Biology subjects

Weber, D. J.

Publications and source records attributed to Weber, D. J..

15 recordsLinked to original sources

bioRxiv2026

ANNet: A first-principles neural network for forward and inverse dynamics

Biological and robotic systems must solve two related computations to move: inverse dynamics, which determines the forces or torques needed to produce a desired movement, and forward dynamics, which maps applied forces to motion. Although these computations are coupled by the same equations of motion, they are usually estimated or implemented as distinct inverse and forward mappings, in both model-based and data-driven formulations. This separation can obscure the shared structure that constrains both problems. Here, we present ANNet, a physics-informed neural network that places both computations on a common learned representation by learning a single scalar quantity from classical mechanics--Appell acceleration energy. The network maps kinematic state and candidate accelerations to this scalar function, and inverse dynamics is obtained by differentiating the learned energy function with respect to acceleration to recover joint torques. Forward dynamics is then calculated without retraining by embedding the same learned energy landscape in an optimization objective whose unconstrained minimum satisfies the Gibbs- Appell equation. The resulting accelerations are integrated forward in time. We evaluate ANNet on a double pendulum paradigm. In trials unseen by the network during training, inverse and optimization-based forward simulations are real-time accurate. Our results provide a first-principles route for using a single learned representation to support both prediction and control. SignificanceRobots and animals must solve two problems to move: computing the forces or torques needed for a desired motion (inverse dynamics) and determining the motion produced by applied forces (forward dynamics), which are usually modeled separately. We show that both problems can be expressed using a single scalar function from classical mechanics, Appell acceleration energy. A neural network trained so that the derivative of this learned function matches reference joint torques performs inverse dynamics. The same network then computes forward dynamics by minimizing an objective built from the learned energy landscape, without retraining. This framework provides a unified representation for prediction and control in both neuroscience and robotics.

neuroscience↗

bioRxiv2025

Dynamic, behavior-dependent interactions between dorsal striatal dopamine and glutamate release predict cognitive flexibility and punishment resistant cocaine use

Cognitive inflexibility covaries with substance use disorder (SUD) risk. To determine if there is a neural relationship between these phenomena, glutamate and dopamine release in the dorsomedial (DMS) and dorsolateral (DLS) striatum were measured as rats performed a discrimination and strategy switching test. Elevations in glutamate release, with reductions in dopamine, at trial initiation (DLS) and prior to choice (DMS and DLS) predicted fast strategy switching and punishment sensitive cocaine seeking. Elevations in DLS and DMS dopamine release at these respective timestamps predicted slow switching and punishment resistance. Orbitofrontal cortex and intralaminar thalamus were significant contributors to DLS and DMS glutamate release, but their relative contributions differed between rats that were fast or slow strategy switchers, and in how they affected behavior. As such, these data describe a neural signature of flexibility and associated circuitry that could be used to predict and treat SUDs in humans.

neuroscience↗

bioRxiv2024

Changes in Gait Asymmetry May Be Caused by Adaptation of Spinal Reflexes

In a recent human study, we found that adaptive changes in step length asymmetry (SLA) are correlated with similar changes in the H-reflex gains of the leg muscles during split-belt treadmill locomotion. While this observation indicated a closer link between gait asymmetry and spinal reflex adaptation, it did not reveal their causal relationship. To better understand this relationship, here we use a neuromuscular model of human walking whose control relies primarily on spinal reflexes. Subjecting the model to split-belt treadmill locomotion with different combinations of belt speed and reflex gain adaptation patterns, we find that belt speed changes increase the variability in SLA but do not result in consistent SLA patterns as observed in human experiments, whereas reflex gain adaptations do. Furthermore, we find that the model produces SLA patterns similar to healthy adults when its reflex gains are adapted in a way similar to the H-reflex changes we observed in our previous human study. The model also predicts SLA patterns similar to the ones observed for cerebellar degeneration patients when the reflexes do not adapt beyond a sudden dip at the time the ipsilateral belt speed is lowered. Our results suggest that SLA does not arise from imposing belt speed changes but requires the adaptation of the reflex gains, and that the dynamic adaptation of these gains may be an essential part of human gait control when encountering unexpected environment changes such as the uneven speed changes in split-belt treadmill locomotion.

