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	<title>bioRxiv Channel: SCORCH</title>
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	This feed contains articles for bioRxiv Channel "SCORCH"
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	<item rdf:about="https://biorxiv.org/cgi/content/short/2022.07.25.501436v1?rss=1">
<title>
<![CDATA[
Morphine Suppresses Peripheral Responses and Transforms Brain Myeloid Gene Expression to Favor Neuropathogenesis in SIV Infection 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2022.07.25.501436v1?rss=1"
</link>
<description><![CDATA[
The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach. We probed systemic parameters and performed single-cell examination of the targets for infection in the brain, microglia and macrophages. Morphine treatment created an immunosuppressive environment, blunting initial responses to infection, which persisted during antiretroviral treatment. Antiretroviral drug concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine treatment. Interestingly, the transcriptional signature of both microglia and brain macrophages was transformed to one of a neurodegenerative phenotype. Notably, the expression of osteopontin, a pleiotropic cytokine, was significantly elevated in microglia. This was especially notable in the white matter, which is also dually affected by HIV and opioids. Increased osteopontin expression was linked to numerous HIV neuropathogenic mechanisms, including those that can maintain a viral reservoir. The opioid morphine is detrimental to SIV/HIV infection, especially in the brain.
]]></description>
<dc:creator>Fox, H. S.</dc:creator>
<dc:creator>Niu, M.</dc:creator>
<dc:creator>Morsey, B. M.</dc:creator>
<dc:creator>Lamberty, B. G.</dc:creator>
<dc:creator>Emanuel, K.</dc:creator>
<dc:creator>Periyasamy, P.</dc:creator>
<dc:creator>Callen, S.</dc:creator>
<dc:creator>Acharya, A.</dc:creator>
<dc:creator>Kubik, G.</dc:creator>
<dc:creator>Eudy, J. D.</dc:creator>
<dc:creator>Guda, C.</dc:creator>
<dc:creator>Dyavar, S. R.</dc:creator>
<dc:creator>Fletcher, C. V.</dc:creator>
<dc:creator>Byrareddy, S.</dc:creator>
<dc:creator>Buch, S.</dc:creator>
<dc:date>2022-07-27</dc:date>
<dc:identifier>doi:10.1101/2022.07.25.501436</dc:identifier>
<dc:title><![CDATA[Morphine Suppresses Peripheral Responses and Transforms Brain Myeloid Gene Expression to Favor Neuropathogenesis in SIV Infection]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2022-07-27</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.02.24.581897v1?rss=1">
<title>
<![CDATA[
ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer's disease. 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.02.24.581897v1?rss=1"
</link>
<description><![CDATA[
Multimodal measurements have become widespread in genomics, however measuring open chromatin accessibility and splicing simultaneously in frozen brain tissues remains unconquered. Hence, we devised Single-Cell-ISOform-RNA sequencing coupled with the Assay-for-Transposase-Accessible-Chromatin (ScISOr-ATAC). We utilized ScISOr-ATAC to assess whether chromatin and splicing alterations in the brain convergently affect the same cell types or divergently different ones. We applied ScISOr-ATAC to three major conditions: comparing (i) the Rhesus macaque (Macaca mulatta) prefrontal cortex (PFC) and visual cortex (VIS), (ii) cross species divergence of Rhesus macaque versus human PFC, as well as (iii) dysregulation in Alzheimers disease in human PFC. We found that among cortical-layer biased excitatory neuron subtypes, splicing is highly brain-region specific for L3-5/L6 IT_RORB neurons, moderately specific in L2-3 IT_CUX2.RORB neurons and unspecific in L2-3 IT_CUX2 neurons. In contrast, at the chromatin level, L2-3 IT_CUX2.RORB neurons show the highest brain-region specificity compared to other subtypes. Likewise, when comparing human and macaque PFC, strong evolutionary divergence on one molecular modality does not necessarily imply strong such divergence on another molecular level in the same cell type. Finally, in Alzheimers disease, oligodendrocytes show convergently high dysregulation in both chromatin and splicing. However, chromatin and splicing dysregulation most strongly affect distinct oligodendrocyte subtypes. Overall, these results indicate that chromatin and splicing can show convergent or divergent results depending on the performed comparison, justifying the need for their concurrent measurement to investigate complex systems. Taken together, ScISOr-ATAC allows for the characterization of single-cell splicing and chromatin patterns and the comparison of sample groups in frozen brain samples.
]]></description>
<dc:creator>Hu, W.</dc:creator>
<dc:creator>Foord, C.</dc:creator>
<dc:creator>Hsu, J.</dc:creator>
<dc:creator>Fan, L.</dc:creator>
<dc:creator>Corley, M. J.</dc:creator>
<dc:creator>Bhatia, T. N.</dc:creator>
<dc:creator>Xu, S.</dc:creator>
<dc:creator>Belchikov, N.</dc:creator>
<dc:creator>He, Y.</dc:creator>
<dc:creator>Pang, A. P.</dc:creator>
<dc:creator>Lanjewar, S. N.</dc:creator>
<dc:creator>Jarroux, J.</dc:creator>
<dc:creator>Joglekar, A.</dc:creator>
<dc:creator>Milner, T. A.</dc:creator>
<dc:creator>Ndhlovu, L.</dc:creator>
<dc:creator>Zhang, J.</dc:creator>
<dc:creator>Butelman, E.</dc:creator>
<dc:creator>Sloan, S. A.</dc:creator>
<dc:creator>Lee, V. M.</dc:creator>
<dc:creator>Gan, L.</dc:creator>
<dc:creator>Tilgner, H. U.</dc:creator>
<dc:date>2024-02-28</dc:date>
<dc:identifier>doi:10.1101/2024.02.24.581897</dc:identifier>
<dc:title><![CDATA[ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer's disease.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-02-28</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.02.03.636129v1?rss=1">
<title>
<![CDATA[
Principled PCA separates signal from noise in omics count data 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.02.03.636129v1?rss=1"
</link>
<description><![CDATA[
Principal component analysis (PCA) is indispensable for processing high-throughput omics datasets, as it can extract meaningful biological variability while minimizing the influence of noise. However, the suitability of PCA is contingent on appropriate normalization and transformation of count data, and accurate selection of the number of principal components; improper choices can result in the loss of biological information or corruption of the signal due to excessive noise. Typical approaches to these challenges rely on heuristics that lack theoretical foundations. In this work, we present Biwhitened PCA (BiPCA), a theoretically grounded framework for rank estimation and data denoising across a wide range of omics modalities. BiPCA overcomes a fundamental difficulty with handling count noise in omics data by adaptively rescaling the rows and columns - a rigorous procedure that standardizes the noise variances across both dimensions. Through simulations and analysis of over 100 datasets spanning seven omics modalities, we demonstrate that BiPCA reliably recovers the data rank and enhances the biological interpretability of count data. In particular, BiPCA enhances marker gene expression, preserves cell neighborhoods, and mitigates batch effects. Our results establish BiPCA as a robust and versatile framework for high-throughput count data analysis.
