Biology subjects

Henry, M.

Publications and source records attributed to Henry, M..

24 records · Page 2Linked to original sources

bioRxiv2020

Locally-invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.

cancer biology↗

bioRxiv2020

Measuring ontogenetic shifts in central-place foraging insects: a case study with honey bees

O_LIMeasuring time-activity budgets over the complete individual lifespan is now possible for many animals with the recent advances of life-long individual monitoring devices. Although analyses of changes in the patterns of time-activity budgets have revealed ontogenetic shifts in birds or mammals, no such technique has been applied to date on insects. C_LIO_LIWe tested an automated breakpoint-based procedure to detect, assess and quantify shifts in the temporal pattern of the flight activities in honey bees. We assumed that the learning and foraging stages of honey bees will differ in several respects, to detect the age at onset of foraging (AOF). C_LIO_LIUsing an extensive dataset covering the life-long monitoring of 2,100 individuals, we compared the AOF outputs with the more conventional approaches based on arbitrary thresholds. We further evaluated the robustness of the different methods comparing the foraging time-activity budget allocations between the presumed foragers and confirmed foragers. C_LIO_LIWe revealed a clear-cut learning-foraging ontogenetic shift that differs in duration, frequency, and time of occurrence of flights. Although AOF appeared to be highly plastic among bees, the breakpoint-based procedure seems better able to detect it than arbitrary threshold-based methods that are unable to deal with inter-individual variation. C_LIO_LIWe developed the aof R-package including a broad range of examples with both simulated and empirical dataset to illustrate the simplicity of use of the procedure. This simple procedure is generic enough to be derived from any individual life-long monitoring devices recording the time-activity budgets of honey bees, and could propose new ecological applications of bio-logging to detect ontogenetic shifts in the behaviour of central-place foraging insects. C_LI

ecology↗

bioRxiv2020

Non-invasive, Real-time Detection of Vascular Disorders in Mice using Bright SWIR-emitting Gold Nanoclusters and Monte Carlo Image Analysis

We present here a new approach for non-invasive high resolution whole-body vascular imaging in depth by combining water-soluble and bright SWIR-emitting gold nanoclusters revealing an anisotropic surface charge with Monte Carlo image processing of the images. We applied and validated this approach to quantify vessel complexity in transgenic mice presenting vascular disorders.

bioengineering↗

bioRxiv2019

Stress-induced neuronal hypertrophy decreases the intrinsic excitability in stress habituation

A rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark stress response to an imminent threat, but its chronic activation can be detrimental. Thus, the long-term survival of animals requires experience-dependent fine-tuning of the stress response. However, the cellular mechanisms underlying the ability to decrease the stress responsiveness of the HPA axis remain largely unsolved. Using a stress habituation model in male mice and slice patch-clamp electrophysiology, we studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis. We found that the intrinsic excitability of these neurons substantially decreased after daily repeated restraint stress in a time course that coincided with their loss of stress responsiveness in vivo. This plasticity of intrinsic excitability co-developed with an expansion of surface membrane area, resulting in an increase in input conductance with minimal changes in conductance density. Moreover, multi-photon and electron microcopy data found that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that efficiently accommodates membrane area expansion with proportionally less expansion of gross cell volume. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.\n\nSignificance statementThe long-term survival of animals requires experience-dependent fine-tuning of stress response. Using a mouse model of repeated stress that develops habituation of the hypothalamic-pituitary-adrenal (HPA) axis, our study demonstrates a robust decrease in the intrinsic excitability of the output neuroendocrine neurons of the HPA axis. Mechanistically, we show that repeated stress increases the cell size of these neurons (i.e. surface membrane area). This cell-size change increases input conductance, and hence decreases excitability. Our findings challenge a conventional view that plasticity of intrinsic excitability relies on changes on membrane excitability resulting from up- and down-regulation of various voltage-gated ion channels. Our study reports a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.

neuroscience↗

bioRxiv2018

CBP/EP300-dependent acetylation and stabilization of HSF2 are compromised in the rare disorder, Rubinstein-Taybi syndrome

Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex and required for brain development. Here, we reveal that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. Using unbiased, biochemical, cell-imaging, and in silico approaches, we show that CBP/EP300 acetylates HSF2 at specific lysine residues, which promotes HSF2 stabilization, whereas the lysine deacetylase HDAC1 catalyzes its proteasomal degradation. The CBP KIX domain and KlX-recognizing motifs in HSF2 are critical for its interaction with acetylating enzymes. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutated CBP or EP300. We show that RSTS patient cells exhibit decreased HSF2 levels and impaired heat shock response. The dysregulated HSF pathway in RSTS opens new avenues for understanding the molecular basis of this multifaceted pathology.

developmental biology↗

bioRxiv2018

Proteogenomic annotation of the Chinese hamster reveals extensive novel translation events and endogenous retroviral elements

A high quality genome annotation greatly facilitates successful cell line engineering. Standard draft genome annotation pipelines are based largely on de novo gene prediction, homology, and RNA-Seq data. However, draft annotations can suffer from incorrectly predictions of translated sequence, incorrect splice isoforms and missing genes. Here we generated a draft annotation for the newly assembled Chinese hamster genome and used RNA-Seq, proteomics, and Ribo-Seq to experimentally annotate the genome. We identified 4,333 new proteins compared to the hamster RefSeq protein annotation and 2,503 novel translational events (e.g., alternative splices, mutations, novel splices). Finally, we used this pipeline to identify the source of translated retroviruses contaminating recombinant products from Chinese hamster ovary (CHO) cell lines, including 131 type-C retroviruses, thus enabling future efforts to eliminate retroviruses by reducing the costs incurred with retroviral particle clearance. In summary, the improved annotation provides a more accurate platform for guiding CHO cell line engineering, including facilitating the interpretation of omics data, defining of cellular pathways, and engineering of complex phenotypes.

bioinformatics↗