38 results on '"Estill M"'
Search Results
2. Evaluating communications system performance effects at a system of systems level
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Miner, Nadine E., primary, Van Leeuwen, Brian P., additional, Welch, Kimberly M., additional, Estill, M. Donan, additional, Smith, Mark A., additional, Le, Hai D., additional, and Lawton, Craig R., additional
- Published
- 2012
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3. From Our Readers.
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Miller, Francis Pickens, McGill, Ralph, Williams, Aubrey, Estill, M. S., and L. D.
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LETTERS to the editor ,LIBERALISM ,PERIODICALS ,COMPROMISE (Ethics) ,GOVERNORS - Abstract
Presents letters to the editor related to several issues. Opinion on a article related to Southern Liberal protest, published in the November 6, 1953 issue of the journal "The New Republic"; Views on the Liberals those have to go about the business of destroying one another, never admitting of compromise. Comments on the anxiety felt by liberals regarding Adlai Stevenson's forthcoming Georgia trip on the invitation of the Governor.
- Published
- 1953
4. Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.
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Serafini RA, Farzinpour Z, Patel V, Kelley AM, Estill M, Pryce KD, Sakloth F, Teague CD, Torres-Berrio A, Nestler EJ, Shen L, Akbarian S, Karkhanis AN, Blitzer RD, and Zachariou V
- Abstract
Abstract: Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain., (Copyright © 2024 International Association for the Study of Pain.)
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- 2024
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5. Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.
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Torres-Berrío A, Estill M, Patel V, Ramakrishnan A, Kronman H, Minier-Toribio A, Issler O, Browne CJ, Parise EM, van der Zee YY, Walker DM, Martínez-Rivera FJ, Lardner CK, Durand-de Cuttoli R, Russo SJ, Shen L, Sidoli S, and Nestler EJ
- Abstract
Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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6. Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens.
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Martínez-Rivera FJ, Holt LM, Minier-Toribio A, Estill M, Yeh SY, Tofani S, Futamura R, Browne CJ, Mews P, Shen L, and Nestler EJ
- Abstract
Substance use disorder is characterized by a maladaptive imbalance wherein drug seeking persists despite negative consequences or drug unavailability. This imbalance correlates with neurobiological alterations some of which are amplified during forced abstinence, thereby compromising the capacity of extinction-based approaches to prevent relapse. Cocaine use disorder (CUD) exemplifies this phenomenon in which neurobiological modifications hijack brain reward regions such as the nucleus accumbens (NAc) to manifest craving and withdrawal-like symptoms. While increasing evidence links transcriptional changes in the NAc to specific phases of addiction, genome-wide changes in gene expression during withdrawal vs. extinction (WD/Ext) have not been examined in a context- and NAc-subregion-specific manner. Here, we used cocaine self-administration (SA) in rats combined with RNA-sequencing (RNA-seq) of NAc subregions (core and shell) to transcriptionally profile the impact of experiencing withdrawal in the home cage or in the previous drug context or experiencing extinction training. As expected, home-cage withdrawal maintained drug seeking in the previous drug context, whereas extinction training reduced it. By contrast, withdrawal involving repetitive exposure to the previous drug context increased drug-seeking behavior. Bioinformatic analyses of RNA-seq data revealed gene expression patterns, networks, motifs, and biological functions specific to these behavioral conditions and NAc subregions. Comparing transcriptomic analysis of the NAc of patients with CUD highlighted conserved gene signatures, especially with rats that were repetitively exposed to the previous drug context. Collectively, these behavioral and transcriptional correlates of several withdrawal-extinction settings reveal fundamental and translational information about potential molecular mechanisms to attenuate drug-associated memories.
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- 2024
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7. Circulating myeloid-derived MMP8 in stress susceptibility and depression.
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Cathomas F, Lin HY, Chan KL, Li L, Parise LF, Alvarez J, Durand-de Cuttoli R, Aubry AV, Muhareb S, Desland F, Shimo Y, Ramakrishnan A, Estill M, Ferrer-Pérez C, Parise EM, Wilk CM, Kaster MP, Wang J, Sowa A, Janssen WG, Costi S, Rahman A, Fernandez N, Campbell M, Swirski FK, Nestler EJ, Shen L, Merad M, Murrough JW, and Russo SJ
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- Animals, Humans, Mice, Extracellular Space metabolism, Mice, Inbred C57BL, Nucleus Accumbens metabolism, Nucleus Accumbens pathology, Parenchymal Tissue metabolism, Single-Cell Gene Expression Analysis, Social Behavior, Social Isolation, Depressive Disorder, Major blood, Depressive Disorder, Major enzymology, Depressive Disorder, Major genetics, Depressive Disorder, Major metabolism, Matrix Metalloproteinase 8 blood, Matrix Metalloproteinase 8 deficiency, Matrix Metalloproteinase 8 genetics, Matrix Metalloproteinase 8 metabolism, Monocytes chemistry, Monocytes immunology, Monocytes metabolism, Stress, Psychological blood, Stress, Psychological genetics, Stress, Psychological immunology, Stress, Psychological metabolism
- Abstract
Psychosocial stress has profound effects on the body, including the immune system and the brain
1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders., (© 2024. The Author(s).)- Published
- 2024
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8. The role of the Toll like receptor 4 signaling in sex-specific persistency of depression-like behavior in response to chronic stress.
