The Digital Public Domain: Foundations for an Open Culture

Digital technology has made culture more accessible than ever before. Texts, audio, pictures and video can easily be produced, disseminated, used and remixed using devices that are increasingly user-friendly and affordable. However, along with this technological democratization comes a paradoxical flipside: the norms regulating culture's use — copyright and related rights — have become increasingly restrictive. This book brings together essays by academics, librarians, entrepreneurs, activists and policy makers, who were all part of the EU-funded Communia project. Together the authors argue that the Public Domain — that is, the informational works owned by all of us, be that literature, music, the output of scientific research, educational material or public sector information — is fundamental to a healthy society. The essays range from more theoretical papers on the history of copyright and the Public Domain, to practical examples and case studies of recent projects that have engaged with the principles of Open Access and Creative Commons licensing. The book is essential reading for anyone interested in the current debate about copyright and the Internet. It opens up discussion and offers practical solutions to the difficult question of the regulation of culture at the digital ag

Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1–2 months later and was associated with poor survival. Ten fractionated urines were collected over 2-days in 29 patients. The median value of the rhythm-adjusted mean of urinary nucleoside excretion varied from 64.3 for pseudouridine down to 0.61 for cytidine. The rhythm amplitudes relative to the 24-h mean of 6 nucleoside excretions were associated with rest duration, supporting a tight link between nucleosides turnover and the rest-activity rhythm. Moreover, the amplitude of the 1-methylguanosine rhythm was correlated with the rest-activity dichotomy index, a significant predictor of survival outcome in prior studies. In conclusion, urinary excretion dynamics of modified nucleosides appeared useful for the characterization of the circadian control of cellular proliferation and for tracking early responses to treatments in colorectal cancer patients

FEM-based oxygen consumption and cell viability models for avascular pancreatic islets

<p>Abstract</p> <p>Background</p> <p>The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans) are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM) based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media.</p> <p>Methods</p> <p>Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration.</p> <p>Results</p> <p>Partial differential equation (PDE) based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 <it>μ</it>m diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations.</p> <p>Conclusion</p> <p>Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for non-vascularised islet and can lead to considerable cell death (necrosis), especially in the core region of larger islets. Such models are of considerable interest to improve the function and viability of cultured, transplanted, or encapsulated islets. The present implementation allows convenient extension to true multiphysics applications that solve coupled physics phenomena such as diffusion and consumption with convection due to flowing or moving media.</p

Urban Transit System Microbial Communities Differ by Surface Type and Interaction with Humans and the Environment

ABSTRACT Public transit systems are ideal for studying the urban microbiome and interindividual community transfer. In this study, we used 16S amplicon and shotgun metagenomic sequencing to profile microbial communities on multiple transit surfaces across train lines and stations in the Boston metropolitan transit system. The greatest determinant of microbial community structure was the transit surface type. In contrast, little variation was observed between geographically distinct train lines and stations serving different demographics. All surfaces were dominated by human skin and oral commensals such as Propionibacterium, Corynebacterium, Staphylococcus, and Streptococcus. The detected taxa not associated with humans included generalists from alphaproteobacteria, which were especially abundant on outdoor touchscreens. Shotgun metagenomics further identified viral and eukaryotic microbes, including Propionibacterium phage and Malassezia globosa. Functional profiling showed that Propionibacterium acnes pathways such as propionate production and porphyrin synthesis were enriched on train holding surfaces (holds), while electron transport chain components for aerobic respiration were enriched on touchscreens and seats. Lastly, the transit environment was not found to be a reservoir of antimicrobial resistance and virulence genes. Our results suggest that microbial communities on transit surfaces are maintained from a metapopulation of human skin commensals and environmental generalists, with enrichments corresponding to local interactions with the human body and environmental exposures. IMPORTANCE: Mass transit environments, specifically, urban subways, are distinct microbial environments with high occupant densities, diversities, and turnovers, and they are thus especially relevant to public health. Despite this, only three culture-independent subway studies have been performed, all since 2013 and all with widely differing designs and conclusions. In this study, we profiled the Boston subway system, which provides 238 million trips per year overseen by the Massachusetts Bay Transportation Authority (MBTA). This yielded the first high-precision microbial survey of a variety of surfaces, ridership environments, and microbiological functions (including tests for potential pathogenicity) in a mass transit environment. Characterizing microbial profiles for multiple transit systems will become increasingly important for biosurveillance of antibiotic resistance genes or pathogens, which can be early indicators for outbreak or sanitation events. Understanding how human contact, materials, and the environment affect microbial profiles may eventually allow us to rationally design public spaces to sustain our health in the presence of microbial reservoirs. Author Video: An author video summary of this article is available

