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Open Access Publications from the University of California

Biomedical Engineering

UC Irvine

Biomedical Engineering - Open Access Policy Deposits

This series is automatically populated with publications deposited by UC Irvine Samueli School of Engineering Biomedical Engineering researchers in accordance with the University of California’s open access policies. For more information see Open Access Policy Deposits and the UC Publication Management System.

Cover page of A single-center, assessor-blinded, randomized controlled clinical trial to test the safety and efficacy of a novel brain-computer interface controlled functional electrical stimulation (BCI-FES) intervention for gait rehabilitation in the chronic stroke population.

A single-center, assessor-blinded, randomized controlled clinical trial to test the safety and efficacy of a novel brain-computer interface controlled functional electrical stimulation (BCI-FES) intervention for gait rehabilitation in the chronic stroke population.

(2024)

BACKGROUND: In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. METHODS: This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. DISCUSSION: BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. TRIAL REGISTRATION: The trial was registered as BCI-FES Therapy for Stroke Rehabilitation on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

Cover page of Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.

Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.

(2024)

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of the potential site. In addition, multi-tier screening was deployed to identify potential binders targeting the potential site. Our efforts to identify a new allosteric site contribute to community-wide initiatives developing therapies using multiple allosteric inhibitors to target distinct pockets on SHP2, in the hope of potentially inhibiting or slowing tumor growth associated with SHP2.

Cover page of Evaluation of Bi-layer Silk Fibroin Grafts for Inlay Vaginoplasty in a Rat Model

Evaluation of Bi-layer Silk Fibroin Grafts for Inlay Vaginoplasty in a Rat Model

(2024)

Background

Autologous tissues derived from bowel, buccal mucosa and skin are primarily used to repair or replace diseased vaginal segments as well as create neovaginas for male-to-female transgenders. These grafts are often limited by scarce tissue supply, donor site morbidity and post-operative complications. Bi-layer silk fibroin (BLSF) biomaterials represent potential alternatives for vaginoplasty given their structural strength and elasticity, low immunogenicity, and processing flexibility. The goals of the current study were to assess the potential of acellular BLSF scaffolds for vaginal tissue regeneration in respect to conventional small intestinal submucosal (SIS) matrices in a rat model of vaginoplasty.

Methods

Inlay vaginoplasty was performed with BLSF and SIS scaffolds (N = 21 per graft) in adult female rats for up to 2 months of implantation. Nonsurgical controls (N = 4) were investigated in parallel. Outcome analyses included histologic, immunohistochemical and histomorphometric evaluations of wound healing patterns; µ-computed tomography (CT) of vaginal continuity; and breeding assessments.

Results

Animals in both scaffold cohorts exhibited 100% survival rates with no severe post-operative complications. At 2 months post-op, µ-CT analysis revealed normal vaginal anatomy and continuity in both graft groups similar to controls. In parallel, BLSF and SIS grafts also induced comparable constructive remodeling patterns and were histologically equivalent in their ability to support formation of vascularized vaginal neotissues with native tissue architecture, however with significantly less smooth muscle content. Vaginal tissues reconstructed with both implants were capable of supporting copulation, pregnancy and similar amounts of live births.

Conclusions

BLSF biomaterials represent potential "off-the-shelf" candidates for vaginoplasty.

Cover page of Cadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs.

Cadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs.

(2024)

The F-box domain is a highly conserved structural motif that defines the largest class of ubiquitin ligases, Skp1/Cullin1/F-box protein (SCF) complexes. The only known function of the F-box motif is to form the protein interaction surface with Skp1. Here we show that the F-box domain can function as an environmental sensor. We demonstrate that the F-box domain of Met30 is a cadmium sensor that blocks the activity of the SCFMet30 ubiquitin ligase during cadmium stress. Several highly conserved cysteine residues within the Met30 F-box contribute to binding of cadmium with a KD of 8 µM. Binding induces a conformational change that allows for Met30 autoubiquitylation, which in turn leads to recruitment of the segregase Cdc48/p97/VCP followed by active SCFMet30 disassembly. The resulting inactivation of SCFMet30 protects cells from cadmium stress. Our results show that F-box domains participate in regulation of SCF ligases beyond formation of the Skp1 binding interface.

Cover page of Reproducibility of a semiautomatic lobar lung tissue assignment technique on noncontrast CT scans: a study on swine animal model.