neuroscience↗

bioRxiv2023

Computational modeling of dorsal root ganglion stimulation using an Injectrode

ObjectiveMinimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated platinum/iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, effectiveness of stimulation relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures. ApproachWe employed a hybrid computational modeling approach to analyze the impact of the Injectrode system design parameters on charge delivery and the neural response to stimulation. We constructed multiple finite element method models of DRG stimulation and multi-compartment models of DRG neurons. We simulated the neural responses using parameters based on prior acute preclinical experiments. Additionally, we developed multiple human-scale computational models of DRG stimulation to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds. Main resultsOur findings were in accordance with acute experimental measurements and indicated that the Injectrode system predominantly engages large-diameter afferents (A{beta}-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (A{delta}-fibers) activity. SignificanceThe Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired A{beta} activation from the undesired A{delta}-fiber activation.

bioengineering↗

bioRxiv2023

Endosomal activation of the Clostridioides difficile binary toxin is Ca2+-dependent

The C. difficile binary toxin (CDT) enters host cells via endosomal delivery like many other AB-type binary toxins. In this study, the cell-binding component of CDT, termed CDTb, was found to bind and form pores in lipid bilayers upon depleting free Ca2+ ion concentrations, and not by lowering pH, as found for other binary toxins (i.e., anthrax). Cryoelectron microscopy, nuclear magnetic resonance spectroscopy, surface plasmon resonance, electrochemical impedance spectroscopy, CDT toxicity studies, and site directed mutagenesis show that dissociation of Ca2+ from a single site in receptor binding domain 1 (RBD1) of CDTb is consistent with a molecular mechanism in which Ca2+ dissociation from RBD1 induces a "trigger" via conformational exchange that enables CDTb to bind and form pores in endosomal membrane bilayers as free Ca2+ concentrations decrease during CDT endosomal delivery. One-Sentence SummaryCa2+ dissociation and unfolding of a receptor binding domain in CDTb activates pore-formation by the C. difficile binary toxin.

biophysics↗

bioRxiv2023

Electrocatalytic on-site oxygenation for transplanted cell-based-therapies

Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host1, 2. Exogenous oxygen production can support cells and tissues, such as pancreatic islets and engineered therapeutic cells. Previous oxygenation strategies have targeted gas circulation or decomposition of solid peroxides. These strategies however require bulky implants, transcutaneous supply lines, and are limited in their total oxygen production or regulation3, 4. Readily integrated and controlled production of oxygen has eluded cell therapy devices. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy production under hypoxic stress and at high cell densities. Nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction (OER) at neutral pH. It enables a lower OER onset and shows selective oxygen production without evolution of toxic side products over a 300 mV window of operation. This electrocatalytic on site oxygenator (ecO2) can sustain high cell loadings (>60k cells/mm3) in hypoxic conditions in vitro and in vivo. Our results demonstrate that exogenous oxygen production devices can be readily integrated into bioelectronic platforms and enable high cell loadings in smaller device footprints with broad applicability.

bioengineering↗

bioRxiv2022

High-Frequency Stimulation Does Not Improve Comfort of Transcutaneous Spinal Cord Stimulation

Spinal cord neuromodulation has gained much attention for demonstrating improved motor recovery in people with spinal cord injury, motivating the development of clinically applicable technologies. Among them, transcutaneous spinal cord stimulation (tSCS) is attractive because of its non-invasive profile. Many tSCS studies employ a high-frequency (10 kHz) carrier, which has been reported to reduce stimulation discomfort. However, these claims have come under scrutiny in recent years. The purpose of this study was to determine whether high-frequency tSCS is more comfortable at therapeutic amplitudes, which evoke posterior root-muscle (PRM) reflexes. In 16 neurologically intact participants, tSCS was delivered using a 1-ms long monophasic pulse with and without a high-frequency carrier. Stimulation amplitude and pulse duration were varied and PRM reflexes were recorded from the soleus, gastrocnemius, and tibialis anterior muscles. Participants rated their discomfort during stimulation from 0-10 at PRM reflex threshold. At PRM reflex threshold, high-frequency stimulation (0.87 {+/-} 0.2) was equally comfortable as conventional stimulation (1.03 {+/-} 0.18) but required approximately double the charge to evoke the PRM reflex (conventional: 32.4 {+/-} 9.2 {micro}C; high-frequency: 62.5 {+/-} 11.1 {micro}C). Strength-duration curves for high-frequency stimulation had a rheobase that was 4.8X greater and a chronaxie that was 5.7X narrower than the conventional monophasic pulse, indicating that high-frequency stimulation was less efficient in recruiting neural activity in spinal roots. High-frequency tSCS is equally as comfortable as conventional stimulation at amplitudes required to stimulate spinal dorsal roots. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/506783v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@f013f3org.highwire.dtl.DTLVardef@1aded5eorg.highwire.dtl.DTLVardef@1bad2e0org.highwire.dtl.DTLVardef@6aaf96_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

