Biology subjects

Vance, S.

Publications and source records attributed to Vance, S..

4 recordsLinked to original sources

bioRxiv2025

Heterosynaptic interactions between dorsal and ventral hippocampus in individual medium spiny neurons of the nucleus accumbens ventromedial shell

Establishing learned associations between rewarding stimuli and the context under which those rewards are encountered is critical for survival. Hippocampal input to the nucleus accumbens (NAc) provides important environmental context to reward processing to support goal-directed behaviors. This connection consists of two independent pathways originating from the dorsal (dHipp) or ventral (vHipp) hippocampus, which have previously been considered functionally and anatomically distinct. Here, we show overlap in dHipp and vHipp terminal fields in the NAc, leading us to reconsider this view and raise new questions regarding the potential interactions between dHipp and vHipp pathways in the NAc. Using optogenetics, electrophysiology, and transsynaptic labeling in mice, we investigated anatomical and functional convergence of dHipp and vHipp inputs in the NAc. Transsynaptic labeling revealed a subpopulation of dually innervated cells in the NAc medial shell, confirmed by independent optogenetic manipulation of dHipp and vHipp inputs during whole-cell electrophysiological recordings. Further analysis revealed closely apposed dHipp and vHipp inputs along dendritic branches, and simultaneous stimulation of both inputs elicited heterosynaptic potentiation. Comparison of observed and theoretical success rates suggests interactions between dHipp-NAc and vHipp-NAc synapses may occur presynaptically. Altogether, these results demonstrate that inputs originating from dHipp and vHipp converge onto a subset of NAc neurons with synapses positioned to enable rapid heterosynaptic interactions, indicating integration of these inputs at the single-neuron level. Exploring the physiological and behavioral implications of this convergence will offer new insights into how individual neurons incorporate information from distinct inputs and how this integration may shape learning. SIGNIFICANCE STATEMENTForming associations between rewards and the circumstances under which they are experienced is vital for survival. Hipp input to the NAc is essential for associating rewards with their environmental context to effectively guide motivated behaviors. This connection consists of two separate pathways originating from dHipp and vHipp that have long been considered distinct. Here, we reveal a subpopulation of neurons in the NAc shell innervated by both Hipp subregions as well as heterosynaptic interactions that occur between dHipp and vHipp synapses. These findings suggest that integration of distinct hippocampal information occurs at the single-neuron level, providing a critical mechanism underlying learning and motivated behavior while also opening new avenues for understanding how diverse contextual and reward signals shape decision-making.

neuroscience↗

bioRxiv2024

Sequence-defined oligophosphoesters for selective inhibition of the KRAS G12D/RAF1 interaction

Rat Sarcoma (RAS) genes are the most frequently mutated genes in cancer, with KRAS being the most predominant oncogene, yet they have proved extremely difficult to drug because they operate primarily through protein-protein interactions (PPIs) which lack an obvious pocket for small molecules. Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules with the size requirements to address entire protein-protein interaction surfaces. We have adapted the phosphoramidite chemistry of oligonucleotide synthesis to produce a library of nearly one million non-nucleosidic oligophosphoester sequences - phosphoestamers - and used a fluorescent-activated bead sorting (FABS) process to select oligomers that inhibit the interaction between KRASG12D (the most prevalent, and undrugged, mutant) and RAF, a downstream effector of RAS whose activation results in cell proliferation. Hits were identified using tandem mass spectrometry, and validation showed effective inhibition with IC50 values as low as 25 nM, and excellent selectivity for the mutant over the wild type form. These findings could lead to new drugs against cancers driven by mutant RAS, and provided proof-of-principle for the phosphoestamer platform against PPIs in general.

cancer biology↗

bioRxiv2020

DCP, First Generation PET Radiotracer for Diagnosis of Radiation Resistant Head and Neck Cancer

Redox metabolism plays essential functions in the pathology of cancer. As tumor redox profiles uniquely reflect cancer stage and in select cases, therapeutic sensitivity, the capability to image redox molecular features is essential to improve diagnosis, treatment, and overall quality-of-life (QOL) of cancer patients. While a number of radiotracers for imaging redox metabolism have been developed, there are no reports of radiotracers for in vivo imaging of protein oxidation. Here we take the first step towards this goal and describe the synthesis and kinetic properties of a new positron emission tomography (PET) [18F]DCP radiotracer for in vivo imaging of protein sulfenylation. Time course biodistribution and PET/CT studies using xenograft animal models of Head and Neck Squamous Cell Cancer (HNSCC) demonstrate feasibility of diagnosing radiation resistant tumors, which display lower [18F]DCP signal. These findings are consistent with our previous reports of decreased protein sulfenylation in clinical specimens of radiation resistant HNSCC. We anticipate further development and implementation of this concept in clinical practice to improve the diagnosis of patients with radiation resistant tumors and the accuracy of prognosis for patients undergoing radiation treatment. Single Sentence SummaryThe study introduces a new PET radiotracer for profiling tumor protein oxidation as a prognostic indicator of resistance to radiation therapy.

cancer biology↗

bioRxiv2018

Stable Genetic Transformation and Heterologous Expression in the Nitrogen-fixing Plant Endosymbiont Frankia alni ACN14a

Genus Frankia is comprised primarily of nitrogen-fixing actinobacteria that form root nodule symbioses with a group of hosts known as the actinorhizal plants. These plants are evolutionarily closely related to the legumes, which are nodulated by the rhizobia. Both host groups utilize homologs of nodulation genes for root-nodule symbiosis, derived from common plant ancestors. However the corresponding endosymbionts, Frankia and the rhizobia, are distantly related groups of bacteria, leading to questions of their symbiotic mechanisms and evolutionary history. To date, a stable system of genetic transformation has been lacking in Frankia. Here, we report the successful electrotransformation of Frankia alni ACN14a, by means of replicating plasmids expressing chloramphenicol-resistance for selection, and the use of GFP as a marker of gene expression. We have identified type IV methyl-directed restriction systems, highly-expressed in a range of actinobacteria, as a likely barrier to Frankia transformation and circumvented this barrier by using unmethylated plasmids, which allowed the transformation of F. alni as well as the maintenance of the plasmid. During nitrogen limitation, Frankia differentiates into two cell types: the vegetative hyphae and nitrogen-fixing vesicles. When the plasmid transformation system was used with expression of egfp under the control of the nif gene cluster promoter, it was possible to demonstrate by fluorescence imaging the expression of nitrogen fixation in vesicles but not hyphae in nitrogen-limited culture.\n\nImportanceTo date, the study of Frankia-actinorhizal symbioses has been complicated by the lack of genetic tools for manipulation of Frankia, especially stable genetic transformation. The transformation system reported here, particularly coupled with marker genes, can be used to differentiate patterns of gene expression between Frankia hyphae and vesicles in symbiosis or in free-living conditions. This will enable deeper comparisons between Frankia-actinorhizal symbioses and rhizobia-legume symbioses in terms of molecular signaling and metabolic exchange that will broaden understanding of the evolution of these symbioses and potentially make possible their application in agriculture. The development of transformation methods will allow further down-stream applications including gene knock-outs and complementation that will, in turn, open up a much broader range of experiments into Frankia and its symbioses.

microbiology↗