Reproducibility of a semiautomatic lobar lung tissue assignment technique on noncontrast CT scans: a study on swine animal model.

(2024)

BACKGROUND: To evaluate the reproducibility of a vessel-specific minimum cost path (MCP) technique used for lobar segmentation on noncontrast computed tomography (CT). METHODS: Sixteen Yorkshire swine (49.9 ± 4.7 kg, mean ± standard deviation) underwent a total of 46 noncontrast helical CT scans from November 2020 to May 2022 using a 320-slice scanner. A semiautomatic algorithm was employed by three readers to segment the lung tissue and pulmonary arterial tree. The centerline of the arterial tree was extracted and partitioned into six subtrees for lobar assignment. The MCP technique was implemented to assign lobar territories by assigning lung tissue voxels to the nearest arterial tree segment. MCP-derived lobar mass and volume were then compared between two acquisitions, using linear regression, root mean square error (RMSE), and paired sample t-tests. An interobserver and intraobserver analysis of the lobar measurements was also performed. RESULTS: The average whole lung mass and volume was 663.7 ± 103.7 g and 1,444.22 ± 309.1 mL, respectively. The lobar mass measurements from the initial (MLobe1) and subsequent (MLobe2) acquisitions were correlated by MLobe1 = 0.99 MLobe2 + 1.76 (r = 0.99, p = 0.120, RMSE = 7.99 g). The lobar volume measurements from the initial (VLobe1) and subsequent (VLobe2) acquisitions were correlated by VLobe1 = 0.98VLobe2 + 2.66 (r = 0.99, p = 0.160, RSME = 15.26 mL). CONCLUSIONS: The lobar mass and volume measurements showed excellent reproducibility through a vessel-specific assignment technique. This technique may serve for automated lung lobar segmentation, facilitating clinical regional pulmonary analysis. RELEVANCE STATEMENT: Assessment of lobar mass or volume in the lung lobes using noncontrast CT may allow for efficient region-specific treatment strategies for diseases such as pulmonary embolism and chronic thromboembolic pulmonary hypertension. KEY POINTS: • Lobar segmentation is essential for precise disease assessment and treatment planning. • Current methods for segmentation using fissure lines are problematic. • The minimum-cost-path technique here is proposed and a swine model showed excellent reproducibility for lobar mass measurements. • Interobserver agreement was excellent, with intraclass correlation coefficients greater than 0.90.

Cover page of Temporal dynamics of the multi-omic response to endurance exercise training

Temporal dynamics of the multi-omic response to endurance exercise training

(2024)

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

Cover page of Google Trends Analysis of Otologic Symptom Searches Following COVID-19.

Google Trends Analysis of Otologic Symptom Searches Following COVID-19.

(2024)

INTRODUCTION: COVID-19 infection was accompanied by otologic symptoms, a pattern that was captured early by Google Trends. The objective of this study is to investigate searches for otologic symptoms and identify correlations with the pandemic onset. MATERIALS AND METHODS: Search interest for otologic symptoms was gathered using Google Trends from two years before and two years following the pandemic start date. A two-tailed Mann-Whitney U test was used to identify significant changes and effect size. RESULTS: In total, search interest for 14 terms was collected, with significant changes identified in 11. Six terms showed increased search interest, with the most significant rises observed for headache (r=0.589, p<0.001), dizziness (r=0.554, p<0.001), and tinnitus (r=0.410, p<0.001). Search interest decreased for five terms, with the most notable declines found in searches for migraine headache (r=0.35, p<0.001) and phonophobia (r=0.22, p=0.002). No significant changes were seen in ear pressure (p=0.142), neck pain (p=0.935), and sudden hearing loss (p=0.863) searches. CONCLUSION: COVID-19 infection is often accompanied otologic symptoms and holds a diagnostic role. Fluctuating search interest may be attributed to a true increase in cases, media trends, or peoples desires to stay informed. Google Trends robustly captured trends in search interest and presented itself as a valuable epidemiological tool.

Cover page of Light-Chain Cardiac Amyloidosis: Cardiac Magnetic Resonance for Assessing Response to Chemotherapy.

Light-Chain Cardiac Amyloidosis: Cardiac Magnetic Resonance for Assessing Response to Chemotherapy.

