Biology subjects

Engel, M.

Publications and source records attributed to Engel, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Bivalent bispecific CD28 antibodies reinforce T-cell responsiveness and revert anergy/quiescence in patients treated with bispecific CD3 antibodies

Bispecific T-cell engagers stimulating CD3 (TCEs) rapidly gain momentum in oncological therapy. We report that single-agent TCE-treatment of cancer patients induces T cell hyporesponsiveness including abolished proliferative and lytic capacity. Single-cell RNA-sequencing identified transcriptional features of anergy/quiescence like upregulation of CBLB and BACH2, and suppression of AP 1-dependent activation programs due to isolated provision of T cell signal-1. To restore T cell functionality, we engineered bispecific costimulators (BiCos) which deliver signal-2 via highly efficient bivalent CD28-binding yet maintain strictly target-restricted activity after binding antigens expressed not only by tumor cells but also the extracellular matrix. Preclinical analyses documented that BiCos potentiate efficacy of single-agent TCE treatment with activity exceeding that of univalent Knob-into-Hole CD28-costimulators and revert T cell hyporesponsiveness. In humanized mice, BiCos induced elimination of established tumors in combination with very low doses of TCE. Finally, BiCos reversed molecular hallmark features of quiescence such as high expression of BACH2 and KLF2 in T cells of TCE-treated patients resulting in complete restoration of cellular function, thereby reinstating durable antitumor immunity.

immunology↗

bioRxiv2025

Differences in layer-specific activation of the insula during interoceptive vs. exteroceptive attention

Attention modulates the relative weighting of information and plays a critical role in modern theories of perception. While its role in exteroceptionthe perception of the external environmenthas been extensively studied, attentional processes in interoception, the perception of bodily states, are less well understood. In this study, we exploited high-field (7 Tesla) functional magnetic resonance imaging and concurrent field monitoring to investigate interoceptive attention at the level of cortical layers during a heartbeat attention task. Voxel-wise analyses reveal increased activity in the bilateral dorsal mid-insula during interoceptive attention (attending to ones heartbeat) compared to exteroceptive attention (attending to auditory white noise). Layer-specific analyses further demonstrate that this difference in activity is significantly higher in upper compared to lower cortical layers. This activation pattern persists after accounting for potential vascular artifacts through a deconvolution analysis with a physiological point spread function (PSF). To our knowledge, these findings represent the first empirical demonstration of layer-specific processes during interoceptive attention in human cortex. They may prove useful to inform and constrain theories of computational principles and physiological implementation of interoception.

neuroscience↗

bioRxiv2025

Desmoglein-2 deficiency results in cardiac dysfunction by compromising both Z-disc- and intercalated disc-mediated mechanotransduction

Desmoglein-2 (DSG2), a critical component of the cardiac desmosome and located at the cardiomyocyte-cardiomyocyte intercalated disc, is essential for cell-cell adhesion, cardiomyocyte mechanical stability, and electrical coupling between cells. However, its relative contribution in maintaining cardiac function at the sarcomere level remains unclear. Using 4-week-old (adolescent) and 16-week-old (adult) homozygous knock-in Dsg2-mutant (Dsg2mut/mut) mice, we found that loss of DSG2 leads to early onset chamber- and age-dependent cardiac dysfunction driven by Z-disc structural defects and increased myosin detachment rate. Interestingly, Ca{superscript 2}-activated force was markedly reduced in adolescent Dsg2mut/mut permeabilized left ventricular cardiac muscle bundles but preserved in permeabilized isolated cardiomyocytes. This disparity demonstrates that DSG2 is not only crucial for mechanical coupling between cardiomyocytes but also for force transmission within and between sarcomeres, revealing a novel role for DSG2 in maintaining contractile integrity at both the cellular and tissue levels.