]]></description>
<dc:creator>Stanley, J. S.</dc:creator>
<dc:creator>Yang, J.</dc:creator>
<dc:creator>Li, R.</dc:creator>
<dc:creator>Lindenbaum, O.</dc:creator>
<dc:creator>Kobak, D.</dc:creator>
<dc:creator>Landa, B.</dc:creator>
<dc:creator>Kluger, Y.</dc:creator>
<dc:date>2025-02-07</dc:date>
<dc:identifier>doi:10.1101/2025.02.03.636129</dc:identifier>
<dc:title><![CDATA[Principled PCA separates signal from noise in omics count data]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-02-07</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.02.05.636667v1?rss=1">
<title>
<![CDATA[
Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.02.05.636667v1?rss=1"
</link>
<description><![CDATA[
For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways are a potential point of deleterious convergence. Here, we profile, at single nucleus resolution, the substantia nigra (SN) transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to SUD. Stepwise, progressive microglial dysregulation, coupled to altered SN dopaminergic and GABAergic signaling, was associated with SUD/HIV dual diagnosis and further with lack of viral suppression in blood. In virologically suppressed donors, SUD comorbidity was associated with microglial transcriptional changes permissive for HIV infection. We report HIV-related downregulation of monoamine reuptake transporters specifically in dopaminergic neurons regardless of SUD status or viral load, and additional transcriptional signatures consistent with selective vulnerability of SN dopamine neurons.
]]></description>
<dc:creator>Wilson, A. M.</dc:creator>
<dc:creator>Jacobs, M. M.</dc:creator>
<dc:creator>Lambert, T. Y.</dc:creator>
<dc:creator>Valada, A.</dc:creator>
<dc:creator>Meloni, G.</dc:creator>
<dc:creator>Gilmore, E.</dc:creator>
<dc:creator>Murray, J.</dc:creator>
<dc:creator>Morgello, S.</dc:creator>
<dc:creator>Akbarian, S.</dc:creator>
<dc:date>2025-02-06</dc:date>
<dc:identifier>doi:10.1101/2025.02.05.636667</dc:identifier>
<dc:title><![CDATA[Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-02-06</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.02.05.636707v1?rss=1">
<title>
<![CDATA[
Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.02.05.636707v1?rss=1"
</link>
<description><![CDATA[
HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map the transcriptomic and epigenetic landscapes of postmortem human brains from 13 healthy individuals and 20 individuals with HIV who have a history of treatment with ART. Our study spanned three distinct regions--the prefrontal cortex, insular cortex, and ventral striatum--enabling a comprehensive exploration of region-specific and cross-regional perturbations. We found widespread and persistent HIV-associated transcriptional and epigenetic alterations across multiple cell types. Detailed analyses of microglia revealed state changes marked by immune activation and metabolic dysregulation, while integrative multiomic profiling of astrocytes identified multiple subpopulations, including a reactive subpopulation unique to HIV-infected brains. These findings suggest that cells from people with HIV exhibit molecular shifts that may underlie ongoing neuroinflammation and CNS dysfunction. Furthermore, cell-cell communication analyses uncovered dysregulated and pro-inflammatory interactions among glial populations, underscoring the multifaceted and enduring impact of HIV on the brain milieu. Collectively, our comprehensive atlas of HIV-associated brain changes reveals distinct glial cell states with signatures of pro-inflammatory signaling and metabolic dysregulation, providing a framework for developing targeted therapies for HIV-associated neurological dysfunction.
