Imaging/Microscopy

Technology Networks

In this episode, we will be speaking with *Paul Andrews, Director of Operations at the National Phenotypic Screening Centre, who will be talking to us about drug screening strategies and preclinical drug development. This series is kindly brought to you by CN Bio, click here to find out more: https://bit.ly/2xFrpC1 *(speaker and sponsor are not affiliated)

TSE Explores Drug Discovery - Testing a Drug Compound: Preclinical Screening S05E03

Aging (Aging-US)

Aging-US published this research paper as the cover for Volume 15, Issue 2, entitled, "Clearance of p16Ink4a-positive cells in a mouse transgenic model does not change β-cell mass and has limited effects on their proliferative capacity" by researchers from the Joslin Diabetes Center, Harvard Medical School, Boston, MA.

DOI - https://doi.org/10.18632/aging.204483

Corresponding author - Cristina Aguayo-Mazzucato - cristina.aguayo-mazzucato@joslin.harvard.edu

Abstract

Type 2 diabetes is partly characterized by decreased β-cell mass and function which have been linked to cellular senescence. Despite a low basal proliferative rate of adult β-cells, they can respond to growth stimuli, but this proliferative capacity decreases with age and correlates with increased expression of senescence effector, p16Ink4a. We hypothesized that selective deletion of p16Ink4a-positive cells would enhance the proliferative capacity of the remaining β-cells due to the elimination of the local senescence-associated secretory phenotype (SASP). We aimed to investigate the effects of p16Ink4a-positive cell removal on the mass and proliferative capacity of remaining β-cells using INK-ATTAC mice as a transgenic model of senolysis. Clearance of p16Ink4a positive subpopulation was tested in mice of different ages, males and females, and with two different insulin resistance models: high-fat diet (HFD) and insulin receptor antagonist (S961). Clearance of p16Ink4a-positive cells did not affect the overall β-cell mass. β-cell proliferative capacity negatively correlated with cellular senescence load and clearance of p16Ink4a positive cells in 1-year-old HFD mice improved β-cell function and increased proliferative capacity in a subset of animals. Single-cell sequencing revealed that the targeted p16Ink4a subpopulation of β-cells is non-proliferative and non-SASP producing whereas additional senescent subpopulations remained contributing to continued local SASP secretion. In conclusion, deletion of p16Ink4a cells did not negatively impact beta-cell mass and blood glucose under basal and HFD conditions and proliferation was restored in a subset of HFD mice opening further therapeutic targets in the treatment of diabetes.

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Keywords - aging, beta cells, mass, proliferation, senolysis, senescence

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Clearance of p16Ink4a-positive Cells in Mice: Effects on β-cell Mass and Proliferation

Aging-US published this research paper as the cover for Volume 15, Issue 1, entitled, "Single-cell transcriptomics of peripheral blood in the aging mouse" by researchers from the Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI; Center for Computational Molecular Biology, Brown University, Providence, RI; Center on the Biology of Aging, Brown University, Providence, RI.

DOI - https://doi.org/10.18632/aging.204471

Corresponding author - Nicola Neretti - nicola_neretti@brown.edu

Abstract

Compositional and transcriptional changes in the hematopoietic system have been used as biomarkers of immunosenescence and aging. Here, we use single-cell RNA-sequencing to study the aging peripheral blood in mice and characterize the changes in cell-type composition and transcriptional profiles associated with age. We identified 17 clusters from a total of 14,588 single cells. We detected a general upregulation of antigen processing and presentation and chemokine signaling pathways and a downregulation of genes involved in ribosome pathways with age. In old peripheral blood, we also observed an increased percentage of cells expressing senescence markers (Cdkn1a, and Cdkn2a). In addition, we detected a cluster of activated T cells exclusively found in old blood, with lower expression of Cd28 and higher expression of Bcl2 and Cdkn2a, suggesting that the cells are senescent and resistant to apoptosis.

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Keywords - aging, single-cell transcriptomics, senescence, peripheral blood

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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Single-cell Transcriptomics of Peripheral Blood in the Aging Mouse

Aging-US published this trending research paper in Volume 14, Issue 24, entitled, "Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs" by researchers from Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD; Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL; Birmingham Veterans Affairs Medical Center, Birmingham, AL; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA; Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Birmingham, AL; Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL.

DOI - https://doi.org/10.18632/aging.204450

Corresponding authors - Myriam Gorospe - GorospeM@grc.nia.nih.gov, Dimitrios Tsitsipatis - dimitrios.tsitsipatis@nih.gov, Peter H. King - phking@uabmc.edu 

Abstract

Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in many diseases. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS compared to normal individuals. By RT-qPCR analysis, we confirmed that 8 circRNAs were significantly elevated and 10 were significantly reduced in ALS, while the linear mRNA counterparts, arising from shared precursor RNAs, generally did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1G93A). Interestingly, a subset of the circRNAs significantly elevated in ALS muscle biopsies were significantly reduced in the spinal cord samples from ALS patients and ALS (SOD1G93A) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.

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Keywords - aging, amyotrophic lateral sclerosis, circular RNAs, neurodegenerative disease, human skeletal muscle, human spinal cord tissue

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
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Transcriptomic Analysis of Human ALS Skeletal Muscle Reveals…

Oncotarget

Oncotarget published this trending research paper in Volume 13, entitled, “Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression" by the researchers from the Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC; Discovery Immunology, Merck Research Institute, Boston, MA; Discovery Oncology, Merck Research Institute, Boston, MA; Bicycle Therapeutics, Lexington, MA.

