Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% ...of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
•hPSC-CM drug screening, disease modelling & Cas9/CRISPR engineering becoming routine.•hPSC-CMs used to refine patient treatment & assist in progressing drugs to clinic.•Transplantation into heart failure pigs and primates now translated to humans.•Barriers to progression include cost of goods, subtype specification & maturation.•2D and 3D hPSC-CM high content phenotyping platforms evolving rapidly.
Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and ...immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.
The polymer polydimethylsiloxane (PDMS) is widely used to build microfluidic devices compatible with cell culture. Whilst convenient in manufacture, PDMS has the disadvantage that it can absorb small ...molecules such as drugs. In microfluidic devices like “Organs-on-Chip”, designed to examine cell behavior and test the effects of drugs, this might impact drug bioavailability. Here we developed an assay to compare the absorption of a test set of four cardiac drugs by PDMS based on measuring the residual non-absorbed compound by High Pressure Liquid Chromatography (HPLC). We showed that absorption was variable and time dependent and not determined exclusively by hydrophobicity as claimed previously. We demonstrated that two commercially available lipophilic coatings and the presence of cells affected absorption. The use of lipophilic coatings may be useful in preventing small molecule absorption by PDMS.
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•Binding of different compounds to PDMS varies greatly.•Previous reported correlations of absorption and LogP values could not be repeated.•Topological polar surface area possibly related to compound absorption.•A lipid based coating partially obviates compound absorption.•Presence of cultured cells affects free drug concentration, but less than substrate.
Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous ...bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A- and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.
Information about regional carbon sources and sinks can be derived from variations in observed atmospheric CO2 concentrations via inverse modelling with atmospheric tracer transport models. A ...consensus has not yet been reached regarding the size and distribution of regional carbon fluxes obtained using this approach, partly owing to the use of several different atmospheric transport models. Here we report estimates of surface-atmosphere CO2 fluxes from an intercomparison of atmospheric CO2 inversion models (the TransCom 3 project), which includes 16 transport models and model variants. We find an uptake of CO2 in the southern extratropical ocean less than that estimated from ocean measurements, a result that is not sensitive to transport models or methodological approaches. We also find a northern land carbon sink that is distributed relatively evenly among the continents of the Northern Hemisphere, but these results show some sensitivity to transport differences among models, especially in how they respond to seasonal terrestrial exchange of CO2. Overall, carbon fluxes integrated over latitudinal zones are strongly constrained by observations in the middle to high latitudes. Further significant constraints to our understanding of regional carbon fluxes will therefore require improvements in transport models and expansion of the CO2 observation network within the tropics.
Predicting the global carbon and water cycle requires a realistic representation of vegetation phenology in climate models. However most prognostic phenology models are not yet suited for global ...applications, and diagnostic satellite data can be uncertain and lack predictive power. We present a framework for data assimilation of Fraction of Photosynthetically Active Radiation absorbed by vegetation (FPAR) and Leaf Area Index (LAI) from the MODerate Resolution Imaging Spectroradiometer (MODIS) to constrain empirical temperature, light, moisture and structural vegetation parameters of a prognostic phenology model. We find that data assimilation better constrains structural vegetation parameters than climate control parameters. Improvements are largest for drought‐deciduous ecosystems where correlation of predicted versus satellite‐observed FPAR and LAI increases from negative to 0.7–0.8. Data assimilation effectively overcomes the cloud‐ and aerosol‐related deficiencies of satellite data sets in tropical areas. Validation with a 49‐year‐long phenology data set reveals that the temperature‐driven start of season (SOS) is light limited in warm years. The model has substantial skill (R = 0.73) to reproduce SOS inter‐annual and decadal variability. Predicted SOS shows a higher inter‐annual variability with a negative bias of 5–20 days compared to species‐level SOS. It is however accurate to within 1–2 days compared to SOS derived from net ecosystem exchange (NEE) measurements at a FLUXNET tower. The model only has weak skill to predict end of season (EOS). Use of remote sensing data assimilation for phenology model development is encouraged but validation should be extended with phenology data sets covering mediterranean, tropical and arctic ecosystems.
