Glucocorticoid efficacy and treatment strategies for drug-induced liver injury: a literature review.

Drug-induced liver injury (DILI) is an adverse reaction to drugs and their metabolites. The activation of adaptive immune and inflammatory responses plays an important role in the pathogenesis of DILI. Glucocorticoids (GCs) have powerful anti-inflammatory and immunosuppressive effects and have been used to treat a variety of immune-mediated liver diseases. Due to the important role of the immune system in DILI, GCs are widely used in the clinical treatment of DILI; however, whether they are beneficial to patients remains controversial. There is no uniform standard for the timing, dosage, and population selection of GCs, which mainly depend on the clinician's experience. Therefore, elucidating whether GCs are beneficial for patients with DILI is an urgent clinical problem. Our review summarizes the recent literature and discusses the clinical efficacy, applicable population, application timing, and efficacy of GCs in special types of DILI, providing a reference for the clinical application of GCs.

Observation of an isothermal glass transition in metallic glasses.

Glass transition, commonly manifested upon cooling a liquid, is continuous and cooling rate dependent. For decades, the thermodynamic basis in liquid-glass transition has been at the center of debate. Here, long-time isothermal annealing was conducted via molecular dynamics simulations for metallic glasses to explore the connection of physical aging in supercooled liquid and glassy states. An anomalous two-step aging is observed in various metallic glasses, exhibiting features of supercooled liquid dynamics in the first step and glassy dynamics in the second step, respectively. Furthermore, the transition potential energy is independent of initial states, proving that it is intrinsic for a metallic glass at a given temperature. We propose that the observed dynamic transition from supercooled liquid dynamics to glassy dynamics could be glass transition manifested isothermally. On this basis, glass transition is no longer cooling rate dependent, but is shown as a clear phase boundary in the temperature-energy phase diagram. Hence, a modified out-of-equilibrium phase diagram is proposed, providing new insights into the nature of glass transition.

Steerable Microneedles Enabling Deep Delivery of Photosensitizers and CRISPR/Cas9 Systems for Effective Combination Cancer Therapy.

Although gene therapy has shown prospects in treating triple-negative breast cancer, it is insufficient to treat such a malignant tumor. Herein, nanoparticles (NPs)-embedded dissolving microneedles (IR780-PL/pFBXO44@MNs) with steerable and flectional property were developed to achieve the codelivery of FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and hydrophobic photosensitizers. For improved NP penetration in tumor tissue, collagenase@MNs were preapplied to degrade the tumor matrix. Under light irradiation, IR780 exhibited remarkable phototherapy, while the escape efficiency of NPs from lysosomes was improved. pFBXO44 was subsequently released in tumor cell cytoplasm via reducing the disulfide bonds of NPs, which could specifically knock out the FBXO44 gene to inhibit the migration and invasion of tumor cells. As a result, tumor cells were eradicated, and lung metastasis was effectively suppressed. This micelle-incorporated microneedle platform broadens the potential of combining gene editing and photo synergistic cancer therapy.

Photoclick and Release: Co-activation of Carbon Monoxide and a Fluorescent Self-reporter, COS or Sulfonamide with Fast Kinetics.

Bioorthogonal prodrugs with both fast reaction kinetics and multiple outputs are highly desirable but are only found sporadically. Herein, we report a novel photoclick-and-release strategy for the co-activation of carbon monoxide and a self-reporter, carbonyl sulfide, or sulfonamide with fast reaction kinetics (k: 1.4-22.6 M-1 s-1 ). Such a photoclick-and-release strategy was successfully applied in live cells to deliver carbon monoxide and a fluorescent self-reporter, both of which exhibited pronounced antiproliferative activity against 4T1 cancer cells. It is conceivable that this photoclick-and-release strategy could find applications in other fields, in which a controlled bond cleavage is preferred.

Quantum Instruction Set Design for Performance.

A quantum instruction set is where quantum hardware and software meet. We develop characterization and compilation techniques for non-Clifford gates to accurately evaluate its designs. Applying these techniques to our fluxonium processor, we show that replacing the iSWAP gate by its square root SQiSW leads to a significant performance boost at almost no cost. More precisely, on SQiSW we measure a gate fidelity of up to 99.72% and averaging at 99.31%, and realize Haar random two-qubit gates with an average fidelity of 96.38%. This is an average error reduction of 41% for the former and a 50% reduction for the latter compared to using iSWAP on the same processor.

