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  1. Article ; Online: Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma.

    Resztak, Justyna A / Choe, Jane / Nirmalan, Shreya / Wei, Julong / Bruinsma, Julian / Houpt, Russell / Alazizi, Adnan / Mair-Meijers, Henriette E / Wen, Xiaoquan / Slatcher, Richard B / Zilioli, Samuele / Pique-Regi, Roger / Luca, Francesca

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 230

    Abstract: Puberty is an important developmental period marked by hormonal, metabolic and immune changes. Puberty also marks a shift in sex differences in susceptibility to asthma. Yet, little is known about the gene expression changes in immune cells that occur ... ...

    Abstract Puberty is an important developmental period marked by hormonal, metabolic and immune changes. Puberty also marks a shift in sex differences in susceptibility to asthma. Yet, little is known about the gene expression changes in immune cells that occur during pubertal development. Here we assess pubertal development and leukocyte gene expression in a longitudinal cohort of 251 children with asthma. We identify substantial gene expression changes associated with age and pubertal development. Gene expression changes between pre- and post-menarcheal females suggest a shift from predominantly innate to adaptive immunity. We show that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.
    MeSH term(s) Humans ; Male ; Child ; Female ; Puberty/genetics ; Menarche ; Asthma/genetics ; Asthma/epidemiology ; Leukocytes ; Age Factors ; Longitudinal Studies
    Language English
    Publishing date 2023-01-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-35742-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single-cell resolution.

    Resztak, Justyna A / Wei, Julong / Zilioli, Samuele / Sendler, Edward / Alazizi, Adnan / Mair-Meijers, Henriette E / Wu, Peijun / Wen, Xiaoquan / Slatcher, Richard B / Zhou, Xiang / Luca, Francesca / Pique-Regi, Roger

    Genome research

    2023  Volume 33, Issue 6, Page(s) 839–856

    Abstract: Synthetic glucocorticoids, such as dexamethasone, have been used as a treatment for many immune conditions, such as asthma and, more recently, severe COVID-19. Single-cell data can capture more fine-grained details on transcriptional variability and ... ...

    Abstract Synthetic glucocorticoids, such as dexamethasone, have been used as a treatment for many immune conditions, such as asthma and, more recently, severe COVID-19. Single-cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single-cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated peripheral blood mononuclear cells from 96 African American children. We used novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we showed that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and showed widespread genetic regulation of the transcriptional dynamics of the gene expression response.
    MeSH term(s) Child ; Humans ; Glucocorticoids/pharmacology ; Glucocorticoids/metabolism ; Leukocytes, Mononuclear/metabolism ; COVID-19/genetics ; Gene Expression Regulation
    Chemical Substances Glucocorticoids
    Language English
    Publishing date 2023-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.276765.122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution.

    Resztak, Justyna A / Wei, Julong / Zilioli, Samuele / Sendler, Edward / Alazizi, Adnan / Mair-Meijers, Henriette E / Wu, Peijun / Wen, Xiaoquan / Slatcher, Richard B / Zhou, Xiang / Luca, Francesca / Pique-Regi, Roger

    bioRxiv : the preprint server for biology

    2022  

    Abstract: Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics ...

    Abstract Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.
    Language English
    Publishing date 2022-10-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.09.30.462672
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Psychosocial experiences modulate asthma-associated genes through gene-environment interactions.

    Resztak, Justyna A / Farrell, Allison K / Mair-Meijers, Henriette / Alazizi, Adnan / Wen, Xiaoquan / Wildman, Derek E / Zilioli, Samuele / Slatcher, Richard B / Pique-Regi, Roger / Luca, Francesca

    eLife

    2021  Volume 10

    Abstract: Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here, we investigated the effect of psychosocial experiences on gene expression in peripheral ... ...

    Abstract Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here, we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 19 variables including psychosocial factors, blood cell composition, and asthma symptoms. Importantly, we found 169 genes associated with asthma or allergic disease that are regulated by psychosocial factors and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.
    MeSH term(s) Adolescent ; Asthma/epidemiology ; Asthma/genetics ; Asthma/metabolism ; Asthma/psychology ; Child ; Female ; Gene-Environment Interaction ; Genotype ; Humans ; Longitudinal Studies ; Male ; Michigan ; Transcriptome/genetics
    Language English
    Publishing date 2021-06-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.63852
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Interspecies variation in hominid gut microbiota controls host gene regulation.

