[Analysis of the prognosis and survival of patients with acute-on-chronic liver failure].

Objective: To explore the influencing factors and the impact of artificial liver treatment on the prognosis and survival of patients with acute-on-chronic liver failure (ACLF). Methods: Clinical data from 201 cases with ACLF from January 2016 to December 2019 was retrospectively analyzed. The survival rate was calculated by the Kaplan-Meier method, the log-rank test of univariate analysis, and the multivariate analysis of the stepwise Cox regression forward method. Results: The median survival time of patients was 6 months, and the survival rates at 6, 9, and 12 months were 51.2%, 38.3%, and 29.9%, respectively. In univariate analysis, age, presence or absence of hypertension and upper gastrointestinal bleeding, treatment method, model for end-stage liver disease (MELD) score, and cholinesterase were associated with prognosis (P < 0.05). Multivariate regression analysis results showed that MELD score was the main factor affecting the 1-year prognosis of ACLF patients (P = 0.002). Artificial liver treatment was beneficial for the 1-year prognosis of ACLF patients aged < 50 years or with a MELD score of ≥20 (P < 0.05 ). The relative risk ratio (RR) of mortality was 2.55 times higher in patients with advanced age (≥50 years old) than that of younger patients (P < 0.001). Regression analysis was performed using age as a stratification factor, and upper gastrointestinal bleeding was related to the prognosis of younger patients, while choline esterase was related to the prognosis of advanced age. Regression analysis after stratified MELD score showed that age and hypertension were related to the prognosis of patients with MELD score < 20, and treatment method and age were related to the prognosis of patients with MELD score≥20. Conclusion: Artificial liver treatment is beneficial for the 1-year prognosis of ACLF patients. Age, MELD score, hypertension, and upper gastrointestinal bleeding are independent risk factors affecting the prognosis of ACLF patients.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Assessing bicycle-vehicle conflicts at urban intersections utilizing a VR integrated simulation approach.

Animosity between drivers and cyclists has existed on urban road networks for many years. Conflicts between these two groups of road users are exceptionally high in the shared right-of-way environments. Benchmarking methods of conflict assessments are mostly based on statistical analysis with limited data sources. The actual crash data would be valuable to understand the features of bike-car collisions, however the available data are spatially and temporally sparse. To this end, this paper proposes a simulation-based bicycle-vehicle conflict data generation and assessment approach. The proposed approach uses a three-dimensional visualization and virtual reality platform, integrating traffic microsimulation to reproduce a naturalistic driving/cycling-enabled experimental environment. The simulation platform is validated to reflect the human-resembled driving/cycling behaviors under different infrastructure designs. Comparative experiments are carried out on bicycle-vehicle interactions under different conditions, with data collected from a total of 960 scenarios. Based on the results of the surrogate safety assessment model (SSAM), the obtained key insights include: (1) scenarios of a high conflict probability do not lead to actual crashes, which suggests that the classic SSM-based measurements such as TTC or PET values may not sufficiently reflect real cyclist-driver interactions; (2) the major cause of conflicts is variation in vehicle acceleration, which suggests that drivers are considered to be the main party responsible for bicycle-vehicle conflict/crash occurrence; (3) the proposed approach is able to generate near-miss events and reproduce interaction patterns between cyclists and drivers, facilitating experiments and data collections which would be typically unavailable for this type of study.

Strong magnetic anisotropy in PrRu2Ga8and PrCo2Al8single crystals.

Single crystals ofLnRu2Ga8andLnCo2Al8(Ln= La and Pr) were grown using a Ga/Al self-flux method. An orthorhombic CaCo2Al8-type structure with space groupPbam(No.55) of them was identified by x-ray diffraction. LaRu2Ga8and LaCo2Al8are Pauli paramagnetic down to 2 K, while PrRu2Ga8and PrCo2Al8show antiferromagnetic (AFM) order at 2.5 and 5 K, respectively. Strong magnetic anisotropy in PrRu2Ga8and PrCo2Al8single crystals was found by an anisotropic magnetic measurement. The field-induced FM state was observed in both PrRu2Ga8and PrCo2Al8forH||c. However, in the case of H⊥c, the AFM state is robust. The strong magnetic anisotropy in PrRu2Ga8FM and PrCo2Al8is due to their anisotropic magnetic interactions that FM interactions are dominant in the case ofH||cwhile AFM interactions forH⊥c.

Giant Exchange-Bias-Like Effect at Low Cooling Fields Induced by Pinned Magnetic Domains in Y2 NiIrO6 Double Perovskite.

Exchange bias (EB) is highly desirable for widespread technologies. Generally, conventional exchange-bias heterojunctions require excessively large cooling fields for sufficient bias fields, which are generated by pinned spins at the interface of ferromagnetic and antiferromagnetic layers. It is crucial for applicability to obtain considerable exchange-bias fields with minimum cooling fields. Here, an exchange-bias-like effect is reported in a double perovskite, Y2 NiIrO6 , which shows long-range ferrimagnetic ordering below 192 K. It displays a giant bias-like field of 1.1 T with a cooling field of only 15 Oe at 5 K. This robust phenomenon appears below 170 K. This fascinating bias-like effect is the secondary effect of the vertical shifts of the magnetic loops, which is attributed to the pinned magnetic domains due to the combination of strong spin-orbit coupling on Ir, and antiferromagnetically coupled Ni- and Ir-sublattices. The pinned moments in Y2 NiIrO6 are present throughout the full volume, not just at the interface as in conventional bilayer systems.

Crystal Growth, Structural Transition, and Magnetic Properties of Ho5Pd4Sn12.

Single crystals and polycrystalline samples of Ho5Pd4Sn12 have been synthesized using flux and arc-melting methods, respectively. Single-crystal X-ray diffraction studies indicate that Ho5Pd4Sn12 crystallizes in a tetragonal structure (I4/m) at room temperature and transforms into a monoclinic structure (C2/m) below ∼194 K. This structural transition is further supported by a transmission electron microscopy study and an anomaly at ∼194 K in the specific heat data. Temperature-dependent resistivity data also show a kink around the structural transition temperature. Ho5Pd4Sn12 is antiferromagnetically ordered below 7 K. Ho5Pd4Sn12 shows magnetic anisotropy, and the isothermal magnetization curve (H⊥c) at 2 K exhibits a field-induced magnetic phase transition around 22.8 kOe.

Enhancing Covid-19 virus spread modeling using an activity travel model.

Coronavirus 2019 (COVID-19) and its variants are still spreading rapidly with deadly consequences and profound impacts on the global health and world economy. Without a suitable vaccine, mobility restriction has been the most effective method so far to prevent its spreading and avoid overwhelming the heath system of the affected country. The compartmental model SIR (or Susceptible, Infected, and Recovered) is the most popular mathematical model used to predict the course of the COVID-19 pandemic in order to plan the control actions and mobility restrictions against its spreading. A major limitation of this model in relation to modeling the spreading of COVID-19, and the mobility limitation strategy, is that the SIR model does not include mobility or take into account changes in mobility within its structure. This paper develops and tests a new hybrid SIR model; SIR-M which is integrated with an urban activity travel model to explore how it might improve the prediction of pandemic course and the testing of mobility limitation strategies in managing virus spread. The paper describes the enhanced methodology and tests a range of mobility limitation strategies on virus spread outcomes. Implications for policy and research futures are suggested.

Single-crystal growth and magnetic anisotropy in PrFe2Ga8.

Single crystals of PrFe2Ga8were successfully grown by using Ga self-flux. PrFe2Ga8crystallizes in the CaCo2Al8-type orthorhombic structure with the space groupPbam(no. 55). By combining the results from the magnetic-susceptibility, specific-heat, and resistivity measurements, we show that PrFe2Ga8exhibits a magnetic order at 14 K. ForH//c, the antiferromagnetic order can be suppressed by magnetic fields. However, the magnetic order is robust against magnetic fields forH⊥c. Our results provide basic physical properties of PrFe2Ga8and will help to further understand the magnetism in this system.

Recording and manipulation of vagus nerve electrical activity in chronically instrumented unanesthetized near term fetal sheep.

BACKGROUND: The chronically instrumented pregnant sheep has been used as a model of human fetal development and responses to pathophysiologic stimuli. This is due to the unique amenability of the unanesthetized fetal sheep to the surgical placement and maintenance of catheters and electrodes, allowing repetitive blood sampling, substance injection, recording of bioelectrical activity, application of electric stimulation, and in vivo organ imaging. Recently, there has been growing interest in the pleiotropic effects of vagus nerve stimulation (VNS) on various organ systems such as innate immunity and inflammation, and metabolism. There is no approach to study this in utero and corresponding physiological understanding is scarce. NEW METHOD: Based on our previous presentation of a stable chronically instrumented unanesthetized fetal sheep model, here we describe the surgical instrumentation procedure allowing successful implantation of a cervical uni- or bilateral VNS probe with or without vagotomy. RESULTS: In a cohort of 68 animals, we present the changes in blood gas, metabolic, and inflammatory markers during the postoperative period. We detail the design of a VNS probe which also allows recording from the fetal nerve. We also present an example of fetal vagus electroneurogram (VENG) recorded from the VNS probe and an analytical approach to the data. COMPARISON WITH EXISTING METHODS: This method represents the first implementation of fetal VENG/VNS in a large pregnant mammalian organism. CONCLUSIONS: This study describes a new surgical procedure allowing to record and manipulate chronically fetal vagus nerve activity in an animal model of human pregnancy.

