Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells.

A fundamental limitation of T cell therapies in solid tumors is loss of inflammatory effector functions, such as cytokine production and proliferation. Here, we target a regulatory axis of T cell inflammatory responses, Regnase-1 and Roquin-1, to enhance antitumor responses in human T cells engineered with two clinical-stage immune receptors. Building on previous observations of Regnase-1 or Roquin-1 knockout in murine T cells or in human T cells for hematological malignancy models, we found that knockout of either Regnase-1 or Roquin-1 alone enhances antitumor function in solid tumor models, but that knockout of both Regnase-1 and Roquin-1 increases function further than knockout of either regulator alone. Double knockout of Regnase-1 and Roquin-1 increased resting T cell inflammatory activity and led to at least an order of magnitude greater T cell expansion and accumulation in xenograft mouse models, increased cytokine activity, and persistence. However double knockout of Regnase-1 and Roguin-1 also led to a lymphoproliferative syndrome and toxicity in some mice. These results suggest that regulators of immune inflammatory functions may be interesting targets to modulate to improve antitumor responses.

Advances in spatial transcriptomics and its applications in cancer research.

Malignant tumors have increasing morbidity and high mortality, and their occurrence and development is a complicate process. The development of sequencing technologies enabled us to gain a better understanding of the underlying genetic and molecular mechanisms in tumors. In recent years, the spatial transcriptomics sequencing technologies have been developed rapidly and allow the quantification and illustration of gene expression in the spatial context of tissues. Compared with the traditional transcriptomics technologies, spatial transcriptomics technologies not only detect gene expression levels in cells, but also inform the spatial location of genes within tissues, cell composition of biological tissues, and interaction between cells. Here we summarize the development of spatial transcriptomics technologies, spatial transcriptomics tools and its application in cancer research. We also discuss the limitations and challenges of current spatial transcriptomics approaches, as well as future development and prospects.

Amplification-Free Analysis of Bladder Cancer MicroRNAs on Wrinkled Silica Nanoparticles with DNA-Functionalized Quantum Dots.

Bladder cancer (BC) occurrence and progression are accompanied by alterations in microRNAs (miRNAs) expression levels. Simultaneous detection of multiple miRNAs contributes to the accuracy and reliability of the BC diagnosis. In this work, wrinkled silica nanoparticles (WSNs) were applied as the microreactor for multiplex miRNAs analysis without enzymes or nucleic acid amplification. Conjugated on the surface of WSNs, the S9.6 antibody was adopted as the universal module for binding DNA/miRNA duplexes, regardless of their sequence. Furthermore, single-stranded DNA (ssDNA) was labeled with quantum dots (QDs) for identifying a given miRNA to form QDs-ssDNA/miRNA, which enabled the specific capture of the corresponding QDs on the wrinkled surface of WSNs. Based on the detection of fluorescence signals that were ultimately focused on WSNs, target miRNAs could be sensitively identified to a femtomolar level (5 fM) with a wide dynamic range of up to 6 orders of magnitude. The proposed strategy achieved high specificity to obviously distinguish single-base mutation sequences and possessed multiplex assay capability. Moreover, the assay exhibited excellent practicability in the multiplex detection of miRNAs in clinical serum specimens.

Comprehensive Investigation of the Temperature-Dependent Electromechanical Behaviors of Carbon Nanotube/Polymer Composites.