Iron deposition in ovarian endometriosis evaluated by magnetic resonance imaging R2* correlates with ovarian function.

RESEARCH QUESTION: Does iron overload in patients with endometriosis affect ovarian function? Can a method be developed to visually reflect this? DESIGN: Magnetic resonance imaging (MRI) R2* was used to evaluate the correlation between iron deposition of ovarian and anti-Müllerian hormone (AMH) in patients with endometriosis. All patients underwent T2* MRI scanning. Serum AMH levels were measured preoperatively. The area of focal iron deposition, iron content of the cystic fluid and AMH levels between the endometriosis and control groups were compared using non-parametric tests. The effects of iron overload on AMH secretion in mouse ovarian granulosa cells were investigated by adding different concentrations of ferric citrate to the medium. RESULTS: A significant difference was found between endometriosis and control groups in area of iron deposition (P < 0.0001), cystic fluid iron content (P < 0.0001), R2* of lesions (P < 0.0001) and R2* of the cystic fluid (P < 0.0001). Negative correlations were found between serum AMH levels and R2* of cystic lesions in patients with endometriosis aged 18-35 years (rs = -0.6484, P < 0.0001), and between serum AMH levels and R2* of cystic fluid (rs = -0.5074, P = 0.0050). Transcription level (P < 0.0005) and secretion level (P < 0.005) of AMH significantly decreased with the increase in iron exposure. CONCLUSION: Iron deposits can impair ovarian function, which is reflected in MRI R2*. Serum AMH levels and R2* of cystic lesions or fluid in patients aged 18-35 years had a negative correlation with endometriosis. R2* can be used to reflect the changes of ovarian function caused by iron deposition.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid.

BACKGROUND: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. AIMS: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. METHODS: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW). RESULTS: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort. CONCLUSIONS: Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.

Fluxonium: An Alternative Qubit Platform for High-Fidelity Operations.

Superconducting qubits provide a promising path toward building large-scale quantum computers. The simple and robust transmon qubit has been the leading platform, achieving multiple milestones. However, fault-tolerant quantum computing calls for qubit operations at error rates significantly lower than those exhibited in the state of the art. Consequently, alternative superconducting qubits with better error protection have attracted increasing interest. Among them, fluxonium is a particularly promising candidate, featuring large anharmonicity and long coherence times. Here, we engineer a fluxonium-based quantum processor that integrates high qubit coherence, fast frequency tunability, and individual-qubit addressability for reset, readout, and gates. With simple and fast gate schemes, we achieve an average single-qubit gate fidelity of 99.97% and a two-qubit gate fidelity of up to 99.72%. This performance is comparable to the highest values reported in the literature of superconducting circuits. Thus our work, within the realm of superconducting qubits, reveals an alternative qubit platform that is competitive with the transmon system.

Enhancing adoptive T cell therapy for solid tumor with cell-surface anchored immune checkpoint inhibitor nanogels.

The efficacy of Adoptive Cell Therapy (ACT) for solid tumor is still mediocre. This is mainly because tumor cells can hijack ACT T cells' immune checkpoint pathways to exert immunosuppression in the tumor microenvironment. Immune Checkpoint Inhibitors such as anti-PD-1 (aPD1) can counter the immunosuppression, but the synergizing effects of aPD1 to ACT was still not satisfactory. Here we demonstrate an approach to safely anchor aPD1-formed nanogels onto T cell surface via bio-orthogonal click chemistry before adoptive transfer. The spatial-temporal co-existence of aPD1 with ACT T cells and the responsive drug release significantly improved the treatment outcome of ACT in murine solid tumor model. The average tumor weight of the group treated by cell-surface anchored aPD1 was only 18 % of the group treated by equivalent dose of free aPD1 and T cells. The technology can be broadly applicable in ACTs employing natural or Chimeric Antigen Receptor (CAR) T cells.

Hidden coexisting firings in fractional-order hyperchaotic memristor-coupled HR neural network with two heterogeneous neurons and its applications.

