Biology subjects

Hubbard, E.

Publications and source records attributed to Hubbard, E..

5 recordsLinked to original sources

bioRxiv2026

Structure-free, site-resolved contrastive learningextends small-molecule discovery beyond the reachof structure-based modeling

Virtual screening asks which molecules, among an enormous space of drug-like chemistry, are worth synthesizing and testing against a protein target. Most modern methods answer by building and scoring an explicit three-dimensional pose through molecular docking, or the co-folding models that now approach experimental accuracy. Building these poses presumes a well-defined pocket, and the non-orthosteric, cryptic, and intrinsically disordered sites where unexplored ligandability lies offer none. There, these methods fail to generalize. Here we present Ptarmigan-1, a contrastive model that co-embeds the residues of a protein with candidate small molecules in a shared latent space, from sequence and two-dimensional chemistry alone, and without ever constructing a pose. Engagement reduces to the proximity of precomputed embeddings. Freed from the pose, Ptarmigan-1 trains directly on chemoproteomic and bioactivity data of mixed resolution, scores a compound in ten milliseconds rather than the tens of seconds a co-folding model demands, and resolves each prediction to the residues a compound engages. On well-folded, orthosteric targets it performs comparably to a collection of co-folding and docking models, and on covalent, cryptic, and disordered sites it matches or exceeds them. It localizes reversible and covalent inhibitors to the pockets they engage, even for targets withheld from training, and screens the entire human proteome against a library of 3.4 billion compounds in under a day. By decoupling molecular recognition from structure, Ptarmigan-1 recasts virtual screening as a reusable index that continuously improves as data accumulate.

molecular biology↗

bioRxiv2025

Native, Spatiotemporal Profiling of the Global Human Regulome

The regulome, comprising transcription factors, cofactors, chromatin remodelers, and other regulatory proteins, forms the core machinery by which cells interpret signals and execute gene expression programs. Despite its central role in development, disease, and drug response, the regulome remains largely uncharted at scale due to its dynamic, low-abundance, and chromatin-associated nature. Here, we present a method for scalable, regulome profiling for global, compartment-resolved quantification of native regulome proteins. By enriching DNA- and chromatin-associated proteins and profiling them using high-throughput, label-free DIA mass spectrometry, regulome profiling captures chromatin-associated proteins across 36 human cell lines and thousands of perturbations. The resulting Regulome Atlas recovers nearly 60% of known human transcription factors, reveals lineage-specific TF localization, and distinguishes active nuclear engagement from latent, unbound states. We demonstrate that regulome profiles resolve acute immune pathway activation prior to transcriptional changes, identify previously unrecognized drug-induced regulome responses, and enable proteome-scale readouts of compound target engagement and complex remodeling. This work establishes a foundational resource for decoding the regulatory proteome and provides a blueprint for integrating regulome data into next-generation models of cellular behavior.

cell biology↗

bioRxiv2024

Neural circuit basis of adolescent THC-induced potentiation of opioid responses in adult mice

Use of one drug of abuse typically influences the behavioral response to other drugs, either administered at the same time or a subsequent time point. The nature of the drugs being used, as well as the timing and dosing, also influence how these drugs interact. Here, we tested the effects of adolescent THC exposure on the development of morphine-induced behavioral adaptations following repeated morphine exposure during adulthood. We found that adolescent THC administration potentiated reward, and paradoxically impaired the development of morphine reward. Following a forced abstinence period, we then mapped the whole-brain response to a moderate dose of morphine, and found that adolescent THC administration led to increased morphine-induced activity in the basal ganglia and increased functional connectivity between frontal cortical regions and the ventral tegmental area. Last, we show using rabies virus-based circuit mapping that adolescent THC exposure triggers a long-lasting elevation in connectivity from the frontal cortex regions onto ventral tegmental dopamine cells. Our study adds to the rich literature on the interaction between drugs of abuse, including THC and opioids, and provides potential circuit substates by which adolescent THC exposure influences responses to morphine later in life.

neuroscience↗

bioRxiv2023

Effects of intensified training with insufficient recovery on joint level and single muscle fibre mechanical function: The role of myofibrillar Ca2+ sensitivity

Intense exercise training with insufficient recovery is associated with reductions in neuromuscular performance. However, it is unclear how single muscle fibre mechanical function and myofibrillar Ca2+ sensitivity contribute to these impairments. We investigated the effects of overload training on joint-level neuromuscular performance and cellular-level mechanical function. Fourteen athletes (4 female, 10 male) underwent a 3-week intensified training protocol consisting of [~]140% of their regular training hours with three additional high-intensity training sessions per week. Neuromuscular performance of the knee extensors was assessed via maximum voluntary contraction (MVC) force, electrically evoked twitch contractions, and a force-frequency relationship. Muscle biopsies were taken from the vastus lateralis to assess single fibre mechanical function. Neither MVC force nor twitch parameters were altered following intensified training (all p>0.05), but a rightward shift in the force-frequency curve was observed with a 6-27% reduction in force at low-frequencies (5-20Hz, all p<0.05). In single fibres, maximal force output was not reduced following intensified training, but there was a rightward shift in the force-pCa curve driven by a 6% reduction in Ca2+ sensitivity as indicated by a lower pCa50 value (i.e., higher [Ca2+]) across fibre types (Pre=6.477{+/-}0.157, Post=6.088{+/-}0.480, p<0.05). These data indicate intensified training leads to impaired Ca2+ sensitivity at the single fibre level, which in part explains impaired neuromuscular function at the joint level during lower frequencies of activation. This is an important consideration for athletes, as performance is often assessed at maximal levels of activation, and these underlying impairments in force generation may be less obvious. New & NoteworthyIntense exercise training with insufficient recovery leads to impaired muscle contractile performance. These impairments often manifest at lower frequencies of muscle stimulation, termed prolonged low-frequency force depression. Impaired myofibrillar calcium sensitivity has been suggested as a potential mechanism of prolonged low-frequency force depression. Our work shows that impaired calcium sensitivity of single muscle fibres coincided with joint level prolonged low-frequency force depression after intense exercise training with insufficient recovery.

physiology↗

bioRxiv2021

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA[->]Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA[->]Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA[->]Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA[->]Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA[->]VTADA[->]Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

neuroscience↗