Milesklitgaard2309

Furthermore, when analyzed by Nanostring immune profiling treatment of Debio-025 with anti-PD1 mAb increased both T cell signaling and innate immune signaling in TME. Implications These data suggest that pharmacological inhibition of CypA may provide a promising and unanticipated consequence in cancer biology, in part by targeting the CypA/Crk II axis that regulates cell migration, tumor metastasis, and host anti-tumor immune evasion. Copyright ©2020, American Association for Cancer Research.OBJECTIVE To define and validate criteria for accurate identification of EEG interictal epileptiform discharges (IEDs) using (1) the 6 sensor space criteria proposed by the International Federation of Clinical Neurophysiology (IFCN) and (2) a novel source space method. Criteria yielding high specificity are needed because EEG over-reading is a common cause of epilepsy misdiagnosis. METHODS Seven raters reviewed EEG sharp transients from 100 patients with and without epilepsy (diagnosed definitively by video-EEG recording of habitual events). Raters reviewed the transients, randomized, and classified them as epileptiform or nonepileptiform in 3 separate rounds in 2, EEG was reviewed in sensor space (scoring the presence/absence of each IFCN criterion for each transient or classifying unrestricted by criteria [expert scoring]); in the other, review and classification were performed in source space. RESULTS Cutoff values of 4 and 5 criteria in sensor space and analysis in source space provided high accuracy (91%, 88%, and 90%, respectively), similar to expert scoring (92%). Two methods had specificity exceeding the desired threshold of 95% using 5 IFCN criteria as cutoff and analysis in source space (both 95.65%); the sensitivity of these methods was 81.48% and 85.19%, respectively. CONCLUSIONS The presence of 5 IFCN criteria in sensor space and analysis in source space are optimal for clinical implementation. By extracting these objective features, diagnostic accuracy similar to expert scorings is achieved. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that IFCN criteria in sensor space and analysis in source space have high specificity (>95%) and sensitivity (81%-85%) for identification of IEDs. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.OBJECTIVE To use network science to model complex diet relationships a decade before onset of dementia in a large French cohort, the 3-City Bordeaux study. METHODS We identified cases of dementia incident to the baseline food frequency questionnaire over 12 years of follow-up. For each case, we randomly selected 2 controls among individuals at risk at the age at case diagnosis and matched for age at diet assessment, sex, education, and season of the survey. We inferred food networks in both cases and controls using mutual information, a measure to detect nonlinear associations, and compared food consumption patterns between groups. RESULTS In the nested case-control study, the mean (SD) duration of follow-up and number of visits were 5.0 (2.5) vs 4.9 (2.6) years and 4.1 (1.0) vs 4.4 (0.9) for cases (n = 209) vs controls (n = 418), respectively. While there were few differences in simple, average food intakes, food networks differed substantially between cases and controls. The network in cases was focused and characterized by charcuterie as the main hub, with connections to foods typical of French southwestern diet and snack foods. In contrast, the network of controls included several disconnected subnetworks reflecting diverse and healthier food choices. buy HSP27 inhibitor J2 CONCLUSION How foods are consumed (and not only the quantity consumed) may be important for dementia prevention. Differences in predementia diet networks, suggesting worse eating habits toward charcuterie and snacking, were evident years before diagnosis in this cohort. Network methods, which are designed to model complex systems, may advance our understanding of risk factors for dementia. © 2020 American Academy of Neurology.Prion diseases are transmissible, lethal neurodegenerative disorders caused by accumulation of the aggregated scrapie form of prion protein (PrPSc) after conversion of cellular prion protein (PrPC). The glycosylphosphatidylinositol (GPI) anchor of PrPC is involved in prion disease pathogenesis, and especially sialic acid in a GPI side-chain reportedly affects the PrPC conversion. Thus, it is important to define the location and structure of the GPI anchor in human PrPC Moreover, the sialic acid linkage-type in the GPI side-chain has not been determined for any GPI-anchored protein. Here, we report GPI-glycan structures of human PrPC isolated from human brain and from brains of a knock-in mouse model in which the mouse prion protein (Prnp) gene was replaced with the human PRNP gene. Liquid chromatography-electrospray ionization MS (LC-ESI-MS) analysis of human PrPC from both biological sources indicated that Gly-229 is the ω site in PrPC to which GPI is attached. Gly-229 in human PrPC does not correspond to Ser-231, the previously reported ω site of Syrian hamster PrPC We found that approximately 41% and 28% of GPI anchors in human PrPCs from human and mouse knock-in brains, respectively, have N-acetylneuraminic acid in the side-chain. Using a sialic acid linkage-specific alkylamidation (SALSA) method to discriminate α2,3-linkage from α2,6-linkage, we found that N-acetylneuraminic acid in PrPC's GPI side-chain is linked to galactose through an α2,3-linkage. In summary, we report the GPI-glycan structure of human PrPC, including the ω-site amino acid for GPI attachment and the sialic acid linkage type. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male KO mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a seven-amino-acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly.