American society of anesthesiologists physical status classification significantly affects the performances of machine learning models in intraoperative hypotension inference.

STUDY OBJECTIVE: To explore how American Society of Anesthesiologists (ASA) physical status classification affects different machine learning models in hypotension prediction and whether the prediction uncertainty could be quantified. DESIGN: Observational Studies SETTING: UofL health hospital PATIENTS: This study involved 562 hysterectomy surgeries performed on patients (≥ 18 years) between June 2020 and July 2021. INTERVENTIONS: None MEASUREMENTS: Preoperative and intraoperative data is collected. Three parametric machine learning models, including Bayesian generalized linear model (BGLM), Bayesian neural network (BNN), a newly proposed BNN with multivariate mixed responses (BNNMR), and one nonparametric model, Gaussian Process (GP), were explored to predict patients' diastolic and systolic blood pressures (continuous responses) and patients' hypotensive event (binary response) for the next five minutes. Data was separated into American Society of Anesthesiologists (ASA) physical status class 1- 4 before being read in by four machine learning models. Statistical analysis and models' constructions are performed in Python. Sensitivity, specificity, and the confidence/credible intervals were used to evaluate the prediction performance of each model for each ASA physical status class. MAIN RESULTS: ASA physical status classes require distinct models to accurately predict intraoperative blood pressures and hypotensive events. Overall, high sensitivity (above 0.85) and low uncertainty can be achieved by all models for ASA class 4 patients. In contrast, models trained without controlling ASA classes yielded lower sensitivity (below 0.5) and larger uncertainty. Particularly, in terms of predicting binary hypotensive event, for ASA physical status class 1, BNNMR yields the highest sensitivity of 1. For classes 2 and 3, BNN has the highest sensitivity of 0.429 and 0.415, respectively. For class 4, BNNMR and GP are tied with the highest sensitivity of 0.857. On the other hand, the sensitivity is just 0.031, 0.429, 0.165 and 0.305 for BNNMR, BNN, GBLM and GP models respectively, when training data is not divided by ASA physical status classes. In terms of predicting systolic blood pressure, the GP regression yields the lowest root mean squared errors (RMSE) of 2.072, 7.539, 9.214 and 0.295 for ASA physical status classes 1, 2, 3 and 4, respectively, but a RMSE of 126.894 if model is trained without controlling the ASA physical status class. The RMSEs for other models are far higher. RMSEs are 2.175, 13.861, 17.560 and 22.426 for classes 1, 2, 3 and 4 respectively for the BGLM. In terms of predicting diastolic blood pressure, the GP regression yields the lowest RMSEs of 2.152, 6.573, 5.371 and 0.831 for ASA physical status classes 1, 2, 3 and 4, respectively; RMSE of 8.084 if model is trained without controlling the ASA physical status class. The RMSEs for other models are far higher. Finally, in terms of the width of the 95% confidence interval of the mean prediction for systolic and diastolic blood pressures, GP regression gives narrower confidence interval with much smaller margin of error across all four ASA physical status classes. CONCLUSIONS: Different ASA physical status classes present different data distributions, and thus calls for distinct machine learning models to improve prediction accuracy and reduce predictive uncertainty. Uncertainty quantification enabled by Bayesian inference provides valuable information for clinicians as an additional metric to evaluate performance of machine learning models for medical decision making.

Current-Induced Magnetization Switching in Light-Metal-Oxide/Ferromagnetic-Metal Bilayers via Orbital Rashba Effect.

The orbital angular momentum (OAM) generation as well as its associated orbital torque is currently a matter of great interest in spin-orbitronics and is receiving increasing attention. In particular, recent theoretical work predicts that the oxidized light metal Cu can serve as an efficient OAM generator through its surface orbital Rashba effect. Here, for the first time, the crucial current-induced magnetic-field-free in-plane magnetization reversal is experimentally demonstrated in CoFeB/CuOx bilayers without any heavy elements. We show that the critical current density can be comparable to that of strong spin-orbit coupling systems with heavy metals (Pt and Ta) and that the magnetization reversal mechanism is governed by coherent rotation in the grains through the second-harmonic and magneto-optical Kerr effect measurements. Our results indicate that light metal oxides can play an equally important role as heavy metals in magnetization reversal, broadening the choice of materials for engineering spintronic devices.

Conformational changes in protein kinase A along its activation cycle are rooted in the folding energetics of cyclic-nucleotide binding domains.

Cyclic-nucleotide binding (CNB) domains are structurally and evolutionarily conserved signaling modules that regulate proteins with diverse folds and functions. Despite a wealth of structural information, the mechanisms by which CNB domains couple cyclic-nucleotide binding to conformational changes involved in signal transduction remain unknown. Here we combined single-molecule and computational approaches to investigate the conformation and folding energetics of the two CNB domains of the regulatory subunit of protein kinase A (PKA). We found that the CNB domains exhibit different conformational and folding signatures in the apo state, when bound to cAMP, or when bound to the PKA catalytic subunit, underscoring their ability to adapt to different binding partners. Moreover, we show while the two CNB domains have near-identical structures, their thermodynamic coupling signatures are divergent, leading to distinct cAMP responses and differential mutational effects. Specifically, we demonstrate mutation W260A exerts local and allosteric effects that impact multiple steps of the PKA activation cycle. Taken together, these results highlight the complex interplay between folding energetics, conformational dynamics, and thermodynamic signatures that underlies structurally conserved signaling modules in response to ligand binding and mutational effects.

Growth, structure, and morphology of van der Waals epitaxy Cr1+δTe2 films.

The preparation of two-dimensional magnetic materials is a key process to their applications and the study of their structure and morphology plays an important role in the growth of high-quality thin films. Here, the growth, structure, and morphology of Cr1+δTe2 films grown by molecular beam epitaxy on mica with variations of Te/Cr flux ratio, growth temperature, and film thickness have been systematically investigated by scanning tunneling microscopy, reflection high-energy electron diffraction, scanning electron microscope, and X-ray photoelectron spectroscopy. We find that a structural change from multiple phases to a single phase occurs with the increase in growth temperature, irrespective of the Cr/Te flux ratios, which is attributed to the desorption difference of Te atoms at different temperatures, and that the surface morphology of the films grown at relatively high growth temperatures (≥ 300 °C) exhibits a quasi-hexagonal mesh-like structure, which consists of nano-islands with bending surface induced by the screw dislocations, as well as that the films would undergo a growth-mode change from 2D at the initial stage in a small film thickness (2 nm) to 3D at the later stage in thick thicknesses (12 nm and 24 nm). This work provides a general model for the study of pseudo-layered materials grown on flexible layered substrates.

Engineering Spin Configurations of Synthetic Antiferromagnet by Controlling Long-Range Oscillatory Interlayer Coupling and Neighboring Ferrimagnetic Coupling.

Controllable manipulation of specific spin configurations of magnetic materials is the key to constructing functional spintronic devices. Here, it is demonstrated by integrating the merits of ferromagnetic, ferrimagnetic, and antiferromagnetic spin configurations into one synthetic antiferromagnetic (SAF) heterostructure by controlling both long-range oscillatory interlayer coupling and neighboring ferrimagnetic coupling. A controllable manipulation of four types of spin configurations of the Pt/[Co/Pt/Co]/Ru/CoTb SAF heterostructures composed of ferromagnetic Co/Pt/Co and ferrimagnetic CoTb layers is successfully achieved. In particular, the compensated magnetization, enhanced anomalous Hall resistance in the remanence state, wide-temperature spin-orbit torque switching of magnetization, and high immunity to the external magnetic field are simultaneously obtained in one of the SAF heterojunctions with macroscopic interlayer antiferromagnetic coupling. This design concept of engineering spin configurations may enable efficient spin manipulation for customized memory and logic applications.

Using Optical Tweezers to Monitor Allosteric Signals Through Changes in Folding Energy Landscapes.

