Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

M-TUBE enables large-volume bacterial gene delivery using a high-throughput microfluidic electroporation platform.

Conventional cuvette-based and microfluidics-based electroporation approaches for bacterial gene delivery have distinct advantages, but they are typically limited to relatively small sample volumes, reducing their utility for applications requiring high throughput such as the generation of mutant libraries. Here, we present a scalable, large-scale bacterial gene delivery approach enabled by a disposable, user-friendly microfluidic electroporation device requiring minimal device fabrication and straightforward operation. We demonstrate that the proposed device can outperform conventional cuvettes in a range of situations, including across Escherichia coli strains with a range of electroporation efficiencies, and we use its large-volume bacterial electroporation capability to generate a library of transposon mutants in the anaerobic gut commensal Bifidobacterium longum.

Dual-field-of-view high-spectral-resolution lidar: Simultaneous profiling of aerosol and water cloud to study aerosol-cloud interaction.

SignificanceAerosol-cloud interaction affects the cooling of Earth's climate, mostly by activation of aerosols as cloud condensation nuclei that can increase the amount of sunlight reflected back to space. But the controlling physical processes remain uncertain in current climate models. We present a lidar-based technique as a unique remote-sensing tool without thermodynamic assumptions for simultaneously profiling diurnal aerosol and water cloud properties with high resolution. Direct lateral observations of cloud properties show that the vertical structure of low-level water clouds can be far from being perfectly adiabatic. Furthermore, our analysis reveals that, instead of an increase of liquid water path (LWP) as proposed by most general circulation models, elevated aerosol loading can cause a net decrease in LWP.

Enhanced Osteolysis Targeted Therapy through Fusion of Exosomes Derived from M2 Macrophages and Bone Marrow Mesenchymal Stem Cells: Modulating Macrophage Polarization.

Aseptic loosening of prostheses is a highly researched topic, and wear particle-induced macrophage polarization is a significant cause of peri-prosthetic osteolysis. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs-Exos) promote M2 polarization and inhibit M1 polarization of macrophages. However, clinical application problems such as easy clearance and lack of targeting exist. Exosomes derived from M2 macrophages (M2-Exos) have good biocompatibility, immune escape ability, and natural inflammatory targeting ability. M2-Exos and BMSCs-Exos fused exosomes (M2-BMSCs-Exos) are constructed, which targeted the osteolysis site and exerted the therapeutic effect of both exosomes. M2-BMSCs-Exos achieved targeted osteolysis after intravenous administration inhibiting M1 polarization and promoting M2 polarization to a greater extent at the targeted site, ultimately playing a key role in the prevention and treatment of aseptic loosening of prostheses. In conclusion, M2-BMSCs-Exos can be used as a precise and reliable molecular drug for peri-prosthetic osteolysis. Fused exosomes M2-BMSCs-Exos  were originally proposed and successfully prepared, and exosome fusion technology provides a new theoretical basis and solution for the clinical application of therapeutic exosomes.

Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.

