Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenza.

BACKGROUND: Highly pathogenic respiratory RNA viruses such as SARS-CoV-2 and its associated syndrome COVID-19 pose a tremendous threat to the global public health. Innate immune responses to SARS-CoV-2 depend mainly upon the NF-κB-mediated inflammation. Identifying unknown host factors driving the NF-κB activation and inflammation is crucial for the development of immune intervention strategies. METHODS: Published single-cell RNA sequencing (scRNA-seq) data was used to analyze the differential transcriptome profiles of bronchoalveolar lavage (BAL) cells between healthy individuals (n = 27) and patients with severe COVID-19 (n = 21), as well as the differential transcriptome profiles of peripheral blood mononuclear cells (PBMCs) between healthy individuals (n = 22) and severely ill patients with COVID-19 (n = 45) or influenza (n = 16). Loss-of-function and gain-of-function assays were performed in diverse viruses-infected cells and male mice models to identify the role of TOMM34 in antiviral innate immunity. FINDINGS: TOMM34, together with a list of genes encoding pro-inflammatory cytokines and antiviral immune proteins, was transcriptionally upregulated in circulating monocytes, lung epithelium and innate immune cells from individuals with severe COVID-19 or influenza. Deficiency of TOMM34/Tomm34 significantly impaired the type I interferon responses and NF-κB-mediated inflammation in various human/murine cell lines, murine bone marrow-derived macrophages (BMDMs) and in vivo. Mechanistically, TOMM34 recruits TRAF6 to facilitate the K63-linked polyubiquitination of NEMO upon viral infection, thus promoting the downstream NF-κB activation. INTERPRETATION: In this study, viral induction of TOMM34 is positively correlated with the hyperinflammation in severely ill patients with COVID-19 and influenza. Our findings also highlight the physiological role of TOMM34 in the innate antiviral signallings. FUNDING: A full list of funding sources can be found in the acknowledgements section.

Secondary activation on plasma-activated water by plasma-treated cotton for restoring and enhancing disinfection effect.

Plasma-activated water (PAW) is a novel antimicrobial agent with negligible toxicity and environmental burden, holding promise as an alternative to chemical disinfectants and antibiotics. In practice, liquid disinfectants are often soaked with cotton materials before further use. Rich in reducing functional groups on the surface, cotton will inevitably react with PAW, leading to the deterioration of PAW's functions. To resolve this issue, this work proposes a new concept of "secondary activation" for retaining and enhancing PAW's bioactivity, i.e., pre-treating cotton with air plasma before soaking PAW. For the first time, we find that the PAW absorbed by raw cotton completely loses its bactericidal effect, while plasma-treated cotton (PTC) restores the disinfection capacity and prolongs its effective duration. This restoration is attributed to the absorption of plasma-generated reactive species by cotton with oxidizing and nitrifying modifications on the fiber surface. Consequently, the concentrations of aqueous species in PAW increase rather than decrease after absorption by PTC. In addition, the PTC after 28-day storage can still enable PAW to achieve a bacterial reduction of ∼3 logs. This work identifies and addresses a crucial limitation in the disinfection application of PAW and elucidates the mechanism underlying PTC production and secondary activation of PAW.

Investigation and Regulation of DNA Nanostructures on Activating cGAS-STING Signaling.

DNA nanostructures have shown great potential in biomedical fields. However, the immune responses, especially the activation of the cGAS-STING signaling (A-cGSs), induced by DNA nanostructures, remain incompletely understood. Here, the ability of various DNA nanostructures from double-stranded DNA (dsDNA), single-stranded tiles (SSTs) to DNA origami is investigated on A-cGSs. Unlike natural dsDNA which triggers potent A-cGSs, the structural interconnectivity of various DNA configurations can substantially reduce the occurrence of A-cGSs, irrespective of their form, dimensions, and conformation. However, wireframe DNA nanostructures can activate the cGAS-STING signaling, suggesting that decreasing A-cGSs is dsDNA compactness-dependent. Based on this, a reconfigurable DNA Origami Domino Array (DODA) is used to systematically interrogate how dsDNA influences the A-cGSs and demonstrates that the length, number, and space of dsDNA array coordinately influence the activation level of cGAS-STING signaling, realizing a regulation of innate immune response. The above data and findings enhance the understanding of how DNA nanostructures affect cellular innate immune responses and new insights into the modulation of innate immune responses by DNA nanomedicine.