Signaling proteins are composed of conserved protein interaction domains that serve as allosteric regulatory elements of enzymatic or binding activities. The ubiquitous, structurally conserved cyclic nucleotide binding (CNB) domain is found covalently linked to proteins with diverse folds that perform multiple biological functions. Given that the structures of cAMP-bound CNB domains in different proteins are very similar, it remains a challenge to determine how this domain allosterically regulates such diverse protein functions and folds. Instead of a structural perspective, we focus our attention on the energy landscapes underlying the CNB domains and their responses to cAMP binding. We show that optical tweezers is an ideal tool to investigate how cAMP binding coupled to interdomain interactions remodel the energy landscape of the regulatory subunit of protein kinase A (PKA), which harbors two CNB domains. We mechanically manipulate and probe the unfolding and refolding behavior of the CNB domains as isolated structures or selectively as part of the PKA regulatory subunit, and in the presence and absence of cAMP. Optical tweezers allows us to dissect the changes in the energy landscape associated with cAMP binding, and to examine the allosteric interdomain interactions triggered by the cyclic nucleotide. This single molecule approach can be used to study other modular, multidomain signaling proteins found in nature.

Combined spinal-epidural analgesia and epidural analgesia induced maternal fever with a similar timing during labor-A randomized controlled clinical trial.

Background: Both epidural and combined spinal-epidural (EA and CSEA) analgesia can induce intrapartum maternal fever. CSEA has a more rapid onset and wider nerve block than EA. Therefore, CSEA might have a different profile of intrapartum maternal fever, including higher temperatures or earlier occurrence. This randomized clinical trial was to determine whether CSEA could cause maternal fever earlier than EA. Methods: A randomized, double-blind, controlled clinical trial was performed on 233 nulliparous full-term pregnant women during vaginal delivery. The pregnant women were randomly allocated into the EA group (n = 113) and the CSEA group (n = 120). The fever latent period, from analgesia start to fever occurrence, was the primary endpoint in this study. The temperature was measured every 30 min using an eardrum thermometer during labor analgesia. The fever was defined as an eardrum temperature of ≥38 °C. Results: No difference was found in the maternal fever rate between the EA and the CSEA groups (10/113 vs. 7/120, P = 0.356). There was no significant difference in the fever latent period between the two groups (4.75 ± 0.86 h vs. 3.79 ± 2.2 h, p = 0.305). The temperatures at all points had no differences between EA and CSEA. Conclusion: CSEA had a similar latent fever period as EA. A further study is warranted to confirm the similar characteristic between CSEA and EA in the development of intrapartum maternal fever. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2000038793.

Field-Free Magnetization Switching in a Ferromagnetic Single Layer through Multiple Inversion Asymmetry Engineering.

A simple, reliable, and self-switchable spin-orbit torque (SOT)-induced magnetization switching in a ferromagnetic single layer is needed for the development of next generation fully electrical controllable spintronic devices. In this work, field-free SOT-induced magnetization switching in a CoPt single layer is realized by broken multiple inversion symmetry through simultaneously introducing both oblique sputtering and a vertical composition gradient. A quantitative analysis indicates that multiple inversion asymmetries can produce dynamical bias fields along both z- and x-axes, leading to the observed field-free deterministic magnetization switching. Our study provides a method to accomplish fully electrical manipulation of magnetization in a ferromagnetic single layer without the external magnetic field and auxiliary heavy metal layer, enabling flexible design for future spin-orbit torque-based memory and logic devices.

Flexible Self-Powered Weak Light Detectors Based on ZnO/CsPbBr3/γ-CuI Heterojunctions.

Halide perovskites (HPs) with marvelous optical and electrical properties are regarded as one of the competitive candidates for building next-generation photodetectors (PDs). However, combining their excellent properties with satisfactory long-term robustness is still challenging, ultimately limiting the practical applications of HP-based PDs. Herein, a high vacuum deposition system is employed to fabricate flexible self-powered PDs with a ZnO/CsPbBr3/γ-CuI structure, which shows excellent stability and outstanding performance in weak light detection. Benefiting from the improved crystallinity and optimized device structure, a high detectivity of 8.1 × 1013 Jones and a rapid response speed (rise/decay time of 3.9/1.8 µs) are obtained in this self-powered device. Furthermore, the unencapsulated device exhibits intriguing environmental stability and mechanical flexibility. The photocurrent remains unchanged after 7000 s of continuous operation or 100 bending cycles. Furthermore, a 15 × 15 PD array is fabricated as an image sensor. A high contrast image of the target object can be obtained owing to the high sensitivity and uniformity of the self-powered PDs. These results demonstrate the feasibility and practicality of the ZnO/CsPbBr3/γ-CuI heterojunction for applications in weak light detection and image formation.