The performances of flexible piezoresistive sensors based on polymer nanocomposites are significantly affected by the environmental temperature; therefore, comprehensively investigating the temperature-dependent electromechanical response behaviors of conductive polymer nanocomposites is crucial for developing high-precision flexible piezoresistive sensors in a wide-temperature range. Herein, carbon nanotube (CNT)/polydimethylsiloxane (PDMS) composites widely used for flexible piezoresistive sensors were prepared, and then the temperature-dependent electrical, mechanical, and electromechanical properties of the optimized CNT/PDMS composite in the temperature range from -150 to 150 °C were systematically investigated. At a low temperature of -150 °C, the CNT/PDMS composite becomes brittle with a compressive modulus of ∼1.2 MPa and loses its elasticity and reversible sensing capability. At a high temperature (above 90 °C), the CNT/PDMS composite softens, shows a fluid-like mechanical property, and loses its reversible sensing capability. In the temperature range from -60 to 90 °C, the CNT/PDMS composite exhibits good elasticity and reversible sensing behaviors and its modulus, resistivity, and sensing sensitivity decrease with an increasing temperature. At room temperature (30 °C), the CNT/PDMS composite exhibits better mechanical and piezoresistive stability than those at low and high temperatures. Given that environmental temperature changes have significant effects on the sensing performances of conductive polymer composites, the effect of ambient temperature changes must be considered when flexible piezoresistive sensors are designed and fabricated.

Off the Shelf Multibranched Endograft for Thoraco-Abdominal and Pararenal Abdominal Aortic Aneurysms: a Prospective, Single Centre Study of the G-Branch Endograft.

OBJECTIVE: To investigate outcomes of a novel, off the shelf multibranched endovascular stent graft for the treatment of thoraco-abdominal aortic aneurysm (TAAA) and pararenal abdominal aortic aneurysm (PAAA). METHODS: A prospective, single centre study including 15 patients (mean age, 63.4 ± 10.7 years; 13 male) with TAAA or PAAA treated from October 2019 to March 2021 with a G-Branch endograft (Lifetech Scientific, Shenzhen, China) featuring a mixed multibranch design with two inner and two outer branches for reconstruction of the visceral and bilateral renal arteries, respectively. Follow up assessments were scheduled before discharge and at 30 days, six and 12 months after the index procedure. Annual telephone interviews were performed beyond the initial 12 months. The Kaplan-Meier method was used to estimate cumulative mortality and morbidity rates after endovascular repair. RESULTS: Technical success was achieved in all 15 patients. Nine patients (60%) had TAAA and six (40%) had PAAA (mean maximum aneurysm diameter, 73.7 ± 15.8 mm). The median follow up was 31.4 months (range, 10.1 - 44.0 months). At 30 days, there was no death and 7% morbidity (one case of temporary spinal cord ischaemia on Day 4). At one year, the mortality rate was 7% (one death from stroke at 10 months) and morbidity was 13% (one other case of renal function decline at six months). There were no aneurysm dilatations, re-interventions, or access related complications, and two (13%) persistent type II endoleaks. The one year primary branch patency rate was 100% for the four renovisceral arteries in all 13 patients who underwent computed tomography examinations. One patient died of hepatocellular carcinoma 29 months post-operatively, resulting in an estimated three year mortality rate of 13%. CONCLUSION: The G-Branch endograft yielded high technical success with good early and midterm outcomes for the treatment of TAAA and PAAA. A large multicentre study is warranted.

Cathepsin B degrades RbcL during freezing-induced programmed cell death in Arabidopsis.

KEY MESSAGE: Cathepsin B plays an important role that degrades the Rubisco large subunit RbcL in freezing stress. Programmed cell death (PCD) has been well documented in both development and in response to environmental stresses in plants, however, PCD induced by freezing stress and its molecular mechanisms remain poorly understood. In the present study, we characterized freezing-induced PCD and explored its mechanisms in Arabidopsis. PCD induced by freezing stress was similar to that induced by other stresses and senescence in Arabidopsis plants with cold acclimation. Inhibitor treatment assays and immunoblotting indicated that cathepsin B mainly contributed to increased caspase-3-like activity during freezing-induced PCD. Cathepsin B was involved in freezing-induced PCD and degraded the large subunit, RbcL, of Rubisco. Our results demonstrate an essential regulatory mechanism of cathepsin B for Rubisco degradation in freezing-induced PCD, improving our understanding of freezing-induced cell death and nitrogen and carbohydrate remobilisation in plants.

Prediction of surgical outcomes in severe encapsulating peritoneal sclerosis using a computed tomography scoring system.