    Muehlbauer, Amanda L / Richards, Allison L / Alazizi, Adnan / Burns, Michael B / Gomez, Andres / Clayton, Jonathan B / Petrzelkova, Klara / Cascardo, Camilla / Resztak, Justyna / Wen, Xiaoquan / Pique-Regi, Roger / Luca, Francesca / Blekhman, Ran

    Cell reports

    2021  Volume 37, Issue 8, Page(s) 110057

    Abstract: The gut microbiome exhibits extreme compositional variation between hominid hosts. However, it is unclear how this variation impacts host physiology across species and whether this effect can be mediated through microbial regulation of host gene ... ...

    Abstract The gut microbiome exhibits extreme compositional variation between hominid hosts. However, it is unclear how this variation impacts host physiology across species and whether this effect can be mediated through microbial regulation of host gene expression in interacting epithelial cells. Here, we characterize the transcriptional response of human colonic epithelial cells in vitro to live microbial communities extracted from humans, chimpanzees, gorillas, and orangutans. We find that most host genes exhibit a conserved response, whereby they respond similarly to the four hominid microbiomes. However, hundreds of host genes exhibit a divergent response, whereby they respond only to microbiomes from specific host species. Such genes are associated with intestinal diseases in humans, including inflammatory bowel disease and Crohn's disease. Last, we find that inflammation-associated microbial species regulate the expression of host genes previously associated with inflammatory bowel disease, suggesting health-related consequences for species-specific host-microbiome interactions across hominids.
    MeSH term(s) Animals ; Bacteria/genetics ; Epithelial Cells/metabolism ; Feces/microbiology ; Gastrointestinal Microbiome/genetics ; Gene Expression/genetics ; Gene Expression Regulation/genetics ; Gorilla gorilla/microbiology ; Hominidae/genetics ; Hominidae/microbiology ; Humans ; Inflammatory Bowel Diseases/genetics ; Microbiota/genetics ; Pan troglodytes/microbiology ; Phylogeny ; Pongo/microbiology ; RNA, Ribosomal, 16S/genetics ; Species Specificity
    Chemical Substances RNA, Ribosomal, 16S
    Language English
    Publishing date 2021-12-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.110057
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Psychosocial experiences modulate asthma-associated genes through gene-environment interactions

    Justyna A Resztak / Allison K Farrell / Henriette Mair-Meijers / Adnan Alazizi / Xiaoquan Wen / Derek E Wildman / Samuele Zilioli / Richard B Slatcher / Roger Pique-Regi / Francesca Luca

    eLife, Vol

    2021  Volume 10

    Abstract: Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here, we investigated the effect of psychosocial experiences on gene expression in peripheral ... ...

    Abstract Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here, we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 19 variables including psychosocial factors, blood cell composition, and asthma symptoms. Importantly, we found 169 genes associated with asthma or allergic disease that are regulated by psychosocial factors and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.
    Keywords eQTLs ; gene expression ; GxE ; asthma ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Determination of total and free voriconazole in human plasma: Application to pharmacokinetic study and therapeutic monitoring.

    Resztak, Matylda / Kosicka, Katarzyna / Zalewska, Paulina / Krawiec, Justyna / Główka, Franciszek K

    Journal of pharmaceutical and biomedical analysis

    2019  Volume 178, Page(s) 112952

    MeSH term(s) Adolescent ; Antifungal Agents/administration & dosage ; Antifungal Agents/blood ; Antifungal Agents/pharmacokinetics ; Child ; Child, Preschool ; Chromatography, High Pressure Liquid/methods ; Drug Monitoring/methods ; Female ; Fluorescence ; Humans ; Male ; Mycoses/blood ; Mycoses/drug therapy ; Reproducibility of Results ; Voriconazole/administration & dosage ; Voriconazole/blood ; Voriconazole/pharmacokinetics
    Chemical Substances Antifungal Agents ; Voriconazole (JFU09I87TR)
    Language English
    Publishing date 2019-10-25
    Publishing country England
    Document type Journal Article ; Validation Study
    ZDB-ID 604917-5
    ISSN 1873-264X ; 0731-7085
    ISSN (online) 1873-264X
    ISSN 0731-7085
    DOI 10.1016/j.jpba.2019.112952
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1850: Show issues Location:
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  8. Article ; Online: Mutants at the 2-Fold Interface of Adeno-associated Virus Type 2 (AAV2) Structural Proteins Suggest a Role in Viral Transcription for AAV Capsids.