biophysics↗

bioRxiv2024

Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic form of heart failure that affects 1 in 5000 people globally and is caused by mutations in cardiac desmosomal proteins including PKP2, DSP, and DSG2. Individuals with ACM suffer from ventricular arrhythmias, sudden cardiac death, and heart failure. There are few effective treatments and heart transplantation remains the best option for many affected individuals. Here we performed single nucleus RNA sequencing (snRNAseq) and spatial transcriptomics on myocardial samples from patients with ACM and control donors. We identified disease-associated spatial niches characterized by co-existence of fibrotic and inflammatory cell types and failing cardiac myocytes. The inflammatory-fibrotic niche co-localized to areas of cardiac myocyte loss and was comprised of FAP (fibroblast activation protein) and POSTN (periostin) expressing fibroblasts and macrophages expressing NLRP3 (NLR family pyrin domain containing 3) and NFB activated genes. Using homozygous Desmoglein-2 mutant (Dsg2mut/mut) mice, we identified analogous populations of Postn expressing fibroblasts and inflammatory macrophage populations that co-localized within diseased areas. Detailed single cell RNA sequencing analysis of inflammatory macrophage subsets that were increased in ACM samples revealed high levels of interleukin-1{beta} (Il1b) expression. To delineate the possible benefit of targeting IL-1{beta} in ACM, we treated Dsg2mut/mut mice with an anti-IL-1{beta} neutralizing antibody and observed attenuated fibrosis, reduced levels of inflammatory cytokines and chemokines, preserved cardiac function, and diminished conduction slowing and automaticity, key mechanisms of arrhythmogenesis. These results suggest that currently approved therapeutics that target IL-1{beta} or IL-1 signaling may improve outcomes for patients with ACM.

immunology↗

bioRxiv2024

Alzheimer's disease induced neurons bearing PSEN1 mutations exhibit reduced excitability

Alzheimers disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined induced pluripotent stem cell (iPSC)-derived NGN2 induced neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding the disease pathogenesis.

cell biology↗

bioRxiv2024

REST and RCOR genes display distinct expression profiles in neurons and astrocytes using 2D and 3D human pluripotent stem cell models

Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection. REST forms a complex with the REST corepressors, CoREST1, CoREST2, or CoREST3 (encoded by RCOR1, RCOR2, and RCOR3, respectively). Emerging evidence suggests that the CoREST family can target unique genes independently of REST, in various neural and glial cell types during different developmental stages. However, there is limited knowledge regarding the expression and function of the CoREST family in human neurodevelopment. To address this gap, we employed 2D and 3D human pluripotent stem cell (hPSC) models to investigate REST and RCOR gene expression levels. Our study revealed a significant increase in RCOR3 expression in glutamatergic cortical and GABAergic ventral forebrain neurons, as well as mature functional NGN2-induced neurons. Additionally, a simplified astrocyte transdifferentiation protocol resulted in a significant decrease in RCOR2 expression following differentiation. REST expression was notably reduced in mature neurons and cerebral organoids, along with RCOR2 in the latter. In summary, our findings provide the first insights into the cell-type-specific expression patterns of RCOR genes in human neuronal and glial differentiation. Specifically, RCOR3 expression increases in neurons, while RCOR2 levels decrease in astrocytes. The dynamic expression patterns of REST and RCOR genes during hPSC neuronal and glial differentiation underscore the potential distinct roles played by REST and CoREST proteins in regulating the development of these cell types in humans. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/584254v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@7be30borg.highwire.dtl.DTLVardef@1771388org.highwire.dtl.DTLVardef@a376aforg.highwire.dtl.DTLVardef@1c4dc83_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIREST and RCOR genes display cell-type specific expression patterns in neural cells C_LIO_LIRCOR3 (encodes CoREST3) is upregulated during neuronal and astrocyte differentiation C_LIO_LIRCOR2 (encodes CoREST2) is downregulated during differentiation of astrocytes C_LIO_LIEvidence of potential cell-type specific functions of the CoREST family C_LI

