Biology subjects

Tseng, G.

Publications and source records attributed to Tseng, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Novel transplantable mouse cell line model recapitulates invasive lobular breast carcinoma (ILC) phenotype and immune microenvironment.

Invasive lobular breast carcinoma (ILC) is the most common special histological subtype of breast cancer, which accounts for 10-15% of all cases. To study the phenotype characteristics, metastatic growth kinetic and immune microenvironment of ILC, we developed an orthotopically transplantable cell line model from the spontaneous mammary fat pad tumor of CDH1-PTEN dual knockout C57BL/6 mouse with Cre-loxP system, designated CPT6. CPT6 recapitulates single-file growth pattern of human ILC, with pleomorphic features and a high mitotic index. RNA sequencing together with whole exome sequencing reveals a luminal A subtype with targetable driver mutations such as Kras G12C. As a novel orthotopically transplantable ILC model in immune competent mice, CPT6 shows robust in vivo growth and metastatic rate, and has moderate immunogenicity which appears to be T-cell independent. We also profiled the immune microenvironment of CPT6, revealing a myeloid-rich environment with dominant M2-macrophage population, which is concordant with human ILC. In summary, this model recapitulates human ILC phenotype and represents a valuable preclinical platform for evaluating immunotherapy and other therapeutic strategies for invasive lobular breast carcinoma.

cancer biology↗

bioRxiv2026

Early-life mucosal T cells direct intestinal stem cell fate via a coordinated developmental program

Although early-life immunity was once considered immature, the human fetal immune system is dynamic and compartmentalized by the second trimester. By 21 weeks of gestation, T lymphocytes become a major immune population in the fetal small intestine (SI), yet their functional roles within this tissue remain largely undefined. To explore their unique contributions to intestinal development, we established an ex vivo co-culture system in which mucosal T cells isolated from fetal, neonatal, or adult SI donors were cultured with tissue-derived 3D SI organoids derived from various ages. Homeostatic early-life (fetal and neonatal) SI T cells uniquely promoted organoid generation, a metric of stem cell renewal, by upregulating cell cycle-associated gene programs. These early-life T cells also directed intestinal stem cell differentiation toward the secretory lineage in both growth and differentiation phase, highlighting that T cells poise stem cells to adopt secretory fates. T cells from infants with necrotizing enterocolitis (NEC) - an inflammatory intestinal disease affecting predominantly preterm infants - failed to activate these same programs, suggesting a pathologic role for T cells in NEC. T cells from the adult SI similarly failed to support organoid growth or differentiation, revealing developmentally specialized, nonimmune functions for early-life T cells in the intestine. Similarly, T cells derived from cord blood did not enhance organoid generation, indicating that this function is not necessarily a generalized feature of early-life T cells but rather is restricted to mucosal T cells. Organoids derived from adults or NEC, however, could re-enter regenerative states when co-cultured with fetal T cells, indicating that fetal T cells can restore stem cell self-renewal across developmentally and disease-imposed states. We further identified that T cell-derived soluble factors alone were insufficient to modulate intestinal stem cell fate, implying the need for physical interactions. Concordant with this finding, we report that T cells heavily localize to the stem cell niche during prenatal development, where they express factors involved in Notch, Wnt, and growth factor signaling to support fetal stem cell function. Collectively, these findings reveal a coordinated developmental program in which fetal SI T cells balance stem cell self-renewal and differentiation, identifying a developmental immune-epithelial axis that can be harnessed to restore intestinal regeneration.

immunology↗

bioRxiv2026

Estrogen receptor-positive cell line xenograft models recapitulate metastatic dissemination and endocrine response of invasive lobular breast carcinoma

HighlightsO_LIER+, CDH1-deficient ILC xenografts recapitulate single-file histology in vivo C_LIO_LISpontaneous metastases faithfully mirror unique ILC clinical dissemination patterns C_LIO_LIER+ leptomeningeal metastases confirmed histologically in ILC xenograft models C_LIO_LIFulvestrant inhibits ILC tumor growth and metastatic burden, improving survival C_LIO_LIER signaling is enriched in ILC brain metastases, with upregulation of RET C_LI Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.

cancer biology↗

bioRxiv2026

Unraveling Tissue-Specific Molecular Signatures and Convergent Pathway Enrichments in Suicidal Behavior

