Publications by Type: Journal Article

Introduction

Computational head injury models are promising tools for understanding and predicting traumatic brain injuries. However, most available head injury models are “average” models that employ a single set of head geometry (e.g., 50th-percentile U.S. male) without considering variability in these parameters across the human population. A significant variability of head shapes exists in U.S. Army soldiers, evident from the Anthropometric Survey of U.S. Army Personnel (ANSUR II). The objective of this study is to elucidate the effects of head shape on the predicted risk of traumatic brain injury from computational head injury models.

Materials and Methods

Magnetic resonance imaging scans of 25 human subjects are collected. These images are registered to the standard MNI152 brain atlas, and the resulting transformation matrix components (called head shape parameters) are used to quantify head shapes of the subjects. A generative machine learning model is used to generate 25 additional head shape parameter datasets to augment our database. Head injury models are developed for these head shapes, and a rapid injurious head rotation event is simulated to obtain several brain injury predictor variables (BIPVs): Peak cumulative maximum principal strain (CMPS), average CMPS, and the volume fraction of brain exceeding an injurious CMPS threshold. A Gaussian process regression model is trained between head shape parameters and BIPVs, which is then used to study the relative sensitivity of the various BIPVs on individual head shape parameters. We distinguish head shape parameters into 2 types: Scaling components Txx⁠, Tyy⁠, and Tzz that capture the breadth, length, and height of the head, respectively, and shearing components (⁠Txy,Txz,Tyx,Tyz,Tzx⁠, and Tzy⁠) that capture the relative skewness of the head shape.

Results

An overall positive correlation is evident between scaling components and BIPVs. Notably, a very high, positive correlation is seen between the BIPVs and the head volume. As an example, a 57% increase in peak CMPS was noted between the smallest and the largest investigated head volume parameters. The variation in shearing components Txy,Txz,Tyx,Tyz,Tzx⁠, and Tzy on average does not cause notable changes in the BIPVs. From the Gaussian process regression model, all 3 BIPVs showed an increasing trend with each of the 3 scaling components, but the BIPVs are found to be most sensitive to the height dimension of the head. From the Sobol sensitivity analysis, the Tzz scaling parameter contributes nearly 60% to the total variance in peak and average CMPS; Tyy contributes approximately 20%, whereas Txx contributes less than 5%. The remaining contribution is from the 6 shearing components. Unlike peak and average CMPS, the VF-CMPS BIPV is associated with relatively evenly distributed Sobol indices across the 3 scaling parameters. Furthermore, the contribution of shearing components on the total variance in this case is negligible.

Conclusions

Head shape has a considerable influence on the injury predictions of computational head injury models. Available “average” head injury models based on a 50th-percentile U.S. male are likely associated with considerable uncertainty. In general, larger head sizes correspond to greater BIPV magnitudes, which point to potentially a greater injury risk under rapid neck rotation for people with larger heads.

Background

Standardized exercise protocols have been shown to improve overall cardiovascular fitness, but direct effects on left ventricular (LV) function, particularly diastolic function and relation to post-transcriptional molecular pathways (microRNAs (miRs)) are poorly understood. This project tested the central hypothesis that adaptive LV remodeling resulting from a large animal exercise training protocol, would be directly associated with specific miRs responsible for regulating pathways relevant to LV myocardial stiffness and geometry.

Methods and results

Pigs (n = 9; 25 Kg) underwent a 4 week exercise training protocol (10 degrees elevation, 2.5 mph, 10 min, 5 days/week) whereby LV chamber stiffness (K_C) and regional myocardial stiffness (rK_m) were measured by Doppler/speckle tracking echocardiography. Age and weight matched non-exercise pigs (n = 6) served as controls. LV K_C fell by approximately 50% and rK_m by 30% following exercise (both p < 0.05). Using an 84 miR array, 34 (40%) miRs changed with exercise, whereby 8 of the changed miRs (miR-19a, miR-22, miR-30e, miR-99a, miR-142, miR-144, miR-199a, and miR-497) were correlated to the change in K_C (r ≥ 0.5 p < 0.05) and mapped to matrix and calcium handling processes. Additionally, miR-22 and miR-30e decreased with exercise and mapped to a localized inflammatory process, the inflammasome (NLRP-3, whereby a 2-fold decrease in NLRP-3 mRNA occurred with exercise (p < 0.05).

