Bourns College of Engineering

Gaussian accelerated molecular dynamics (GaMD) is a robust computational method for simultaneous unconstrained enhanced sampling and free energy calculations of biomolecules. It works by adding a harmonic boost potential to smooth biomolecular potential energy surface and reduce energy barriers. GaMD greatly accelerates biomolecular simulations by orders of magnitude. Without the need to set predefined reaction coordinates or collective variables, GaMD provides unconstrained enhanced sampling and is advantageous for simulating complex biological processes. The GaMD boost potential exhibits a Gaussian distribution, thereby allowing for energetic reweighting via cumulant expansion to the second order (i.e., "Gaussian approximation"). This leads to accurate reconstruction of free energy landscapes of biomolecules. Hybrid schemes with other enhanced sampling methods, such as the replica exchange GaMD (rex-GaMD) and replica exchange umbrella sampling GaMD (GaREUS), have also been introduced, further improving sampling and free energy calculations. Recently, new "selective GaMD" algorithms including the ligand GaMD (LiGaMD) and peptide GaMD (Pep-GaMD) enabled microsecond simulations to capture repetitive dissociation and binding of small-molecule ligands and highly flexible peptides. The simulations then allowed highly efficient quantitative characterization of the ligand/peptide binding thermodynamics and kinetics. Taken together, GaMD and its innovative variants are applicable to simulate a wide variety of biomolecular dynamics, including protein folding, conformational changes and allostery, ligand binding, peptide binding, protein-protein/nucleic acid/carbohydrate interactions, and carbohydrate/nucleic acid interactions. In this review, we present principles of the GaMD algorithms and recent applications in biomolecular simulations and drug design.

Heterogeneous networks, HetNets, are known to enhance the bandwidth efficiency and throughput of wireless networks by more effectively utilizing the network resources. However, the higher density of users and access points in HetNets introduces significant inter-user interference that needs to be mitigated through complex and sophisticated interference cancellation schemes. Moreover, due to significant channel attenuation and the presence of hardware impairments, e.g. phase noise and amplifier nonlinearities, the vast bandwidth in the millimeterwave band has not been fully utilized to date. In order to enable the development of multi-Gigabit per second wireless networks, we introduce a novel millimeter-wave HetNet paradigm, termed hybrid HetNet, which exploits the vast bandwidth and propagation characteristics in the 60 GHz and 70-80 GHz bands to reduce the impact of interference in HetNets. Simulation results are presented to illustrate the performance advantage of hybrid HetNets with respect to traditional networks. Next, two specific transceiver structures that enable hand-offs from the 60 GHz band, i.e. the V-band to the 70-80 GHz band, i.e. the E-band, and vice versa are proposed. Finally, the practical and regulatory challenges for establishing a hybrid HetNet are outlined.

The antimalarial drug-resistance conundrum which threatens to reverse the great strides taken to curb the malaria scourge warrants an urgent need to find novel chemical scaffolds to serve as templates for the development of new antimalarial drugs. Plants represent a viable alternative source for the discovery of unique potential antiplasmodial chemical scaffolds. To expedite the discovery of new antiplasmodial compounds from plants, the aim of this study was to use phylogenetic analysis to identify higher plant orders and families that can be rationally prioritised for antimalarial drug discovery. We queried the PubMed database for publications documenting antiplasmodial properties of natural compounds isolated from higher plants. Thereafter, we manually collated compounds reported along with plant species of origin and relevant pharmacological data. We systematically assigned antiplasmodial-associated plant species into recognised families and orders, and then computed the resistance index, selectivity index and physicochemical properties of the compounds from each taxonomic group. Correlating the generated phylogenetic trees and the biological data of each clade allowed for the identification of 3 hot plant orders and families. The top 3 ranked plant orders were the (i) Caryophyllales, (ii) Buxales, and (iii) Chloranthales. The top 3 ranked plant families were the (i) Ancistrocladaceae, (ii) Simaroubaceae, and (iii) Buxaceae. The highly active natural compounds (IC50 ≤ 1 µM) isolated from these plant orders and families are structurally unique to the legacy antimalarial drugs. Our study was able to identify the most prolific taxa at order and family rank that we propose be prioritised in the search for potent, safe and drug-like antimalarial molecules.

Laser-based diagnostics and therapeutics show promise for many neurological disorders. However, the poor transparency of cranial bone (calvaria) limits the spatial resolution and interaction depth that can be achieved, thus constraining opportunity in this regard. Herein, we report preliminary results from efforts seeking to address this limitation through use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). Using optical coherence tomography (OCT) imaging of underlying brain in an acute murine model, we show that signal strength is improved when imaging through nc-YSZ implants relative to native cranium. As such, this provides initial evidence supporting the feasibility of nc-YSZ as a transparent cranial implant material. Furthermore, it represents a crucial first step towards realization of an innovative new concept we are developing, which seeks to eventually provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies.

