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  1. Article ; Online: AAV Deployment of Enhancer-Based Expression Constructs In Vivo in Mouse Brain.

    Warren, Tracy L / Lambert, Jason T / Nord, Alex S

    Journal of visualized experiments : JoVE

    2022  , Issue 181

    Abstract: Enhancers are binding platforms for a diverse array of transcription factors that drive specific expression patterns of tissue- and cell-type-specific genes. Multiple means of assessing non-coding DNA and various chromatin states have proven useful in ... ...

    Abstract Enhancers are binding platforms for a diverse array of transcription factors that drive specific expression patterns of tissue- and cell-type-specific genes. Multiple means of assessing non-coding DNA and various chromatin states have proven useful in predicting the presence of enhancer sequences in the genome, but validating the activity of these sequences and finding the organs and developmental stages they are active in is a labor-intensive process. Recent advances in adeno-associated virus (AAV) vectors have enabled the widespread delivery of transgenes to mouse tissues, enabling in vivo enhancer testing without necessitating a transgenic animal. This protocol shows how a reporter construct that expresses EGFP under the control of a minimal promoter, which does not drive significant expression on its own, can be used to study the activity patterns of candidate enhancer sequences in the mouse brain. An AAV-packaged reporter construct is delivered to the mouse brain and incubated for 1-4 weeks, after which the animal is sacrificed, and brain sections are observed under a microscope. EGFP appears in cells in which the tested enhancer is sufficient to initiate gene expression, pinpointing the location and developmental stage in which the enhancer is active in the brain. Standard cloning methods, low-cost AAV packaging, and expanding AAV serotypes and methods for in vivo delivery and standard imaging readout make this an accessible approach for the study of how gene expression is regulated in the brain.
    MeSH term(s) Animals ; Brain/metabolism ; Dependovirus/genetics ; Dependovirus/metabolism ; Genetic Vectors/genetics ; Mice ; Promoter Regions, Genetic ; Transgenes
    Language English
    Publishing date 2022-03-31
    Publishing country United States
    Document type Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/62650
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

    Warren, Tracy L / Tubbs, Justin D / Lesh, Tyler A / Corona, Mylena B / Pakzad, Sarvenaz S / Albuquerque, Marina D / Singh, Praveena / Zarubin, Vanessa / Morse, Sarah J / Sham, Pak Chung / Carter, Cameron S / Nord, Alex S

    Molecular psychiatry

    2024  

    Abstract: A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients ... ...

    Abstract A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
    Language English
    Publishing date 2024-03-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-024-02457-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4812: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

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  3. Article: Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

    Warren, Tracy L / Tubbs, Justin D / Lesh, Tyler A / Corona, Mylena B / Pakzad, Sarvenaz / Albuquerque, Marina / Singh, Praveena / Zarubin, Vanessa / Morse, Sarah / Sham, Pak Chung / Carter, Cameron S / Nord, Alex S

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients ... ...

    Abstract A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 206 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
    Language English
    Publishing date 2023-11-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.24.23290465
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Parallel functional testing identifies enhancers active in early postnatal mouse brain.

    Lambert, Jason T / Su-Feher, Linda / Cichewicz, Karol / Warren, Tracy L / Zdilar, Iva / Wang, Yurong / Lim, Kenneth J / Haigh, Jessica L / Morse, Sarah J / Canales, Cesar P / Stradleigh, Tyler W / Castillo Palacios, Erika / Haghani, Viktoria / Moss, Spencer D / Parolini, Hannah / Quintero, Diana / Shrestha, Diwash / Vogt, Daniel / Byrne, Leah C /
    Nord, Alex S

    eLife

    2021  Volume 10

    Abstract: Enhancers ... ...

    Abstract Enhancers are
    MeSH term(s) Animals ; Brain/growth & development ; Brain/metabolism ; Enhancer Elements, Genetic ; High-Throughput Nucleotide Sequencing ; Mice
    Language English
    Publishing date 2021-10-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.69479
    Database MEDical Literature Analysis and Retrieval System OnLINE

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