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In this work, the high entropy oxide A2CuO4 Ruddlesden-Popper (La0.2Pr0.2Nd0.2Sm0.2Eu0.2)2CuO4 is explored by charge doping with Ce+4 and Sr+2 at concentrations known to induce superconductivity in the simple parent compounds, Nd2CuO4 and La2CuO4. Electron doped (La0.185Pr0.185Nd0.185Sm0.185Eu0.185Ce0.075)2CuO4 and hole doped (La0.18Pr0.18Nd0.18Sm0.18Eu0.18Sr0.1)2CuO4 are synthesized and shown to be single crystal, epitaxially strained, and highly uniform. Transport measurements demonstrate that all as-grown films are insulating regardless of doping. Annealing studies show that resistivity can be tuned by modifying oxygen stoichiometry and inducing metallicity but without superconductivity. These results in turn are connected to extended x-ray absorption fine structure (EXAFS) results indicating that the lack of superconductivity in the high entropy cuprates likely originates from a large distortion within the Cu-O plane ({\sigma}2>0.015 {\AA}2) due to A-site cation size variance, which drives localization of charge carriers. These findings describe new opportunities for controlling charge- and orbital-mediated functional responses in Ruddlesden-Popper crystal structures, driven by balancing of cation size and charge variances that may be exploited for functionally important behaviors such as superconductivity, antiferromagnetism, and metal-insulator transitions, while opening less understood phase spaces hosting doped Mott insulators, strange metals, quantum criticality, pseudogaps, and ordered charge density waves.

Background The role of CT angiography-derived fractional flow reserve (CT-FFR) in pre-transcatheter aortic valve replacement (TAVR) assessment is uncertain. Purpose To evaluate the predictive value of on-site machine learning-based CT-FFR for adverse clinical outcomes in candidates for TAVR. Materials and Methods This observational retrospective study included patients with severe aortic stenosis referred to TAVR after coronary CT angiography (CCTA) between September 2014 and December 2019. Clinical end points comprised major adverse cardiac events (MACE) (nonfatal myocardial infarction, unstable angina, cardiac death, or heart failure admission) and all-cause mortality. CT-FFR was obtained semiautomatically using an on-site machine learning algorithm. The ability of CT-FFR (abnormal if ≤0.75) to predict outcomes and improve the predictive value of the current noninvasive work-up was assessed. Survival analysis was performed, and the C-index was used to assess the performance of each predictive model. To compare nested models, the likelihood ratio χ2 test was performed. Results A total of 196 patients (mean age ± standard deviation, 75 years ± 11; 110 women [56%]) were included; the median time of follow-up was 18 months. MACE occurred in 16% (31 of 196 patients) and all-cause mortality in 19% (38 of 196 patients). Univariable analysis revealed CT-FFR was predictive of MACE (hazard ratio [HR], 4.1; 95% CI: 1.6, 10.8; P = .01) but not all-cause mortality (HR, 1.2; 95% CI: 0.6, 2.2; P = .63). CT-FFR was independently associated with MACE (HR, 4.0; 95% CI: 1.5, 10.5; P = .01) when adjusting for potential confounders. Adding CT-FFR as a predictor to models that include CCTA and clinical data improved their predictive value for MACE (P = .002) but not all-cause mortality (P = .67), and it showed good discriminative ability for MACE (C-index, 0.71). Conclusion CT angiography-derived fractional flow reserve was associated with major adverse cardiac events in candidates for transcatheter aortic valve replacement and improved the predictive value of coronary CT angiography assessment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Choe in this issue.

HaloTag is a small self-labeling protein that is frequently used for creating fluorescent reporters in living cells. The small-molecule dyes used with HaloTag are almost exclusively based on rhodamine scaffolds, which are often expensive and challenging to synthesize. Herein, we report the engineering of HaloTag for use with a chemically accessible, inexpensive fluorophore based on the dimethylamino-styrylpyridium dye. Through directed evolution, the maximum fluorogenicity and the apparent second-order bioconjugation rate constants could be improved up to 4-fold and 42-fold, respectively. One of the top variants, HT-SP5, enabled reliable imaging in mammalian cells, with a 113-fold fluorescence enhancement over the parent protein. Additionally, crystallographic characterization of selected mutants suggests the chemical origin of the fluorescent enhancement. The improved dye system offers a valuable tool for imaging and illustrates the viability of engineering self-labeling proteins for alternative fluorophores.

Although liver biopsies (LBs) are being increasingly performed under endoscopic ultrasound (EUS) guidance, there are limited data comparing outcomes with current standard-of-care, transabdominal ultrasound (US)-guided percutaneous (PC) methods. In a randomised trial, we observed that the PC, US-guided method yielded significantly more optimal specimens, defined as specimen length of 25 mm or greater and presence of at least 11 complete portal tracts, compared with the EUS-guided method (57.9% vs 23.8%, p=0.028). Also, the PC method resulted in worse initial postprocedural pain but was less costly (US$1824 vs US$3240, p

The influence of hole doping on magnetic properties is mapped for the compositionally complex high-entropy oxide ${AB\mathrm{O}}_{3}$ perovskite ${\mathrm{La}}_{1\text{\ensuremath{-}}x}{\mathrm{Sr}}_{x}({\mathrm{Cr}}_{0.2}{\mathrm{Mn}}_{0.2}{\mathrm{Fe}}_{0.2}{\mathrm{Co}}_{0.2}{\mathrm{Ni}}_{0.2}){\mathrm{O}}_{3}$ $(0\ensuremath{\le}x\ensuremath{\le}0.5)$. It is found that aliovalent A-site substitution is a viable means to manipulate the magnetically active B-site sublattice. A series of single-crystal films are synthesized and show a general trend toward stronger ferromagnetic response and a shift in magnetic anisotropy as the Sr concentration increases. Magnetometry demonstrates complex and nonuniform responses similar to rigid and uncoupled composites at intermediate dopings. This behavior points to the presence of locally inhomogeneous magnetic phase competition, where ferromagnetic and antiferromagnetic magnetic contributions create a frustrated matrix containing uncompensated spins at the boundaries between these regions. The observations are discussed in the context of known responses to hole doping in the less complex ternary $\mathrm{La}{T}_{M}{\mathrm{O}}_{3}$ $({T}_{M}=\mathrm{Cr},\mathrm{Mn},\mathrm{Fe},\mathrm{Co},\mathrm{Ni})$ oxides, and they are found to be different from a simple sum of the doped parents. The results are summarized in a preliminary magnetic phase diagram.

Artificial metalloenzymes (ArMs) combine characteristics of both homogeneous catalysts and enzymes. Merging abiotic and biotic features allows for the implementation of new-to-nature reactions in living organisms. Here, we present the directed evolution of an artificial metalloenzyme based on Escherichia coli surfacedisplayed streptavidin (SavSD hereafter). Through the binding of a ruthenium-pianostool cofactor to SavSD, an artificial allylic deallylase (ADAse hereafter) is assembled, which displays catalytic activity toward the deprotection of alloc-protected 3-hydroxyaniline. The uncaged aminophenol acts as a gene switch and triggers the overexpression of a fluorescent green fluorescent protein (GFP) reporter protein. This straightforward readout of ADAse activity allowed the simultaneous saturation mutagenesis of two amino acid residues in Sav near the ruthenium cofactor, expediting the screening of 2762 individual clones. A 1.7-fold increase of in vivo activity was observed for SavSD S112T-K121G compared to the wild-type SavSD (wt-SavSD). Finally, the best performing Sav isoforms were purified and tested in vitro (SavPP hereafter). For SavPP S112M-K121A, a total turnover number of 372 was achieved, corresponding to a 5.9-fold increase vs wt-SavPP. To analyze the marked difference in activity observed between the surface-displayed and purified ArMs, the oligomeric state of SavSD was determined. For this purpose, crosslinking experiments of E. coli cells overexpressing SavSD were carried out, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDSPAGE) and Western blot. The data suggest that SavSD is most likely displayed as a monomer on the surface of E. coli. We hypothesize that the difference between the in vivo and in vitro screening results may reflect the difference in the oligomeric state of SavSD vs soluble SavPP (monomeric vs tetrameric). Accordingly, care should be applied when evolving oligomeric proteins using E. coli surface display., ACS Catalysis, 11 (17), ISSN:2155-5435