The firing patterns of each bursting neuron are different because of the heterogeneity, which may be derived from the different parameters or external drives of the same kind of neurons, or even neurons with different functions. In this paper, the different electromagnetic effects produced by two fractional-order memristive (FOM) Hindmarsh-Rose (HR) neuron models are selected for characterizing different firing patterns of heterogeneous neurons. Meanwhile, a fractional-order memristor-coupled heterogeneous memristive HR neural network is constructed via coupling these two heterogeneous FOM HR neuron models, which has not been reported in the adjacent neuron models with memristor coupling. With the study of initial-depending bifurcation behaviors of the system, it is found that the system exhibits abundant hidden firing patterns, such as periods with different topologies, quasiperiodic firings, chaos with different topologies, and even hyperchaotic firings. Particularly, the hidden hyperchaotic firings are perfectly detected by two-dimensional Lyapunov stability graphs in the two-parameter space. Meanwhile, the hidden coexisting firing patterns of the system are excited from two scattered attraction domains, which can be confirmed from the local attraction basins. Furthermore, the color image encryption based on the system and the DNA approach owns great keyspace and a good encryption effect. Finally, the digital implementations based on Advanced RISC Machine are in good coincidence with numerical simulations.

Transition-Metal Oxides Anchored on Nitrogen-Enriched Carbon Ribbons for High-Performance Pseudocapacitors.

Increasing demand for effective energy-storage systems derived from low-cost and ecofriendly raw materials has aroused wide concern. In this contribution, we propose nitrogen-abundant amorphous micron-sized carbon ribbons (AMCRs) originating from biomass raupo as a novel substrate due to their specific quasi 2D morphologies and outstanding dispersion ability. Owing to the innate nitrogen atoms on the surface of AMCRs, ultrathin binary and ternary metal oxide (NiO, CoO, and NiCo2 O4 ) nanosheets can be uniformly developed under benign conditions. These three composites were separately fabricated as electrodes for supercapacitors in a three-electrode system and exhibited favorable activities. Among them, the ternary metal oxide composites NiCo2 O4 @AMCRs delivered the supreme specific capacitance of 1691 F g-1 and best cycling stability (89 % capacity retention over 10,000 cycles). Moreover, symmetric supercapacitors (NiCo2 O4 @AMCRs//NiCo2 O4 @AMCRs) were assembled inside sleeve devices with 2 m KOH aqueous electrolyte, which demonstrated admirable cyclic stability (79.1 % capacity retention over 8,000 cycles), and an excellent energy density of 26 Wh kg-1 at the power density of 1.8 kW kg-1 .

Tunable growth of perpendicular cobalt ferrite nanosheets on reduced graphene oxide for energy storage.

Ultrathin cobalt ferrite nanosheets have been successfully assembled on the surface of reduced graphene oxide (rGO) via only adjusting the volume ratio of ethanol and deionized (DI) water and a post calcination treatment. The perpendicular ultrathin cobalt ferrite nanosheets supported by rGO sheets (CoFe2O4 NSs@rGO) can be obtained when the volume ratio of ethanol and DI water is 10:30. Correspondingly, the hierarchical porous films covering the total rGO sheets will be formed nanosheets. When evaluated as the electrodes for lithium ion batteries (LIBs) and supercapacitors (SCs), the resultant CoFe2O4 NSs@rGO hybrids exhibit highly enhanced electrochemical performance. Even after 200 charge-discharge cycles at 400 mA g-1, the electrodes as the anode material for LIBs still exhibit a reversible discharge capacity of 835.6 mAh g-1. In addition, this electrode for SCs also exhibits specific capacitance of ca 1120 F g-1 after 3000 cycles. These superior results imply that CoFe2O4 NSs with novel hybrid structure of rGO could potentially lead to an excellent electrochemical performance for energy storage.

Study on Enhanced Dissolution of Azilsartan-Loaded Solid Dispersion, Prepared by Combining Wet Milling and Spray-Drying Technologies.

The purpose of this study was to develop a combination method of wet milling and spray-drying technologies to prepare the solid dispersion and improve the dissolution rate of poorly water-soluble drug candidates. Azilsartan (AZL) was selected as the model drug for its poor water solubility. In the study, AZL-loaded solid dispersion was prepared with polyethylene glycol 6000 (PEG6000) and hydroxypropyl cellulose with super low viscosity (HPC-SL) as stabilizers by using combination of wet grinding and spray-drying methods. The high AZL loading solid dispersion was then characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Besides, dissolution test was carried out by the paddle method and stability investigation was also conducted. As a result, the dissolution rate of the solid dispersion tablets was found to be greater than conventional tablets, but in close agreement with market tablets. Furthermore, the formulation was shown to be stable at 40 ± 2°C and 75 ± 5% for at least 6 months, owing to its decreased particle size, morphology, and its crystal form. It was concluded that the combination of wet milling and spray-drying approaches to prepare solid dispersion would be a prospective method to improve the dissolution rate of poorly water-soluble drugs.