From the clinical editor

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Immobilization of tissue-samples for atomic for microscopy (AFM) is typically done using either semi-dry tissue or by gluing the tissue sample down, both of which can introduce artifacts. Here, we describe the design of a Soft- Clamping Immobilizing Retainer of Tissue (SCIRT) for consistent and nondestructive immobilization of tissues for AFM analysis. We compare the performance of our SCIRT method with glue-immobilization for two difficult to handle tissue types: human trabecular meshwork (HTM) and rabbit cornea (RC). Our results demonstrate that the SCIRT method has several advantages, including: (i) allowing for small sample sizes, (ii) enabling continuous hydration, (iii) eliminating contact with glue or associated solvents, (iv) permitting sample recovery following measurement, and (v) ease of use. In conclusion, the SCIRT method is a simple and effective means of immobilizing soft, hydrated tissue samples consistently and without artifacts.

Targeting effectual epitopes is essential for therapeutic antibodies to accomplish their desired biological functions. This study developed a competitive dual color fluorescence-activated cell sorting (FACS) to maturate a matrix metalloprotease 14 (MMP-14) inhibitory antibody. Epitope-specific screening was achieved by selection on MMP-14 during competition with N-terminal domain of tissue inhibitor of metalloproteinase-2 (TIMP-2) (nTIMP-2), a native inhibitor of MMP-14 binding strongly to its catalytic cleft. 3A2 variants with high potency, selectivity, and improved affinity and proteolytic stability were isolated from a random mutagenesis library. Binding kinetics indicated that the affinity improvements were mainly from slower dissociation rates. In vitro degradation tests suggested the isolated variants had half lives 6-11-fold longer than the wt. Inhibition kinetics suggested they were competitive inhibitors which showed excellent selectivity toward MMP-14 over highly homologous MMP-9. Alanine scanning revealed that they bound to the vicinity of MMP-14 catalytic cleft especially residues F204 and F260, suggesting that the desired epitope was maintained during maturation. When converted to immunoglobulin G, B3 showed 5.0 nM binding affinity and 6.5 nM inhibition potency with in vivo half-life of 4.6 days in mice. In addition to protease inhibitory antibodies, the competitive FACS described here can be applied for discovery and engineering biosimilars, and in general for other circumstances where epitope-specific modulation is needed.

Certain organophosphorus molecules are infamous due to their use as highly toxic nerve agents. The filtration materials currently in common use for protection against chemical warfare agents were designed before organophosphorus compounds were used as chemical weapons. A better understanding of the surface chemistry between simulant molecules and the individual filtration-material components is a critical precursor to the development of more effective materials for filtration, destruction, decontamination, and/or sensing of nerve agents. Here, we report on the surface adsorption and reactions of a sarin simulant molecule, dimethyl methylphosphonate (DMMP), with cupric oxide surfaces. In situ ambient pressure X-ray photoelectron and infrared spectroscopies are coupled with density functional calculations to propose mechanisms for DMMP decomposition on CuO. We find extensive room temperature decomposition of DMMP on CuO, with the majority of decomposition fragments bound to the CuO surface. We observe breaking of PO-CH3, P-OCH3, and P-CH3 bonds at room temperature. On the basis of these results, we identify specific DMMP decomposition mechanisms not seen on other metal oxides. Participation of lattice oxygen in the decomposition mechanism leads to significant changes in chemical and electronic surface environment, which are manifest in the spectroscopic and computational data. This study establishes a computational baseline for the study of highly toxic organophosphorous compounds on metal oxide surfaces.

Fluoroalkylether substances (ether PFAS) constitute a large group of emerging PFAS with uncertain environmental fate. Among them, GenX is the well-known alternative to perfluorooctanoic acid and one of the six proposed PFAS to be regulated by the U.S. Environmental Protection Agency. This study investigated the structure-biodegradability relationship for 12 different ether PFAS with a carboxylic acid headgroup in activated sludge communities. Only polyfluorinated ethers with at least one -CH₂- moiety adjacent to or a C=C bond in the proximity of the ether bond underwent active biotransformation via oxidative and hydrolytic O-dealkylation. The bioreactions at ether bonds led to the formation of unstable fluoroalcohol intermediates subject to spontaneous defluorination. We further demonstrated that this aerobic biotransformation/defluorination could complement the advanced reduction process in a treatment train system to achieve more cost-effective treatment for GenX and other recalcitrant perfluorinated ether PFAS. These findings provide essential insights into the environmental fate of ether PFAS, the design of biodegradable alternative PFAS, and the development of cost-effective ether PFAS treatment strategies.

