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Currently, the treatment of bone defects in arthroplasty is a challenge in clinical practice. Nonetheless, commercially available orthopaedic scaffolds have shown limited therapeutic effects for large bone defects, especially for massiveand irregular defects. Additively manufactured porous tantalum, in particular, has emerged as a promising material for such scaffolds and is widely used in orthopaedics for its exceptional biocompatibility, osteoinduction, and mechanical properties. Porous tantalum has also exhibited unique advantages in personalised rapid manufacturing, which allows for the creation of customised scaffolds with complex geometric shapes for clinical applications at a low cost and high efficiency. However, studies on the effect of the pore structure of additively manufactured porous tantalum on bone regeneration have been rare. In this study, our group designed and fabricated a batch of precision porous tantalum scaffolds via laser powder bed fusion (LPBF) with pore sizes of 250 µm (Ta 250), 450 µm (Ta 450), 650 µm (Ta 650), and 850 µm (Ta 850). We then performed a series of in vitro experiments and observed that all four groups showed good biocompatibility. In particular, Ta 450 demonstrated the best osteogenic performance. Afterwards, our team used a rat bone defect model to determine the in vivo osteogenic effects. Based on micro-computed tomography and histology, we identified that Ta 450 exhibited the best bone ingrowth performance. Subsequently, sheep femur and hip defect models were used to further confirm the osteogenic effects of Ta 450 scaffolds. Finally, we verified the aforementioned in vitro and in vivo results via clinical application (seven patients waiting for revision total hip arthroplasty) of the Ta 450 scaffold. The clinical results confirmed that Ta 450 had satisfactory clinical outcomes up to the 12-month follow-up. In summary, our findings indicate that 450 µm is the suitable pore size for porous tantalum scaffolds. This study may provide a new therapeutic strategy for the treatment of massive, irreparable, and protracted bone defects in arthroplasty.

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Regeneración Ósea , Tantalio , Andamios del Tejido , Tantalio/química , Regeneración Ósea/efectos de los fármacos , Porosidad , Animales , Andamios del Tejido/química , Ratas , Ratas Sprague-Dawley , Osteogénesis/efectos de los fármacos , Humanos , Masculino , Prueba de Estudio Conceptual , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Femenino

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Background: Patients with unprotected left main (UPLM) disease who underwent percutaneous coronary intervention (PCI) were found to have inconsistent results compared to those treated with coronary artery bypass grafting (CABG). Methods: We identified and enrolled randomized controlled trials (RCTs) and observational studies (OSs) comparing PCI versus CABG for UPLM disease. A meta-analysis was performed using Stata 17.0. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCEs). Additionally, all-cause death, cardiac death, myocardial infarction (MI), stroke, target vessel revascularization (TVR), and stent thrombosis (ST) were included as secondary endpoints. The odds ratios and 95% confidence intervals (CIs) were calculated. Sensitivity analyses were implemented if I 2 > 50% or p < 0.01. Publication bias analysis was conducted if more than 10 studies were included. Results: A total of 5 RCTs and 18 OSs involving 35,409 patients were included. The CABG strategy had a significantly lower incidence of MACCEs, primarily due to TVR. A significantly lower stroke rate was observed with the PCI strategy, as well as a significantly lower all-cause death, cardiac death, MI, and ST rate compared with the CABG strategy. Conclusions: MACCE rates were significantly lower in patients who underwent CABG, primarily due to TVR, but stroke rates were higher. RCTs with different study types need further investigation to confirm the most effective strategy.

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STUDY OBJECTIVES: Examine sleep patterns in children with sleep-disordered breathing (SDB) who habitually bedshare. METHODS: We evaluated associations of bedsharing with parent-reported (n=457) and actigraphy-based (n=258) sleep patterns in a diverse child sample (mean age 6.6±2.3 years, range 3.0-12.9) with mild SDB using baseline data from the Pediatric Adenotonsillectomy Trial for Snoring. Multivariable linear regressions examined associations between sleep patterns and bedsharing, adjusting for sociodemographic, child, and parent/environmental factors. Moderation effects were investigated using interaction terms. Analyses were stratified by age, categorizing children as younger (<6) and older (≥6) years. RESULTS: Bedsharing rates were 38%, with higher rates in younger (48%) vs. older (30%) children (p<0.001). In adjusted models, bedsharing was associated with about 30 minutes shorter actigraphy-derived nocturnal sleep duration (p=0.005) and parent-reported later sleep midpoint (p< 0.005) in younger children. In older children, associations of bedsharing with shorter parent-reported sleep duration were more pronounced in children with greater SDB symptom burden (p=0.02), and in children with higher ratings of anxiety (p=0.048) and depressive symptoms (p=0.02). CONCLUSIONS: In children with mild SDB, bedsharing is associated with shorter sleep duration and later sleep timing in younger children. In older children, these relationships were modified by child factors, including SDB symptom burden and internalizing symptoms. These findings suggest that whereas age and parenting factors may play a greater role in the younger group, SDB and internalizing symptoms may play more of a role in older children who bedshare, suggesting the need to address co-occurring medical and emotional problems in children with SDB. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Pediatric Adenotonsillectomy for Snoring (PATS); Identifier: NCT02562040.