]]></description>
<dc:creator>Yang, J.</dc:creator>
<dc:creator>Agrawal, K.</dc:creator>
<dc:creator>Stanley, J. S.</dc:creator>
<dc:creator>Li, R.</dc:creator>
<dc:creator>Jacobs, N.</dc:creator>
<dc:creator>Wang, H.</dc:creator>
<dc:creator>Lu, C.</dc:creator>
<dc:creator>Qu, R.</dc:creator>
<dc:creator>Clarke, D.</dc:creator>
<dc:creator>Chen, Y.</dc:creator>
<dc:creator>Jiang, Y.</dc:creator>
<dc:creator>Bai, D.</dc:creator>
<dc:creator>Zheng, S.</dc:creator>
<dc:creator>Fox, H.</dc:creator>
<dc:creator>Ho, Y.-C.</dc:creator>
<dc:creator>Huttner, A.</dc:creator>
<dc:creator>Gerstein, M.</dc:creator>
<dc:creator>Kluger, Y.</dc:creator>
<dc:creator>Zhang, L.</dc:creator>
<dc:creator>Spudich, S.</dc:creator>
<dc:date>2025-02-08</dc:date>
<dc:identifier>doi:10.1101/2025.02.05.636707</dc:identifier>
<dc:title><![CDATA[Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-02-08</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.04.04.588047v1?rss=1">
<title>
<![CDATA[
Microglia and macrophages alterations in the CNS during acute SIV infection: a single-cell analysis in rhesus macaques 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.04.04.588047v1?rss=1"
</link>
<description><![CDATA[
Human Immunodeficiency Virus (HIV) is widely acknowledged for its profound impact on the immune system. Although HIV primarily affects peripheral CD4 T cells, its influence on the central nervous system (CNS) cannot be overlooked. Within the brain, microglia and CNS-associated macrophages (CAMs) serve as the primary targets for HIV, as well as for the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological effects and the establishment of a viral reservoir. Given the gaps in our understanding of how these cells respond in vivo to acute CNS infection, we conducted single-cell RNA sequencing (scRNA-seq) on myeloid cells from the brains of three rhesus macaques 12-days after SIV infection, along with three uninfected controls. Our analysis revealed six distinct microglial clusters including homeostatic microglia, preactivated microglia, and activated microglia expressing high levels of inflammatory and disease-related molecules. In response to acute SIV infection, the population of homeostatic and preactivated microglia decreased, while the activated and disease-related microglia increased. All microglial clusters exhibited upregulation of MHC class I molecules and interferon-related genes, indicating their crucial roles in defending against SIV during the acute phase. All microglia clusters also upregulated genes linked to cellular senescence. Additionally, we identified two distinct CAM populations: CD14lowCD16hi and CD14hiCD16low CAMs. Interestingly, during acute SIV infection, the dominant CAM population changed to one with an inflammatory phenotype. Notably, specific upregulated genes within one microglia and one macrophage cluster were associated with neurodegenerative pathways, suggesting potential links to neurocognitive disorders. This research sheds light on the intricate interactions between viral infection, innate immune responses, and the CNS, providing valuable insights for future investigations.

AUTHOR SUMMARY

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/588047v1_ufig1.gif" ALT="Figure 1">
View larger version (13K):
org.highwire.dtl.DTLVardef@1d9fadcorg.highwire.dtl.DTLVardef@1e491daorg.highwire.dtl.DTLVardef@1238f91org.highwire.dtl.DTLVardef@1a6a548_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIVs entry into the central nervous system (CNS) can lead to neurological dysfunction, including HIV-associated neurocognitive disorders (HAND), and the establishment of a viral reservoir. While microglia and CNS-associated macrophages (CAMs) are the primary targets of HIV in the CNS, their responses during acute HIV infection remain poorly defined. To address this, we employed the scRNA-seq technique to study microglial and CAM populations in rhesus macaques during acute SIV infection. By identifying signature genes associated with different phenotypes and mapping them to various biological and pathological pathways, we discovered two myeloid cell clusters strongly linked to neurodegenerative disorders. Additionally, other clusters were associated with inflammatory pathways, suggesting varying degrees of activation among different myeloid cell populations in the brain, possibly mediated by distinct signaling pathways. All microglia clusters developed signs of the cellular senescence pathway. These findings shed light on the immunological and pathological effects of different myeloid phenotypes in the brain during acute SIV infection, providing valuable insights for future therapeutic strategies targeting this critical stage and aiming to eliminate the viral reservoir.
]]></description>
<dc:creator>Xu, X.</dc:creator>
<dc:creator>Niu, M.</dc:creator>
<dc:creator>Lamberty, B. G.</dc:creator>
<dc:creator>Emanuel, K.</dc:creator>
<dc:creator>Trease, A. J.</dc:creator>
<dc:creator>Tabassum, M.</dc:creator>
<dc:creator>Lifson, J. D.</dc:creator>
<dc:creator>Fox, H. S.</dc:creator>
<dc:date>2024-04-04</dc:date>
<dc:identifier>doi:10.1101/2024.04.04.588047</dc:identifier>
<dc:title><![CDATA[Microglia and macrophages alterations in the CNS during acute SIV infection: a single-cell analysis in rhesus macaques]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-04-04</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.12.16.628794v1?rss=1">
<title>
<![CDATA[
BACH2-driven tissue resident memory programs promote HIV-1 persistence 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.12.16.628794v1?rss=1"
</link>
<description><![CDATA[
Transcription repressor BACH2 redirects short-lived terminally differentiated effector into long-lived memory cells. We postulate that BACH2-mediated long-lived memory programs promote HIV-1 persistence in gut CD4+ T cells. We coupled single-cell DOGMA-seq and TREK-seq to capture chromatin accessibility, transcriptome, surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in 100,744 gut T cells from ten aviremic HIV-1+ individuals and five HIV-1- donors. BACH2 was the leading transcription factor that shaped gut tissue resident memory T cells (TRMs) into long-lived memory with restrained interferon-induced effector function. We found that HIV-1-infected cells were enriched in TRMs (80.8%). HIV-1-infected cells had increased BACH2 transcription factor accessibility, TRM (CD49a, CD69, CD103) and survival (IL7R) gene expression, and Th17 polarization (RORC, CCR6). In vitro gut CD4+ T cell infection revealed preferential infection and persistence of HIV-1 in CCR6+ TRMs. Overall, we found BACH2-driven TRM program promotes HIV-1 persistence and BACH2 as a new therapeutic target.
