Biology subjects

Jones, D. G.

Publications and source records attributed to Jones, D. G..

7 recordsLinked to original sources

bioRxiv2026

B7-H3-targeted natural killer cells effectively kill atypical teratoid / rhabdoid tumors and extend survival in orthotopic xenografts

BackgroundAtypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants, and patients suffer from low survival rates and treatment-related morbidities. These tumors frequently overexpress the pan-cancer antigen B7-H3 (CD276), which can be targeted with immunotherapy. We hypothesized that adding a B7-H3-targeting cytotoxic chimeric antigen receptor (CAR) to NK cells can enhance killing against AT/RTs. MethodsWe designed a library of variable affinity B7-H3-targeted CARs, which were transduced into primary healthy donor-derived NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines and further engineered luciferase and nuclear GFP-expressing AT/RT (CHLA-04, CHLA-06, BT12, BT37) as well as a CHLA-06-derived B7-H3 knockout. We tested CAR-NK cell functionality using in vitro co-culture cytotoxicity assays. We delivered anti-B7-H3 CAR-NK cells intratumorally or intracerebroventricularly (ICV) to AT/RT orthotopic xenografts and monitored for tumor growth and animal survival. ResultsB7-H3-targeted CAR-NK cells demonstrated target-specific cytotoxicity when compared to unmodified NK cells. Knockout of B7-H3 in target cells abolished the increased CAR-mediated target killing. When delivered intratumorally to CHLA-06 orthotopic xenograft-bearing mice, anti-B7-H3 CAR-NK cells eliminated tumor cells and prolonged survival. When CAR-NK cells were delivered ICV against a CNS disseminated tumor model of BT12, treated mice had significantly improved survival. ConclusionsAnti-B7-H3 CAR-NK cells effectively kill AT/RTs in multiple pre-clinical in vitro and in vivo models in an antigen-specific manner. Evidence of efficacy in translationally relevant models provides support for using B7-H3-targeting CAR-NK cells in high-risk AT/RT patients.

cancer biology↗

bioRxiv2022

Host-enemy interactions provide limited biotic resistance for a range-expanding species via reduced apparent competition

As species ranges shift in response to anthropogenic change, they lose coevolved or coadapted interactions and gain novel ones in recipient communities. Range-expanding species may lose or experience weak antagonistic interactions with competitors and enemies, and traits of interacting species will determine the strength of interactions. We leveraged a poleward range expansion of an oak gall wasp that co-occurs on its host plant with other gall wasp species and interacts with shared natural enemies (largely parasitoid wasps). We created quantitative host-parasitoid interaction networks by sampling galls on 400 trees. We compared network structure and function and traits of hosts and parasitoids in the native and expanded range. Interaction networks were less diverse in the expanded range, with low complementarity of parasitoid assemblages among hosts. While whole networks were more generalized in the expanded range, interactions with the range-expanding species were more specialized. This was not due to a loss of specialist enemies but weak apparent competition by shared generalist enemies. Phenological divergence of enemy assemblages attacking the novel and co-occurring hosts was greater in the expanded range that may contribute to weak apparent competition. Given the rate and extent of anthropogenic-driven range expansions, it is pressing to uncover how complex biotic interactions are reassembled.

ecology↗

bioRxiv2022

Latitudinal gradient in species diversity provides high niche opportunities for a range-expanding phytophagous insect

O_LIWhen species undergo poleward range expansions in response to anthropogenic change, they likely encounter less diverse communities in new locations. If low diversity communities provide weak biotic interactions, such as reduced competition for resources or predation, range-expanding species may experience high niche opportunities. C_LIO_LIHere, we uncover if oak gall wasp communities experience a latitudinal diversity gradient (LDG) and weaker interactions at the poles that might create high niche opportunities for a range-expanding community member. C_LIO_LIWe performed systematic surveys of oak gall wasps on a dominant oak, Quercus garryana, throughout most of its range, from northern California to Vancouver Island, British Columbia. On 540 trees at 18 sites, we identified 23 species in three guilds (leaf detachable, leaf integral, and stem galls). We performed regressions between oak gall wasp diversity, latitude, and other abiotic and habitat factors to reveal if cynipid communities follow an LDG. To uncover patterns in local interactions, we performed partial correlations on oak gall wasps co-occurring on trees within regions. Finally, we performed regressions between abundances of co-occurring gall wasps on trees to reveal potential interactions. C_LIO_LIQ. garryana-gall wasp communities followed an LDG, with lower diversity at higher latitudes, particularly with a loss of detachable leaf gall species. Detachable leaf gall wasps, including the range-expanding species, co-occurred most on trees and had weak interactions in the northern region. Abundances of the range-expander and detachable and integral leaf galls co-occurring on trees were negatively related, suggesting antagonistic interactions. Overall, we found that LDGs create communities with weaker antagonistic interactions at the poles that might facilitate ecological release in a range-expanding community member. C_LIO_LIHere, we uncover how regional and local scale patterns and processes create high niche opportunities for a range-expanding community member. This research provides insight into how biogeographical patterns in communities and species interactions influence the outcome of range expansions. Given the ubiquity of LDGs, these outcomes might be expected in other phytophagous insect communities. C_LI

ecology↗

bioRxiv2020

Constructing plasticity phenotypes to classify experience-dependent development of the visual cortex