Distinguishing Quantum Phases through Cusps in Full Counting Statistics.

Measuring physical observables requires averaging experimental outcomes over numerous identical measurements. The complete distribution function of possible outcomes or its Fourier transform, known as the full counting statistics, provides a more detailed description. This method captures the fundamental quantum fluctuations in many-body systems and has gained significant attention in quantum transport research. In this Letter, we propose that cusp singularities in the full counting statistics are a novel tool for distinguishing between ordered and disordered phases. As a specific example, we focus on the superfluid-to-Mott transition in the Bose-Hubbard model. Through both analytical analysis and numerical simulations, we demonstrate that the full counting statistics exhibit a cusp singularity as a function of the phase angle in the superfluid phase when the subsystem size is sufficiently large, while it remains smooth in the Mott phase. This discontinuity can be interpreted as a first-order transition between different semiclassical configurations of vortices. We anticipate that our discoveries can be readily tested using state-of-the-art ultracold atom and superconducting qubit platforms.

Centralized exhaust system simulation and parameter optimization.

With the increase in high-rise buildings in cities, public flue exhaust systems have a direct impact on residential air quality and the living environment. Although existing studies have analyzed the problems in public flue exhaust systems through computational fluid dynamics (CFD) numerical simulations and experimental tests, these studies often lack an in-depth exploration of the specific impacts of individual components in the system. To solve this problem, this study not only thoroughly analyzes the key components in the public flue system, such as branch pipes, check valves, and tee pipes, but also develops a parametric public flue simulation system software based on C# and verifies the accuracy of the simulation through experiments. The study first determines the key parameters affecting the comprehensive resistance coefficient of the branch pipe, check valve, tee pipe, and other components through CFD simulation and experimental testing. Subsequently, a visualization program is developed using the C# language, which can quickly simulate and visualize the flow changes in the flue according to different building parameters such as the number of floors, height of floors, and size of the flue. The results confirm that the program can efficiently predict the flow distribution under different design options, providing a practical tool for the optimal design and performance evaluation of public flues, which is important for improving the air quality of the living environment.

Nanoarchitectonics of Injectable Biomimetic Conjugates for Cartilage Protection and Therapy Based on Degenerative Osteoarthritis Progression.

Osteoarthritis (OA) is a common age-related degenerative disease characterized by changes in the local tissue environment as inflammation progresses. Inspired by the wind-dispersal mechanism of dandelion seeds, this study develops responsive biomimetic microsphere-drug conjugate for OA therapy and protection. The conjugate integrates dibenzaldehyde polyethylene glycol (DFPEG) with chitosan and polyethylene glycol diacrylate (PEGDA) through dynamic covalent bonds to form a dual-network hydrogel microsphere. Based on the progression of OA, the conjugate with the surface-anchored cyclic peptide cortistatin-14 (CST-14) achieves targeted drug therapy and a self-regulating hydrogel network. In cases of progressing inflammation (pH < 5), CST-14 dissociates from the microsphere surface (viz. the drug release rate increased) and inhibits TNF-α signaling to suppress OA. Concurrently, the monomer DFPEG responsively detaches from the hydrogel network and scavenges reactive oxygen species (ROS) to protect the cartilage tissue. The ROS scavenging of DFPEG is comparable to that of coenzyme Q10 and vitamin C. The degraded PEGDA microspheres provide tissue lubrication through reused conjugates. The rat OA model successfully achieved a synergistic therapeutic effect greater than the additive effect (1 + 1 > 2). This strategy offers an approach for anchoring amine-containing drugs and has marked potential for OA treatment and protection.

Pd(0)/Xantphos-Catalyzed Benzylic C(sp3)-O Arylation of Benzyl Heteroaryl Ethers: Reduction of Pd(II) to Pd(0) by Xantphos.