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Yang EJ, Frolinger T, Iqbal U, Estill M, Shen L, Trageser KJ, and Pasinetti GM
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- Animals, Female, Male, Mice, Microglia metabolism, Signal Transduction, Stress, Psychological metabolism, Depression, Depressive Disorder, Major metabolism, Toll-Like Receptor 4 metabolism
- Abstract
Chronic stress is a major risk factor for Major Depressive Disorder (MDD), and it has been shown to impact the immune system and cause microglia activation in the medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. The aim of this study is to further investigate cellular and molecular mechanisms underlying persistent depression behavior in sex specific manner, which is observed clinically. Here, we report that both male and female mice exhibited depression-like behavior following exposure to chronic stress. However, only female mice showed persistent depression-like behavior, which was associated with microglia activation in mPFC, characterized by distinctive alterations in the phenotype of microglia. Given these findings, to further investigate the underlying molecular mechanisms associated with persistent depression-like behavior and microglia activation in female mice, we used translating-ribosome affinity purification (TRAP). We find that Toll like receptor 4 (TLR4) signaling is casually related to persistent depression-like behavior in female mice. This is supported by the evidence that the fact that genetic ablation of TLR4 expression in microglia significantly reduced the persistent depression-like behavior to baseline levels in female mice. This study tentatively supports the hypothesis that the TLR4 signaling in microglia may be responsible for the sex differences in persistent depression-like behavior in female., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
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- 2024
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9. Aryl hydrocarbon receptor restricts axon regeneration of DRG neurons in response to injury.
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Wang Y, Halawani D, Estill M, Ramakrishnan A, Shen L, Friedel RH, and Zou H
- Abstract
Injured neurons sense environmental cues to balance neural protection and axon regeneration, but the mechanisms are unclear. Here, we unveil aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, as molecular sensor and key regulator of acute stress response at the expense of axon regeneration. We demonstrate responsiveness of DRG sensory neurons to ligand-mediated AhR signaling, which functions to inhibit axon regeneration. Ahr deletion mimics the conditioning lesion in priming DRG to initiate axonogenesis gene programs; upon peripheral axotomy, Ahr ablation suppresses inflammation and stress signaling while augmenting pro-growth pathways. Moreover, comparative transcriptomics revealed signaling interactions between AhR and HIF-1α, two structurally related bHLH-PAS α units that share the dimerization partner Arnt/HIF-1β. Functional assays showed that the growth advantage of AhR-deficient DRG neurons requires HIF-1α; but in the absence of Arnt, DRG neurons can still mount a regenerative response. We further unveil a link between bHLH-PAS transcription factors and DNA hydroxymethylation in response to peripheral axotomy, while neuronal single cell RNA-seq analysis revealed a link of the AhR regulon to RNA polymerase III regulation and integrated stress response (ISR). Altogether, AhR activation favors stress coping and inflammation at the expense of axon regeneration; targeting AhR can enhance nerve repair., Competing Interests: Competing Interests Statement: All authors declare no competing interests.
- Published
- 2023
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10. Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain.
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Serafini RA, Estill M, Pekarskaya EA, Sakloth F, Shen L, Javitch JA, and Zachariou V
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- Humans, Mice, Animals, Antidepressive Agents therapeutic use, Hyperalgesia drug therapy, Antidepressive Agents, Tricyclic pharmacology, Antidepressive Agents, Tricyclic therapeutic use, Disease Models, Animal, Neuralgia drug therapy
- Abstract
Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
- Published
- 2023
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11. Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine.
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Browne CJ, Mews P, Zhou X, Holt LM, Estill M, Futamura R, Schaefer A, Kenny PJ, Hurd YL, Shen L, Zhang B, and Nestler EJ
- Abstract
Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs. To better understand common and divergent molecular mechanisms governing SUD pathology, our goal was to survey cell-type-specific restructuring of the NAc transcriptional landscape in after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across drug classes during exposure, whereas D2 MSNs manifest mostly divergent responses between cocaine and morphine, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions shared between cocaine and morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. These studies establish a landmark, cell-type-specific atlas of transcriptional regulation induced by cocaine and by morphine that can serve as a foundation for future studies towards mechanistic understanding of SUDs. Our findings, and future work leveraging this dataset, will pave the way for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for cocaine use disorder and enhancing the existing strategies for opioid use disorder., Competing Interests: Competing Interests The authors declare no competing financial interests.
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- 2023
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12. Cell Type-Specific Whole-Genome Landscape of ΔFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure.
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Yeh SY, Estill M, Lardner CK, Browne CJ, Minier-Toribio A, Futamura R, Beach K, McManus CA, Xu SJ, Zhang S, Heller EA, Shen L, and Nestler EJ
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- Mice, Male, Female, Animals, Mice, Transgenic, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-fos metabolism, Nucleus Accumbens metabolism, Mice, Inbred C57BL, Cocaine pharmacology, Cocaine metabolism, Cocaine-Related Disorders
- Abstract
Background: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated., Methods: We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons-D1 or D2 medium spiny neurons-after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses., Results: The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors., Conclusions: These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons.