Suicide is a leading cause of death worldwide, yet the biological mechanisms underlying suicide remain poorly understood. A clearer understanding at the molecular level is essential for developing objective biomarkers and targeted interventions. In this study, we used transcriptomic profiling to investigate gene expression patterns associated with suicidal thoughts and behaviors across peripheral blood (n=264) and postmortem brain tissue from two prefrontal regions (dorsolateral prefrontal cortex, DLPFC; subgenual anterior cingulate cortex, sgACC) of individuals with and without psychiatric illness (n=249). Peripheral analyses revealed broad transcriptional changes associated with suicidal thoughts and behaviors, marked by dysregulated immune-related and inflammatory processes. Longitudinal modeling further revealed gene co-expression modules that predicted future suicide attempts over a 12-month follow-up, highlighting processes related to apoptosis, mitochondrial function, and immune regulation. By contrast, transcriptomic analyses of postmortem tissue derived from the DLPFC and sgACC revealed largely suppressed neuroimmune activity. Gene co-expression analyses in the brain identified suicide-associated modules enriched for synaptic plasticity, oxidative stress, and neuroimmune function, some of which displayed regional specificity. Cross-tissue comparison showed minimal gene-level overlap between brain and blood, although shared pathway-level themes emerged in immune, sensory, and cellular stress processes. Taken together, these findings suggest that suicide is associated with distinct but functionally convergent transcriptional alterations across brain and blood. By integrating tissue-specific and systems-level molecular signatures, this work provides insight into the biological architecture of suicide and lays the groundwork for developing novel biomarkers and therapeutic targets to improve prevention and treatment outcomes.

neuroscience↗

bioRxiv2024

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

Chemoresistance is a major driver of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single cell culture to identify, retrieve, and RNA-Seq profile primary quiescent ovarian cancer cells (qOvCa). We found that many qOvCa differentially expressed genes are transcriptional targets of the Myocardin Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway. We also found that genetic disruption of MRTF-SRF interaction, or an MRTF/SRF inhibitor (CCG257081) impact qOvCa gene expression and induce a quiescent state in cancer cells. Suggesting a broad role for this pathway in quiescence, CCG257081 treatment induced quiescence in breast, lung, colon, pancreatic and ovarian cancer cells. Furthermore, CCG081 (i) maintained a quiescent state in patient derived breast cancer organoids and, (ii) induced tumor growth arrest in ovarian cancer xenografts. Together, these data suggest that MRTF/SRF pathway is a critical regulator of quiescence in cancer and a possible therapeutic target. SignificanceQuiescence is a critical driver of chemoresistance. The MRFT-SRF pathway regulates cancer cell quiescence and inhibiting the MRTF-SRF pathway can prevent the outgrowth of quiescent cancer cells and improve cancer outcomes.

cancer biology↗

bioRxiv2024

Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women

Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. The peak incidence of diagnosis occurs around age 70, even though these post-menopausal patients have low circulating levels of estradiol (E2). Despite the hormone sensitivity of age-related tumors, we have a limited understanding of the interplay between systemic and local hormones, chronic inflammation, and immune changes that contribute to the growth and development of these tumors. Here, we show that aged F344 rats treated with the dimethylbenz(a)anthracene / medroxyprogestrone acetate (DMBA/MPA) carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment promotes tumor initiation and impacts growth. Single-nuclei RNA-seq (snRNA-seq) of the tumors showed broad local immune dysfunction that was associated with circulating chronic inflammation. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with an estrone (E1)-predominant estrogen disposition in the systemic circulation, tumors in older patients increase HSD17B7 expression to convert E1 to E2 in the tumor microenvironment (TME) and have local E2 levels similar to pre-menopausal patients. Concurrently, trackable increases in several chemokines, defined most notably by CCL2, promote a chronically inflamed but immune dysfunctional TME. This unique milieu in the aged TME, characterized by high local E2 and chemokine-enriched chronic inflammation, promotes both accumulation of tumor-associated macrophages (TAMs), which serve as signaling hubs, as well as polarization of TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients. Translational SummaryWe uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/616978v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ecd90borg.highwire.dtl.DTLVardef@9d7ac8org.highwire.dtl.DTLVardef@e7fb74org.highwire.dtl.DTLVardef@2da524_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Comparative transcriptomic rhythms in the mouse and human prefrontal cortex

