Biology subjects

Goetz, J.

Publications and source records attributed to Goetz, J..

7 recordsLinked to original sources

bioRxiv2026

Electrocorticographic Network Feature Space Constriction as a Preictal Biomarker

In patients with epilepsy, seizures are associated with pathological neural synchronization. However, the preictal period preceding a seizure often exhibits reduced spatial synchronization compared to normal cognition. This observation aligns with the concept of the brain as a complex dynamical system, where a reduction in dimensionality and resilience can precede a phase transition. The Critical Brain Hypothesis suggests a connection between the loss of healthy scale-free behavior and various disorders, including epilepsy. Our study investigates preictal changes by utilizing network features, such as mean node degree and mean clustering coefficient, derived from thresholded correlation matrices of patient intracranial electrocorticographic electrode data. We observed a suppression of intermittent high-synchronization periods within the feature space during the minutes leading up to seizure onset. This constriction of the explored hypervolume in the preictal state indicates a breakdown in the brains ability to maintain normal coherence. We use these preictal changes to predict the probability of seizure onset using a Support Vector Machine algorithm. These discrete predictions can then be combined into real-time continuous seizure risk forecasts via Bayesian updating. This innovative and computationally lightweight approach has the potential to significantly improve upon static predictions, providing opportunities for more adaptable, quantitative, and interpretable tools for managing seizures.

neuroscience↗

bioRxiv2025

Serum albumin coated stellate mesoporous silica nanocomposites inhibit metastatic outgrowth in zebrafish embryos

Mesoporous silica-based nanoparticles (NPs) are promising tools for developing targeted therapeutic interventions in cancer. Endowed with a large pore silica shell suitable for drug encapsulation and with a responsive magnetic core, iron oxide stellate mesoporous silica (IO STMS) NPs stand out. Yet, their impact and potential toxicity on relevant in vivo models has not been carefully tested yet. Herein, we assessed the impact of these IO STMS nanocomposites in a syngeneic metastasis assay in zebrafish. NPs were surface-modified with human serum albumin (HSA) and loaded or not with the chemotherapeutic doxorubicin (DOX). In vitro, DOX-loaded NPs were expectedly more toxic to zebrafish melanoma (Zmel) cells than no-DOX NPs. In zebrafish embryos, the NPs were rapidly distributed through blood circulation and were found to colocalize over time with the vascular endothelium and local macrophages. Suprisingly, the NPs efficiently reduced the outgrowth of Zmel tumoral masses in an experimental metastasis assay in zebrafish embryos regardless of their loading with DOX. The anti-metastatic effect of these NPs was further improved by increasing the amount of HSA coating, also resulting in higher embryo survival. Altogether, IO STMS NPs showed promising cytotoxic effects on a relevant zebrafish metastasis model, inhibiting metastatic outgrowth in vivo independently of the drug loading. This opens the door to further testing for better exploiting their targeting and drug delivery potentialities.

cancer biology↗

bioRxiv2025

Caspase-1 self-terminates protease activity to enforce homeostasis and prevent inflammasome-driven diseases

Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by the caspase-1 (CASP1) protease, to allow inflammation to resolve and reinstate tissue homeostasis. It is unknown how CASP1 terminates its activity in vivo. Here, we use a knock-in mouse model in which the CASP1 CARD domain linker (CDL) is mutated to prevent self-cleavage (Casp1.CDL mice) to show that CASP1 CDL autoproteolysis terminates CASP1 activity in vivo. We examined these mice under homeostatic conditions and in response to major physiological challenges. In the brain, CASP1 CDL mutation caused anxiety-like behaviour under homeostatic conditions, and exacerbated hippocampal spatial learning deficits in the APP23 genetic model of amyloid-induced neurodegeneration. In the bone marrow, CASP1 CDL mutation promoted steady-state granulopoiesis. In a model of diet-induced liver disease, CASP1 CDL mutation accelerated liver steatosis and promoted liver immune cell infiltration, inflammation and damage. In a liver healing model, CASP1 CDL mutation delayed disease resolution, indicating that CASP1 autocleavage is required to restore homeostasis after a major challenge to organ function. Our data reveal that CASP1 CDL self-cleavage terminates CASP1 inflammatory programs in vivo to maintain homeostasis in steady-state, restore homeostasis after a major challenge to organ function, and suppress inflammasome-driven diseases. These data identify CASP1 as a prime anti-inflammatory drug target, as CASP1 inhibitors may enforce homeostasis and prevent inflammasome-driven diseases.

