Biology subjects

Blanchard, T.

Publications and source records attributed to Blanchard, T..

4 recordsLinked to original sources

bioRxiv2025

A comprehensive view of somatic mosaicism by single-cell DNA analysis

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

genomics↗

bioRxiv2023

Integrin-alpha V beta 3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player

Medulloblastoma (MB) is the most frequent solid tumor in children, localized in the brains posterior fossa. Its standard of care comprises maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. Relevant targets for naive and recurrent MB are urgently needed. Primary and recurrent MBs are characterized by aggressive invasion into surrounding brain tissue, active angiogenesis, and radioresistance. Integrin-v{beta}3 was a major driver of these features in glioblastoma. Nevertheless, such observations have not yet been reported in MB. Integrin-v{beta}3 was found to be expressed in a subset of MB patients. We investigated the role of integrin-v{beta}3 using MB-derived cell lines with {beta}3-subunit depletion or overexpression both in vitro and in vivo. Radioresistant MB cell lines were generated and showed increased integrin-v{beta}3 expression, which correlated with increased susceptibility to pharmacological integrin-v{beta}3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/magnetic resonance imaging (MRI) studies on orthotopic models using a radiolabeled integrin-v{beta}3 ligand (99mTc-RAFT-RGD). This approach offers the prospect of a novel predictive imaging modality in MB. Altogether, our data pave the way for SPECT/MRI-based selection of a subpopulation of MB patients eligible for integrin-v{beta}3-directed therapies. SIGNIFICANCEThis study demonstrates integrin-v{beta}3s fundamental role in MB tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.

cancer biology↗

bioRxiv2022

SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology

Major cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from "brain diseases". Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimers, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimers-like neuropathology with manifestations of {beta}-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimers individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimers-like gene programs in healthy neurons and exacerbates Alzheimers neuropathology. A gene signature defined as an Alzheimers infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimers-like program.

neuroscience↗

bioRxiv2021

Macaques preferentially attend to intermediately surprising information

Normative learning theories dictate that we should preferentially attend to informative sources, but only up to the point that our limited learning systems can process their content. Humans, including infants, show this predicted strategic deployment of attention. Here we demonstrate that rhesus monkeys, much like humans, attend to events of moderate surprisingness over both more and less surprising events. They do this in the absence of any specific goal or contingent reward, indicating that the behavioral pattern is spontaneous. We suggest this U-shaped attentional preference represents an evolutionarily preserved strategy for guiding intelligent organisms toward material that is maximally useful for learning.

animal behavior and cognition↗