]]></description>
<dc:creator>Wei, Y.</dc:creator>
<dc:creator>Ma, H. K.</dc:creator>
<dc:creator>Wang, M. E.</dc:creator>
<dc:creator>Papasavvas, E.</dc:creator>
<dc:creator>Konnikova, L.</dc:creator>
<dc:creator>Tebas, P.</dc:creator>
<dc:creator>Morgenstern, R.</dc:creator>
<dc:creator>Montaner, L. J.</dc:creator>
<dc:creator>Ho, Y.-C.</dc:creator>
<dc:date>2024-12-20</dc:date>
<dc:identifier>doi:10.1101/2024.12.16.628794</dc:identifier>
<dc:title><![CDATA[BACH2-driven tissue resident memory programs promote HIV-1 persistence]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-12-20</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.10.22.619617v1?rss=1">
<title>
<![CDATA[
A Transcriptional Signature of Induced Neurons Differentiates Virologically Suppressed People Living With HIV from People Without HIV 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.10.22.619617v1?rss=1"
</link>
<description><![CDATA[
Neurocognitive impairment is a prevalent and important co-morbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. Here, we explored for the first time, use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age-and disease-related features of the donors, providing unique opportunities to reveal novel aspects of neurological disorders. We obtained primary dermal fibroblasts from six virologically suppressed PLWH (range: 27 - 64 years, median: 53); 83% Male; 50% White) and seven matched people without HIV (PWOH) (range: 27 - 66, median: 55); 71% Male; 57% White). iNs were generated using transcription factors NGN2 and ASCL1, and validated by immunocytochemistry and single-cell-RNAseq. Transcriptomic analysis using bulk-RNAseq identified 29 significantly differentially expressed genes between iNs from PLWH and PWOH. Of these, 16 genes were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicates that iNs from PLWH exhibit differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in iNs from PLWH, which complements independent post-mortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue, indicating that iN generation reconstitutes this pathway. Finally, we observed that expression of the FOXL2NB-FOXL2-LINC01391 genome locus is reduced in iNs from PLWH and negatively correlates with neurocognitive impairment. Thus, we have identified an iN gene signature of HIV through direct reprogramming of skin fibroblasts into neurons revealing novel mechanisms of neurocognitive impairment in PLWH.

One sentence summaryDirect reprogramming of skin fibroblasts into neurons reveals unique gene signatures indicative of HIV infection in the context of viral suppression.
]]></description>
<dc:creator>Ostermann, P. N.</dc:creator>
<dc:creator>Wu, Y.</dc:creator>
<dc:creator>Bowler, S. A.</dc:creator>
<dc:creator>Siddiqui, M. A.</dc:creator>
<dc:creator>Herrera, A.</dc:creator>
<dc:creator>Sidharta, M.</dc:creator>
<dc:creator>Ramnarine, K.</dc:creator>
<dc:creator>Martinez-Meza, S.</dc:creator>
<dc:creator>St. Bernard, L. A.</dc:creator>
<dc:creator>Nixon, D. F.</dc:creator>
<dc:creator>Jones, R. B.</dc:creator>
<dc:creator>Yamashita, M.</dc:creator>
<dc:creator>Ndhlovu, L. C.</dc:creator>
<dc:creator>Zhou, T.</dc:creator>
<dc:creator>Evering, T. H.</dc:creator>
<dc:date>2024-10-22</dc:date>
<dc:identifier>doi:10.1101/2024.10.22.619617</dc:identifier>
<dc:title><![CDATA[A Transcriptional Signature of Induced Neurons Differentiates Virologically Suppressed People Living With HIV from People Without HIV]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-10-22</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.08.01.606165v1?rss=1">
<title>
<![CDATA[
Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.08.01.606165v1?rss=1"
</link>
<description><![CDATA[
Therapeutically targeting the brain requires interactions with endothelial cells, pericytes, and astrocytes at the blood brain barrier (BBB). We evaluated regional and cell-type specific drug metabolism and transport mechanisms using rhesus macaques and in vitro treatment of primary human cells. Here, we report heterogenous distribution of representative drugs, tenofovir (TFV), emtricitabine (FTC), and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rivaled hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity, rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition.
]]></description>
<dc:creator>Wilkins, H. N.</dc:creator>
<dc:creator>Knerler, S. A.</dc:creator>
<dc:creator>Warshanna, A.</dc:creator>
<dc:creator>Ortiz, R. C.</dc:creator>
<dc:creator>Haas, K.</dc:creator>
<dc:creator>Orsburn, B. C.</dc:creator>
<dc:creator>Williams, D. W.</dc:creator>
<dc:date>2024-08-05</dc:date>
<dc:identifier>doi:10.1101/2024.08.01.606165</dc:identifier>
<dc:title><![CDATA[Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-08-05</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2023.07.28.551042v1?rss=1">
<title>
<![CDATA[
Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2023.07.28.551042v1?rss=1"
</link>
<description><![CDATA[
BackgroundAppropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage.

MethodsWe used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability.

ResultsWe determined that cocaine had a selective impact on ART extravasation, where it increased FTCs ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts.

ConclusionOur findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.