immunology↗

bioRxiv2024

Reinforced polymer-nanoparticle hydrogels for subcutaneous and sustained delivery of trastuzumab

In oncology, the advent of monoclonal antibody (mAbs) therapeutics represents a major breakthrough in various cancer diseases. However, these biotherapies often necessitate iterative hospital visits for intravenous infusion that can alter patients quality of life and contribute to the chronic saturation of hospitals. Interestingly, subcutaneous formulations of various mAbs offer a promising alternative facilitating faster administration compared with traditional intravenous methods, while still maintaining the same dosing schedule and providing time-saving advantages. Here, we developed an injectable mAb delivery platform using -cyclodextrin (CD)-reinforced polymer-nanoparticle hydrogels to perform a subcutaneous injection but also to delay the release of mAbs. By leveraging the versatility of our platform, we formulated hyaluronic acid- and alginate-based injectable drug depots by simply mixing components that are generally regarded as safe (GRAS). We used trastuzumab for the polymer-antibody complexation. The hydrogel depots delayed mAb release up to at least 3 days in both in vitro and in vivo mice models, outperforming clinically approved Herceptin subcutaneous formulation composed of trastuzumab with recombinant human hyaluronidase (rHuPH20).

bioengineering↗

bioRxiv2021

Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimers disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.

neuroscience↗

bioRxiv2021

Unified classification of mouse retinal ganglion cells using function, morphology, and gene expression

Classification and characterization of neuronal types are critical for understanding their function and dysfunction. Neuronal classification schemes typically rely on measurements of electrophysiological, morphological, and molecular features, but aligning such datasets has been challenging. Here, we present a unified classification of mouse retinal ganglion cells (RGCs), the sole retinal output neurons. We used visually-evoked responses to classify 1859 mouse RGCs into 42 types. We also obtained morphological or transcriptomic data from subsets and used these measurements to align the functional classification to publicly available morphological and transcriptomic data sets. We created an online database that allows users to browse or download the data and to classify RGCs from their light responses using a machine learning algorithm. This work provides a resource for studies of RGCs, their upstream circuits in the retina, and their projections in the brain, and establishes a framework for future efforts in neuronal classification and open data distribution.

neuroscience↗

bioRxiv2018

Live tracking of inter-organ communication by endogenous exosomes in vivo

Extracellular vesicles (EVs) are released by most cell types but the definitive demonstration of their functional relevance remains challenging due to the lack of appropriate model organisms. Here we developed an in vivo model to study EV physiology by expressing CD63-pHluorin in zebrafish embryos. A combination of microscopy techniques and proteomic analysis allowed us to study the biogenesis, composition, transfer, uptake and fate of individual endogenous EVs in vivo. We identified an exosome population released in a syntenin-dependent manner from the Yolk Syncytial Layer into the blood circulation. These exosomes were specifically captured, endocytosed and degraded by patrolling macrophages and endothelial cells in the Caudal Vein Plexus (CVP) in a scavenger receptor and dynamin-dependent manner. Interference with exosome secretion affected CVP growth, supporting their trophic role. Altogether, our work provides a unique model to track in vivo inter-organ communication by endogenous exosomes at individual vesicle level and high spatio-temporal accuracy.\n\nHighlights- Single endogenous EVs can be live-visualized in the whole embryo with CD63-pHluorin\n- In the YSL, syntenin regulates exosome release into the blood for their propagation\n- YSL exosomes reach the tail to be taken up by macrophages and endothelial cells\n- Uptake is scavenger receptor and dynamin-dependent and provides trophic support\n\n\nBlurbWe propose zebrafish embryos expressing a fluorescent reporter for exosomes as a relevant model organism to live-track production, journey and fate of individual extracellular vesicles in vivo. Our model allows investigation of the composition of EVs and the molecular mechanisms controlling their biogenesis and fate and functions in receiving cells.

cell biology↗