A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets

<p>Abstract</p> <p>Background</p> <p>Because insulin is the main regulator of glucose homeostasis, quantitative models describing the dynamics of glucose-induced insulin secretion are of obvious interest. Here, a computational model is introduced that focuses not on organism-level concentrations, but on the quantitative modeling of local, cellular-level glucose-insulin dynamics by incorporating the detailed spatial distribution of the concentrations of interest within isolated avascular pancreatic islets.</p> <p>Methods</p> <p>All nutrient consumption and hormone release rates were assumed to follow Hill-type sigmoid dependences on local concentrations. Insulin secretion rates depend on both the glucose concentration and its time-gradient, resulting in second-and first-phase responses, respectively. Since hypoxia may also be an important limiting factor in avascular islets, oxygen and cell viability considerations were also built in by incorporating and extending our previous islet cell oxygen consumption model. A finite element method (FEM) framework is used to combine reactive rates with mass transport by convection and diffusion as well as fluid-mechanics.</p> <p>Results</p> <p>The model was calibrated using experimental results from dynamic glucose-stimulated insulin release (GSIR) perifusion studies with isolated islets. Further optimization is still needed, but calculated insulin responses to stepwise increments in the incoming glucose concentration are in good agreement with existing experimental insulin release data characterizing glucose and oxygen dependence. The model makes possible the detailed description of the intraislet spatial distributions of insulin, glucose, and oxygen levels. In agreement with recent observations, modeling also suggests that smaller islets perform better when transplanted and/or encapsulated.</p> <p>Conclusions</p> <p>An insulin secretion model was implemented by coupling local consumption and release rates to calculations of the spatial distributions of all species of interest. The resulting glucose-insulin control system fits in the general framework of a sigmoid proportional-integral-derivative controller, a generalized PID controller, more suitable for biological systems, which are always nonlinear due to the maximum response being limited. Because of the general framework of the implementation, simulations can be carried out for arbitrary geometries including cultured, perifused, transplanted, and encapsulated islets.</p

Differential Inhibitory Effects of CysLT1 Receptor Antagonists on P2Y6 Receptor-Mediated Signaling and Ion Transport in Human Bronchial Epithelia

BACKGROUND: Cysteinyl leukotriene (CysLT) is one of the proinflammatory mediators released by the bronchi during inflammation. CysLTs exert their biological effects via specific G-protein-coupled receptors. CysLT(1) receptor antagonists are available for clinical use for the treatment of asthma. Recently, crosstalk between CysLT(1) and P2Y(6) receptors has been delineated. P2Y receptors are expressed in apical and/or basolateral membranes of virtually all polarized epithelia to control the transport of fluid and electrolytes. Previous research suggests that CysLT(1) receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors. However, the detailed molecular mechanism underlying the inhibition remains unresolved. METHODOLOGY/PRINCIPAL FINDINGS: In this study, western blot analysis confirmed that both CysLT(1) and P2Y(6) receptors were expressed in the human bronchial epithelial cell line 16HBE14o-. All three CysLT(1) antagonists inhibited the uridine diphosphate (UDP)-evoked I(SC), but only montelukast inhibited the UDP-evoked [Ca(2+)](i) increase. In the presence of forskolin or 8-bromoadenosine 3'5' cyclic monophosphate (8-Br-cAMP), the UDP-induced I(SC) was potentiated but was reduced by pranlukast and zafirlukast but not montelukast. Pranlukast inhibited the UDP-evoked I(SC) potentiated by an Epac activator, 8-(4-Chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-CPT-2'-O-Me-cAMP), while montelukast and zafirlukast had no such effect. Pranlukast inhibited the real-time increase in cAMP changes activated by 8-CPT-2'-O-Me-cAMP as monitored by fluorescence resonance energy transfer imaging. Zafirlukast inhibited the UDP-induced I(SC) potentiated by N(6)-Phenyladenosine-3',5'-cyclic monophosphorothioate, Sp-isomer (Sp-6-Phe-cAMP; a PKA activator) and UDP-activated PKA activity. CONCLUSIONS/SIGNIFICANCE: In summary, our data strongly suggest for the first time that in human airway epithelia, the three specific CysLT(1) receptor antagonists exert differential inhibitory effects on P2Y(6) receptor-coupled Ca(2+) signaling pathways and the potentiating effect on I(SC) mediated by cAMP and Epac, leading to the modulation of ion transport activities across the epithelia

The Use of Biomaterials in Islet Transplantation

Pancreatic islet transplantation is a therapeutic option to replace destroyed β cells in autoimmune diabetes. Islets are transplanted into the liver via the portal vein; however, inflammation, the required immunosuppression, and lack of vasculature decrease early islet viability and function. Therefore, the use of accessory therapy and biomaterials to protect islets and improve islet function has definite therapeutic potential. Here we review the application of niche accessory cells and factors, as well as the use of biomaterials as carriers or capsules, for pancreatic islet transplantation