Tl2Ir2O7: A Pauli Paramagnetic Metal, Proximal to a Metal Insulator Transition.

A polycrystalline sample of Tl2Ir2O7 was synthesized by high-pressure and high-temperature methods. Tl2Ir2O7 crystallizes in the cubic pyrochlore structure with space group Fd3̅m (No. 227). The Ir4+ oxidation state is confirmed by Ir-L3 X-ray absorption near-edge spectroscopy. Combined temperature-dependent magnetic susceptibility, resistivity, specific heat, and DFT+DMFT calculation data show that Tl2Ir2O7 is a Pauli paramagnetic metal, but it is close to a metal-insulator transition. The effective ionic size of Tl3+ is much smaller than that of Pr3+ in metallic Pr2Ir2O7; hence, Tl2Ir2O7 would be expected to be insulating according to the established phase diagram of the pyrochlore iridate compounds, A3+2Ir4+2O7. Our experimental and theoretical studies indicate that Tl2Ir2O7 is uniquely different from the current A3+2Ir4+2O7 phase diagram. This uniqueness is attributed primarily to the electronic configuration difference between Tl3+ and rare-earth ions, which plays a substantial role in determining the Ir-O-Ir bond angle, and the corresponding electrical and magnetic properties.

Studying freeway merging conflicts using virtual reality technology.

INTRODUCTION: This research aims to investigate the perceptions and reactions of drivers regarding freeway merging situation, utilizing a new approach with the basis of a multilevel simulation platform which incorporates virtual reality (VR) technology. METHODS: A VR driving environment integrated with traffic micro-simulation was developed to evaluate driving behaviors and the impact of merging decisions in terms of traffic conflicts. The driving experiments were conducted under a variety of circumstances, including varying traffic flows and the presence of ramp metering. The Surrogate Safety Assessment Model (SSAM) was utilized to extract the number of conflicts from the micro-simulation results. RESULTS: The final results indicated that the probability of conflict has a positive correlation with traffic flow, while conflict frequency at freeway merges is affected by the presence of ramp metering due to its potentiality to enhance driver decisions and reduce the drivers' pressure when they make maneuvers. Practical Applications: The findings reveal that the proposed VR simulation platform is a useful tool to improve the safety of freeway merging. It has the potential to enhance driver skills and can also be used in the study of human-machine interaction.

Percolation of heterogeneous flows uncovers the bottlenecks of infrastructure networks.

Whether it be the passengers' mobility demand in transportation systems, or the consumers' energy demand in power grids, the primary purpose of many infrastructure networks is to best serve this flow demand. In reality, the volume of flow demand fluctuates unevenly across complex networks while simultaneously being hindered by some form of congestion or overload. Nevertheless, there is little known about how the heterogeneity of flow demand influences the network flow dynamics under congestion. To explore this, we introduce a percolation-based network analysis framework underpinned by flow heterogeneity. Thereby, we theoretically identify bottleneck links with guaranteed decisive impact on how flows are passed through the network. The effectiveness of the framework is demonstrated on large-scale real transportation networks, where mitigating the congestion on a small fraction of the links identified as bottlenecks results in a significant network improvement.

Bougainvinones NP, three new flavonoids from Bougainvillea spectabilis.

In an effort to identify natural bioactive compounds, three new flavonoids (1-3) and six known compounds (4-9) were isolated from the stem bark of Bougainvillea spectabilis. The structures of these compounds were accomplished using comprehensive spectroscopic methods, including 1D and 2D NMR spectra with references to the literatures, as well as high-resolution mass spectrometric analysis. Their cytotoxicity against KB and HeLa S-3 cell lines was also evaluated.

High-Pressure Synthesis of Double Perovskite Ba2NiIrO6: In Search of a Ferromagnetic Insulator.

Double perovskite oxides with d8-d3 electronic configurations are expected to be ferromagnetic from the Goodenough-Kanamori rules, such as ferromagnetic La2NiMnO6. In search of new ferromagnetic insulators, double perovskite Ba2NiIrO6 was successfully synthesized by high-pressure and high-temperature methods (8 GPa and 1573 K). Ba2NiIrO6 crystallizes in a cubic double perovskite structure (space group: Fm3̅m), with an ordered arrangement of NiO6 and IrO6 octahedra. X-ray absorption near-edge spectroscopy confirms the nominal Ni(II) and Ir(VI) valence states. Ba2NiIrO6 displays an antiferromagnetic order at 51 K. The positive Weiss temperature, however, indicates that ferromagnetic interactions are dominant. Isothermal magnetization curves at low temperatures support a field-induced spin-flop transition.