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Halawani D, Wang Y, Ramakrishnan A, Estill M, He X, Shen L, Friedel RH, and Zou H
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- Animals, Mice, Axons, Circadian Clocks genetics, Dioxygenases, Epigenesis, Genetic, Nerve Regeneration genetics, Sensory Receptor Cells
- Abstract
Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration., (© 2023. Springer Nature Limited.)
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- 2023
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14. R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription.
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LaMarca EA, Saito A, Plaza-Jennings A, Espeso-Gil S, Hellmich A, Fernando MB, Javidfar B, Liao W, Estill M, Townsley K, Florio A, Ethridge JE, Do C, Tycko B, Shen L, Kamiya A, Tsankova NM, Brennand KJ, and Akbarian S
- Abstract
Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro . Therefore, R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells., Competing Interests: DECLARATION OF INTERESTS The authors declare no conflicts of interest.
- Published
- 2023
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15. Recapitulation of pathophysiological features of AD in SARS-CoV-2-infected subjects.
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Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, and Pasinetti GM
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- Humans, SARS-CoV-2, Blood-Brain Barrier, Cognition, Disease Progression, COVID-19, Alzheimer Disease
- Abstract
Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition in some patients with post-acute sequelae of SARS-CoV-2 (PASC). To evaluate neuropathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Brodmann area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer's disease (AD), and SARS-CoV-2-infected AD individuals compared to age- and gender-matched neurological cases. Here, we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2-infected AD individuals. Distribution of microglial changes reflected by the increase in Iba-1 reveals nodular morphological alterations in SARS-CoV-2-infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help in informing decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD., Competing Interests: EG, KT, SN, EY, BM, GV, LH, ME, LS, TF, GP No competing interests declared, NJ receives grant funding paid to her institution from NINDS (NIH U24NS107201, NIH IU54NS100064, 3R01CA202911-05S1, R21NS122389, R01HL161847). Some of these grants are COVID-19 related but focus on the neuroimaging findings
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- 2023
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16. Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.
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Trageser KJ, Yang EJ, Smith C, Iban-Arias R, Oguchi T, Sebastian-Valverde M, Iqbal UH, Wu H, Estill M, Al Rahim M, Raval U, Herman FJ, Zhang YJ, Petrucelli L, and Pasinetti GM
- Subjects
- Animals, Mice, Microglia metabolism, Inflammasomes, C9orf72 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Neuroinflammatory Diseases, DNA Repeat Expansion genetics, Dipeptides, Amyotrophic Lateral Sclerosis metabolism, Frontotemporal Dementia genetics, Frontotemporal Dementia pathology
- Abstract
Intronic G
4 C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4 C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1β, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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17. Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice.
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Dunn AD, Robinson SA, Nwokafor C, Estill M, Ferrante J, Shen L, Lemchi CO, Creus-Muncunill J, Ramirez A, Mengaziol J, Brynildsen JK, Leggas M, Horn J, Ehrlich ME, and Blendy JA
- Abstract
Introduction: Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of somatic withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The heterogeneity of in utero opioid exposure, particularly exposure to polypharmacy, makes it difficult to investigate the underlying molecular mechanisms that could inform early diagnosis and treatment of NOWS, and challenging to investigate consequences later in life., Methods: To address these issues, we developed a mouse model of NOWS that includes gestational and post-natal morphine exposure that encompasses the developmental equivalent of all three human trimesters and assessed both behavior and transcriptome alterations., Results: Opioid exposure throughout all three human equivalent trimesters delayed developmental milestones and produced acute withdrawal phenotypes in mice reminiscent of those observed in infants. We also uncovered different patterns of gene expression depending on the duration and timing of opioid exposure (3-trimesters, in utero only, or the last trimester equivalent only). Opioid exposure and subsequent withdrawal affected social behavior and sleep in adulthood in a sex-dependent manner but did not affect adult behaviors related to anxiety, depression, or opioid response., Discussion: Despite marked withdrawal and delays in development, long-term deficits in behaviors typically associated with substance use disorders were modest. Remarkably, transcriptomic analysis revealed an enrichment for genes with altered expression in published datasets for Autism Spectrum Disorders, which correlate well with the deficits in social affiliation seen in our model. The number of differentially expressed genes between the NOWS and saline groups varied markedly based on exposure protocol and sex, but common pathways included synapse development, the GABAergic and myelin systems, and mitochondrial function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dunn, Robinson, Nwokafor, Estill, Ferrante, Shen, Lemchi, Creus-Muncunill, Ramirez, Mengaziol, Brynildsen, Leggas, Horn, Ehrlich and Blendy.)
- Published
- 2023
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18. Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice.
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Browne CJ, Futamura R, Minier-Toribio A, Hicks EM, Ramakrishnan A, Martínez-Rivera FJ, Estill M, Godino A, Parise EM, Torres-Berrío A, Cunningham AM, Hamilton PJ, Walker DM, Huckins LM, Hurd YL, Shen L, and Nestler EJ
- Subjects
- Humans, Mice, Male, Animals, Genome-Wide Association Study, Brain, Reward, Recurrence, Heroin adverse effects, Opioid-Related Disorders
- Abstract
Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.
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- 2023
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19. Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress.