ConspectusCross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp2-hybridized carbon atoms and contribute to the formation of "flat" molecules. Evidence that three-dimensional structures often have improved physicochemical properties for pharmaceutical applications has contributed to growing demand for cross-coupling methods with sp3-hybridized reaction partners. Substituents attached to sp3 carbon atoms are intrinsically displayed in three dimensions. These considerations have led to efforts to establish reactions with sp3 cross-coupling partners, including alkyl halides, amines, alcohols, and carboxylic acids. As C(sp3)-H bonds are much more abundant that these more conventional coupling partners, we have been pursuing C(sp3)-H cross-coupling reactions that achieve site-selectivity, synthetic utility, and scope competitive with conventional coupling reactions.In this Account, we outline Cu-catalyzed oxidative cross-coupling reactions of benzylic C(sp3)-H bonds with diverse nucleophilic partners. These reactions commonly use N-fluorobenzenesulfonimide (NFSI) as the oxidant. The scope of reactivity is greatly improved by using a "redox buffer" that ensures that the Cu catalyst is available in the proper redox state to promote the reaction. Early precedents of catalytic Cu/NFSI oxidative coupling reactions, including C-H cyanation and arylation, did not require a redox buffer, but reactions with other nucleophiles, such as alcohols and azoles, were much less effective under similar conditions. Mechanistic studies show that some nucleophiles, such as cyanide and arylboronic acids, promote in situ reduction of CuII to CuI, contributing to successful catalytic turnover. Poor reactivity was observed with nucleophiles, such as alcohols, that do not promote CuII reduction in the same manner. This insight led to the identification of sacrificial reductants, termed "redox buffers", that support controlled generation of CuI during the reactions and enable successful benzylic C(sp3)-H cross-coupling with diverse nucleophiles. Successful reactions include those that feature direct coupling of (hetero)benzylic C-H substrates with coupling partners (alcohols, azoles) and sequential C(sp3)-H functionalization/coupling reactions. The latter methods feature generation of a synthetic linchpin that can undergo subsequent reaction with a broad array of nucleophiles. For example, halogenation/substitution cascades afford benzylic amines, (thio)ethers, and heterodiarylmethane derivatives, and an isocyanation/amine-addition sequence generates diverse benzylic ureas.Collectively, these Cu-catalyzed (hetero)benzylic C(sp3)-H cross-coupling reactions rapidly access diverse molecules. Analysis of their physicochemical and topological properties highlights the "drug-likeness" and enhanced three-dimensionality of these products relative to existing bioactive molecules. This consideration, together with the high benzylic C-H site-selectivity and the broad scope of reactivity enabled by the redox buffering strategy, makes these C(sp3)-H cross-coupling methods ideally suited for implementation in high-throughput experimentation platforms to explore novel chemical space for drug discovery and related applications.

Fluorogenic in-situ Labelling of Gelatin Polymer in Aqueous Solution and Hydrogel.

Gelatin polymers made from partially degraded collagen are important biomaterials, but their in-situ analysis suffers from uncontrollable covalent labelling and poor spatio-temporal imaging resolution. Herein, three tetrazolate-tagged tetraphenylethylene fluorophores (TPE-TAs) are introduced for practical fluorogenic labelling of gelatin in aqueous phase and hydrogels. These probes with aggregation-induced emission characteristics offer negligible background and elicit turn-on fluorescence by simply mixing with the gelatin in aqueous phase, giving a detection limit of 0.15 mg/L over a linear dynamic range up to 100 mg/L. This method does not work for collagens and causes minimal interference with gelatin properties. Mechanistic studies reveal a key role for multivalent electrostatic interactions between the abundant basic residues in gelatin (e.g., lysine, hydroxylysine, arginine) and anionic tetrazolate moieties of the lipophilic fluorophore synergistically in spatially rigid macromolecular encapsulation to achieve fluorogenic labelling. The AIE strategy by forming non-covalent fluorophore-gelatin complexes was developed for novel hydrogels that exhibited reversible fluorescence in response to dynamic microstructural changes in the hydrogel scaffold upon salting-in/out treatments, and enabled high spatio-temporal imaging of the fiber network in lyophilized samples. This work may open up avenues for in-situ imaging analysis and evaluation of gelatin-based biomaterials during processes such as in vivo degradation and mineralization.

GLUT1 promotes cell proliferation via binds and stabilizes phosphorylated EGFR in lung adenocarcinoma.

BACKGROUND: While previous studies have primarily focused on Glucose transporter type 1 (GLUT1) related glucose metabolism signaling, we aim to discover if GLUT1 promotes tumor progression through a non-metabolic pathway. METHODS: The RNA-seq and microarray data were comprehensively analyzed to evaluate the significance of GLUT1 expression in lung adenocarcinoma (LUAD). The cell proliferation, colony formation, invasion, and migration were used to test GLUT1 's oncogenic function. Co-immunoprecipitation and mass spectrum (MS) were used to uncover potential GLUT1 interacting proteins. RNA-seq, DIA-MS, western blot, and qRT-PCR to probe the change of gene and cell signaling pathways. RESULTS: We found that GLUT1 is highly expressed in LUAD, and higher expression is related to poor patient survival. GLUT1 knockdown caused a decrease in cell proliferation, colony formation, migration, invasion, and induced apoptosis in LUAD cells. Mechanistically, GLUT1 directly interacted with phosphor-epidermal growth factor receptor (p-EGFR) and prevented EGFR protein degradation via ubiquitin-mediated proteolysis. The GLUT1 inhibitor WZB117 can increase the sensitivity of LUAD cells to EGFR-tyrosine kinase inhibitors (TKIs) Gefitinib. CONCLUSIONS: GLUT1 expression is higher in LUAD and plays an oncogenic role in lung cancer progression. Combining GLUT1 inhibitors and EGFR-TKIs could be a potential therapeutic option for LUAD treatment.

