Using 3D gastrointestinal tract in vitro models with microfold cells and mucus secreting ability to assess the hazard of copper oxide nanomaterials

Abstract: Background: Copper oxide nanomaterials (CuO NMs) are exploited in many products including inks, cosmetics, textiles, wood preservatives and food contact materials. Their incorporation into these products may enhance oral exposure in consumer, environmental and occupational settings. Undifferentiated and differentiated monocultures of Caco-2 cells are commonly used to assess NM toxicity to the intestine in vitro. However, the integration of other cell types into Caco-2 in vitro models increases their physiological relevance. Therefore, the aim of this study is to evaluate the toxicity of CuO NMs and copper sulphate ( CuSO4) to intestinal microfold (M) cell (Caco-2/Raji B) and mucus secreting (Caco-2/HT29-MTX) co-culture in vitro models via assessment of their impact on barrier integrity, viability and interleukin (IL)-8 secretion. The translocation of CuO NMs and CuSO4 across the intestinal barrier was also investigated in vitro. Results: CuO NMs and CuSO4 impaired the function of the intestinal barrier in the co-culture models [as indicated by a reduction in transepithelial electrical resistance (TEER) and Zonular occludens (ZO-1) staining intensity]. Cu translocation was observed in both models but was greatest in the Caco-2/Raji B co-culture. CuO NMs and CuSO4 stimulated an increase in IL-8 secretion, which was greatest in the Caco-2/HT29-MTX co-culture model. CuO NMs and CuSO4 did not stimulate a loss of cell viability, when assessed using light microscopy, nuclei counts and scanning electron microscopy. CuO NMs demonstrated a relatively similar level of toxicity to CuO4 in both Caco-2/Raji B and Caco-2/ HT29-MTX co- culture models. Conclusions: The Caco-2/Raji B co-culture model was more sensitive to CuO NM and CuSO4 toxicity than the Caco-2/HT29-MTX co-culture model. However, both co-culture models were less sensitive to CuO NM and CuSO4 toxicity than simple monocultures of undifferentiated and differentiated Caco-2 cells, which are more routinely used to investigate NM toxicity to the intestine. Obtained data can therefore feed into the design of future studies which assess the toxicity of substances (e.g. NMs) and pathogens to the intestine (e.g. by informing model and endpoint selection). However, more testing with a wider panel of NMs would be beneficial in order to help select which in vitro models and endpoints to prioritise when screening the safety of ingested NMs. Comparisons with in vivo findings will also be essential to identify the most suitable in vitro model to screen the safety of ingested NMs

Tetra-porphyrin molecular tweezers: two binding sites linked via a polycyclic scaffold and rotating phenyl diimide core

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.The synthesis of a tetra-porphyrin molecular tweezer with two binding sites is described. The bis-porphyrin binding sites are aligned by a polycyclic scaffold and linked via a freely rotating phenyl diimide core. Synthesis was achieved using a divergent approach employing a novel coupling method for linking two polycyclic units to construct the core, with a copper(II)-mediated phenyl boronic acid coupling found to extend to our polycyclic imide derivative. We expect this chemistry to be a powerful tool in accessing functional polycyclic supramolecular architectures in applications where north/south reactivity and/or directional interactions between modules are important. Porphyrin receptor functionalisation was undertaken last, by a four-fold ACE coupling reaction on the tetra-epoxide derivative of the core

Magnon Localization in Mattis Glass

We study the spectral and transport properties of magnons in a model of a disordered magnet called Mattis glass, at vanishing average magnetization. We find that in two dimensional space, the magnons are localized with the localization length which diverges as a power of frequency at small frequencies. In three dimensional space, the long wavelength magnons are delocalized. In the delocalized regime in 3d (and also in 2d in a box whose size is smaller than the relevant localization length scale) the magnons move diffusively. The diffusion constant diverges at small frequencies. However, the divergence is slow enough so that the thermal conductivity of a Mattis glass is finite, and we evaluate it in this paper. This situation can be contrasted with that of phonons in structural glasses whose contribution to thermal conductivity is known to diverge (when inelastic scattering is neglected).Comment: 11 page

Improving the interpretation of quality of life evidence in meta-analyses: the application of minimal important difference units

Systematic reviews of randomized trials that include measurements of health-related quality of life potentially provide critical information for patient and clinicians facing challenging health care decisions. When, as is most often the case, individual randomized trials use different measurement instruments for the same construct (such as physical or emotional function), authors typically report differences between intervention and control in standard deviation units (so-called "standardized mean difference" or "effect size"). This approach has statistical limitations (it is influenced by the heterogeneity of the population) and is non-intuitive for decision makers. We suggest an alternative approach: reporting results in minimal important difference units (the smallest difference patients experience as important). This approach provides a potential solution to both the statistical and interpretational problems of existing methods

Acceptance of Simulated Oral Rabies Vaccine Baits by Urban Raccoons

In summer 1986, a study was conducted to evaluate raccoon (Procyon lotor) acceptance of oral baits that could be used for rabies vaccination, One thousand wax-coated sponge bait cubes were filled with 5 mg of a seromarker (iophenoxic acid), placed in polyethylene bags, and hand-distributed in an 80 ha area within an urban National Park in Washington, D.C. (USA), After 3 wk, target and nontarget animals were trapped and blood samples collected to evaluate bait uptake. Thirty-three of 52 (63%) raccoons had elevated blood iodine levels indicating they had eaten at least one bait, 13 (25%) were negative, and six (12%) had marginal values, These results indicate that sponge baits hand-placed at a density of 12,4/ha can reach a significant proportion of an urban raccoon population. Implications for oral rabies vaccination of raccoons are discussed

