Biology subjects

Bernstein, A.

Publications and source records attributed to Bernstein, A..

6 recordsLinked to original sources

bioRxiv2025

Conditioning electrical stimulation enhances functional rewiring in a mouse model of nerve transfer to treat chronic spinal cord injury

Nerve transfer surgery is a state-of-the-art surgical approach to restore hand and arm function in individuals living with tetraplegia, significantly impacting daily life. While nearly a third of all individuals with chronic SCI may benefit from this intervention, variability in outcomes can limit the functional impact. A bedside-to-bench approach was taken to address the variable response of tetraplegic individuals to nerve transfer surgery. We used a hierarchical multiple factor analysis to evaluate the effects of conditioning electrical stimulation (CES) on outcomes in a mouse model of nerve transfer to treat chronic cervical spinal cord injury. We found that CES of donor nerves one week prior to nerve transfer surgery enhanced anatomical and functional measures of innervation of targeted muscles. Furthermore, CES increased the rate of recovery of naturalistic behavior. While the model has some limitations due to the small size of the rodent, our results support the use of CES as an effective approach to improve outcomes in clinical nerve repair settings.

neuroscience↗

bioRxiv2024

Mitochondrial and Microtubule Defects in Exfoliation Glaucoma

Exfoliation Syndrome (XFS) is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG), a secondary open-angle glaucoma. XFG is a complex, multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as altered cellular processes with increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from Normal (No Glaucoma) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species (ROS) accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with an increase in mitochondrial localization to lysosomes and slowed mitophagy flux. Mitochondrial dysfunction in the XFG TFs was associated with an increase in the dynamics of the microtubule cytoskeleton, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, NAD+ precursor, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate abnormal mitochondria in XFG TFs and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.

cell biology↗

bioRxiv2024

A Kinematic Deviation Index (KDI) for Evaluation of Forelimb Function in Rodents

Rodent models are widely used to study neurological conditions and assess forelimb movement to measure function performance, deficit, recovery and treatment effectiveness. Traditional assessment methods based on endpoints such as whether the task is accomplished, while easy to implement, provide limited information on movement patterns important to assess different functional strategies. On the other side, detailed kinematic analysis provides granular information on the movement patterns but is difficult to compare across laboratories, and may not translate to clinical metrics of upper limb function. To address these limitations, we developed and validated a kinematic deviation index (KDI) for rodents that mimics current trends in clinical research. The KDI is a unitless summary score that quantifies the difference between an animal movement during a task and its optimal performance derived from spatiotemporal marker sequences without pre-specifying movements. We demonstrate the utility of KDI in assessing reaching and grasping in mice and validate its discrimination between trial endpoints in healthy animals. Furthermore, we show KDI sensitivity to interventions, including acute and chronic spinal cord injury and optogenetic disruption of sensorimotor circuits. The KDI provides a comprehensive measure of motor function that bridges the gap between detailed kinematic analysis and simple success/failure metrics, offering a valuable tool for assessing recovery and compensation in rodent models of neurological disorders.

neuroscience↗

bioRxiv2021

Absence of enterotypes in the human gut microbiomes reanalyzed with non-linear dimensionality reduction methods

Enterotypes of the human gut microbiome have been proposed to be a powerful prognostic tool to evaluate the correlation between lifestyle, nutrition, and disease. However, the number of enterotypes suggested in the literature ranged from two to four. The growth of available metagenome data and the use of exact, non-linear methods of data analysis challenges the very concept of clusters in the multidimensional space of bacterial microbiomes. Using several published human gut microbiome datasets, we demonstrate the presence of a lower-dimensional structure in the microbiome space, with high-dimensional data concentrated near a low-dimensional non-linear submanifold, but the absence of distinct and stable clusters that could represent enterotypes. This observation is robust with regard to diverse combinations of dimensionality reduction techniques and clustering algorithms.

bioinformatics↗

bioRxiv2020

Temporal regulation of motor behavior on a modified forelimb dexterity test in mice

Hand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution.

neuroscience↗

bioRxiv2019

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control.

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.\n\nMethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.\n\nResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.\n\nConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

bioengineering↗