]]></description>
<dc:creator>Fridman, L. B.</dc:creator>
<dc:creator>Knerler, S.</dc:creator>
<dc:creator>Price, A.-S.</dc:creator>
<dc:creator>Colon Ortiz, R.</dc:creator>
<dc:creator>Mercado, A.</dc:creator>
<dc:creator>Wilkins, H.</dc:creator>
<dc:creator>Flores, B. R.</dc:creator>
<dc:creator>Orsburn, B.</dc:creator>
<dc:creator>Williams, D.</dc:creator>
<dc:date>2023-07-29</dc:date>
<dc:identifier>doi:10.1101/2023.07.28.551042</dc:identifier>
<dc:title><![CDATA[Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2023-07-29</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.06.25.661563v1?rss=1">
<title>
<![CDATA[
Spatial isoform sequencing at sub-micrometer single-cell resolution reveals novel patterns of spatial isoform variability in brain cell types 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.06.25.661563v1?rss=1"
</link>
<description><![CDATA[
Spatial long-read technologies are becoming increasingly common but lack nanometer and therefore often single-cell resolution. This leaves the question unanswered of whether spatially variable isoforms represent spatial variability within one cell type or differences in cell-type composition between different regions. Here, we developed Spl-ISO-Seq2 (220nm spot size and 500nm resolution), and the accompanying software packages Spl-IsoQuant-2 and Spl-IsoFind, enabling long-read sequencing using up to 500 million barcodes compared to 80,000 previously. Applying this to the adult mouse brain, we compared spatial variability by examining (a) differential isoform abundance between known brain regions and (b) spatial isoform patterns that do not align with predefined regions. While the former revealed more spatial isoform differences, both approaches identified overlapping hits, e.g., Rps24 in oligodendrocytes. For Snap25, previously known to exhibit spatial isoform variation, we now show that this variability occurs in excitatory neurons. The second approach also uncovered patterns not captured by predefined-region comparisons, e.g., Tnnc1 in excitatory neurons. Furthermore, we show that a surprising number of spatial isoform signals is not driven by cell-type composition alone. Finally, we applied our software to newly generated Visium HD 3 long-read data to demonstrate its applicability and strong reproducibility across protocols and biological replicates. Taken together, our experimental and analytical methods enrich spatial transcriptomics with a so-far elusive isoform view of spatial variation for individual cell types.
]]></description>
<dc:creator>Michielsen, L.</dc:creator>
<dc:creator>Prjibelski, A. D.</dc:creator>
<dc:creator>Foord, C.</dc:creator>
<dc:creator>Hu, W.</dc:creator>
<dc:creator>Jarroux, J.</dc:creator>
<dc:creator>Hsu, J.</dc:creator>
<dc:creator>Tomescu, A. I.</dc:creator>
<dc:creator>Hajirasouliha, I.</dc:creator>
<dc:creator>Tilgner, H. U.</dc:creator>
<dc:date>2025-06-25</dc:date>
<dc:identifier>doi:10.1101/2025.06.25.661563</dc:identifier>
<dc:title><![CDATA[Spatial isoform sequencing at sub-micrometer single-cell resolution reveals novel patterns of spatial isoform variability in brain cell types]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-06-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.07.08.663082v1?rss=1">
<title>
<![CDATA[
Quantitative Economon Model of Transactions for Drugs and Other Commodities 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.07.08.663082v1?rss=1"
</link>
<description><![CDATA[
BackgroundAn economon is a dyadic economic unit of two participants who exchange mutually reinforcing commodities (e.g., addictive drugs for money). A human economon often consists of a buyer providing money to a supplier, while the supplier reciprocally provides some commodity to the buyer. Here, we develop the Quantitative Economon Model (QEM) by reviewing basic principles of behavioral economics and translating those principles into a quantitative model characterizing transactional behavior between buyers and suppliers that would be applicable to transactions involving drugs specifically, as well as other commodities. According to the model, transactions between a buyer and supplier depend on their respective economic demand for the commodities exchanged. Additionally, the model assumes that demand for commodities fluctuates across sequential transactions due to satiation and deprivation associated with consumption of those commodities, of particular relevance to addictive drugs.

MethodsWe used a computational approach to simulate data from the QEM according to four conditions representing parametric manipulations of high or low levels of deprivation crossed with high or low levels of satiation (i.e., a 2x2 matrix of conditions).

ResultsSimulations revealed patterns of transactional behavior that may be characteristic of a range of commodities. In particular, when deprivation-effects were high and satiation-effects were low, simulated transaction rates were characteristic of the high consumption rates observed with addictive drugs. In other conditions, transaction rates varied along patterns characteristic of consumption for other commodities like food. In sum, the QEM provides a framework for modeling, investigating, and predicting patterns of human transactional behavior.
]]></description>
<dc:creator>Haynes, J. M.</dc:creator>
<dc:creator>Correa da Rosa, J. M.</dc:creator>
<dc:creator>Butelman, E.</dc:creator>
<dc:creator>Hursh, S. R.</dc:creator>
<dc:creator>Negus, S. S.</dc:creator>
<dc:date>2025-07-11</dc:date>
<dc:identifier>doi:10.1101/2025.07.08.663082</dc:identifier>
<dc:title><![CDATA[Quantitative Economon Model of Transactions for Drugs and Other Commodities]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-07-11</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2023.08.28.554970v1?rss=1">
<title>
<![CDATA[
SIMVI reveals intrinsic and spatial-induced states in spatial omics data 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2023.08.28.554970v1?rss=1"
</link>
<description><![CDATA[
Spatial omics technologies enable the analysis of gene expression and interaction dynamics in relation to tissue structure and function. However, existing computational methods may not properly distinguish cellular intrinsic variability and intercellular interactions, and may thus fail to capture spatial regulations for further biological discoveries. Here, we present Spatial Interaction Modeling using Variational Inference (SIMVI), an annotation-free framework that disentangles cell intrinsic and spatial-induced latent variables for modeling gene expression in spatial omics data. We derive theoretical support for SIMVI in disentangling intrinsic and spatial-induced variations. By this disentanglement, SIMVI enables estimation of spatial effects (SE) at a single-cell resolution, and opens up various opportunities for novel downstream analyses. To demonstrate the potential of SIMVI, we applied SIMVI to spatial omics data from diverse platforms and tissues (MERFISH human cortex, Slide-seqv2 mouse hippocampus, Slide-tags human tonsil, spatial multiome human melanoma, cohort-level CosMx melanoma). In all tested datasets, SIMVI effectively disentangles variations and infers accurate spatial effects compared with alternative methods. Moreover, on these datasets, SIMVI uniquely uncovers complex spatial regulations and dynamics of biological significance. In the human tonsil data, SIMVI illuminates the cyclical spatial dynamics of germinal center B cells during maturation. Applying SIMVI to both RNA and ATAC modalities of the multiome melanoma data reveals potential tumor epigenetic reprogramming states. Application of SIMVI on our newly-collected cohort-level CosMx melanoma dataset uncovers space-and-outcome-dependent macrophage states and the underlying cellular communication machinery in the tumor microenvironments.
