Biology subjects

Williams, C. C.

Publications and source records attributed to Williams, C. C..

6 recordsLinked to original sources

bioRxiv2025

Altered Decision-Making Across Acute and Chronic Pain States: A Bias Towards Context-Dependent Valuations

Chronic pain is often characterized by the entrenchment of maladaptive behaviors -- avoidance, inactivity, and hypervigilance -- that outlast tissue damage. A central but mechanistically underspecified question is how behaviors acquired during acute pain become locked in as pain chronifies. Influential accounts, including the fear-avoidance model, suggest that behavioral patterns learned in a specific context -- such as avoidance during acute injury -- overgeneralize to situations where they are no longer advantageous. Whether this reflects altered learning or changes in how learned information guides decisions has remained unclear. To address this, we administered a probabilistic reinforcement learning task to 239 individuals with chronic pain, acute pain, or no pain, designed to dissociate two decision strategies: reliance on recent reinforcement history -- what was reinforced in a prior context -- versus global expected value -- the objective worth of an option regardless of context. Learning performance was comparable across all groups, confirming intact associative learning. However, groups differed significantly in decision-making: individuals with chronic pain favored options with stronger context-dependent reinforcement history over those with higher global expected value; however, those without pain showed no preference for one over the other, with the acute pain group showing an intermediate pattern. Computational modeling confirmed this, with chronic pain patients showing significantly reduced weighting toward global expected value. Critically, this shift tracked pain duration rather than intensity -- suggesting prolonged pain exposure gradually biases decisions away from global expected value towards a context-dependent history. These findings offer a computational explanation for behavioral persistence in chronic pain, and this duration-dependent shift, already evident in the acute pain group, may represent an early cognitive signature of chronification.

neuroscience↗

bioRxiv2025

EEG-GAN: A Generative EEG Augmentation Toolkit for Enhancing Neural Classification

Electroencephalography (EEG) is a widely applied method for decoding neural activity, offering insights into cognitive function and driving advancements in neurotechnology. However, decoding EEG data remains challenging, as classification algorithms typically require large datasets that are expensive and time-consuming to collect. Recent advances in generative artificial intelligence have enabled the creation of realistic synthetic EEG data, yet no method has consistently demonstrated that such synthetic data can lead to improvements in EEG decodability across diverse datasets. Here, we introduce EEG-GAN, an open-source generative adversarial network (GAN) designed to augment EEG data. In the most comprehensive evaluation study to date, we assessed its capacity to generate realistic EEG samples and enhance classification performance across four datasets, five classifiers, and seven sample sizes, while benchmarking it against six established augmentation techniques. We found that EEG-GAN, when trained to generate raw single-trial EEG signals, produced signals that reproduce grand-averaged waveforms and time-frequency patterns of the original data. Furthermore, training classifiers on additional synthetic data improved their ability to decode held-out empirical data. EEG-GAN achieved up to a 16% improvement in decoding accuracy, with enhancements consistent across datasets but varying among classifiers. Data augmentations were particularly effective for smaller sample sizes (30 and below), significantly improving 70% of these classification analyses and only significantly impairing 4% of analyses. Moreover, EEG-GAN significantly outperformed all benchmark techniques in 69% of the comparisons across datasets, classifiers, and sample sizes and was only significantly outperformed in 3% of comparisons. These findings establish EEG-GAN as a robust toolkit for generating realistic EEG data, which can effectively reduce the costs associated with real-world EEG data collection for neural decoding tasks.

neuroscience↗

bioRxiv2025

Oviduct fluid metabolic regulation of embryonic genome methylation

Adverse maternal health and lifestyle during pregnancy can program offspring susceptibility to noncommunicable diseases in adulthood. Oviduct fluid facilitates key preimplantation milestones, including embryonic genome activation. However, the regulatory mechanisms governing oviduct fluid composition, and the developmental consequences of its disruption, remain unclear. Capitalizing on conserved dynamics between human and bovine embryonic genome activation, we first established and characterized bovine oviduct epithelial organoids as a model system. Organoids were then exposed to {Delta}-tetrahydrocannabinol (THC) and cannabidiol (CBD) to test the hypothesis that exocannabinoids alter intra-organoid fluid composition. Treatment altered the organoid transcriptome and intra-organoid fluid metabolome, notably elevating 5'-deoxyadenosine levels. Subsequent embryo culture with 5'-deoxyadenosine during embryonic genome activation resulted in aberrant DNA methylation patterning - independently of direct THC and CBD exposure. These findings identify a novel, indirect, mechanism by which maternal exposures disrupt embryonic development through changes in oviductal metabolite secretions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/659599v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@19ac750org.highwire.dtl.DTLVardef@935709org.highwire.dtl.DTLVardef@13723a8org.highwire.dtl.DTLVardef@105f473_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

cell biology↗

bioRxiv2024

A tethering mechanism underlies Pin1-catalyzed proline cis-trans isomerization at a noncanonical site