neuroscience↗

bioRxiv2023

Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy

Inhibition of nuclear factor kappa-B (NF{kappa}B) signaling prevents disease in Dsg2mut/mut mice, a model of arrhythmogenic cardiomyopathy (ACM). Moreover, NF{kappa}B is activated in ACM patient-derived iPSC-cardiac myocytes under basal conditions in vitro. Here, we used genetic approaches and sequencing studies to define the relative pathogenic roles of immune signaling in cardiac myocytes vs. inflammatory cells in Dsg2mut/mutmice. We found that NF{kappa}B signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. It does this by mobilizing cells expressing C-C motif chemokine receptor-2 (CCR2+ cells) to the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA sequencing and cellular indexing of transcriptomes and epitomes (CITE-seq) studies revealed marked pro-inflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts and CCR2+ cells. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mutmice were modulated by actions of CCR2+ cells. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM. BRIEF SUMMARYWe have uncovered a therapeutically targetable innate immune mechanism regulating myocardial injury and cardiac function in a clinically relevant mouse model of Arrhythmogenic Cardiomyopathy (ACM).

immunology↗

bioRxiv2022

Visualization of Incrementally Learned Projection Trajectories for Longitudinal Data

Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (Incrementally Learned Visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal Multi-Electrode Array data from brain cortical organoids when exposed to different levels of Quinolinic Acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimers disease, and its blocking antibody. We uncover valuable insights into the organoids electrophysiological maturation and response patterns over time under these conditions.

bioinformatics↗

bioRxiv2022

3D Bioprinting of Stem Cell-Derived Central Nervous System Cells Enables Astrocyte Growth, Vasculogenesis and Enhances Neural Differentiation/Function

Current research tools for pre-clinical drug development such as rodent models and 2D immortalised monocultures have failed to serve as effective translational models for human CNS disorders. Recent advancements in the development of iPSCs and 3D culturing can improve the in vivo-relevance of pre-clinical models, while generating 3D cultures though novel bioprinting technologies can offer increased scalability and replicability. As such, there is a need to develop platforms that combine iPSC-derived cells with 3D bioprinting to produce scalable, tunable and biomimetic cultures for preclinical drug discovery applications. We report a biocompatible PEG-based matrix which incorporates RGD and YIGSR peptide motifs and full length collagen IV at a stiffness similar to the human brain (1.5 kPa). Using a high-throughput commercial bioprinter we report the viable culture and morphological development of iPSC-derived astrocytes, brain microvascular endothelial cells, neural progenitors and neurons in our novel matrix. We also show that this system supports endothelial vasculogenesis and enhances neural differentiation and spontaneous activity. This platform forms a foundation for more complex, multicellular models to facilitate high-throughput translational drug discovery for CNS disorders.

neuroscience↗

bioRxiv2022

A 3D bioprintable hydrogel with tuneable stiffness for exploring cells encapsulated in matrices of differing stiffnesses

In vitro cell models have undergone a shift from 2D models on glass slides to 3D models that better reflect the native 3D microenvironment. 3D bioprinting promises to progress the field by allowing the high throughput production of reproducible cell-laden structures with high fidelity. As this technology is relatively new, the current stiffness range of printable matrices surrounding the cells that mimics the extracellular matrix environment remains limited. The work presented here aims to expand the range of stiffnesses by utilising a 4-armed polyethylene glycol with maleimide functionalised arms. The complementary crosslinkers comprised a matrix metalloprotease (MMP)-degradable peptide and a 4-armed thiolated polymer which were adjusted in ratio to tune the stiffness. The modularity of this system allows for a simple method of controlling stiffness and the addition of biological motifs. The application of this system in drop-on-demand printing is validated in this work using MCF-7 cells which were monitored for viability and proliferation. This study shows the potential of this system for the high-throughput investigation of the effects of stiffness and biological motif compositions in relation to cell behaviours.

cell biology↗

bioRxiv2021

A high-throughput 3D bioprinted cancer cell migration and invasion model with versatile and broad biological applicability