Operative courses of laparoscopic cholecystectomies vary widely due to differing pathologies. Efforts to assess intra-operative difficulty include the Parkland grading scale (PGS), which scores inflammation from the initial view of the gallbladder on a 1-5 scale. We investigated the impact of PGS on intra-operative outcomes, including laparoscopic duration, attainment of the critical view of safety (CVS), and gallbladder injury. We additionally trained an artificial intelligence (AI) model to identify PGS.One surgeon labeled surgical phases, PGS, CVS attainment, and gallbladder injury in 200 cholecystectomy videos. We used multilevel Bayesian regression models to analyze the PGS's effect on intra-operative outcomes. We trained AI models to identify PGS from an initial view of the gallbladder and compared model performance to annotations by a second surgeon.Slightly inflamed gallbladders (PGS-2) minimally increased duration, adding 2.7 [95% compatibility interval (CI) 0.3-7.0] minutes to an operation. This contrasted with maximally inflamed gallbladders (PGS-5), where on average 16.9 (95% CI 4.4-33.9) minutes were added, with 31.3 (95% CI 8.0-67.5) minutes added for the most affected surgeon. Inadvertent gallbladder injury occurred in 25% of cases, with a minimal increase in gallbladder injury observed with added inflammation. However, up to a 28% (95% CI - 2, 63) increase in probability of a gallbladder hole during PGS-5 cases was observed for some surgeons. Inflammation had no substantial effect on whether or not a surgeon attained the CVS. An AI model could reliably (Krippendorff's α = 0.71, 95% CI 0.65-0.77) quantify inflammation when compared to a second surgeon (α = 0.82, 95% CI 0.75-0.87).An AI model can identify the degree of gallbladder inflammation, which is predictive of cholecystectomy intra-operative course. This automated assessment could be useful for operating room workflow optimization and for targeted per-surgeon and per-resident feedback to accelerate acquisition of operative skills.

BackgroundThe growing interest in analysis of surgical video through machine learning has led to increased research efforts; however, common methods of annotating video data are lacking. There is a need to establish recommendations on the annotation of surgical video data to enable assessment of algorithms and multi-institutional collaboration.MethodsFour working groups were formed from a pool of participants that included clinicians, engineers, and data scientists. The working groups were focused on four themes: (1) temporal models, (2) actions and tasks, (3) tissue characteristics and general anatomy, and (4) software and data structure. A modified Delphi process was utilized to create a consensus survey based on suggested recommendations from each of the working groups.ResultsAfter three Delphi rounds, consensus was reached on recommendations for annotation within each of these domains. A hierarchy for annotation of temporal events in surgery was established.ConclusionsWhile additional work remains to achieve accepted standards for video annotation in surgery, the consensus recommendations on a general framework for annotation presented here lay the foundation for standardization. This type of framework is critical to enabling diverse datasets, performance benchmarks, and collaboration.

Engineered enzyme cascades offer powerful tools to convert renewable resources into value-added products. Man-made catalysts give access to new-to-nature reactivities that may complement the enzyme’s repertoire. Their mutual incompatibility, however, challenges their integration into concurrent chemo-enzymatic cascades. Herein we show that compartmentalization of complex enzyme cascades within E. coli whole cells enables the simultaneous use of a metathesis catalyst, thus allowing the sustainable one-pot production of cycloalkenes from oleic acid. Cycloheptene is produced from oleic acid via a concurrent enzymatic oxidative decarboxylation and ring-closing metathesis. Cyclohexene and cyclopentene are produced from oleic acid via either a six- or eight-step enzyme cascade involving hydration, oxidation, hydrolysis and decarboxylation, followed by ring-closing metathesis. Integration of an upstream hydrolase enables the usage of olive oil as the substrate for the production of cycloalkenes. This work highlights the potential of integrating organometallic catalysis with whole-cell enzyme cascades of high complexity to enable sustainable chemistry., Cycloalkenes are bulk petrochemicals that are currently obtained from fossil fuels. Here, the authors developed multi enzyme pathways in combination with a Ru-catalyzed metathesis reaction for the one-pot production of cyclopentene, cyclohexene, and cycloheptene from olive oil-derived intermediates.

As the relationship between CT scout landmarks and chest CT boundaries is not known, the selected scan length is often greater than necessary for the CT scan, resulting in increased radiation dose to the neck and upper abdomen. The purpose of this study is to establish the relationship between CT scout landmarks with the superior and inferior boundaries of the lungs on chest CT. Retrospective comparison of the location of the top of the first rib on frontal scout and the most inferior costophrenic angle on lateral scout to the chest CT slice just above and below the lungs. The percent of scans that would exclude part of the lung based on CT initiated at several distances above or below these landmarks was calculated. There was 2.7 times greater variability between scout landmarks and lung boundaries inferiorly than superiorly on chest CT (p

Photochemistry usually functions on a one-photon-one-electron basis, leading to unstable radical intermediates that must be intercepted rapidly to allow efficient product formation. This can render multi-electron reductions and enantioselective reactions particularly challenging. In this minireview, we discuss recent advances in the area of photo-driven multi-electron transfer with a particular focus on our own work on reductive amination and the enantioselective synthesis of amines by combined photoredox and enzyme catalysis. Polarity-matched hydrogen atom transfer (HAT) between photochemically-generated alpha-amino alkyl radicals and thiols is a key step in these reactions. A cyclic reaction network comprised of light-driven imine reduction by an Ir-photocatalyst and enantioselective amine oxidation by the enzyme monoamine oxidase (MAO-N-9) was used to obtain enantioenriched amines from imines.