Herein, we report the synthesis of 1,1-diarylmethanes via palladium-catalyzed benzylic C(sp3)-O arylation of benzyl alcohol derivatives. An efficient, straightforward approach to synthesizing Pd(0)(xantphos)2 was developed through in situ reduction of Pd(II) to Pd(0) with the bidentate tertiary phosphine xantphos, which proved to be a highly active precatalyst in the Suzuki-Miyaura cross-coupling reaction of benzyl heteroaryl ethers.

VEGF-B prevents chronic hyperglycemia-induced retinal vascular leakage by regulating the CDC42-ZO1/VE-cadherin pathway.

Non-proliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy (DR) and is a chronic oxidative stress-related ocular disease. Few treatments are approved for early DR. This study aimed to investigate the pathogenic mechanisms underlying the retinal micro-vasculopathy induced by diabetes and to explore an early potential for treating early DR in a mouse model. The mouse model of type 1 diabetes was established by intraperitoneal injection of streptozotocin (STZ, 180 mg/kg), which was used as the early DR model. The body weight and blood glucose mice were measured regularly; The retinal vascular leakage in the early DR mice was determined by whole-mount staining; Label-free quantitative proteomic analysis and bioinformatics were used to explore the target proteins and signaling pathways associated with the retinal tissues of early DR mice; To detect the effects of target protein on endothelial cell proliferation, migration, and tube formation, knockdown and overexpression of VEGF-B were performed in human retinal vascular endothelial cells (HRECs); Western blotting was used to detect the expression of target proteins in vitro and in vivo; Meanwhile, the therapeutic effect of VEGF-B on vascular leakage has also been evaluated in vitro and in vivo. The protein expressions of vascular endothelial growth factor (VEGF)-B and the Rho GTPases family member CDC42 were reduced in the retinal tissues of early DR. VEGF-B upregulated the expression of CDC42/ZO1/VE-cadherin and prevented hyperglycemia-induced vascular leakage in HRECs. Standard intravitreal VEGF-B injections improved the retinal vascular leakage and neurovascular response in early DR mice. Our findings demonstrated, for the first time, that in diabetes, the retinal vessels are damaged due to decreased VEGF-B expression through downregulation of CDC42/ZO1/VE-cadherin expression. Therefore, VEGF-B could be used as a novel therapy for early DR.

Synergism of colistin and globular endolysins against multidrug-resistant gram-negative bacteria.

Endolysins (lysins), a novel class of antibacterial agents derived from bacteriophages, efficiently lyse bacteria by degrading the peptidoglycan layer within the bacterial wall. Colistin, a classic peptide antibiotic with the ability to permeabilize the outer membrane, has recently shown great promise in synergizing with lysins against gram-negative bacteria. However, the exact mechanisms responsible for their synergy remain unclear. Here, we first demonstrated the synergistic bacterial killing of various lysin and colistin combinations. With a model lysin, LysAB2, we then confirmed that there is a threshold concentration of colistin causing sufficient permeabilization of the outer membrane for lysin to access the peptidoglycan layer and subsequently exert its lytic ability. The threshold colistin concentrations were found to range 0.2-0.8 µM for the tested bacteria, with the exact value largely depending on the density of lipopolysaccharides on the outer membrane. Beyond the threshold colistin level, LysAB2 could synergize with colistin at a concentration as low as 0.31 µM. Next, we proved for the first time that lysin-induced degradation of the peptidoglycan layer facilitated the disruption of cytoplasmic membrane by colistin, elevated the level of reactive oxygen species in bacterial cells, and boosted the killing effect of colistin. Additionally, the colistin-lysin combination could effectively eliminate established biofilms due to the biofilm dispersal ability of lysin. The in-vivo efficacy was preliminary confirmed in a Galleria mellonella infection model for combination with colistin doses (≥ 1.8 µg/larvae), which could reach beyond the threshold concentration, and a fixed LysAB2 dose (10 µg/larvae). In summary, our study provided the first experimental evidence unravelling the mechanisms behind the synergy of colistin and lysins. All these findings provided important insights in guiding the dosing strategy for applying this combination in future development.