- Author
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Torres-Berrío A, Estill M, Ramakrishnan A, Kronman H, Patel V, Minier-Toribio A, Issler O, Browne CJ, Parise EM, van der Zee Y, Walker D, Martínez-Rivera FJ, Lardner CK, Cuttoli RD, Russo SJ, Shen L, Sidoli S, and Nestler EJ
- Abstract
Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region. Stress induction of H3K27me1 was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which is induced by chronic stress and controls H3K27 methylation patterns. Overexpression of the VEFS domain led to social, emotional, and cognitive abnormalities, and altered excitability of NAc D1 mediums spiny neurons. Together, we describe a novel function of H3K27me1 in brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.
- Published
- 2023
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20. Transcriptome profiles associated with resilience and susceptibility to single prolonged stress in the locus coeruleus and nucleus accumbens in male sprague-dawley rats.
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Nahvi RJ, Tanelian A, Nwokafor C, Godino A, Parise E, Estill M, Shen L, Nestler EJ, and Sabban EL
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- Rats, Animals, Male, Rats, Sprague-Dawley, Transcriptome, Locus Coeruleus metabolism, Anxiety, Stress, Psychological, Nucleus Accumbens metabolism, Stress Disorders, Post-Traumatic metabolism
- Abstract
Although most people are subjected to traumatic stress at least once in their lifetime, only a subset develop long-lasting, stress-triggered neuropsychiatric disorders, such as PTSD. Here we examined different transcriptome profiles within the locus coeruleus (LC) and nucleus accumbens (NAc) that may contribute to stress susceptibility. Sprague Dawley male rats were exposed to the single prolonged stress (SPS) model for PTSD. Two weeks later they were tested for their anxiety/avoidance behavior on the Elevated Plus Maze (EPM) and were divided into high and low anxiety-like subgroups. RNA (n = 5 per group) was subsequently isolated from LC and NAc and subjected to RNAseq. Transcriptome analysis was used to identify differentially-expressed genes (DEGs) which differed by at least 50 % with significance of 0.01. The LC had more than six times the number of DEGs than the NAc. Only one DEG was regulated similarly in both locations. Many of the DEGs in the LC were associated with morphological changes, including regulation of actin cytoskeleton, growth factor activity, regulation of cell size, brain development and memory, with KEGG pathway of regulation of actin cytoskeleton. The DEGs in the NAc were primarily related to DNA repair and synthesis, and differential regulation of cytokine production. The analysis identified MTPN (myotrophin) and NR3C1 (glucocorticoid receptor) as important upstream regulators of stress susceptibility in the LC. Overall the study provides new insight into molecular pathways in the LC and NAc that are associated with anxiety-like behavior triggered by stress susceptibility or resilience., Competing Interests: Conflict of interest The authors have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2023
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21. Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.
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Cathomas F, Lin HY, Chan KL, Li L, Durand-de Cuttoli R, Parise LF, Aubry AV, Muhareb S, Desland F, Shimo Y, Ramakrishnan A, Estill M, Ferrer-Pérez C, Parise EM, Wang J, Sowa A, Janssen WG, Costi S, Rahman A, Fernandez N, Swirski FK, Nestler EJ, Shen L, Merad M, Murrough JW, and Russo SJ
- Abstract
Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain
1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5 , the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.- Published
- 2023
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22. Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit.
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Browne CJ, Futamura R, Minier-Toribio A, Hicks EM, Ramakrishnan A, Martínez-Rivera F, Estill M, Godino A, Parise EM, Torres-Berrío A, Cunningham AM, Hamilton PJ, Walker DM, Huckins LM, Hurd YL, Shen L, and Nestler EJ
- Abstract
Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., "relapse"). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an "addiction index" uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.
- Published
- 2023
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23. Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer's disease individuals.
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Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, and Pasinetti GM
- Abstract
Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer's disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD., Teaser: SARS-CoV-2 and Alzheimer's disease share similar neuroinflammatory processes, which may help explain neuro-PASC.
- Published
- 2022
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24. Macrophages facilitate peripheral nerve regeneration by organizing regeneration tracks through Plexin-B2.
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Li Y, Kang S, Halawani D, Wang Y, Junqueira Alves C, Ramakrishnan A, Estill M, Shen L, Li F, He X, Friedel RH, and Zou H
- Subjects
- Axons physiology, Cell Adhesion Molecules, Macrophages metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Schwann Cells metabolism, Nerve Regeneration genetics, Peripheral Nerves metabolism
- Abstract
The regeneration of peripheral nerves is guided by regeneration tracks formed through an interplay of many cell types, but the underlying signaling pathways remain unclear. Here, we demonstrate that macrophages are mobilized ahead of Schwann cells in the nerve bridge after transection injury to participate in building regeneration tracks. This requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophages in injured nerves. Conditional deletion of Plexin-B2 in myeloid lineage resulted in not only macrophage misalignment but also matrix disarray and Schwann cell disorganization, leading to misguided axons and delayed functional recovery. Plexin-B2 is not required for macrophage recruitment or activation but enables macrophages to steer clear of colliding axons, in particular the growth cones at the tip of regenerating axons, leading to parallel alignment postcollision. Together, our studies unveil a novel reparative function of macrophages and the importance of Plexin-B2-mediated collision-dependent contact avoidance between macrophages and regenerating axons in forming regeneration tracks during peripheral nerve regeneration., (© 2022 Li et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2022
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25. Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions.