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Since aircraft icing will decrease the ability of aircraft to generate lift, it is significant to consider the aircraft deicing problem. The paper presents an aircraft deicing method based on the cracking of the ice layer caused by the large deformations of wings. To describe the deformation of wings, the absolute coordinate-based formulation is used. The aircraft with high aspect ratio wings is simplified as a hub-beam system. Such a rigid-flexible system with the fast rotation speed of hub and the large deformation of the beam is modeled using absolute coordinate-based formulation accurately. The maneuver of the rigid body will lead to the large deformation of wings to do the de-icing. Numerical examples are presented to reveal that the maximum tensile strength on the wing surface with sinusoidal control torques with some amplitudes and frequencies is larger than the ice's tensile strength. Hence, the proposed de-icing method based on the aircraft maneuvering is potential.

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Aeronaves , Resistencia a la Tracción , Vibración , Modelos Teóricos

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BACKGROUND: Evaluating the clinical performance of Elecsys HIV Duo assay for primary human immunodeficiency virus (HIV) screening and acute HIV infection detection. METHODS: This study was conducted from April 2022 to April 2023 and involved two distinct populations. For the HIV screening population, three HIV Duo results [HIV Duo, HIV antigen (Ag), and HIV antibody (Ab)] in primary screening were obtained (January 2021 to June 2021). In the diagnosed HIV population, retrospective samples from November 2016 to March 2023 were measured. RESULTS: The HIV screening population included 111,383 samples from a real-world screening program. The assay demonstrated a specificity of 99.91 % (95 % CI: 99.89 %, 99.93 %) and a PPV of 0.8516 (95 % CI: 0.8225, 0.8776). Regarding the diagnosed HIV population, 836 HIV patients were enrolled, including 14 acute HIV infectious patients with only HIV Ag + and a Western Blot (WB) confirmation rate of 0 %. The median (IQR) of the numeric cut-off index (COI) ratios of HIV Duo Ab and Ag significantly differed among the Ag + Ab-, Ag-Ab+, and Ag + Ab + subgroups. CONCLUSION: The Elecsys HIV Duo assay is suitable for primary HIV screening and can be integrated into a novel laboratory HIV testing algorithm to improve acute HIV detection in Chinese clinical practice. ABBREVIATIONS: HIV, Human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; Ag, antigen; Ab, antibody; WB, Western Blot; COI, numeric cut-off index; CI, confidence interval; NAT, nucleic acid tests; EDC, electronic data capture systems; CDC, Chinese Centers for Disease Control and Prevention; IQR, interquartile range; PPV, positive predictive value; HCV, hepatitis C virus; HBV, hepatitis B virus; CI, confidence interval; ND, not able to define; F, female; M, male.

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The removal of nitrogen trifluoride (NF3) is of significant importance in atmospheric chemistry, as NF3 is an important anthropogenic greenhouse gas. However, the radical species OH and O(1D) in atmospheric conditions are nonreactive towards NF3. It is necessary to explore possible ways to remove NF3 in atmosphere. Therefore, the participation of water molecules in the reaction of NF3 with OH was discussed, as water is abundant in the atmosphere and can form very stable complexes due to its ability to act as both a hydrogen bond donor and acceptor. Systemic DFT calculations carried out at the CBS-QB3 and ωB97XD/aug-cc-pVTZ level of theory suggest that water molecules could affect the NF3 + OH reaction as well. The energy barrier of the SN2 mechanism was decreased by 8.52 kcal/mol and 10.58 kcal/mol with the assistance of H2O and (H2O)2, respectively. Moreover, the presence of (H2O)2 not only reduced the energy barrier of the reaction, but also changed the product channels, i.e., formation of NF2O + (H2O)2-HF instead of NF2OH + (H2O)2-F. Therefore, the removal of NF3 by reaction with OH is possible in the presence of water molecules. The results presented in this study should provide useful information on the atmospheric chemistry of NF3.