Bacterial outer membrane vesicle-cancer cell hybrid membrane-coated nanoparticles for sonodynamic therapy in the treatment of breast cancer bone metastasis.

Breast cancer bone metastasis is a terminal-stage disease and is typically treated with radiotherapy and chemotherapy, which causes severe side effects and limited effectiveness. To improve this, Sonodynamic therapy may be a more safe and effective approach in the future. Bacterial outer membrane vesicles (OMV) have excellent immune-regulating properties, including modulating macrophage polarization, promoting DC cell maturation, and enhancing anti-tumor effects. Combining OMV with Sonodynamic therapy can result in synergetic anti-tumor effects. Therefore, we constructed multifunctional nanoparticles for treating breast cancer bone metastasis. We fused breast cancer cell membranes and bacterial outer membrane vesicles to form a hybrid membrane (HM) and then encapsulated IR780-loaded PLGA with HM to produce the nanoparticles, IR780@PLGA@HM, which had tumor targeting, immune regulating, and Sonodynamic abilities. Experiments showed that the IR780@PLGA@HM nanoparticles had good biocompatibility, effectively targeted to 4T1 tumors, promoted macrophage type I polarization and DC cells activation, strengthened anti-tumor inflammatory factors expression, and presented the ability to effectively kill tumors both in vitro and in vivo, which showed a promising therapeutic effect on breast cancer bone metastasis. Therefore, the nanoparticles we constructed provided a new strategy for effectively treating breast cancer bone metastasis.

Synergistic monitoring of PM2.5 and CO2 based on active and passive remote sensing fusion during the 2022 Beijing Winter Olympics.

Green and low-carbon are the keywords of the 2022 Beijing Winter Olympic Games (WOG) and the core of sustainable development. Beijing's P M 2.5 and C O 2 emissions attracted worldwide attention during WOG. However, the complex emission sources and frequently changing weather patterns make it impossible for a single monitoring approach to meet the high-resolution, full-coverage monitoring requirements. Therefore, we proposed an active-passive remote sensing fusion method to address this issue. The haze layer height (HLH) was first retrieved from vertical aerosol profiles measured by our high-spectral-resolution lidar located near Olympic venues, which provides new insights into the nonuniform boundary layer and the residual aerosol aloft above it. Second, we developed a bootstrap aggregating (bagging) method that assimilates the lidar-based HLH, satellite-based AOD, and meteorological data to estimate the hourly P M 2.5 with 1 km resolution. The P M 2.5 at Beijing region, Bird's Nest, and Yanqing venues during WOG was 23.00±18.33, 22.91±19.48, and 16.33±10.49µg/m 3, respectively. Third, we also derived the C O 2 enhancements, C O 2 spatial gradients resulting from human activities, and annual growth rate (AGR) to estimate the performance of carbon emission management in Beijing. Based on the top-down method, the results showed an average C O 2 enhancement of 1.62 ppm with an annual decline rate of 2.92 ppm. Finally, we compared the monitoring data with six other international cities. The results demonstrated that Beijing has the largest P M 2.5 annual decline rate of 7.43µg/m 3, while the C O 2 AGR is 1.46 ppm and keeps rising, indicating Beijing is still on its way to carbon peaking and needs to strive for carbon neutrality.

A near-infrared AIE fluorescent probe for myelin imaging: From sciatic nerve to the optically cleared brain tissue in 3D.

