Contagious itch behavior informs conspecifics of adverse environment and is crucial for the survival of social animals. Gastrin-releasing peptide (GRP) and its receptor (GRPR) in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates contagious itch behavior in mice. Here, we show that intrinsically photosensitive retina ganglion cells (ipRGCs) convey visual itch information, independently of melanopsin, from the retina to GRP neurons via PACAP-PAC1R signaling. Moreover, GRPR neurons relay itch information to the paraventricular nucleus of the thalamus (PVT). Surprisingly, neither the visual cortex nor superior colliculus is involved in contagious itch. In vivo calcium imaging and extracellular recordings reveal contagious itch-specific neural dynamics of GRPR neurons. Thus, we propose that the retina-ipRGC-SCN-PVT pathway constitutes a previously unknown visual pathway that probably evolved for motion vision that encodes salient environmental cues and enables animals to imitate behaviors of conspecifics as an anticipatory mechanism to cope with adverse conditions.
ABSTRACT Two FINDS Tools, operated by Eastman Whipstock on behalf of Ferranti Eastman Survey have been on contract to Shell UK Exploration and Production and have completed 63 surveys in a two year period. They have maintained their accuracy specifications with a high reliability which combine to give measurable economic benefits. Comparisons of results from conventional magnetic single shots, MWD surveys and gyroscopic multiple shot surveys demonstrate that large errors can go unrecognised. The 'Systematic Error Model' of Wolff and De Wardt for instruments of this type is shown to have substantial validity.
Abstract Background Parenteral nutrition (PN) remains a critical therapeutic option in patients who cannot tolerate enteral feeding. However, although lifesaving, PN is associated with significant side effects, including liver injury, the etiology of which is multifactorial. Carbamazepine (CBZ), an antiepileptic medication, is known to modulate hepatic fibrosis and hepatocellular injury in a variety of liver diseases. We hypothesized that CBZ could prevent PN‐associated liver disease (PNALD), which we tested by using our novel ambulatory PN piglet model. Methods Piglets were fitted with jugular catheters and infusion pumps for PN and randomized to enteral nutrition ( n = 7), PN ( n = 6), or PN with parenteral CBZ ( n = 6) for 2 weeks. Serum and liver tissue were analyzed via light microscopy, quantification of serum liver injury markers, Ki67 and cytokeratin‐7 indexing, and real‐time quantitative polymerase chain reaction. Results PN‐fed piglets in our model developed manifestations of PNALD—particularly, increased serum bilirubin, gamma‐glutamyltransferase, liver cholestasis, and Ki67 expression compared with that of EN‐fed animals ( P < 0.03). CBZ therapy in PN‐fed animals led to a significant reduction in these markers of injury ( P < 0.05). Investigation into the mechanism of these therapeutic effects revealed increased expression of sterol regulatory element‐binding protein 1 (SREBP‐1), peroxisome proliferator‐activated receptor alpha (PPAR‐α), and fatty acid binding protein (FABP) in PN‐fed animals receiving CBZ ( P < 0.03). Further investigation revealed increased LC3 expression and decreased lysosomal‐associated membrane protein (LAMP1) expression with CBZ ( P < 0.03). Conclusion CBZ administration mitigates PNALD severity, suggesting a novel therapeutic strategy targeting PN‐associated side effects, and may present a paradigm change to current treatment options.
Almost 9%of deceased donor livers are discarded as marginal donor livers (MDL) due to concern of severe ischemia reperfusion injury (IRI). Emerging data supports ferroptosis (iron regulated hepatocellular death) as an IRI driver, however lack of robust preclinical model limits therapeutic testing. In this manuscript we describe the development of a novel rigorous internal control system utilizing normothermic perfusion of split livers to test ferroptosis regulators modulating IRI.Upon institutional approval, split human MDLs were placed on our normothermic perfusion machine, Perfusion Regulated Organ Therapeutics with Enhanced Controlled Testing (PROTECT), pumping arterial and portal blood. Experiment 1 compared right (UR) and left (UL) lobes to validate PROTECT. Experiment 2 assessed ferroptosis regulator Deferoxamine in Deferoxamine Agent Treated (DMAT) vs. No Agent Internal Control (NAIC) lobes. Liver serology, histology, and ferroptosis genes were assessed.Successful MDL perfusion validated PROTECT with no ALT or AST difference between UR and UL (∆ALT UR: 235, ∆ALT UL: 212; ∆AST UR: 576, ∆AST UL: 389). Liver injury markers increased in NAIC vs. DMAT (∆ALT NAIC: 586, ∆ALT DMAT: -405; ∆AST NAIC: 617, ∆AST DMAT: -380). UR and UL had similar expression of ferroptosis regulators RPL8,HO-1 and HIFα. Significantly decreased intrahepatic iron (p = .038), HO-1 and HIFα in DMAT (HO-1 NAIC: 6.93, HO-1 DMAT: 2.74; HIFαNAIC: 8.67, HIFαDMAT: 2.60)and no hepatocellular necrosis or immunohistochemical staining (Ki67/Cytokeratin-7) differences were noted.PROTECT demonstrates the therapeutic utility of a novel normothermic perfusion split liver system for drug discovery and rapid translatability of therapeutics, driving a paradigm change in organ recovery and transplant medicine. Our study using human livers, provides preliminary proof of concept for the novel role of ferroptosis regulators in driving IRI.
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