CD36 homologs determine microbial resistance to the Lyme disease spirochete

Pattern recognition receptors sense pathogens in arthropods and mammals through distinct immune processes. Whether these molecules share a similar function and recognize the same microbe in evolutionarily distant species remain ill-defined. Here, we establish that the CD36 superfamily is required for Borrelia burgdorferi resistance in both the arthropod vector and humans. Using the blacklegged tick Ixodes scapularis and an electronic health record-linked biobank, we demonstrate that CD36 members elicit immunity to the Lyme disease spirochete. In ticks, the CD36-like protein Croquemort recognizes lipids and initiates the immune deficiency and jun N-terminal kinase pathways against B. burgdorferi. In humans, exome sequencing and clinical information reveal that individuals with CD36 loss-of-function variants have increased prevalence of Lyme disease. Altogether, we discovered a conserved mechanism of anti-bacterial immunity. One Sentence SummaryLipid receptors belonging to the CD36 superfamily exhibit a shared immune function in both ticks and humans.

immunology↗

bioRxiv2021

Augmented Transcutaneous Stimulation Using an Injectable Electrode

Minimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode(R) is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. The Injectrode serves as a low-impedance conduit to guide current to the deep on-target nerve, reducing activation thresholds by an order of magnitude compared to using only surface stimulation electrodes. To minimize off-target recruitment of cutaneous fibers, the energy transfer efficiency from the surface electrodes to the Injectrode must be optimized. TES energy is transferred to the Injectrode through both capacitive and resistive mechanisms. Electrostatic finite element models generally used in TES research consider only the resistive means of energy transfer by defining tissue conductivities. Here, we present an electroquasistatic model, taking into consideration both the conductivity and permittivity of tissue, to understand transcutaneous power delivery to the Injectrode. The model was validated with measurements taken from (n=4) swine cadavers. We used the validated model to investigate system and anatomic parameters that influence the coupling efficiency of the Injectrode energy delivery system. Our work suggests the relevance of electroquasistatic models to account for capacitive charge transfer mechanisms when studying TES, particularly when high-frequency voltage components are present, such as those used for voltage-controlled pulses and sinusoidal nerve blocks.

bioengineering↗

bioRxiv2021

Stimulation of the Dorsal Root Ganglion using an Injectrode

ObjectiveThe goal of this work was to compare afferent fiber recruitment by dorsal root ganglion (DRG) stimulation using an injectable polymer electrode (Injectrode(R)) and a more traditional cylindrical metal electrode. ApproachWe exposed the L6 and L7 DRG in four cats via a partial laminectomy or burr hole. We stimulated the DRG using an Injectrode or a stainless steel electrode using biphasic pulses at three different pulse widths (80, 150, 300 s) and pulse amplitudes spanning the range used for clinical DRG stimulation. We recorded antidromic evoked compound action potentials (ECAPs) in the sciatic, tibial, and common peroneal nerves using nerve cuffs. We calculated the conduction velocity of the ECAPs and determined the charge-thresholds and recruitment rates for ECAPs from A, A{beta}, and A{delta} fibers. We also performed electrochemical impedance spectroscopy measurements for both electrode types. Main ResultsThe ECAP thresholds for the Injectrode did not differ from the stainless steel electrode across all primary afferents (A, A{beta}, A{delta}) and pulse widths; charge-thresholds increased with wider pulse widths. Thresholds for generating ECAPs from A{beta} fibers were 100.0 {+/-} 32.3 nC using the stainless steel electrode, and 90.9 {+/-} 42.9 nC using the Injectrode. The ECAP thresholds from the Injectrode were consistent over several hours of stimulation. The rate of recruitment was similar between the Injectrodes and stainless steel electrode and decreased with wider pulse widths. SignificanceThe Injectrode can effectively excite primary afferents when used for DRG stimulation within the range of parameters used for clinical DRG stimulation. The Injectrode can be implanted through minimally invasive techniques while achieving similar neural activation to conventional electrodes, making it an excellent candidate for future DRG stimulation and neuroprosthetic applications.