Conclusion

Chronic exercise reduced LV chamber and myocardial stiffness and was correlated to miRs that map to myocardial relaxation processes as well as local inflammatory pathways. These unique findings set the stage for utilization of myocardial miR profiling to identify underlying mechanisms by which exercise causes changes in LV myocardial structure and function.

Background:

Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents.

Methods:

We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs.

Results:

Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs.

Conclusion:

Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV K_c) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (n = 6) served as controls. LV function was measured by echocardiography and LV K_c by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n = 10, n = 9, respectively). LV samples from LVPO and controls (n = 6, respectively) were subjected to RNA sequencing. LV mass and K_c increased by over 40% with LVPO (P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV K_c (P < 0.05) that mapped to functional domains relevant to K_c such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.

G-protein-coupled receptors (GPCRs) mediate many critical physiological processes. Their spatial organization in plasma membrane (PM) domains is believed to encode signaling specificity and efficiency. However, the existence of domains and, crucially, the mechanism of formation of such putative domains remain elusive. Here, live-cell imaging (corrected for topography-induced imaging artifacts) conclusively established the existence of PM domains for GPCRs. Paradoxically, energetic coupling to extremely shallow PM curvature (<1 µm-1) emerged as the dominant, necessary and sufficient molecular mechanism of GPCR spatiotemporal organization. Experiments with different GPCRs, H-Ras, Piezo1 and epidermal growth factor receptor, suggest that the mechanism is general, yet protein specific, and can be regulated by ligands. These findings delineate a new spatiomechanical molecular mechanism that can transduce to domain-based signaling any mechanical or chemical stimulus that affects the morphology of the PM and suggest innovative therapeutic strategies targeting cellular shape.

Drug-coated balloon (DCB) therapy is a promising endovascular treatment for obstructive arterial disease. The goal of DCB therapy is restoration of lumen patency in a stenotic vessel, whereby balloon deployment both mechanically compresses the offending lesion and locally delivers an antiproliferative drug, most commonly paclitaxel (PTX) or derivative compounds, to the arterial wall. Favorable long-term outcomes of DCB therapy thus require predictable and adequate PTX delivery, a process facilitated by coating excipients that promotes rapid drug transfer during the inflation period. While a variety of excipients have been considered in DCB design, there is a lack of understanding about the coating-specific biophysical determinants of essential device function, namely, acute drug transfer. We consider two hydrophilic excipients for PTX delivery, urea (UR) and poly(ethylene glycol) (PEG), and examine how compositional and preparational variables in the balloon surface spray-coating process impact resultant coating microstructure and in turn acute PTX transfer to the arterial wall. Specifically, we use scanning electron image analyses to quantify how coating microstructure is altered by excipient solid content and balloon-to-nozzle spray distance during the coating procedure and correlate obtained microstructural descriptors of coating aggregation to the efficiency of acute PTX transfer in a one-dimensional ex vivo model of DCB deployment. Experimental results suggest that despite the qualitatively different coating surface microstructures and apparent PTX transfer mechanisms exhibited with these excipients, the drug delivery efficiency is generally enhanced by coating aggregation on the balloon surface. We illustrate this microstructure–function relation with a finite element-based computational model of DCB deployment, which along with our experimental findings suggests a general design principle to increase drug delivery efficiency across a broad range of DCB designs.

