Biology subjects

Chavez, M.

Publications and source records attributed to Chavez, M..

25 records · Page 2Linked to original sources

bioRxiv2021

Kdm6a Deficiency Restricted to Mouse Hematopoietic Cells Causes an Age- and Sex-dependent Myelodysplastic Syndrome-Like Phenotype

AbstractKdm6a/Utx, a gene on the X chromosome, encodes a histone K27me3 demethylase that has an orthologue on the Y chromosome (Uty)[1]. We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis by altering the epigenetic state of HSPCs.

genetics↗

bioRxiv2021

Biomolecular solid-state NMR spectroscopy at highest field: the gain in resolution at 1200 MHz

Progress in NMR in general and in biomolecular applications in particular is driven by increasing magnetic-field strengths leading to improved resolution and sensitivity of the NMR spectra. Recently, persistent superconducting magnets at a magnetic field strength (magnetic induction) of 28.2 T corresponding to 1200 MHz proton resonance frequency became commercially available. We present here a collection of high-field NMR spectra of a variety of proteins, including molecular machines, membrane proteins and viral capsids and others. We show this large panel in order to provide an overview over a range of representative systems under study, rather than a single best performing model system. We discuss both carbon-13 and proton-detected experiments, and show that in 13C spectra substantially higher numbers of peaks can be resolved compared to 850 MHz while for 1H spectra the most impressive increase in resolution is observed for aliphatic side-chain resonances.

biophysics↗

bioRxiv2020

Selective neuromodulation induced by alpha-based neurofeedback learning: A double-blind randomized study

The neuromodulation induced by neurofeedback training (NFT) remains a matter of debate. Investigating the modulation of brain activity specifically associated with NF requires controlling for multiple factors, such as reward, performance, congruency between task and targeted brain activity. This can be achieved using sham feedback (FB) control condition, equating all aspects of the experiment but the link between brain activity and FB. We aimed at investigating the modulation of individual alpha EEG activity induced by NFT in a double-blind, randomized, sham-controlled study. Forty-eight healthy participants were assigned to either NF (n=25) or control (n=23) group and performed alpha upregulation training (over 12 weeks) with a wearable EEG device. Participants of the NF group received FB based on their individual alpha activity. The control group received the auditory FB of participants of the NF group. An increase of alpha activity across training sessions was observed in the NF group only (p<0.001). This neuromodulation was selective in that it was not observed for theta (4-8Hz) and low beta (13-18Hz) activities. While alpha upregulation was found in the NF group only, psychological outcome variables showed increased feeling of control, decreased anxiety level and increased relaxation feeling in both the NF and control groups, without any significant difference between groups. This is interpreted in terms of learning context and placebo effects. Our results pave the way to self-learnt, NF-based neuromodulation with light-weighted, wearable EEG systems.

neuroscience↗

bioRxiv2020

Deeper insights into long-term survival heterogeneity of Pancreatic Ductal Adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

BackgroundPancreatic ductal adenocarcinoma (PDAC) is categorized as the seventh leading cause of cancer mortality worldwide. Its predictive markers for long-term survival are not well known. Therefore, it is interesting to delineate individual-specific perturbed genes when comparing long-term (LT) and short-term (ST) PDAC survivors, and to exploit the integrative individual- and group-based transcriptome profiling. MethodUsing a discovery cohort of 19 PDAC patients from CHU-Liege (Belgium), we first performed differential gene expression (DGE) analysis comparing LT to ST survivor. Second, we adopted unsupervised systems biology approaches to obtain gene modules linked to clinical features. Third, we created individual-specific perturbation profiles and identified key regulators across the LT patients. Furthermore, we applied two gene prioritization approaches: random walk-based Degree-Aware disease gene prioritizing (DADA) method to develop PDAC disease modules; Network-based Integration of Multi-omics Data (NetICS) to integrate group-based and individual-specific perturbed genes in relation to PDAC LT survival. FindingsWe identified 173 differentially expressed genes (DEGs) in ST and LT survivors and five modules (including 38 DEGs) showing associations to clinical traits such as tumor size and chemotherapy. DGE analysis identified differences in genes involved in metabolic and cell cycle activity. Validation of DEGs in the molecular lab suggested a role of REG4 and TSPAN8 in PDAC survival. Individual-specific omics changes across LT survivors revealed biological signatures such as focal adhesion and extracellular matrix receptors, implying a potential role in molecular-level heterogeneity of LT PDAC survivors. Via NetICS and DADA we not only identified various known oncogenes such as CUL1, SCF62, EGF, FOSL1, MMP9, and TGFB1, but also highlighted novel genes (TAC1, KCNH7, IRS4, DKK4). InterpretationOur proposed analytic workflow shows the advantages of combining clinical and omics data as well as individual- and group-level transcriptome profiling. It suggested novel potential transcriptome marks of LT survival heterogeneity in PDAC. FundingTelevie-FRS-FNRS

