Facilitating the commercialization and use of organ platforms generated by the microphysiological systems (Tissue Chip) program through public–private partnerships

AbstractMicrophysiological systems (organs-on-chips, tissue chips) are devices designed to recapitulate human physiology that could be used to better understand drug responses not easily addressed using other in vivo systems or in vitro animal models. Although still in development, initial results seem promising as tissue chips exhibit in vivo systems-like functional responses. The National Center for Advancing Translation Science (NCATS) identifies this technology as a potential tool that could improve the process of getting safer, more effective treatments to patients, and has led to the Tissue Chip Program, which aims to develop, integrate and validate major organ systems for testing. In addition to organ chip development, NCATS emphasizes disseminating the technology to researchers. Commercialization has become an important issue, reflecting the difficulty of translation from discovery to adoption and wide availability. Therefore, NCATS issued a Request for Information (RFI) targeted to existing partnerships for commercializing tissue chips. The goal was to identify successes, failures and the best practices that could provide useful guidance for future partnerships aiming to make tissue chip technology widely available

Distinct Proteostasis Circuits Cooperate in Nuclear and Cytoplasmic Protein Quality Control

Protein misfolding is linked to a wide array of human disorders, including Alzheimer’s disease, Parkinson’s disease and type II diabetes1,2. Protective cellular protein quality control (PQC) mechanisms have evolved to selectively recognize misfolded proteins and limit their toxic effects3,4,5,6,7,8,9, thus contributing to the maintenance of the proteome (proteostasis). Here we examine how molecular chaperones and the ubiquitin–proteasome system cooperate to recognize and promote the clearance of soluble misfolded proteins. Using a panel of PQC substrates with distinct characteristics and localizations, we define distinct chaperone and ubiquitination circuitries that execute quality control in the cytoplasm and nucleus. In the cytoplasm, proteasomal degradation of misfolded proteins requires tagging with mixed lysine 48 (K48)- and lysine 11 (K11)-linked ubiquitin chains. A distinct combination of E3 ubiquitin ligases and specific chaperones is required to achieve each type of linkage-specific ubiquitination. In the nucleus, however, proteasomal degradation of misfolded proteins requires only K48-linked ubiquitin chains, and is thus independent of K11-specific ligases and chaperones. The distinct ubiquitin codes for nuclear and cytoplasmic PQC appear to be linked to the function of the ubiquilin protein Dsk2, which is specifically required to clear nuclear misfolded proteins. Our work defines the principles of cytoplasmic and nuclear PQC as distinct, involving combinatorial recognition by defined sets of cooperating chaperones and E3 ligases. A better understanding of how these organelle-specific PQC requirements implement proteome integrity has implications for our understanding of diseases linked to impaired protein clearance and proteostasis dysfunction

Micromagnetic simulations of spinel ferrite particles

This paper presents the results of simulations of the magnetization field {\it ac} response (at $2$ to $12$ GHz) of various submicron ferrite particles (cylindrical dots). The ferrites in the present simulations have the spinel structure, expressed here by M$_{1-n}$Zn$_{n}$Fe$_2$O$_4$ (where M stands for a divalent metal), and the parameters chosen were the following: (a) for $n=0$: M = \{ Fe, Mn, Co, Ni, Mg, Cu \}; (b) for $n=0.1$: M = \{ Fe, Mg \} (mixed ferrites). These runs represent full 3D micromagnetic (one-particle) ferrite simulations. We find evidences of confined spin waves in all simulations, as well as a complex behavior nearby the main resonance peak in the case of the M = \{ Mg, Cu \} ferrites. A comparison of the $n=0$ and $n=0.1$ cases for fixed M reveals a significant change in the spectra in M = Mg ferrites, but only a minor change in the M = Fe case. An additional larger scale simulation of a $3$ by $3$ particle array was performed using similar conditions of the Fe$_3$O$_4$ (magnetite; $n=0$, M = Fe) one-particle simulation. We find that the main resonance peak of the Fe$_3$O$_4$ one-particle simulation is disfigured in the corresponding 3 by 3 particle simulation, indicating the extent to which dipolar interactions are able to affect the main resonance peak in that magnetic compound.Comment: 35 pages, 11 figures, Journal of Magnetism and Magnetic Materials, in press

Influence of incubation, diet, and sex on avian uncoupling protein expression and oxidative stress in market age broilers following exposure to acute heat stress

Genetic selection for rapid growth in broilers has inadvertently resulted in increased susceptibility to heat stress, particularly in male birds. Increased oxidative stress associated with hyperthermia may be reduced by avian uncoupling protein (avUCP), which has been proposed to modulate free radical production. However, the relationship between avUCP expression and current heat stress management strategies is unclear. Embryonic acclimation or thermal manipulation (TM) and dietary fat source are 2 heat stress interventions that may alter avUCP expression and oxidative stress, but the literature is inconclusive. The objective of this trial was to investigate the effect of TM and dietary fat source on avUCP gene expression and oxidative damage in the breast meat of market age broilers before and after acute heat challenge. The influence of bird sex was also evaluated as broilers exhibit a high degree of sexual dimorphism in growth and stress susceptibility. Concentration of thiobarbituric acid reactive substances (TBARS) was measured as a marker of oxidative damage. Embryonic TM occurred from incubation d 7 to 16 for 12 h daily at 39.5°C. Dietary treatments were applied during the finisher period using either poultry fat, soya oil, or olive oil supplemented at 4.5% in the diet. Acute heat stress (AHS) occurred on d 43 at 32°C for 4 h. Bird performance was decreased by TM, but no significant differences were noted between dietary fat source treatments. Neither avUCP nor TBARS concentrations were significantly influenced by TM or dietary fat source. Downregulation of avUCP was observed following AHS, concurrent with an increase in TBARS concentration. Male birds exhibited higher levels of both avUCP expression and TBARS compared to females and a significant interaction was noted for heat stress by sex, with avUCP expression being greatest in males prior to AHS. The increase in avUCP expression and TBARS concentrations in male birds may be associated with an increased susceptibility to stress arising from the increased growth rate noted for male broilers.https://www.journals.elsevier.com/poultry-sciencedm2022Animal and Wildlife Science

Challenging the 'New Professionalism': from managerialism to pedagogy?

In recent years there have been changes made to the conceptualisation of continuing professional development for teachers in both the Scottish and English systems of education. These changes have been instigated by successive UK governments (and more recently, by the Scottish Executive), together with the General teaching Council for Scotland (GTCS) and the General Teaching Council for England (GTCE). This paper argues that these changes have not provided a clear rationale for CPD, but instead have introduced tensions between the concept of teacher education and that of training. The need for a less confused understanding of CPD and its purposes is underlined, as is the need for school based approaches to continuing teacher education. Arguably, teacher education must move from technicist emphases to a model which integrates the social processes of change within society and schools with the individual development and empowerment of teachers

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer’s disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer (11)C-BU99008, (18)F-FDG and (18)F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aβ)-positive patients showed greater (11)C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased (11)C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer’s disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced (11)C-BU99008 uptake in Aβ-positive patients compared to controls, such as the temporal lobe, also showed reduced (18)F-FDG uptake and grey matter volume, although the correlations with (18)F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced (11)C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased (11)C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aβ-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong

Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

International audiencePURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of \textgreater2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate