Biology subjects

Morin, R.

Publications and source records attributed to Morin, R..

6 recordsLinked to original sources

bioRxiv2025

Resynchronization of the biological clock using exposure to low oxygen levels in humans: an exploratory study

IntroductionCircadian desynchronization, evident in scenarios such as jet lag, shift work, and circadian rhythm sleep disorders, detrimentally affects sleep quality and overall health, both acutely and chronically. Aligning the circadian system with environmental time cues is therefore essential for maintaining physiological and psychological well-being. While luminotherapy and melatonin supplementation are widely used to facilitate circadian realignment, emerging evidence suggests that fluctuations in oxygen levels may also help in circadian realignment. However, the effect of hypoxia on the synchronisation of the circadian clock in humans remains largely unexplored. MethodsUsing a randomized controlled crossover study design, 11 healthy participants (6 men, 5 women, mean age 23.3 {+/-} 1.9 years) completed one baseline condition and two 48-h experimental conditions. The baseline condition (BL) was used to establish circadian markers. Both experimental conditions simulated a phase advance of 4 hours. In condition 1 (Hypo), participants underwent a 2-hour normobaric hypoxic exposure (FiO2 = 12%), starting 2 h after habitual wake time. In condition 2 (Lum+Mel), participants received a 3-hour luminotherapy session (500 nm, 506 lux) at the same time point, combined with 5 mg of exogenous melatonin administered 6 hours before usual bedtime. Salivary melatonin levels were measured in each phase of the study to assess circadian phase shifts. Data were analyzed using linear mixed models. ResultsSalivary melatonin levels increased progressively over time in all conditions (p < 0.001), with significant differences observed between experimental conditions (p < 0.001), but no interaction effect (p = 0.854). Exposure to hypoxia significantly reduced oxyhemoglobin saturation (p < 0.05) and increased heart rate and subjective symptoms of fatigue. In terms of circadian phase, the dim light melatonin onset (DLMO) occurred 1.30 hour (78 minutes) earlier in the Lum+Mel condition compared to baseline (p=0.001). In the hypoxia condition, the DLMO occurred on average 0.58 hour (34.8 minutes) earlier than baseline, but this change did not reach statistical significance (p=0.156). ConclusionsThis study provides preliminary evidence that normobaric hypoxia may modestly advance the human circadian phase, although not to a statistically significant extent. In contrast, combined phototherapy and melatonin administration produced a robust and significant phase advance in salivary melatonin onset. These findings suggest that while hypoxia may influence circadian timing, established interventions like light and melatonin remain more effective for circadian realignment. Further research is warranted to elucidate the mechanisms and optimize the application of hypoxia in circadian modulation.

physiology↗

bioRxiv2025

Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations were consistently associated with poor prognosis, whereas ATM mutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFN, TNF) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8 T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared to ATM-perturbed tumors, TP53-perturbed tumors exhibited enriched SOX11 tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-altered MCL.

cancer biology↗

bioRxiv2020

Direct tracking of single proviruses reveals HIV-1/LEDGF complexes excluded from virus-induced membraneless organelles

HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny, alternatively the virus is also able to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodeling of the nuclear landscape. Indeed, HIV-1 triggers the nuclear clustering of the host factor CPSF6, but the underlying mechanism is poorly understood. Our data indicate that HIV usurps a recently discovered biological phenomenon, called liquid-liquid phase separation (LLPS), to hijack the host cell. We observed CPSF6 clusters as part of HIV-induced membraneless organelles (HIV-1 MLOs) in macrophages, which are one of the main HIV target cells. We describe that HIV-1 MLOs follow phase separation rules and represent functional biomolecular condensates. We highlight HIV-1 MLOs as hubs of nuclear reverse transcription, while the double stranded viral DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize outside, but near HIV-1 MLOs, in LEDGF-abundant regions, known to be active chromatin sites. Therefore, HIV-1 MLOs orchestrate viral events prior to the integration step and create a favorable environment for the viral replication. This study uncovers single functional host-viral complexes in their nuclear landscape, which is markedly restructured by HIV-1.

microbiology↗

bioRxiv2019

Coding and regulatory drivers of mantle cell lymphoma identified through exome and genome sequencing

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.\n\nKey pointsO_LIRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL\nC_LIO_LIThe majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing\nC_LI

genomics↗

bioRxiv2019

SUBSTRA: Supervised Bayesian Patient Stratification

Patient stratification methods are key to the vision of precision medicine. Here, we consider transcriptional data to segment the patient population into subsets relevant to a given phenotype. Whereas most existing patient stratification methods focus either on predictive performance or interpretable features, we developed a method striking a balance between these two important goals. We introduce a Bayesian method called SUBSTRA that uses regularized biclustering to identify patient subtypes and interpretable subtype-specific transcript clusters. The method iteratively re-weights feature importance to optimize phenotype prediction performance by producing more phenotype-relevant patient subtypes. We investigate the performance of SUBSTRA in finding relevant features using simulated data and successfully benchmark it against state-of-the-art unsupervised stratification methods and supervised alternatives. Moreover, SUBSTRA achieves predictive performance competitive with supervised benchmark methods and provides interpretable transcriptional features in diverse biological settings, such as drug response prediction, cancer diagnosis, or kidney transplant rejection.

bioinformatics↗

bioRxiv2016

Enhancing Knowledge Discovery from Cancer Genomics Data with Galaxy

We present a collection of Galaxy tools representing many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We implemented methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability on cloud-based infrastructure and commodity hardware. Some tools represents extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate several of these to perform some standard data integration and visualization tasks are demonstrated on a cohort of 96 diffuse large B-cell lymphomas, enabling the discovery of multiple candidate lymphoma-related genes that have not been reported previously.

genomics↗