]]></description>
<dc:creator>Dong, M.</dc:creator>
<dc:creator>Kluger, H.</dc:creator>
<dc:creator>Fan, R.</dc:creator>
<dc:creator>Kluger, Y.</dc:creator>
<dc:date>2023-08-30</dc:date>
<dc:identifier>doi:10.1101/2023.08.28.554970</dc:identifier>
<dc:title><![CDATA[SIMVI reveals intrinsic and spatial-induced states in spatial omics data]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2023-08-30</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2023.11.11.566161v1?rss=1">
<title>
<![CDATA[
Deep identifiable modeling of single-cell atlases enables zero-shot query of cellular states 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2023.11.11.566161v1?rss=1"
</link>
<description><![CDATA[
How to identify true biological differences across samples while overcoming batch effects has been a persistent challenge in single-cell RNA-seq data analysis, hindering analyses across datasets for transferable biological findings. In this work, we show that scaling up deep identifiable models leads to a surprisingly effective solution for this challenging task. We developed scShift, a deep variational inference framework with theoretical support in disentangling batch-dependent and independent variations. By training the model with compendiums of scRNA-seq atlases, scShift shows remarkable zero-shot capabilities in revealing representations of cell types and biological states in single-cell data while overcoming batch effects. We employed scShift to systematically compare lung fibrosis states across different datasets, tissues and experimental systems. scShift uniquely extrapolates lung fibrosis states to previously unseen post-COVID-19 fibrosis, characterizing universal myeloid-fibrosis signatures, potential repurposing drug targets and fibrosis-associated cell interactions. Evaluations of over 200 trained scShift models demonstrate emergent zero-shot capabilities and a scaling law beyond a transition threshold, with respect to dataset diversity. With its scaling performance on massive single-cell compendiums and exceptional zero-shot capabilities, scShift represents an important advance toward next-generation computational models for single-cell analysis.
]]></description>
<dc:creator>Dong, M.</dc:creator>
<dc:creator>Kluger, Y.</dc:creator>
<dc:date>2023-11-15</dc:date>
<dc:identifier>doi:10.1101/2023.11.11.566161</dc:identifier>
<dc:title><![CDATA[Deep identifiable modeling of single-cell atlases enables zero-shot query of cellular states]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2023-11-15</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2024.03.15.584610v1?rss=1">
<title>
<![CDATA[
FABEL: Forecasting Animal Behavioral Events with Deep Learning-Based Computer Vision 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2024.03.15.584610v1?rss=1"
</link>
<description><![CDATA[
Behavioral neuroscience aims to provide a connection between neural phenomena and emergent organism-level behaviors. This requires perturbing the nervous system and observing behavioral outcomes, and comparing observed post-perturbation behavior with predicted counterfactual behavior and therefore accurate behavioral forecasts. In this study we present FABEL, a deep learning method for forecasting future animal behaviors and locomotion trajectories from historical locomotion alone. We train an offline pose estimation network to predict animal body-part locations in behavioral video; then sequences of pose vectors are input to deep learning time-series forecasting models. Specifically, we train an LSTM network that predicts a future food interaction event in a specified time window, and a Temporal Fusion Transformer that predicts future trajectories of animal body-parts, which are then converted into probabilistic label forecasts. Importantly, accurate prediction of food interaction provides a basis for neurobehavioral intervention in the context of compulsive eating. We show promising results on forecasting tasks between 100 milliseconds and 5 seconds timescales. Because the model takes only behavioral video as input, it can be adapted to any behavioral task and does not require specific physiological readouts. Simultaneously, these deep learning models may serve as extensible modules that can accommodate diverse signals, such as in-vivo fluorescence imaging and electrophysiology, which may improve behavior forecasts and elucidate invervention targets for desired behavioral change.
]]></description>
<dc:creator>Catto, A.</dc:creator>
<dc:creator>O'Connor, R.</dc:creator>
<dc:creator>Braunscheidel, K. M.</dc:creator>
<dc:creator>Kenny, P. J.</dc:creator>
<dc:creator>Shen, L.</dc:creator>
<dc:date>2024-03-17</dc:date>
<dc:identifier>doi:10.1101/2024.03.15.584610</dc:identifier>
<dc:title><![CDATA[FABEL: Forecasting Animal Behavioral Events with Deep Learning-Based Computer Vision]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2024-03-17</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.04.23.650260v1?rss=1">
<title>
<![CDATA[
Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.04.23.650260v1?rss=1"
</link>
<description><![CDATA[
Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimers disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5xFAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.