Programmable Spin-Orbit Torque Multistate Memory and Spin Logic Cell.

Controllable spin-orbit torque based nonvolatile memory is highly desired for constructing energy efficient reconfigurable logic-in-memory computing suitable for emerging data-intensive applications. Here, we report our exploration of the IrMn/Co/Ru/CoPt/CoO heterojunction as a potential candidate for applications in both multistate memory and programmable spin logic. The studied heterojunction can be programmed into four different magnetic configurations at will by tuning both the in-plane exchange bias at the interface of IrMn and Co layers and the out-of-plane exchange bias at the interface of CoPt and CoO layers. Moreover, on the basis of the controllable exchange bias effect, 10 states of nonvolatile memory and multiple logic-in-memory functions have been demonstrated. Our findings indicate that IrMn/Co/Ru/CoPt/CoO multilayered structures can be used as a building block for next-generation logic-in-memory and multifunctional multidimensional spintronic devices.

Controllable field-free switching of perpendicular magnetization through bulk spin-orbit torque in symmetry-broken ferromagnetic films.

Programmable magnetic field-free manipulation of perpendicular magnetization switching is essential for the development of ultralow-power spintronic devices. However, the magnetization in a centrosymmetric single-layer ferromagnetic film cannot be switched directly by passing an electrical current in itself. Here, we demonstrate a repeatable bulk spin-orbit torque (SOT) switching of the perpendicularly magnetized CoPt alloy single-layer films by introducing a composition gradient in the thickness direction to break the inversion symmetry. Experimental results reveal that the bulk SOT-induced effective field on the domain walls leads to the domain walls motion and magnetization switching. Moreover, magnetic field-free perpendicular magnetization switching caused by SOT and its switching polarity (clockwise or counterclockwise) can be reversibly controlled in the IrMn/Co/Ru/CoPt heterojunctions based on the exchange bias and interlayer exchange coupling. This unique composition gradient approach accompanied with electrically controllable SOT magnetization switching provides a promising strategy to access energy-efficient control of memory and logic devices.

The EMS vehicle patient transportation problem during a demand surge.

We consider a real-time emergency medical service (EMS) vehicle patient transportation problem in which vehicles are assigned to patients so they can be transported to hospitals during an emergency. The objective is to minimize the total travel time of all vehicles while satisfying two types of time window constraints. The first requires each EMS vehicle to arrive at a patient's location within a specified time window. The second requires the vehicle to arrive at the designated hospital within another time window. We allow an EMS vehicle to serve up to two patients instead of just one. The problem is shown to be NP-complete. We, therefore, develop a simulated annealing (SA) heuristic for efficient solution in real-time. A column generation algorithm is developed for determining a tight lower bound. Numerical results show that the proposed SA heuristic provides high-quality solutions in much less CPU time, when compared to the general-purpose solver. Therefore, it is suitable for implementation in a real-time decision support system, which is available via a web portal (www.rtdss.org).

The Protection Role of Magnesium Ions on Coupled Transcription and Translation in Lyophilized Cell-Free System.

