Biology subjects

Olson, J. W.

Publications and source records attributed to Olson, J. W..

2 recordsLinked to original sources

bioRxiv2023

Differential Contribution of Sensorimotor Cortex and Subthalamic Nucleus to Unimanual and Bimanual Hand Movements

Why does unilateral subthalamic nucleus deep brain stimulation improve motor function bilaterally? To address this clinical observation, we collected parallel neural recordings from sensorimotor cortex and the subthalamic nucleus during repetitive ipsilateral, contralateral, and bilateral hand movements in patients with Parkinsons disease undergoing subthalamic nucleus deep brain stimulation. We used a cross-validated electrode-wise encoding model to map EMG data to the neural signals. Electrodes in the subthalamic nucleus encoded movement in a comparable manner for both hands during unimanual and bimanual movements, whereas sensorimotor cortex electrodes displayed a strong contralateral bias. To examine representational overlap in encoding across the two hands, we trained the model with data from one condition (contralateral hand) and used the trained weights to predict neural activity for movements produced with the other hand (ipsilateral hand). Overall, between-hand generalization was poor and this limitation was evident in both SMC and STN. A similar method was used to probe representational overlap across different task contexts (unimanual vs. bimanual). Task context was more important for the STN compared to the SMC indicating that neural activity in the STN showed greater divergence between the unimanual and bimanual conditions. These results indicate that whereas SMC activity is strongly lateralized and relatively context-free, STN integrates contextual information with the ongoing behavior. Significance StatementUnilateral subthalamic nucleus deep brain stimulation (DBS) improves both contralateral and ipsilateral motor symptoms of Parkinsons disease. To explore mechanisms for bilateral improvement, parallel neural recordings from the sensorimotor cortex (SMC) and subthalamic nucleus (STN) were recorded in patients with Parkinsons disease undergoing DBS. Neural activity and muscle activity from the hands were collected while patients performed unimanual and bimanual repetitive hand movements. Activity in SMC primarily encoded contralateral movements and was relatively context-free. In contrast, STN encoded movements in a comparable manner for both hands and was sensitive to the behavioral context.

neuroscience↗

bioRxiv2019

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a novel macromolecular assembly

Targeting Clostridium difficile infection (CDI) is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent CDI often has a binary toxin termed the C. difficile toxin (CDT), in addition to the enterotoxins TsdA and TsdB. CDT has an enzymatic component, termed CDTa, and a pore-forming or delivery subunit termed CDTb. CDTb was characterized here using a combination of single particle cryoEM, X-ray crystallography, NMR, and other biophysical methods. In the absence of CDTa, two novel di-heptamer structures for activated CDTb (aCDTb; 1.0 MDa) were solved at atomic resolution including a symmetric (SymCDTb; 3.14 [A]) and an asymmetric form (AsymCDTb; 2.84 [A]). Roles played by two receptor-binding domains of aCDTb were of particular interest since RBD1 lacks sequence homology to any other known toxin, and the RBD2 domain is completely absent in other well-studied heptameric toxins (i.e. anthrax). For AsymCDTb, a novel Ca2+ binding site was discovered in RBD1 that is important for its stability, and RBD2 was found to be critical for host cell toxicity and the novel di-heptamer fold for both forms of aCDTb. Together, these studies represent a starting point for structure-based drug-discovery strategies to targeting CDT in the most severe strains of CDI. SIGNIFICANCE STATEMENTThere is a high burden from C. difficile infection (CDI) throughout the world, and the Center for Disease Control (CDC) reports more than 500,000 cases annually in the United States, resulting in an estimated 15,000 deaths. In addition to the large clostridial toxins, TcdA/TcdB, a third C. difficile binary toxin (CDT) is associated with the most serious outbreaks of drug resistant CDI in the 21st century. Here, structural biology and biophysical approaches were used to characterize the cell binding component of CDT, termed CDTb, at atomic resolution. Surprisingly, two novel structures were solved from a single sample that help to explain the molecular underpinnings of C. difficile toxicity. These structures will also be important for targeting this human pathogen via structure-based therapeutic design methods.

biophysics↗