In the recent decades, the design and development of biomimetic micro air vehicles have gained increased interest by the global scientific and engineering communities. This has given greater motivation to study and understand the aerodynamics involved with winged insects. Dragonflies demonstrate unique and superior flight performance than most of the other insect species and birds. They are capable of sustained gliding flight as well as hovering and able to change direction very rapidly. Pairs of independently controlled forewings and hindwings give them an agile flying ability. This article presents a review of all published journal articles, listed in the Thomson-Reuters Web-of-Science database (1985–2018), that are related to the flight aerodynamics of dragonflies or micro air vehicles that biomimic them. The effects of dragonfly wing motions and interactions (between forewing and hindwing) that are necessary to generate the appropriate aerodynamic forces in different flight modes are described. The associated power requirements of these modes are also addressed. This article aims to provide a valuable reference to the aerodynamic design and control of dragonfly-inspired biomimetic micro air vehicles.

Artificial metalloenzymes (ArMs) result from the incorporation of an abiotic metal cofactor within a protein scaffold. From the earliest techniques of transition metals adsorbed on silk fibers, the field of ArMs has expanded dramatically over the past 60 years to encompass a range of reaction classes and inspired approaches: Assembly of the ArMs has taken multiple forms with both covalent and supramolecular anchoring strategies, while the scaffolds have been intuitively selected and evolved, repurposed, or designed in silico. Herein, we discuss some of the most prominent recent examples of ArMs to highlight the challenges and opportunities presented by the field., Artificial metalloenzymes result from the incorporation of an abiotic metal cofactor within a protein scaffold. We summarize recent examples highlighting the challenges and opportunities.

Cyclic oligochalcogenides (COCs) are emerging as promising systems to penetrate cells. Clearly better than and different to the reported diselenolanes and epidithiodiketopiperazines, we introduce the benzopolysulfanes (BPS), which show efficient delivery, insensitivity to inhibitors of endocytosis, and compatibility with substrates as large as proteins. This high activity coincides with high reactivity, selectively toward thiols, exceeding exchange rates of disulfides under tension. The result is a dynamic‐covalent network of extreme sulfur species, including cyclic oligomers, from dimers to heptamers, with up to nineteen sulfurs in the ring. Selection from this unfolding adaptive network then yields the reactivities and selectivities needed to access new uptake pathways. Contrary to other COCs, BPS show high retention on thiol affinity columns. The identification of new modes of cell penetration is important because they promise new solutions to challenges in delivery and beyond.

The use of evidence-based assessment practices seems to be a straightforward process to endorse. Having evidence that ties a practice to prediction, prescription, or process has the potential to advance overall practice in School Psychology in ways that have already been seen in medicine and, to a lesser degree, clinical psychology. However, the transition to an EBA focus would require substantial changes in how measures are created and validated, how new practitioners are taught to perform assessments and how current practitioners are educated into a new process, how interventions are conceptualized and tested, and how the progress of individuals receiving those interventions is monitored.

Olefin metathesis is one of the most powerful C–C double-bond-forming reactions. Metathesis reactions have had a tremendous impact in organic synthesis, enabling a variety of applications in polymer chemistry, drug discovery and chemical biology. Although challenging, the possibility to perform aqueous metatheses has become an attractive alternative, not only because water is a more sustainable medium, but also to exploit biocompatible conditions. This review focuses on the progress made in aqueous olefin metatheses and their applications in chemical biology.

In classical morphotropic piezoelectric materials, rhombohedral and tetragonal phase variants can energetically compete to form a mixed phase regime with improved functional properties. While the discovery of morphotropic-like phases in multiferroic BiFeO3 films has broadened this definition, accessing these phase spaces is still typically accomplished through isovalent substitution or heteroepitaxial strain which do not allow for continuous modification of phase composition postsynthesis. Here, we show that it is possible to use low-energy helium implantation to tailor morphotropic phases of epitaxial BiFeO3 films postsynthesis in a continuous and iterative manner. Applying this strain doping approach to morphotropic films creates a new phase space based on internal and external lattice stress that can be seen as an analogue to temperature–composition phase diagrams of classical morphotropic ferroelectric systems.

