Carnosic Acid: A Novel Selective Inhibitor of ERAP1 by Direct Binding and Its Modulation of Antigen Processing and Presentation.

ERAP1 is an emerging target for a large subclass of severe autoimmune diseases known as "MHC-I-opathy", together with tumor immunity. Nevertheless, effective inhibitors targeting ERAP1 remain a challenge. In this study, a novel food-derived natural product ERAP1-targeting inhibitor, carnosic acid, was identified, and to our knowledge, it is one of the best active compounds among the highly selective inhibitors targeting the orthosteric site of ERAP1. The results reveal that carnosic acid could bind strongly, like a key to the ERAP1 active site in the biased S1' pocket, which is different from the binding mode of the existing orthosteric site inhibitors. HLA-B27-mediated cell modeling validated that carnosic acid has the activity to reverse the AS-associated cellular phenotype brought on by ERAP1 through inhibition. Our findings provide insights into the design of potent inhibitors against the ERAP1 orthosteric site and the discovery of a key direct target of carnosic acid.

Sustainable Sea of Internet of Things: Wind Energy Harvesting System for Unmanned Surface Vehicles.

Harvesting wind energy from the environment and integrating it with the internet of things and artificial intelligence to enable intelligent ocean environment monitoring are effective approach. There are some challenges that limit the performance of wind energy harvesters, such as the larger start-up torque and the narrow operational wind speed range. To address these issues, this paper proposes a wind energy harvesting system with a self-regulation strategy based on piezoelectric and electromagnetic effects to achieve state monitoring for unmanned surface vehicles (USVs). The proposed energy harvesting system comprises eight rotation units with centrifugal adaptation and four piezoelectric units with a magnetic coupling mechanism, which can further reduce the start-up torque and expand the wind speed range. The dynamic model of the energy harvester with the centrifugal effect is explored, and the corresponding structural parameters are analyzed. The simulation and experimental results show that it can obtain a maximum average power of 23.25 mW at a wind speed of 8 m/s. Furthermore, three different magnet configurations are investigated, and the optimal configuration can effectively decrease the resistance torque by 91.25% compared with the traditional mode. A prototype is manufactured, and the test result shows that it can charge a 2200 µF supercapacitor to 6.2 V within 120 s, which indicates that it has a great potential to achieve the self-powered low-power sensors. Finally, a deep learning algorithm is applied to detect the stability of the operation, and the average accuracy reached 95.33%, which validates the feasibility of the state monitoring of USVs.

[Research progress in raw and processed Raphani Semen and prediction of quality markers].

Raphani Semen, with both edible and medicinal values, is a typical Chinese herbal medicine with different effects before and after processing. The raw helps ascending and the cooked helps descending. This paper comprehensively summarizes the differences in chemical constituents and pharmacological effects between raw and processed Raphani Semen that are reported in recent years. Based on the principle of quality markers(Q-markers) of traditional Chinese medicines, the chemical constituent sources, chemical constituent detection techniques, and correlation between bidirectional regulatory efficacy and chemical constituents are compared between raw and processed Raphani Semen. The results suggest that sulforaphene and glucoraphanin could be used as candidate Q-markers of raw and processed Raphani Semen, respectively. This review is expected to provide a reference for further research on the processing, new drug development, and improvement of safety and effectiveness of Raphani Semen in clinical application.

Hypoglycemic TCM formulas (Huangqi-Gegen drug pair) have the potential as an Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurological disorder. There is a considerable unmet medical need among those suffering from it. HYPOTHESIS AND PURPOSE: Given the link between type-2 diabetes mellitus (T2DM) and AD, hypoglycemic traditional Chinese medicine formulas (TCMFs) may be a treatment for AD. We investigated the possibility of identifying anti-AD medicines in hypoglycemic TCMFs and presented another option for the screening of AD medications. STUDY DESIGN AND METHODS: Paralysis of the transgenic Caenorhabditis elegans (C. elegans) strain CL4176 (caused by amyloid beta (Aß)1-42 aggregates) was used to evaluate the anti-AD effect. The toxicity and neurodegeneration induced by neuronal expression of Aß in the transgenic C. elegans strain CL2355 were determined using a 5-hydroxytryptamine (5-HT) assay. The transgenic Aß-expressing strain CL 2006 and transgenic tau-expressing strain BR5270 were used to explore the effect of TCMFs on protein expression in C. elegans using ELISAs. Then, network pharmacology was used to determine the mechanism of action. The Traditional Chinese Medicine Inheritance Support System platform was used to investigate prescription patterns, core drugs, and optimum combinations of hypoglycemic TCMFs for AD. RESULTS: Sixteen hypoglycemic TCMFs prolonged the PT50 (half paralysis time) of the CL4176 strain of C. elegans, reduced the percentage of worms paralyzed. The results of network pharmacology showed that prostaglandin-endoperoxide synthase 2 (PTGS2) and acetylcholine esterase (AChE) are main targets of hypoglycemic TCMFs. Enriched pathway analysis showed that the cholinergic receptor-related pathway was the core pathway of hypoglycemic TCMFs. According to the "four qi and five flavors" system of TCM theory, the main pharmacological qualities were "cold" and "sweet." Through the analysis by TCMISS, we found that Huangqi-Gegen drug pair as the significant Chinese herbs of hypoglycemic TCMFs. The Huangqi-Gegen pairing had the most robust therapeutic effect when delivered at a 2:1 (v/v) ratio. It reduced the paralysis caused by 5-HT, decreased protein expression of AChE and PTGS2, and reduced Aß deposition in the brain of the CL2006 strain of C. elegans. CONCLUSIONS: Huangqi-Gegen is a promising treatment of AD, and its mechanism may be induced by suppressing the protein production of AChE and PTGS2, reducing 5-HT intake, and then decreasing Aß deposition.

Iron-based materials functionalized with carbon and phosphorus recovered from sludge enhanced the formation of stable minerals to passivate lead and chromium in wastewater and soil.

The bioaccumulation and toxicity of heavy metals are serious threats to human activities and ecological health. The exploitation of environmentally friendly passivated materials is major importance for the remediation of heavy metal contaminated soil. This research developed a new type of environmental functional material with a core-shell structure, which is an iron-based material functionalized with phosphorus and carbon from sludge for heavy metal pollution remediation. The results indicated that the C/P@Fe exhibits excellent heavy metal removal ability, and the maximum removal rates of the two heavy metals in simulated wastewater could reach 100% under optimum reaction conditions. It also effectively converts the labile Cr/Pb into the stable fraction after 28 days of incubation, which increased the maximum residual fraction percentage of Cr and Pb by 32.43% and 160% in soil. Further analysis found that the carbon layer wrapped around the iron base could improve the electron transport efficiency of reducing iron, phosphorus and ferrum could react with heavy metal ions to form stable minerals, such as FeCr2O4, FeO·Cr2O3, Pb5(PO4)3OH, PbCO3, 2PbCO3·Pb(OH)2 and PbS, after reacting with C/P@Fe. The study demonstrated that the Iron-based materials functionalized with carbon and phosphorus from sludge provided a more efficient way to remove heavy metals.

Micromirror Array with Adjustable Reflection Characteristics Based on Different Microstructures and Its Application.

The conventional reflective optical surface with adjustable reflection characteristics requires a complex external power source. The complicated structure and preparation process of the power system leads to the limited modulation of the reflective properties and difficulty of use in large-scale applications. Inspired by the biological compound eye, different microstructures are utilized to modulate the optical performance. Convex aspheric micromirror arrays (MMAs) can increase the luminance gain while expanding the field of view, with a luminance gain wide angle > 90° and a field-of-view wide angle close to 180°, which has the reflective characteristics of a large gain wide angle and a large field-of-view wide angle. Concave aspheric micromirror arrays can increase the luminance gain by a relatively large amount of up to 2.66, which has the reflective characteristics of high gain. Industrial-level production and practical applications in the projection display segment were carried out. The results confirmed that convex MMAs are able to realize luminance gain over a wide spectrum and a wide range of angles, and concave MMAs are able to substantially enhance luminance gain, which may provide new opportunities in developing advanced reflective optical surfaces.

Controlling the Selectivity of Electrocatalytic NO Reduction through pH and Potential Regulation on Single-Atom Catalysts.

Electrocatalytic nitrogen oxide reduction (NOxRR) emerges as an effective way to bring the disrupted nitrogen cycle back into balance. However, efficient and selective NOxRR is still challenging partly due to the complex reaction mechanism, which is influenced by experimental conditions such as pH and electrode potential. Here, we have studied the enzyme-inspired iron single-atom catalysts (Fe-N4-C) and identified that the selectivity roots in the first step of the nitric oxide reduction. Combining the constrained molecular dynamics (MD) simulations with the quasi-equilibrium approximation, the effects of electrode potential and pH on the reaction free energy were considered explicitly and predicted quantitatively. Systematic heat maps for selectivity between single-N and N-N-coupled products in a wide pH-potential space are further developed, which have reproduced the experimental observations of NOxRR. The approach presented in this study allows for a realistic simulation of the electrocatalytic interfaces and a quantitative evaluation of interfacial effects. Our results in this study provide valuable and straightforward guidance for selective NOx reduction toward desired products by precisely designing the experimental conditions.

