Biology subjects

Schultz, B.

Publications and source records attributed to Schultz, B..

8 recordsLinked to original sources

bioRxiv2026

Loss of calcium-binding protein Cbp53E leads to delayed repolarization of photoreceptor cells in Drosophila

Calcium functions as an important second messenger in a wide variety of intracellular processes. In photoreceptor cells, calcium is involved in activation, deactivation, and adaptation in response to light stimuli. Calcium-binding protein 53E (Cbp53E, also known as calbindin-32 or cbn), a protein with 6 EF-Hand domains thought to act as a calcium buffer, was previously identified to have elevated expression levels in the eye of drosophila. While a recent study showed that transgenic flies lacking Cbp53E have aberrant axonal arborization at the neuromuscular junction, nothing is known about the role of Cbp53E in the visual system. We performed electroretinogram (ERG) recordings on Cbp53E mutant flies to test whether eye function was affected. Here, we report that Cbp53E null mutants exhibit a prolonged repolarization (or slow termination) phenotype which can be rescued by expressing Cbp53E in photoreceptor cells. The human homologs Calbindin 2, Calbindin 1, and S100G also rescue the Drosophila ERG phenotype. This supports a role for Cbp53E in regulating intracellular calcium levels of photoreceptor cells and contributing to normal sensory neuron response dynamics in vivo in Drosophila and suggests a similar function in human photoreceptor cells as well.

neuroscience↗

bioRxiv2025

Bridging Stem Cell Models and Medicine: Integrated 3D Human Cerebral Organoids and Pediatric Serum Reveal Mechanisms and Biomarkers of Anesthetic-Induced Neurotoxicity

BackgroundGeneral anesthetics have been shown to cause acute pathological changes in the developing brain, including neuronal cell death. These effects contribute to long-term cognitive and behavioral impairments observed in animal models. Epidemiological and prospective clinical studies have also reported associations between early-life exposure to anesthesia and neurodevelopmental deficits in children, raising significant concerns about pediatric anesthesia and highlighting the urgent need to understand the molecular mechanisms and biomarkers of anesthetic-induced developmental neurotoxicity (AIDN) using human-relevant models. MethodsThis study employed human induced pluripotent stem cell-derived cerebral organoids that were exposed to varying doses of anesthetic propofol for 1 to 6 hours, including single and repeated exposures. In parallel, serum samples were collected pre- and post-surgery from pediatric patients under 4 years old (n = 10 per group) who underwent either short (<1 hour) or prolonged anesthesia (>3 hours) at the Childrens Hospital of Wisconsin between September 2018 and October 2019. Pathological changes in organoids were assessed using chemical assays, electron microscopy, and western blotting. Brain injury-related proteins in patient serum were quantified via ELISA. Genome-wide expression profiling was conducted on 18,855 mRNAs and 27,427 lncRNAs in organoids and serum using microarray and bioinformatics. ResultsHigher doses, longer duration, and repeated exposures to propofol led to increased apoptosis in organoids. Six-hour exposure induced autophagy as evidenced by LC3-II elevation and led to dysregulation of 553 mRNAs and 792 lncRNAs in organoids, along with their co-expressed signaling networks, affecting pathways related to synaptic integrity, mitochondrial function, and inflammation. ELISA and serum analysis of pediatric patients (<4 years old) exposed to anesthesia (>3 hours) demonstrated elevated brain cell injury-associated proteins (e.g., increased NSE) and brain cell type-specific gene expression changes. Serum findings corroborated organoid data, identifying 21 mRNAs and 12 lncRNAs that were dysregulated in both models and associated with cell injury, neuronal development, inflammation, and learning deficits. ConclusionsThis study represents the first integrative transcriptomic analysis of AIDN using both 3D human cerebral organoids and pediatric patient serum--two complementary, human-relevant models. By identifying consistently dysregulated coding and non-coding RNAs across both platforms, we provide compelling evidence of shared molecular signatures linked to neuronal injury, inflammation, and neurodevelopmental disruption. These findings offer not only mechanistic insights but also lay the groundwork for the development of minimally invasive biomarkers and future therapeutic strategies. This dual-model approach bridges experimental discovery with clinical relevance, advancing the translational understanding of pediatric anesthetic neurotoxicity and supporting efforts to improve long-term neurological outcomes in vulnerable patient populations.

neuroscience↗

bioRxiv2024

SynDRep: A Knowledge Graph-Enhanced Tool based on Synergistic Partner Prediction for Drug Repurposing

