Biology subjects

Reed, T. J.

Publications and source records attributed to Reed, T. J..

3 recordsLinked to original sources

bioRxiv2026

Targeted quantification assays for DNA repair and handling proteins and interactions in Huntington's disease models

Huntingtons disease (HD) is a life-altering genetic neurodegenerative disorder, with cognitive, motor, and psycho-social effects that have consequential impacts on the individuals and their families. While current treatments improve disease symptoms, there are no FDA-approved therapies that prevent disease progression. Converging lines of evidence from human GWAS and mouse models point to DNA repair and handling (R/H) proteins as promising therapeutic targets due to their ability to modulate somatic expansion of the CAG repeat of HTT. The roles of DNA R/H HD modulator proteins are incompletely understood, in part, due to their relatively low cellular abundance and technical challenges in quantification. Here, we developed and validated targeted mass spectrometry assays quantifying DNA R/H proteins, spanning functions in mismatch repair, Fanconi anemia, and transcriptional regulation, using complementary workflows for timsTOF and Orbitrap platforms. We built species-specific experiment spectral libraries that outperformed in silico libraries for target detection. Applying this pipeline to an HTT-Q140 knock-in mouse HD model, we observed that DNA R/H protein abundances were largely unchanged in HD mice, while HTT and HAP40 showed increased nuclear association with disease progression. To facilitate translational research applications, we further developed a stable isotope dilution assay for absolute quantification of 11 human mismatch repair-associated proteins and generated an HTT knock-out human neuroblastoma cell line. Additionally, we used thermal proximity coaggregation profiling to characterize the endogenous interactomes of MMR proteins. We observed that HTT KO caused proteome down-regulation in selected DNA R/H proteins and reshaped the MMR protein interactome, with the most pronounced changes observed for MLH1 and PMS1 interactions. Overall, we established a validated, transferable assay for quantifying DNA R/H proteins in perturbation studies using human and mouse HD model systems and provide evidence that HTT influences the abundance and interaction landscape of proteins central to CAG repeat instability.

neuroscience↗

bioRxiv2026

ReviewBench: An Extensible Framework for Benchmarking Human and AI Manuscript Review

AO_SCPLOWBSTRACTC_SCPLOWThe volume of scientific manuscripts is rising faster than the available pool of expert reviewers, and AI tools are emerging as a possible response, ranging from frontier large language models applied directly to peer review to purpose-built multi-agent systems. Scalable, standardized benchmarks are needed to regularly evaluate how these tools compare to one another and to human reviewers. We present ReviewBench, an open-source, venue-agnostic framework that compares human and AI reviews across structure, alignment with a papers major claims, impact, and critique category. We apply ReviewBench to 145,021 review comments from human reviewers, frontier large language models (GPT-5.2, and Gemini 3 Pro), and Reviewer3.com (R3), a multi-agent peer review system. The dataset spans papers in computer science (ICLR 2025, n = 1,000), social science (Nature Human Behaviour, n = 142), and life science (eLife, n = 1,000). Across disciplines, AI reviews are more structured and engage more directly with a papers major claims, with R3 more often surfacing consequential comments, defined as comments capable of undermining those claims. When restricting to critical comments, however, human reviewers rank first on consequential rate on more individual papers than any AI source, despite a lower average. We identify a bimodal reviewer distribution with peaks near 0% and 100%, indicating that many reviewers outperform AI on this metric, but a substantial fraction of reviewers near 0% brings the average down. Critique typing demonstrates systematic differences, where humans emphasize contribution and clarity, while AI emphasizes validity, sufficiency, and transparency. Together, these findings argue against framing AI as a replacement for human review and instead support a complementary model in which AI scales technical verification of major claims while human judgment remains essential for evaluating contribution and shaping editorial decisions.

scientific communication and education↗

bioRxiv2024

Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures

Huntingtons disease (HD) is a debilitating neurodegenerative disorder affecting an individuals cognitive and motor abilities. HD is caused by mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. Use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established an HTT association with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, we find HTT modulates the subcellular localization and assembly of Mediator. We demonstrated striatal enriched and functional interactions with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology.

neuroscience↗