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Chandrasekaran S, Espeso-Gil S, Loh YE, Javidfar B, Kassim B, Zhu Y, Zhang Y, Dong Y, Bicks LK, Li H, Rajarajan P, Peter CJ, Sun D, Agullo-Pascual E, Iskhakova M, Estill M, Lesch BJ, Shen L, Jiang Y, and Akbarian S
- Subjects
- Animals, Cerebral Cortex cytology, Cerebral Cortex metabolism, Chromosomes genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endogenous Retroviruses genetics, Evolution, Molecular, Gene Amplification, Gene Silencing, Genes, Intracisternal A-Particle genetics, Genome, Viral genetics, Gliosis genetics, Gliosis metabolism, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Mice, Microglia metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurons virology, Proviruses genetics, Virion genetics, Virion metabolism, Chromosomes metabolism, Neurons metabolism, Retroelements genetics
- Abstract
Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B
2 NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2 NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2 NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism., (© 2021. The Author(s).)- Published
- 2021
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26. Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.
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Westfall S, Caracci F, Estill M, Frolinger T, Shen L, and Pasinetti GM
- Subjects
- Animals, Anxiety etiology, Anxiety immunology, Depression etiology, Depression immunology, Male, Mice, Inbred C57BL, Stress, Psychological complications, Mice, Gastrointestinal Microbiome physiology, Neuroimmunomodulation immunology, Stress, Psychological immunology, Synbiotics
- Abstract
Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Westfall, Caracci, Estill, Frolinger, Shen and Pasinetti.)
- Published
- 2021
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27. Long read, isoform aware sequencing of mouse nucleus accumbens after chronic cocaine treatment.
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Estill M, Ribeiro E, Francoeur NJ, Smith ML, Sebra R, Yeh SY, Cunningham AM, Nestler EJ, and Shen L
- Subjects
- Animals, Cocaine pharmacology, Computational Biology methods, Mice, Molecular Sequence Annotation, Sequence Analysis, DNA, Cocaine adverse effects, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Transcriptome
- Abstract
To better understand the full-length transcriptome of the nucleus accumbens (NAc)-a key brain reward region-in chronic cocaine treatment, we perform the first single molecule, long-read sequencing analysis using the Iso-seq method to detect 42,114 unique transcripts from mouse NAc polyadenylated RNA. Using GENCODE annotation as a reference, we find that over half of the Iso-seq derived transcripts are annotated, while 46% of them harbor novel splicing events in known genes; around 1% of them correspond to other types of novel transcripts, such as fusion, antisense and intergenic. Approximately 34% of the novel transcripts are matched with a compiled transcriptome assembled from published short-read data from various tissues, with the remaining 69% being unique to NAc. These data provide a more complete picture of the NAc transcriptome than existing annotations and can serve as a comprehensive reference for future transcriptomic analyses of this important brain reward region.
- Published
- 2021
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28. Optimization of probiotic therapeutics using machine learning in an artificial human gastrointestinal tract.
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Westfall S, Carracci F, Estill M, Zhao D, Wu QL, Shen L, Simon J, and Pasinetti GM
- Subjects
- Algorithms, Gastrointestinal Microbiome, Gastrointestinal Tract metabolism, Gastrointestinal Tract microbiology, Humans, Gastrointestinal Tract physiology, Machine Learning, Probiotics therapeutic use
- Abstract
The gut microbiota's metabolome is composed of bioactive metabolites that confer disease resilience. Probiotics' therapeutic potential hinges on their metabolome altering ability; however, characterizing probiotics' metabolic activity remains a formidable task. In order to solve this problem, an artificial model of the human gastrointestinal tract is introduced coined the ABIOME (A Bioreactor Imitation of the Microbiota Environment) and used to predict probiotic formulations' metabolic activity and hence therapeutic potential with machine learning tools. The ABIOME is a modular yet dynamic system with real-time monitoring of gastrointestinal conditions that support complex cultures representative of the human microbiota and its metabolome. The fecal-inoculated ABIOME was supplemented with a polyphenol-rich prebiotic and combinations of novel probiotics that altered the output of bioactive metabolites previously shown to invoke anti-inflammatory effects. To dissect the synergistic interactions between exogenous probiotics and the autochthonous microbiota a multivariate adaptive regression splines (MARS) model was implemented towards the development of optimized probiotic combinations with therapeutic benefits. Using this algorithm, several probiotic combinations were identified that stimulated synergistic production of bioavailable metabolites, each with a different therapeutic capacity. Based on these results, the ABIOME in combination with the MARS algorithm could be used to create probiotic formulations with specific therapeutic applications based on their signature metabolic activity.
- Published
- 2021
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29. Caregiver Needs Assessment in Primary Care: Views of Clinicians, Staff, Patients, and Caregivers.