MotivationDrug repurposing is gaining interest due to its high cost-effectiveness, low risks, and improved patient outcomes. However, most drug repurposing methods depend on drug-disease-target semantic connections of a single drug rather than insights from drug combination data. In this study, we propose SynDRep, a novel drug repurposing tool based on enriching knowledge graphs (KG) with drug combination effects. It predicts the synergistic drug partner with a commonly prescribed drug for the target disease, leveraging graph embedding and machine learning techniques. This partner drug is then repurposed as a single agent for this disease by exploring pathways between them in KG. ResultsHolE was the best-performing embedding model (with 84.58% of true predictions for all relations), and random forest emerged as the best ML model with an ROC-AUC value of 0.796. Some of our selected candidates, such as miconazole and albendazole for Alzheimers disease, have been validated through literature, while others lack either a clear pathway or literature evidence for their use for the disease of interest. Therefore, complementing SynDRep with more specialized KG, and additional training data, would enhance its efficacy and offer cost-effective and timely solutions for patients. Availability and ImplementationSynDRep is available as an open-source Python package at https://github.com/SynDRep/SynDRep under the Apache 2.0 License.

bioinformatics↗

bioRxiv2024

Distinctive Transcriptional and Microbial Signature in Cutaneous Acute Graft-vs-Host-Disease

Skin acute graft-vs-host disease (aGVHD) is often first manifestation of GVHD, yet very few preclinical and clinical studies have focused on this target organ, leaving a critical information gap in the pathophysiology of GVHD. We hypothesized that analysis of host and microbiome gene expression could yield novel insights into the molecular and immunologic mechanisms underlying skin GVHD. Our objectives were to determine the differential host gene expression and microbiome profile of human skin aGVHD samples compared to normal skin, and aGVHD corticosteroid responders to non-responders. We performed RNA-Sequencing on lower arm biopsies from 45 patients compared to 10 healthy controls. Our findings suggest a distinctive transcriptional signature of cutaneous aGVHD, that could identify potentially actionable targets for prevention or treatment corticosteroid refractory disease. Our analysis suggests a key role of dendritic cells and macrophages, potentially mediated by differential expression of MIF, in the development of cutaneous aGVHD and corticosteroid responsiveness. Additionally, we describe a unique microbial signature in cutaneous aGVHD that includes skin microbes not previously described in this population.

genomics↗

bioRxiv2023

The first chromosome-level annotated reference genome for Chrosomus eos, the northern redbelly dace

Hybridization amongst teleost fish species is an ongoing phenomenon with unclear implications. Chrosomus eos, the northern redbelly dace, is a species with an especially complex and fascinating history of hybridization with the closely related species Chrosomous neogaeus, the finescale dace. The two species historically hybridized during the last glacial maximum, forming a rare unisexual F1 hybrid lineage that utilizes gynogenetic reproduction. This hybridization event is currently thought to have only occurred during the glacial period, with subsequent dispersal of parents and hybrids into contemporary ranges during glacial recession and a cessation of further hybridization. All three maintain sympatric relationships, with limited evidence suggesting recent or contemporary hybridization between the parental species. To enable future research, a novel, high-quality, chromosome-level genome was produced through Dovetail Genomics and analyzed for completeness and the syntenic relationship between itself and the high-quality, well cited zebrafish Danio rerio genome.

genomics↗

bioRxiv2022

AI reveals insights into link between CD33 and cognitive impairment in Alzheimer's Disease

Modeling biological mechanisms is a key for disease understanding and drug-target identification. However, formulating quantitative models in the field of Alzheimers Disease is challenged by a lack of detailed knowledge of relevant biochemical processes. Additionally, fitting differential equation systems usually requires time resolved data and the possibility to perform intervention experiments, which is difficult in neurological disorders. This work addresses these challenges by employing the recently published Variational Autoencoder Modular Bayesian Networks (VAMBN) method, which we here trained on combined clinical and patient level gene expression data while incorporating a disease focused knowledge graph. Our approach, called iVAMBN, resulted in a quantitative model that allowed us to simulate a down-expression of the putative drug target CD33, including potential impact on cognitive impairment and brain pathophysiology. Experimental validation demonstrated a high overlap of molecular mechanism predicted to be altered by CD33 perturbation with cell line data. Altogether, our modeling approach may help to select promising drug targets. Author SummaryFor the last 20 years the field of Alzheimers Disease (AD) is marked by a series of continuous failures to deliver demonstrably effective medications to patients. This is also highlighted by the highly controversial recent approval of Aduhelm (Biogen) by the FDA, which is now investigated internally due to the lack of clear efficacy. One of the reasons for the continuous failure of trials in AD is the choice of the wrong target mechanism. In essence there is a lack of understanding, how targeting a certain molecule would affect cognitive impairment in human. One way to address this issue is the development of quantitative system level models connecting the molecular level with the phenotype. However, formulating such models in the field of Alzheimers Disease is challenged by a lack of detailed knowledge of relevant biochemical processes and the connection of molecular mechanisms to cognitive impairment. Additionally, fitting of differential equation systems, which are often used in systems biology, requires time resolved data and the possibility to perform intervention experiments, which is difficult in neurological disorders due to the lack of realistic model systems. Our work addresses these challenges by employing a novel hybrid Artificial Intelligence (AI) approach combining variational autoencoders with Bayesian Networks. Our proposed approach, named Integrative Variational Autoencoder Modular Bayesian Networks (iVAMBN), was trained on combined clinical and patient level gene expression data while incorporating a disease focused knowledge graph. Our method resulted in an interpretable, quantitative model. It showed connections between various biological mechanisms playing a role in AD. Furthermore, iVAMBN directly connected the molecular level to the disease phenotype. Our model allowed us to simulate a down-expression of the putative drug target CD33. Results showed a significantly increased cognition and predicted perturbation of a number of biological mechanisms. We experimentally validated these predictions using gene expression data from a knock-out THP-1 monocyte cell line. This experiment confirmed our model predictions up to a very high extend. To our knowledge we thus developed the first experimentally validated, quantitative, multi-scale model connecting molecular mechanisms with clinical outcomes in the AD field.