The prolyl isomerase Pin1 catalyzes the cis-trans isomerization of proline peptide bonds, a noncovalent post-translational modification that influences cellular and molecular processes, including protein-protein interactions. Pin1 is a two-domain enzyme containing a WW domain that recognizes phosphorylated serine/threonine-proline (pS/pT-P) canonical motifs and an enzymatic PPIase domain that catalyzes proline cis-trans isomerization of pS/pT-P motifs. Here, we show that Pin1 uses a tethering mechanism to bind and catalyze proline cis-trans isomerization of a noncanonical motif in the disordered N-terminal activation function-1 (AF-1) domain of the human nuclear receptor PPAR{gamma}. NMR reveals multiple Pin1 binding regions within the PPAR{gamma} AF-1, including a canonical motif (pS112-P113) that when phosphorylated by the kinase ERK2 binds the Pin1 WW domain with high affinity. NMR methods reveal that Pin1 also binds and accelerates cis-trans isomerization of a noncanonical motif containing a tryptophan-proline motif (W39-P40) previously shown to be involved in an interdomain interaction with the C-terminal ligand-binding domain (LBD) of PPAR{gamma}. Cellular transcription studies combined with mutagenesis and Pin1 inhibitor treatment reveal a functional role for Pin1-mediated acceleration of cis-trans isomerization of the PPAR{gamma} W39-P40 motif. Our data inform a refined model of the Pin1 catalytic mechanism where the WW domain can bind a canonical pS/T-P motif and tether Pin1 to a target, which enables the PPIase domain to exert catalytic cis-trans isomerization at a distal noncanonical site. SIGNIFICANCEPin1 is a multidomain prolyl isomerase enzyme that catalyzes the isomerization of proline peptide bonds, which naturally occur in cis and trans conformations that exchange on a timescale of seconds to minutes, allowing for switch-like effects on target protein structure and function. Previous mechanistic studies using small peptides derived from target substrates revealed Pin1 specifically binds to and displays enzymatic catalysis specificity for substrates containing a phosphorylated serine or threonine followed by a proline (pS/pT-P). Using a large substrate domain from the nuclear receptor peroxisome proliferator activated receptor gamma (PPAR{gamma}), we found that Pin1-catalyzed isomerization can occur at a noncanonical proline distal to a canonical pS/pT-P binding site. Our findings expand the understanding of Pin1-catalyzed enzymatic activities and target substrate functions.

biophysics↗

bioRxiv2022

Structural basis of interdomain communication in PPARγ

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates transcription via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD), and an N-terminal disordered AF-1 domain (NTD or A/B region) that functions through poorly understood structural mechanisms. Here, we show the PPAR{gamma} AF-1 contains an evolutionary conserved Trp-Pro motif that undergoes cis/trans isomerization, populating two long-lived conformations that participate in intradomain AF-1 and interdomain interactions including two surfaces in the C-terminal LBD ({beta}-sheet and the AF-2 surface), which are predicted in AlphaFold 3 models but not AlphaFold 2. NMR and chemical crosslinking mass spectrometry show that interdomain interactions occur for soluble isolated AF-1 and LBD proteins, as well as in full-length PPAR{gamma} in a phase separated state. Mutation of the region containing the Trp-Pro motif, which abrogates cis/trans isomerization of this region, impacts LBD interaction and reduces basal PPAR{gamma}-mediated transcription and agonist-dependent activation of PPAR{gamma}. Our findings provide structural insight into published in vitro and cellular studies that reported interdomain functional communication between the PPAR{gamma} AF-1 and LBD suggesting some of these effects may be mediated via AF-1/LBD interactions.

biochemistry↗

bioRxiv2019

Engineered Enzymes that Retain and Regenerate their Cofactors Enable Continuous-Flow Biocatalysis

Introduction Introduction Results Conclusions Author Contributions Competing Interests Statement General DNA manipulation G3PDEc NoxCa GlpKTk AceKMs GlpKTk-AceKMs G3PDEc-NOXCa GlpKTk-AceKMsE2Aa G3PDEc-NOXCa-Est2Aa FruASc-Est2Aa Engineered Fusion Protein... Expression of individual enzymes... Expression of GlpKTk-AceKMs-E2Aa Expression and purification of... Expression and purification of... Protein Expression and... Synthesis of N6-2AE-ADP ...

synthetic biology↗