Strongly active and environmentally friendly WO3/C3N4 photocatalysts for converting cyclohexane to cyclohexanone under ambient conditions.

C-H bond activation under mild conditions remains a great challenge in the chemical industry, while catalytic cyclohexane oxidation is inefficient and often requires organic solvents and strong oxidants. This study constructed a C3N4/WO3 Z-type heterojunction catalyst to efficiently convert cyclohexane into cyclohexanone and cyclohexanol (KA oil) through aqueous phase oxidation by O2 under visible light irradiation. With strong redox performance and high photogenerated carrier separation ability, the proposed composite catalyst can produce the key active species for cyclohexane oxidation in the H2O-O2 system. The reaction mechanism was clarified through experiment and DFT theory calculation. Cyclohexane was converted into cyclohexyl radical under the action of ·OH, and ·O2- converted most products into cyclohexanone. The catalyst can be recycled under optimized process conditions while reaching a KA oil yield of 139.73 µmol g-1 h-1 and a selectivity of 93.1%.

Achieving high-durability aqueous Zn-ion batteries enabled by reanimating inactive Zn on Zn anodes.

The heavy by-products generated on Zn anode surface decrease the active surface of Zn anodes and thus induce uneven Zn deposition, seriously reducing the service life of aqueous Zn-ion batteries (AZIBs). Herein, we propose an elimination strategy enabled by the coordination chemistry to dissolve the main by-products (Zn4SO4(OH)6·xH2O). Urea as a proof-of-concept has been applied as the reactivator in the electrolyte to catalytically produce highly active NH3 on the surface of the by-products. Then the NH3 can powerfully coordinate with the Zn2+ ion in the by-products to form the soluble complex [Zn(NH3)4]2+. Consequently, the proposed electrolyte can not only lead to the timely decomposition of the by-products to prevent the Zn anode from inactivation during cycling, but also repair the waste Zn anodes for reutilization. The action mechanism has been systematically demonstrated via theoretical simulation and experimental study. As a result, the high durability with ultrahigh cumulative capacity of 10,600 mAh cm-2 for the Zn||Zn symmetric cell has been achieved at 40 mA cm-2. Particularly, the dead Zn||Zn symmetric cells and Zn||LiFePO4 full cells have been successfully reactivated. This study lights a new route to extend the cell lifespan and reuse waste Zn-ion batteries.

Non-stationary modeling and simulation of strong winds.

Wind velocity is usually assumed to obey a stationary stochastic process in wind engineering, and this may cause significant bias in describing extremely severe strong wind such as typhoons and thunderstorms. To take into account the non-stationary characteristics of extreme wind, a novel evolutionary power spectral density (EPSD) model is proposed, and the spectral representation method (SRM) is introduced to simulate the whole process of strong winds. Firstly, the wavelet transform (WT) method is adopted to capture the three-dimensional time-varying properties of the low-frequency mean winds, and the associated turbulence features, including turbulent intensity, gust factor, probability density function, and power spectrum, are analyzed in depth. Secondly, the measured horizontal EPSD of strong winds are estimated. Thirdly, the performance of the proposed EPSD model is validated. Finally, the whole process of non-stationary strong winds are simulated and discussed. The results show that the proposed EPSD models are in good agreement with the measured EPSD, and the time-frequency features of the power spectrum of the simulated winds are well reproduced, which provides a powerful tool for large eddy simulation and wind engineering studies under non-stationary extreme wind climate.

Beyond hype: unveiling the Real challenges in clinical translation of 3D printed bone scaffolds and the fresh prospects of bioprinted organoids.

