Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone

Aims: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH). Methods: Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion. Results: The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60-kg subject to 32.1 L/h for a 100-kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). Conclusion: The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans

Spheroids-on-a-chip: Recent advances and design considerations in microfluidic platforms for spheroid formation and culture

© 2018 Elsevier B.V. A cell spheroid is a three-dimensional (3D) aggregation of cells. Synthetic, in-vitro spheroids provide similar metabolism, proliferation, and species concentration gradients to those found in-vivo. For instance, cancer cell spheroids have been demonstrated to mimic in-vivo tumor microenvironments, and are thus suitable for in-vitro drug screening. The first part of this paper discusses the latest microfluidic designs for spheroid formation and culture, comparing their strategies and efficacy. The most recent microfluidic techniques for spheroid formation utilize emulsion, microwells, U-shaped microstructures, or digital microfluidics. The engineering aspects underpinning spheroid formation in these microfluidic devices are therefore considered. In the second part of this paper, design considerations for microfluidic spheroid formation chips and microfluidic spheroid culture chips (μSFCs and μSCCs) are evaluated with regard to key parameters affecting spheroid formation, including shear stress, spheroid diameter, culture medium delivery and flow rate. This review is intended to benefit the microfluidics community by contributing to improved design and engineering of microfluidic chips capable of forming and/or culturing three-dimensional cell spheroids

Systematic in situ hydration neutron reflectometry study on Nafion thin films

Reported herein is a neutron reflectometry (NR) study on hydrated Nafion thin films (∼30 nm) on a silicon substrate with native oxide. The Nafion morphology is investigated systematically across the whole relative humidity range using both H2O and D2O vapours to enable a comparative study. By utilising this systematic approach two key results have been obtained. The first is that by leveraging the strong positive scattering signal from the D2O vapour, a complete and systematic water adsorption isotherm (Type II) for a Nafion thin film is produced. Utilising the slight negative scattering signal of the H2O enabled the quantification of the hydration dependent evolution of the formation of Nafion/water lamellae near the substrate surface. The number of lamellae layers increases continuously with hydration, and does not form abruptly. We also report the effects of swelling on the thin films across the relative humidity ranges. The work reported should prove useful in quantifying other hydration dependent properties of Nafion thin films such as conductivity and understanding Nafion/semiconductor based devices, as well as showcasing a NR methodology for other hydrophilic polymers

An explicit hybridizable discontinuous Galerkin method for the 3D time-domain Maxwell equations

International audienceWe present an explicit hybridizable discontinuous Galerkin (HDG) method for numerically solving the system of three-dimensional (3D) time-domain Maxwell equations. The method is fully explicit similarly to classical so-called DGTD (Dis-continuous Galerkin Time-Domain) methods, is also high-order accurate in both space and time and can be seen as a generalization of the classical DGTD scheme based on upwind fluxes. We provide numerical results aiming at assessing its numerical convergence properties by considering a model problem and we present preliminary results of the superconvergence property on the H curl norm

Characterisation of Peptide5 systemic administration for treating traumatic spinal cord injured rats

© 2017, Springer-Verlag GmbH Germany. Systemic administration of a Connexin43 mimetic peptide, Peptide5, has been shown to reduce secondary tissue damage and improve functional recovery after spinal cord injury (SCI). This study investigated safety measures and potential off-target effects of Peptide5 systemic administration. Rats were subjected to a mild contusion SCI using the New York University impactor. One cohort was injected intraperitoneally with a single dose of fluorescently labelled Peptide5 and euthanised at 2 or 4 h post-injury for peptide distribution analysis. A second cohort received intraperitoneal injections of Peptide5 or a scrambled peptide and was culled at 8 or 24 h post-injury for the analysis of connexin proteins and systemic cytokine profile. We found that Peptide5 did not cross the blood-spinal cord barrier in control animals, but reached the lesion area in the spinal cord-injured animals without entering non-injured tissue. There was no evidence that the systemic administration of Peptide5 modulates Connexin43 protein expression or hemichannel closure in the heart and lung tissue of SCI animals. The expression levels of other major connexin proteins including Connexin30 in astrocytes, Connexin36 in neurons and Connexin47 in oligodendrocytes were also unaltered by systemic delivery of Peptide5 in either the injured or non-injured spinal cords. In addition, systemic delivery of Peptide5 had no significant effect on the plasma levels of cytokines, chemokines or growth factors. These data indicate that the systemic delivery of Peptide5 is unlikely to cause any off-target or adverse effects and may thus be a safe treatment option for traumatic SCI

Electrochemical sensor based on epoxy-functionalized BEA nanozeolite and graphene oxide modified glassy carbon electrode for bisphenol E determination

