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He, A.

Publications and source records attributed to He, A..

At least 19 recordsLinked to original sources

Chromosome-scale Juglans genomes focus fungal defense gene divergence in gene presence and absence instead of copy number

Butternut (Juglans cinerea) is a North American hardwood in steep decline, driven largely by an introduced fungal pathogen that causes butternut canker disease. Tolerance exists within the genus, with the Asian Juglans ailantifolia comparatively tolerant and hybridizing readily with J. cinerea, yet the genomic basis of that difference is poorly resolved. Chromosome-scale reference genomes are presented for J. ailantifolia and for a second J. cinerea accession from the species primary range, with independent scaffolding and uniform annotation across all compared assemblies. Gene family evolution was assessed across twelve Juglandaceae genomes, one per species, and a four accession pangenome was built from J. ailantifolia and J. mandshurica representing section Cardiocaryon and two J. cinerea accessions, Brenton and New Brunswick, representing section Trachycaryon. Neither J. cinerea accession is a putative tolerant selection, so their contrast provides a null against which section-level differences are calibrated. Spanning two sections separated by approximately 30 My, the pangenome partitions many tandem arrays by accession instead of by gene, so copy number is interpreted after merging homology nodes representing the same gene. Section-level variation resides primarily in gene presence and absence, where pathogenesis-related proteins, cysteine-rich receptor-like kinases, wall-associated kinases and lectin-domain receptor kinases are over-represented in the lineage-specific complement of both sections, indicating rapid bidirectional turnover. A smaller set of families is asymmetric, with chitinases and chitin-binding proteins and NB-LRR receptors biased toward the tolerant section and dehydrins, pectin-modifying enzymes and the CBF regulon toward the susceptible one. The largest copy number difference in the dataset separates the two conspecific accessions, at a senescence-associated cysteine protease. The two butternuts are further distinguished by their demographic histories and by the functional composition of their accession-specific gene content: the northern New Brunswick accession retains lower heterozygosity, a distinct coalescent trajectory, and enrichment for calcium transport across channels, pumps and homeostasis, for salt stress response regulation, and for raffinose family oligosaccharide biosynthesis, spanning both the perception and the cryoprotective effectors of freezing tolerance. These findings support recognition of the northern population as a cryptic glacial refugium and a conservation priority.

genomics↗

Transcriptomic and proteomic responses to gas vesicle collapse in native and engineered bacterial systems

Gas vesicles (GVs) are air-filled protein nanostructures produced by microbes to regulate buoyancy and have emerged as powerful tools in biomedical imaging, particularly as acoustic reporter genes. Their mechanically robust shells enclose a stable air compartment, which collapses irreversibly when subjected to sufficient hydrostatic or acoustic pressure, leaving behind large protein sheets. This collapse phenomenon underlies key applications such as differential imaging and controlled cavitation and is also believed to occur naturally during buoyancy regulation, yet its physiological consequences remain poorly understood. Here, we used transcriptomic and proteomic approaches to investigate cellular responses to GV collapse. In the native GV-producing cyanobacterium Dolichospermum flos-aquae, RNA sequencing revealed a distinct transcriptional response characterized by the upregulation of heat shock proteins, indicative of a stress reaction to intracellular protein aggregation. In contrast, bioluminescence reporter assays in E. coli heterologously expressing GVs showed no comparable activation of heat shock promoters. To test the hypothesis that collapsed GVs can be recognized by specific proteins inside cells, we conducted LC-MS/MS-based pull-down assays in both species but did not identify strong candidate binders. While no definitive recognition mechanism was uncovered, our omics-based study provides a rich dataset for cellular responses to GV collapse in both the native and heterologous systems. These findings suggest that cellular responses to collapsed GVs may be more complex than previously recognized, and that both improved assay sensitivity and additional focused experiments will be needed to elucidate how cells detect and manage large intracellular protein aggregates such as collapsed gas vesicles. Proteomics data are available via ProteomeXchange (PXD060779), and RNA sequencing data via NCBI GEO (GSE289028).

synthetic biology↗

LSD1 ablation promotes mammary tumor metastasis by attenuating NK cell-mediated anti-tumor immunity