In his ethical writings, Duns Scotus emphasized both divine freedom and natural goodness, and these seem to conflict with each other in various ways. I offer an interpretation of Scotus which takes seriously these twin emphases and shows how they cohere. I argue that, for Scotus, all natural laws obtain just by the natures of actual things. Divine commands, such as the Ten Commandments, contingently track natural laws but do not make natural laws to be natural laws. I present textual evidence for this claim. I also show how this view of Scotus on the natural law is consistent with a number of troubling passages. Scotus’s ethical theory implies that there are genuinely moral reasons for acting which are not absolutely binding (because subject to a divine command or permission otherwise) and also some moral reasons for acting which are absolutely binding (because not thus subject).

The authors wish to make the following corrections to this paper [1] [...]

Analyzing surgical workflow is crucial for surgical assistance robots to understand surgeries. With the understanding of the complete surgical workflow, the robots are able to assist the surgeons in intra-operative events, such as by giving a warning when the surgeon is entering specific keys or high-risk phases. Deep learning techniques have recently been widely applied to recognizing surgical workflows. Many of the existing temporal neural network models are limited in their capability to handle long-term dependencies in the data, instead, relying upon the strong performance of the underlying per-frame visual models. We propose a new temporal network structure that leverages task-specific network representation to collect long-term sufficient statistics that are propagated by a sufficient statistics model (SSM). We implement our approach within an LSTM backbone for the task of surgical phase recognition and explore several choices for propagated statistics. We demonstrate superior results over existing and novel state-of-the-art segmentation techniques on two laparoscopic cholecystectomy datasets: the publicly available Cholec80 dataset and MGH100, a novel dataset with more challenging and clinically meaningful segment labels.

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation predisposing to schizophrenia. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

The growing interest in analysis of surgical video through machine learning has led to increased research efforts; however, common methods of annotating video data are lacking. There is a need to establish recommendations on the annotation of surgical video data to enable assessment of algorithms and multi-institutional collaboration.Four working groups were formed from a pool of participants that included clinicians, engineers, and data scientists. The working groups were focused on four themes: (1) temporal models, (2) actions and tasks, (3) tissue characteristics and general anatomy, and (4) software and data structure. A modified Delphi process was utilized to create a consensus survey based on suggested recommendations from each of the working groups.After three Delphi rounds, consensus was reached on recommendations for annotation within each of these domains. A hierarchy for annotation of temporal events in surgery was established.While additional work remains to achieve accepted standards for video annotation in surgery, the consensus recommendations on a general framework for annotation presented here lay the foundation for standardization. This type of framework is critical to enabling diverse datasets, performance benchmarks, and collaboration.

Disorder can have a dominating influence on correlated and quantum materials leading to novel behaviors which have no clean limit counterparts. In magnetic systems, spin and exchange disorder can provide access to quantum criticality, frustration, and spin dynamics, but broad tunability of these responses and a deeper understanding of strong limit disorder is lacking. In this work, we demonstrate that high entropy oxides present an unexplored route to designing quantum materials in which the presence of strong local compositional disorder hosted on a positionally ordered lattice can be used to generate highly tunable emergent magnetic behavior--from macroscopically ordered states to frustration-driven dynamic spin interactions. Single crystal La(Cr0.2Mn0.2Fe0.2Co0.2Ni0.2)O3 films are used as a structurally uniform model system hosting a magnetic sublattice with massive microstate disorder in the form of site-to-site spin and exchange type inhomogeneity. A classical Heisenberg model is found to be sufficient to describe how compositionally disordered systems can paradoxically host long-range magnetic uniformity and demonstrates that balancing the populating elements based on their discrete quantum parameters can be used to give continuous control over ordering types and critical temperatures. Theory-guided experiments show that composite exchange values derived from the complex mix of microstate interactions can be used to design the required compositional parameters for a desired response. These predicted materials are synthesized and found to possess an incipient quantum critical point when magnetic ordering types are designed to be in direct competition; this leads to highly controllable exchange bias sensitivity in the monolithic single crystal films previously accessible only in intentionally designed bilayer heterojunctions.

Magnetic insulators are important materials for a range of next-generation memory and spintronic applications. Structural constraints in this class of devices generally require a clean heterointerface that allows effective magnetic coupling between the insulating layer and the conducting layer. However, there are relatively few examples of magnetic insulators that can be synthesized with surface qualities that would allow these smooth interfaces and precisely tuned interfacial magnetic exchange coupling, which might be applicable at room temperature. In this work, we demonstrate an example of how the configurational complexity in the magnetic insulator layer can be used to realize these properties. The entropy-assisted synthesis is used to create single-crystal (Mg