BACKGROUND/PURPOSE: Encapsulating peritoneal sclerosis (EPS) is a rare and potential lethal complication of peritoneal dialysis characterized by bowel obstruction. Surgical enterolysis is the only curative therapy. Currently, there are no tools for predicting postsurgical prognosis. This study aimed to identify a computed tomography (CT) scoring system that could predict mortality after surgery in patients with severe EPS. METHODS: This retrospective study enrolled patients with severe EPS who underwent surgical enterolysis in a tertiary referral medical center. The association of CT score with surgical outcomes including mortality, blood loss, and bowel perforation was analyzed. RESULTS: Thirty-four patients who underwent 37 procedures were recruited and divided into a survivor and non-survivor group. The survivor group had higher body mass indices (BMIs, 18.1 vs. 16.7 kg/m2, p = 0.035) and lower CT scores (11 vs. 17, p < 0.001) than the non-survivor group. The receiver operating characteristic curve revealed that a CT score of ≥15 could be considered a cutoff point to predict surgical mortality, with an area under the curve of 0.93, sensitivity of 88.9%, and specificity of 82.1%. Compared with the group with CT scores of <15, the group with CT scores of ≥15 had a lower BMI (19.7 vs. 16.2 kg/m2, p = 0.004), higher mortality (4.2% vs. 61.5%, p < 0.001), greater blood loss (50 vs. 400 mL, p = 0.007), and higher incidence of bowel perforation (12.5% vs. 61.5%, p = 0.006). CONCLUSION: The CT scoring system could be useful in predicting surgical risk in patients with severe EPS receiving enterolysis.

Nanosecond-pulsed plasma protects against bacterial fruit blotch and promotes melon seedling growth.

BACKGROUND: Bacterial fruit blotch (BFB), known as the 'cancer' of cucurbits, is a seed-borne disease of melons caused by Acidovorax citrulli. Traditional chemical treatments for BFB are ineffective and adversely affect the environment. Using dielectric barrier discharge (DBD) nanosecond-pulsed plasma technology, melon seeds were treated to promote germination and growth and to control BFB. RESULTS: Based on the evaluation parameters of seed germination, seedling growth, leaf yellowing and bacterial infection after seed plasma treatments, 9 min at 20 kV was selected as the optimal plasma discharge parameter. In this study, seedling growth was significantly improved after treating melon seeds carrying A. citrulli using this discharge parameter. The number of first true leaves measured on the eighth day was 2.3 times higher and the disease index was reduced by 60.5% compared to the control group. Attenuated total reflectance-Fourier transform infrared measurements show that plasma treatments penetrate the seed coat and denature polysaccharides and proteins in the seed kernel, affecting their growth and sterilization properties. CONCLUSION: Pre-sowing treatment of melon seeds carrying A. citrulli using nanosecond-pulsed plasma technology can effectively control seedling BFB disease and promote melon seedling growth by optimizing DBD parameters. © 2024 Society of Chemical Industry.

[Network Meta-analysis of different Chinese medicine injections combined with conventional western medicine in treatment of acute heart failure].