Bone defects pose significant challenges in healthcare, with over 2 million bone repair surgeries performed globally each year. As a burgeoning force in the field of bone tissue engineering, 3D printing offers novel solutions to traditional bone transplantation procedures. However, current 3D-printed bone scaffolds still face three critical challenges in material selection, printing methods, cellular self-organization and co-culture, significantly impeding their clinical application. In this comprehensive review, we delve into the performance criteria that ideal bone scaffolds should possess, with a particular focus on the three core challenges faced by 3D printing technology during clinical translation. We summarize the latest advancements in non-traditional materials and advanced printing techniques, emphasizing the importance of integrating organ-like technologies with bioprinting. This combined approach enables more precise simulation of natural tissue structure and function. Our aim in writing this review is to propose effective strategies to address these challenges and promote the clinical translation of 3D-printed scaffolds for bone defect treatment.

A General Approach for the Synthesis of Cyanoisopropyl Bicyclo[1.1.1]pentane (BCP) Motifs by Energy Transfer Process.

Bicyclo[1.1.1]pentane (BCP) heteroaryls make up an important class of BCP derivatives in drug discovery. Herein, we report the visible-light-mediated synthesis of cyanoisopropyl BCP-heteroaryls motifs from N-containing heterocycles, [1.1.1]propellane, and AIBN (2,2'-azobis(isobutyronitrile)) through three-component cascade reaction. Importantly, this protocol is compatible with pyrazinones, quinoxaline-2(1H)-one, azauracils, quinoline derivatives, and imidazo[1,2-b]pyridazine, as well as various phenyl disulfide derivatives; thus, this operationally simple and general methodology could enable rapid library generation of sought-after BCP derivatives for drug development.

A causal effect study of cortical morphology and related covariate networks in classical trigeminal neuralgia patients.

Structural covariance networks and causal effects within can provide critical information on gray matter reorganization and disease-related hierarchical changes. Based on the T1WI data of 43 classical trigeminal neuralgia patients and 45 controls, we constructed morphological similarity networks of cortical thickness, sulcal depth, fractal dimension, and gyrification index. Moreover, causal structural covariance network analyses were conducted in regions with morphological abnormalities or altered nodal properties, respectively. We found that patients showed reduced sulcal depth, gyrification index, and fractal dimension, especially in the salience network and the default mode network. Additionally, the integration of the fractal dimension and sulcal depth networks was significantly reduced, accompanied by decreased nodal efficiency of the bilateral temporal poles, and right pericalcarine cortex within the sulcal depth network. Negative causal effects existed from the left insula to the right caudal anterior cingulate cortex in the gyrification index map, also from bilateral temporal poles to right pericalcarine cortex within the sulcal depth network. Collectively, patients exhibited impaired integrity of the covariance networks in addition to the abnormal gray matter morphology in the salience network and default mode network. Furthermore, the patients may experience progressive impairment in the salience network and from the limbic system to the sensory system in network topology, respectively.

Repeat administration of human umbilical cord mesenchymal stem cells improves left ventricular diastolic function in mice with heart failure with preserved ejection fraction.

Currently, no therapy is proven to effectively improve heart failure with preserved ejection fraction (HFpEF). Although stem cell therapy has demonstrated promising results in treating ischemic heart disease, the effectiveness of treating HFpEF with human umbilical cord mesenchymal stem cells (hucMSCs) remains unclear. To answer this question, we administered hucMSCs intravenously (i.v.), either once or repetitively, in a mouse model of HFpEF induced by a high-fat diet and NG-nitroarginine methyl ester hydrochloride. hucMSC treatment improved left ventricular diastolic dysfunction, reduced heart weight and pulmonary edema, and attenuated cardiac modeling (inflammation, interstitial fibrosis, and hypertrophy) in HFpEF mice. Repeat hucMSC administration had better outcomes than a single injection. In vitro, hucMSC culture supernatants reduced maladaptive remodeling in neonatal-rat cardiomyocytes. Ribonucleic acid sequencing and protein level analysis of left ventricle (LV) tissues suggested that hucMSCs activated the protein kinase B (Akt)/forkhead box protein O1 (FoxO1) signaling pathway to treat HFpEF. Inhibition of this pathway reversed the efficacy of hucMSC treatment. In conclusion, these findings indicated that hucMSCs could be a viable therapeutic option for HFpEF.

Use of an autonomous robotic system for removal of fiber posts during endodontic retreatment: A clinical report.