Epigenetic deregulation can alter the expression of cancer-related genes in tumor cells and may promote metastasis by influencing interactions between tumor cells and their immune microenvironment. However, the underlying immune mechanisms remain poorly understood. LSD1 (KDM1A) is a histone demethylase that has been proposed to function as a tumor and metastasis suppressor in breast cancer. Here, using the MMTV-PyMT breast cancer mouse model, we show that natural killer (NK) cells play a critical role in suppressing tumor cell metastasis to the lung, and that ablation of LSD1 leads to increased lung metastasis. This phenotype is accompanied by pronounced upregulation of immune-related genes, including major histocompatibility complex class I (MHC-I) genes, in tumor cells and by extensive remodeling of the tumor immune microenvironment, characterized by reduced abundance and maturation of NK cells. Consistent with these observations, NK cells exhibit reduced cytotoxicity toward Lsd1-null PyMT tumor cells. Notably, NK cell-mediated killing can be restored by disrupting expression of the non-classical MHC-I molecule Qa-1, a ligand for the inhibitory NK receptor CD94/NKG2A, in tumor cells. In transplantation experiments, Lsd1-null PyMT tumor cells formed significantly larger lung metastatic lesions than Lsd1-wildtype tumor cells in SCID mice, which possess functional NK cells, but not in NSG mice that lack NK cells. Collectively, these findings suggest that epigenetic deregulation in LSD1-deficient mammary tumor cells reprograms the tumor immune microenvironment, resulting in impaired NK cell-mediated tumor surveillance and enhanced metastatic progression.

cancer biology↗

G3DCT: An Interpretable Spatial Grid-based Framework with Temporal Convolution-Transformer for EEG Artifact Identification

Electroencephalography (EEG) serves as a fundamental tool in modern neurology, cognitive neuroscience, and brain-computer interfaces, but its practical application is often compromised by artifacts. Physiological artifacts are particularly intractable due to overlapping spectral features with neural signals, hindering reliable EEG interpretation. In this work, we propose Grid-based 3D Convolution-Transformer (G3DCT), an interpretable deep learning framework for EEG artifact identification. The framework embeds multi-channel EEG signals into fixed grids to leverage electrode spatial topology, employs parallel multi-branch temporal convolutions and Transformers to handle complex artifacts, and incorporates an attention module to visualize scalp activation patterns, which enhances physiological interpretability. Our evaluation on three datasets demonstrates that G3DCT outperforms existing state-of-the-art models. For challenging combined artifacts, it secures a gain of 2.8% in F1-score over the second-best model. These results demonstrate that G3DCT provides an efficient and robust solution for EEG artifact identification, which has the potential to enhance the reliability of EEG-based applications in practice.

neuroscience↗

Stimulated human cortical waves: spatiotemporal dynamics across development

Traveling waves of neural activity are fundamental to cortical function, yet their spatiotemporal dynamics and structural constraints remain less understood in human brain. Conventional analyses focus on network topology and spatial geometry of neural signals, with limited emphasis on wave dynamics at high spatiotemporal resolutions. Here, we applied a manifold-based optical flow algorithm to an open-access intracranial electroencephalography (iEEG) dataset from the single-pulse stimulation cortico-cortical evoked potentials (CCEPs) paradigm, enabling direct construction of high-temporal-resolution cortical neural activity velocity fields. Spatiotemporal mode decomposition revealed a hierarchical organization: large-scale plane waves (mediating global propagation) dominate, complemented by local patterns for local computation. Dominant plane wave directions correlate with underlying white matter fibre tract orientations, indicating anatomical guidance of cortical dynamics. Velocity field singularities (sources, sinks, spirals and saddles) are non-randomly distributed, associating with default mode network (DMN) hubs. We further identified a nonlinear relationship between cortical wave speed and age, with developmental phases paralleling white matter maturation and aging. Our findings link cortical wave dynamics to anatomy, functional networks, and neurodevelopment, establishing wave speed as a potential yet important biomarker for brain function and health.

neuroscience↗

DREADD agonist Clozapine-N-oxide, but not Compound 21, impairs spatial memory encoding

