Showing papers by "University of Texas at Dallas published in 2022"

Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors

Abstract: Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha (CALCA) expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.

Role of surface steps in activation of surface oxygen sites on Ir nanocrystals for oxygen evolution reaction in acidic media

Abstract: Ir and its oxide are the only available oxygen evolution reaction (OER) electrocatalysts with reasonably high activity and stability for commercial proton-exchange membrane electrolyzers. However, the establishment of structure–performance relationships for the design of better Ir-based electrocatalysts is hindered by their uncontrolled surface reconstruction during OER in acidic media. Herein, we monitor the structural evolution of two model Ir nanocrystals (one with a flat surface enclosed by (100) facets and the other with a concave surface containing numerous high-index planes) under acidic OER conditions. Operando X-ray absorption spectroscopy measurements reveal that the promotion of surface IrOx formation during the OER by the concave Ir surface with high-index planes results in a gradual OER activity increase, while a decrease in activity and limited oxide formation are observed for the flat Ir surface. After the activation process, the Ir concave surface exhibits ~ 10 times higher activity than the flat surface. Density functional theory computations reveal that Ir high-index surfaces are thermodynamically preferred for the adsorption of oxygen atoms and the formation of surface oxides under OER conditions. Thus, our work establishes a structure–performance relationship for Ir nanocrystals under operating conditions, providing new principles for the design of nanoscale OER electrocatalysts.

Detection of Ongoing Mass Loss from HD 63433c, a Young Mini-Neptune

Abstract: We detect Lyman $\alpha$ absorption from the escaping atmosphere of HD 63433c, a $R=2.67 R_\oplus$, $P=20.5$ d mini Neptune orbiting a young (440 Myr) solar analogue in the Ursa Major Moving Group. Using HST/STIS, we measure a transit depth of $11.1 \pm 1.5$% in the blue wing and $8 \pm 3$% in the red. This signal is unlikely to be due to stellar variability, but should be confirmed by an upcoming second visit with HST. We do not detect Lyman $\alpha$ absorption from the inner planet, a smaller $R=2.15 R_\oplus$ mini Neptune on a 7.1 d orbit. We use Keck/NIRSPEC to place an upper limit of 0.5% on helium absorption for both planets. We measure the host star's X-ray spectrum and FUV flux with XMM-Newton, and model the outflow from both planets using a 3D hydrodynamic code. This model provides a reasonable match to the light curve in the blue wing of the Lyman $\alpha$ line and the helium non-detection for planet c, although it does not explain the tentative red wing absorption or reproduce the excess absorption spectrum in detail. Its predictions of strong Lyman $\alpha$ and helium absorption from b are ruled out by the observations. This model predicts a much shorter mass loss timescale for planet b, suggesting that b and c are fundamentally different: while the latter still retains its hydrogen/helium envelope, the former has likely lost its primordial atmosphere.

Transition-metal nitride halide dielectrics for transition-metal dichalcogenide transistors

Abstract: Using first-principles calculations, we investigate six transition-metal nitride halides (TMNHs): HfNBr, HfNCl, TiNBr, TiNCl, ZrNBr, and ZrNCl as potential van der Waals (vdW) dielectrics for transition metal dichalcogenide (TMD) channel transistors. We calculate the exfoliation energies and bulk phonon energies and find that the six TMNHs are exfoliable and thermodynamically stable. We calculate both the optical and static dielectric constants in the in-plane and out-of-plane directions for both monolayer and bulk TMNHs. In monolayers, the out-of-plane static dielectric constant ranges from 5.04 (ZrNCl) to 6.03 (ZrNBr) whereas in-plane dielectric constants range from 13.18 (HfNBr) to 74.52 (TiNCl). We show that the bandgap of TMNHs ranges from 1.53 eV (TiNBr) to 3.36 eV (HfNCl) whereas the affinity ranges from 4.01 eV (HfNBr) to 5.60 eV (TiNCl). Finally, we estimate the dielectric leakage current density of transistors with six TMNH bilayer dielectrics with five monolayer channel TMDs (MoS2, MoSe2, MoTe2, WS2, and WSe2). For p-MOS TMD channel transistors 25 out of 30 combinations have a smaller leakage current than hexagonal boron nitride (hBN), a well-known vdW dielectric. The smallest bilayer leakage current of 1.15 × 10-2 A cm-2 is predicted for a p-MOS MoSe2 transistor with HfNCl as a gate dielectric. HfNBr, ZrNBr, and ZrNCl are also predicted to yield small leakage currents in certain p-MOS TMD transistors.