bioengineering↗

bioRxiv2021

Dynamic Detection and Reversal of Myocardial Ischemia Using an Artificially Intelligent Bioelectronic Medicine

SummaryMyocardial ischemia is spontaneous, usually asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, biological neural networks cannot reliably detect and correct myocardial ischemia on their own. In this study, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements biological neural networks enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of [~]92%. ANN-controlled vagus nerve stimulation (VNS) reversed the major biomarkers of myocardial ischemia with no side effects. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse correlates of myocardial ischemia. Lastly, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress states. Overall, these results demonstrate that ANNs can supplement deficient biological neural networks via an artificially intelligent bioelectronic medicine system.

bioengineering↗

bioRxiv2020

Engineering protein-specific proteases: targeting active RAS

We describe the design, kinetic properties, and structures of engineered subtilisin proteases that degrade the active form of RAS by cleaving a conserved sequence in switch 2. RAS is a signaling protein that, when mutated, drives a third of human cancers. To generate high specificity for the RAS target sequence, the active site was modified to be dependent on a cofactor (imidazole or nitrite) and protease sub-sites were engineered to create a linkage between substrate and cofactor binding. Selective proteolysis of active RAS arises from a 2-step process wherein sub-site interactions promote productive binding of the cofactor, enabling cleavage. Proteases engineered in this way specifically cleave active RAS in vitro, deplete the level of RAS in a bacterial reporter system, and also degrade RAS in human cell culture. Although these proteases target active RAS, the underlying design principles are fundamental and will be adaptable to many target proteins.

biochemistry↗

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↗

bioRxiv2019

Augmenting Quadriplegic Hand Function Using a Sensorimotor Demultiplexing Neural Interface

BackgroundThe sense of touch is a key component of motor function. Severe spinal cord injury (SCI) should essentially eliminate sensory information transmission to the brain, that originates from skin innervated from below the lesion. We assessed the hypothesis that, following SCI, residual hand sensory information is transmitted to the brain, can be decoded amongst competing sensorimotor signals, and used to enhance the sense of touch via an intracortically controlled closed-loop brain-computer interface (BCI) system.\n\nMethodsExperiments were performed with a participant who has an AIS-A C5 SCI and an intracortical recording array implanted in left primary motor cortex (M1). Sensory stimulation and standard clinical sensorimotor functional assessments were used throughout a series of several mechanistic experiments.\n\nFindingsOur results demonstrate that residual afferent hand sensory signals surprisingly reach human primary motor cortex and can be simultaneously demultiplexed from ongoing efferent motor intention, enabling closed-loop sensory feedback during brain-computer interface (BCI) operation. The closed-loop sensory feedback system was able to detect residual sensory signals from up to the C8 spinal level. Using the closed-loop sensory feedback system enabled significantly enhanced object touch detection, sense of agency, movement speed, and other sensorimotor functions.\n\nInterpretationTo our knowledge, this is the first demonstration of simultaneously decoding multiplexed afferent and efferent activity from human cortex to control multiple assistive devices, constituting a sensorimotor demultiplexing BCI. Overall, our results support the hypothesis that sub-perceptual neural signals can be decoded reliably and transformed to conscious perception, significantly augmenting function.\n\nFundingInternal funding was provided for this study from Battelle Memorial Institute and The Ohio State University Center for Neuromodulation.

neuroscience↗

bioRxiv2019

A Truly Injectable Neural Stimulation Electrode Made From an In-Body Curing Polymer/Metal Composite

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, we have developed a novel electrode that begins as an uncured, flowable pre-polymer that can be injected around a neuroanatomical target to minimize surgical manipulation. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, we performed detailed electrochemical and microscopy characterization of its material properties and validated the feasibility of using it to electrically stimulate the nervous system in rats and swine. The silicone-metal-particle composite performed very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of being simpler than traditional electrode designs, less invasive, and more cost-effective, the Injectrode has the potential to increase the adoption of neuromodulation therapies for existing and new indications.

bioengineering↗