Determining Call-To-Entry Rate and Recruitment Barriers in Clinical Studies For Community Clinics Serving Low-income Populations: a Cohort Study

BACKGROUND: Recruitment for clinical studies is challenging. to overcome barriers, investigators have previously established call-to-entry rates to assist in planning. However, rates specific to low-income minority populations are needed to account for additional barriers to enrolment these individuals face. OBJECTIVE: to obtain a call-to-entry rate in a low-income uninsured Hispanic population with chronic disease. METHODS: We used data from four of our randomised clinical studies to determine the call-to-entry rate for individuals (n=1075) with or at risk for type 2 diabetes: participants needed/potential participants contacted=recruitment rate (yield). Research staff contacted potential participants to enrol in a study that evaluated 6 month diabetes programmes at community clinics from 2015 to 2020. We recorded call-to-entry rates, reasons for declining the study, show rates, and attrition. RESULTS: The call-to-entry rate was 14.5%. Forty per cent of potential participants could not be contacted, and 30.6%, 19.1%, and 5.4% responded CONCLUSIONS: We described a call-to-entry rate and detailed recruitment data, including reasons to decline the study. This valuable information can assist investigators in study planning and overcoming enrolment barriers in low-income populations. Telehealth-based or strategies that limit transportation needs may increase participant involvement. TRIAL REGISTRATION NUMBER: NCT03394456

Monodehydroascorbate reductase mediates TNT toxicity in plants

The explosive 2,4,6-trinitrotoluene (TNT) is a highly toxic and persistent environmental pollutant. Due to the scale of affected areas, one of the most cost-effective and environmentally friendly means of removing explosives pollution could be the use of plants. However, mechanisms of TNT phytotoxicity have been elusive. Here, we reveal that phytotoxicity is caused by reduction of TNT in the mitochondria, forming a nitro radical that reacts with atmospheric oxygen, generating reactive superoxide. The reaction is catalyzed by monodehydroascorbate reductase 6 (MDHAR6), with Arabidopsis deficient in MDHAR6 displaying enhanced TNT tolerance. This discovery will contribute toward the remediation of contaminated sites. Moreover, in an environment of increasing herbicide resistance, with a shortage in new herbicide classes, our findings reveal MDHAR6 as a valuable plant-specific target

Pain Squad+ smartphone app to support real-time pain treatment for adolescents with cancer: protocol for a randomised controlled trial.

INTRODUCTION: Pain negatively affects the health-related quality of life (HRQL) of adolescents with cancer. The Pain Squad+ smartphone-based application (app), has been developed to provide adolescents with real-time pain self-management support. The app uses a validated pain assessment and personalised pain treatment advice with centralised decision support via a registered nurse to enable real-time pain treatment in all settings. The algorithm informing pain treatment advice is evidence-based and expert-vetted. This trial will longitudinally evaluate the impact of Pain Squad+, with or without the addition of nurse support, on adolescent health and cost outcomes. METHODS AND ANALYSIS: This will be a pragmatic, multicentre, waitlist controlled, 3-arm parallel-group superiority randomised trial with 1:1:1 allocation enrolling 74 adolescents with cancer per arm from nine cancer centres. Participants will be 12 to 18 years, English-speaking and with ≥3/10 pain. Exclusion criteria are significant comorbidities, end-of-life status or enrolment in a concurrent pain study. The primary aim is to determine the effect of Pain Squad+, with and without nurse support, on pain intensity in adolescents with cancer, when compared with a waitlist control group. The secondary aims are to determine the immediate and sustained effect over time of using Pain Squad+, with and without nurse support, as per prospective outcome measurements of pain interference, HRQL, pain self-efficacy and cost. Linear mixed models with baseline scores as a covariate will be used. Qualitative interviews with adolescents from all trial arms will be conducted and analysed. ETHICS AND DISSEMINATION: This trial is approved by the Hospital for Sick Children Research Ethics Board. Results will provide data to guide adolescents with cancer and healthcare teams in treating pain. Dissemination will occur through partnerships with stakeholder groups, scientific meetings, publications, mass media releases and consumer detailing. TRIAL REGISTRATION NUMBER: NCT03632343

The Extreme Scattering Event Toward PKS 1741-038: VLBI Images

(Abridged) We report multi-epoch VLBI observations of the source PKS 1741-038 as it underwent an extreme scattering event. Observations at four epochs were obtained, and images were produced at three of these. During the event the source consisted of a dominant, compact component, essentially identical to the structure seen outside the event. However, the source's diameter increased slightly at 13 cm during the ESE. An increase in the source's diameter is inconsistent with a simple refractive model. We also see no evidence for ESE-induced substructure within the source or the formation of multiple images, as would occur in a strongly refractive lens. However, a model in which the decrease in flux density during the ESE occurs solely because of stochastic broadening within the lens requires a larger broadening diameter during the ESE than is observed. Thus, the ESE toward 1741-038 involved both stochastic broadening and refractive defocussing within the lens. If the structure responsible for the ESE has a size of order 1 AU, the level of scattering within an ESE lens may be a factor of 10^7 larger than that in the ambient medium. A filamentary structure could reduce the difference between the strength of scattering in the lens and ambient medium, but we conclude that, if ESEs arise from filamentary structures, they occur when the filamentary structures are seen lengthwise. We predict the amount of pulse broadening that would result from a comparable lens passing in front of a pulsar. The pulse broadening would be no more than 1.1 microseconds, consistent with the lack of pulse broadening detected during ESEs toward the pulsars PSR B1937+21 and PSR J1643-1224.Comment: 19 pages, LaTeX2e with AASTeX-4.0, 1 LaTeX table and 5 figures in 9 PostScript files, to be published in the ApJ, minor change in Figures 2a, 3a, and 4a to correct a labe