Myelin, the structure that surrounds and insulates neuronal axons, is an important component of the central nervous system. The visualization of the myelinated fibers in brain tissues can largely facilitate the diagnosis of myelin-related diseases and understand how the brain functions. However, the most widely used fluorescent probes for myelin visualization, such as Vybrant DiD and FluoroMyelin, have strong background staining, low-staining contrast, and low brightness. These drawbacks may originate from their self-quenching properties and greatly limit their applications in three-dimensional (3D) imaging and myelin tracing. Chemical probes for the fluorescence imaging of myelin in 3D, especially in optically cleared tissue, are highly desirable but rarely reported. We herein developed a near-infrared aggregation-induced emission (AIE)-active probe, PM-ML, for high-performance myelin imaging. PM-ML is plasma membrane targeting with good photostability. It could specifically label myelinated fibers in teased sciatic nerves and mouse brain tissues with a high-signal-to-background ratio. PM-ML could be used for 3D visualization of myelin sheaths, myelinated fibers, and fascicles with high-penetration depth. The staining is compatible with different brain tissue-clearing methods, such as ClearT and ClearT2 The utility of PM-ML staining in demyelinating disease studies was demonstrated using the mouse model of multiple sclerosis. Together, this work provides an important tool for high-quality myelin visualization across scales, which may greatly contribute to the study of myelin-related diseases.

All-Optical Valley Polarization Switch via Controlling Spin-Triplet and Spin-Singlet Interlayer Exciton Emission in WS2/WSe2 Heterostructure.

Although selective singlet and triplet interlayer exciton (IX) emission of transition metal dichalcogenides (TMD) heterostructures can be achieved by applying an electric or magnetic field, the device structure is complex and a low temperature is usually required. Here, we demonstrate a simple all-optical approach to selectively enhance the emission of singlet and triplet IX by selectively coupling singlet or triplet IX of a WS2/WSe2 heterostructure to a SiO2 microsphere cavity. Angle-resolved photoluminescene reveals that the transition dipole of triplet IX is almost along the out-of-plane direction, while singlet IX only has 69% out-of-plane dipole moment contribution. Since the out-of-plane dipole presents a higher Purcell factor within the cavity, we can simultaneously enhance the emission intensity of IX and control the emissive IX species at room temperature in an all-optical route. Importantly, we demonstrate an all-optical valley polarization switch with a record high on/off ratio of 35.

Investigation of the Impact of Childhood Immune Imprinting on Birth Year-Specific Risk of Clinical Infection During Influenza A Virus Epidemics in Hong Kong.

Influenza imprinting reduces risks of influenza A virus clinical infection by 40%-90%, estimated from surveillance data in western countries. We analyzed surveillance data from 2010 to 2019 in Hong Kong. Based on the best model, which included hemagglutinin group-level imprinting, we estimated that individuals imprinted to H1N1 or H2N2 had a 17% (95% confidence interval [CI], 3%-28%) lower risk of H1N1 clinical infection, and individuals imprinted to H3N2 would have 12% (95% CI, -3% to 26%) lower risk of H3N2 clinical infection. These estimated imprinting protections were weaker than estimates in western countries. Identifying factors affecting imprinting protections is important for control policies and disease modeling.

Benzylic C-H Esterification with Limiting C-H Substrate Enabled by Photochemical Redox Buffering of the Cu Catalyst.

Copper-catalyzed radical-relay reactions provide a versatile strategy for selective C-H functionalization; however, reactions with peroxide-based oxidants often require excess C-H substrate. Here, we report a photochemical strategy to overcome this limitation by using a Cu/2,2'-biquinoline catalyst that supports benzylic C-H esterification with limiting C-H substrate. Mechanistic studies indicate that blue-light irradiation promotes carboxylate-to-copper charge transfer, reducing resting-state CuII to CuI, which activates the peroxide to generate an alkoxyl radical hydrogen-atom-transfer species. This "photochemical redox buffering" introduces a unique strategy to sustain the activity of Cu catalysts in radical-relay reactions.

Uncanonical Semireduction of Quinolines and Isoquinolines via Regioselective HAT-Promoted Hydrosilylation.

Heterocycles are the backbone of modern medical chemistry and drug development. The derivatization of "an olefin" inside aromatic rings represents an ideal approach to access functionalized saturated heterocycles from abundant aromatic building blocks. Here, we report an operationally simple, efficient, and practical method to selectively access hydrosilylated and reduced N-heterocycles from bicyclic aromatics via a key diradical intermediate. This approach is expected to facilitate complex heterocycle functionalizations that enable access to novel medicinally relevant scaffolds.