Development of D-π-A organic dyes for discriminating HSA from BSA and study on dye-HSA interaction.

HSA (human serum albumin), a most abundant protein in blood serum, plays a key role in maintaining human health. Abnormal HSA level is correlated with many diseases, and thus has been used as an essential biomarker for therapeutic monitoring and biomedical diagnosis. Development of small-molecule fluorescent probes allowing the selective and sensitive recognition of HSA in in vitro and in vivo is of fundamental importance in basic biological research as well as medical diagnosis. Herein, we reported a series of new synthesized fluorescent dyes containing D-π-A constitution, which exhibited different optical properties in solution and solid state. Among them, dye M-H-SO3 with a hydrophilic sulfonate group at electron-acceptor part displayed selectivity for discrimination of HSA from BSA and other enzymes. Upon binding of dye M-H-SO3 with HSA, a significant fluorescence enhancement with a turn-on ratio about 96-fold was triggered. The detection limit was estimated to be âˆ¼ 40 nM. Studies on the interaction mechanism revealed that dye M-H-SO3 could bind to site III of HSA with a 1:1 binding stoichiometry. Furthermore, dye M-H-SO3 has been applied to determine HSA in real urine samples with good recoveries, which provided a useful method for HSA analysis in biological fluids.

3D Printed Conductive Hydrogel Patch Incorporated with MSC@GO for Efficient Myocardial Infarction Repair.

Myocardial infarction (MI) results in an impaired heart function. Conductive hydrogel patch-based therapy has been considered as a promising strategy for cardiac repair after MI. In our study, we fabricated a three-dimensional (3D) printed conductive hydrogel patch made of fibrinogen scaffolds and mesenchymal stem cells (MSCs) combined with graphene oxide (GO) flakes (MSC@GO), capitalizing on GO's excellent mechanical property and electrical conductivity. The MSC@GO hydrogel patch can be attached to the epicardium via adhesion to provide strong electrical integration with infarcted hearts, as well as mechanical and regeneration support for the infarcted area, thereby up-regulating the expression of connexin 43 (Cx43) and resulting in effective MI repair in vivo. In addition, MI also triggers apoptosis and damage of cardiomyocytes (CMs), hindering the normal repair of the infarcted heart. GO flakes exhibit a protective effect against the apoptosis of implanted MSCs. In the mouse model of MI, MSC@GO hydrogel patch implantation supported cardiac repair by reducing cell apoptosis, promoting gap connexin protein Cx43 expression, and then boosting cardiac function. Together, this study demonstrated that the conductive hydrogel patch has versatile conductivity and mechanical support function and could therefore be a promising candidate for heart repair.

A rapidly time-varying equatorial jet in Jupiter's deep interior.

Planetary magnetic fields provide a window into the otherwise largely inaccessible dynamics of a planet's deep interior. In particular, interaction between fluid flow in electrically conducting interior regions and the magnetic field there gives rise to observable secular variation (time dependency) of the externally observed magnetic field. Secular variation of Jupiter's field has recently been revealed1-3 and been shown to arise, in part, from an axisymmetric, equatorial jet2. Whether this jet is time dependent has not previously been addressed, yet it is of critical importance for understanding the dynamics of the planet's interior. If steady, it would probably be a manifestation of deep dynamo convective flow (and jets are anticipated as part of that flow4-9) but if time dependent on a timescale much shorter than the convective turnover timescale of several hundred years, it would probably have a different origin. Here we show that the jet has a wavelike fluctuation with a period of roughly 4 years, strongly suggestive of the presence of a torsional oscillation10 (a cylindrically symmetric oscillating flow about the rotation axis) or a localized Alfvén wave in Jupiter's metallic hydrogen interior. This opens a pathway towards revealing otherwise hidden aspects of the magnetic field within the metallic hydrogen region and hence constraining the dynamo that generates Jupiter's magnetic field.

Successful surgical treatment of impending paradoxical embolism with pulmonary embolism and myocardial infarction.

