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Relational memory, or the ability to form contextual associations among items encountered closely in time, is impaired in schizophrenia. The ability to bind items into a relational memory is dependent on the hippocampus, a region that is abnormal in schizophrenia. However, the hippocampus is also involved in exploratory behavior, leaving open the question whether relational memory deficits in schizophrenia are due to failure of relational binding or diminished visual exploration of individual items during encoding. We studied visual exploration patterns during the encoding of face-scene pairs in 66 healthy control subjects and 69 early psychosis patients, to test the hypothesis that differences in visual exploration during the encoding phase can explain task accuracy differences between the two groups. Psychosis patients had lower explicit test accuracy and were less likely to transition from mouth to eyes during encoding. The visual exploration pattern differences between groups did not mediate the relationship between group and explicit test accuracy. We conclude that early psychosis patients have an abnormal pattern of binding items together during encoding that warrants further research.
Copyright © 2020 Elsevier B.V. All rights reserved.
Long-lived proteins (LLPs) are present in numerous tissues within the human body. With age, they deteriorate, often leading to the formation of irreversible modifications such as peptide bond cleavage and covalent cross-linking. Currently understanding of the mechanism of formation of these cross-links is limited. As part of an ongoing study, proteomics was used to characterise sites of novel covalent cross-linking in the human lens. In this process, Lys residues were found cross-linked to C-terminal aspartates that had been present in the original protein as Asn residues. Cross-links were identified in major lens proteins such as αA-crystallin, αB-crystallin and aquaporin 0. Quantification of the level of an AQP0/AQP0 cross-linked peptide showed increased cross-linking with age and in cataract lenses. Using model peptides, a mechanism of cross-link formation was elucidated that involves spontaneous peptide bond cleavage on the C-terminal side of Asn residues resulting in the formation of a C-terminal succinimide. This succinimide does not form cross-links, but can hydrolyse to a mixture of C-terminal Asn and C-terminal Asp amide peptides. The C-terminal Asp amide is unstable at neutral pH and decomposes to a succinic anhydride. If the side chain of Lys attacks the anhydride, a covalent cross-link will be formed. This multi-step mechanism represents a link between two spontaneous events: peptide bond cleavage at Asn and covalent cross-linking. Since Asn deamidation and cleavage are abundant age-related modifications in LLPs, this finding suggests that such susceptible Asn residues should also be considered as potential sites for spontaneous covalent cross-linking.
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
BACKGROUND - Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis.
METHODS - We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory.
RESULTS - Healthy control subjects rapidly (within 250-500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group.
CONCLUSIONS - This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.
Copyright © 2019 Elsevier B.V. All rights reserved.
With age, long-lived proteins in the human body deteriorate, which can have consequences both for aging and disease. The aging process is often associated with the formation of covalently crosslinked proteins. Currently our knowledge of the mechanism of formation of these crosslinks is limited. In this study, proteomics was used to characterize sites of covalent protein-protein crosslinking and identify a novel mechanism of protein-protein crosslinking in the adult human lens. In this mechanism, Lys residues are crosslinked to C-terminal Asp residues that are formed by non-enzymatic protein truncation. Ten different crosslinks were identified in major lens proteins such as αA-crystallin, αB-crystallin and AQP0. Crosslinking in AQP0 increased significantly with age and also increased significantly in cataract lenses compared with normal lenses. Using model peptides, a mechanism of formation of the Lys-Asp crosslink was elucidated. The mechanism involves spontaneous peptide cleavage on the C-terminal side of Asp residues which can take place in the pH range 5-7.4. Cleavage appears to involve attack by the side chain carboxyl group on the adjacent peptide bond, resulting in the formation of a C-terminal Asp anhydride. This anhydride intermediate can then either react with water to form Asp, or with a nucleophile, such as a free amine group to form a crosslink. If an ε-amino group of Lys or an N-terminal amine group attacks the anhydride, a covalent protein-protein crosslink will be formed. This bi-phasic mechanism represents the first report to link two spontaneous events: protein cleavage and crosslinking that are characteristic of long-lived proteins.
Copyright © 2019 Elsevier B.V. All rights reserved.
Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen presenting cells including dendritic cells (DCs) play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG-adduct formation in myeloid antigen presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high salt diets. In humans and mice, high salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a sub-pressor dose of angiotensin II. Mice fed a high salt diet exhibited increased intestinal inflammation including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG-protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high salt-fed mice to germ-free mice predisposed them to increased intestinal inflammation and hypertension. These findings provide novel insight into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.
Although the use of model systems for studying the mechanism of mutations that have a large effect is common, we highlight here the ways that zebrafish-model-system studies of a gene, GRIK5, that contributes to the polygenic liability to develop eye diseases have helped to illuminate a mechanism that implicates vascular biology in eye disease. A gene-expression prediction derived from a reference transcriptome panel applied to BioVU, a large electronic health record (EHR)-linked biobank at Vanderbilt University Medical Center, implicated reduced GRIK5 expression in diverse eye diseases. We tested the function of GRIK5 by depletion of its ortholog in zebrafish, and we observed reduced blood vessel numbers and integrity in the eye and increased vascular permeability. Analyses of EHRs in >2.6 million Vanderbilt subjects revealed significant comorbidity of eye and vascular diseases (relative risks 2-15); this comorbidity was confirmed in 150 million individuals from a large insurance claims dataset. Subsequent studies in >60,000 genotyped BioVU participants confirmed the association of reduced genetically predicted expression of GRIK5 with comorbid vascular and eye diseases. Our studies pioneer an approach that allows a rapid iteration of the discovery of gene-phenotype relationships to the primary genetic mechanism contributing to the pathophysiology of human disease. Our findings also add dimension to the understanding of the biology driven by glutamate receptors such as GRIK5 (also referred to as GLUK5 in protein form) and to mechanisms contributing to human eye diseases.