Cell-free protein synthesis (CFPS) is a promising platform for protein engineering and synthetic biology. The storage of a CFPS system usually involves lyophilization, during which preventing the conformational damage of involved enzymes is critical to the activity. Herein, we report the protection role of magnesium ions on coupled transcription and translation in a lyophilized cell-free system. Mg2+ prevents the inactivation of the CFPS system from direct colyophilization of enzymes and substrates (nucleotides, and amino acids), and furthermore activates the CFPS system. We propose two-metal-ion regulation of Mg2+: Mg2+ (I) acts as an allosteric role for enzymes to prevent the conformational damage of enzymes from direct binding with substrates during lyophilization which locks up inactive enzyme-substrate complex; Mg2+ (II) consequently binds to enzymes to activate the CFPS system. Our work provides important implications for maximizing protein yields by using a cell-free system in protein engineering and understanding the functions of Mg2+ in biological systems.

Amorphous nonstoichiometric oxides with tunable room-temperature ferromagnetism and electrical transport.

Material functionalities strongly depend on the stoichiometry, crystal structure, and homogeneity. Here we demonstrate an approach of amorphous nonstoichiometric inhomogeneous oxides to realize tunable ferromagnetism and electrical transport at room temperature. In order to verify the origin of the ferromagnetism, we employed a series of structural, chemical, and electronic state characterizations. Combined with electron microscopy and transport measurements, synchrotron-based grazing incident wide angle X-ray scattering, soft X-ray absorption and circular dichroism clearly reveal that the room-temperature ferromagnetism originates from the In0.23Co0.77O1-v amorphous phase with a large tunable range of oxygen vacancies. The room-temperature ferromagnetism is tunable from a high saturation magnetization of 500 emu cm-3 to below 25 emu cm-3, with the evolving electrical resistivity from 5 × 103 µΩ cm to above 2.5 × 105 µΩ cm. Inhomogeneous nano-crystallization emerges with decreasing oxygen vacancies, driving the system towards non-ferromagnetism and insulating regime. Our work unfolds the novel functionalities of amorphous nonstoichiometric inhomogeneous oxides, which opens up new opportunities for developing spintronic materials with superior magnetic and transport properties.

Gene Circuit Compartment on Nanointerface Facilitatating Cascade Gene Expression.

Cellular genes that are functionally related to each other are usually confined in specialized subcellular compartments for efficient biochemical reactions. Construction of spatially controlled biosynthetic systems will facilitate the study of biological design principles. Herein, we fabricated a gene circuit compartment by coanchoring two function-related genes on surface of gold nanoparticles and investigated the compartment effect on cascade gene expression in a cell-free system. The gene circuit consisted of a T7 RNA polymerase (T7 RNAP) expression cassette as regulatory gene and a fluorescent protein expression cassette as regulated reporter gene. Both the expression cassettes were attached on a Y-shaped DNA nanostructure whose other two branches were mercapto-modified in order to steadily anchor the gene expression cassettes on the surface of gold nanoparticles. Experimental results demonstrated that both the yield and initial expression rate of the fluorescent reporter protein in the gene circuit compartment system were enhanced compared with those in free gene circuit system. Mechanism investigation revealed that the gene circuit compartment on nanoparticle made the regulatory gene and regulated reporter gene spatially proximal at nanoscale, thus effectively improving the transfer efficiency of the regulatory proteins (T7 RNAP) from regulatory genes to the regulated reporter genes in the compartments, and consequently, the biochemical reaction efficiency was significantly increased. This work not only provided a simplified model for rational molecular programming of genes circuit compartments on nanointerface but also presented implications for the cellular structure-function relationship.

Saccharides Create a Crowding Environment for Gene Expression in Cell-Free Systems.

Cellular physical microenvironment such as crowding shows great influence on enzymatic reactions. Herein, we report a new finding that saccharides with low molecular weight create an effective crowding microenvironment for gene expression in cell-free protein synthesis, which provides valuable implications for living systems. Four saccharides including sorbose, galactose, sucrose, and cellobiose are screened out as effective crowders. At a low concentration range of saccharides, both the mRNA and protein amounts present an upward trend with the concentration increment of saccharides; when the concentrations exceed a critical value, the mRNA and protein amounts decrease. A mechanism is proposed that at low concentrations of saccharides, the effective concentrations of reactants increase due to the coexistence of crowders and reactants in a finite volume; when the concentrations exceed a critical value, the molecular diffusion of reactants is dominantly restricted due to the increased viscosity. Our finding opens a new view that saccharides with low molecular weight could be crowders and provides a new insight that substances with low molecular weight in cells would produce a crowding effect on biochemical reactions in living systems.