BACKGROUND: Paradoxical embolism is a rare cause of acute arterial occlusion. This phenomenon arises when embolic material travels from the venous system crosses an abnormal shunt such as patent foramen ovale, atrial septal defects, ventricular septal defects, or pulmonary arteriovenous malformations, into the arterial system. Impending paradoxical embolism refers to the presence of an entrapped thrombus in the patent foramen ovale. CASE PRESENTATION: We report a case of a 68-year-old female patient who presented with an impending paradoxical embolism, alongside both concomitant pulmonary embolism and myocardial infarction with ST-segment elevation. Swiftly addressed through emergency cardiac surgery and systemic anticoagulation, the patient's condition was effectively treated. CONCLUSIONS: While the ideal treatment strategy for impending paradoxical embolism remains a topic of debate due to limited and inconclusive evidence, emergent open surgery should be contemplated in patients as it signifies a critical clinical emergency.

An integrated methodology for quality assessment of therapeutic antibodies with potential long circulation half-life in harvested cell culture fluid using FcRn immobilized hydrophilic magnetic graphene.

Designing modified therapeutic antibodies with enhanced FcRn-binding affinity holds promise in the extension of circulation half-lives and potential refinement of pharmacokinetics. During the development of these new-generation therapeutic antibodies, FcRn binding affinity of IgGs is emphasized and monitored as a critical quality attribute (CQA), alongside other critical assessments including titer and aggregation level. However, the traditional workflow for assessing the overall quality of expressed IgGs in harvested cell culture fluid (HCCF) is blamed to be cumbersome and time-consuming. This study presents an integrated methodology for the rapid quality assessment of IgGs in HCCF by selectively extracting IgGs with favorable high FcRn affinity for subsequent analysis using size exclusion chromatography (SEC). The approach utilizes innovative adsorbents known as FcRn immobilized hydrophilic magnetic graphene (MG@PDA@PAMAM-FcRn) in a magnetic solid-phase extraction (MSPE) process. To simulate the in vivo binding dynamics, MSPE binding and dissociation was performed at pH 6.0 and 7.4, respectively. The composite have demonstrated enhanced extraction efficiency and impurity removal ability in comparison to commercially available magnetic beads. The SEC monomer peak area value provides the output of this method, the ranking of which enabled the facile identification of superior HCCF samples with high overall quality of IgG. Optimization of MSPE parameters was performed, and the method was validated for specificity, precision, sensitivity, and accuracy. The proposed method exhibited an analytical time of 0.6 h, which is 7-22 times shortened in comparison to the conventional workflow.

Constant Potential Thermodynamic Integration for Obtaining the Free Energy Profile of Electrochemical Reaction.

In this work, we advanced an efficient free energy sampling method based on constrained ab initio molecular dynamics (cAIMD) with a fully explicit solvent layer to depict the electrochemical reaction process at constant surface charge density, named the "Constant-Potential Thermodynamic Integration (CPTI)" method. For automatically adjusting surface charge density at different states, we built an "on-the-fly" procedure which is capable of managing all the necessary steps during cAIMD simulations, including the system pre-equilibrium, surface charge density updating, and force sampling. We applied it to predict the potential-dependent free energy profiles of CO2 adsorption on a single-atom catalyst. The results show that our method can not only account for changes in electrostatic potential energy associated with potential but also consider the potential-induced solvation effects. Our approach enables the accurate simulation of electrochemical environment by presenting the complete solid-liquid interface and efficient computation of electrocatalytic reaction energetics based on a robust potential descriptor.

Cerebral Embolism and MINOCA Secondary to Left Atrial Myxoma after Occlusion of Atrial Septal Defect by Amplatzer Occluder: A Case Report.

Primary heart tumors are rare, with atrial myxomas being the most common type. Atrial myxomas can lead to embolisms, heart obstruction, and systemic symptoms. Herein, we report a case of 72-year-old woman who presented with a left atrial myxoma at the atrial septal defect occluder, a new acute cerebral infarction, and MINOCA (myocardial infarction with no obstructive coronary atherosclerosis). Left atrial myxoma is a common primary cardiac tumor; however, left atrial myxomas arising after percutaneous atrial septal defect occlusion are rare. Additionally, the patient presented with a new case of multiple systemic emboli. The patient underwent surgical resection of a left atrial myxoma, occluder, and left atrium, and atrial septal repair, and was discharged with good recovery for outpatient follow-up. The possibility of a cardiac tumor, especially an atrial myxoma, which can lead to a series of complications, should be considered at the closure site after percutaneous atrial septal closure. Therefore, active surgical treatment and long-term follow-up are warranted in such cases.