genomics↗

bioRxiv2019

Perturbation-based mapping of natural frequencies with direct intracranial stimulation of the human brain

Theoretical and experimental evidence suggest that the induction of oscillatory activity by an external rhythmic source on a specific brain area is maximally efficient if the input pattern matches its so-called natural frequency, defined as the predominant neural rhythm at which the activity of this area tends to fluctuate spontaneously. Based on this principle, single pulse Transcranial Magnetic Stimulation (TMS) coupled to scalp electroencephalography (EEG) has provided evidence of frequency-specific power increases within a unique natural frequency band, considered common to the whole lobe.\n\nIn an attempt to gain deeper insight into this phenomenon and set the basis for a finer-grained atlas of natural frequencies, here we analyzed intracranial EEG (iEEG) signals modulated by single pulses of direct electrical brain stimulation in human patients implanted with depth multielectrodes. Our analyses revealed changes in local EEG activity emerging from local oscillators and contributing to a complex distribution of frequency-specific natural rhythmic responses throughout cortical regions. Moreover, challenging the notion of natural oscillations featuring a predominant frequency band characteristic for an entire lobe, our data support a rich diversity of spectral fingerprints (narrowband, vs. broadband or multiband) with single or multiple frequency peaks, often encompassing contiguous frequency bands, operating at a very local scale.\n\nOur findings contribute novel insights on which specific brain areas could be more likely to be synchronized at a given frequencies band and their preferred coupling frequencies, features that could ultimately inform on their structural and functional organization. Our results may also increase our mechanistic understanding of invasive and noninvasive brain stimulation and promote further developments of these approaches for the manipulation of brain oscillations subtending normal and impaired cognition.

neuroscience↗

bioRxiv2018

Domains of the TF protein important in regulating its own palmitoylation

Sindbis virus particles contain the viral proteins capsid, E1 and E2, and low levels of a small membrane protein called TF. TF is produced during a (-1) programmed ribosomal frameshifting event during the translation of the structural polyprotein. TF from Sindbis virus-infected cells is present in two palmitoylated states, basal and maximal; unpalmitoylated TF is not detectable. Mutagenesis studies demonstrated that without palmitoylation, TF is not incorporated into released virions, suggesting palmitoylation of TF is a regulated step in virus assembly. In this work, we identified Domains within the TF protein that regulate its palmitoylation state. Mutations and insertions in Domain III, a region proposed to be in the cytoplasmic loop of TF, increase levels of unpalmitoylated TF found during an infection and even allow incorporation of unpalmitoylated TF into virions. Mutations in Domain IV, the TF unique region, are likely to impact the balance between basal and maximal palmitoylation.

molecular biology↗

bioRxiv2018

Spatiotemporal neural correlates of brain-computer interface learning

Brain-computer interfaces have been largely developed to allow communication, control, and neurofeedback in human beings. Despite their great potential, BCIs perform inconsistently across individuals. Moreover, the neural processes activated by training that enable humans to achieve good control remain poorly understood. In this study, we show that BCI skill acquisition is paralleled by a progressive reinforcement of task-related activity and by the reduction of connectivity between regions beyond those primarily targeted during the experiments. Notably, these patterns of activity and connectivity reflect growing automaticity and predict future BCI performance. Altogether, our findings provide new insights in the neural mechanisms underlying BCI learning, which have implications for the use of this technology in a broad range of real-life applications.

neuroscience↗