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  1. Article: Age-Invariant Genes: Multi-Tissue Identification and Characterization of Murine Reference Genes.

    González, John T / Thrush, Kyra / Meer, Margarita / Levine, Morgan E / Higgins-Chen, Albert T

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes ( ...

    Abstract Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes (often called housekeeping genes) in expression studies. Reference genes have mostly been identified and validated in young organisms, and no systematic investigation has been done across the lifespan. Here, we build upon a common pipeline for identifying reference genes in RNA-seq datasets to identify age-invariant genes across seventeen C57BL/6 mouse tissues (brain, lung, bone marrow, muscle, white blood cells, heart, small intestine, kidney, liver, pancreas, skin, brown, gonadal, marrow, and subcutaneous adipose tissue) spanning 1 to 21+ months of age. We identify 9 pan-tissue age-invariant genes and many tissue-specific age-invariant genes. These genes are stable across the lifespan and are validated in independent bulk RNA-seq datasets and RT-qPCR. We find age-invariant genes have shorter transcripts on average and are enriched for CpG islands. Interestingly, pathway enrichment analysis for age-invariant genes identifies an overrepresentation of molecular functions associated with some, but not all, hallmarks of aging. Thus, though hallmarks of aging typically involve changes in cell maintenance mechanisms, select genes associated with these hallmarks resist fluctuations in expression with age. Finally, our analysis concludes no classical reference gene is appropriate for aging studies in all tissues. Instead, we provide tissue-specific and pan-tissue genes for assays utilizing reference gene normalization (i.e., RT-qPCR) that can be applied to animals across the lifespan.
    Language English
    Publishing date 2024-04-13
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.09.588721
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage.

    Ruz-Maldonado, Inmaculada / Gonzalez, John T / Zhang, Hanming / Sun, Jonathan / Bort, Alicia / Kabir, Inamul / Kibbey, Richard G / Suárez, Yajaira / Greif, Daniel M / Fernández-Hernando, Carlos

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 1247

    Abstract: Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution ... ...

    Abstract Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.
    MeSH term(s) Animals ; Liver Regeneration/physiology ; Liver/metabolism ; Hepatocytes/metabolism ; Liver Diseases/metabolism ; Disease Models, Animal ; Cell Proliferation
    Language English
    Publishing date 2024-02-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-45439-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of a long non-coding RNA regulator of liver carcinoma cell survival.

    Rybakova, Yulia / Gonzalez, John T / Bogorad, Roman / Chauhan, Vikash P / Dong, Yize L / Whittaker, Charles A / Zatsepin, Timofei / Koteliansky, Victor / Anderson, Daniel G

    Cell death & disease

    2021  Volume 12, Issue 2, Page(s) 178

    Abstract: Genomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of ... ...

    Abstract Genomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We demonstrated that HCC cell death upon ASTILCS knockdown is associated with apoptosis induction and downregulation of a neighboring gene, protein tyrosine kinase 2 (PTK2), a crucial protein for HCC cell survival. Taken together, our study describes a new, non-coding RNA regulator of HCC.
    MeSH term(s) Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Survival/physiology ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
    Chemical Substances RNA, Long Noncoding
    Language English
    Publishing date 2021-02-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-03453-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo.

    Rybakova, Yulia / Kowalski, Piotr S / Huang, Yuxuan / Gonzalez, John T / Heartlein, Michael W / DeRosa, Frank / Delcassian, Derfogail / Anderson, Daniel G

    Molecular therapy : the journal of the American Society of Gene Therapy

    2019  Volume 27, Issue 8, Page(s) 1415–1423

    Abstract: Antibody-based drugs are a leading class of biologics used to treat a variety of diseases, including cancer. However, wide antibody implementation is hindered by manufacturing challenges and high production cost. Use of in-vitro-transcribed mRNA (IVT- ... ...

    Abstract Antibody-based drugs are a leading class of biologics used to treat a variety of diseases, including cancer. However, wide antibody implementation is hindered by manufacturing challenges and high production cost. Use of in-vitro-transcribed mRNA (IVT-mRNA) for endogenous protein expression has the potential to circumvent many of the shortcomings of antibody production and therapeutic application. Here, we describe the development of an IVT-mRNA system for in vivo delivery of a humanized anti-HER2 (also known as ERBB2) antibody, trastuzumab, and demonstrate its anticancer activity. We engineered the IVT-mRNA sequence to maximize expression, then formulated the IVT-mRNA into lipid-based nanoparticles (LNPs) to protect the mRNA from degradation and enable efficient in vivo delivery. Systemic delivery of the optimized IVT-mRNA loaded into LNPs resulted in antibody serum concentrations of 45 ± 8.6 μg/mL for 14 days after LNP injection. Further studies demonstrated an improved pharmacokinetic profile of the produced protein compared to injection of trastuzumab protein. Finally, treatment of tumor-bearing mice with trastuzumab IVT-mRNA LNPs selectively reduced the volume of HER2-positive tumors and improved animal survival. Taken together, the results of our study demonstrate that using IVT-mRNA LNPs to express full-size therapeutic antibodies in the liver can provide an effective strategy for cancer treatment and offers an alternative to protein administration.
    MeSH term(s) Animals ; Antibodies, Monoclonal/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/therapy ; Disease Models, Animal ; Drug Delivery Systems ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy ; Humans ; Lipids ; Mice ; Molecular Targeted Therapy ; Nanoparticles ; RNA, Messenger/administration & dosage ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; Receptor, ErbB-2/antagonists & inhibitors ; Trastuzumab/administration & dosage ; Trastuzumab/genetics ; Trastuzumab/pharmacokinetics ; Xenograft Model Antitumor Assays
    Chemical Substances Antibodies, Monoclonal ; Lipids ; RNA, Messenger ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
    Language English
    Publishing date 2019-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2019.05.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  5. Article ; Online: Microfluidic Squeezing Enables MHC Class I Antigen Presentation by Diverse Immune Cells to Elicit CD8

    Booty, Matthew G / Hlavaty, Kelan A / Stockmann, Adam / Ozay, Emrah Ilker / Smith, Carolyne / Tian, Lina / How, Edylle / Subramanya, Disha / Venkitaraman, Anita / Yee, Christian / Pryor, Olivia / Volk, Kelly / Blagovic, Katarina / Vicente-Suarez, Ildefonso / Yarar, Defne / Myint, Melissa / Merino, Amy / Chow, Jonathan / Abdeljawad, Tarek /
    An, Harry / Liu, Sophia / Mao, Shirley / Heimann, Megan / Talarico, LeeAnn / Jacques, Miye K / Chong, Eritza / Pomerance, Lucas / Gonzalez, John T / von Andrian, Ulrich H / Jensen, Klavs F / Langer, Robert / Knoetgen, Hendrik / Trumpfheller, Christine / Umaña, Pablo / Bernstein, Howard / Sharei, Armon / Loughhead, Scott M

    Journal of immunology (Baltimore, Md. : 1950)

    2022  Volume 208, Issue 4, Page(s) 929–940

    Abstract: ... ...

    Abstract CD8
    MeSH term(s) Adoptive Transfer ; Animals ; Antigen Presentation ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Antigens, Neoplasm/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Culture Techniques ; Female ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunization ; Immunophenotyping ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Mice ; Mice, Knockout ; Microfluidics/methods ; Models, Biological ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
    Chemical Substances Antigens, Neoplasm ; Histocompatibility Antigens Class I
    Language English
    Publishing date 2022-01-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100656
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.37: Show issues Location:
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