Biology subjects

Britz, G. W.

Publications and source records attributed to Britz, G. W..

4 recordsLinked to original sources

bioRxiv2026

Multifunctional nanozyme therapy accelerates hematoma clearance and attenuates genome damage and senescence after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a devastating form of stroke characterized by rapid hematoma formation in the brain, resulting in multiple pathological events due to mass effect and toxicity of extravasated blood and its blood products. ICH leads to poor long-term outcomes despite advances in hematoma management, largely due to secondary injury mechanisms. Hemin and iron released in the peri-hematomal environment trigger genome damage, transient senescence, and inflammatory signaling that may initially limit ferroptosis but ultimately contribute to persistent neurodegeneration. Given the multiple pathological events initiated following ICH, it is not surprising that no single neuroprotective strategy has been effective. In this study, we investigated these interconnected pathways in a rodent model of ICH and evaluated the therapeutic potential of DEF-OAC-PEG, a pleiotropic synthetic oxidized carbon nano-enzyme that has catalytic mitochondrial and cellular protective actions, covalently bonded to the iron chelator deferoxamine and shown in our previous work to have strong in vitro protective effects against hemin and iron toxicity and in vivo evidence of reduction in genome damage. Here, we examined mechanisms of action in an in vivo ICH mouse model. Autologous whole blood injection into the mouse brain striatum induced robust astroglial and microglial activation, increased neuronal Heme Ooxygenase-1 expression, and DNA damage and senescence in neurons and oligodendrocytes. Systemic intraperitoneal administration of DEF-OAC-PEG, initiated 3 hours after ICH, resulted in robust brain penetration in wild-type mice, with preferential accumulation in peri-hematomal regions of ICH mice. Surprisingly, nanozyme treatment produced a rapid, significant acceleration of hematoma clearance compared with untreated ICH animals. This effect was associated with enhanced detection of CD68-positive microglia/macrophages, which also showed internalized nanozymes, suggesting that nanozyme promotes immune-mediated hematoma resolution. Importantly, DEF-OAC-PEG also markedly attenuated ICH-induced DNA damage and senescence in neurons and oligodendrocytes. Together, these findings identify genome instability and senescence as key consequences of hemorrhagic brain injury and demonstrate that multifunctional nanozyme therapy can simultaneously promote hematoma resolution and mitigate secondary neurodegenerative injury following ICH.

neuroscience↗

bioRxiv2026

Acute electrical neuromodulation paradigms restore firing behavior and inhibition in secondary brain injury: A computational study.

Secondary Brain Injury (SBI) occurs after the initial physical insult caused due to traumatic brain injuries and strokes. SBI leads to a massive loss of brain functionalities if timely intervention is not administered. This work analyses the delineated effects of three acute SBI processes in two-neuron motifs and shows that the right stimulation paradigm during specific key SBI events help restore firing rate trends in neurons. The Hodgkin-Huxley neuron is extended to theoretically model two categories of two-neuron motifs: a feedforward excitatory motif (Motif 1: Two pyramidal neurons with glutamatergic synapses) and a feedforward inhibitory motif (Motif 2: One pyramidal neuron and one interneuron with GABAergic synapses). Three important SBI processes in the motifs were modeled: glutamate excitotoxicity, increased extracellular potassium ion concentration, and cellular energy deficit. Firing rate trend analysis is performed for increasing severity of SBI processes, and interesting points (key events) are identified. A wide range of ACS and DBS stimulation parameters are applied to the motifs during these key events to assess the firing rate response during stimulation. Increasing SBI severity caused an overall increase in excitation, synchronizing neuronal activities in Motif 1 and reducing inhibition in Motif 2. Alternate current stimulation paradigms were found to desynchronize and regulate neuronal firing in Motif 1. Deep brain stimulation parameters were found to increase inhibition in Motif 2, thereby helping to maintain the excitation-inhibition balance. The right stimulation paradigm administered at appropriate key events helps regulate neuronal firing, thereby reducing the metabolic burden on the neurons during acute SBI. Author SummaryTraumatic Brain Injuries (TBIs) and strokes affect millions causing issues such as motor and speech disorders, memory and cognitive decline adding to high global economic burden. Secondary Brain Injury (SBI) is the aftermath of TBIs and strokes, which causes loss of brain functionalities, leading to disabilities. Early intervention reduces disabilities and improves quality of survivors life. Therapeutic electrical brain stimulation has gained prominence to help restore brain functionalities post brain injuries. It is usually administered chronically post injury, when disabilities have set. Here, we investigate if electrical brain stimulation during acute SBI leads to prevention of neurodegeneration, thereby retention of brain functionalities using biophysics. We model fundamental two neuron motifs exhibiting feedforward excitatory and feedforward inhibitory behavior (form the backbone of neuronal networks) and add SBI pathways and brain stimulation models to this scenario. On analyzing neuronal firing during various stimulation strategies at key SBI events, we found that specific Alternate Current Stimulation parameters can desynchronize and regulate firing, and Deep Brain Stimulation parameters could restore inhibition when the underlying neuronal properties are known and leveraged. Hence, we show that acute electrical stimulation regulates neuronal firing with appropriate stimulation parameters and SBI conditions, thereby suggesting possible effective early intervention strategies.

neuroscience↗

bioRxiv2025

Quantitative evaluation of normal cerebrospinal fluid flow in the Sylvian aqueduct and perivascular spaces of the middle cerebral artery and circle of Willis via 2D phase-contrast MR imaging

Recently, it was proposed that CSF flow constitutes a critical part of the glymphatic system, playing a critical role in various brain abnormalities from Alzheimers disease to hydrocephalus. Thus, measurement of CSF flow has been increasingly used for diagnostic and clinical monitoring purposes. Phase-contrast MRI has been used to determine CSF flow. However, CSF flow in the periarterial spaces of the circle of Willis and the middle cerebral artery which are important conduits remain unexplored. We employed phase-contrast MRI to explore CSF flow along the perivascular spaces of the circle of Willis and the middle cerebral artery to establish baseline parameters of CSF and compare them with the Sylvian aqueduct. To analyze CSF flow in the perivascular space, we developed a new, semi-automated method for outlining the perivascular space and extracting CSF flow parameters. The twenty-four healthy participants were recruited to achieve an even distribution by age (mean: 40 {+/-} 11) and gender (13 males). We validated our routine for CSF flow measurements by comparing CSF flow in the Sylvian aqueduct (0.00700 mL/s) with the range of literature values, 0.0049-0.0432 mL/s. For all CSF parameters, the circle of Willis and middle cerebral artery were differed from the Sylvian aqueduct. For most CSF flow parameters, the 95% confidence intervals of the circle of Willis and middle cerebral artery overlap. The linear mixed models and general linear mixed models for flow indicate strong effects of the conduits. CSF velocity in these conduits were lower 0.159 cm/s and 0.198 cm/s respectively than in the Sylvian aqueduct. Overall, differences in CSF flow parameters between sex and age groups were negligible. In this study, we have validated our routine and established baseline values of CSF flow along the circle of Willis and the middle cerebral artery as well as highlighted the limited influence of sex and/or age.

neuroscience↗

bioRxiv2024

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

biochemistry↗