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Access to web-based platforms has enabled scientists to perform research remotely. A critical aspect of mass spectrometry data analysis is the inspection, analysis, and visualization of the raw data to validate data quality and confirm statistical observations. We developed the GNPS Dashboard, a web-based data visualization tool, to facilitate synchronous collaborative inspection, visualization, and analysis of private and public mass spectrometry data remotely.

Blebbing is an important biological indicator in determining the health of human embryonic stem cells (hESC). Especially, areas of a bleb sequence in a video are often used to distinguish two cell blebbing behaviors in hESC: dynamic and apoptotic blebbings. This paper analyzes various segmentation methods for bleb extraction in hESC videos and introduces a bio-inspired score function to improve the performance in bleb extraction. Full bleb formation consists of bleb expansion and retraction. Blebs change their size and image properties dynamically in both processes and between frames. Therefore, adaptive parameters are needed for each segmentation method. A score function derived from the change of bleb area and orientation between consecutive frames is proposed which provides adaptive parameters for bleb extraction in videos. In comparison to manual analysis, the proposed method provides an automated fast and accurate approach for bleb sequence extraction.

Affective computing - the emergent field in which computers detect emotions and project appropriate expressions of their own - has reached a bottleneck where algorithms are not able to infer a person's emotions from natural and spontaneous facial expressions captured in video. While the field of emotion recognition has seen many advances in the past decade, a facial emotion recognition approach has not yet been revealed which performs well in unconstrained settings. In this paper, we propose a principled method which addresses the temporal dynamics of facial emotions and expressions in video with a sampling approach inspired from human perceptual psychology. We test the efficacy of the method on the Audio/Visual Emotion Challenge 2011 and 2012, Cohn-Kanade and the MMI Facial Expression Database. The method shows an average improvement of 9.8 percent over the baseline for weighted accuracy on the Audio/Visual Emotion Challenge 2011 video-based frame-level subchallenge testing set.

We suggest a technique for constructing lower (existence) bounds for the fault-tolerant threshold to scalable quantum computation applicable to degenerate quantum codes with sublinear distance scaling. We give explicit analytic expressions combining probabilities of erasures, depolarizing errors, and phenomenological syndrome measurement errors for quantum low-density parity-check codes with logarithmic or larger distances. These threshold estimates are parametrically better than the existing analytical bound based on percolation.

Controlling the interactions between macrophages and biomaterials is critical for modulating the response to implants. While it has long been thought that biomaterial surface chemistry regulates the immune response, recent studies have suggested that material geometry may in fact dominate. Our previous work demonstrated that elongation of macrophages regulates their polarization toward a pro-healing phenotype. In this work, we elucidate how surface topology might be leveraged to alter macrophage cell morphology and polarization state. Using a deep etch technique, we fabricated titanium surfaces containing micro- and nanopatterned grooves, which have been previously shown to promote cell elongation. Morphology, phenotypic markers, and cytokine secretion of murine bone marrow derived macrophages on different groove widths were analyzed. The results suggest that micro- and nanopatterned grooves influenced macrophage elongation, which peaked on substrates with 400-500 nm wide grooves. Surface grooves did not affect inflammatory activation but drove macrophages toward an anti-inflammatory, pro-healing phenotype. While secretion of TNF-alpha remained low in macrophages across all conditions, macrophages secreted significantly higher levels of anti-inflammatory cytokine, IL-10, on intermediate groove widths compared to cells on other Ti surfaces. Our findings highlight the potential of using surface topography to regulate macrophage function, and thus control the wound healing and tissue repair response to biomaterials.

Heterostructured materials are an emerging class of materials with superior performances that are unattainable by their conventional homogeneous counterparts. They consist of heterogeneous zones with dramatic (>100%) variations in mechanical and/or physical properties. The interaction in these hetero-zones produces a synergistic effect where the integrated property exceeds the prediction by the rule-of-mixtures. The heterostructured materials field explores heterostructures to control defect distributions, long-range internal stresses, and nonlinear inter-zone interactions for unprecedented performances. This paper is aimed to provide perspectives on this novel field, describe the state-of-the-art of heterostructured materials, and identify and discuss key issues that deserve additional studies.

Welding of ceramics is a key missing component in modern manufacturing. Current methods cannot join ceramics in proximity to temperature-sensitive materials like polymers and electronic components. We introduce an ultrafast pulsed laser welding approach that relies on focusing light on interfaces to ensure an optical interaction volume in ceramics to stimulate nonlinear absorption processes, causing localized melting rather than ablation. The key is the interplay between linear and nonlinear optical properties and laser energy-material coupling. The welded ceramic assemblies hold high vacuum and have shear strengths comparable to metal-to-ceramic diffusion bonds. Laser welding can make ceramics integral components in devices for harsh environments as well as in optoelectronic and/or electronic packages needing visible-radio frequency transparency.