Anatomy and Neuroscience - Research Publications

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    Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication
    Miotto, PM ; Yang, C-H ; Keenan, SN ; De Nardo, W ; Beddows, CA ; Fidelito, G ; Dodd, GT ; Parker, BL ; Hill, AF ; Burton, PR ; Loh, K ; Watt, MJ (NATURE PORTFOLIO, 2024-02)
    Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.
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    Control of Neuronal Survival and Development Using Conductive Diamond
    Falahatdoost, S ; Prawer, YDJ ; Peng, D ; Chambers, A ; Zhan, H ; Pope, L ; Stacey, A ; Ahnood, A ; Al Hashem, HN ; De Leon, SE ; Garrett, DJ ; Fox, K ; Clark, MB ; Ibbotson, MR ; Prawer, S ; Tong, W (AMER CHEMICAL SOC, 2024-01-17)
    This study demonstrates the control of neuronal survival and development using nitrogen-doped ultrananocrystalline diamond (N-UNCD). We highlight the role of N-UNCD in regulating neuronal activity via near-infrared illumination, demonstrating the generation of stable photocurrents that enhance neuronal survival and neurite outgrowth and foster a more active, synchronized neuronal network. Whole transcriptome RNA sequencing reveals that diamond substrates improve cellular-substrate interaction by upregulating extracellular matrix and gap junction-related genes. Our findings underscore the potential of conductive diamond as a robust and biocompatible platform for noninvasive and effective neural tissue engineering.
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    Topographical organization and morphology of substance P (SP)-immunoreactive axons in the whole stomach of mice
    Ma, J ; Mistareehi, A ; Madas, J ; Kwiat, AMM ; Bendowski, K ; Nguyen, D ; Chen, J ; Li, D-P ; Furness, JB ; Powley, TL ; Cheng, ZJ (WILEY, 2023-02)
    Nociceptive afferents innervate the stomach and send signals centrally to the brain and locally to stomach tissues. Nociceptive afferents can be detected with a variety of different markers. In particular, substance P (SP) is a neuropeptide and is one of the most commonly used markers for nociceptive nerves in the somatic and visceral organs. However, the topographical distribution and morphological structure of SP-immunoreactive (SP-IR) axons and terminals in the whole stomach have not yet been fully determined. In this study, we labeled SP-IR axons and terminals in flat mounts of the ventral and dorsal halves of the stomach of mice. Flat-mount stomachs, including the longitudinal and circular muscular layers and the myenteric ganglionic plexus, were processed with SP primary antibody followed by fluorescent secondary antibody and then scanned using confocal microscopy. We found that (1) SP-IR axons and terminals formed an extensive network of fibers in the muscular layers and within the ganglia of the myenteric plexus of the whole stomach. (2) Many axons that ran in parallel with the long axes of the longitudinal and circular muscles were also immunoreactive for the vesicular acetylcholine transporter (VAChT). (3) SP-IR axons formed very dense terminal varicosities encircling individual neurons in the myenteric plexus; many of these were VAChT immunoreactive. (4) The regional density of SP-IR axons and terminals in the muscle and myenteric plexus varied in the following order from high to low: antrum-pylorus, corpus, fundus, and cardia. (5) In only the longitudinal and circular muscles, the regional density of SP-IR axon innervation from high to low were: antrum-pylorus, corpus, cardia, and fundus. (6) The innervation patterns of SP-IR axons and terminals in the ventral and dorsal stomach were comparable. Collectively, our data provide for the first time a map of the distribution and morphology of SP-IR axons and terminals in the whole stomach with single-cell/axon/synapse resolution. This work will establish an anatomical foundation for functional mapping of the SP-IR axon innervation of the stomach and its pathological remodeling in gastrointestinal diseases.
