Biology subjects

Bauer, R.

Publications and source records attributed to Bauer, R..

44 records · Page 3Linked to original sources

bioRxiv2021

MEMS enabled miniaturized light-sheet microscopy with all optical control

We have designed and implemented a compact, cost-efficient miniaturised light-sheet microscopy system based on optical Microelectromechanical Systems (MEMS) scanners and tunable lenses. The system occupies a footprint of 20 x 28 x 13 cm3 and combines off-the-shelf optics and optomechanics with 3D-printed structural and optical elements, and an economically costed objective lens, excitation laser and camera. All-optical volume scanning enables imaging of 340 x 190 x 60 {micro}m3 volumes with 0.25 vps and minimum lateral and axial resolution of 0.9 {micro}m and 2.95 {micro}m respectively. An open-top geometry allows imaging of samples on flat bottomed holders, allowing integration with microfluidic devices, multi-well plates and slide mounted samples, with applications envisaged in biomedical research and pre-clinical settings.

biophysics↗

bioRxiv2021

Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis through dye-functionalized lipid nanocarriers

Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-{gamma} (PI3K{gamma}) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3K{gamma} inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed PI3K{gamma}-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality. One-Sentence SummaryDye-functionalized liposomes allow delivery of a PI3K{gamma} inhibitor to hepatocytes to resolve sepsis-related liver failure without off-target effects on immunity. Graphical AbstractTargeting PI3K{gamma} in hepatocytes by dye-functionalized liposomes to resolve sepsis-related liver failure without off-target effects on immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/427305v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@d52fdeorg.highwire.dtl.DTLVardef@39bf3aorg.highwire.dtl.DTLVardef@13999c7org.highwire.dtl.DTLVardef@9edfa0_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2020

BioDynaMo: an agent-based simulation platform for scalable computational biology research

MotivationAgent-based modeling is an indispensable tool for studying complex biological systems. However, existing simulators do not always take full advantage of modern hardware and often have a field-specific software design. ResultsWe present a novel simulation platform called BioDynaMo that alleviates both of these problems. BioDynaMo features a general-purpose and high-performance simulation engine. We demonstrate that BioDynaMo can be used to simulate use cases in: neuroscience, oncology, and epidemiology. For each use case we validate our findings with experimental data or an analytical solution. Our performance results show that BioDynaMo performs up to three orders of magnitude faster than the state-of-the-art baseline. This improvement makes it feasible to simulate each use case with one billion agents on a single server, showcasing the potential BioDynaMo has for computational biology research. AvailabilityBioDynaMo is an open-source project under the Apache 2.0 license and is available at www.biodynamo.org. Instructions to reproduce the results are available in supplementary information. Contactlukas.breitwieser@inf.ethz.ch, a.s.hesam@tudelft.nl, omutlu@ethz.ch, r.bauer@surrey.ac.uk Supplementary informationAvailable at https://doi.org/10.5281/zenodo.4501515.

systems biology↗

bioRxiv2020

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

The unfolded protein response (UPR) is associated with the hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in UPR. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR, and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2 enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in humans with fatty liver disease, with only males showing an accumulation of CRELD2 protein in the liver. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

molecular biology↗

bioRxiv2020

Creative destruction: a basic computational model of cortical layer formation

One of the most characteristic properties of many vertebrate neural systems is the layered organization of different cell types. This cytoarchitecture exists in the cortex, the retina, the hippocampus and many other parts of the central nervous system. The developmental mechanisms of neural layer formation have been subject to substantial experimental efforts. Here, we provide a general computational model for cortical layer formation in 3D physical space. We show that this multi-scale, agent-based model comprising two distinct stages of apoptosis, can account for the wide range of neuronal numbers encountered in different cortical areas and species. Our results demonstrate the phenotypic richness of a basic state diagram structure, and suggest a novel function for apoptosis. Moreover, slightly changed gene regulatory dynamics recapitulate characteristic properties observed in neurodevelopmental diseases. Overall, we propose a novel computational model using gene-type rules, exhibiting many characteristics of normal and pathological cortical development.

developmental biology↗

bioRxiv2020

Laser-facilitated epicutaneous immunotherapy with hypoallergenic beta-glucan neoglycoconjugates suppresses lung inflammation and avoids local side effects in a mouse model of allergic asthma

BackgroundAllergen-specific immunotherapy via the skin targets an area rich in antigen presenting cells, but can be associated with local and systemic side effect. Allergen-polysaccharide neoglycogonjugates can increase immunization efficacy by targeting and activating dendritic cells via C-type lectin receptors and reduce side effects. ObjectiveWe investigated the immunogenicity, allergenicity and therapeutic efficacy of laminarin-ovalbumin neoglycoconjugates (LamOVA). MethodsThe biological activity of LamOVA was characterized in vitro using bone marrow derived dendritic cells. Immunogenicity and therapeutic efficacy was analyzed in BALB/c mice. Epicutaneous immunotherapy (EPIT) was performed using fractional infrared laser ablation to generate micropores in the skin and the effects of LamOVA on blocking IgG, IgE, cellular composition of BAL, lung, and spleen, lung function, and T cell polarization was assessed. ResultsConjugation of laminarin to ovalbumin reduced its IgE binding capacity 5-fold and increased its immunogenitiy 3-fold in terms of IgG generation. EPIT with LamOVA induced significantly higher IgG levels than OVA, matching the levels induced by s.c. injection of OVA/alum (SCIT). EPIT was equally effective as SCIT in terms of blocking IgG induction and suppression of lung inflammation and airway hyperresponsiveness, but SCIT was associated with a higher level of therapy induced IgE and TH2 cytokines. EPIT with LamOVA induced significantly lower local skin reactions during therapy compared to unconjugated OVA. ConclusionConjugation of the allergen to laminarin increased its immunogenicity while at the same time reducing local side effects. LamOVA EPIT via laser generated micropores is safe and equally effective to SCIT with alum, without the need for adjuvant.

immunology↗

bioRxiv2019

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

Macrophages drive atherosclerotic plaque progression and rupture, hence attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

immunology↗

bioRxiv2018

A Generative Growth Model for Thalamocortical Axonal Branching in Primary Visual Cortex

Axonal morphology displays large variability and complexity, yet the canonical regularities of the cortex suggest that such wiring is based on the repeated initiation of a small set of genetically encoded rules. Extracting underlying developmental principles can hence shed light on what genetically encoded instructions must be available during cortical development. Within a generative model, we investigate growth rules for axonal branching patterns in cat area 17, originating from the lateral geniculate nucleus of the thalamus. This target area of synaptic connections is characterized by extensive ramifications and a high bouton density, characteristics thought to preserve the spatial resolution of receptive fields and to enable connections for the ocular dominance columns. We compare individual and global statistics, such as a newly introduced asymmetry index and the global segment-length distribution, of generated and real branching patterns as the benchmark for growth rules. We show that the proposed model surpasses the statistical accuracy of the Galton-Watson model, which is the most commonly employed model for biological growth processes. In contrast to the Galton-Watson model, our model can recreate the log-normal segment-length distribution of the experimental dataset and is considerably more accurate in recreating individual axonal morphologies. To provide a biophysical interpretation for statistical quantifications of the axonal branching patterns, the generative model is ported into the physically accurate simulation framework of Cx3D. In this simulation environment we demonstrate how the proposed growth process can be formulated as an interactive process between genetic growth rules and chemical cues in the local environment.

neuroscience↗