Chemogenetic studies using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable the precise manipulation of neuronal activity in specific brain regions and cell types. DREADDs are widely used to dissect neural circuits underlying animal behavior, including learning and memory. Clozapine-N-Oxide (CNO), a metabolite of clozapine and one of the earliest-developed ligands for muscarinic DREADDs, was initially considered pharmacologically inert. However, CNO is now known to undergo back-metabolism to clozapine, leading to undesired off-target behavioral effects, including alterations in locomotion and anxiety-related behaviors. New ligands such as Compound 21 (C21) have been developed to improve selectivity and reduce these effects. However, despite their widespread use, no studies to date have directly compared the effects of CNO and C21 themselves on specific cognitive processes such as hippocampus-dependent memory formation. Here, we measured acute effects of CNO and C21 on spatial memory encoding, using an object-location memory (OLM) paradigm in male and female mice. We also quantified encoding-associated hippocampal principal neuron and parvalbumin (PV+) interneuron activity by measuring cFos expression in these populations. Across dorsal hippocampal subregions, neither ligand altered overall neuronal activity nor PV+ interneuron activity during encoding. Nonetheless, we find that CNO administration impairs OLM encoding, while C21 does not. Together, these findings highlight a previously unrecognized behavioral effect of CNO administration on hippocampus-dependent memory formation--even in the absence of DREADD expression--and indicate that C21 may be a preferable ligand for chemogenetic studies examining memory and hippocampal function.

neuroscience↗

PhysioMotion Artifact: A Task-Driven EEG Dataset with Channel-Level Motion Artifact Annotations

Physiological artifacts pose persistent challenges in electroencephalo-gram (EEG) data acquisition, often compromising interpretation and post-analysis of EEG signals across research and clinical applications. To address such limitations, including various artifact types, insufficient annotations, and low spatial resolutions, we present PhysioMotion Artifact, a large-scale, task-driven EEG dataset with channel-level artifact annotations. EEG data was acquired from 30 healthy participants performing 16 systematically designed single-type and multi-type movement tasks, inducing 14 distinct types of physiological artifacts. To demonstrate the utility of the dataset, we implemented a Convolutional Neural Networks-Transformer hybrid model for artifact detection and classification, achieving 98% accuracy in binary classification and 85% in 14-class classification tasks.

neuroscience↗

VO: The Vaccine Ontology

With the widespread use of vaccines in research and clinical settings, there is an urgent need to standardize vaccine representation, integrate information across diverse vaccine types, and support computer-assisted reasoning. Accordingly, we have since 2007 developed the community-based Vaccine Ontology (VO), which aligns with the Basic Formal Ontology and adheres to OBO Foundry principles. VO models ontologically vaccines, vaccine components, vaccine immune responses, vaccine investigation studies and other vaccine-related topics. VO represents more than 10,000 vaccines targeting 289 infectious pathogens and cancers in humans and over 30 nonhuman animal species. VO provides mappings to external resources such as RxNorm, CVX, FDA, and USDA. Various VO use cases exist. VO facilitates vaccine standardization in resources such as the VIOLIN vaccine database, ImmPort, and the Vaccine Adjuvant Compendium (VAC). Semantic queries can be made to query VO. VO has been shown to enhance experimental and clinical vaccine data analysis and vaccine literature mining. Overall, VO standardizes vaccine modeling and representation and greatly supports vaccine AI research in the Semantic Web era.

bioinformatics↗

Dentate gyrus network regulation by somatostatin- and parvalbumin-expressing interneurons differentially impacts hippocampal spatial memory processing

GABAergic interneurons regulate circuit dynamics in hippocampal structures such as CA1 that appear to be essential for memory processing. The dentate gyrus (DG) is known to play a role in pattern recognition and spatial working memory. However, the role of the DG in different stages of long-term spatial memory is poorly understood. Moreover, the roles of the predominant interneuron subtypes within the DG - somatostatin-expressing (SST+) and parvalbumin-expressing (PV+) - in different stages of memory processing are unknown. We tested how chemogenetic manipulation of DG SST+ and PV+ interneurons in mice influences the encoding, consolidation, and retrieval of hippocampus-dependent object-location memory (OLM). We find that activation of DG SST+ interneurons impairs both OLM encoding and retrieval, dramatically suppresses DG granule cell cFos expression, and (in the case of encoding) suppresses downstream CA1 network activity. Among individual mice, the degree of DG granule cell suppression is proportional to the extent of SST+ interneuron activation, and predicts the extent of OLM deficits. In striking contrast, PV+ interneuron activation selectively disrupts encoding, but not retrieval, of OLM, and minimally impacts DG or downstream hippocampal network activity. These findings demonstrate that regulation of the DG network by SST+ and PV+ interneurons differentially contributes to the various stages of spatial memory processing, and suggest that distinct network mechanisms are engaged in the hippocampus during each processing stage. Significance statementNeuronal activity within the dentate gyrus (DG) of the hippocampus is regulated by multiple populations of inhibitory interneurons. To understand how inhibitory regulation contributes to spatial memory processing, we experimentally activated two major classes of DG inhibitory interneurons in mice - either during spatial learning, spatial memory storage, or memory recall. We find spatial learning is disrupted by activation of either SST+ or PV+ interneuron populations, although the two manipulations differentially affect hippocampal activity. Somewhat surprisingly, activation of neither inhibitory population affects spatial memory storage, only SST+ interneuron activation disrupts recall, and the hippocampal activity patterns affected by inhibition differ between learning and recall. These data provide a clearer understanding of the circuits engaged by different steps of spatial memory processing.