The removal of fiber posts for the retreatment of root canals can be challenging. An autonomous robotic (ATR) system was used for accurate and minimally invasive endodontic retreatment in a patient who presented with symptomatic apical periodontitis and pain emanating from the mandibular left first molar, which had been previously restored with 3 fiber posts. Intraoral scanning data, radiographic data, and bur sizes were integrated into preoperative software program to design a treatment plan. The ATR system enabled precise and efficient post removal. The remnant filling material was removed before endodontic retreatment, and radiographs at 3 months after the procedure showed satisfactory healing. This treatment demonstrated the accuracy and efficiency of the ATR system for the removal of fiber posts from pretreated teeth, while minimizing the duration of the procedure and avoiding excessive tissue removal.

Effect of inserting Cr in promoting the deep oxidation of dichloromethane over Co/WNb catalysts at low temperatures.

Enhancing catalytic activity while inhibiting the generation of chlorine byproducts is essential in the catalytic oxidation process of chlorinated volatile organic compounds (CVOCs). In this study, Cr-modified Co/WNb catalysts were synthesized and utilized for the degradation of dichloromethane (DCM). It was found that the moderate introduction of Cr exposed more Cr6+ on the catalyst surface due to the interaction between cobalt and chromium oxides, which promoted the generation of more chemisorbed oxygen on the surface, thus improving the redox properties and enhancing the activity of the catalysts. Additionally, the introduction of Cr increased the B acid sites of the catalysts, promoting the breaking of C-Cl bonds and the removal of dissociated Cl- Meanwhile, the improved redox properties also allowed further oxidation of the dissociated activated intermediate products and inhibited the generation of chlorine byproducts. The catalyst activity was optimal when the Cr to Co molar ratio was 4, which the T90 of DCM was 256 °C and the monochloromethane selectivity was only 1.7 %. Moreover, Co4Cr/WNb showed excellent chlorine and water resistance, making it an ideal candidate for CVOC degradation.

Exogenous melatonin alleviates sodium chloride stress and increases vegetative growth in Lonicera japonica seedlings via gene regulation.

Melatonin (Mt) functions as a growth regulator and multifunctional signaling molecule in plants, thereby playing a crucial role in promoting growth and orchestrating protective responses to various abiotic stresses. However, the mechanism whereby exogenous Mt protects Lonicera japonica Thunb. (L. japonica) against salt stress has not been fully elucidated. Therefore, this study aimed to elucidate how exogenous Mt alleviates sodium chloride (NaCl) stress in L. japonica seedlings. Salt-sensitive L. japonica seedlings were treated with an aqueous solution containing 150 mM of NaCl and aqueous solutions containing various concentrations of Mt. The results revealed that treatment of NaCl-stressed L. japonica seedlings with a 60 µM aqueous solution of Mt significantly enhanced vegetative plant growth by scavenging reactive oxygen species and thus reducing oxidative stress. The latter was evidenced by decreases in electrical conductivity and malondialdehyde (MDA) concentrations. Moreover, Mt treatment led to increases in the NaCl-stressed L. japonica seedlings' total chlorophyll content, soluble sugar content, and flavonoid content, demonstrating that Mt treatment improved the seedlings' tolerance of NaCl stress. This was also indicated by the NaCl-stressed L. japonica seedlings exhibiting marked increases in the activities of antioxidant enzymes (superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase) and in photosynthetic functions. Furthermore, Mt treatment of NaCl-stressed L. japonica seedlings increased their expression of phenylalanine ammonia-lyase 1 (PAL1), phenylalanine ammonia-lyase 2 (PAL2), calcium-dependent protein kinase (CPK), cinnamyl alcohol dehydrogenase (CAD), flavanol synthase (FLS), and chalcone synthase (CHS). In conclusion, our results demonstrate that treatment of L. japonica seedlings with a 60 µM aqueous solution of Mt significantly ameliorated the detrimental effects of NaCl stress in the seedlings. Therefore, such treatment has substantial potential for use in safeguarding medicinal plant crops against severe salinity.