Biology subjects

Pearson, K.

Publications and source records attributed to Pearson, K..

6 recordsLinked to original sources

bioRxiv2026

In Vivo Selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model

Glioblastoma (GBM) is an aggressive, high-grade glioma with a near-universally fatal prognosis. Therapeutic failure is often attributed to the highly selective blood brain barrier (BBB), the diffuse infiltrative nature of the tumor, and the marked intratumoral heterogeneity of GBM. Although antibody drug conjugates ADCs have shown promise for high grade gliomas such as GBM, efficacy is limited by ADC size. Aptamers--short, synthetic, single-stranded DNA or RNA molecules--can be [~]6-fold lower in molecular weight than IgG antibodies and have the potential to cross the intact BBB. Unlike other nucleic acid-based therapies, aptamer function arises from three-dimensional shape rather than genetic coding. Here we aim to replace the targeting component of the ADC paradigm with a DNA aptamer, thus creating an aptamer-drug conjugate (ApDC). We employed in vivo SELEX using an orthotopic patient-derived xenograft (PDX) GBM mouse model and a vast ([~]100 trillion 80-mer sequences) ApDC library. We report the results from this first in vivo ApDC selection of its kind. We characterize target tissue binding ex vivo, cell association, biodistribution, and pharmacokinetics from this selection. This study exemplifies an unbiased approach to a problem that rational design has yet to overcome, offering a new direction for GBM therapeutic development.

cancer biology↗

bioRxiv2024

DNA aptamers that modulate biological activity of model neurons

There is an urgent need for agents that promote health and regeneration of cells and tissues, specifically to treat diseases of the aging nervous system. Age-associated nervous system degeneration and various diseases are driven by many different biochemical stresses, often making it difficult to target any one disease cause. Our laboratory has previously identified DNA aptamers with apparent regenerative properties in murine models of multiple sclerosis by selecting aptamers that bind oligodendrocyte membrane preparations. Here, we screened vast libraries of molecules ([~]1014 unique DNAs) for the ability to bind cultured human SH-SY5Y neuroblastoma cells as model neurons to demonstrate the feasibility of identifying biologically active aptamers by cycles of cell selection. Many of these DNA aptamers bind undifferentiated and differentiated cultured SH-SY5Y cells. Several of these aptamers modulate the biological activity of SH-SY5Y cells upon treatment in culture.

neuroscience↗

bioRxiv2023

Differing effects of alcohol use on epigenetic and brain age in adult children of alcoholic parents

It is known that being the adult child of an alcoholic (ACoA) can confer a wide variety of increased health and psychological risks, including higher rates of anxiety, depression, and posttraumatic stress disorder symptoms. Additionally, ACoAs are at greater risk of developing substance use disorders than individuals from non-alcoholic families. To better understand the psychobiological factors underlying these risks, ACoA individuals with risky hazardous alcohol use (n=14) and those not engaged in hazardous use (n=14) were compared to a group of healthy controls. We examined structural brain differences and applied machine learning algorithms to predict biological brain and DNA methylation ages to investigate differences between these groups. Contrary to our hypothesis, we found that hazardous and non-hazardous ACoA groups had lower predicted brain ages than the healthy control group (n=100), which may result from neuro-developmental differences between ACoA groups and controls. When examining specific brain regions, we observed decreased cortical volume within bilateral pars orbitalis and frontal poles, as well as the left middle temporal gyrus and entorhinal cortex within the hazardous alcohol ACoA group, all areas consistent with previous research examining how alcohol use affects brain structure. When looking at the epigenetic aging data, the hazardous ACoA participants had increased predicted epigenetic age difference scores compared to the control group (n=34) and the non-hazardous ACoA participant groups. In summary, the results demonstrate a decreased brain age in the ACoAs compared to control, concurrent with increased epigenetic age specifically in the hazardous ACoA group, laying the foundation for future research to identify individuals that may have an increased susceptibility to developing hazardous alcohol use. Together, these results provide a better understanding of the associations between epigenetic factors, brain structure, and alcohol use disorders.

neuroscience↗

bioRxiv2022

DNA Modifications Enabling Proximity Biotinylation

Advances in peroxidase- and biotin ligase-mediated signal amplification have enabled high-resolution subcellular mapping of endogenous RNA localization and protein-protein interactions. Application of these technologies has been limited to RNA and proteins because of the reactive groups required for biotinylation in each context. Here we report several novel methods for proximity biotinylation of exogenous oligodeoxyribonucleotides by application of well-established and convenient enzymatic tools. We describe approaches using simple and efficient conjugation chemistries to modify deoxyribonucleotides with "antennae" sensitive to phenoxy radical or biotinoyl-5-adenylate. In addition, we report chemical details of a previously undescribed adduct between tryptophan and a phenoxy radical group. These developments have potential application in the selection of exogenous nucleic acids capable of unaided entry into living cells.

biochemistry↗

bioRxiv2021

A chemical screen for suppressors of dioxygenase inhibition in a yeast model of familial paraganglioma

A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite, and other metabolic derangements. Here we exploit a S. cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically-active compounds we identified meclofenoxate HCL, and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This work raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

biochemistry↗

bioRxiv2017

Marginal Returns And Levels Of Research Grant Support Among Scientists Supported By The National Institutes Of Health

The current era of worsening hypercompetition in biomedical research has drawn attention to the possibility of decreasing marginal returns from research funding. Recent work has described decreasing marginal returns as a function of annual dollars granted to individual scientists. However, different fields of research incur varying cost structures. Therefore, we developed a Grant Support Index (GSI) that focuses on grant activity code, as opposed to field of study or cost. In a cohort of over 71,000 unique scientists funded by NIH between 1996 and 2014 we analyzed the association of grant support (as measured by annual GSI) with 3 bibliometric outcomes, maximum Relative Citation Ratio (which arguably reflects a scientists most influential work), median Relative Citation Ratio, and annual weighted Relative Citation Ratio (which is more dependent on publication counts). We found that for all 3 measures marginal returns decline as annual GSI increases. Thus, we confirm prior findings of decreasing marginal returns with higher levels of research funding support.

scientific communication and education↗