Branched DNA Architectures Produced by PCR-Based Assembly as Gene Compartments for Cell-Free Gene-Expression Reactions.

The physical distance between genes plays important roles in controlling gene expression reactions in vivo. Herein, we report the design and synthesis of a branched gene architecture in which three transcription units are integrated into one framework through assembly based on the polymerase chain reaction (PCR), together with the exploitation of these constructs as "gene compartments" for cell-free gene expression reactions, probing the impact of this physical environment on gene transcription and translation. We find that the branched gene system enhances gene expression yields, in particular at low concentrations of DNA and RNA polymerase (RNAP); furthermore, in a crowded microenvironment that mimics the intracellular microenvironment, gene expression from branched genes maintains a relatively high level. We propose that the branched gene assembly forms a membrane-free gene compartment that resembles the nucleoid of prokaryotes and enables RNAP to shuttle more efficiently between neighboring transcription units, thus enhancing gene expression efficiency. Our branched DNA architecture provides a valuable platform for studying the influence of "cellular" physical environments on biochemical reactions in simplified cell-free systems.

Switching of the folding-energy landscape governs the allosteric activation of protein kinase A.

Protein kinases are dynamic molecular switches that sample multiple conformational states. The regulatory subunit of PKA harbors two cAMP-binding domains [cyclic nucleotide-binding (CNB) domains] that oscillate between inactive and active conformations dependent on cAMP binding. The cooperative binding of cAMP to the CNB domains activates an allosteric interaction network that enables PKA to progress from the inactive to active conformation, unleashing the activity of the catalytic subunit. Despite its importance in the regulation of many biological processes, the molecular mechanism responsible for the observed cooperativity during the activation of PKA remains unclear. Here, we use optical tweezers to probe the folding cooperativity and energetics of domain communication between the cAMP-binding domains in the apo state and bound to the catalytic subunit. Our study provides direct evidence of a switch in the folding-energy landscape of the two CNB domains from energetically independent in the apo state to highly cooperative and energetically coupled in the presence of the catalytic subunit. Moreover, we show that destabilizing mutational effects in one CNB domain efficiently propagate to the other and decrease the folding cooperativity between them. Taken together, our results provide a thermodynamic foundation for the conformational plasticity that enables protein kinases to adapt and respond to signaling molecules.

Distinguishing Interface Magnetoresistance and Bulk Magnetoresistance through Rectification of Schottky Heterojunctions.

High performance of many spintronic devices strongly depends on the spin-polarized electrical transport, especially the magnetoresistance (MR) in magnetic heterojunctions. However, it has been a great challenge to distinguish the bulk MR and interface MR by transport measurements because the bulk resistance and interface resistance formed a series circuit in magnetic heterojunctions. Here, a unique interface-sensitive rectification MR method is proposed to distinguish the interface MR and bulk MR of nonmagnetic In/GeO x/n-Ge and magnetic Co/GeO x/n-Ge diode-like heterojunctions. It is demonstrated that the low-field "butterfly" hysteresis loop observed only in the conventional MR curve originates from the anisotropic MR of ferromagnetic bulk Co layer, whereas the orbit-related large nonsaturating positive MR contains contributions from both the Schottky interface and bulk Ge substrate. This rectification MR method could be extended to magnetic heterojunctions with asymmetric potential barriers to realize a deeper understanding of the fundamental interface-related functionalities.

Cavity Mediated Manipulation of Distant Spin Currents Using a Cavity-Magnon-Polariton.

Using electrical detection of a strongly coupled spin-photon system comprised of a microwave cavity mode and two magnetic samples, we demonstrate the long distance manipulation of spin currents. This distant control is not limited by the spin diffusion length, instead depending on the interplay between the local and global properties of the coupled system, enabling systematic spin current control over large distance scales (several centimeters in this work). This flexibility opens the door to improved spin current generation and manipulation for cavity spintronic devices.