Many neural mechanisms regulate experience-dependent plasticity in the visual cortex (V1) and new techniques for quantifying large numbers of proteins or genes are transforming how plasticity is studied into the era of big data. With those large data sets comes the challenge of extracting biologically meaningful results about visual plasticity from data-driven analytical methods designed for high-dimensional data. In other areas of neuroscience, high-information content methodologies are revealing more subtle aspects of neural development and individual variations that give rise to a richer picture of brain disorders. We have developed an approach for studying V1 plasticity that takes advantage of the known functions of many synaptic proteins for regulating visual plasticity and using that to rebrand the results of high-dimensional analyses into a plasticity phenotype. Here we provide a primer for analyzing experience-dependent plasticity in V1 using example R code to identify high-dimensional changes in a group of proteins. We describe using PCA to classify high-dimensional plasticity features and use them to construct a plasticity phenotype. In the examples, we show how the plasticity phenotype can be visualized and used to identify neurobiological features in V1 that change during development or after different visual rearing conditions. We include an R package "v1hdexplorer" that aggregates the various coding packages and custom visualization scripts written in R Studio.

neuroscience↗

bioRxiv2019

Recovery of glutamatergic and GABAergic protein expression in visual cortex after monocular deprivation

A collection of glutamatergic and GABAergic proteins participate in regulating experience-dependent plasticity in the visual cortex (V1). Many studies have characterized changes to those proteins caused by monocular deprivation (MD) during the critical period (CP), but less is known about changes that occur when MD stops. We measured the effects of 3 types of visual experience after MD (n=24, 10 male and 14 female); reverse occlusion (RO), binocular deprivation (BD), or binocular vision, on the expression of synaptic proteins in V1 including glutamatergic and GABAergic receptor subunits. Synapsin expression was increased by RO but not affected by the other treatments. BD shifted the balance between glutamatergic and GABAergic receptor subunits to favor GABAA1. In contrast, BV shifted expression to favor the glutamatergic mechanisms by increasing NMDAR and decreasing GABAA1 subunits. None of the conditions returned normal expression levels to all of the proteins, but BV was the closest.

neuroscience↗

bioRxiv2019

A primer on high-dimensional data analysis workflows for studying visual cortex development and plasticity

New techniques for quantifying large numbers of proteins or genes are transforming the study of plasticity mechanisms in visual cortex (V1) into the era of big data. With those changes comes the challenge of applying new analytical methods designed for high-dimensional data. Studies of V1, however, can take advantage of the known functions that many proteins have in regulating experience-dependent plasticity to facilitate linking big data analyses with neurobiological functions. Here we discuss two workflows and provide example R code for analyzing high-dimensional changes in a group of proteins (or genes) using two data sets. The first data set includes 7 neural proteins, 9 visual conditions, and 3 regions in V1 from an animal model for amblyopia. The second data set includes 23 neural proteins and 31 ages (20d-80yrs) from human post-mortem samples of V1. Each data set presents different challenges and we describe using PCA, tSNE, and various clustering algorithms including sparse high-dimensional clustering. Also, we describe a new approach for identifying high-dimensional features and using them to construct a plasticity phenotype that identifies neurobiological differences among clusters. We include an R package "v1hdexplorer" that aggregates the various coding packages and custom visualization scripts written in R Studio.

neuroscience↗

bioRxiv2019

Classification of visual cortex plasticity phenotypes following treatment for amblyopia

Monocular deprivation (MD) during the critical period (CP) has enduring effects on visual acuity and the functioning of the visual cortex (V1). This experience-dependent plasticity has become a model for studying the mechanisms, especially glutamatergic and GABAergic receptors, that regulate amblyopia. Less is known, however, about treatment-induced changes to those receptors and if those changes differentiate treatments that support the recovery of acuity versus persistent acuity deficits. Here we use an animal model to explore the effects of 3 visual treatments started during the CP (n=24, 10 male and 14 female); binocular vision (BV) that promotes good acuity versus reverse occlusion (RO) and binocular deprivation (BD) that causes persistent acuity deficits. We measured recovery of a collection of glutamatergic and GABAergic receptor subunits in V1 and modeled recovery of kinetics for NMDAR and GABAAR. There was a complex pattern of protein changes that prompted us to develop an unbiased data-driven approach for these high-dimensional data analyses to identify plasticity features and construct plasticity phenotypes. Cluster analysis of the plasticity phenotypes suggests that BV supports adaptive plasticity while RO and BD promote a maladaptive pattern. The RO plasticity phenotype appeared more similar to adults with high expression of GluA2 and the BD phenotypes were dominated by GABAA1, highlighting that multiple plasticity phenotypes can underlie persistent poor acuity. After 2-4 days of BV the plasticity phenotypes resembled normals, but only one feature, the GluN2A:GluA2 balance, returned to normal levels. Perhaps, balancing Hebbian (GluN2A) and homeostatic (GluA2) mechanisms is necessary for the recovery of vision.

neuroscience↗