neuroscience↗

MTARC1 Regulates Lipid Droplet Degradation via Phospholipid Remodeling in Metabolic Fatty Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of liver disease, including simple fatty liver, hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, with limited treatment options. MTARC1 p.A165T variant is associated with reduced risk of MASLD. We previously showed that this variant promotes MTARC1 protein degradation, suggesting MTARC1 inactivation may represent a potential therapeutic strategy. Here, we report that global or liver specific Mtarc1 knockout markedly suppresses diet-induced hepatic TG accumulation, liver injury, inflammation, and fibrosis in a manner dependently on lipolysis and lipophagy. MTARC1 inactivation post-transcriptionally upregulates PEMT and CEPT1 expression, consequently elevating GPL levels, including PC, PE, and lyso-PE, three major GPLs of hepatic LDs. Furthermore, we observed that MTARC1-deficient hepatocytes exhibited smaller but more numerous LDs compared to controls, under comparable cellular TG levels during lipolysis/lipophagy inhibition. Importantly, inhibition of CEPT1 or PEMT could attenuated the hepatoprotective effect of MTARC1 deficiency. Mechanistically, subcellular GPL remodeling induced by MTARC1 deficiency reduce LD size while increase their surface-to-volume ratio, which in turn promote TG degradation through lipolysis and lipophagy. Collectively, our findings identify MTARC1-GPL biosynthesis-LD degradation axis as a key regulator of fatty liver disease and highlight MTARC1 inhibition as a promising therapeutic strategy for MASLD.

cell biology↗

NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin

Heterochromatin has been widely recognized to exert pivotal functions of silencing specific genes and maintenance of genome stability. However, the mechanisms underlying heterochromatin formation and maintenance remain to be fully elucidated. Here, we discovered that the critical mitotic regulator NuMA, as a nucleoskeleton protein, is required for constitutive heterochromatin organization at the level of nucleosomes in the interphase. Depletion of NuMA results in shortened nucleosome repeat length (NRL), dispersed nucleosome clutches and increased chromatin accessibility in heterochromatin regions. Afterwards, epigenetic maintenance and transcription repression in constitutive heterochromatin are disrupted upon NuMA-depletion, particularly the up-regulated transcription level of the non-coding long terminal repeat (LTR) elements, indicating the crucial roles of NuMA in cell differentiation and senescence. We revealed that such functions of NuMA rely on its interaction with linker histone H1, which stabilizes H1s binding to chromatin and facilitates nucleosome stacking. We provided direct structural evidence of NuMAs stabilization effect at the highest spatial resolution of nucleosomes through in situ cryo-ET. Notably, we found that NuMA oligomerizes into quasi-meshwork in nucleoplasm and highly co-localizes with H1 on the chromatin, providing the organization basis for NuMA as a nucleoskeleton protein in chromatin architecture regulation. Collectively, our findings illuminate the concerted effect of nucleoskeleton protein and linker histone on chromatin compaction at the level of nucleosomes, which unveil a new layer of mechanisms by which nucleoskeleton regulates heterochromatin formation and maintenance.

biophysics↗

Evaluation of the nano Liquid Chromatography coupled with Zeno TOF 7600 Mass Spectrometer for Cell Type-Resolved Spatial Proteomics

In this study, we systematically evaluated the nanoLC-Zeno TOF platform using data-independent acquisition (DIA) and identified 3,142 to 7,059 protein groups from 1 to 200 ng of standard K562 digest. Additionally, a targeted acquisition strategy detected 184 peptides with enhanced signal using Zeno activation. To achieve spatial cell-type resolved proteomics, we developed a workflow integrating image-guided laser capture microdissection for analysis of gastric cancer tissue. A 30-minute nanoLC gradient facilitated the quantification of 2,514 proteins from 0.2 mm{superscript 2} regions representing cancer cells, cancer-associated fibroblasts (CAFs), and immune cells, as defined by multiplex immunohistochemistry. This spatial proteomics approach revealed cellular heterogeneity within the tumor microenvironment of a clinical gastric cancer sample, and targeted validation identified differential expression of 12 cancer-associated proteins comprising 103 peptides between cancer cell-enriched and CAFs-enriched regions. This workflow offers a practical strategy for spatial visual proteomic analysis in clinical tissue samples.

