Biology subjects

Staff, N. P.

Publications and source records attributed to Staff, N. P..

4 recordsLinked to original sources

bioRxiv2026

A Translational Platform for Brain-Computer Interfaces and Adaptive Neuromodulation: Technical Characterization, Long-Term Validation, and Implementation of the CorTec Brain Interchange--BCI2000 Ecosystem

Objective: Adaptive neuromodulation systems and implantable brain-computer interfaces (BCIs) are promising therapies for neurological and psychiatric disorders. However, their broader translation into research and clinical practice remains limited by technological complexity, restricted access to implantable research platforms, and the lack of standardized, reproducible experimental workflows. We therefore aimed to develop and validate an open, general-purpose translational ecosystem that enables rapid development, evaluation, and dissemination of novel neuromodulation and implantable BCI paradigms. Approach: The CorTec Brain Interchange (BIC) implantable neural sensing and stimulation device was integrated with the open-source BCI2000 platform to create a modular, extensible neuromodulation ecosystem. We established a standardized battery of quantitative assessments to characterize implantable neuromodulation systems to comprehensively evaluate the CorTec BIC device through benchtop characterization, long-term preclinical in vitro and in vivo validation, and a human proof-of-concept demonstration. Results: Benchtop and saline testing provided a comprehensive technical ex vivo characterization of the BIC device, independently validating previously reported performance while extending its characterization through quantification of the recording noise floor, stimulation and acquisition latencies and impedance measurement accuracy. Long-term in vivo validation in five canines, with the longest implantation exceeding three years, demonstrated stable chronic recordings while capturing progressive channel deterioration and its underlying mechanical causes. The ecosystem enabled active functional decoding more than two years after implantation, implementation of closed-loop stimulation using arbitrary spectral biomarkers, detection and modulation of epilepsy-associated biomarkers, and brain stimulation evoked potential recordings. In addition, we translated an established one-dimensional BCI cursor control paradigm to the BIC benchtop evaluation kit and demonstrated its feasibility in a human participant. Finally, we openly provide standardized surgical, imaging, and analysis pipelines together with datasets and software to facilitate reproducible neuromodulation research. Significance: We present a versatile, open-source translational ecosystem that supports a wide range of neuromodulation and implantable BCI applications with minimal modification. This battery of quantitative assessments can be applied generally as a blueprint for systematic characterization of implantable neuromodulation systems. By combining comprehensive hardware characterization with standardized software tools and experimental workflows, this work provides both an essential reference for researchers adopting the Brain Interchange platform. The ecosystem lowers technical barriers to implantable neurotechnology research, promotes reproducibility, and provides a foundation for accelerating the development and clinical translation of next-generation adaptive neuromodulation and implantable BCI therapies for patients with neurological and psychiatric disorders.

bioengineering↗

bioRxiv2025

ALG13 loss-of-function alters glycosylation, impairs neuronal maturation, and drives network hypoactivity in a cortical organoid model of CDG

BackgroundCongenital disorders of glycosylation (CDGs) are a group of rare metabolic diseases recognized for their neurological presentations, including developmental delay and seizures. However, the link between glycosylation defects and cortical brain network pathology remains elusive. MethodsTo address this unmet need, we generated iPSC derived human cortical organoids (hCOs) for ALG13-CDG, which is the second most common CDG that is also X-linked. To comprehensively understand the impact of glycosylation defects on cortical pathology in CDG, we combined electrophysiological recordings using multi-electrode arrays (MEA) with comprehensive molecular profiling via multiomics, including scRNA-seq, proteomics, glycoproteomics, N-glycan imaging, lipidomics, and metabolomics. X-inactivation status was also evaluated in both iPSCs and organoids. ResultsALG13-CDG hCOs revealed reduced glycosylation of proteins critical for extracellular matrix (ECM), neuronal migration, lipid metabolism, calcium ion homeostasis, and neuronal excitability. Dysregulation in related pathways was corroborated by proteomics and scRNA-seq, which also showed altered communication patterns in these pathways. Trajectory analysis revealed an inversion in neuronal development, with early inhibitory and delayed excitatory development, indicating an excitatory and inhibitory (E/I) imbalance. MEA recordings demonstrated early network hypoactivity with reduced firing rates, immature burst dynamics, and shorter axonal extensions. Despite this, transcriptomic and proteomic data revealed upregulation of excitatory receptors suggesting latent hyperexcitability. Altered lipid and sugar (GlcNAc) metabolism and skewed X-inactivation were also observed. ConclusionsOur study provides the first evidence of glycosylation defects in an ALG13-CDG human cortical organoid (hCO) model and links these defects to disrupted neuronal developmental trajectories and dysregulation of key pathways essential for brain function. We identify mistimed neuronal maturation and an excitatory/inhibitory (E/I) imbalance as early drivers of network hypoactivity and immature burst dynamics, with downstream compensatory hyperexcitability that may contribute to seizure susceptibility. While specific to ALG13-CDG, these mechanisms likely extend to other glycosylation disorders with overlapping neurological features. This work offers new mechanistic insight into cortical dysfunction associated with impaired protein glycosylation and highlights potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2025

PGM1 deficiency disrupts sarcomere and mitochondrial function in a stem-cell cardiomyocyte model

BackgroundPhosphoglucomutase-1 (PGM1) plays a pivotal role in glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause PGM1-congenital disorder of glycosylation (PGM1-CDG), a multisystem disorder with cardiac involvement. While glycosylation abnormalities in PGM1-CDG are treatable with galactose, cardiomyopathy does not improve suggesting a glycosylation-independent pathomechanism. Recently, mitochondrial abnormalities have been shown in a heart of a PGM1-deficicient patient and PGM1-mouse model. In addition, PGM1 has been associated with LDB3 (ZASP/Cypher), a sarcomeric Z-disk protein also associated with cardiomyopathy. However, the cardiac-specific role of PGM1 remains poorly understood, and targeted therapies for PGM1-related cardiomyopathy are currently lacking. MethodsInduced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays. ResultsPGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy. ConclusionPGM1 is a key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/662580v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@17da449org.highwire.dtl.DTLVardef@1acb669org.highwire.dtl.DTLVardef@1fbbeecorg.highwire.dtl.DTLVardef@b38b6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity

Taxanes are chemotherapeutic agents that induce microtubule modifications in cancer cells, resulting in cell cycle modifications and tumor remission. Here we show that paclitaxel, a widely used taxane, also induces microtubule modifications in healthy epidermal keratinocytes leading to chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel activates the cell cycle regulator, Kinesin-5 (Eg5), which promotes microtubule detyrosination and fasciculation (dfMT). Eg5 loss protects neurons from paclitaxel neurotoxicity, whereas keratinocyte-specific overexpression promotes axon degeneration. In vivo imaging and 3D reconstructions of dfMTs and nuclei, combined with mechanotransduction studies further show that dfMTs constrict keratinocyte nuclei, leading to nuclear Nox-dependent reactive oxygen species (X-ROS) formation upstream of MMP-13 and cutaneous sensory axon degeneration. This new insight facilitates our understanding of chemotherapy side effects and highlights the need for targeted therapies.

cell biology↗