Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they ...self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models.
The goal of this study was to determine the effects of genetic variation in the organic cation transporter 1, OCT1, on the pharmacokinetics of the antidiabetic drug, metformin. Twenty healthy ...volunteers with known OCT1 genotype agreed to participate in the study. Each subject received two oral doses of metformin followed by collection of blood and urine samples. OCT1 genotypes had a significant (P<0.05) effect on metformin pharmacokinetics, with a higher area under the plasma concentration–time curve (AUC), higher maximal plasma concentration (Cmax), and lower oral volume of distribution (V/F) in the individuals carrying a reduced function OCT1 allele (R61C, G401S, 420del, or G465R). The effect of OCT1 on metformin pharmacokinetics in mice was less than in humans possibly reflecting species differences in hepatic expression level of the transporter. Our studies suggest that OCT1 genotype is a determinant of metformin pharmacokinetics.
Clinical Pharmacology & Therapeutics (2008) doi:10.1038/sj.clpt.6100275
Additive manufacture (AM) is receiving significant attention globally, reflected in the volume of research being carried out to support the commercialisation of the technology for industrial ...applications and the interest shown by government and policy makers in the technology. The lack of distinction between 3D printing and AM, as well as the portrayal of some highly publicised applications, may imply that the technology is now firmly established. However, this is not the case. The aim of this study is to identify the current barriers to the progression of AM for end-use products from an industrial perspective and to understand the nature of those barriers. Case study research has been conducted with organisations in the UK aerospace, automotive, defence, heavy machinery and medical device industries. Eighteen barriers are identified: education, cost, design, software, materials, traceability, machine constraints, in-process monitoring, mechanical properties, repeatability, scalability, validation, standards, quality, inspection, tolerances, finishing and sterilisation. Explanation building and logic models are used to generalise the findings. The results are discussed in the context of current academic research on AM. The outcomes of this study help to inform the frontiers of research in AM and how AM research agendas can be aligned with the requirements for industrial applications.
•A paradigm shift in education is required to increase graduates understanding of AM.•Design for AM requires increased creativity reinforced by knowledge and experience.•Software is severely fragmented, it requires streamlining and tailoring for AM.•Industry requires parameter dependent operational windows for materials.•Developing inspection and finishing methods are a focus in research and industry.
African climate is generally considered to have evolved towards progressively drier conditions over the past few million years, with increased variability as glacial-interglacial change intensified ...worldwide. Palaeoclimate records derived mainly from northern Africa exhibit a 100,000-year (eccentricity) cycle overprinted on a pronounced 20,000-year (precession) beat, driven by orbital forcing of summer insolation, global ice volume and long-lived atmospheric greenhouse gases. Here we present a 1.3-million-year-long climate history from the Lake Malawi basin (10°-14° S in eastern Africa), which displays strong 100,000-year (eccentricity) cycles of temperature and rainfall following the Mid-Pleistocene Transition around 900,000 years ago. Interglacial periods were relatively warm and moist, while ice ages were cool and dry. The Malawi record shows limited evidence for precessional variability, which we attribute to the opposing effects of austral summer insolation and the temporal/spatial pattern of sea surface temperature in the Indian Ocean. The temperature history of the Malawi basin, at least for the past 500,000 years, strongly resembles past changes in atmospheric carbon dioxide and terrigenous dust flux in the tropical Pacific Ocean, but not in global ice volume. Climate in this sector of eastern Africa (unlike northern Africa) evolved from a predominantly arid environment with high-frequency variability to generally wetter conditions with more prolonged wet and dry intervals.
The Very Large Array Sky Survey (VLASS) is a synoptic, all-sky radio sky survey with a unique combination of high angular resolution ( 2 5), sensitivity (a 1 goal of 70 Jy/beam in the coadded data), ...full linear Stokes polarimetry, time domain coverage, and wide bandwidth (2-4 GHz). The first observations began in 2017 September, and observing for the survey will finish in 2024. VLASS will use approximately 5500 hr of time on the Karl G. Jansky Very Large Array (VLA) to cover the whole sky visible to the VLA (decl. > −40°), a total of 33 885 deg 2 . The data will be taken in three epochs to allow the discovery of variable and transient radio sources. The survey is designed to engage radio astronomy experts, multi-wavelength astronomers, and citizen scientists alike. By utilizing an "on the fly" interferometry mode, the observing overheads are much reduced compared to a conventional pointed survey. In this paper, we present the science case and observational strategy for the survey, and also results from early survey observations.
