Biology subjects

Pradervand, S.

Publications and source records attributed to Pradervand, S..

9 recordsLinked to original sources

bioRxiv2022

Deletion of the ion channel Trpm4 increases cardiac inflammatory markers and fibrosis after myocardial infarction in mice

BACKGROUNDThe first cause of mortality worldwide is ischemic heart disease. In myocardial infarction (MI), the ischemic event causes cell death, which triggers a large inflammatory response responsible for removing necrotic material and inducing tissue repair. Endothelial cells, immune cells and fibroblasts play a key role in orchestrating this healing process. TRPM4 is a Ca2+-activated ion channel permeable to monovalent cations and its silencing or knocking out was shown to critically modify cellular functions of these non-myocytic cell types. OBJECTIVEOur aims were to 1) evaluate the role of TRPM4 on mice survival and cardiac function after MI; and 2) investigate the role of TRPM4 in the post-MI acute and chronic inflammatory response. METHODSWe performed ligation of the left anterior descending coronary artery or sham intervention on 154 Trpm4 WT or KO male mice and monitored survival for up to 5 weeks as well as cardiac function using echocardiography at 72h and five weeks. We drew blood at different acute time points (6h, 12h, 24h) and performed time-of-flight mass spectrometry to analyze the sera proteomes. Further, we sacrificed sub-groups of mice at 24h and 72h after surgery and performed single-cell RNA sequencing on the non-myocytic cells. Lastly, we assessed fibrosis and angiogenesis at five weeks using type I collagen and CD31 immunostaining respectively. RESULTSWe observed no significant differences in survival or cardiac function post-MI between both genotypes. However, our serum proteomics data showed significantly decreased tissue injury markers such as creatine kinase M and VE-Cadherin in KO compared to WT 12h after MI. On the other hand, inflammation characterized by serum amyloid P component in the serum, as well as higher number of recruited granulocytes, M1 macrophages, M1 monocytes, Mac-6 macrophages, and expression of pro-inflammatory genes such as Il1b, Lyz2 and S100a8/a9 was significantly higher in endothelial cells, macrophages and fibroblasts of KO than of WT. This correlated with increased cardiac fibrosis and angiogenesis 5 weeks after MI in KO. CONCLUSIONOur data suggest that knocking out Trpm4 drastically increases acute inflammation post-MI, is associated with increased chronic fibrosis and does not improve survival at 5 weeks post-MI. Thus, targeting TRPM4 in the context of MI should be pondered carefully and approaches that nuance the timing of the inhibition or cellular target may be required.

molecular biology↗

bioRxiv2021

Reduced light access promotes hypocotyl growth via autophagy-mediated recycling

Plant growth ultimately depends on fixed carbon, thus the available light for photosynthesis. Due to canopy light absorption properties, vegetative shade combines reduced light and a low red to far-red ratio (LRFR). In shade-avoiding plants, these two conditions independently promote growth adaptations to enhance light access. However, how these conditions, differing in photosynthetically-available light, similarly promote growth remains unknown. Here, we show that Arabidopsis seedlings adjust metabolism according to light conditions to supply resources for hypocotyl growth enhancement. Transcriptome analyses indicate that reduced light induces starvation responses, suggesting a switch to a catabolic state to promote growth. Accordingly, reduced light promotes autophagy. In contrast, LRFR promotes anabolism including biosynthesis of plasma-membrane sterols downstream of PHYTOCHROME-INTERACTING FACTORs (PIFs) acting in hypocotyls. Furthermore, sterol biosynthesis and autophagy are indispensable for shade-induced hypocotyl growth. We conclude that vegetative shade enhances hypocotyl growth by combining autophagy-mediated recycling and promotion of specific anabolic processes. HIGHLIGHTSO_LIReduced light and LRFR induce catabolism and anabolism, respectively C_LIO_LIReduced light promotes autophagy to enhance hypocotyl growth in vegetative shade C_LIO_LILRFR enhances hypocotyl growth by promoting plasma membrane lipid biosynthesis C_LIO_LIIn LRFR, PIFs promote sterol biosynthesis specifically in the hypocotyl C_LI

plant biology↗

bioRxiv2021

Olfactory receptor-dependent receptor repression in Drosophila

In olfactory systems across phyla, most sensory neurons transcribe a single olfactory receptor gene selected from a large genomic repertoire. We describe novel receptor gene-dependent mechanisms that ensure singular expression of receptors encoded by a tandem gene array in Drosophila. Transcription from upstream genes in the cluster runs through the coding region of downstream loci to inhibit their expression in cis, via transcriptional interference. Moreover, one receptor blocks expression of other receptor proteins in trans through a post-transcriptional mechanism. These repression mechanisms operate in endogenous neurons to ensure their unique expression. Our data provide evidence for inter-olfactory receptor regulation in invertebrates, and highlight unprecedented, but potentially widespread, mechanisms for ensuring exclusive expression of chemosensory receptors, and other protein families, encoded by tandemly-arranged genes.