DOI - https://doi.org/10.18632/oncotarget.28330

Correspondence to - Robert I. Glazer - glazerr@georgetown.edu 

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Keywords - PD-1, NeuT, Wnt, macrophages, mammary tumorigenesis, breast cancer

Abstract

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune tolerant microenvironment. To determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1), NeuT/ATTAC mice, a conditional model of mammary fibrosis that we recently developed, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab, and drug response was monitored by tumor development, imaging mass cytometry, immunohistochemistry and tumor gene expression by RNAseq. Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1 and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors.

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us:

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Resistance of MMTV-NeuT/ATTAC Mice to Anti-PD-1 Immune Checkpoint Therapy ...

Aging-US published this research paper in Volume 14, Issue 22, entitled, "The potential benefit of metformin to reduce delirium risk and mortality: a retrospective cohort study" by researchers from Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Palo Alto, CA; University of Iowa Carver College of Medicine, Department of Psychiatry, Iowa City, IA; Tottori University Faculty of Medicine, Department of Neuropsychiatry, Yonago-Shi, Tottori, Japan; University of Iowa Carver College of Medicine, Department of Emergency Medicine, Iowa City, IA; University of Iowa College of Public Health, Department of Biostatistics, Iowa City, IA; University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, IA.
#openaccess   #aging   #metformin   #mortality    #researchpaper   #peerreview   #openscience #delirium #diabetes   

DOI - https://doi.org/10.18632/aging.204393

Corresponding author - Gen Shinozaki - gens@stanford.edu 

Abstract

Purpose: Metformin has been reported to improve age-related disorders, including dementia, and to lower mortality. This study was conducted to investigate whether metformin use lower delirium risk, as well as long-term mortality.

Methods: In this retrospective cohort study, previously recruited 1,404 subjects were analyzed. The relationship between metformin use and delirium, and the relationship between metformin use and 3-year mortality were investigated.

Main findings: 242 subjects were categorized into a type 2 diabetes mellitus (DM)-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for confounding factors. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for confounding factors (HR, 0.69 [95% CI, 0.48 to 0.98]).

Conclusions: Metformin use may lower the risk of delirium and mortality in DM patients.

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Keywords - delirium, metformin, diabetes mellitus, mortality, aging

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
Pinterest - https://www.pinterest.com/AgingUS/

Media Contact
18009220957
MEDIA@IMPACTJOURNALS.COM

The Potential Benefit of Metformin to Reduce Delirium Risk and Mortality

Speaking at the Advances in Drug Discovery & Development 2022 online symposium, Srinivas Niranj Chandrasekaran delivered his talk on drug discovery via image-based profiling.

Transforming Drug Discovery via Image-Based Profiling

Teach Me in 10

In this episode of Teach Me in 10, we are joined by Matt Hammond who is an applications and collaborations manager of protein quantitation at Bio-Rad Laboratories. 
Matt teaches us about the strengths of using a total protein signal as the reference signal in a western lot experiment, as well as how to use Bio-Rad’s Stain Free technology to provide this signal easily and reliably.

Total Protein Normalization in the Western Blotting Workflow

Aging-US published this research paper as the cover of Volume 14, Issue 22, entitled, "Glutaminase inhibitors rejuvenate human skin via clearance of senescent cells: a study using a mouse/human chimeric model" by researchers from the Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo, Japan.

DOI - https://doi.org/10.18632/aging.204391

Corresponding author - Kento Takaya - kento-takaya312@keio.jp

Abstract

Skin aging caused by various endogenous and exogenous factors results in structural and functional changes to skin components. However, the role of senescent cells in skin aging has not been clarified. To elucidate the function of senescent cells in skin aging, we evaluated the effects of the glutaminase inhibitor BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl)ethyl sulfide) on human senescent dermal fibroblasts and aged human skin. Here, primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, ionizing radiation, and treatment with doxorubicin, an anticancer drug. Cell viability of HDFs was assessed after BPTES treatment. A mouse/human chimeric model was created by subcutaneously transplanting whole skin grafts from aged humans into nude mice. The model was treated intraperitoneally with BPTES or vehicle for 30 days. Skin samples were collected and subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, and histological analysis. BPTES selectively eliminated senescent dermal fibroblasts regardless of the method used to induce senescence; aged human skin grafts treated with BPTES exhibited increased collagen density, increased cell proliferation in the dermis, and decreased aging-related secretory phenotypes, such as matrix metalloprotease and interleukin. These effects were maintained in the grafts 1 month after termination of the treatment. In conclusion, selective removal of senescent dermal fibroblasts can improve the skin aging phenotype, indicating that BPTES may be an effective novel therapeutic agent for skin aging.

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Press release - https://www.aging-us.com/news_room/glutaminase-inhibitors-rejuvenate-human-skin-via-clearance-of-senescent-cells-a-study-using-a-mouse-human-chimeric-model

Keywords - aging, glutaminase inhibitor, human skin, senescent cell, therapeutic agent

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
Pinterest - https://www.pinterest.com/AgingUS/

Media Contact
18009220957
MEDIA@IMPACTJOURNALS.COM

Imaging/Microscopy

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