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

Thermal stability, pH dependence and inhibition of four murine kynurenine aminotransferases

<p>Abstract</p> <p>Background</p> <p>Kynurenine aminotransferase (KAT) catalyzes the transamination of kynunrenine to kynurenic acid (KYNA). KYNA is a neuroactive compound and functions as an antagonist of alpha7-nicotinic acetylcholine receptors and is the only known endogenous antagonist of N-methyl-D-aspartate receptors. Four KAT enzymes, KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1, KAT II/aminoadipate aminotransferase, KAT III/cysteine conjugate beta-lyase 2, and KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase, have been reported in mammalian brains. Because of the substrate overlap of the four KAT enzymes, it is difficult to assay the specific activity of each KAT in animal brains.</p> <p>Results</p> <p>This study concerns the functional expression and comparative characterization of KAT I, II, III, and IV from mice. At the applied test conditions, equimolar tryptophan with kynurenine significantly inhibited only mouse KAT I and IV, equimolar methionine inhibited only mouse KAT III and equimolar aspartate inhibited only mouse KAT IV. The activity of mouse KAT II was not significantly inhibited by any proteinogenic amino acids at equimolar concentrations. pH optima, temperature preferences of four KATs were also tested in this study. Midpoint temperatures of the protein melting, half life values at 65°C, and pKa values of mouse KAT I, II, III, and IV were 69.8, 65.9, 64.8 and 66.5°C; 69.7, 27.4, 3.9 and 6.5 min; pH 7.6, 5.7, 8.7 and 6.9, respectively.</p> <p>Conclusion</p> <p>The characteristics reported here could be used to develop specific assay methods for each of the four murine KATs. These specific assays could be used to identify which KAT is affected in mouse models for research and to develop small molecule drugs for prevention and treatment of KAT-involved human diseases.</p

Genic population structure and gene flow in the Northern Flicker (Colaptes Auratus) hybrid zone

The Yellow-shafted Flicker (Colaptes auratus auratus) and Red-shafted Flicker (C. a. cafer) form a stable, narrow hybrid zone on the western Great Plains of North America. Allozyme data were obtained from 31 structural gene loci for 33 samples representing 246 Northern Flickers from throughout the Great Plains. Flickers were approximately equivalent to other birds in terms of proportion of polymorphic loci (P = 0.207) and average heterozygosity (H = 0.056). There was no concordant variation between plumage characters and allelic frequencies. Gene-diversity analysis indicated that 92.5% of the genic variation occurred as within-deme heterozygosity (GD = 0.925), approximately 7% occurred among individual demes (GST= 0.07), and only 0.9% occurred among major river drainages (GST = 0.009). Even less diversity was found among parental and hybrid groups (GST = 0.002). There is substantial allozymic structuring of the Northern Flicker species population, but the structuring is not associated with the hybrid zone, and there is, at most, very weak structuring into riparian zones of habitat. The electrophoretic data support the inference that gene flow among Northern Flicker populations is high (Nm = 1.9-4.4/generation). If the high gene-flow estimates are correct, then geographical selection gradients would be the most likely mechanism maintaining the narrow hybrid zone of plumage and morphometric traits

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington\u27s disease

Neurons in Huntington\u27s disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington\u27s disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry

Stem cell-derived models to improve mechanistic understanding and prediction of human drug induced liver injury

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135984/1/hep28886.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135984/2/hep28886_am.pd

Extracellular RNAs as potential biomarkers for cancer

The discovery that all cells secrete extracellular vesicles (EVs) to shuttle proteins and nucleic acids to recipient cells suggested they play an important role in intercellular communication. EVs are widely distributed in many body fluids, including blood, cerebrospinal fluid, urine and saliva. Exosomes are nano-sized EVs of endosomal origin that regulate many pathophysiological processes including immune responses, inflammation, tumour growth, and infection. Healthy individuals release exosomes with a cargo of different RNA, DNA, and protein contents into the circulation, which can be measured non-invasively as biomarkers of healthy and diseased states. Cancer-derived exosomes carry a unique set of DNA, RNA, protein and lipid reflecting the stage of tumour progression, and may serve as diagnostic and prognostic biomarkers for various cancers. However, many gaps in knowledge and technical challenges in EVs and extracellular RNA (exRNA) biology, such as mechanisms of EV biogenesis and uptake, exRNA cargo selection, and exRNA detection remain. The NIH Common Fund-supported exRNA Communication Consortium was launched in 2013 to address major scientific challenges in this field. This review focuses on scientific highlights in biomarker discovery of exosome-based exRNA in cancer and its possible clinical application as cancer biomarkers

Pivoting Novel Exosome-Based Technologies for the Detection of SARS-CoV-2

The National Institutes of Health (NIH) launched the Rapid Acceleration of Diagnostics (RADx) initiative to meet the needs for COVID-19 diagnostic and surveillance testing, and to speed its innovation in the development, commercialization, and implementation of new technologies and approaches. The RADx Radical (RADx-Rad) initiative is one component of the NIH RADx program which focuses on the development of new or non-traditional applications of existing approaches, to enhance their usability, accessibility, and/or accuracy for the detection of SARS-CoV-2. Exosomes are a subpopulation of extracellular vesicles (EVs) 30&ndash;140 nm in size, that are critical in cell-to-cell communication. The SARS-CoV-2 virus has similar physical and molecular properties as exosomes. Therefore, the novel tools and technologies that are currently in development for the isolation and detection of exosomes, may prove to be invaluable in screening for SARS-CoV-2 viral infection. Here, we describe how novel exosome-based technologies are being pivoted for the detection of SARS-CoV-2 and/or the diagnosis of COVID-19. Considerations for these technologies as they move toward clinical validation and commercially viable diagnostics is discussed along with their future potential. Ultimately, the technologies in development under the NIH RADx-Rad exosome-based non-traditional technologies toward multi-parametric and integrated approaches for SARS-CoV-2 program represent a significant advancement in diagnostic technology, and, due to a broad focus on the biophysical and biochemical properties of nanoparticles, the technologies have the potential to be further pivoted as tools for future infectious agents

Organs-on-chips: into the next decade

Organs-on-chips (OoCs), also known as microphysiological systems or ‘tissue chips’ (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term. In the past decade, the OoC field has seen dramatic advances in the sophistication of biology and engineering, in the demonstration of physiological relevance and in the range of applications. These advances have also revealed new challenges and opportunities, and expertise from multiple biomedical and engineering fields will be needed to fully realize the promise of OoCs for fundamental and translational applications. This Review provides a snapshot of this fast-evolving technology, discusses current applications and caveats for their implementation, and offers suggestions for directions in the next decade