]]></description>
<dc:creator>Yao, M.</dc:creator>
<dc:creator>Sun, N.</dc:creator>
<dc:creator>Linville, R.</dc:creator>
<dc:creator>Wei, Z.</dc:creator>
<dc:creator>Kakazu, A.</dc:creator>
<dc:creator>Ouyang, Y.</dc:creator>
<dc:creator>Li, R.</dc:creator>
<dc:creator>Du, L.</dc:creator>
<dc:creator>Wang, H.</dc:creator>
<dc:creator>Zhou, Y.</dc:creator>
<dc:creator>Jiang, Y.</dc:creator>
<dc:creator>Zhang, Z.</dc:creator>
<dc:creator>Li, A.</dc:creator>
<dc:creator>Lu, H.</dc:creator>
<dc:creator>Xu, J.</dc:creator>
<dc:creator>Kellis, M.</dc:creator>
<dc:creator>Heiman, M.</dc:creator>
<dc:creator>Duan, W.</dc:creator>
<dc:date>2025-04-29</dc:date>
<dc:identifier>doi:10.1101/2025.04.23.650260</dc:identifier>
<dc:title><![CDATA[Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-04-29</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.06.10.658877v1?rss=1">
<title>
<![CDATA[
A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types. 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.06.10.658877v1?rss=1"
</link>
<description><![CDATA[
Genome-wide single-cell and spatial long-read approaches have gained traction, but mostly lack single-cell resolution - and yield limited read lengths. Here, we introduce spatial ISOform sequencing (Spl-ISO-Seq), which reveals exons and polyadenylation sites from long reads with near-single-cell resolution. Spl-ISO-Seq selects long cDNAs and doubles to triples read lengths compared to standard preparations. Adding a highly specific software tool (Spl-ISOquant) and comparing human post-mortem pre-puberty samples of the visual cortex (8-11 years) to post-puberty samples (16-19 years), we find that cortical layers harbor stronger splicing and poly(A)-site regulation than the adjacent white matter, with enrichment of multiple protein-domain types. For oligodendrocytes however, developmental splicing changes are stronger in white matter. Among cortical layers, layer 4 has the most developmental changes in alternative-exon inclusion in excitatory neurons and in poly(A) sites. We also find many repeat elements, especially ERV1 long terminal repeats downstream of developmentally-regulated layer 4 exons. Overall, alternative splicing changes are linked to synapses - specifically at the post-synapse. Age-linked splicing changes in layers 1-3 and 4 are associated with autism spectrum disorder but not with schizophrenia, amyotrophic lateral sclerosis and Alzheimers disease. These results root developmental splicing changes during puberty and the resulting protein changes in specific layers and cell types. More generally, our new technologies enable new observations for any complex tissue.
]]></description>
<dc:creator>Foord, C.</dc:creator>
<dc:creator>Prjibelski, A. D.</dc:creator>
<dc:creator>Hu, W.</dc:creator>
<dc:creator>Michielsen, L.</dc:creator>
<dc:creator>Vandelli, A.</dc:creator>
<dc:creator>Narykov, O.</dc:creator>
<dc:creator>Evans, B.</dc:creator>
<dc:creator>Hsu, J.</dc:creator>
<dc:creator>Belchikov, N.</dc:creator>
<dc:creator>Jarroux, J.</dc:creator>
<dc:creator>He, Y.</dc:creator>
<dc:creator>Ross, M. E.</dc:creator>
<dc:creator>Hajirasouliha, I.</dc:creator>
<dc:creator>Tartaglia, G. G.</dc:creator>
<dc:creator>Korkin, D.</dc:creator>
<dc:creator>Tomescu, A. I.</dc:creator>
<dc:creator>Tilgner, H. U.</dc:creator>
<dc:date>2025-06-10</dc:date>
<dc:identifier>doi:10.1101/2025.06.10.658877</dc:identifier>
<dc:title><![CDATA[A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-06-10</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2023.04.02.535281v1?rss=1">
<title>
<![CDATA[
Single-cell long-read mRNA isoform regulation is pervasive across mammalian brain regions, cell types, and development 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2023.04.02.535281v1?rss=1"
</link>
<description><![CDATA[
RNA isoforms influence cell identity and function. Until recently, technological limitations prevented a genome-wide appraisal of isoform influence on cell identity in various parts of the brain. Using enhanced long-read single-cell isoform sequencing, we comprehensively analyze RNA isoforms in multiple mouse brain regions, cell subtypes, and developmental timepoints from postnatal day 14 (P14) to adult (P56). For 75% of genes, full-length isoform expression varies along one or more axes of phenotypic origin, underscoring the pervasiveness of isoform regulation across multiple scales. As expected, splicing varies strongly between cell types. However, certain gene classes including neurotransmitter release and reuptake as well as synapse turnover, harbor significant variability in the same cell type across anatomical regions, suggesting differences in network activity may influence cell-type identity. Glial brain-region specificity in isoform expression includes strong poly(A)-site regulation, whereas neurons have stronger TSS regulation. Furthermore, developmental patterns of cell-type specific splicing are especially pronounced in the murine adolescent transition from P21 to P28. The same cell type traced across development shows more isoform variability than across adult anatomical regions, indicating a coordinated modulation of functional programs dictating neural development. As most cell-type specific exons in P56 mouse hippocampus behave similarly in newly generated data from human hippocampi, these principles may be extrapolated to human brain. However, human brains have evolved additional cell-type specificity in splicing, suggesting gain-of-function isoforms. Taken together, we present a detailed single-cell atlas of full-length brain isoform regulation across development and anatomical regions, providing a previously unappreciated degree of isoform variability across multiple scales of the brain.
]]></description>
<dc:creator>Joglekar, A.</dc:creator>
<dc:creator>Hu, W.</dc:creator>
<dc:creator>Zhang, B.</dc:creator>
<dc:creator>Narykov, O.</dc:creator>
<dc:creator>Diekhans, M.</dc:creator>
<dc:creator>Balacco, J.</dc:creator>
<dc:creator>Ndhlovu, L.</dc:creator>
<dc:creator>Milner, T. A.</dc:creator>
<dc:creator>Fedrigo, O.</dc:creator>
<dc:creator>Jarvis, E. D.</dc:creator>
<dc:creator>Sheynkman, G. M.</dc:creator>
<dc:creator>Korkin, D.</dc:creator>
<dc:creator>Ross, M. E.</dc:creator>
<dc:creator>Tilgner, H. U.</dc:creator>
<dc:date>2023-04-04</dc:date>
<dc:identifier>doi:10.1101/2023.04.02.535281</dc:identifier>
<dc:title><![CDATA[Single-cell long-read mRNA isoform regulation is pervasive across mammalian brain regions, cell types, and development]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2023-04-04</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2023.06.10.544455v1?rss=1">
<title>
<![CDATA[
Roadmap for Canonical and Extended Endocannabinoid System Receptors in Peripheral Organs of Preclinical Animal Models 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2023.06.10.544455v1?rss=1"
</link>
<description><![CDATA[
The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.
