Multiple Immunostainings with Different Epitope Retrievals-The FOLGAS Protocol.
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ABSTRACT:
SUBMITTER: von Schoenfeld A
PROVIDER: S-EPMC8745613 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVES:Aging can reduce the specificity with which memory episodes are represented as distributed patterns of brain activity. It remains unclear, however, whether repeated encoding and retrieval of stimuli modulate this decline. Memory repetition is thought to promote semanticization, a transformative process during which episodic memory becomes gradually decontextualized and abstracted. Because semantic memory is considered more resilient to aging than context-rich episodic memory, we hypothesized that repeated retrieval would affect cortical reinstatement differently in young versus older adults. METHODS:We reanalyzed data from young and older adults undergoing functional magnetic resonance imaging while repeatedly viewing and recalling short videos. We derived trial-unique multivariate measures of similarity between video-specific brain activity patterns elicited at perception and at recall, which we compared between age groups at each repetition. RESULTS:With repetition, memory representation became gradually more distinct from perception in young adults, as reinstatement specificity converged downward toward levels observed in the older group. In older adults, alternative representations that were item-specific but orthogonal to patterns elicited at perception became more salient with repetition. DISCUSSION:Repetition transformed dominant patterns of memory representation away and orthogonally from perception in young and older adults, respectively. Although distinct, both changes are consistent with repetition-induced semanticization.
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Project description:The retrieval of fear memories induces two opposing processes, reconsolidation, and extinction. The memory reconsolidation is an active process that involves gene expression and updates an existing memory. It is hypothesized that blockade of reconsolidation by manipulating the neurobiological factors, which are mechanistically involved in the process, could weaken or disrupt the original fear memory. The N-methyl-D-aspartate (NMDA) receptor and hippocampal neurogenesis play crucial roles in hippocampus-dependent memory processes, including reconsolidation. Using contextual fear conditioning paradigm with multiple retrievals, we attempted to weaken the original contextual fear memory by repeatedly disrupting retrieval-induced reconsolidation via downregulation of NMDA receptor signaling and inhibition of neurogenesis. In the first experiment, prior to fear conditioning, NMDA receptor signaling was downregulated by the genetic reduction of its co-agonist, D-serine, and the neurogenesis was dampened by focal X-ray irradiation on the hippocampus. We found that simultaneous D-serine reduction and neurogenesis dampening resulted in a progressive decrease in freezing following each retrieval, leading to an attenuation of remote contextual fear memory on day 28. In the second experiment using the same behavioral protocols, after conditioning, pharmacological approaches were conducted to simultaneously block D-serine signaling and neurogenesis, resulting in a similar suppressive effect on the remote fear memory. The present findings provide insights for understanding the role of D-serine-mediated NMDA receptor signaling and neurogenesis in memory retrieval and the maintenance of remote fear memory, and improving the efficacy of exposure-based therapy for the treatment of post-traumatic stress disorder (PTSD).
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Project description:SMARTseq2 scRNAseq analysis was performed on Tet+ induced with 3 different epitope specificities (BDC2.5mi/IAg7, FLA2(462-472)/IAb and FLA2(501-515)/IAb) to study transcriptional homogeneity and clonality to different pMHCII-NPs and in different genetic backgrounds (NOD, B6)
2023-03-27 | GSE173601 | GEO
Project description:Monoclonal antibodies have become an important class of therapeutics in the last 30 years. Because the mechanism of action of therapeutic antibodies is intimately linked to their binding epitopes, identification of the epitope of an antibody to the antigen plays a central role during antibody drug development. The gold standard of epitope mapping, X-ray crystallography, requires a high degree of proficiency with no guarantee of success. Here, we evaluated six widely used alternative methods for epitope identification (peptide array, alanine scan, domain exchange, hydrogen-deuterium exchange, chemical cross-linking, and hydroxyl radical footprinting) in five antibody-antigen combinations (pembrolizumab+PD1, nivolumab+PD1, ipilimumab+CTLA4, tremelimumab+CTLA4, and MK-5890+CD27). The advantages and disadvantages of each technique are demonstrated by our data and practical advice on when and how to apply specific epitope mapping techniques during the drug development process is provided. Our results suggest chemical cross-linking most accurately identifies the epitope as defined by crystallography.
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Project description:SO2 column densities from Ozone Monitoring Instrument provide important information on emission trends and missing sources, but there are discrepancies between different retrieval products. We employ three Ozone Monitoring Instrument SO2 retrieval products (National Aeronautics and Space Administration (NASA) standard (SP), NASA prototype, and BIRA) to study the magnitude and trend of SO2 emissions. SO2 column densities from these retrievals are most consistent when viewing angles and solar zenith angles are small, suggesting more robust emission estimates in summer and at low latitudes. We then apply a hybrid 4D-Var/mass balance emission inversion to derive monthly SO2 emissions from the NASA SP and BIRA products. Compared to HTAPv2 emissions in 2010, both posterior emission estimates are lower in United States, India, and Southeast China, but show different changes of emissions in North China Plain. The discrepancies between monthly NASA and BIRA posterior emissions in 2010 are less than or equal to 17% in China and 34% in India. SO2 emissions increase from 2005 to 2016 by 35% (NASA)-48% (BIRA) in India, but decrease in China by 23% (NASA)-33% (BIRA) since 2008. Compared to in situ measurements, the posterior GEOS-Chem surface SO2 concentrations have reduced NMB in China, the United States, and India but not in South Korea in 2010. BIRA posteriors have better consistency with the annual growth rate of surface SO2 measurement in China and spatial variability of SO2 concentration in China, South Korea, and India, whereas NASA SP posteriors have better seasonality. These evaluations demonstrate the capability to recover SO2 emissions using Ozone Monitoring Instrument observations.
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Project description:ObjectivesFor most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Pediatric-onset MS provides an opportunity to study early disease processes.MethodsUsing antigen microarrays, including CNS-related proteins, lipids, and other autoantigens, we studied early immunologic events involved in clinical onset of pediatric MS. Serum samples were collected at the time of incident acquired CNS demyelinating syndromes (ADS) in children who, in subsequent prospective follow-up, were ascertained to have either pediatric MS (ADS-MS) or a monophasic illness (ADS-mono). Samples were obtained both at the time of ADS presentation and 3 months into follow-up. We used an initial training set of samples to implicate antibody signatures associated with each group, and then a test set. An additional set of follow-up samples (stability set) was used as a form of internal validation.ResultsChildren with ADS-MS tended to have distinguishable serum antibody patterns both at the time of ADS presentation and 3 months into follow-up. At the time of ADS, serum samples from patients with ADS-MS or ADS-mono reacted against similar numbers of CNS antigens, although CNS antigens implicated in adult MS were more often targeted in children with ADS-MS. The follow-up ADS-MS samples reacted against a broader panel of CNS antigens, while corresponding ADS-mono samples exhibited a contraction of the initial antibody response.ConclusionsOur findings in this prospective cohort of pediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions.
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