This study aims to evaluate the efficacy and safety of Chinese medicine injection in the treatment of acute heart failure. PubMed, Cochrane Library, EMbase, Web of Science, CNKI, VIP, Wanfang, and SinoMed were searched for the randomized controlled trial(RCT) of Chinese medicine injection combined with conventional western medicines in the treatment of acute heart failure with the time interval from the inception to July 10, 2023. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Stata 15.1 was used to perform network Meta-analysis. A total of 117 RCTs were included, involving 10 529 patients and 7 Chinese medicine injections: Shenfu Injection, Shenmai Injection, Danhong Injection, Puera-rin Injection, Xinmailong Injection, Shengmai Injection, and Yiqi Fumai Injection. Network Meta-analysis yielded the following results.(1) In terms of improving the total response rate, the surface under the cumulative ranking curve(SUCRA) ranking was Shengmai Injection + conventional western medicine > Danhong Injection + conventional western medicine > Shenmai Injection + conventio-nal western medicine > Shenfu Injection + conventional western medicine > Xinmailong Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > Puerarin Injection + conventional western medicine > conventional western medicine.(2)In terms of reducing brain natriuretic peptide(BNP), the SUCRA ranking was Danhong Injection + conventional western medicine > Xinmailong Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > Shenfu Injection + conventional western medicine > Shenmai Injection + conventional western medicine > Puerarin Injection + conventional wes-tern medicine > Shengmai Injection + conventional western medicine > conventional western medicine.(3)In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the SUCRA ranking was Shenmai Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > Xinmailong Injection + conventional western medicine > Shengmai Injection + conventional western medicine > Shenfu Injection + conventional western medicine > Puerarin Injection + conventional western medicine > Danhong Injection + conventional western medicine > conventional western medicine.(4) In terms of improving the left ventricular ejection fraction(LVEF), the SUCRA ranking was Shenmai Injection + conventional western medicine > Xinmailong Injection + conventional western medicine > Shenfu Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > Puerarin Injection + conventional western medicine > Danhong Injection + conventional western medicine > Shengmai Injection + conventional western medicine > conventional western medicine.(5) In terms of decreasing the left ventricular end-diastolic diameter(LVEDD), the SUCRA ranking was Shenmai Injection + conventional western medicine > Shenfu Injection + conventional western medicine=Xinmailong Injection + conventional western medicine > Shengmai Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > conventional western medicine > Puerarin Injection + conventional western medicine.(6) In terms of increasing the 6-min walk trail(6MWT), the SUCRA ranking was Xinmailong Injection + conventional western medicine > Shenfu Injection + conventional western medicine > Shenmai Injection + conventional western medicine > Yiqi Fumai Injection + conventional western medicine > conventional western medicine.(7) In terms of reducing the Minnesota heart failure quality of life scale(MLHFQ) scores, the SUCRA ranking was Xinmailong Injection + conventional western medicine > Shenmai Injection + conventional western medicine > Shenfu Injection + conventional western medicine > conventional western medicine.(8)In terms of safety, the group of Chinese medicine injection combined with conventional western medicine had lower incidence of adverse reactions than the control group. The current evidence shows that combining Chinese medicine injection with conventional western medicine treatment can improve the therapeutic effect on acute heart failure, with high safety. Due to the limited number and quality of included studies, the above conclusions need to be verified by more high-quality studies.

Modulating Charges of Dual Sites in Multivariate Metal-Organic Frameworks for Boosting Selective Aerobic Epoxidation of Alkenes.

Selective aerobic epoxidation of alkenes without any additives is of great industrial importance but still challenging because the competitive side reactions including C═C bond cleavage and isomerization are difficult to avoid. Here, we show fabricating Cu(I) single sites in pristine multivariate metal-organic frameworks (known as CuCo-MOF-74) via partial reduction of Cu(II) to Cu(I) ions during solvothermal reaction. Impressively, CuCo-MOF-74 is characteristic with single Cu(I), Cu(II), and Co(II) sites, and they exhibit the substantially enhanced selectivity of styrene oxide up to 87.6% using air as an oxidant at almost complete conversion of styrene, ∼25.8% selectivity increased over Co-MOF-74, as well as good catalytic stability. Contrast experiments and theoretical calculation indicate that Cu(I) sites contribute to the substantially enhanced selectivity of epoxides catalyzed by Co(II) sites. The adsorption of two O2 molecules on dual Co(II) and Cu(I) sites is favorable, and the projected density of state of the Co-3d orbital is closer to the Fermi level by modulating with Cu(I) sites for promoting the activation of O2 compared with dual-site Cu(II) and Co(II) and Co(II) and Co(II), thus contributing to the epoxidation of the C═C bond. When other kinds of alkenes are used as substrates, the excellent selectivity of various epoxides is also achieved over CuCo-MOF-74. We also prove the universality of fabricating Cu(I) sites in other MOF-74 with various divalent metal nodes.

CO2 Reduction Mechanism on the Cu2 O(110) Surface: A First-Principles Study.