systems biology↗

bioRxiv2020

The effect of noise trauma and high-frequency stimulation on thalamic sensory gating in rodents

BackgroundThe medial geniculate body (MGB) of the thalamus plays a central role in tinnitus pathophysiology. Breakdown of sensory gating in this part of the auditory thalamus is a potential mechanism underlying tinnitus. The alleviation of tinnitus-like behavior by high-frequency stimulation (HFS) of the MGB might mitigate dysfunctional sensory gating. ObjectiveThe study aims at exploring the role of the MGB in sensory gating as a mandatory relay area in auditory processing in noise-exposed and control subjects, and to assess the effect of MGB HFS on this function. MethodsNoise-exposed rats and controls were tested. Continuous auditory sequences were presented to allow assessment of sensory gating effects associated with pitch, binary grouping, and temporal regularity. Evoked potentials (EP) were recorded from the MGB and acquired before and after HFS (100 Hz). ResultsNoise-exposed rats showed differential modulation of MGB EP amplitudes, confirmed by significant main effects of stimulus type, pair position and temporal regularity. Noise-exposure selectively abolished the effect of temporal regularity on EP amplitudes. A significant three-way interaction between HFS phase, temporal regularity and rat condition (noise-exposed, control) revealed that only noise-exposed rats showed significantly reduced EP amplitudes following MGB HFS. ConclusionThis is the first report that shows thalamic filtering of incoming auditory signals based on different sound features. Noise-exposed rats further showed higher EP amplitudes in most conditions and did not differentiate the temporal regularity. Critically, MGB HFS was effective in reducing amplitudes of the EP responses in noise-exposed animals. HighlightsO_LIEP findings indicate sensory gating in the MGB in rats. C_LIO_LINoise exposure alters EP amplitudes in the MGB. C_LIO_LIHFS selectively suppresses EP responses in noise-exposed animals. C_LI

neuroscience↗

bioRxiv2019

Novel engraftment and T cell differentiation of human hematopoietic cells in Art-/- IL2RG-/ SCID pigs

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. In this work we have generated T- B- NK- SCID pigs through site directed CRISPR/Cas9 mutagenesis of IL2RG within a naturally occurring DCLRE1C (Artemis)-/- genetic background. We confirmed Art-/- IL2RG-/Y pigs lacked T, B, and NK cells in both peripheral blood and lymphoid tissues. Additionally, we and successfully performed a bone marrow transplant on one Art-/- IL2RG-/Y male SCID pig with a bone marrow from a complete swine leukocyte antigen (SLA) matched donor without conditioning to reconstitute porcine T and NK cells. Next, we performed in utero injections of cultured human CD34+ selected cord blood cells into the fetal Art-/- IL2RG-/Y SCID pigs. At birth, human CD45+ CD3{varepsilon}+ cells were detected in peripheral blood of in utero injected SCID piglets. Human leukocytes were also detected within the bone marrow, spleen, liver, thymus, and mesenteric lymph nodes of these animals. Taken together, we describe critical steps forwards the development of an immunologically humanized SCID pig model.\n\nOne sentence summaryWe have generated a T- B- NK- SCID pig model through site directed mutagenesis of IL2RG in a naturally occurring Artemis null background and show successful engraftment of human T and B cells in blood and lymphoid organs after in utero injection of human hematopoietic stem cells.

immunology↗