Biology subjects

Smith, H. C.

Publications and source records attributed to Smith, H. C..

6 recordsLinked to original sources

bioRxiv2026

Naturalistic Movie Viewing Reveals a Distributed Network Supporting Audiovisual Speech Processing

Traditional paradigms in cognitive neuroscience often fail to capture the richness of real-world experiences. To bridge this gap, researchers increasingly use naturalistic stimuli such as movies, which provide complex, multisensory input. Speech perception is a prime example of such complexity: it is inherently multisensory, involving the integration of auditory cues, lip movements, and facial expressions. Prior studies suggest that the left posterior superior temporal sulcus (pSTS) and superior temporal gyrus (STG) play a critical role in this integration. However, most studies of audiovisual speech have relied on simplified or artificial stimuli, limiting ecological validity. To address these gaps, we analyzed fMRI data from human participants watching two full-length films (500 Days of Summer, Citizenfour) to assess the consistency of multisensory speech processes across distinct genres and narratives. We manually annotated word onset times and modality (audiovisual vs. auditory-only). Across two movies and 38 participants we observed consistent speech-related activation in the pSTS and STG across speech types. Compared to auditory-only speech, audiovisual speech recruited a broad left-lateralized network including the angular gyrus, posterior temporal cortex, temporal pole, and inferior frontal gyrus, along with the right cerebellum. These findings were also consistently present in single-subject data. Importantly, most of the regions observed in our analyses have been implicated in multisensory function in the nonhuman primate literature despite receiving relatively little focus in human neuroimaging. Together our results demonstrate that speech processing during naturalistic viewing recruits a distributed network extending substantially beyond regions traditionally emphasized in audiovisual speech research.

neuroscience↗

bioRxiv2026

Neural tracking of surprisal and semantic distance in naturalistic movie viewing

Understanding speech requires listeners to integrate incoming input with prior linguistic and thematic knowledge to access meaning, a task greatly aided by prediction. Surprisal and related phenomena (e.g., next word prediction) tend to be associated with broad activation of language regions during listening. A major challenge for interpreting the neural correlates of surprisal is that lexical expectancies are constrained both by syntactic and semantic information. In contrast, semantic distance yields more of a pure metric of relatedness between one language constituent (e.g., word, phrase, n-gram) and another within a high-dimensional semantic space. We contrasted surprisal and semantic distance in running discourse during naturalistic audiovisual language comprehension. We analyzed fMRI scans from 20 English-speaking adults who viewed the full-length film 500 Days of Summer. Our focus was on brain sensitivity to either surprisal or semantic distance as language unfolded word-by-word. To this end, we implemented a series of hierarchical voxelwise encoding models. After accounting for low-level auditory and visual features, the addition of either surprisal or semantic distance improved prediction in bilateral superior temporal gyrus (STG), left inferior frontal gyrus, and right cerebellum. Critically, both semantic distance and surprisal explained unique variation in bilateral temporal cortex after accounting for the other. These results support the notion that the brain tracks both broad probabilistic prediction as well as semantic integration. More generally, these findings extend previous work on auditory-only speech by demonstrating that surprisal and semantic distance predict meaningful neural variation even within a rich audiovisual context.

neuroscience↗

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2023

Sex-dependent effects of angiotensin type 2 receptor expressing medial prefrontal cortex (mPFC) interneurons in fear extinction learning

BackgroundThe renin-angiotensin system (RAS) has been identified as a potential therapeutic target for PTSD, though its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. We therefore used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R-expressing neuron involvement in fear learning. MethodsTo characterize mPFC-AT2R-expressing neurons in the mPFC, AT2R-Cre/td-Tomato male and female mice were used for immunohistochemistry (IHC). mPFC brain sections were stained with glutamatergic or interneuron markers, and density of AT2R+ cells and colocalization with each marker was quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using an AAV-Cre virus. Mice then underwent Pavlovian auditory fear conditioning, approach/avoidance, and locomotion testing. ResultsIHC results revealed that AT2R is densely expressed in the mPFC. Furthermore, AT2R is primarily expressed in somatostatin interneurons in females but not males. Following fear conditioning, mPFC-AT2R deletion impaired extinction in female but not male mice. Locomotion was unaltered by mPFC-AT2R deletion in males or females, while AT2R-deleted females had increased exploratory behavior. ConclusionThese results lend support for mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons that influence fear extinction in a sex-dependent manner. This furthers underscores the role of mPFC in top-down regulation and a unique role for peptidergic (ie., angiotensin) mPFC regulation of fear and sex differences.

neuroscience↗

bioRxiv2022

A Biological Signature for the Inhibition of Outer Membrane Lipoprotein Biogenesis

The outer membrane (OM) of Gram-negative bacteria is an essential organelle that acts as a formidable barrier to antibiotics. Increasingly prevalent resistance to existing drugs has exacerbated the need for antibiotic discovery efforts targeting the OM. Acylated proteins, known as lipoproteins, are essential in every pathway needed to build the OM. The central role of OM lipoproteins makes their biogenesis a uniquely attractive therapeutic target, but it also complicates in vivo identification of on-pathway inhibitors, as inhibition of OM lipoprotein biogenesis broadly disrupts OM assembly. Here, we use genetics to probe the eight essential proteins involved in OM lipoprotein biogenesis. We define a biological signature consisting of three simple assays that can characteristically identify OM lipoprotein biogenesis defects in vivo. The few known chemical inhibitors of OM lipoprotein biogenesis conform to the biological signature. We also examine MAC13243, a proposed inhibitor of OM lipoprotein biogenesis, and find that it fails to conform to the biological signature. Indeed, we demonstrate that MAC13243 activity relies entirely on a target outside of the OM lipoprotein biogenesis pathway. Hence, our signature offers simple tools to easily assess whether antibiotic lead compounds target an essential pathway that is the hub of OM assembly. IMPORTANCEGram-negative bacteria have an outer membrane, which acts as a protective barrier and excludes many antibiotics. The limited number of antibiotics active against Gram-negative bacteria, along with rising rates of antibiotic resistance, highlights the need for efficient antibiotic discovery efforts. Unfortunately, finding the target of lead compounds, especially ones targeting outer membrane construction, remains difficult. The hub of outer membrane construction is the lipoprotein biogenesis pathway. We show that defects in this pathway result in a signature cellular response that can be used to quickly and accurately validate pathway inhibitors. Indeed, we found that MAC13243, a compound previously proposed to target outer membrane lipoprotein biogenesis, does not fit the signature, and we show that it instead targets an entirely different cellular pathway. Our findings offer a streamlined approach to discovery and validation of lead antibiotics against a conserved and essential pathway in Gram-negative bacteria.

microbiology↗

bioRxiv2019

Tet2 negatively regulates memory fidelity

Despite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate that Tet2 functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergic Tet2 haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link between Tet2 activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.

neuroscience↗