Biology subjects

Larsson, M.

Publications and source records attributed to Larsson, M..

27 records · Page 2Linked to original sources

bioRxiv2022

Voxel-Wise Brain Graphs from Diffusion MRI: Intrinsic Eigenspace Dimensionality and Application to fMRI

Structural brain graphs are conventionally limited to defining nodes as gray matter regions from an atlas, with edges reflecting the density of axonal projections between pairs of nodes. Here we explicitly model the entire set of voxels within a brain mask as nodes of high-resolution, subject-specific graphs. We define the strength of local voxel-to-voxel connections using diffusion tensors and orientation distribution functions derived from diffusion MRI data. We study the graphs Laplacian spectral properties on data from the Human Connectome Project. We then assess the extent of inter-subject variability of the Laplacian eigenmodes via a procrustes validation scheme. Finally, we demonstrate the extent to which functional MRI data are shaped by the underlying anatomical structure via graph signal processing. The graph Laplacian eigen-modes manifest highly resolved spatial profiles, reflecting distributed patterns that correspond to major white matter pathways. We show that the intrinsic dimensionality of the eigenspace of such high-resolution graphs is only a mere fraction of the graph dimensions. By projecting task and resting-state data on low-frequency graph Laplacian eigenmodes, we show that brain activity can be well approximated by a small subset of low-frequency components. The proposed graphs open new avenues in studying the brain, be it, by exploring their organisational properties via graph or spectral graph theory, or by treating them as the scaffold on which brain function is observed at the individual level.

neuroscience↗

bioRxiv2022

Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes

ZC3H11A is a stress-induced mRNA binding protein required for efficient growth of nuclear-replicating viruses, while being dispensable for the viability of cultured human cells. The cellular functions of ZC3H11A during embryo development are unknown. Here we report the generation and phenotypic characterization of Zc3h11a knock-out mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a-/- embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a-/- embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a-/- embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. Furthermore, CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Altogether, the results show that ZC3H11A is participating in export and post-transcriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional knock-out did not lead to obvious phenotypic defects.

cell biology↗

bioRxiv2022

Lasting alterations in monocyte and dendritic cell subsets in individuals after hospitalization for COVID-19

After more than two years the COVID-19 pandemic continues to burden healthcare systems and economies worldwide, and it is evident that long-term effects of the disease can persist for months post-recovery in some individuals. The activity of myeloid cells such as monocytes and dendritic cells (DC) is essential for correct mobilization of the innate and adaptive responses to a pathogen. Impaired levels and responses of monocytes and DC to SARS-CoV-2 is likely to be a driving force behind the immune dysregulation that characterizes severe COVID-19. Here, we followed, for 6-7 months, a cohort of COVID-19 patients hospitalized during the early waves of the pandemic. The levels and phenotypes of circulating monocyte and DC subsets were assessed to determine both the early and long-term effects of the SARS-CoV-2 infection. We found increased monocyte levels that persisted for 6-7 months, mostly attributed to elevated levels of classical monocytes. While most DC subsets recovered from an initial decrease, we found elevated levels of cDC2/cDC3 at the 6-7 month timepoint. Analysis of functional markers on monocytes and DC revealed sustained reduction in PD-L1 expression but increased CD86 expression across almost all cell types examined. Finally, viral load and CRP correlated to the appearance of circulating antibodies and levels of circulating DC and monocyte subsets, respectively. By elucidating some of the long-term effects that SARS-CoV-2 infection has on these key innate myeloid cells, we have shed more light on how the immune landscape remains affected in the months following severe COVID-19.

immunology↗

bioRxiv2022

Rescue of Escherichia coli auxotrophy by de novo small proteins

Increasing numbers of small proteins with diverse physiological roles are being identified and characterized in both prokaryotic and eukaryotic systems, but the origins and evolution of these proteins remain unclear. Recent genomic sequence analyses in several organisms suggest that new functions encoded by small open reading frames (sORFs) may emerge de novo from noncoding sequences. However, experimental data demonstrating if and how randomly generated sORFs can confer beneficial effects to cells are limited. Here we show that by up-regulating hisB expression, de novo small proteins ([≤] 50 amino acids in length) selected from random sequence libraries can rescue Escherichia coli cells that lack the conditionally essential SerB enzyme. The recovered small proteins are hydrophobic and confer their rescue effect by binding to the 5 end regulatory region of the his operon mRNA, suggesting that protein binding promotes structural rearrangements of the RNA that allow increased hisB expression. This study adds RNA regulatory elements as another interacting partner for de novo proteins isolated from random sequence libraries, and provides further experimental evidence that small proteins with selective benefits can originate from the expression of nonfunctional sequences.

evolutionary biology↗

bioRxiv2022

Long-term T cell perturbations and waning antibody levels in individuals needing hospitalization for COVID-19