Stable Formation of Gold Nanoparticles onto Redox-Active Solid Biosubstrates Made of Squid Suckerin Proteins.

The use of biomolecules to synthesize inorganic nanomaterials, including metallic nanoparticles, offers the ability to induce controlled growth under mild environmental conditions. Here, recently discovered silk-like "suckerin" proteins are used to induce the formation of gold nanoparticles (AuNPs). Advantage is taken of the distinctive biological and physico-chemical characteristics of suckerins, namely their facile recombinant expression, their solubility in aqueous solutions, and their modular primary structure with high molar content of redox-active tyrosine (Tyr) residues to induce the formation of AuNPs not only in solution, but also from nanostructured solid substrates fabricated from suckerins.

Ligand-exchange assisted formation of Au/TiO2 Schottky contact for visible-light photocatalysis.

Plasmonic noble metal nanoparticles have emerged as a promising material in sensitizing wide-bandgap semiconductors for visible-light photocatalysis. Conventional methods in constructing such heterocatalysts suffer from either poor control over the size of the metal nanoparticles or inefficient charge transfer through the metal/semiconductor interface, which limit their photocatalytic activity. To solve this problem, in this work we construct Au/TiO2 photocatalysts by depositing presynthesized colloidal Au nanoparticles with well-controlled sizes to TiO2 nanocrystals and then removing capping ligands on the Au surface through a delicately designed ligand-exchange method, which leads to close Au/TiO2 Schottky contact after a mild annealing process. Benefiting from this unique synthesis strategy, the obtained photocatalysts show superior activity to conventionally prepared photocatalysts in dye decomposition and water-reduction hydrogen production under visible-light illumination. This study not only opens up new opportunities in designing photoactive materials with high stability and enhanced performance for solar energy conversion but also provides a potential solution for the well-recognized challenge in cleaning capping ligands from the surface of colloidal catalyst nanoparticles.

Biomimetic production of silk-like recombinant squid sucker ring teeth proteins.

The sucker ring teeth (SRT) of Humboldt squid exhibit mechanical properties that rival those of robust engineered synthetic polymers. Remarkably, these properties are achieved without a mineral phase or covalent cross-links. Instead, SRT are exclusively made of silk-like proteins called "suckerins", which assemble into nanoconfined ß-sheet reinforced supramolecular networks. In this study, three streamlined strategies for full-length recombinant suckerin protein production and purification were developed. Recombinant suckerin exhibited high solubility and colloidal stability in aqueous-based solvents. In addition, the colloidal suspensions exhibited a concentration-dependent conformational switch, from random coil to ß-sheet enriched structures. Our results demonstrate that recombinant suckerin can be produced in a facile manner in E. coli and processed from mild aqueous solutions into materials enriched in ß-sheets. We suggest that recombinant suckerin-based materials offer potential for a range of biomedical and engineering applications.

Novel self-assembly endows human serum albumin nanoparticles with an enhanced antitumor efficacy.

Protein-based nanomedicine plays an important role in tumor chemotherapy due to their merits in bioavailability, biocompatibility, biodegradability, and low toxicity. In this study, we developed a novel method of preparing human serum albumin (HSA) nanoparticles for targeted delivery of paclitaxel (PTX) to tumors. HSA-PTX nanoparticles (NPs-PTX) were fabricated via unfolding of HSA in appropriate solution to expose more hydrophobic domains and consequent self-assembling into nanoparticles with added PTX. Via this self-assembly method, a desirable particle size (around 120 nm), a high drug loading (>20%), and a high encapsulation efficiency (near 100%) were obtained. PTX dispersed as an amorphous state in NPs-PTX and the secondary structures of HSA were maintained. In a cytotoxicity study, NPs-PTX displayed an enhanced cytotoxicity in MCF-7 and A549 cells. Confocal microscopy and flow cytometry revealed that the uptake of NPs-PTX was mediated by secreted protein acidic and rich in cysteine and "caveolar" transport. In H22 tumor-bearing mice, NPs-PTX displayed an increasing and everlasting tumor distribution, leading to slower tumor growth and longer mice survival than PTX. Therefore, this novel self-assembly method offers a much easier method to prepare PTX nanoparticles, provides better antitumor efficacy in vitro and in vivo, and more importantly, sets up a delivery platform for other hydrophobic drugs to improve their effectiveness in cancer therapy.