The performance of tracheotomy is a common procedural request by critical care departments to the surgical services of general surgery, thoracic surgery and otolaryngology - head & neck surgery. A ...Canadian Society of Otolaryngology - Head & Neck Surgery (CSO-HNS) task force was convened with multi-specialty involvement from otolaryngology-head & neck surgery, general surgery, critical care and anesthesiology to develop a set of recommendations for the performance of tracheotomies during the COVID-19 pandemic.
The tracheotomy procedure is highly aerosol generating and directly exposes the entire surgical team to the viral aerosol plume and secretions, thereby increasing the risk of transmission to healthcare providers. As such, we believe extended endotracheal intubation should be the standard of care for the entire duration of ventilation in the vast majority of patients. Pre-operative COVID-19 testing is highly recommended for any non-emergent procedure.
The set of recommendations in this document highlight the importance of avoiding tracheotomy procedures in patients who are COVID-19 positive if at all possible. Recommendations for appropriate PPE and environment are made for COVID-19 positive, negative and unknown patients requiring consideration of tracheotomy. The safety of healthcare professionals who care for ill patients and who keep critical infrastructure operating is paramount.
The shear behaviour of a rough rock joint depends largely on the surface properties of the joint, as well as the boundary conditions applied across the joint interface. This paper proposes a new ...analytical model to describe the complete shear behaviour of rough joints under constant normal stiffness (CNS) boundary conditions by incorporating the effect of damage to asperities. In particular, the effects of initial normal stress levels and joint surface roughness on the shear behaviour of joints under CNS conditions were studied, and the analytical model was validated through experimental results. Finally, the practical application of the model to a jointed rock slope stability analysis is presented.
The association of liver abnormalities with carcass grading performance, value, and dressed yield was evaluated on data from 76,191 carcasses housed in 2 databases. Liver abnormalities were assigned ...as follows: normal = edible liver; A- = 1 to 2 small abscesses or inactive scars; A = 1 to 2 large abscesses or multiple small abscesses; A+ = multiple large abscesses; A+AD = liver adhered to gastrointestinal tract or diaphragm or both; A+OP = open liver abscess; cirrhosis; distoma; and telangiectasis. Overall liver abnormality rates among both databases were A- = 5.0%, A = 2.6%, A+ = 2.0%, A+AD = 2.7%, A+OP = 1.4%, cirrhosis = 0.1%, distoma = 5.4%, and telangiectasis = 0.3%, with 80.5% of livers being normal. In database 1 (n = 3,936), BW was 33.3 kg less (P < 0.01) for carcasses with cirrhotic livers compared with carcasses with normal livers. Dressed yields for carcasses with A-, A+, A+AD, A+OP, and cirrhosis liver abnormalities were 0.28 to 0.89 percentage points less (P < 0.05) than carcasses with normal livers. In database 2 (n = 72,255), carcasses with A-, A+, A+AD, A+OP, cirrhosis, distoma, and telangiectasis liver abnormalities had reduced (P < 0.05) HCW and reduced (P < 0.05) LM area as compared with carcasses with a normal liver. Less (P < 0.05) 12th-rib subcutaneous fat was observed for carcasses with A-, A, A+, A+AD, A+OP, cirrhosis, and distoma abnormalities compared with carcasses with normal livers. Estimated KPH was less (P < 0.05) for carcasses with A-, A+, A+AD, A+OP, cirrhosis, and distoma abnormalities. Calculated yield grade was less (P < 0.05) for carcasses with A+AD, A+OP, cirrhosis, and distoma abnormalities compared with carcasses with normal livers. Marbling score of carcasses that had livers with A+AD or A+OP abscess scores or distoma was less (P < 0.05) than that of carcasses with normal livers. In database 2, market price per 45.35 kg did not differ (P = 0.32) among liver classification. Gross carcass value analyses indicated carcasses with A-, A, A+, A+AD, A+OP, cirrhosis, and distoma liver abnormalities were less valuable (P < 0.05) than carcasses with normal livers. These data delineate the association of liver abnormalities present at harvest with subsequent changes in carcass characteristics and ultimately lost carcass value.
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