neuroscience↗

bioRxiv2021

Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and non-cell-autonomous mechanisms lead to the selective degeneration of motoneurons. Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of fast-fatigable motoneurons until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIb muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/re-innervation events. The transcriptome profiling of spinal cord motoneurons shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes provides therapeutic effects enhancing motoneuron plasticity and improving neuromuscular function in ALS mice.

neuroscience↗

bioRxiv2020

GDSL-domain containing proteins mediate suberin biosynthesis and degradation, enabling developmental plasticity of the endodermis during lateral root emergence

ABSTRACTRoots anchor plants and deliver water and nutrients from the soil. The root endodermis provides the crucial extracellular diffusion barrier by setting up a supracellular network of lignified cell walls, called Casparian strips, supported by a subsequent formation of suberin lamellae. Whereas lignification is thought to be irreversible, formation of suberin lamellae was demonstrated to be dynamic, facilitating adaptation to different soil conditions. Plants shape their root system through the regulated formation of lateral roots emerging from within the endodermis, requiring local breaking and re-sealing of the endodermal diffusion barriers. Here, we show that differentiated endodermal cells have a distinct auxin-mediated transcriptional response that regulates cell wall remodelling. Based on this data set we identify a set of GDSL-lipases that are essential for suberin formation. Moreover, we find that another set of GDSL-lipases mediates suberin degradation, which enables the developmental plasticity of the endodermis required for normal lateral root emergence.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗

bioRxiv2019

Variants in the degron of AFF3 cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

The ALF transcription factor paralogs, AFF1, AFF2, AFF3 and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role of AFF3 variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe KIdney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for Seizures, H for Hypertrichosis, I for Intellectual disability and P for Pulmonary involvement), partially overlapping the AFF4 associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif of AFF3 exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.\n\nWhereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.\n\nTranscriptome analyses as well as the partial phenotypic overlap of syndromes associated with AFF3 and AFF4 variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested

genetics↗

bioRxiv2019

Functional integration of \"undead\" neurons in the olfactory system

Programmed cell death (PCD) is widespread during neurodevelopment, typically eliminating the surpluses of neuronal production. Employing the Drosophila olfactory system, we examined the potential of cells fated to die to contribute to circuit evolution. Inhibition of PCD is sufficient to generate many new cells that express neural markers and exhibit odor-evoked activity. These \"undead\" neurons express a subset of olfactory receptors that, intriguingly, is enriched for recent receptor duplicates and include some normally found in other chemosensory organs and life-stages. Moreover, undead neuron axons integrate into the olfactory circuitry in the brain, forming novel receptor/glomerular couplings. Comparison of homologous olfactory lineages across drosophilids reveals natural examples of fate changes from death to a functional neuron. Finally, we provide evidence that PCD contributes to evolutionary differences in carbon dioxide-sensing circuit formation in Drosophila and mosquitoes. These results reveal the remarkable potential of alterations in PCD patterning to evolve new neural pathways.

neuroscience↗

bioRxiv2019

System analysis of the functional cross-talk between PPAR , LXR and FXR in the human HepaRG liver cells

Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPAR, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPAR agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases polyploidy of hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and a higher polyploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation.

physiology↗

bioRxiv2017

A RESTful API to serve BAM file with OAuth2 compatible authorization

SummaryBam-server is an open-source RESTful service to query slices of BAM files securely and manage their user accesses. A typical use case is the visualization of local read alignments in a web interface for variant calling diagnostic, without exposing sensitive data to unauthorized users through the network, and without moving the original - heavy - file. Bam-server follows the standard implementation of a protected resource server in the context of a typical token-based authorization protocol, supporting HMAC- and RSA-hashed signatures from an authorization server of choice.\n\nAvailabilityThe source code is available at https://github.com/chuv-ssrc/bam-server-scala, and a complete documentation can be found at http://bam-server-scala.readthedocs.io/en/latest/.\n\nContactsylvain.pradervand@chuv.ch

bioinformatics↗