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Riffin C, Wolff JL, Estill M, Prabhu S, and Pillemer KA
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Interviews as Topic, Male, Qualitative Research, Caregivers psychology, Health Personnel psychology, Health Personnel statistics & numerical data, Needs Assessment, Primary Health Care
- Abstract
Objectives: To understand current practices, challenges, and opportunities for a systematic assessment of family caregivers' needs and risks in primary care., Design: Qualitative study consisting of in-depth semi-structured interviews., Setting: Four primary care practices located in urban and rural settings., Participants: Primary care clinicians, staff, and administrators (N = 30), as well as older adult patients and family caregivers (N = 40), recruited using purposive and maximum variation sampling., Measurements: Current experiences, challenges, and opportunities for integrating standardized caregiver assessment into primary care delivery. Interviews were audio-recorded and transcribed; transcripts were analyzed using the constant comparative method of data analysis., Results: Participating clinicians had been in practice for an average of 12.8 years (range = 1-36 y). Patients had a mean age of 84.0 years (standard deviation [SD] = 9.7); caregivers had a mean age of 67.0 years (SD = 9.3). There was wide variability in current practices for identifying caregivers' needs and risks, encompassing direct and indirect approaches, when such issues are considered. Participants posited that integrating standardized caregiver assessment into primary care delivery could help improve patient care, enhance clinician-caregiver communication, and validate caregivers' efforts. Barriers to assessment included insufficient time and reimbursement, liability concerns, lack of awareness of community resources, and concerns about patient autonomy. To facilitate future uptake of caregiver assessment, participants recommended brief self-administered assessment tools and post-screen discussions with practice staff., Conclusion: Identification of caregivers' needs and risks in primary care is highly variable. Integration of standardized caregiver assessment into practice requires coordinated changes to policy, revision of practice workflows, and an interdisciplinary approach to the development of appropriate assessment tools. J Am Geriatr Soc 68:1262-1270, 2020., (© 2020 The American Geriatrics Society.)
- Published
- 2020
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30. Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity.
- Author
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Swanson GM, Estill M, Diamond MP, Legro RS, Coutifaris C, Barnhart KT, Huang H, Hansen KR, Trussell JC, Coward RM, Zhang H, Goodrich R, and Krawetz SA
- Subjects
- Adult, Body Mass Index, Chromatin Assembly and Disassembly, DNA Methylation, Gene Regulatory Networks, Humans, Male, Obesity metabolism, RNA Processing, Post-Transcriptional, Obesity genetics, Spermatozoa metabolism, Transcriptome
- Abstract
In the United States almost 33% of adults are considered obese (BMI > 30 kg/m
2 ). Both animal models and to a lesser extent human studies, have associated BMI, a measure of obesity, with alterations in sperm DNA methylation and RNAs. Sperm RNAs from the Assessment of Multiple Gestations from Ovarian Stimulation trial, were isolated and sequenced. A Generalized Linear Model identified 487 BMI associated human sperm RNA elements (short exon-sized sequences). They partitioned into four patterns; a continual increase with BMI, increase once obese (BMI>30 kg/m2 ); a steady decrease with BMI; and decrease once overweight (BMI 25 - 30 kg/m2 ). Gene Ontology revealed a unique relationship between BMI and transcripts associated with chromosome organization, adipogenesis, cellular stress and obesity-related inflammation. Coregulatory networks linked by Chromatin remodeler cofactors, RNA interactors, Erasers and Writers (CREWs) were uncovered to reveal a hierarchical epigenetic response pathway.- Published
- 2020
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31. The effects of di-butyl phthalate exposure from medications on human sperm RNA among men.
- Author
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Estill M, Hauser R, Nassan FL, Moss A, and Krawetz SA
- Subjects
- DNA Damage drug effects, Humans, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases pathology, Male, Mesalamine chemistry, Mesalamine therapeutic use, Oxidative Stress drug effects, RNA, Long Noncoding metabolism, RNA, Small Nuclear metabolism, Spermatogenesis drug effects, Spermatozoa metabolism, Dibutyl Phthalate toxicity, Endocrine Disruptors toxicity, RNA metabolism, Spermatozoa drug effects
- Abstract
Endocrine disruptors, such as phthalates, are suspected of affecting reproductive function. The Mesalamine and Reproductive Health Study (MARS) was designed to address the physiological effect of in vivo phthalate exposure on male reproduction in patients with Inflammatory Bowel Disease (IBD). As part of this effort, the effect on sperm RNAs to DBP exposure were longitudinally assessed using a cross-over cross-back binary design of high or background, exposures to DBP. As the DBP level was altered, numerous sperm RNA elements (REs) were differentially expressed, suggesting that exposure to or removal from high DBP produces effects that require longer than one spermatogenic cycle to resolve. In comparison, small RNAs were minimally affected by DBP exposure. While initial study medication (high or background) implicates different biological pathways, initiation on the high-DBP condition activated oxidative stress and DNA damage pathways. The negative correlation of REs with specific genomic repeats suggests a regulatory role. Using ejaculated sperm, this work provides insight into the male germline's response to phthalate exposure.
- Published
- 2019
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32. A RNA-Seq Analysis to Describe the Boar Sperm Transcriptome and Its Seasonal Changes.
- Author
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Gòdia M, Estill M, Castelló A, Balasch S, Rodríguez-Gil JE, Krawetz SA, Sánchez A, and Clop A
- Abstract
Understanding the molecular basis of cell function and ultimate phenotypes is crucial for the development of biological markers. With this aim, several RNA-seq studies have been devoted to the characterization of the transcriptome of ejaculated spermatozoa in relation to sperm quality and fertility. Semen quality follows a seasonal pattern and decays in the summer months in several animal species. The aim of this study was to deeply profile the transcriptome of the boar sperm and to evaluate its seasonal changes. We sequenced the total and the short fractions of the sperm RNA from 10 Pietrain boars, 5 collected in summer and 5 five sampled in winter, and identified a complex and rich transcriptome with 4,436 coding genes of moderate to high abundance. Transcript fragmentation was high but less obvious in genes related to spermatogenesis, chromatin compaction and fertility. Short non-coding RNAs mostly included piwi-interacting RNAs, transfer RNAs and microRNAs. We also compared the transcriptome of the summer and the winter ejaculates and identified 34 coding genes and 7 microRNAs with a significantly distinct distribution. These genes were mostly related to oxidative stress, DNA damage and autophagy. This is the deepest characterization of the boar sperm transcriptome and the first study linking the transcriptome and the seasonal variability of semen quality in animals. The annotation described here can be used as a reference for the identification of markers of sperm quality in pigs.