(2024)

OBJECTIVE: Cardiac magnetic resonance (CMR) is a diagnostic tool that provides precise and reproducible information about cardiac structure, function, and tissue characterization, aiding in the monitoring of chemotherapy response in patients with light-chain cardiac amyloidosis (AL-CA). This study aimed to evaluate the feasibility of CMR in monitoring responses to chemotherapy in patients with AL-CA. MATERIALS AND METHODS: In this prospective study, we enrolled 111 patients with AL-CA (50.5% male; median age, 54 [interquartile range, 49-63] years). Patients underwent longitudinal monitoring using biomarkers and CMR imaging. At follow-up after chemotherapy, patients were categorized into superior and inferior response groups based on their hematological and cardiac laboratory responses to chemotherapy. Changes in CMR findings across therapies and differences between response groups were analyzed. RESULTS: Following chemotherapy (before vs. after), there were significant increases in myocardial T2 (43.6 ± 3.5 ms vs. 44.6 ± 4.1 ms; P = 0.008), recovery in right ventricular (RV) longitudinal strain (median of -9.6% vs. -11.7%; P = 0.031), and decrease in RV extracellular volume fraction (ECV) (median of 53.9% vs. 51.6%; P = 0.048). These changes were more pronounced in the superior-response group. Patients with superior cardiac laboratory response showed significantly greater reductions in RV ECV (-2.9% [interquartile range, -8.7%-1.1%] vs. 1.7% [-5.5%-7.1%]; P = 0.017) and left ventricular ECV (-2.0% [-6.0%-1.3%] vs. 2.0% [-3.0%-5.0%]; P = 0.01) compared with those with inferior response. CONCLUSION: Cardiac amyloid deposition can regress following chemotherapy in patients with AL-CA, particularly showing more prominent regression, possibly earlier, in the RV. CMR emerges as an effective tool for monitoring associated tissue characteristics and ventricular functional recovery in patients with AL-CA undergoing chemotherapy, thereby supporting its utility in treatment response assessment.

Cover page of A new hip fracture risk index derived from FEA-computed proximal femur fracture loads and energies-to-failure.

A new hip fracture risk index derived from FEA-computed proximal femur fracture loads and energies-to-failure.

(2024)

UNLABELLED: Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur. We developed a global FEA-computed fracture risk index to increase the prediction accuracy of hip fracture incidence. PURPOSE: Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur to compute the force (fracture load) and energy necessary to break the proximal femur in a particular loading condition. The fracture loads and energies-to-failure are individually associated with incident hip fracture, and provide different structural information about the proximal femur. METHODS: We used principal component analysis (PCA) to develop a global FEA-computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies-to-failure in four loading conditions of 110 hip fracture subjects and 235 age- and sex-matched control subjects from the AGES-Reykjavik study. Using a logistic regression model, we compared the prediction performance for hip fracture based on the stratified resampling. RESULTS: We referred the first principal component (PC1) of the FE parameters as the global FEA-computed fracture risk index, which was the significant predictor of hip fracture (p-value < 0.001). The area under the receiver operating characteristic curve (AUC) using PC1 (0.776) was higher than that using all FE parameters combined (0.737) in the males (p-value < 0.001). CONCLUSIONS: The global FEA-computed fracture risk index increased hip fracture risk prediction accuracy in males.

Cover page of Characterization of a novel rabbit model of Peyronies disease.

Characterization of a novel rabbit model of Peyronies disease.

(2024)

Peyronies disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the penile tunica albuginea. In the present study, we developed a novel rabbit model of PD via subtunical injection of recombinant transforming growth factor (TGF)-β1 protein and characterized erectile function and histopathological endpoints following plaque formation. Ten adult male, New Zealand white rabbits were randomized into 3 experimental groups including nonsurgical controls (NSC, N = 3) and those receiving subtunical injections of vehicle (N = 3) or TGF-β1 protein (0.5 µg/50 µl; N = 4). Following 1 month post-op, focal fibrous plaques composed of disorganized collagen type I and III bundles as well as fragmented elastin fibers at TGF-β1 injection sites were observed in contrast to control groups. Cavernosometric and cavernosographic evaluations revealed no significant differences in maximum intracorporal pressures or substantial curvature during papaverine-induced erection in either the vehicle or TGF-β1 cohorts. Immunohistochemical and histomorphometric analyses demonstrated significant increases in elastase 2B expression in TGF-β1-induced plaques as well as significant declines in matrix metalloproteinase (MMP)-2 and -9 expression relative to control levels. Our results demonstrate that PD-like fibrotic plaques can be created in the rabbit penile tunica albuginea following TGF-β1 injection.