Understanding the underlying mechanisms of migration and metastasis is a key focus of cancer research. There is an urgent need to develop in vitro 3D tumor models that can mimic physiological cell-cell and cell-extracellular matrix interactions, with high reproducibility and that are suitable for high throughput (HTP) drug screening. Here, we developed a HTP 3D bioprinted migration model using a bespoke drop-on-demand bioprinting platform. This HTP platform coupled with tunable hydrogel systems enables (i) the rapid encapsulation of cancer cells within in vivo tumor mimicking matrices, (ii) in situ and real-time measurement of cell movement, (iii) detailed molecular analysis for the study of mechanisms underlying cell migration and invasion, and (iv) the identification of novel therapeutic options. This work demonstrates that this HTP 3D bioprinted cell migration platform has broad applications across quantitative cell and cancer biology as well as drug screening.

cell biology↗

bioRxiv2021

Historical biogeography of early diverging termite lineages (Isoptera: Teletisoptera)

Termites are social cockroaches distributed throughout warm temperate and tropical ecosystems. The ancestor of modern termites (crown-Isoptera) occurred during the earliest Cretaceous, approximately 140 million years ago, suggesting that both vicariance through continental drift and overseas dispersal may have shaped the distribution of early diverging termite lineages. We reconstruct the historical biogeography of three early diverging termite families - Stolotermitidae, Hodotermitidae, and Archotermopsidae - using the nuclear rRNA genes and mitochondrial genomes of 27 samples. Our analyses confirmed the monophyly of Stolotermitidae + Hodotermitidae + Archotermopsidae (clade Teletisoptera), with Stolotermitidae diverging from a monophyletic Hodotermitidae + Archotermopsidae approximately 100.3 Ma (94.3-110.4 Ma, 95% HPD), and with Archotermopsidae paraphyletic to a monophyletic Hodotermitidae. The Oriental Archotermopsis and the Nearctic Zootermopsis diverged 50.8 Ma (40.7-61.4 Ma, 95% HPD) before land connections between the Palearctic region and North America ceased to exist. The African Hodotermes + Microhodotermes diverged from Anacanthotermes, a genus found in Africa and Asia, 32.1 Ma (24.8-39.9 Ma, 95% HPD), and the most recent common ancestor of Anacanthotermes lived 10.7 Ma (7.3-14.3 Ma, 95% HPD), suggesting that Anacanthotermes dispersed to Asia using the land bridge connecting Africa and Eurasia [~]18-20 Ma. In contrast, the common ancestors of modern Porotermes and Stolotermes lived 20.2 Ma (15.7-25.1 Ma, 95% HPD) and 26.6 Ma (18.3-35.6 Ma, 95% HPD), respectively, indicating that the presence of these genera in South America, Africa, and Australia involved over-water dispersals. Our results suggest that early diverging termite lineages acquired their current distribution through a combination of over-water dispersals and dispersal via land bridges. We clarify the classification by resolving the paraphyly of Archotermopsidae, restricting the family to Archotermopsis and Zootermopsis, and elevating Hodotermopsinae (Hodotermopsis) as Hodotermopsidae (status novum).

evolutionary biology↗

bioRxiv2021

Transoceanic voyages of drywood termites (Isoptera: Kalotermitidae) inferred from extant and extinct species

Termites are major decomposers of organic matter in terrestrial ecosystems and the second most diverse lineage of social insects. The Kalotermitidae, the second-largest termite family, are widely distributed across tropical and subtropical ecosystems, where they typically live in small colonies confined to single wood items inhabited by individuals with no foraging abilities. How the Kalotermitidae have acquired their global distribution patterns remains unresolved. Similarly, it is unclear whether foraging is ancestral to Kalotermitidae or was secondarily acquired in a few species. These questions can be addressed in a phylogenetic framework. We inferred time-calibrated phylogenetic trees of Kalotermitidae using mitochondrial genomes and nuclear ribosomal RNA genes of [~]120 species, about 27% of kalotermitid diversity, including representatives of 22 of the 23 kalotermitid genera. We found that extant kalotermitids shared a common ancestor 81 Mya (72-91 Mya 95% HPD), indicating that a few disjunctions among early-diverging kalotermitid lineages may predate Gondwana breakup. However, most of the [~]40 disjunctions among biogeographic realms were dated at less than 50 Mya, indicating that transoceanic dispersals, and more recently human-mediated dispersals, have been the major drivers of the global distribution of Kalotermitidae. Our phylogeny also revealed that the capacity to forage is often found in early-diverging kalotermitid lineages, implying that the ancestors of Kalotermitidae were able to forage among multiple wood pieces. Our phylogenetic estimates provide a platform for a critical taxonomic revision of the family and for future comparative analyses of Kalotermitidae.