Progress in Utilizing Dynamic Bonds to Fabricate Structurally Adaptive Self‐Healing, Shape Memory, and Liquid Crystal Polymers

Abstract: Stimuli-responsive structurally dynamic polymers are capable of mimicking the biological systems to adapt themselves to the surrounding environmental changes and subsequently exhibiting a wide range of responses ranging from self-healing to complex shape-morphing. Dynamic self-healing polymers (SHPs), shape-memory polymers (SMPs), and liquid crystal elastomers (LCEs), which are three representative examples of stimuli-responsive structurally dynamic polymers, have been attracting broad and growing interest in recent years because of their potential applications in the fields of electronic skin, sensors, soft robots, artificial muscles, and so on. Recent advances and challenges in the developments toward dynamic SHPs, SMPs, and LCEs are reviewed, focusing on the chemistry strategies and the dynamic reaction mechanisms that enhance the performances of the materials including self-healing, reprocessing, and reprogramming. The different dynamic chemistries and their mechanisms on the enhanced functions of the materials are compared and discussed, where three summary tables are presented: A library of dynamic bonds and the resulting characteristics of the materials. Finally, a critical outline of the unresolved issues and future perspectives on the emerging developments is provided.

Ducted Chorus Waves Cause Sub‐Relativistic and Relativistic Electron Microbursts

Abstract: During magnetospheric storms, radiation belt electrons are produced and then removed by collisions with the lower atmosphere on varying timescales. An efficient loss process is microbursts, strong, transient precipitation of electrons over a wide energy range, from tens of keV to sub-relativistic and relativistic energies (100s keV and above). However, the detailed generation mechanism of microbursts, especially over sub-relativistic and relativistic energies, remains unknown. Here, we show that these energetic electron microbursts may be caused by ducted whistler-mode lower-band chorus waves. Using observations of equatorial chorus waves nearby low-altitude precipitation as well as data-driven simulations, we demonstrate that the observed microbursts are the result of resonant interaction of electrons with ducted chorus waves rather than nonducted ones. Revealing the physical mechanism behind the microbursts advances our understanding of radiation belt dynamics and its impact on the lower atmosphere and space weather.

Zeolitic Imidazolate Framework Nanoencapsulation of CpG for Stabilization and Enhancement of Immunoadjuvancy

Abstract: Metal–organic frameworks (MOFs) have been used to improve vaccine formulations by stabilizing proteins and protecting them against thermal degradation. This has led to increased immunogenicity of these proteinaceous therapeutics. In this work, we show that MOFs can also be used to protect the single-stranded DNA oligomer CpG to increase its immunoadjuvancy. By encapsulation of the phosphodiester CpG in the zinc-based MOF, zeolitic imidazolate framework-8, the DNA oligomer is protected from nuclease degradation and exhibits improved cellular uptake. As a result, we have been able to achieve drastically enhanced B-cell activation in splenocyte cultures comparable to the current state-of-the-art phosphorothioate CpG. Furthermore, we have made a direct comparison of micro- and nanosized MOFs for optimization of the particulate delivery of immunoadjuvants to maximize immune activation.

American Cochlear Implant Alliance Task Force Guidelines for Determining Cochlear Implant Candidacy in Children

Abstract: This article summarizes the available evidence on pediatric cochlear implantation to provide current guidelines for clinical protocols and candidacy recommendations in the United States. Candidacy determination involves specification of audiologic and medical criteria per guidelines of the Food and Drug Administration. However, recommendations for a cochlear implant evaluation also should maintain flexibility and consider a child’s skill progression (i.e., month-for-month progress in speech, language, and auditory development) and quality of life with appropriately fit hearing aids. Moreover, evidence supports medical and clinical decisions based on other factors, including (a) ear-specific performance, which affords inclusion of children with asymmetric hearing loss and single-sided deafness as implant candidates; (b) ear-specific residual hearing, which influences surgical technique and device selection to optimize hearing; and (c) early intervention to minimize negative long-term effects on communication and quality of life related to delayed identification of implant candidacy, later age at implantation, and/or limited commitment to an audiologic rehabilitation program. These evidence-based guidelines for current clinical protocols in determining pediatric cochlear implant candidacy encourage a team-based approach focused on the whole child and the family system.

Aberrant large-scale brain modules in deficit and non-deficit schizophrenia.