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    A novel model for hands-on laparoscopic pelvic surgery training on Genelyn-embalmed body: an initial feasibility study
    Kong, CY ; Fogg, QA ; Allam, M (SPRINGER, 2023-01)
    The human donor body provides a well-accepted ex vivo model for laparoscopic surgical training. Unembalmed, or fresh-frozen, bodies comprise high-fidelity models. However, their short life span and high cost relatively limit the hands-on training benefits. In contrast, soft embalmed body of donors has a relatively longer usability without compromising tissue flexibility. This study reports the initial experience of the utility and feasibility of human donor Genelyn-embalmed body as a novel soft-embalmed cadaveric model for laparoscopic surgical training. An expert laparoscopic surgeon, who organised many fresh-frozen body donor courses, performed deep laparoscopic pelvic dissection and laparoscopic surgical tasks including suturing and electrosurgery on a single Genelyn-embalmed body. The three sessions were performed over a course of 3 weeks. The body was fully embalmed using the Genelyn technique. The technique consisted of a single-point closed arterial perfusion of embalming solution via the carotid artery with no further exposure to or immersion in embalming fluids thereafter. The donor's Genelyn-embalmed body provided a feasible model for laparoscopic surgical training. Initial experience shows evidence of this model being feasible and realistic. There was reproducibility of these qualities across a minimum of 3 weeks in this single-donor study. Initial experience shows that donor's Genelyn-embalmed body provides a novel model for laparoscopic surgical training, which possesses fidelity and is feasible for laparoscopic training. While further studies are needed to validate these findings, this technical note provides perspectives from an expert trainer regarding this model and provides a photographic and videographic atlas of this model's use in laparoscopy.
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    SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha 1(II) collagen gene
    Lefebvre, V ; Huang, WD ; Harley, VR ; Goodfellow, PN ; deCrombrugghe, B (AMER SOC MICROBIOLOGY, 1997-04)
    The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia, a severe skeletal malformation syndrome, and the abundant expression of Sox9 in mouse chondroprogenitor cells and fully differentiated chondrocytes during embryonic development have suggested the hypothesis that SOX9 might play a role in chondrogenesis. Our previous experiments with the gene (Col2a1) for collagen II, an early and abundant marker of chondrocyte differentiation, identified a minimal DNA element in intron 1 which directs chondrocyte-specific expression in transgenic mice. This element is also a strong chondrocyte-specific enhancer in transient transfection experiments. We show here that Col2a1 expression is closely correlated with high levels of SOX9 RNA and protein in chondrocytes. Our experiments indicate that the minimal Col2a1 enhancer is a direct target for Sox9. Indeed, SOX9 binds to a sequence of the minimal Col2a1 enhancer that is essential for activity in chondrocytes, and SOX9 acts as a potent activator of this enhancer in cotransfection experiments in nonchondrocytic cells. Mutations in the enhancer that prevent binding of SOX9 abolish enhancer activity in chondrocytes and suppress enhancer activation by SOX9 in nonchondrocytic cells. Other SOX family members are ineffective. Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes. Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells. We speculate that in campomelic dysplasia a decrease in SOX9 activity would inhibit production of collagen II, and eventually other cartilage matrix proteins, leading to major skeletal anomalies.
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    The role of the gastrointestinal barrier in obesity-associated systemic inflammation
    Acciarino, A ; Diwakarla, S ; Handreck, J ; Bergola, C ; Sahakian, L ; Mcquade, RM (WILEY, 2024-03)
    Systemic inflammation is a key contributor to the onset and progression of several obesity-associated diseases and is thought to predominantly arise from the hyperplasia and hypertrophy of white adipose tissue. However, a growing body of works suggests that early changes in the gastrointestinal (GI) barrier may contribute to both local, within the GI lining, and systemic inflammation in obesity. Intestinal barrier dysfunction is well-characterized in inflammatory GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and is known to contribute to systemic inflammation. Thus, drawing parallels between GI disorders, where intestinal permeability and systemic inflammation are prominent features, and obesity-induced GI manifestations may provide insights into the potential role of the intestinal barrier in systemic inflammation in obesity. This review summarizes the current literature surrounding intestinal barrier dysfunction in obesity and explores the potential role of intestinal hyperpermeability and intestinal barrier dysfunction in the development of systemic inflammation and GI dysfunction in obesity.