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INTRODUCTION: Mirror people have difficulty with PICC placement due to inversion of organs. Intracavitary electrocardiography (IC-ECG) guided peripherally inserted central catheter (PICC) tip location technique has been widely applied in clinical practice. CASE DESCRIPTION: Herein, we admitted a 59-year-old man diagnosed with esophageal cancer (EC). Chest X-ray and computed tomography (CT) revealed that the patient was with a mirror-image dextrocardia and situs inversus totalis: the heart and stomach located in the right side of the body, whereas the liver located in the left side. Echocardiography suggested that the apex of the heart pointed toward the right, while the left and right chambers were inverted. The relationship of the heart chambers, structure, and function were normal: left ventricular ejection fraction was 0.67, left atrial diameter was 31 mm, and heart output was 4.7 L/min. Surface ECG showed typical features of a dextrocardia: P-wave inverted on lead I. Amplitude of the R-wave and S-wave decreased gradually on lead chest from V1 to V5. Compared with the normal ECG image, the waves completely exchanged on lead II and III, so as on aVR and aVL. METHODS: Column of saline technique can assist operator estimate the tip position in real-time according to P-wave changes. When the height of P-wave reaches to its highest, it means that the tip of catheter has advanced to the target position of cavo-atrial junction (CAJ). OUTCOMES: Patient was inserted catheter and no adverse events were reported. CONCLUSIONS: Measuring the predicted length of catheter is still an indispensible procedure to help precisely adjusting the tip position in IC-ECG guided PICC. Our work provides both supplement for clinical data to facilitate further research and better understanding of special types of PICC to clinicians.

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INTRODUCTION: Lignin is a principal constituent of the secondary cell wall, which plays a role in both plant growth and defensing against stress, such as low temperature and pest infestation. Additionally, it also accumulates in fleshy fruits and negatively affects fruit quality. Red-fleshed loquat is temperature sensitive and exhibits cold-induced lignification. A number of technologies have been developed, for example, Low Temperature Conditioning (LTC) treatment, which has been applied in order to relieve the symptom of cold injury. OBJECTIVES: The present study seeks to elucidate the regulatory mechanism underlying cold-induced lignification in loquat fruit. METHODS: The target genes were isolated through the analysis of transcriptome. The gene function was analyzed by transient transgenic method in tobacco leaves and loquat fruit, respectively, as well as stable overexpression in liverwort. The regulatory mechanism study was achieved by in vitro protein-protein interaction assays, dual-luciferase assay, and EMSA. RESULTS: In the present study, the Xylem NAC Domain transcription factor EjXND1 was identified as a repressor of loquat fruit lignification. It was demonstrated that EjXND1 could interact with the characterized lignin activator EjHB1, resulting in a diminution of the activation of EjHB1 on EjPRX12 promoter. Furthermore, two highly methylated regions were identified in the promoter of EjXDN1. One of these regions exhibited a negative correlation between methylation level and EjXND1 expression. Additionally, it was shown that hypermethylation of this region weaken the binding affinity of EjXND1 activators to its promoter. CONCLUSION: The EjXND1 plays a role in modified Low Temperature Conditioning (mLTC) treatment that alleviates cold-induced lignification in red-fleshed loquat fruit by targeting the EjHB1-EjPRX12 module and EjXND1 is regulated by the dynamic of DNA methylation level in the promoter.

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Changes in both lignin biosynthesis and DNA methylation have been reported to be associated with chilling stress in plants. When stored at low temperatures, red-fleshed loquat is prone to lignification, with increased lignin content and fruit firmness, which has deleterious effects on taste and eating quality. Here, we found that 5°C storage mitigated the increasing firmness and lignin content of red-fleshed 'Dahongpao' ('DHP') loquat fruit that occurred during 0°C storage. EjNAC5 was identified by integrating RNA sequencing with whole-genome bisulfite sequencing analysis of 'DHP' loquat fruit. The transcript levels of EjNAC5 were positively correlated with changes in firmness and negatively correlated with changes in DNA methylation level of a differentially methylated region (DMR) in the EjNAC5 promoter. In white-fleshed 'Baisha' ('BS') loquat fruit, which do not undergo chilling-induced lignification at 0°C, the transcripts of EjNAC5 remained low and the methylation levels of the DMR in the EjNAC5 promoter was higher, compared to 'DHP' loquat fruit. Transient overexpression of EjNAC5 in loquat fruit and stable overexpression in Arabidopsis and liverwort led to an increase in lignin content. Furthermore, EjNAC5 interacts with EjERF39 and EjHB1 and activates the transcription of Ej4CL1 and EjPRX12 genes involved in lignin biosynthesis. This regulatory network involves different TFs to those involved in lignification pathway. Our study indicates that EjNAC5 promoter methylation modulates EjNAC5 transcript levels and identifies novel EjNAC5-EjERF39-Ej4CL1 and EjNAC5-EjHB1-EjPRX12 regulatory modules involved in chilling induced-lignification.