Biological nanopores are increasingly used in molecular sensing due to their single-molecule sensitivity. The detection of per- and polyfluoroalkyl substances (PFAS) like perfluorooctanoic acid and perfluorooctane sulfonic acid is critical due to their environmental prevalence and toxicity. Here, we investigate selective interactions between PFAS and four cyclodextrin (CD) variants (α-, β-, γ-, and 2-hydroxypropyl-γ-CD) within an α-hemolysin nanopore. We demonstrate that PFAS molecules can be electrochemically sensed by interacting with a γ-CD in a nanopore. Using HP-γ-CDs with increased steric resistance, we can identify homologs of the perfluoroalkyl carboxylic acid and the perfluoroalkyl sulfonic acid families and detect common PFAS in drinking water at 0.4 to 2 parts per million levels, which are further lowered to 400 parts per trillion by sample preconcentration. Molecular dynamics simulations reveal the underlying chemical mechanism of PFAS-CD interactions. These insights pave the way toward nanopore-based in situ detection with promises in environmental protection against PFAS pollution.

Developing fouling-resistant materials is of paramount interest in marine industries and biomedical applications. In this work, we studied the interfacial hydration and surface–protein interactions of the amphiphilic brush surface functionalized with hybrid hydrophilic trimethylamine N-oxide (TMAO) and hydrophobic pentafluoroethyl groups using a combination of atomistic molecular dynamics simulations and free-energy computations. Our results show that while the interfacial hydration density of the amphiphilic surface slightly decreases with the introduction of small fluorocarbons compared to that of the pure TMAO-functionalized surface, the amphiphilic surface remains relatively strong in resisting protein adsorption. The nanosized clustering of hydrophobic fluorine atoms on the top of the amphiphilic brush surface introduces weak protein adsorption; however, due to the strong interfacial hydration and weak hydrophobic interaction, the amphiphilic surface exhibits sufficient antibiofouling activities. Our fundamental studies will be critical for the discovery of marine fouling-resistant coating surfaces.

Fouling-resistant coating materials have important applications in marine industry and biomedicine. Zwitterionic carboxybetaine polymers have demonstrated robust antibiofouling functionalities in experiments. In this work, we performed atomistic molecular dynamics simulations to study the molecular mechanism of hydration and antibiofouling of poly(carboxybetaine acrylamide) (polyCBAA) brush surfaces. We focused on the zwitterionic carboxybetaine, which has only a short methylene spacer between the positive quaternary ammonium and the negative carboxylate groups. Our study shows that a large amount of water is present within the polyCBAA surface, and a condensed water layer of single-molecular thickness covers the top of the polymer surface. Moreover, the clustering of the zwitterionic chains results in an amorphous structure of the polymer surface, a reduced degree of order in the interfacial water molecules, and weak protein attachment. The low protein desorption free energy demonstrates that the polyCBAA surface exhibits strong fouling resistance due to its significant interfacial hydration and the small dipole moment of the carboxybetaine group, minimizing protein–surface electrostatic interactions. Our study at the molecular level will be important to the future development of zwitterionic materials.

Noninvasive measurements of brain deformation in human participants in vivo are needed to develop models of brain biomechanics and understand traumatic brain injury (TBI). Tagged magnetic resonance imaging (tagged MRI) and magnetic resonance elastography (MRE) are two techniques to study human brain deformation; these techniques differ in the type of motion and difficulty of implementation. In this study, oscillatory strain fields in the human brain caused by impulsive head acceleration and measured by tagged MRI were compared quantitatively to strain fields measured by MRE during harmonic head motion at 10 and 50 Hz. Strain fields were compared by registering to a common anatomical template, then computing correlations between the registered strain fields. Correlations were computed between tagged MRI strain fields in six participants and MRE strain fields at 10 Hz and 50 Hz in six different participants. Correlations among strain fields within the same experiment type were compared statistically to correlations from different experiment types. Strain fields from harmonic head motion at 10 Hz imaged by MRE were qualitatively and quantitatively similar to modes excited by impulsive head motion, imaged by tagged MRI. Notably, correlations between strain fields from 10 Hz MRE and tagged MRI did not differ significantly from correlations between strain fields from tagged MRI. These results suggest that low-frequency modes of oscillation dominate the response of the brain during impact. Thus, low-frequency MRE, which is simpler and more widely available than tagged MRI, can be used to illuminate the brain's response to head impact.