A knowledge-enhanced interpretable network for early recurrence prediction of hepatocellular carcinoma via multi-phase CT imaging.

BACKGROUND: Predicting early recurrence (ER) of hepatocellular carcinoma (HCC) accurately can guide treatment decisions and further enhance survival. Computed tomography (CT) imaging, analyzed by deep learning (DL) models combining domain knowledge, has been employed for the prediction. However, these DL models utilized late fusion, restricting the interaction between domain knowledge and images during feature extraction, thereby limiting the prediction performance and compromising decision-making interpretability. METHODS: We propose a novel Vision Transformer (ViT)-based DL network, referred to as Dual-Style ViT (DSViT), to augment the interaction between domain knowledge and images and the effective fusion among multi-phase CT images for improving both predictive performance and interpretability. We apply the DSViT to develop pre-/post-operative models for predicting ER. Within DSViT, to balance the utilization between domain knowledge and images within DSViT, we propose an adaptive self-attention mechanism. Moreover, we present an attention-guided supervised learning module for balancing the contributions of multi-phase CT images to prediction and a domain knowledge self-supervision module for enhancing the fusion between domain knowledge and images, thereby further improving predictive performance. Finally, we provide the interpretability of the DSViT decision-making. RESULTS: Experiments on our multi-phase data demonstrate that DSViTs surpass the existing models across multiple performance metrics and provide the decision-making interpretability. Additional validation on a publicly available dataset underscores the generalizability of DSViT. CONCLUSIONS: The proposed DSViT can significantly improve the performance and interpretability of ER prediction, thereby fortifying the trustworthiness of artificial intelligence tool for HCC ER prediction in clinical settings.

Error-controlled adaptive machining of aeronautical cabin structures by laser triangulation on-machine measurement.

Laser Triangulation On-Machine Measurement (LTOMM) is being implemented increasingly to inspect aeronautical components accurately and efficiently, with its enhanced application in adaptive machining. This work proposes an error compensation and controlling method for measuring the typical features of steps, holes, and freeform surfaces to improve accuracy. Then, the global path to inspect the cabin's structures is planned by introducing optimization algorithms, thus providing an appropriate sequence to shorten the traveling length. After these, the test piece was designed, measured, and manufactured using the adaptive machining process that integrates the LTOMM. The results show that the measurement errors of steps, holes, and freeform surfaces are +0.0092, -0.006, and +0.0406 mm, respectively, and further reduced to +0.0013, -0.0019, and +0.0083 mm after error controlling. The cabin's freeform surface was fabricated with the maximum positive and minimum negative errors of +0.184 and -0.123 mm, which is evaluated by the mechanical probe. The measured data-driven machining process can guarantee that the error satisfies the required tolerance, promoting the application of the LTOMM process in aeronautical intelligent manufacturing.

Prescribed Fixed-Time Control for Constrained Uncertain Nonlinear Cyber-Physical Systems Against Deception Attacks.

In this note, a novel prescribed fixed-time adaptive tracking control scheme is developed to cope with the fixed-time tracking control issue for a category of constrained MIMO nonlinear cyber-physical systems (CPSs) with exogenous perturbations, which suffer from deception attacks started in controller-actuator (C-A) channel. Distinguished from the conservative dynamic surface control (DSC) schemes with a linear filter, a novel nonlinear filter is designed in our strategy, which can tackle the intrinsic issue of explosion of computational complexity and promote the system performance. Besides, a new barrier Lyapunov function (BLF) is designed to ulteriorly enhance the tracking performance on the basis of the prescribed performance function (PPF) approach. Prominently, the proposed control strategy could accommodate the exogenous interferences and deception attacks simultaneously. Furthermore, we have substantiated that the developed approach can not only make certain that all the tracking errors of the resulting closed-loop system, including output tracking errors and virtual tracking errors, enter a prespecified small region near equilibrium point with fixed-time convergence rate, but also guarantee them obey the corresponding constraints throughout the entire control operation, where the regulation time and the tracking accuracy level keep prior known and could be prespecified arbitrarily. Finally, the validity and effectiveness of the proposed control scheme are illustrated through a representative application instance.