COVID-19 is being extensively studied, and much remains unknown regarding the long-term consequences of the disease on immune cells. The different arms of the immune system are interlinked, with humoral responses and the production of high-affinity antibodies being largely dependent on T cell immunity. Here, we longitudinally explored the effect COVID-19 has on T cell populations and the virus-specific T cells, as well as neutralizing antibody responses, for 6-7 months following hospitalization. The CD8+ TEMRA and exhausted CD57+CD8+ T cells were markedly affected with elevated levels that lasted long into convalescence. Further, markers associated with T-cell activation were upregulated at the inclusion, and in the case of CD69+CD4+ T cells this lasted all through the study duration. The levels of T cells expressing negative immune checkpoint molecules were increased in COVID-19 patients and sustained for a prolonged duration following recovery. Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19. Our study revealed significant and long-term alterations in T cell populations and key events associated with COVID-19 pathogenesis.

immunology↗

bioRxiv2021

HIV-1 Induction of Tolerogenic DCs is Mediated by Cellular Interaction with Suppressive T Cells

HIV-1 infection gives rise to a multilayered immune impairment in most infected individuals. The crosstalk between Dendritic cells and T cells plays an important part in the induction of immune responses. The chronic presence of human immunodeficiency virus (HIV)-1 during the dendritic cells (DCs) priming and activation of T cells promotes the expansion of suppressor cells in a contact dependent manner. The mechanism behind the T cell side of this HIV induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs in this setting. Here we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The DCs in the HIV exposed DC-T cell coculture obtained a more tolerogenic/suppressive phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by their cellular interaction with T cells. The transcriptomic analysis showed a clear type I IFN response profile as well as an activation of pathways involved in T cell exhaustion. Taken together, our data indicate that the prolonged and strong IFN type I signaling induced by the presence of HIV during DC-T cell cross talk could play an important role in the induction of the tolerogenic DCs and suppressed immune response.

immunology↗

bioRxiv2020

Diffusion-Informed Spatial Smoothing of fMRI Data in White Matter Using Spectral Graph Filters

Brain activation mapping using functional magnetic resonance imaging (fMRI) has been extensively studied in brain gray matter (GM), whereas in large disregarded for probing white matter (WM). This unbalanced treatment has been in part due to controversies in relation to the nature of the blood oxygenation level-dependent (BOLD) contrast in WM and its detachability. However, an accumulating body of studies has provided solid evidence of the functional significance of the BOLD signal in WM and has revealed that it exhibits anisotropic spatio-temporal correlations and structure-specific fluctuations concomitant with those of the cortical BOLD signal. In this work, we present an anisotropic spatial filtering scheme for smoothing fMRI data in WM that accounts for known spatial constraints on the BOLD signal in WM. In particular, the spatial correlation structure of the BOLD signal in WM is highly anisotropic and closely linked to local axonal structure in terms of shape and orientation, suggesting that isotropic Gaussian filters conventionally used for smoothing fMRI data are inadequate for denoising the BOLD signal in WM. The fundamental element in the proposed method is a graph-based description of WM that encodes the underlying anisotropy observed across WM, derived from diffusion-weighted MRI data. Based on this representation, and leveraging graph signal processing principles, we design subject-specific spatial filters that adapt to a subjects unique WM structure at each position in the WM that they are applied at. We use the proposed filters to spatially smooth fMRI data in WM, as an alternative to the conventional practice of using isotropic Gaussian filters. We test the proposed filtering approach on two sets of simulated phantoms, showcasing its greater sensitivity and specificity for the detection of slender anisotropic activations, compared to that achieved with isotropic Gaussian filters. We also present WM activation mapping results on the Human Connectome Projects 100-unrelated subject dataset, across seven functional tasks, showing that the proposed method enables the detection of streamline-like activations within axonal bundles.

neuroscience↗

bioRxiv2019

Dissection of the cellular function of the ZBED6 transcription factor in mouse myoblast cells using gene editing, RNAseq and proteomics

The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2{Delta}GGCT) or complete ablation of Zbed6 leads to ~20-fold up-regulation of IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2{Delta}GGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2{Delta}GGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 up-regulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2{Delta}GGCT myotubes, with an enrichment of up-regulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2{Delta}GGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study suggests that the interaction between ZBED6-Igf2 may be a therapeutic target for human diseases where anabolism is impaired.

molecular biology↗

bioRxiv2018

Sarek: A portable workflow for whole-genome sequencing analysis of germline and somatic variants

SummaryWhole-genome sequencing (WGS) is a cornerstone of precision medicine, but portable and reproducible open-source workflows for WGS analyses of germline and somatic variants are lacking. We present Sarek, a modular, comprehensive, and easy-to-install workflow, combining a range of software for the identification and annotation of single-nucleotide variants (SNVs), insertion and deletion variants (indels), structural variants, tumor sample heterogeneity, and karyotyping from germline or paired tumor/normal samples. Sarek is implemented in a bioinformatics workflow language (Nextflow) with Docker and Singularity compatible containers, ensuring easy deployment and full reproducibility at any Linux based compute cluster or cloud computing environment. Sarek supports the human reference genomes GRCh37 and GRCh38, and can readily be used both as a core production workflow at sequencing facilities and as a powerful stand-alone tool for individual research groups.\n\nAvailabilitySource code and instructions for local installation are available at GitHub (https://github.com/SciLifeLab/Sarek) under the MIT open-source license, and we invite the research community to contribute additional functionality as a collaborative open-source development project.

bioinformatics↗