- Published
- 2019
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33. Dibutyl-phthalate exposure from mesalamine medications and serum thyroid hormones in men.
- Author
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Nassan FL, Korevaar TIM, Coull BA, Skakkebæk NE, Krawetz SA, Estill M, Hait EJ, Korzenik JR, Ford JB, De Poortere RA, Broeren MA, Moss AC, Zoeller TR, and Hauser R
- Subjects
- Adult, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Humans, Inflammatory Bowel Diseases drug therapy, Male, Mesalamine administration & dosage, Middle Aged, Prospective Studies, Young Adult, Dibutyl Phthalate adverse effects, Thyroid Hormones blood
- Abstract
Background: Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as mesalamine for treatment inflammatory bowel disease (IBD)., Objectives: To determine whether high-DBP from some mesalamine medications alters thyroid function., Methods: Seventy men with IBD, without thyroid disease or any radiation history participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background exposure) at baseline crossed-over to DBP-mesalamine (high exposure) then crossed-back to non-DBP mesalamine (B
1 HB2 -arm) and vice versa for men on DBP-mesalamine at baseline (H1 BH2 -arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb)., Results: After crossover in B1 HB2 -arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (-20%, -2%) and 15% (-23%, -5%), respectively; after crossback, they increased. When men in the H1 BH2 -arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: -11%, -2%) and T3/T4 ratio decreased 6% (CI: -9%, -2%). After crossback, only TgAb increased and FT4 decreased., Conclusions: High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed., (Copyright © 2018 Elsevier GmbH. All rights reserved.)- Published
- 2019
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34. Sperm RNA elements as markers of health.
- Author
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Burl RB, Clough S, Sendler E, Estill M, and Krawetz SA
- Subjects
- Databases, Genetic, Female, Gene Expression Profiling methods, Gene Regulatory Networks, Genetic Markers, Humans, Infertility diagnosis, Infertility physiopathology, Live Birth, Male, Pregnancy, Systems Biology, Fertility genetics, Infertility genetics, RNA, Messenger genetics, Reproductive Health, Spermatozoa chemistry, Transcriptome
- Abstract
Idiopathic infertility, an etiology not identified as part of standard clinical assessment, represents approximately 20% of all infertility cases. Current male infertility diagnosis focuses on the concentration, motility, and morphology of spermatozoa. This is of limited value when predicting birth success and of limited utility when selecting the optimum treatment. At fertilization, spermatozoa provide their genomic contribution, as well as a set of RNAs and proteins that have distinct roles in development. The potential of spermatozoal RNAs to be used as a prognostic of live birth has been shown [Jodar et al. (2015) Science Translational Medicine 7(295):295re6]. This relied on a set of 648 sperm RNA elements derived from 285 genes that are perhaps indicative of future health status. To address this tenet, the present study correlated the levels of each transcript among all samples to assess linkage between transcript absence, birth success, and possible disease association. Correlations between transcript levels of the 285 genes were analyzed amongst themselves, and within the context of the entire transcript population for these samples. The transcripts ACE, GIGYF2, and ODF2 had many negative correlations and form the majority of correlations, suggesting an important function for these transcripts. Eleven of the 285 queried genes had disease-associated variants within a sperm RNA element. Three genes, GPX4, NDRG1, and RPS24 had SREs were absent in at least one individual from the test cohort. GPX4 and RPS24 are associated with developmental defects and/or neonatal lethality. This leaves the intriguing possibility that, while sperm RNAs delivered to the oocyte inform the success of live birth, they may also be predictors of human health., Abbreviations: GO: Gene Ontology; ART: assisted reproductive technology; IVF: in vitro fertilization; ICSI: intra-cytoplasmic sperm injection; RNA-seq: RNA-sequencing; TIC: timed intercourse; IUI: intrauterine insemination; SRE: sperm RNA elements; HPA: Human Protein Atlas; SMDS: sedaghatian-type spondylometaphyseal dysplasia; DBA: Diamond-Blackfan anemia; RPKM: reads per kilobase per million; TPM: transcripts per million; IPA: Ingenuity Pathway Analysis; OMIM: Online Mendelian Inheritance in Man.
- Published
- 2018
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35. Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions.