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Arrestins play a key role in homologous desensitization of G protein-coupled receptors (GPCRs) and regulate several other vital signaling pathways in cells. Considering the critical roles of these proteins in cellular signaling, surprisingly few disease-causing mutations in human arrestins were described. Most of these are loss-of-function mutations of visual arrestin-1 that cause excessive rhodopsin signaling and hence night blindness. Only one dominant arrestin-1 mutation was discovered so far. It reduces the thermal stability of the protein, which likely results in photoreceptor death via unfolded protein response. In case of the two nonvisual arrestins, only polymorphisms were described, some of which appear to be associated with neurological disorders and altered response to certain treatments. Structure-function studies revealed several ways of enhancing arrestins' ability to quench GPCR signaling. These enhanced arrestins have potential as tools for gene therapy of disorders associated with excessive signaling of mutant GPCRs.
© 2019 Elsevier Inc. All rights reserved.
Purpose - The purpose of this study was to characterize the palmitoyl-proteome in lens fiber cells. S-palmitoylation is the most common form of protein S-acylation and the reversible nature of this modification functions as a molecular switch to regulate many biological processes. This modification could play important roles in regulating protein functions and protein-protein interactions in the lens.
Methods - The palmitoyl-proteome of bovine lens fiber cells was investigated by combining acyl-biotin exchange (ABE) chemistry and mass-spectrometry analysis. Due to the possibility of false-positive results from ABE experiment, a method was also developed for direct detection of palmitoylated peptides by mass spectrometry for validating palmitoylation of lens proteins MP20 and AQP5. Palmitoylation levels on AQP5 in different regions of the lens were quantified after iodoacetamide (IAA)-palmitate exchange.
Results - The ABE experiment identified 174 potential palmitoylated proteins. These proteins include 39 well-characterized palmitoylated proteins, 92 previously reported palmitoylated proteins in other tissues, and 43 newly identified potential palmitoylated proteins including two important transmembrane proteins in the lens, AQP5 and MP20. Further analysis by direct detection of palmitoylated peptides confirmed palmitoylation of AQP5 on C6 and palmitoylation of MP20 on C159. Palmitoylation of AQP5 was found to only occur in a narrow region of the inner lens cortex and does not occur in the lens epithelium, in the lens outer cortex, or in the lens nucleus.
Conclusions - AQP5 and MP20 are among 174 palmitoylated proteins found in bovine lens fiber cells. This modification to AQP5 and MP20 may play a role in their translocation from the cytoplasm to cell membranes during fiber cell differentiation.
Frontal eye field (FEF) in macaque monkeys contributes to visual attention, visual-motor transformations and production of eye movements. Traditionally, neurons in FEF have been classified by the magnitude of increased discharge rates following visual stimulus presentation, during a waiting period, and associated with eye movement production. However, considerable heterogeneity remains within the traditional visual, visuomovement, and movement categories. Cluster analysis is a data-driven method of identifying self-segregating groups within a dataset. Because many cluster analysis techniques exist and outcomes vary with analysis assumptions, consensus clustering aggregates over multiple analyses, identifying robust groups. To describe more comprehensively the neuronal composition of FEF, we applied a consensus clustering technique for unsupervised categorization of patterns of spike rate modulation measured during a memory-guided saccade task. We report 10 functional categories, expanding on the traditional 3 categories. Categories were distinguished by latency, magnitude, and sign of visual response; the presence of sustained activity; and the dynamics, magnitude and sign of saccade-related modulation. Consensus clustering can include other metrics and can be applied to datasets from other brain regions to provide better information guiding microcircuit models of cortical function.
BACKGROUND/AIMS - Enucleation for retinoblastoma is performed less often in the past decade due to increasingly widespread alternative therapies, but enucleation remains an important option. There is a paucity of reports on the current incidence of metastases and metastatic deaths in unilateral retinoblastoma from US centres.
METHODS - Retrospective chart review at five tertiary retinoblastoma centres in the USA for unilateral retinoblastoma patients treated with primary enucleation, 2007-2017, with 1 year of follow-up or treatment failure.
RESULTS - Among 228 patients (228 eyes), there were nine metastases (3.9%) and four deaths (1.7%). The Kaplan-Meier estimate at 5 years for metastasis-free survival was 96% (95% CI, 94% to 99 %), and for overall survival was 98% (95% CI 96% to 100%). All metastases were evident within 12 months. Histopathology revealed higher risk pathology (postlaminar optic nerve and/or massive choroidal invasion) in 62 of 228 eyes (27%). Of these higher risk eyes, 39 received adjuvant chemotherapy. There were four subsequent metastases in this higher risk pathology with adjuvant chemotherapy group, with three deaths. Of the nine overall with metastases, seven (78%) showed higher risk pathology. All metastatic patients were classified as Reese-Ellsworth V and International Classification of Retinoblastoma Groups D or E. Initial metastases presented as orbital invasion in seven of nine cases.
CONCLUSIONS - Primary enucleation for unilateral retinoblastoma results in a low rate of metastatic death, but is still associated with a 3.9% chance of metastases within a year of enucleation. Most but not all patients who developed metastases had higher risk histopathological findings.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.