evolutionary biology↗

bioRxiv2021

Enabling high throughput target-based drug discovery in 3D cell cultures through novel bioprinting workflow

Advanced three-dimensional cell culture techniques have been adopted in many laboratories to better model in vivo tissue by recapitulating multi-cellular architecture and the presence of extracellular matrix features. We describe here a 3D cell culture platform in a small molecule screening workflow that uses traditional biomarker and intracellular kinase end point assay readouts. By combining the high throughput bioprinter Rastrum with the high throughput screening assay AlphaLISA, we demonstrate the utility of the workflow in 3D synthetic hydrogel cultures with breast cancer (MDA-MB-231 and MCF-7) and fibroblast cells. To establish and validate the workflow, we treated the breast cancer cultures with doxorubicin, while fibroblast cultures were stimulated with the pro-inflammatory lipopolysaccharide. 3D and 2D MDA-MB-231 cultures were equally susceptible to doxorubicin treatment, while showing opposite ERK phosphorylation changes. Doxorubicin readily entered embedded MCF-7 spheroids and markedly reduced intracellular GSK3{beta} phosphorylation. Furthermore, quantifying extracellular interleukin 6 levels showed a very similar activation profile for fibroblasts in 2D and 3D cultures, with 3D fibroblast networks being more resistant against the immune challenge. Through these validation experiments we demonstrate the full compatibility of the bioprinted 3D cell cultures with several widely-used 2D culture assays. The efficiency of the workflow, minimal culture handling, and applicability of traditional screening assays, demonstrates that advanced encapsulated 3D cell cultures can be used in 2D cell culture screening workflows, while providing a more holistic view on cell biology to increase the predictability to in vivo drug response.

cell biology↗

bioRxiv2020

Identification of repurposable cytoprotective drugs for Vanishing White Matter Disease

Vanishing white matter disease (VWMD) is a rare leukodystrophy involving loss of function mutations of the guanine exchange factor eIF2B and typically presenting with juvenile onset. We aimed to identify repurposable FDA approved drugs in an in vitro drug screen using patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes. Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under proteasomal stress conditions. A drug screen from a 2400 FDA approved drug library with EIF2B5 disease patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of MG132-stressed EIF2B2 and EIF2B5 disease VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. ISRIB but not other drugs significantly affected eIF2 phosphorylation and GADD34 expression. Ursodiol demonstrated capacity to reduce complex I subunit upregulation, ameliorate oxidative stress, loss of mitochondrial membrane potential and upregulation of eIF2B subunits in VWMD astrocytes, highlighting its potential as a cytoprotective compound for VWMD.