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents. Here, we use RNA sequencing to lay the groundwork for translational studies of molecular rhythms through a sex-specific, cross species comparison of transcriptomic rhythms between the mouse medial PFC (mPFC) and two subregions of the human PFC, the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). We find that while circadian rhythm signaling is conserved across species and subregions, there is a phase shift in the expression of core clock genes between the mouse mPFC and human PFC subregions that differs by sex. Furthermore, we find that the identity of rhythmic transcripts is largely unique between the mouse mPFC and human PFC subregions, with the most overlap (20%, 236 transcripts) between the mouse mPFC and the human ACC in females. Nevertheless, we find that basic biological processes are enriched for rhythmic transcripts across species, with key differences between regions and sexes. Together, this work highlights both the evolutionary conservation of transcriptomic rhythms and the advancement of the human PFC, underscoring the importance of considering cross-species differences when using animal models.

neuroscience↗

bioRxiv2024

In utero human intestine contains maternally derived bacterial metabolites

Understanding when host-microbiome interactions are first established is crucial for comprehending normal development and identifying disease prevention strategies. Furthermore, bacterially derived metabolites play critical roles in shaping the intestinal immune system. Recent studies have demonstrated that memory T cells infiltrate human intestinal tissue early in the second trimester, suggesting that intestinal immune education begins in utero. Our previous study reported a unique fetal intestinal metabolomic profile with an abundance of several bacterially derived metabolites and aryl hydrocarbon receptor (AHR) ligands implicated in mucosal immune regulation. To follow up on this work, in the current study, we demonstrate that a number of microbial byproducts present in fetal intestines in utero are maternally derived and vertically transmitted to the fetus. Notably, these bacterially derived metabolites, particularly short chain fatty acids and secondary bile acids, are likely biologically active and functional in regulating the fetal immune system and preparing the gastrointestinal tract for postnatal microbial encounters, as the transcripts for their various receptors and carrier proteins are present in second trimester intestinal tissue through single-cell transcriptomic data.

microbiology↗

bioRxiv2024

Comprehensive evaluation and practical guideline of gating methods for high-dimensional cytometry data: manual gating, unsupervised clustering, and auto-gating

Cytometry is an advanced technique for simultaneously identifying and quantifying many cell surface and intracellular proteins at a single-cell resolution. Analyzing high-dimensional cytometry data involves identifying and quantifying cell populations based on their marker expressions. This study provided a quantitative review and comparison of various ways to phenotype cellular populations within the cytometry data, including manual gating, unsupervised clustering, and supervised auto-gating. Six datasets from diverse species and sample types were included in the study, and manual gating with two hierarchical layers was used as the truth for evaluation. For manual gating, results from five researchers were compared to illustrate the gating consistency among different raters. For unsupervised clustering, 22 tools were quantitatively compared in terms of accuracy with the truth and computing cost. While no method outperformed all others, several tools, including PAC-MAN, CCAST, FlowSOM, flowClust, and DEPECHE, generally demonstrated strong performance. For supervised auto-gating methods, four algorithms were evaluated, where DeepCyTOF and CyTOF Linear Classifier performed the best. We further provided practical recommendations on prioritizing gating methods based on different application scenarios. This study offers comprehensive insights for biologists to understand diverse gating methods and choose the best-suited ones for their applications.

bioinformatics↗

bioRxiv2024

Molecular and cellular rhythms in excitatory and inhibitory neurons in the mouse prefrontal cortex

