<h2>Summary</h2> Cellular senescence refers to an irreversible state of cell-cycle arrest and plays important roles in aging and cancer biology. Because senescence is associated with increased cell size, we used reversible cell-cycle arrests combined with growth rate modulation to study how excessive growth affects proliferation. We find that enlarged cells upregulate p21, which limits cell-cycle progression. Cells that re-enter the cell cycle encounter replication stress that is well tolerated in physiologically sized cells but causes severe DNA damage in enlarged cells, ultimately resulting in mitotic failure and permanent cell-cycle withdrawal. We demonstrate that enlarged cells fail to recruit 53BP1 and other non-homologous end joining (NHEJ) machinery to DNA damage sites and fail to robustly initiate DNA damage-dependent p53 signaling, rendering them highly sensitive to genotoxic stress. We propose that an impaired DNA damage response primes enlarged cells for persistent replication-acquired damage, ultimately leading to cell division failure and permanent cell-cycle exit. 

Genome homeostasis defects drive enlarged cells into senescence.

Abstract Senescence, a state of irreversible cell-cycle withdrawal, is difficult to distinguish from quiescence, a state of reversible cell-cycle withdrawal. This difficulty arises because quiescent and senescent cells are defined by overlapping biomarkers, raising the question of whether these states are truly distinct. To address this, we use single-cell time-lapse imaging to distinguish slow-cycling cells that spend long periods in quiescence from cells that never cycle after recovery from senescence-inducing treatments, followed by staining for various senescence biomarkers. We find that the staining intensity of multiple senescence biomarkers is graded rather than binary and reflects the duration of cell-cycle withdrawal, rather than senescence per se. Together, our data show that quiescent and apparent senescent cells are nearly molecularly indistinguishable from each other at a snapshot in time. This suggests that cell-cycle withdrawal itself is graded rather than binary, where the intensities of senescence biomarkers integrate the duration of past cell-cycle withdrawal. 

The intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal

An autoantibody signature predictive for multiple sclerosis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding

Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells

Rapid‐onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co‐occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti‐neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.

/pdf/zscan1-autoantibodies-are-associated-with-pediatric-1n0ydcgy.pdf

ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD

Increasing cell size drives changes to the proteome, which affects cell physiology. As cell size increases, some proteins become more concentrated while others are diluted. As a result, the state of the cell changes continuously with increasing size. In addition to these proteomic changes, large cells have a lower growth rate (protein synthesis rate per unit volume). That both the cell’s proteome and growth rate change with cell size suggests they may be interdependent. To test this, we used quantitative mass spectrometry to measure how the proteome changes in response to the mTOR inhibitor rapamycin, which decreases the cellular growth rate and has only a minimal effect on cell size. We found that large cell size and mTOR inhibition, both of which lower the growth rate of a cell, remodel the proteome in similar ways. This suggests that many of the effects of cell size are mediated by the size-dependent slowdown of the cellular growth rate. For example, the previously reported size-dependent expression of some senescence markers could reflect a cell’s declining growth rate rather than its size per se. In contrast, histones and other chromatin components are diluted in large cells independently of the growth rate, likely so that they remain in proportion with the genome. Finally, size-dependent changes to the cell’s growth rate and proteome composition are still apparent in cells continually exposed to a saturating dose of rapamycin, which indicates that cell size can affect the proteome independently of mTORC1 signaling. Taken together, our results clarify the dependencies between cell size, growth, mTOR activity, and the proteome remodeling that ultimately controls many aspects of cell physiology.

/pdf/delineation-of-proteome-changes-driven-by-cell-size-and-cmk3nr6d.pdf

Delineation of proteome changes driven by cell size and growth rate

OBJECTIVES
Systemic juvenile idiopathic arthritis (sJIA) is a chronic pediatric inflammatory disease of unknown etiology, characterized by fever, rash, hepatosplenomegaly, serositis and arthritis. We hypothesized that intercellular communication, mediated by extracellular vesicles (EVs), contributes to sJIA pathogenesis and that the number and cellular sources of EVs would differ between inactive and active states of sJIA and healthy controls.


METHODS
We evaluated plasma from healthy pediatric controls and sJIA patients with active systemic flare or inactive disease. We isolated EVs by size-exclusion chromatography and determined total EV abundance and size distribution using microfluidic resistive pulse sensing. Cell-specific EV subpopulations were measured by nanoscale flow cytometry. Isolated EVs were validated using a variety of ways, including Nanotracking and Cryo-EM. EV protein content was analyzed in pooled samples using mass spectrometry.


RESULTS
Total EV concentration did not significantly differ between controls and sJIA patients. EVs with diameters <200 nm were the most abundant, including the majority of cell-specific EV subpopulations. sJIA patients had significantly higher levels of EVs from activated platelets, intermediate monocytes, and chronically activated endothelial cells, with the latter significantly more elevated in active sJIA relative to inactive disease and controls. Protein analysis of isolated EVs from active patients showed a pro-inflammatory profile, uniquely expressing heat shock protein 47 (HP47), a stress-inducible protein.


CONCLUSION
Our findings indicate that multiple cell types contribute to altered EV profiles in sJIA. The EV differences between sJIA disease states and healthy controls implicate EV-mediated cellular crosstalk as a potential driver of sJIA disease activity.

Extracellular Vesicles in Systemic Juvenile Idiopathic Arthritis.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

F. McCarthy

Author Tools

Chat about Author

Papers

ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD

Delineation of proteome changes driven by cell size and growth rate

Extracellular Vesicles in Systemic Juvenile Idiopathic Arthritis.