neuroscience↗

bioRxiv2019

Advances in Spiral fMRI: A High-resolution Study with Single-shot Acquisition

Spiral fMRI has been put forward as a viable alternative to rectilinear echo-planar imaging, in particular due to its enhanced average k-space speed and thus high acquisition efficiency. This renders spirals attractive for contemporary fMRI applications that require high spatiotemporal resolution, such as laminar or columnar fMRI. However, in practice, spiral fMRI is typically hampered by its reduced robustness and ensuing blurring artifacts, which arise from imperfections in both static and dynamic magnetic fields. Recently, these limitations have been overcome by the concerted application of an expanded signal model that accounts for such field imperfections, and its inversion by iterative image reconstruction. In the challenging ultra-high field environment of 7 Tesla, where field inhomogeneity effects are aggravated, both multi-shot and single-shot 2D spiral imaging at sub-millimeter resolution was demonstrated with high depiction quality and anatomical congruency. In this work, we further these advances towards a time series application of spiral readouts, namely, single-shot spiral BOLD fMRI at 0.8 mm in-plane resolution. We demonstrate that high-resolution spiral fMRI at 7 T is not only feasible, but delivers both excellent image quality, BOLD sensitivity, and spatial specificity of the activation maps, with little artifactual blurring. Furthermore, we show the versatility of the approach with a combined in/out spiral readout at a more typical resolution (1.5 mm), where the high acquisition efficiency allows to acquire two images per shot for improved sensitivity by echo combination. HighlightsO_LIThis work reports the first fMRI study at 7T with high-resolution spiral readout gradient waveforms. C_LIO_LIWe achieve spiral fMRI with sub-millimeter resolution (0.8 mm, FOV 230 mm), acquired in a single shot (36 slices in 3.3 s). C_LIO_LISpiral images exhibit intrinsic geometric congruency to anatomical scans, and spatially specific activation patterns. C_LIO_LIImage reconstruction rests on a signal model expanded by measured trajectories and static field maps, inverted by cg-SENSE. C_LIO_LIWe assess generalizability of the approach for spiral in/out readouts, providing two images per shot (1.5 mm resolution). C_LI

neuroscience↗

bioRxiv2019

Feasibility of spiral fMRI based on an LTI gradient model

Spiral imaging is very well suited for functional MRI, however its use has been limited by the fact that artifacts caused by gradient imperfections and B0 inhomogeneity are more difficult to correct compared to EPI. Effective correction requires accurate knowledge of the traversed k-space trajectory. With the goal of making spiral fMRI more accessible, we have evaluated image reconstruction using trajectories predicted by the gradient impulse response function (GIRF), which can be determined in a one-time calibration step. GIRF-predicted reconstruction was tested for high-resolution (0.8 mm) fMRI at 7T. Image quality and functional results of the reconstructions using GIRF-prediction were compared to reconstructions using the delay-corrected nominal trajectory and concurrent field monitoring. The reconstructions using nominal spiral trajectories contain substantial artifacts and the activation maps contain misplaced activation. Image artifacts are substantially reduced when using the GIRF-predicted reconstruction, and the activation maps for the GIRF-predicted and monitored reconstructions largely overlap. The GIRF reconstruction provides a large increase in the spatial specificity of the activation compared to the nominal reconstruction. The GIRF-reconstruction generates image quality and fMRI results similar to using a concurrently monitored trajectory. The presented approach does not prolong or complicate the fMRI acquisition. Using GIRF-predicted trajectories has the potential to enable high-quality spiral fMRI in situations where concurrent trajectory monitoring is not available. HighlightsO_LIThis work investigates the feasibility of using a one-time system calibration to account for k-space trajectory deviations in spiral fMRI. C_LIO_LIThis versatile calibration is based on a linear time-invariant gradient model, the gradient impulse response function (GIRF). C_LIO_LIWe show that the image quality and the spatial specificity of the fMRI activation are substantially improved when using the GIRF-predicted trajectories. C_LIO_LIBasing reconstructions on nominal gradient inputs, on the other hand, induces image artifacts and misplaced fMRI activation. C_LIO_LIWe demonstrate that system characterization via the GIRF can enable spiral fMRI in situations where concurrent trajectory monitoring is unavailable. C_LI

neuroscience↗

bioRxiv2019

Probability-based detection of phosphoproteomic uncertainty reveals rare signaling events driven by oncogenic kinase gene fusion

We describe a novel Bayesian method for estimating protein concentration and phosphorylation site occupancy ratios from mass spectrometry experiments. Our variance model assigns standard deviations to all quantitative ratios, even when only a single peptide is observed, increasing the number of quantifiable observations in a sample compared to conventional methods. We further demonstrate the application of this method using a dataset investigating the impact of the PRKAR1A-RET gene fusion in immortalized thyroid cells.

systems biology↗