Cu2 O is an attractive catalyst for the selective reduction of CO2 to methanol. However, the mechanism of the reaction and the role of the Cu species in different oxidation states are not well understood yet. In this work, by first-principles calculations, we investigate the mechanism of the reaction on the Cu2 O(110) surface, which is the most selective for methanol, in different degrees of reduction: ideal surface, slightly reduced surface (SRS), and partially reduced surface (PRS). The most favorable reaction pathways on the three surfaces were identified. We found that Cu(I) on the ideal surface is not capable of chemisorbing CO2 , but surface oxygen serves as the active site which selectively converts CO2 to CH3 OH with a limiting potential of -0.77 V. The Cu(0) on the SRS and PRS promotes the adsorption and reduction of CO2 , while the removal of the residue O* becomes potential/rate limiting with a more negative limiting potential than the ideal surface. The SRS is selective to methanol while the PRS becomes selective to methane. The result suggests that the key to high methanol selectivity is to avoid the reduction of Cu(I), which provides a new strategy for the design of more efficient catalysts for selective CO2 reduction to methanol.

Unifying the Nitrogen Reduction Activity of Anatase and Rutile TiO2 Surfaces.

TiO2 is a model transition metal oxide that has been applied frequently in both photocatalytic and electrocatalytic nitrogen reduction reactions (NRR). However, the phase which is more NRR active still remains a puzzle. This work presents a theoretical study on the NRR activity of the (001), (100), (101), and (110) surfaces of both anatase and rutile TiO2 . We found that perfect surfaces are not active for NRR, while the oxygen vacancy can promote the reaction by providing excess electrons and low-coordinated Ti atoms that enhance the binding of the key intermediate (HNN*). The NRR activity of the eight facets can be unified into a single scaling line. The anatase TiO2 (101) and rutile TiO2 (101) surfaces were found to be the most and the second most active surfaces with a limiting potential of -0.91 V and -0.95 V respectively, suggesting that the TiO2 NRR activity is not very phase-sensitive. For photocatalytic NRR, the results suggest that the anatase TiO2 (101) surface is still the most active facet. We further found that the binding strength of key intermediates scale well with the formation energy of oxygen vacancy, which is determined by the oxygen coordination number and the degree of relaxation of the surface after the creation of oxygen vacancy. This work provides a comprehensive understanding of the activity of TiO2 surfaces. The results should be helpful for the design of more efficient TiO2 -based NRR catalysts.

Stable Polyhedron-Cluster-Based Rigid Fluoride Framework toward Zero-Thermal-Quenching Near-Infrared Emission for Prolonged LED Applications.

Development of highly thermally stable broadband near-infrared (NIR) luminescence materials is crucial for advancing the prolonged stable application of smart NIR light sources. In this study, a zero-thermal-quenching and reversible temperature-dependent broadband NIR-emitting Cs2NaAl3F12:Cr3+ phosphor is demonstrated, benefiting from its stable polyhedron-cluster-building rigid structure. The excellent thermal stability of Cs2NaAl3F12:Cr3+ is rooted in its stable [Al6Na4F45] cluster building unit, which provides a rigid structure with a weak electron-phonon coupling effect and a wide band gap with a huge thermal activated barrier. Such characteristics are well revealed by multiple studies on crystal structure, electronic structure, Huang-Rhys factor S, configuration coordinate model, and Debye temperature. The incorporation of Li or K instead of Na weakens the luminescence thermal stability, directly proving the importance of the stable [Al6Na4F45] cluster for stable Cr3+ substitution and rigid structure construction. Furthermore, Cs2NaAl3F12:Cr3+ presents much superior thermal stability compared to traditional rigid garnet-type fluorides Na3X2Li3F12:Cr3+ (X = Al, Ga, In). A high-power NIR LED is presented, utilizing the high quantum efficiency (∼71%) and extremely thermally stable broadband NIR emission around 750 nm of Cs2NaAl3F12:Cr3+. It realizes clear vein and cartilage imaging in the human hand, demonstrating its potential in medical diagnosis applications. This result provides important insights for designing new-type rigid crystal structures using stable polyhedron clusters as basic units, advancing the development of highly thermally stable NIR-emitting phosphors.

