3β (GSK3β). Whereas active GSK3β negatively regulates growth and down-regulates cellular protein synthesis, activation of the mTOR pathway promotes protein expression and cell growth. Here we report that depletion of mTOR via siRNA mediated knockdown causes marked down-regulation of GSK3β protein in cardiac myocytes. As a result, GSK3β target protein β-catenin becomes stabilized and translocates into the nucleus. Moreover, mTOR knockdown leads to increase in cardiac myocyte surface area and produces an up-regulation of the fetal gene program. Our findings suggest a new type of convergence of mTOR and GSK3β activities, indicating that GSK3β-dependent stabilization of β-catenin in cardiac myocytes is influenced by mTOR

An evaluation of surface meteorology and fluxes over the Iceland and Greenland Seas in ERA5 reanalysis: the impact of sea ice distribution

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Renfrew, I. A., Barrell, C., Elvidge, A. D., Brooke, J. K., Duscha, C., King, J. C., Kristiansen, J., Cope, T. L., Moore, G. W. K., Pickart, R. S., Reuder, J., Sandu, I., Sergeev, D., Terpstra, A., Vage, K., & Weiss, A. An evaluation of surface meteorology and fluxes over the Iceland and Greenland Seas in ERA5 reanalysis: the impact of sea ice distribution. Quarterly Journal of the Royal Meteorological Society, (2020): 1-22, doi:10.1002/qj.3941.The Iceland and Greenland Seas are a crucial region for the climate system, being the headwaters of the lower limb of the Atlantic Meridional Overturning Circulation. Investigating the atmosphere–ocean–ice processes in this region often necessitates the use of meteorological reanalyses—a representation of the atmospheric state based on the assimilation of observations into a numerical weather prediction system. Knowing the quality of reanalysis products is vital for their proper use. Here we evaluate the surface‐layer meteorology and surface turbulent fluxes in winter and spring for the latest reanalysis from the European Centre for Medium‐Range Weather Forecasts, i.e., ERA5. In situ observations from a meteorological buoy, a research vessel, and a research aircraft during the Iceland–Greenland Seas Project provide unparalleled coverage of this climatically important region. The observations are independent of ERA5. They allow a comprehensive evaluation of the surface meteorology and fluxes of these subpolar seas and, for the first time, a specific focus on the marginal ice zone. Over the ice‐free ocean, ERA5 generally compares well to the observations of surface‐layer meteorology and turbulent fluxes. However, over the marginal ice zone, the correspondence is noticeably less accurate: for example, the root‐mean‐square errors are significantly higher for surface temperature, wind speed, and surface sensible heat flux. The primary reason for the difference in reanalysis quality is an overly smooth sea‐ice distribution in the surface boundary conditions used in ERA5. Particularly over the marginal ice zone, unrepresented variability and uncertainties in how to parameterize surface exchange compromise the quality of the reanalyses. A parallel evaluation of higher‐resolution forecast fields from the Met Office's Unified Model corroborates these findings.This study was part of the Iceland Greenland Seas Project. Funding was from the NERC AFIS grant (NE/N009754/1), the ALERTNESS (Advanced models and weather prediction in the Arctic: enhanced capacity from observations and polar process representations) project (Research Council of Norway project number 280573), the Trond Mohn Foundation (BFS2016REK01), and the National Science Foundation grant OCE‐1558742. The Leosphere WindCube v2 and the Wavescan buoy are part of the OBLO (Offshore Boundary Layer Observatory) infrastructure funded by the Research Council of Norway (project number 227777)