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    An adeno-associated viral labeling approach to visualize the meso- and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder
    Wiedmann, NM ; Fuller-Jackson, J-P ; Osborne, PB ; Keast, JR (WILEY, 2024-01)
    The urinary bladder is supplied by a rich network of sensory and autonomic axons, commonly visualized by immunolabeling for neural markers. This approach demonstrates overall network patterning but is less suited to understanding the structure of individual motor and sensory terminals within these complex plexuses. There is a further limitation visualizing the lightly myelinated (A-delta) class of sensory axons that provides the primary mechanosensory drive for initiation of voiding. Whereas most unmyelinated sensory axons can be revealed by immunolabeling for specific neuropeptides, to date no unique neural marker has been identified to immunohistochemically label myelinated visceral afferents. We aimed to establish a non-surgical method to visualize and map myelinated afferents in the bladder in rats. We found that in rats, the adeno-associated virus (AAV), AAV-PHP.S, which shows a high tropism for the peripheral nervous system, primarily transduced myelinated dorsal root ganglion neurons, enabling us to identify the structure and regional distribution of myelinated (mechanosensory) axon endings within the muscle and lamina propria of the bladder. We further identified the projection of myelinated afferents within the pelvic nerve and lumbosacral spinal cord. A minority of noradrenergic and cholinergic neurons in pelvic ganglia were transduced, enabling visualization and regional mapping of both autonomic and sensory axon endings within the bladder. Our study identified a sparse labeling approach for investigating myelinated sensory and autonomic axon endings within the bladder and provides new insights into the nerve-bladder interface.
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    The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
    Alexander, SPH ; Christopoulos, A ; Davenport, AP ; Kelly, E ; Mathie, AA ; Peters, JA ; Veale, EL ; Armstrong, JF ; Faccenda, E ; Harding, SD ; Davies, JA ; Abbracchio, MP ; Abraham, G ; Agoulnik, A ; Alexander, W ; Al-hosaini, K ; Back, M ; Baker, JG ; Barnes, NM ; Bathgate, R ; Beaulieu, J-M ; Beck-Sickinger, AG ; Behrens, M ; Bernstein, KE ; Bettler, B ; Birdsall, NJM ; Blaho, V ; Boulay, F ; Bousquet, C ; Brauner-Osborne, H ; Burnstock, G ; Calo, G ; Castano, JP ; Catt, KJ ; Ceruti, S ; Chazot, P ; Chiang, N ; Chini, B ; Chun, J ; Cianciulli, A ; Civelli, O ; Clapp, LH ; Couture, R ; Cox, HM ; Csaba, Z ; Dahlgren, C ; Dent, G ; Douglas, SD ; Dournaud, P ; Eguchi, S ; Escher, E ; Filardo, EJ ; Fong, T ; Fumagalli, M ; Gainetdinov, RR ; Garelja, ML ; de Gasparo, M ; Gerard, C ; Gershengorn, M ; Gobeil, F ; Goodfriend, TL ; Goudet, C ; Gratz, L ; Gregory, KJ ; Gundlach, AL ; Hamann, J ; Hanson, J ; Hauger, RL ; Hay, DL ; Heinemann, A ; Herr, D ; Hollenberg, MD ; Holliday, ND ; Horiuchi, M ; Hoyer, D ; Hunyady, L ; Husain, A ; Ijzerman, AP ; Inagami, T ; Jacobson, KA ; Jensen, RT ; Jockers, R ; Jonnalagadda, D ; Karnik, S ; Kaupmann, K ; Kemp, J ; Kennedy, C ; Kihara, Y ; Kitazawa, T ; Kozielewicz, P ; Kreienkamp, H-J ; Kukkonen, JP ; Langenhan, T ; Larhammar, D ; Leach, K ; Lecca, D ; Lee, JD ; Leeman, SE ; Leprince, J ; Li, XX ; Lolait, SJ ; Lupp, A ; Macrae, R ; Maguire, J ; Malfacini, D ; Mazella, J ; McArdle, CA ; Melmed, S ; Michel, MC ; Miller, LJ ; Mitolo, V ; Mouillac, B ; Mueller, CE ; Murphy, PM ; Nahon, J-L ; Ngo, T ; Norel, X ; Nyimanu, D ; O'Carroll, A-M ; Offermanns, S ; Panaro, MA ; Parmentier, M ; Pertwee, RG ; Pin, J-P ; Prossnitz, ER ; Quinn, M ; Ramachandran, R ; Ray, M ; Reinscheid, RK ; Rondard, P ; Rovati, GE ; Ruzza, C ; Sanger, GJ ; Schoeneberg, T ; Schulte, G ; Schulz, S ; Segaloff, DL ; Serhan, CN ; Singh, KD ; Smith, CM ; Stoddart, LA ; Sugimoto, Y ; Summers, R ; Tan, VP ; Thal, D ; Thomas, WW ; Timmermans, PBMWM ; Tirupula, K ; Toll, L ; Tulipano, G ; Unal, H ; Unger, T ; Valant, C ; Vanderheyden, P ; Vaudry, D ; Vaudry, H ; Vilardaga, J-P ; Walker, CS ; Wang, JM ; Ward, DT ; Wester, H-J ; Willars, GB ; Williams, TL ; Woodruff, TM ; Yao, C ; Ye, RD (WILEY, 2023-10)