Previous studies have shown that there are rhythms in gene expression in the mouse prefrontal cortex (PFC); however, the contribution of different cell types and potential variation by sex has not yet been determined. Of particular interest are excitatory pyramidal cells and inhibitory parvalbumin (PV) interneurons, as interactions between these cell types are essential for regulating the excitation/inhibition balance and controlling many of the cognitive functions regulated by the PFC. In this study, we identify cell-type specific rhythms in the translatome of PV and pyramidal cells in the mouse PFC and assess diurnal rhythms in PV cell electrophysiological properties. We find that while core molecular clock genes are conserved and synchronized between cell types, pyramidal cells have nearly twice as many rhythmic transcripts as PV cells (35% vs. 18%). Rhythmic transcripts in pyramidal cells also show a high degree of overlap between sexes, both in terms of which transcripts are rhythmic and in the biological processes associated with them. Conversely, in PV cells, rhythmic transcripts from males and females are largely distinct. Moreover, we find sex-specific effects of phase on action potential properties in PV cells that are eliminated by environmental circadian disruption. Together, this study demonstrates that rhythms in gene expression and electrophysiological properties in the mouse PFC vary by both cell type and sex. Moreover, the biological processes associated with these rhythmic transcripts may provide insight into the unique functions of rhythms in these cells, as well as their selective vulnerabilities to circadian disruption. Significance statementThis is the first study to examine translatomic rhythms in the mouse PFC with cell-type specificity. We find that the core molecular clock cycles in phase across cell types, indicating that previously described daily oscillations in the cortical excitation/inhibition balance are not the consequence of a phase offset between PV and pyramidal cells. Nevertheless, rhythmic transcripts and their associated biological processes differ by both sex and cell type, suggesting that molecular rhythms may play a unique role in different cell types and between sexes. Therefore, our results, such as the enrichment of transcripts associated with mitochondrial function in PV cells from males, point towards possible cell and sex-specific mechanisms that could contribute to psychiatric and cognitive diseases upon rhythm disruption.

neuroscience↗

bioRxiv2024

Mutual information for detecting multi-class biomarkers when integrating multiple bulk or single-cell transcriptomic studies

MotivationBiomarker detection plays a pivotal role in biomedical research. Integrating omics studies from multiple cohorts can enhance statistical power, accuracy and robustness of the detection results. However, existing methods for horizontally combining omics studies are mostly designed for two-class scenarios (e.g., cases versus controls) and are not directly applicable for studies with multi-class design (e.g., samples from multiple disease subtypes, treatments, tissues, or cell types). ResultsWe propose a statistical framework, namely Mutual Information Concordance Analysis (MICA), to detect biomarkers with concordant multi-class expression pattern across multiple omics studies from an information theoretic perspective. Our approach first detects biomarkers with con-cordant multi-class patterns across partial or all of the omics studies using a global test by mutual information. A post hoc analysis is then performed for each detected biomarkers and identify studies with concordant pattern. Extensive simulations demonstrate improved accuracy and successful false discovery rate control of MICA compared to an existing MCC method. The method is then applied to two practical scenarios: four tissues of mouse metabolism-related transcriptomic studies, and three sources of estrogen treatment expression profiles. Detected biomarkers by MICA show intriguing biological insights and functional annotations. Additionally, we implemented MICA for single-cell RNA-Seq data for tumor progression biomarkers, highlighting critical roles of ribosomal function in the tumor microenvironment of triple-negative breast cancer and underscoring the potential of MICA for detecting novel therapeutic targets. Availabilityhttps://github.com/jianzou75/MICA

bioinformatics↗

bioRxiv2023

Differential Effects of Cocaine and Morphine on the Diurnal Regulation of the Mouse Nucleus Accumbens Proteome

Substance use disorders (SUDs) are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based (LC-MS/MS) quantitative proteomics, along with a data-independent acquisition (DIA) analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveals cocaine and morphine differentially alters diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome.

neuroscience↗

bioRxiv2023

EstroGene database reveals diverse temporal, context-dependent and directional estrogen receptor regulomes in breast cancer

As one of the most successful cancer therapeutic targets, estrogen receptor- (ER/ESR1) has been extensively studied in decade-long. Sequencing technological advances have enabled genome-wide analysis of ER action. However, reproducibility is limited by different experimental design. Here, we established the EstroGene database through centralizing 246 experiments from 136 transcriptomic, cistromic and epigenetic datasets focusing on estradiol-treated ER activation across 19 breast cancer cell lines. We generated a user-friendly browser (https://estrogene.org/) for data visualization and gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, documentation-based meta-analysis revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. We defined temporal estrogen response metasignatures and showed the association with specific transcriptional factors, chromatin accessibility and ER heterogeneity. Unexpectedly, harmonizing 146 transcriptomic analyses uncovered a subset of E2-bidirectionally regulated genes, which linked to immune surveillance in the clinical setting. Furthermore, we defined context dependent E2 response programs in MCF7 and T47D cell lines, the two most frequently used models in the field. Collectively, the EstroGene database provides an informative resource to the cancer research community and reveals a diverse mode of ER signaling.