Radioprotective efficacy of Astilbin in mitigating radiation-induced lung injury through inhibition of p53 acetylation.

Radiation-induced lung injury (RILI) is a common side effect in thoracic tumor patients undergoing radiotherapy. At present, there is no ideal radio-protective agent which is widely used in RILI treatment. Astilbin (AST), a bioactive flavonoid, exhibits various biological effects, including anti-inflammatory, antioxidant, and anti-fibrotic activities, which partly result from reducing oxidative stress and inflammation in various pathogenic conditions. However, the protective efficacy of AST to ameliorate RILI has not been reported. In this study, we employed network pharmacology, RNA sequencing, and experimental evaluation to reveal the effects and pharmacological mechanism of AST to treat RILI in vivo and in vitro. We observed that AST reduced radiation-induced apoptosis, DNA damage, inflammatory reactions, and the reactive oxygen species (ROS) level in human normal lung epithelial cells BEAS-2B. Further study showed that AST treatment significantly ameliorated RILI by reducing the radiation-induced pathology changes and inflammatory reaction of lung tissue in C57BL/6J mice. Mechanistically, the expression of epithelial-mesenchymal transition (EMT) markers and radiation-triggered acetylation of the p53 protein were alleviated by AST treatment. Furthermore, AST alleviated the acetylation of p53 after intervention of Trichostatin A (TSA). Our data indicate that AST can alleviate RILI by inhibiting inflammatory reactions and the EMT process through decreasing the expression of p53 acetylation. In conclusion, our study suggests that AST has great potential to be a new protective and therapeutic compound for RILI.

Fate-mapping analysis of cochlear cells expressing Atoh1 mRNA via a new Atoh13*HA-P2A-Cre knockin mouse strain.

BACKGROUND: Atoh1 is recognized to be essential for cochlear hair cell (HC) development. However, Atoh1 temporal and spatial expression patterns remain widely debated. Here, we aimed to obtain evidence to resolve the controversies regarding Atoh1 expression by generating a new knockin mouse strain: Atoh13*HA-P2A-Cre . RESULTS: Fate-mapping analysis of Atoh13*HA-P2A-Cre/+ ; Rosa26-CAG-LSL-tdTomato (Ai9)/+ mice enabled us to concurrently characterize the temporal expression of Atoh1 protein (through HA-tag immunostaining) and visualize the cells expressing Atoh1 mRNA (as tdTomato+ cells). Our findings show that whereas Atoh1 mRNA expression is rapidly turned on in early cochlear progenitors, Atoh1 protein is only detected in differentiating HCs or progenitors just committed to the HC fate. Cre activity is also stronger in Atoh13*HA-P2A-Cre/+ than in previous mouse models, because almost all cochlear HCs and nearby supporting cells here are tdTomato+. Furthermore, tdTomato, but not HA, is expressed in middle and apical spiral ganglion neurons. CONCLUSION: Collectively, our findings indicate that Atoh13*HA-P2A-Cre can serve as a powerful genetic model in the developmental biology field.

Pathogenic bacteria characteristics and drug resistance in acute, delayed, and chronic periprosthetic joint infection: A retrospective analysis of 202 patients.