]]></description>
<dc:creator>Rosado-Franco, J. J.</dc:creator>
<dc:creator>Ellison, A. L.</dc:creator>
<dc:creator>White, C. J.</dc:creator>
<dc:creator>Price, A. S.</dc:creator>
<dc:creator>Moore, C. F.</dc:creator>
<dc:creator>Williams, R. E.</dc:creator>
<dc:creator>Fridman, L. B.</dc:creator>
<dc:creator>Weerts, E. M.</dc:creator>
<dc:creator>Williams, D. W.</dc:creator>
<dc:date>2023-06-10</dc:date>
<dc:identifier>doi:10.1101/2023.06.10.544455</dc:identifier>
<dc:title><![CDATA[Roadmap for Canonical and Extended Endocannabinoid System Receptors in Peripheral Organs of Preclinical Animal Models]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2023-06-10</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.09.25.678534v1?rss=1">
<title>
<![CDATA[
Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.09.25.678534v1?rss=1"
</link>
<description><![CDATA[
Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection. We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques. This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia. Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-{kappa}b and STAT1 activation when mediating its antiviral and anti-inflammatory effects. These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.
]]></description>
<dc:creator>Ellison, A. L.</dc:creator>
<dc:creator>Rosado-Franco, J. J.</dc:creator>
<dc:creator>Mamun, L.</dc:creator>
<dc:creator>Knerler, S.</dc:creator>
<dc:creator>Daniali, M.</dc:creator>
<dc:creator>Mehta, K.</dc:creator>
<dc:creator>Williams-McLeod, S.</dc:creator>
<dc:creator>Alvarez, J.</dc:creator>
<dc:creator>Joyner, S. S.</dc:creator>
<dc:creator>Vandrey, R.</dc:creator>
<dc:creator>Weerts, E. M.</dc:creator>
<dc:creator>Gaskill, P. J.</dc:creator>
<dc:creator>Corley, M. J.</dc:creator>
<dc:creator>Ndhlovu, L. C.</dc:creator>
<dc:creator>Williams, D. W.</dc:creator>
<dc:date>2025-09-25</dc:date>
<dc:identifier>doi:10.1101/2025.09.25.678534</dc:identifier>
<dc:title><![CDATA[Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-09-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://biorxiv.org/cgi/content/short/2025.12.06.692767v1?rss=1">
<title>
<![CDATA[
Investigation of CNS damage following HIV infection and methamphetamine exposure using human iPSC-derived microglia and 3D cerebral assembloid models 
]]>
</title>
<link>
https://biorxiv.org/cgi/content/short/2025.12.06.692767v1?rss=1"
</link>
<description><![CDATA[
HIV-associated neurocognitive disorder (HAND) is characterized by glial activation and neuroinflammation emerging from HIV infection. Moreover, methamphetamine (METH) is a highly addictive psychostimulant whose use is linked to high HIV prevalence, significantly worsening clinical outcomes for people living with HIV and hastening onset of systemic illness. Overall, pathologies associated with HIV infection/METH use comorbidity include neuroinflammation, neurotoxicity, synaptodendritic damage, and resulting cognitive dysfunction. However, mechanisms underlying this neuropathogenesis remain elusive due to the scarcity of human brain-specific experimental model systems. Therefore, we created a next-generation three-dimensional (3D) human brain model derived from human induced pluripotent stem cells (hiPSCs). Specifically, this 3D in vitro cerebral assembloid model integrates functional microglia derived from hiPSCs with cerebral organoids. Microglia are key contributors to HAND symptoms associated with HIV/METH comorbidity. We show that the presence of microglia in this assembloid model allows productive infection with HIV, which is enhanced by METH exposure, resulting in increased glial activation, inflammatory responses (namely IL-1{beta} and IL-6 release), and neurotoxicity marked by neuronal cell death and synaptic protein loss. Importantly, in this model, we observed markedly decreased levels of the microglial receptor TREM2, which is implicated in microglial functions including phagocytosis, apoptosis and inflammatory responses following HIV infection and METH treatment. Analysis of our model showed that decreased TREM2 function may lead to HIV- and METH-associated pathological changes. Overall, our assembloid model could be a valuable tool for future analyses of HIV/METH/CNS interactions and mechanisms underlying HAND, which could lead to novel therapeutic approaches to decreasing the CNS viral reservoir.
]]></description>
<dc:creator>Tiwari, S. K.</dc:creator>
<dc:creator>Baidwan, G.</dc:creator>
<dc:creator>Trescott, S.</dc:creator>
<dc:creator>Jakhmola, S.</dc:creator>
<dc:creator>Coufal, N. G.</dc:creator>
<dc:creator>Rana, T. M.</dc:creator>
<dc:date>2025-12-10</dc:date>
<dc:identifier>doi:10.64898/2025.12.06.692767</dc:identifier>
<dc:title><![CDATA[Investigation of CNS damage following HIV infection and methamphetamine exposure using human iPSC-derived microglia and 3D cerebral assembloid models]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory Press</dc:publisher>
<prism:publicationDate>2025-12-10</prism:publicationDate>
<prism:section></prism:section>
</item>
</rdf:RDF>