The Community Land Model version 3 (CLM3.0) simulates land‐atmosphere exchanges in response to climatic forcings. CLM3.0 has known biases in the surface energy partitioning as a result of ...deficiencies in its hydrological and biophysical parameterizations. Such models, however, need to be robust for multidecadal global climate simulations. FLUXNET now provides an extensive data source of carbon, water and energy exchanges for investigating land processes, and it encompasses a global range of ecosystem‐climate interactions. Data from 15 FLUXNET sites are used to identify and improve model deficiencies. Including a prognostic aquifer, a bare soil evaporation resistance formulation and numerous other changes in the model result in a significantly improved soil hydrology and energy partitioning. Terrestrial water storage increased by up to 300 mm in warm climates and decreased in cold climates. Nitrogen control of photosynthesis is revealed as another missing process in the model. These improvements increase the correlation coefficient of hourly and monthly latent heat fluxes from a range of 0.5–0.6 to the range of 0.7–0.9. RMSE of the simulated sensible heat fluxes decrease by 20–50%. Primary production is overestimated during the wet season in mediterranean and tropical ecosystems. This might be related to missing carbon‐nitrogen dynamics as well as to site‐specific parameters. The new model (CLM3.5) with an improved terrestrial water cycle should lead to more realistic land‐atmosphere exchanges in coupled simulations. FLUXNET is found to be a valuable tool to develop and validate land surface models prior to their application in computationally expensive global simulations.
Monthly CO2 fluxes are estimated across 1988–2003 for 22 emission regions using data from 78 CO2 measurement sites. The same inversion (method, priors, data) is performed with 13 different ...atmospheric transport models, and the spread in the results is taken as a measure of transport model error. Interannual variability (IAV) in the winds is not modeled, so any IAV in the measurements is attributed to IAV in the fluxes. When both this transport error and the random estimation errors are considered, the flux IAV obtained is statistically significant at P ≤ 0.05 when the fluxes are grouped into land and ocean components for three broad latitude bands, but is much less so when grouped into continents and basins. The transport errors have the largest impact in the extratropical northern latitudes. A third of the 22 emission regions have significant IAV, including the Tropical East Pacific (with physically plausible uptake/release across the 1997–2000 El Niño/La Niña) and Tropical Asia (with strong release in 1997/1998 coinciding with large‐scale fires there). Most of the global IAV is attributed robustly to the tropical/southern land biosphere, including both the large release during the 1997/1998 El Niño and the post‐Pinatubo uptake.
THE COMMON LAND MODEL Dai, Yongjiu; Zeng, Xubin; Dickinson, Robert E. ...
Bulletin of the American Meteorological Society,
08/2003, Volume:
84, Issue:
8
Journal Article
Peer reviewed
Open access
The Common Land Model (CLM) was developed for community use by a grassroots collaboration of scientists who have an interest in making a general land model available for public use and further ...development. The major model characteristics include enough unevenly spaced layers to adequately represent soil temperature and soil moisture, and a multilayer parameterization of snow processes; an explicit treatment of the mass of liquid water and ice water and their phase change within the snow and soil system; a runoff parameterization following the TOPMODEL concept; a canopy photosynthesis–conductance model that describes the simultaneous transfer of CO₂ and water vapor into and out of vegetation; and a tiled treatment of the subgrid fraction of energy and water balance. CLM has been extensively evaluated in offline mode and coupling runs with the NCAR Community Climate Model (CCM3). The results of two offline runs, presented as examples, are compared with observations and with the simulation of three other land models the Biosphere–Atmosphere Transfer Scheme (BATS), Bonan's Land Surface Model (LSM), and the 1994 version of the Chinese Academy of Sciences Institute of Atmospheric Physics LSM (IAP94).
We explored concentration-toxicity relationships for itraconazole among 216 patients. Logistic regression revealed a progressive increase in the probability of toxicity with increasing concentrations ...of itraconazole. Classification and regression tree analysis suggested that 17.1 mg/L of itraconazole (measured using a bioassay) was the concentration level at which the population of patients was separated into 2 groups, each with a high and a low probability of toxicity.
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