Molecular mechanisms of noncoding RNA and epigenetic regulation in obesity with consequent diabetes mellitus development.

Diabetes mellitus (DM) and obesity have become two of the most prevalent and challenging diseases worldwide, with increasing incidence and serious complications. Recent studies have shown that noncoding RNA (ncRNA) and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity. Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation. Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies. In this review, we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets, and the research prospects for DM complicated with obesity.

Superhydrophobic Multifocal Microlens Array with Depth-of-Field Detection for a Humid Environment.

Microlens array (MLA) has been widely applied in augmented reality and optical imaging. When used in a humid environment or medical endoscopy, MLA needs to be both superhydrophobic and multifocal. However, it is not easy to achieve both superhydrophobic and multifocal function by integrating superhydrophobic and multifocal structures on the same surface by means of a simple, efficient, and precise method. In this paper, the superhydrophobic multifocal MLA with superhydrophobic properties and multifocal functions is successfully designed for preparation based on a method of 3D lithography and soft lithography. The 3D lithography can further help the preparation of a multifocal MLA with varying apertures and a multistep superhydrophobic structure with a round dome. The superhydrophobic multifocal MLA with periods 50 and 120 µm has perfect superhydrophobic property. The water droplet can slide and bounce off the surface at a roll angle of less than 12.9° with both multifocal and integrated imaging function, as well as up to 397 µm depth-of-field (DOF) detection range; this greatly exceeds the conventional MLA. The perfect superhydrophobic and optical property can be achieved in an extremely humid environment. The superhydrophobic multifocal MLA proposed in this paper has a promising prospect for actual practices.

Parameter optimization analysis of rotary electromagnetic vibration energy harvester for performance enhancement under free vibration.

In this paper, three new important aspects of rotary electromagnetic vibration energy harvesting technology (RE-VEH) are concerned and investigated: (i) vibro-electric coupling mechanism of the RE-VEH system is studied through theoretical modeling; (ii) quantitative analysis of system parameters based on numerical simulation method is carried out for the optimal design of RE-VEH; and (iii) dynamic power output performance of the RE-VEH system in free vibration is discussed. The parameter adjusting methods of the RE-VEH system in free vibration mode are obtained through theoretical analysis and numerical simulation. The experimental results show that the power output performance of RE-VEH in free vibration mode matches the numerical simulation results. The simulation and experimental results show that the maximum voltage output and power output of the RE-VEH with different structure parameters under free vibration can be up to the level of 100∼101 V/watt. The above results indicate that RE-VEH in a free vibration environment has significant energy output performance.

Quantitative determination of microbial materials activity based on infrared extinction properties.

Microbial bacteria play an irreplaceable role in natural and human production and life; thus, determining their activities is an important issue. This study proposed a method to quantitatively determine the activity of microbial materials through extinction property calculation using infrared spectroscopy. Complex refractive indices of different active biomaterials were calculated based on their infrared spectra, and their extinction properties were determined using the discrete dipole approximation method. Using partial least squares (PLS), support vector regression (SVR), and extreme learning machine (ELM) regression, quantitative determination models of microbial materials based on infrared extinction properties were established to predict their activity. The results demonstrated that the model of least angle regression (LAR) combined with PLS exhibited better potential for the determination of biomaterial activity. The coefficient of determination (R2) values acquired by the optimal model for the three biomaterials were 0.9699, 0.9744, and 0.9621, respectively. These findings suggested that a rapid and accurate quantitative determination of microbial activity can be achieved based on extinction property.

Structural insights into the oligomeric effects on catalytic activity of a decameric feruloyl esterase and its application in ferulic acid production.

Oligomeric feruloyl esterase (FAE) has great application prospect in industry due to its potentially high stability and fine-tuned activity. However, the relationship between catalytic capability and oligomeric structure remains undetermined. Here we identified and characterized a novel, cold-adapted FAE (BtFae) derived from Bacteroides thetaiotaomicron. Structural studies unraveled that BtFae adopts a barrel-like decameric architecture unique in esterase families. By disrupting the interface, the monomeric variant exhibited significantly reduced catalytic activity and stability toward methyl ferulate, potentially due to its impact on the flexibility of the catalytic triad. Additionally, our results also showed that the monomerization of BtFae severely decreased the ferulic acid release from de-starched wheat bran and insoluble wheat arabinoxylan by 75 % and 80 %, respectively. Collectively, this study revealed novel connections between oligomerization and FAE catalytic function, which will benefit for further protein engineering of FAEs at the quaternary structure level for improved industrial applications.