cancer biology↗

Optimizing canine T cell activation, expansion, and transduction

Dogs are becoming an important model for human cancers, and successfully troubleshooting issues with genetically modified T cell immunotherapy for round cell and solid neoplasms in dogs provides a unique opportunity to improve efficacy, safety, and affordability for humans as well. Unfortunately, T cell activation in dogs for optimal viral transduction has not been determined, restricting advancements in canine T cell immunotherapy. Two CD3 and two CD28 antibody clones for canine T cell stimulation have been described in the literature, but no studies have been undertaken to evaluate which CD3/CD28 combination is most effective, nor has anyone directly compared the efficacy of the two most popular antibody presentation strategies: antibody-coated plates and antibody-conjugated beads. In evaluating the effects of plate- or bead-bound CD3 stimulation alone versus CD3/CD28 in combination, we tested 12 possible antibody stimulation strategies in addition to evaluating two largely unexplored mitogens in canine T cell transduction, phorbol myristate acetate (PMA) with ionomycin and concanavalin A (ConA). We investigated the impact of these stimulation strategies on canine T cell activation, expansion, and transduction. For stimulation strategies producing the best results, we also examined how each strategy affected the proportions of CD4/CD8 T cell subsets and regulatory T cell (Treg) prevalence. We determined that, in general, plate-bound antibodies were far superior to bead-bound antibodies for canine T cell stimulation, and that plate-bound CD3 clone CA17.6F9 in combination with CD28 clone 5B8 or the mitogen PMA with ionomycin produced better activation and expansion profiles, better transduction, and more desirable T cell subsets that are more likely to improve patient outcomes in dogs suffering from round cell and solid tumors.

immunology↗

Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy

Chimeric Antigen Receptor T (CAR-T) therapies have revolutionized the treatment of cancers such as relapsed and refractory B cell malignancies. However, the precise therapeutic mechanism of CAR-T action remain to be elucidated. In this study, we systematically analyzed CAR signaling via phosphotyrosine (pTyr) proteomics in CAR-T cells from both clinical patients and healthy donors. We found that CAR-T products from clinical patients displayed heightened tyrosine phosphorylation, particularly in the JAK-STAT, MAPK and TCR signaling cascades. We also identified the significantly regulated pTyr sites in primary CAR-T cells under tonic signaling or upon stimulation by antigen-presenting CD19-K562 cells. Although both CD28{zeta} and 4-1BB{zeta} CAR-T cells exhibited comparable pTyr changes, CD28{zeta} CAR-T cells displayed a more pronounced activation in the TCR signaling pathway. Additionally, comparative analysis between clinical and primary CAR-T cells suggested that CAR-T products were subject to heightened tonic signaling, which may be related to therapeutic relapse. Our findings reveal the state of clinical CAR-T products and refine the CAR-T signal transduction network, providing comprehensive insights and informed guidance for CAR-T therapies.

immunology↗

Using Functional Genomic Data in Monocytes/Macrophages and Genotyping to Nominate Disease-Driving Single Nucleotide Polymorphisms and Target Genes in Juvenile Idiopathic Arthritis

IntroductionGWAS have identified multiple regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single nucleotide polymorphisms (SNPs) that drive disease risk is impeded by the SNPs that identify risk loci being in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and use genetic information to inform patient care. We used genotyping and functional data in primary human monocytes/macrophages to nominate disease-driving SNPs on JIA risk haplotypes and identify their likely target genes. MethodsWe identified JIA risk haplotypes using Immunochip data from Hinks et al (Nature Gen 2013) and the meta-analysis from McIntosh et al (Arthritis Rheum 2017). We used genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs that: (1) were situated within open chromatin in multiple immune cell types and (2) were more common in children with JIA than the controls (p< 0.05). We intersected the chosen SNPs (n=846) with regions of bi-directional transcription initiation characteristic of non-coding regulatory regions detected using dREG to analyze GRO-seq data. Finally, we used MicroC data to identify gene promoters interacting with the regulatory regions harboring the candidate causal SNPs. ResultsWe identified 190 SNPs that overlap with dREG peaks in monocytes and126 SNPs that overlap with dREG peaks in macrophages. Of these SNPs, 101 were situated within dREG peaks in both monocytes and macrophages, suggesting that these SNPs exert their effects independent of the cellular activation state. MicroC data in monocytes identified 20 genes/transcripts whose promoters interact with the enhancers harboring the SNPs of interest. ConclusionSNPs in JIA risk regions that are candidate causal variants can be further screened using functional data such as GRO-seq. This process identifies a finite number of candidate causal SNPs, the majority of which are likely to exert their biological effects independent of cellular activation state in monocytes. Three-dimensional chromatin data generated with MicroC identifies genes likely to be influenced by these SNPs. These studies demonstrate the importance of investigations into the role of innate immunity in JIA.