    Aydemir, Fikret / Salganik, Maxim / Resztak, Justyna / Singh, Jasbir / Bennett, Antonette / Agbandje-McKenna, Mavis / Muzyczka, Nicholas

    Journal of virology

    2016  Volume 90, Issue 16, Page(s) 7196–7204

    Abstract: Unlabelled: We previously reported that an amino acid substitution, Y704A, near the 2-fold interface of adeno-associated virus (AAV) was defective for transcription of the packaged genome (M. Salganik, F. Aydemir, H. J. Nam, R. McKenna, M. Agbandje- ... ...

    Abstract Unlabelled: We previously reported that an amino acid substitution, Y704A, near the 2-fold interface of adeno-associated virus (AAV) was defective for transcription of the packaged genome (M. Salganik, F. Aydemir, H. J. Nam, R. McKenna, M. Agbandje-McKenna, and N. Muzyczka, J Virol 88:1071-1079, 2013, doi: http://dx.doi.org/10.1128/JVI.02093-13). In this report, we have characterized the defect in 6 additional capsid mutants located in a region ∼30 Å in diameter on the surface of the AAV type 2 (AAV2) capsid near the 2-fold interface. These mutants, which are highly conserved among primate serotypes, displayed a severe defect (3 to 6 logs) in infectivity. All of the mutants accumulated significant levels of uncoated DNA in the nucleus, but none of the mutants were able to accumulate significant amounts of genomic mRNA postinfection. In addition, wild-type (wt) capsids that were bound to the conformational antibody A20, which is known to bind the capsid surface in the region of the mutants, were also defective for transcription. In all cases, the mutant virus particles, as well as the antibody-bound wild-type capsids, were able to enter the cell, travel to the nucleus, uncoat, and synthesize a second strand but were unable to transcribe their genomes. Taken together, the phenotype of these mutants provides compelling evidence that the AAV capsid plays a role in the transcription of its genome, and the mutants map this functional region on the surface of the capsid near the 2-fold interface. This appears to be the first example of a viral structural protein that is also involved in the transcription of the viral genome that it delivers to the nucleus.
    Importance: Many viruses package enzymes within their capsids that assist in expressing their genomes postinfection, e.g., retroviruses. A number of nonenveloped viruses, including AAV, carry proteases that are needed for capsid maturation or for capsid modification during infection. We describe here what appears to be the first example of a nonenveloped viral capsid that appears to have a role in promoting transcription. A total of six mutants at the AAV capsid 2-fold interface were shown to have a severe defect in expressing their genomes, and the defect was at the level of mRNA accumulation. This suggests that AAV capsids have a novel role in promoting the transcription of the genomes that they have packaged. Since wt virions could not complement the mutant viruses, and the mutant viruses did not effectively inhibit wt gene expression, our results suggest that the capsid exerts its effect on transcription in cis.
    MeSH term(s) Amino Acid Substitution ; Capsid/physiology ; Dependovirus/genetics ; Genome, Viral/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Models, Molecular ; Mutation/genetics ; Parvoviridae Infections/genetics ; Parvoviridae Infections/metabolism ; Parvoviridae Infections/virology ; Phenotype ; RNA, Viral/genetics ; Transcription, Genetic/genetics ; Viral Structural Proteins/chemistry ; Viral Structural Proteins/genetics ; Viral Structural Proteins/metabolism ; Virion
    Chemical Substances RNA, Viral ; Viral Structural Proteins
    Language English
    Publishing date 2016-08-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00493-16
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 609: Show issues Location:
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