Abstract: Objective Schizophrenia is a heterogenous psychiatric disease, and deficit schizophrenia (DS) is a clinical subgroup with primary and enduring negative symptoms. Although previous neuroimaging studies have identified functional connectome alterations in schizophrenia, the modular organizations in DS and nondeficit schizophrenia (NDS) remains poorly understood. Therefore, this study aimed to investigate the modular-level alterations in DS patients compared with the NDS and healthy control (HC) groups. Methods A previously collected dataset was re-analyzed, in which 74 chronic male schizophrenia patients (33 DS and 41 NDS) and 40 HC underwent resting-state functional magnetic resonance imaging with eyes closed in a Siemens 3 T scanner (scanning duration = 8 min). Modular- (intramodule and intermodule connectivity) and nodal- [normalized within-module degree (Zi) and participation coefficient (PCi)] level graph theory properties were computed and compared among the three groups. Receiver operating characteristic curve (ROC) analyses were performed to examine the classification ability of these measures, and partial correlations were conducted between network measures and symptom severity. Validation analyses on head motion, network sparsity, and parcellation scheme were also performed. Results Both schizophrenia subgroups showed decreased intramodule connectivity in salience network (SN), somatosensory-motor network (SMN), and visual network (VN), and increased intermodule connectivity in SMN-default mode network (DMN) and SMN-frontoparietal network (FPN). Compared with NDS patients, DS patients showed weaker intramodule connectivity in SN and stronger intermodule connectivity in SMN-FPN and SMN-VN. At the nodal level, the schizophrenia-related alterations were distributed in SN, SMN, VN, and DMN, and 7 DS-specific nodal alterations were identified. Intramodule connectivity of SN, intermodule connectivity of SMN-VN, and Zi of left precuneus successfully distinguished the three groups. Partial correlational analyses revealed that these measures were related to negative symptoms, general psychiatric symptoms, and neurocognitive function. Conclusion Our findings suggest that functional connectomes, especially SN, SMN, and VN, may capture the distinct and common disruptions of DS and NDS. These findings may help to understand the neuropathology of negative symptoms of schizophrenia and inform targets for treating different schizophrenia subtypes.

Constitutive behavior of granular materials under high rate of uniaxial strain loading

Abstract: The uniaxial compressive behavior of Colorado Mason sand at high strain rates was investigated on a split Hopkinson pressure bar. The sand grains were placed inside a hardened steel tube and end-capped by tungsten carbide rods. This assembly, with a desired bulk mass density for sand, was then sandwiched between incident and transmission bar ends for dynamic compression. Unsorted dry sand and partially saturated sand were impacted at high strain rates to determine the volumetric and deviatoric behavior. Quasi-static compression under the same confinement was also conducted to compare with the high strain rate data. The effect of initial mass density and moisture content level on the constitutive behavior was investigated. The constitutive behavior of dry sand was analyzed using a recently developed adaptive particle fracture algorithm implemented in the poly-ellipsoidal discrete element method, to further understand the mesoscale behavior of sand under high-rate compressive deformations.

Higher-Order Moment-Based Anomaly Detection

Abstract: The identification of anomalies is a critical component of operating complex, large-scale and geographically distributed cyber-physical systems While designing anomaly detectors, it is common to assume Gaussian noise models to maintain tractability; however, this assumption can lead to the actual false alarm rate being significantly higher than expected Here we design a distributionally robust threshold of detection using finite and fixed higher-order moments of the detection measure data such that it guarantees the actual false alarm rate to be upper bounded by the desired one Further, we bound the states reachable through the action of a stealthy attack and identify the trade-off between this impact of attacks that cannot be detected and the worst-case false alarm rate Through numerical experiments, we illustrate how knowledge of higher-order moments results in a tightened threshold, thereby restricting an attacker’s potential impact

Identification of a novel cationic glycolipid in Streptococcus agalactiae that contributes to brain entry and meningitis

Abstract: Bacterial membrane lipids are critical for membrane bilayer formation, cell division, protein localization, stress responses, and pathogenesis. Despite their critical roles, membrane lipids have not been fully elucidated for many pathogens. Here, we report the discovery of a novel cationic glycolipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG), which is synthesized in high abundance by the bacterium Streptococcus agalactiae (Group B Streptococcus, GBS). To our knowledge, Lys-Glc-DAG is more positively charged than any other known lipids. Lys-Glc-DAG carries 2 positive net charges per molecule, distinct from the widely described lysylated phospholipid lysyl-phosphatidylglycerol (Lys-PG) that carries one positive net charge due to the presence of a negatively charged phosphate moiety. We use normal phase liquid chromatography (NPLC) coupled with electrospray ionization (ESI) high-resolution tandem mass spectrometry (HRMS/MS) and genetic approaches to determine that Lys-Glc-DAG is synthesized by the enzyme MprF in GBS, which covalently modifies the neutral glycolipid Glc-DAG with the cationic amino acid lysine. GBS is a leading cause of neonatal meningitis, which requires traversal of the endothelial blood-brain barrier (BBB). We demonstrate that GBS strains lacking mprF exhibit a significant decrease in the ability to invade BBB endothelial cells. Further, mice challenged with a GBSΔmprF mutant developed bacteremia comparably to wild-type (WT) infected mice yet had less recovered bacteria from brain tissue and a lower incidence of meningitis. Thus, our data suggest that Lys-Glc-DAG may contribute to bacterial uptake into host cells and disease progression. Importantly, our discovery provides a platform for further study of cationic lipids at the host-pathogen interface.