Longitudinal sampling is required to maximize detection of intrahost A/H3N2 virus variants.

Seasonal human influenza viruses continually change antigenically to escape from neutralizing antibodies. It remains unclear how genetic variation in the intrahost virus population and selection at the level of individual hosts translates to the fast-paced evolution observed at the global level because emerging intrahost antigenic variants are rarely detected. We tracked intrahost variants in the hemagglutinin and neuraminidase surface proteins using longitudinally collected samples from 52 patients infected by A/H3N2 influenza virus, mostly young children, who received oseltamivir treatment. We identified emerging putative antigenic variants and oseltamivir-resistant variants, most of which remained detectable in samples collected at subsequent days, and identified variants that emerged intrahost immediately prior to increases in global rates. In contrast to most putative antigenic variants, oseltamivir-resistant variants rapidly increased to high frequencies in the virus population. Importantly, the majority of putative antigenic variants and oseltamivir-resistant variants were first detectable four or more days after onset of symptoms or start of treatment, respectively. Our observations demonstrate that de novo variants emerge, and may be positively selected, during the course of infection. Additionally, based on the 4-7 days post-treatment delay in emergence of oseltamivir-resistant variants in six out of the eight individuals with such variants, we find that limiting sample collection for routine surveillance and diagnostic testing to early timepoints after onset of symptoms can potentially preclude detection of emerging, positively selected variants.

[Research progress on energy metabolism of Plasmodium at erythrocytic stage].

As a single-cell organism, Plasmodium has a large and complex metabolic network system. There is a close relationship between various metabolic pathways to maintain the transformation of Plasmodium's own energy and substances. Plasmodium energy metabolism pathways mainly include glycolysis and oxidative phosphorylation. Among them, Plasmodium at the erythrocytic stage takes glycolysis as the main energy supply method, and less energy is generated by oxidative phosphorylation. In addition, the two carbon metabolism pathways closely relating to energy metabolism are the tricarboxylic acid(TCA) cycle pathway and glutamate metabolism pathway. As the core of metabolism, the TCA cycle connects glycolysis and glutamate metabolism; glutamate metabolism, as the main carbon metabolism pathway, also participates in various metabolic pathways, such as pyrimidine metabolism, porphyrin metabolism, and protein biosynthesis. This article reviews the energy metabolism pathways of Plasmodium and carbon metabolism pathways that are closely related to energy metabolism, in order to deepen the understanding of the energy metabolism of Plasmodium at the erythrocytic stage, and then provide the theoretical basis and references for studying the mechanisms of action and the drug resistance of antimalarial drugs.

Fifty Years of Accident Analysis & Prevention: A Bibliometric and Scientometric Overview.

Accident Analysis & Prevention (AA&P) is a leading academic journal established in 1969 that serves as an important scientific communication platform for road safety studies. To celebrate its 50th anniversary of publishing outstanding and insightful studies, a multi-dimensional statistical and visualized analysis of the AA&P publications between 1969 and 2018 was performed using the Web of Science (WoS) Core Collection database, bibliometrics and mapping-knowledge-domain (MKD) analytical methods, and scientometric tools. It was shown that the annual number of AA&P's publications has grown exponentially and that over the course of its development, AA&P has been a leader in the field of road safety, both in terms of innovation and dissemination. By determining its key source countries and organizations, core authors, highly co-cited published documents, and high burst-strength publications, we showed that AA&P's areas of focus include the "effects of hazard and risk perception on driving behavior", "crash frequency modeling analysis", "intentional driving violations and aberrant driving behavior", "epidemiology, assessment and prevention of road traffic injuries", and "crash-injury severity modeling analysis". Furthermore, the key burst papers that have played an important role in advancing research and guiding AA&P in new directions - particularly those in the fields of crash frequency and crash-injury severity modeling analyses were identified. Finally, a modified Haddon matrix in the era of intelligent, connected and autonomous transportation systems is proposed to provide new insights into the emerging generation of road safety studies.

Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation.

The field of chemical modification of proteins has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently, we have developed oxaziridine chemistry for highly selective modification of methionine called redox-activated chemical tagging (ReACT) but have not broadly tested the molecular parameters for efficient and stable protein modification. Here we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, used for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and excellent reaction efficiencies with a panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than 10-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, presumably because of their reduced access to water. There was also a 10-fold variation in stability depending on the nature of the oxaziridine, which was determined to be inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs were sufficient to support their use as antibody drug conjugates and potent in a breast cancer mouse xenograft model over a month. These studies provide key parameters for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation to native or engineered methionines.