    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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    Exploring mobile mixed reality for critical thinking in nursing and healthcare education: A systematic review
    Stretton, T ; Cochrane, T ; Sevigny, C ; Rathner, J (CHURCHILL LIVINGSTONE, 2024-02)
    BACKGROUND: The shortage of nursing and healthcare clinical placements has prompted the investigation of ways to supplement authentic learning. Mobile mixed reality has become increasingly available, however, the affordances and design principles for the facilitation of critical thinking are yet to be explored. OBJECTIVE: To examine how mobile mixed reality facilitates critical thinking in nursing and healthcare higher education. DESIGN: Systematic review. REVIEW METHODS: A search in seven databases (MEDLINE, PsychINFO, AMED, ERIC, Scopus, Cochrane, and Web of Science) was conducted with 3488 titles and abstracts screened. The quality of the included studies was evaluated using the Mixed Methods Assessment Tool (MMAT). RESULTS: A total of 12 studies with 1108 participants were included. The breadth of healthcare disciplines was limited to five disciplines that utilised bespoke scenarios on head-mounted displays. Most scenarios were emergency or critical response, with limited time for pre-brief, debrief, or overall user time. Only two studies directly measured critical thinking, with others including indirect reference to diagnoses, interpretation, analysis, or evaluation of healthcare scenarios. Affordances and design principles for the future development of mobile mixed reality for critical thinking in nursing and healthcare higher education are identified. CONCLUSIONS: While some pedagogical affordances of mobile mixed reality can be identified in a narrow number of healthcare disciplines, there remain to be limited valid measures of critical thinking used to quantify effectiveness. Future studies would benefit from considering scenarios beyond emergency and critical responses, including longitudinal studies that reflect the development of critical thinking over time, and exploration of co-designed scenarios with and by nursing and healthcare students.
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    Fear extinction is regulated by the activity of long noncoding RNAs at the synapse
    Liau, W-S ; Zhao, Q ; Bademosi, A ; Gormal, RS ; Gong, H ; Marshall, PR ; Periyakaruppiah, A ; Madugalle, SU ; Zajaczkowski, EL ; Leighton, LJ ; Ren, H ; Musgrove, M ; Davies, J ; Rauch, S ; He, C ; Dickinson, BC ; Li, X ; Wei, W ; Meunier, FA ; Fernandez-Moya, SM ; Kiebler, MA ; Srinivasan, B ; Banerjee, S ; Clark, M ; Spitale, RC ; Bredy, TW (NATURE PORTFOLIO, 2023-11-22)
    Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules that are involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are localized to the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq, we identified a specific set of lncRNAs that accumulate in the synaptic compartment within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these was a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single-molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3BP2 and CAPRIN1, regulates the activity-dependent trafficking and clustering of RNA granules. In addition, we found that cell-type-specific, activity-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and RNA condensates in the synaptic compartment.