Review of Geochronologic and Geochemical Data of the Greater Antilles Volcanic Arc and Implications for the Evolution of Oceanic Arcs

Abstract: The Greater Antilles islands of Cuba, Hispaniola, Puerto Rico and Jamaica plus the Virgin Islands host fragments of the fossil convergent margin that records Cretaceous subduction (operated for about 90 m.y.) of the American plates beneath the Caribbean plate and ensuing arc-continent collision in Late Cretaceous-Eocene time. The “soft” collision between the Greater Antilles Arc (GAA) and the Bahamas platform (and the margin of the Maya Block in western Cuba) preserved much of the convergent margin. This fossil geosystem represents an excellent natural laboratory for studying the formation and evolution of an intra-oceanic convergent margin. We compiled geochronologic (664 ages) and geochemical data (more than 1,500 analyses) for GAA igneous and metamorphic rocks. The data was classified with a simple fourfold subdivision: fore-arc mélange, fore-arc ophiolite, magmatic arc, and retro-arc to inspect the evolution of GAA through its entire lifespan. The onset of subduction recorded by fore-arc units, together with the oldest magmatic arc sequence shows that the GAA started in Early Cretaceous time and ceased in Paleogene time. The arc was locally affected (retro-arc region in Hispaniola) by the Caribbean Large Igneous Province (CLIP) in Early Cretaceous and strongly in Late Cretaceous time. Despite multiple biases in the database presented here, this work is intended to help overcome some of the obstacles and motivate systematic study of the GAA. Our results encourage exploration of offshore regions, especially in the east where the forearc is submerged. Offshore explorations are also encouraged in the south, to investigate relations with the CLIP.

Cell cycle-independent integration of stress signals by Xbp1 promotes Non-G1/G0 quiescence entry.

Abstract: Cellular quiescence is a nonproliferative state required for cell survival under stress and during development. In most quiescent cells, proliferation is stopped in a reversible state of low Cdk1 kinase activity; in many organisms, however, quiescent states with high-Cdk1 activity can also be established through still uncharacterized stress or developmental mechanisms. Here, we used a microfluidics approach coupled to phenotypic classification by machine learning to identify stress pathways associated with starvation-triggered high-Cdk1 quiescent states in Saccharomyces cerevisiae. We found that low- and high-Cdk1 quiescent states shared a core of stress-associated processes, such as autophagy, protein aggregation, and mitochondrial up-regulation, but differed in the nuclear accumulation of the stress transcription factors Xbp1, Gln3, and Sfp1. The decision between low- or high-Cdk1 quiescence was controlled by cell cycle-independent accumulation of Xbp1, which acted as a time-delayed integrator of the duration of stress stimuli. Our results show how cell cycle-independent stress-activated factors promote cellular quiescence outside G1/G0.

Coupling a Live Cell Directed Evolution Assay with Coevolutionary Landscapes to Engineer an Improved Fluorescent Rhodopsin Chloride Sensor

Abstract: Our understanding of chloride in biology has been accelerated through the application of fluorescent protein-based sensors in living cells. These sensors can be generated and diversified to have a range of properties using laboratory-guided evolution. Recently, we established that the fluorescent proton-pumping rhodopsin wtGR from Gloeobacter violaceus can be converted into a fluorescent sensor for chloride. To unlock this non-natural function, a single point mutation at the Schiff counterion position (D121V) was introduced into wtGR fused to cyan fluorescent protein (CFP) resulting in GR1-CFP. Here, we have integrated coevolutionary analysis with directed evolution to understand how the rhodopsin sequence space can be explored and engineered to improve this starting point. We first show how evolutionary couplings are predictive of functional sites in the rhodopsin family and how a fitness metric based on a sequence can be used to quantify the known proton-pumping activities of GR-CFP variants. Then, we couple this ability to predict potential functional outcomes with a screening and selection assay in live Escherichia coli to reduce the mutational search space of five residues along the proton-pumping pathway in GR1-CFP. This iterative selection process results in GR2-CFP with four additional mutations: E132K, A84K, T125C, and V245I. Finally, bulk and single fluorescence measurements in live E. coli reveal that GR2-CFP is a reversible, ratiometric fluorescent sensor for extracellular chloride with an improved dynamic range. We anticipate that our framework will be applicable to other systems, providing a more efficient methodology to engineer fluorescent protein-based sensors with desired properties.