SARS-CoV-2 infection activates CREB/CBP in cellular cyclic AMP-dependent pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global coronavirus disease 2019 (COVID-19) pandemic that has affected the lives of billions of individuals. However, the host-virus interactions still need further investigation to reveal the underling mechanism of SARS-CoV-2 pathogenesis. Here, transcriptomics analysis of SARS-CoV-2 infection highlighted possible correlation between host-associated signaling pathway and virus. In detail, cAMP-protein kinase (PKA) pathway has an essential role in SARS-CoV-2 infection, followed by the interaction between cyclic AMP response element binding protein (CREB) and CREB-binding protein (CBP) could be induced and leading to the enhancement of CREB/CBP transcriptional activity. The replication of Delta and Omicron BA.5 were inhibited by about 49.4% and 44.7% after knockdown of CREB and CBP with small interfering RNAs, respectively. Furthermore, a small organic molecule naphthol AS-E (nAS-E), which targets on the interaction between CREB and CBP, potently inhibited SARS-CoV-2 wild-type (WT) infection with comparable the half-maximal effective concentration (EC50 ) 1.04 µM to Remdesivir 0.57 µM. Compared with WT virus, EC50 in Calu-3 cells against Delta, Omicron BA.2, and Omicron BA.5 were, on average, 1.5-fold, 1.1-fold, and 1.5-fold higher, respectively, nAS-E had a satisfied antiviral effect against Omicron variants. Taken together, our study demonstrated the importance of CREB/CBP induced by cAMP-PKA pathway during SARS-CoV-2 infection, and further provided a novel CREB/CBP interaction therapeutic drug targets for COVID-19.

Integrative analysis of miRNA in cartilage-derived extracellular vesicles and single-cell RNA-seq profiles in knee osteoarthritis.

Extracellular vesicular miRNAs (EV-miRNAs) play essential roles as intercellular communication molecules in knee Osteoarthritis (OA). We isolated cartilage-derived extracellular vesicles (EVs), to perform miRNA sequencing, which revealed EV-miRNA profiles and identified differentially expressed miRNAs (DE-miRNAs) between cartilage injury and cartilage non-injury groups. The target genes of known and novel DE-miRNAs were predicted with multiMiR package in 14 miRNA-target interaction databases. Meanwhile, single-cell RNA sequencing (scRNA-seq) was performed to identify chondrocyte clusters and their gene signatures in knee OA. Then we performed comparative analysis between target genes of the cartilage-derived EV-DE-miRNAs target genes and cluster-specific maker genes of characteristic chondrocyte clusters. Finally, the functional analysis of the cartilage-derived EVs DE-miRNA target genes and cluster-specific marker genes of each cell population were performed. The EV-miRNA profile analysis identified 13 DE-miRNAs and 7638 target genes. ScRNA-seq labelled seven clusters by cell type according to the expression of multiple characteristic markers. The results identified 735, 184, 303 and 879 common genes between EV-DE-miRNA target genes and cluster-specific marker genes in regulatory chondrocytes (RegCs), fibrocartilage chondrocytes (FC), prehypertrophic chondrocytes (PreHTCs) and mitochondrial chondrocytes (MTC), respectively. We firstly integrated the association between the cartilage-derived EV-DE-miRNA target genes and distinguished cluster-specific marker genes of each chondrocyte clusters. KEGG pathway analysis further identified that the DE-miRNAs target genes were significantly enriched in MAPK signaling pathway, Focal adhesion and FoxO signaling pathway. Our results provided some new insights into cartilage injury and knee OA pathogenesis which could improve the new diagnosis and treatment methods for OA.

ITHscore: comprehensive quantification of intra-tumor heterogeneity in NSCLC by multi-scale radiomic features.

OBJECTIVES: To quantify intra-tumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) from computed tomography (CT) images. METHODS: We developed a quantitative ITH measurement-ITHscore-by integrating local radiomic features and global pixel distribution patterns. The associations of ITHscore with tumor phenotypes, genotypes, and patient's prognosis were examined on six patient cohorts (n = 1399) to validate its effectiveness in characterizing ITH. RESULTS: For stage I NSCLC, ITHscore was consistent with tumor progression from stage IA1 to IA3 (p < 0.001) and captured key pathological change in terms of malignancy (p < 0.001). ITHscore distinguished the presence of lymphovascular invasion (p = 0.003) and pleural invasion (p = 0.001) in tumors. ITHscore also separated patient groups with different overall survival (p = 0.004) and disease-free survival conditions (p = 0.005). Radiogenomic analysis showed that the level of ITHscore in stage I and stage II NSCLC is correlated with heterogeneity-related pathways. In addition, ITHscore was proved to be a stable measurement and can be applied to ITH quantification in head-and-neck cancer (HNC). CONCLUSIONS: ITH in NSCLC can be quantified from CT images by ITHscore, which is an indicator for tumor phenotypes and patient's prognosis. KEY POINTS: • ITHscore provides a radiomic quantification of intra-tumor heterogeneity in NSCLC. • ITHscore is an indicator for tumor phenotypes and patient's prognosis. • ITHscore has the potential to be generalized to other cancer types such as HNC.