cancer biology↗

bioRxiv2022

The ultradian transcriptome of the human prefrontal cortex and abnormalities in schizophrenia

Twelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in the human brain. Here we identify 12 h rhythms in transcripts which either peak at sleep/wake transitions (~9 AM/PM) or static times (~3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in schizophrenia, suggesting suboptimal timing of these essential processes that may contribute to cognitive deficits commonly found in schizophrenia.

neuroscience↗

bioRxiv2022

Experimental Design and Power Calculation in Omics Circadian Rhythmicity Detection

Circadian clocks are 24-hour endogenous oscillators in physiological and behavioral processes. Though recent transcriptomic studies have been successful in revealing the circadian rhythmicity in gene expression, the power calculation for omics circadian analysis have not been fully explored. In this paper, we develop a statistical method, namely CircaPower, to perform power calculation for circadian pattern detection. Our theoretical framework is determined by three key factors in circadian gene detection: sample size, intrinsic effect size and sampling design. Via simulations, we systematically investigate the impact of these key factors on circadian power calculation. We not only demonstrate that CircaPower is fast and accurate, but also show its underlying cosinor model is robust against variety of violations of model assumptions. In real applications, we demonstrate the performance of CircaPower using mouse pan-tissue data and human post-mortem brain data, and illustrate how to perform circadian power calculation using mouse skeleton muscle RNA-Seq pilot as case study. Our method CircaPower has been implemented in an R package, which is made publicly available on GitHub (https://github.com/circaPower/circaPower).

genomics↗

bioRxiv2021

CAMO: A molecular congruence analysis framework for evaluating model organisms

CAMO provides a rigorous and user-friendly solution for quantification and mechanistic exploration of omics congruence in model organisms and humans. It performs threshold-free differential analysis, quantitative concordance/discordance scoring, pathway-centric investigation, and topological subnetwork detection. Instead of dichotomous claims of "poorly" or "greatly" mimicking humans, CAMO facilitates discovery and visualization of specific molecular mechanisms that are best or least mimicked, providing foundations for hypothesis generation and subsequent translational investigations.

genomics↗

bioRxiv2021

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Severe and persistent disruptions to sleep and circadian rhythms are common features of people with opioid use disorder (OUD). Preclinical findings suggest altered molecular rhythms in the brain are involved in opioid reward and dependence. However, whether molecular rhythms are disrupted in brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. We previously used subjects times of death (TOD) as a marker of time of day to investigate transcriptional rhythm alterations in psychiatric disorders. Using TOD and RNA sequencing, we discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in opioid addiction, were largely distinct between OUD and unaffected comparison subjects. Further, fewer rhythmic transcripts were identified in DLPFC of OUD subjects compared to unaffected subjects, but nearly double the number of rhythmic transcripts were found in the NAc of OUD subjects. In OUD, rhythmic transcripts in the NAc peaked either in the evening or near sunrise, and were associated with dopamine, opioid, and GABAergic neurotransmission. Co-expression network analysis identified several OUD-specific modules in the NAc, enriched for transcripts involved in the modulation of dopamine and GABA synapses, including glutamatergic signaling and extracellular matrices. Integrative analyses with human GWAS revealed that rhythmic transcripts in DLPFC and NAc were enriched for genomic loci associated with sleep duration and insomnia. Overall, our results connect transcriptional rhythm changes in dopamine, opioid, and GABAergic synaptic signaling in human brain to sleep-related phenotypes and OUD.

neuroscience↗

bioRxiv2021

Human placental villi immune cells help maintain homeostasis in utero

Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after T cell receptor (TCR) stimulation and when exposed to maternal uterine antigens. Finally, we report that cytokine production by PV T cells is sensitive to TCR stimulation and varies between mid-gestation, preterm (26-35 weeks) and term deliveries (37-40 weeks). Collectively, we elucidated the complexity and functional maturity of fetal immune cells within the PV and highlighted their immunosuppressive potential.

immunology↗