To assist orthopaedic surgeons in choosing appropriate antibiotics, this study attempted to identify the common microorganisms that cause periprosthetic joint infection (PJI) and their respective drug resistance spectrums. The clinical data of 202 patients with PJI after primary hip and knee arthroplasty between January 2017 and December 2021 were retrospectively analysed. There were 84 males and 118 females, aged (63.03 ± 13.10) years (range: 24-89 years). A total of 102 and 100 patients underwent total hip and total knee arthroplasty, respectively. Based on the time of postoperative infection, the patients were divided into acute (25 cases), delayed (91 cases), and chronic (86 cases) PJI groups. The results of pathogen species, composition ratio, and drug susceptibility tests were collected. Gram-positive bacteria were the primary causative pathogens of PJI (58.91%, 119/202), and their culture-positive rates in patients with acute, delayed, and chronic PJI were 32.00% (8/25), 62.64% (57/91), and 62.79% (54/86), respectively. Staphylococcus epidermidis and Staphylococcus aureus were the major gram-positive bacteria detected, followed by gram-negative bacteria (29/202, 14.36%), and fungi (4/202, 1.98%). Gram-positive bacteria showed higher resistance to penicillin (81.25%), oxacillin (63.33%), erythromycin (61.17%), and clindamycin (48.35%) and 100% sensitivity to linezolid, vancomycin, daptomycin, and tigecycline. In gram-negative bacteria, the drug resistance rates to cefazolin, gentamicin, furantoin, cefuroxime, ticacillin/clavulanic acid, ceftriaxone, ciprofloxacin, and tobramycin were >50%. However, no vancomycin-resistant bacteria were discovered in the current study. The drug resistance rate to carbapenems was low, ranging from 0% to 3.57%. Gram-positive bacteria are the main causative pathogens of PJI, and the resistance rate of pathogens of chronic PJI is higher than those of delayed and acute PJI. Use of cefuroxime and clindamycin in patients with PJIs should proceed with caution because of the high drug resistance rate. Vancomycin can be used as a first-line antibiotic against gram-positive bacteria. Carbapenems can be used as the first choice against gram-negative bacteria because of to their high sensitivity.

A theoretical study of the role of the non-innocent phenolate ligand of a nickel complex in water oxidation.

Water oxidation is the bottleneck of artificial photosynthesis. A novel nickel phenolate complex with a redox-active ligand has been designed to manage multiple electron transfers during water oxidation (D. Wang and C. O. Bruner, Inorg. Chem., 2017, 56, 13638). However, the mechanism of the reaction is not well understood and verified from a theoretical aspect. Density functional theory calculations were conducted to investigate the mechanism of water oxidation catalyzed by the nickel(II)-phenolate complex. Because only two cyclic voltammogram (CV) peaks were observed and the phenolate ligand is redox-active, the active species was proposed to be NiIII-OH by the experiment. Based on the calculated results, the first CV peak is phenolate ligand-centered and the second peak is a single two-proton-coupled-two-electron process. In addition, the activation barrier of O-O bond formation of NiIII-OH is higher than that of NiIV-2OH by 15.3 kcal mol-1. Thus, the redox-active phenolate ligand does not lower the oxidation state of Ni in the active species to NiIII. The oxidation state of the active species is still NiIV, the same as other Ni complexes for WOCs. As the phenolate ligand and the hydroxyl ligand can act as an internal base, three pathways are compared for O-O bond formation: normal WNA, phenolate-involving single electron transfer (SET)-WNA, and OH-involving SET-WNA. The OH-involving SET-WNA pathway is the most favorable because the hydroxyl ligand is more nucleophilic than the oxygen radical of the phenolate ligand. Based on the experimental observation and theoretical results, the phenolate ligand is not stable and easily oxidized because of the hydrogen at the benzyl position. Thus, WOC candidates should not have the presence of hydrogen at the benzyl position near the active center.

Understanding the role of Cl doping in the oxygen evolution reaction on cuprous oxide by DFT.

Designing highly active and earth-abundant oxygen evolution reaction (OER) electrocatalysts for electrochemical water splitting remains a challenge. Recently, Cl-doped Cu2O has emerged as a very promising non-noble-metal electrocatalyst candidate for the OER. However, the mechanism of the OER catalyzed by Cl-doped Cu2O has not been explored systematically. Herein, a comprehensive density functional theory (DFT) study is employed to study the role of Cl doping via comparing the OER on pure and Cl-doped Cu2O surfaces with/without Cu vacancies. Our results reveal that Cl doping increases the adsorption ability of Cu2O(111) by providing an excess electron, while a Cu vacancy decreases its adsorption ability by changing the geometric structure of the adsorption sites and the electronic structures. Cl-Cu2O(111) (η = 0.58 V) and VCu-Cl-Cu2O(111) (η = 0.46 V) have comparable or even better OER activity than those of widely used OER electrocatalysts such as the IrO2 catalyst (η = 0.56 V). It is facile to have a Cu vacancy when Cu2O(111) is doped with Cl because of a large strain introduced by Cl doping. Thus, VCu-Cl-Cu2O(111) should be the most feasible catalyst for the OER catalyzed by Cl-doped Cu2O material. The dual role of Cl doping is that it not only increases the OER activity but also helps to form a Cu vacancy. The results show that Cu2O(111) activity can be greatly enhanced via electronic and geometric structure modulation, which is helpful for the design of more efficient Cu2O-based catalysis.

Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.

INTRODUCTION: Senescent cells play a key role in the initiation and development of various age-related diseases. Human umbilical vein endothelial cells (HUVECs) senescence is closely associated with age-related cardiovascular diseases. Accumulating evidence has demonstrated that senolytics, the combination of dasatinib and quercetin (D+Q), could selectively eliminate senescent cells. N6-methyladenosine (m6A), the most abundant internal transcript modification, greatly influences RNA metabolism and modulates gene expression. We aimed to investigate whether RNA m6A functions in lipopolysaccharide (LPS)-induced HUVECs senescence and D+Q suppress HUVECs senescence by regulating RNA m6A. METHODS: Senescence-associated ß-galactosidase activity, western blot, and real-time quantitative polymerase chain reaction were performed to demonstrate that D+Q suppress HUVECs senescence. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and RIP-qPCR confirmed that RNA m6A plays a key role in the suppression of HUVECs senescence by D+Q. Chromatin immunoprecipitation and mRNA stability assay were carried out to prove that D+Q alleviate HUVECs senescence in a YTHDF2-dependent manner. RESULTS: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs. CONCLUSION: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.

Quantitative dual-energy computed tomography texture analysis predicts the response of primary small hepatocellular carcinoma to radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) is one of the effective therapeutic modalities in patients with hepatocellular carcinoma (HCC). However, there is no proper method to evaluate the HCC response to RFA. This study aimed to establish and validate a clinical prediction model based on dual-energy computed tomography (DECT) quantitative-imaging parameters, clinical variables, and CT texture parameters. METHODS: We enrolled 63 patients with small HCC. Two to four weeks after RFA, we performed DECT scanning to obtain DECT-quantitative parameters and to record the patients' clinical baseline variables. DECT images were manually segmented, and 56 CT texture features were extracted. We used LASSO algorithm for feature selection and data dimensionality reduction; logistic regression analysis was used to build a clinical model with clinical variables and DECT-quantitative parameters; we then added texture features to build a clinical-texture model based on clinical model. RESULTS: A total of six optimal CT texture analysis (CTTA) features were selected, which were statistically different between patients with or without tumor progression (P < 0.05). When clinical variables and DECT-quantitative parameters were included, the clinical models showed that albumin-bilirubin grade (ALBI) [odds ratio (OR) = 2.77, 95% confidence interval (CI): 1.35-6.65, P = 0.010], λAP (40-100 keV) (OR = 3.21, 95% CI: 3.16-5.65, P = 0.045) and ICAP (OR = 1.25, 95% CI: 1.01-1.62, P = 0.028) were associated with tumor progression, while the clinical-texture models showed that ALBI (OR = 2.40, 95% CI: 1.19-5.68, P = 0.024), λAP (40-100 keV) (OR = 1.43, 95% CI: 1.10-2.07, P = 0.019), and CTTA-score (OR = 2.98, 95% CI: 1.68-6.66, P = 0.001) were independent risk factors for tumor progression. The clinical model, clinical-texture model, and CTTA-score all performed well in predicting tumor progression within 12 months after RFA (AUC = 0.917, 0.962, and 0.906, respectively), and the C-indexes of the clinical and clinical-texture models were 0.917 and 0.957, respectively. CONCLUSIONS: DECT-quantitative parameters, CTTA, and clinical variables were helpful in predicting HCC progression after RFA. The constructed clinical prediction model can provide early warning of potential tumor progression risk for patients after RFA.