genetics↗

Causal Associations of Circulating Helicobacter pylori Antibodies with 5 Skin Disorders: A Mendelian Randomization Analysis

Helicobacter pylori (H. pylori) infection, a prevalent bacterial ailment affecting the stomach, has been linked to diverse gastrointestinal disorders. Nevertheless, the correlation between H. pylori infection and skin disorders has not been definitively established. We use Mendelian randomization analysis to explore causal relationships with seven pylori antibody levels and five skin diseases, such as rosacea, psoriasis, alopecia areata, pruritus and urticaria. The primary analytical method employed was inverse variance weighted (IVW), and a sensitivity analysis was executed to evaluate the robustness of the primary findings. The results revealed a positive causal relationship between H. pylori catalase antibody levels and AA (IVW: OR = 1.32, 95% CI = 1.07 to 1.61, P = 0.008), as well as a positive causal relationship between H. pylori UreA antibody levels and pruritus (IVW: OR = 1.17, 95% CI = 1.05 to 1.31, P = 0.006). These effects were robust to sensitivity analyses. Our results suggested that H. pylori infection was a risk factor for AA and pruritus. This finding may have implications for the prevention and treatment of these skin disorders.

genomics↗

Brief sleep disruption alters synaptic structures among hippocampal and neocortical somatostatin-expressing interneurons

Study objectivesBrief sleep loss alters cognition and synaptic structures of principal neurons in hippocampus and neocortex. However, while in vivo recording and bioinformatic data suggest that inhibitory interneurons are more strongly affected by sleep loss, it is unclear how sleep and sleep deprivation affect interneurons synapses. Disruption of the SST+ interneuron population seems to be a critical early sign of neuropathology in Alzheimers dementia, schizophrenia, and bipolar disorder - and the risk of developing all three is increased by habitual sleep loss. We aimed to test how the synaptic structures of SST+ interneurons in various brain regions are affected by brief sleep disruption. MethodsWe used Brainbow 3.0 to label SST+ interneurons in the dorsal hippocampus, prefrontal cortex, and visual cortex of male SST-CRE transgenic mice, then compared synaptic structures in labeled neurons after a 6-h period of ad lib sleep, or gentle handling sleep deprivation (SD) starting at lights on. ResultsDendritic spine density among SST+ interneurons in both hippocampus and neocortex was altered in a subregion-specific manner, with increased overall and thin spine density in CA1, dramatic increases in spine volume and surface area in CA3, and small but significant changes (primarily decreases) in spine size in CA1, PFC and V1. ConclusionsOur suggest that the synaptic connectivity of SST+ interneurons is significantly altered in a brain region-specific manner by a few hours of sleep loss. This suggests a cell type-specific mechanism by which sleep loss disrupts cognition and alters excitatory-inhibitory balance in brain networks. Significance StatementChanges to the function of somatostatin-expressing (SST+) interneurons have been implicated in the etiology of psychiatric and neurological disorders in which both cognition and sleep behavior are affected. Here, we measure the effects of very brief experimental sleep deprivation on synaptic structures of SST+ interneurons in hippocampus and neocortex, in brain structures critical for sleep-dependent memory processing. We find that only six hours of sleep deprivation restructures SST+ interneurons dendritic spines, causing widespread and subregion-specific changes to spine density and spine size. These changes have the potential to dramatically alter excitatory-inhibitory balance across these brain networks, leading to cognitive disruptions commonly associated with sleep loss.

neuroscience↗

Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of cancer that affects primarily adolescents and young adults. FLC tumors are typically associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC is challenging to study because of its rarity and limited pre-clinical models. Here we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA expression in the liver of mouse embryos results in perinatal lethality associated with liver developmental defects, while DNAJ1B-PKA expression in the liver of adult mice initiates tumors resembling FLC at low penetrance. We sought to develop ex vivo cell models from these tumors but failed to establish long-term cell lines. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancer and may help identify novel therapeutic strategies.

cancer biology↗