An epoxy-functionalized beta type nanozeolite (BEA)/graphene oxide nanocomposite modified glassy carbon electrode (GCE/BEA/APTMS/GA/GO/NF) has been created for the differential pulse voltammetric determination of bisphenol E (BPE). The modified electrode presented an enhanced current response in comparison with bare GCE. A linear dependence of anodic peak current (Ip) and scan rate (ν) was observed, which showed that the electrochemical process was adsorption-controlled. Differential pulse voltammetry (DPV) was employed and optimized for the sensitive determination of BPE. Under the optimized conditions, the anodic peak current was linearly proportional to BPE concentration in the range between 0.07 and 4.81 µM, with a correlation coefficient of 0.995 and limit of detection 0.056 μM (S/N = 3). The electrode showed good repeatability and storage stability, and a low response to interfering compounds. Comparison was made to the determination of bisphenol A. To confirm the electrode analytical performance, recovery tests were performed, and deviations lower than 10% were found. The BEA zeolite-GO nanocomposite proved to be a promising sensing platform for bisphenol determination. Graphical abstract: [Figure not available: see fulltext.]

Performance analysis of MIMO-SESS with Alamouti scheme over Rayleigh fading channels

Las unidades fraseológicas han estado presentes en los repertorios desde los comienzos de la lexicografía. Y no solamente en los diccionarios generales, sino también en las catalogaciones especializadas, tanto de naturaleza monolingüe como bilingüe. No obstante, siempre ha existido dificultad terminológica para la categorización de los diferentes fenómenos del discurso repetido. Si bien esto no ha sido un inconveniente para que se hayan publicado numerosas compilaciones, sobre todo de refranes en un principio, ya que en la actualidad, fundamentalmente, gracias al auge de los estudios teóricos sobre fraseología, han proliferado otras obras (algunas aplicadas a la glosodidáctica, dada su importancia hoy en día) en las que se da cabida con mayor frecuencia a enunciados de valor específico y a locuciones; en unas ocasiones, ahondando en el origen que les dio entidad y, en otras, estableciendo etiquetados precisos que hasta el momento solían estar ausentes, pero con la finalidad, al fin y al cabo, de desentrañar el sentido, dada la escasa deducibilidad que presentan estas secuencias fijadas por la simple suma de sus elementos constitutivos. Un análisis de estos repertorios a través de los siglos, es, por tanto, el objetivo de este trabajo.Since the beginning of lexicography, phraseological units have been included in repertoires; not only in general dictionaries, but also in monolingual and bilingual specialized catalogues. However, there have always been terminological difficulties for classifying various phenomena of repeated speech. Although this has not been inconvenient for publishing many compilations of sayings, especially at the beginning, because nowadays they frequently include utterances with precise value and idioms, mainly due to the rise of theoretical studies on phraseology (some applied to ASL Linguistics, given its importance today). In them, sometimes, the origin of the phraseological unit is included and, in others, accurate labels that were absent before are determined in order, finally and ultimately, to unravel the meaning, given the reduced deductibility that these sequences present from the simple sum of their constituent elements. The objective of this work is, therefore, an analysis of these repertories throughout the centuries

GIVE: portable genome browsers for personal websites.

Growing popularity and diversity of genomic data demand portable and versatile genome browsers. Here, we present an open source programming library called GIVE that facilitates the creation of personalized genome browsers without requiring a system administrator. By inserting HTML tags, one can add to a personal webpage interactive visualization of multiple types of genomics data, including genome annotation, "linear" quantitative data, and genome interaction data. GIVE includes a graphical interface called HUG (HTML Universal Generator) that automatically generates HTML code for displaying user chosen data, which can be copy-pasted into user's personal website or saved and shared with collaborators. GIVE is available at: https://www.givengine.org/

Continuous, Semi-discrete, and Fully Discretized Navier-Stokes Equations

The Navier--Stokes equations are commonly used to model and to simulate flow phenomena. We introduce the basic equations and discuss the standard methods for the spatial and temporal discretization. We analyse the semi-discrete equations -- a semi-explicit nonlinear DAE -- in terms of the strangeness index and quantify the numerical difficulties in the fully discrete schemes, that are induced by the strangeness of the system. By analyzing the Kronecker index of the difference-algebraic equations, that represent commonly and successfully used time stepping schemes for the Navier--Stokes equations, we show that those time-integration schemes factually remove the strangeness. The theoretical considerations are backed and illustrated by numerical examples.Comment: 28 pages, 2 figure, code available under DOI: 10.5281/zenodo.998909, https://doi.org/10.5281/zenodo.99890

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

Background: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. / Methods: C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. / Findings: 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. / Interpretation: Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. / Funding: This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network