- Author
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Southwood CM, Fykkolodziej B, Maheras KJ, Garshott DM, Estill M, Fribley AM, and Gow A
- Subjects
- 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase genetics, 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase metabolism, Animals, Animals, Newborn, Apoptosis physiology, Cell Line, Tumor, Evoked Potentials, Auditory, Brain Stem genetics, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity genetics, Nerve Fibers, Myelinated pathology, Nerve Fibers, Myelinated ultrastructure, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Optic Nerve pathology, Psychomotor Performance physiology, Signal Transduction genetics, Spinal Cord pathology, Transcription Factor CHOP genetics, Nerve Fibers, Myelinated metabolism, Phenotype, Stress, Physiological physiology, Transcription Factor CHOP metabolism
- Abstract
Unlabelled: The PKR-like endoplasmic reticulum kinase (PERK) pathway of the unfolded protein response (UPR) is protective against toxic accumulations of misfolded proteins in the endoplasmic reticulum, but is thought to drive cell death via the transcription factor, CHOP. However, in many cell types, CHOP is an obligate step in the PERK pathway, which frames the conundrum of a prosurvival pathway that kills cells. Our laboratory and others have previously demonstrated the prosurvival activity of the PERK pathway in oligodendrocytes. In the current study, we constitutively overexpress CHOP in myelinating cells during development and into adulthood under normal or UPR conditions. We show that this transcription factor does not drive apoptosis. Indeed, we observe no detriment in mice at multiple levels from single cells to mouse behavior and life span. In light of these data and other studies, we reinterpret PERK pathway function in the context of a stochastic vulnerability model, which governs the likelihood that cells undergo cell death upon cessation of UPR protection and while attempting to restore homeostasis., Significance Statement: Herein, we tackle the biggest controversy in the UPR literature: the function of the transcription factor CHOP as a protective or a prodeath factor. This manuscript is timely in light of the 2014 Lasker award for the UPR. Our in vivo data show that CHOP is not a prodeath protein, and we demonstrate that myelinating glial cells function normally in the presence of high CHOP expression from development to adulthood. Further, we propose a simplified view of UPR-mediated cell death after CHOP induction. We anticipate our work may turn the tide of the dogmatic view of CHOP and cause a reinvestigation of its function in different cell types. Accordingly, we believe our work will be a watershed for the UPR field., (Copyright © 2016 the authors 0270-6474/16/366803-17$15.00/0.)
- Published
- 2016
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36. Dissection of the PHO pathway in Schizosaccharomyces pombe using epistasis and the alternate repressor adenine.
- Author
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Estill M, Kerwin-Iosue CL, and Wykoff DD
- Subjects
- Adenine metabolism, Gene Expression Regulation, Fungal, Protein Kinases metabolism, Schizosaccharomyces, Schizosaccharomyces pombe Proteins metabolism, Sequence Deletion, Signal Transduction genetics, Acid Phosphatase genetics, Epistasis, Genetic, Phosphates metabolism, Protein Kinases genetics, Schizosaccharomyces pombe Proteins genetics, Transcription Factors genetics
- Abstract
In Saccharomyces cerevisiae, intracellular phosphate levels are maintained by the PHO pathway, activation of which is assayed by increased phosphatase activity. The PHO pathway of Schizosaccharomyces pombe upregulates phosphatase activity (encoded by pho1 (+)) during low extracellular phosphate levels, but the underlying mechanism is poorly understood. We utilized an alternate repressor of pho1 (+) expression (adenine supplementation) along with epistasis analysis to develop a model of how S. pombe PHO pathway components interact. Analyzing Pho1 activity in S. pombe PHO pathway deletion mutants during adenine starvation, we observed most mutants with a phosphatase defect in phosphate starvation also had a defect in adenine starvation. Pho7, a transcription factor in the PHO pathway, is necessary for an adenine starvation-mediated increase in Pho1 activity. Comparing adenine starvation to phosphate starvation, there are differences in the degree to which individual mutants regulate the two responses. Through epistasis studies, we identified two positive regulatory arms and one repressive arm of the PHO pathway. PKA activation is a positive regulator of Pho1 activity under both environmental conditions and is critical for transducing adenine concentrations in the cell. The synthesis of IP7 also appears critical for the induction of Pho1 activity during adenine starvation, but IP7 is not critical during phosphate starvation, which differs from S. cerevisiae. Finally, Csk1 is critical for repression of pho1 (+) expression during phosphate starvation. We believe all of these regulatory arms converge to increase transcription of pho1 (+) and some of the regulation acts through pho7 (+).
- Published
- 2015
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37. Epidural and intrathecal analgesia in a rural setting.
- Author
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Anderson-Estill M and Neary J
- Subjects
- Clinical Protocols, Humans, Nursing Records, Nursing Staff, Hospital education, Patient Care Planning, Analgesia, Epidural nursing, Nurse Anesthetists education, Rural Health
- Abstract
Epidural anesthesia--alone or in combination with general anesthetic agents--is beneficial to physiological and cardiovascular stability during surgery. The placement of an epidural catheter at the time of surgery also provides access for the administration of epidural narcotics for postoperative analgesia. This article describes how a rural acute care facility initiated a program of epidural analgesia administered by the nursing staff under the direction of the anesthesia department utilizing AANA protocol.* In such a setting, an educated nursing staff can serve as an extension of the anesthetist in overseeing patient response to epidural and intrathecal narcotics.
- Published
- 1993
38. Ileocecal tuberculosis in an Asian male immigrant: case report and literature review.
- Author
-
Estill MR
- Subjects
- Adult, Humans, Male, Cecal Diseases diagnosis, Ileal Diseases diagnosis, Tuberculosis, Gastrointestinal diagnosis
- Published
- 1992
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