Biology subjects

Bak, M.

Publications and source records attributed to Bak, M..

5 recordsLinked to original sources

bioRxiv2026

Vagal Signaling Decline in Age-related Macular Degeneration Drives Spleen-Dependent Retinal Inflammation

Under relaxed physiological conditions, vagal innervation via the splenic nerve restrains the release of inflammatory cytokines from splenic macrophages and helps preserve systemic homeostasis, constituting the efferent cholinergic anti-inflammatory arm of the inflammatory reflex. Our analysis of Danish National Patient Registry data revealed that vagotomy for peptic ulcer disease, particularly truncal vagotomy, markedly increased the risk of developing age-related macular degeneration (AMD). Consistently, experimental truncal vagotomy or splenic denervation in mice exacerbated laser- and light-induced subretinal inflammation, both models of late AMD. The pro-inflammatory effects of vagotomy were abolished by concurrent splenectomy or pharmacologically augmenting acetylcholine signaling. Mechanistically, vagotomy activated a pro-inflammatory transcriptional program in splenic monocytes while suppressing tissue-retention genes Cxcr4 and Fn1, leading to enhanced monocyte egress from the spleen and increased infiltration into the injured retina. In the laser-injured retina, single-cell RNA sequencing (scRNAseq) of mononuclear phagocytes revealed a broad set of vagotomy-induced transcripts in infiltrating monocytes and activated microglia. Remarkably, more than one-third of these were normalized by splenectomy. Together, these findings identify a vagus nerve-spleen-retina axis that connects stress and vagal tone to AMD pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/703339v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@677032org.highwire.dtl.DTLVardef@f6fc78org.highwire.dtl.DTLVardef@1393d3dorg.highwire.dtl.DTLVardef@e39a7a_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefUsing population-level human data and complementary mouse models, this study demonstrates that loss of vagal signaling enhances subretinal inflammation and increases susceptibility to age-related macular degeneration (AMD). Mechanistically, vagotomy reprograms splenic monocytes toward a pro-inflammatory state, promoting their egress and infiltration into the injured retina, where they amplify local inflammation. These effects identify a vagus nerve-spleen-retina axis that links reduced vagal tone to AMD pathogenesis. HighlightsO_LIVagotomy increases AMD risk in humans and exacerbates subretinal inflammation in mouse models of late-stage AMD. C_LIO_LILoss of vagal signaling drives pro-inflammatory reprogramming and enhanced egress of splenic monocytes via suppression of tissue-retention genes. C_LIO_LISingle-cell transcriptomics reveals vagotomy-induced inflammatory signatures in retinal monocytes and microglia that are largely reversed by splenectomy. C_LI

immunology↗

bioRxiv2023

Selective sweep probabilities in spatially expanding populations

Evolution during range expansions shapes biological systems from microbial communities and tumours up to invasive species. A fundamental question is whether, when a beneficial mutation arises during a range expansion, it will evade clonal interference and sweep through the population to fixation. However, most theoretical investigations of range expansions have been confined to regimes in which selective sweeps are effectively impossible, while studies of selective sweeps have either assumed constant population size or have ignored spatial structure. Here we use mathematical modelling and analysis to investigate selective sweep probabilities in the alternative yet biologically relevant scenario in which mutants can outcompete and displace a slowly spreading wildtype. Assuming constant radial expansion speed, we derive probability distributions for the arrival time and location of the first surviving mutant and hence find surprisingly simple approximate and exact expressions for selective sweep probabilities in one, two and three dimensions, which are independent of mutation rate. Namely, the selective sweep probability is approximately (1 - cwt/cm)d, where cwt and cm are the wildtype and mutant radial expansion speeds, and d the spatial dimension. Using agent-based simulations, we show that our analytical results accurately predict selective sweep frequencies in the two-dimensional spatial Moran process. We further compare our results with those obtained for alternative growth laws. Parameterizing our model for human tumours, we find that selective sweeps are predicted to be rare except during very early solid tumour growth, thus providing a general, pan-cancer explanation for findings from recent sequencing studies.

evolutionary biology↗

bioRxiv2022

Frequent co-regulation of splicing and polyadenylation by RNA-binding proteins inferred with MAPP

Maturation of eukaryotic pre-mRNAs via splicing, 3 end cleavage and polyadenylation is modulated across cell types and conditions by a variety of RNA-binding proteins (RBPs). Although over 1500 proteins are associated with RNAs in human cells, their binding motifs, targets and functions still remain to be elucidated, especially in the complex environment of human tissues and in the context of diseases. To overcome the lack of methods for systematic and automated detection of sequence motif-guided changes in pre-mRNA processing based on RNA sequencing (RNA-seq) data we have developed MAPP (Motif Activity on Pre-mRNA Processing). We demonstrate MAPPs functionality by applying it to RNA-seq data from 284 RBP knock-down experiments in the ENCODE project, from which MAPP not only infers position-dependent impact profiles of known regulators, but also reveals RBPs that modulate both the inclusion of cassette exons and the poly(A) site choice. Among these, the Polypyrimidine Tract Binding Protein 1 (PTBP1) has a similar activity in glioblastoma samples. This highlights the ability of MAPP to unveil global regulators of mRNA processing under physiological and pathological conditions.

systems biology↗

bioRxiv2021

ZARP: An automated workflow for processing of RNA-seq data

RNA sequencing (RNA-seq) is a crucial technique for many scientific studies and multiple models, and software packages have been developed for the processing and analysis of such data. Given the plethora of available tools, choosing the most appropriate ones is a time-consuming process that requires an in-depth understanding of the data, as well as of the principles and parameters of each tool. In addition, packages designed for individual tasks are developed in different programming languages and have dependencies of various degrees of complexity, which renders their installation and execution challenging for users with limited computational expertise. The use of workflow languages and execution engines with support for virtualization and encapsulation options such as containers and Conda environments facilitates these tasks considerably. Computational workflows defined in those languages can be reliably shared with the scientific community, enhancing reusability, while improving reproducibility of results by making individual analysis steps more transparent. Here we present ZARP, a general purpose RNA-seq analysis workflow which builds on state-of-the-art software in the field to facilitate the analysis of RNA-seq data sets. ZARP is developed in the Snakemake workflow language using best software development practices. It can run locally or in a cluster environment, generating extensive reports not only of the data but also of the options utilized. It is built using modern technologies with the ultimate goal to reduce the hands-on time for bioinformaticians and non-expert users. ZARP is available under a permissive Open Source license and open to contributions by the scientific community. Contactmihaela.zavolan@unibas.ch, alexander.kanitz@unibas.ch

bioinformatics↗

bioRxiv2020

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

genetics↗