Biology subjects

Turner, L.

Publications and source records attributed to Turner, L..

25 records · Page 2Linked to original sources

bioRxiv2022

Reciprocal inflammatory signaling in an ex-vivo explant model for neurofibromatosis type 1-related cutaneous neurofibromas

Cutaneous neurofibromas (CNF) are benign tumors that occur in the dermis of individuals with neurofibromatosis type 1 (NF), an inherited tumor predisposition syndrome. CNFs cause disfigurement, pain, burning, and itching, resulting in reduced quality of life in NF patients. However, due to their benign nature there are few in vitro or in vivo models of CNFs, which has limited the research of CNF biology and drug discovery efforts. To address this, we developed a patient derived explant (PDE) ex vivo culture model of CNF tumors and normal skin from NF patients. CNF PDEs remain viable in culture for over 9 days and recapitulate the cellular composition and molecular signaling of CNFs. We identified reciprocal inflammatory signaling in CNF PDEs, in which tumors rely on either prostaglandin or leukotriene mediated signaling pathways. Ex vivo glucocorticoid treatment reduced expression of pro-inflammatory genes, confirming CNF PDEs are a useful model for mechanistic studies and preclinical drug testing.

cell biology↗

bioRxiv2021

Spatial and temporal autocorrelation weave human brain networks

High-throughput experimental methods in neuroscience have led to an explosion of techniques for measuring complex interactions and multi-dimensional patterns. However, whether sophisticated measures of emergent phenomena can be traced back to simpler low-dimensional statistics is largely unknown. To explore this question, we examine resting state fMRI (rs-fMRI) data using complex topology measures from network neuroscience. We show that spatial and temporal autocorrelation are reliable statistics which explain numerous measures of network topology. Surrogate timeseries with subject-matched spatial and temporal autocorrelation capture nearly all reliable individual and regional variation in these topology measures. Network topology changes during aging are driven by spatial autocorrelation, and multiple serotonergic drugs causally induce the same topographic change in temporal autocorrelation. This reductionistic interpretation of widely-used complexity measures may help link them to neurobiology.

neuroscience↗

bioRxiv2020

Common virulence gene expression in naive and severe malaria cases

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naive (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDR1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naive immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.

molecular biology↗

bioRxiv2020

Longitudinal analysis of naturally acquired antibodies to PfEMP1 CIDR domain variants and their association with malaria protection

Malaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum infected erythrocytes to the microvasculature mediated via specific interactions between PfEMP1 variant domains to host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria. We evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission. Using longitudinal data, we found that IgG to the pathogenic domain variants CIDR1.7 and CIDR1.8 were acquired the earliest. Furthermore, IgG to CIDR{gamma}3 was associated with reduced prospective risk of febrile malaria and recurrent malaria episodes. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant-specific antibodies.

immunology↗

bioRxiv2019

Structure-guided design of a synthetic mimic of an EPCR-binding PfEMP1 protein

Structure-guided vaccine design provides a route to elicit a focused immune response against the most functionally important regions of a pathogen surface. This can be achieved by identifying epitopes for neutralizing antibodies through structural methods and recapitulating these epitopes by grafting their core structural features onto smaller scaffolds. In this study, we have conducted a modified version of this protocol. We focused on the PfEMP1 protein family found on the surfaces of erythrocytes infected with Plasmodium falciparum. A subset of PfEMP1 proteins bind to endothelial protein C receptor (EPCR), and their expression correlates with development of the symptoms of severe malaria. Structural studies revealed the PfEMP1 to present a helix-kinked-helix motif which forms the core of the EPCR binding site. Using Rosetta-based design we successfully grafted this motif onto a three-helical bundle scaffold. We show that this synthetic binder interacts with EPCR with nanomolar affinity and adopts the expected structure. We also assessed its ability to bind to antibodies found in immunized animals and in humans from malaria endemic regions. Finally, we tested its capacity to effectively elicit antibodies that prevent EPCR binding and analysed the degree of cross-reactivity of these antibodies across a diverse repertoire of EPCR-binding PfEMP1. This provides a case study of immunogen design, assessing the effect of designing a focused immunogen that contains the core features of a ligand binding site, rather than those of a neutralizing antibody epitope.

microbiology↗

bioRxiv2019

Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression

Depression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. We used multi-parametric flow cytometry to investigate 14 subsets of peripheral blood cells in 206 cases of major depressive disorder (MDD) and 77 age- and sex-matched controls. There were significant case-control differences, by univariate and multivariate analysis: cases showed increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis demonstrated significant association between the severity of depressive symptoms and increased myeloid and CD4+ cell counts. MDD cases could be partitioned into two groups by forced binary clustering of cell counts: the inflamed depression group (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased C-reactive protein (CRP) and interleukin 6 (IL-6), and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven clustering identified four subgroups of MDD cases: two of these subgroups (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed from each other in the relative weighting of myeloid and lymphoid cell counts. Case-control and within-group results were robust to statistical control for the potentially confounding effects of age, sex, BMI, recent infection status, and tobacco use. Peripheral blood immunophenotyping can be used to identify a candidate cellular biomarker of inflamed depression, and to further decompose that binary partition, suggesting that there is more than one mechanistic pathway underlying inflamed depression.\n\nOne Sentence SummaryTwo subgroups of depressed cases (about two-thirds of all 206 cases) were identified by peripheral blood biomarker evidence of distinctive cellular immunophenotypes, biased towards the myeloid or lymphoid lineages in different subgroups, but consistently associated with increased blood concentrations of inflammatory proteins and greater severity of depressive symptoms.

immunology↗

bioRxiv2018

Derivation of a simple postoperative delirium incidence and severity prediction model

BackgroundDelirium is an important postoperative complication, yet a simple and effective delirium prediction model remains elusive. We hypothesized that the combination of the National Surgical Quality Improvement Program (NSQIP) risk calculator for serious complications (NSQIP-SC) or risk of death (NSQIP-D), and cognitive tests of executive function (Trail Making Test A and B [TMTA, TMTB]), could provide a parsimonious model to predict postoperative delirium incidence or severity.\n\nMethodsData were collected from 100 adults ([≥]65yo) undergoing major non-cardiac surgery. In addition to NSQIP-SC, NSQIP-D, TMTA and TMTB, we collected participant age, sex, ASA score, tobacco use, type of surgery, depression, Framingham risk score, and preoperative blood pressure. Delirium was diagnosed with the Confusion Assessment Method (CAM), and the Delirium Rating Scale-R-98 (DRS) was used to assess symptom severity. LASSO and Best Subsets logistic and linear regression were employed in line with TRIPOD guidelines.\n\nResultsThree participants were excluded due to intraoperative deaths (2) and alcohol withdrawal (1). Ninety-seven participants with a mean age of 71.68{+/-}4.55, 55% male (31/97 CAM+, 32%) and a mean Peak DRS of 21.5{+/-}6.40 were analyzed. Of the variables included, only NSQIP-SC and TMTB were identified to be predictors of postoperative delirium incidence (p<0.001, AUROC 0.81, 95% CI: 0.72, 0.90) and severity (p<0.001, Adj. R2: 0.30).\n\nConclusionsIn this cohort, preoperative NSQIP-SC and TMTB were identified as predictors of postoperative delirium incidence and severity. Future studies should verify whether this two-factor model could be used for accurate delirium prediction.

clinical trials↗