PLGA nanoparticles engineering extracellular vesicles from human umbilical cord mesenchymal stem cells ameliorates polyethylene particles induced periprosthetic osteolysis.

The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis.

Tranexamic Acid Causes Chondral Injury Through Chondrocytes Apoptosis Induced by Activating Endoplasmic Reticulum Stress.

PURPOSE: To investigate whether tranexamic acid (TXA) is cytotoxic in chondrocyte and cartilage tissues, as well as explore the mechanisms behind the possible toxicity in detail. METHODS: We detected the cell viability of chondrocytes in vitro and the change of morphology and specific in vivo contents of cartilage after TXA treatment. Furthermore, we detected apoptosis in cartilage. We used apoptosis-specific staining, reactive oxygen species detection, mitochondrial membrane potential detection, flow cytometry, and western blot for apoptosis detection. Finally, we detected the activation of endoplasmic reticulum stress (ERS) in TXA-treated chondrocytes to clarify the mechanism behind chondrocyte apoptosis. RESULTS: TXA presented an increasing toxic effect with increasing concentrations, especially in the 100 mg/mL group. In addition, we found that 50 mg/mL and 100 mg/mL TXA significantly increased apoptosis in cartilage and subchondral bone. TXA could induce chondrocyte apoptosis in cell and protein levels with reactive oxygen species generation and mitochondrial membrane depolarization. An apoptosis inhibitor could inhibit the induced apoptosis. Next, TXA induced calcium overload in chondrocytes and increased ERS-specific protein expression, whereas ERS inhibitor blocked ERS activation and further inhibited chondrocyte apoptosis. CONCLUSIONS: We concluded that TXA had a toxic effect on chondrocytes by inducing apoptosis through ERS activation, especially in 50 mg/mL and 100 mg/mL groups. We recommend TXA concentrations of less than 50 mg/mL in joint surgeries. CLINICAL RELEVANCE: It is still unclear whether TXA has a toxic effect on cartilage when topically used in joint surgeries. The concentration also varies. This study provides additional evidence that TXA at high concentrations will cause cartilage damage, which will help to provide a new understanding of the clinical administration of TXA.

Novel risk-factor analysis and risk-evaluation model of falls in patients receiving maintenance hemodialysis.

This study investigated the prevalence of falls in maintenance hemodialysis (MHD) patients, and established a nomogram model for evaluating the fall risk of MHD patients. This study enrolled 303 MHD patients from the dialysis department of a tertiary hospital in July 2021. The general data of the participants, as well as the scores on the FRAIL scale, Sarcopenia Screening Questionnaire (SARC-F), Short Physical Performance Battery (SPPB) Scale, and of anxiety and depression, and the occurrence of falls were recorded. Using R language, data were assigned to the training set (n = 212) and test set (n = 91), and a logistic regression model was established. The regression model was verified by the receiver operating characteristic (ROC) curve, area under the curve (AUC), and the calibration curve. As a result, the prevalence of falls in MHD patients was 20.46%. Risk factors for falls in the optimal multivariate logistic regression model included hearing impairment, the depression score, and the SPPB score, of which a higher depression score (odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09-1.49, p = 0.002) and SPPB ≤ 6 (ORvsSPPB9-12: 3.69, 95% CI: 1.04-13.14, p = 0.043) conferred independent risk for falls. AUC of the nomogram in the training was 0.773, which in the test group was 0.663. The calibration and standard curves were fitted closely, indicated that the evaluation ability of the model was good. Thus, a higher depression score and SPPB ≤ 6 are independent risk factors for falls in MHD patients, and the nomogram with good accuracy and discrimination that was established in this study has clinical application value.