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Objective: To study the distribution and drug resistance characteristics of pathogenic bacteria in the elderly population of China by collecting and analyzing the standardized case data on the pathogens of infections in elderly patients, and to facilitate the establishment of a standardized layered surveillance system for pathogenic bacteria in China. Methods: We collected the case data of elderly patients (≥65 years old) from 62 sentinel hospitals across the country in 2021. Then, we statistically analyzed the data by patient age, their geographical region, the distribution of pathogenic bacteria, and the drug resistance characteristics of main pathogens. Results: A total of 3468 cases from across the country were included in the study. The top three sources of patients were the intensive care unit (13.2%), the department of respiratory medicine (11.2%), and the department of general surgery (8.4%). The top three types of specimens were urine (25.5%), sputum (20.6%), and blood (18.7%). A total of 3468 strains of pathogens were isolated, among which, 78.9% were gram-negative bacteria and 21.1% were gram-positive bacteria. The top five types of bacteria were Escherichia coli (20.9%), Klebsiella pneumoniae (18.3%), Pseudomonas aeruginosa (11.2%), Staphylococcus aureus (9.0%), and Acinetobacter baumannii (7.0%). The isolation rates of common important drug-resistant bacteria were 38.0% for methicillin-resistant Staphylococcus aureus (MRSA), 68.7% for carbapenem-resistant Acinetobacter baumannii (CRAB), and 38.2% for carbapenem-resistant Pseudomonas aeruginosa (CRPA), 20.1% for carbapenem-resistant Klebsiella pneumoniae (CRKP), 5.2% for carbapenem-resistant Escherichia coli (CRECO), and 2.1% for vancomycin-resistant Enterococcus (VRE). There were differences in the isolation rates of CRAB and CRKP in clinical care in the elderly population in seven geographical regions of China (P<0.05). Klebsiella pneumoniae is the most important pathogen in the elderly population ≥85 years old, and the isolation rates of CRKP showed significant differences in different age groups (P<0.05). Conclusion: There are significant differences in the drug resistance of pathogenic bacteria in the elderly populations of different regions and age groups in China. Therefore, monitoring the distribution and drug resistance of pathogenic bacteria in the elderly population and formulating targeted treatment plans according to the characteristics of the specific regions and age groups are of great significance to the improvement in the treatment outcomes and prognosis of the elderly population.

Asunto(s)

Antibacterianos , Klebsiella pneumoniae , Humanos , Anciano , China/epidemiología , Antibacterianos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/aislamiento & purificación , Anciano de 80 o más Años , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/aislamiento & purificación , Farmacorresistencia Bacteriana , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Farmacorresistencia Bacteriana Múltiple , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/epidemiología , Pruebas de Sensibilidad Microbiana , Masculino , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Bacterias/clasificación , Femenino , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación

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Introduction: Obesity, a pervasive global epidemic, has heightened susceptibility to chronic ailments and diminished the overall life expectancy on a global scale. Probiotics and inulin (IN) have been documented to mitigate obesity by exerting an influence on the composition of the gut microbiota. Whether heat-killed Bifidobacterium longum BBMN68 (MN68) and IN have an anti-obesity effect remains to be investigated. Methods: In this study, Wistar rats were fed a high-fat diet (HFD), and orally administered heat-killed MN68 (2 × 1011 CFU/kg) and/or inulin (0.25 kg/kg) for 12 weeks. Histological analysis, serology analysis and 16S rRNA gene sequencing were performed. Results: Heat-killed MN68 + IN treatment showed an enhanced effect on preventing weight gain, diminishing fat accumulation, and regulating lipid metabolism, compared to either heat-killed MN68 treatment or inulin treatment. Gut microbiota results showed that heat-killed MN68 + IN treatment significantly increased the relative abundance of Bacteroidota, Oscillospira, Intestinimonas, Christensenella, and Candidatus_Stoquefichus, and reduced the relative abundance of Enterococcus. Furthermore, heat-killed MN68 + IN significantly increased the SCFA levels, which were correlated with changes in the gut microbiota. Discussion: This research provides support for the application of heat-killed MN68 and IN in the treatment of obesity, and highlights the combination of heat-killed BBMN68 and IN as functional food ingredients.

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OBJECTIVE: To optimize the technical parameters related to the preparation of novel frozen human platelets and formulate corresponding protocol for its preparation. METHODS: Novel frozen human platelets were prepared with O-type bagged platelet-rich plasma (PRP), the key technical parameters (DMSO addition, incubation time, centrifugation conditions, etc.) of the preparation process were optimized, and the quality of the frozen platelets was evaluated by routine blood tests, apoptosis rate, platelet activation rate and surface protein expression level. RESULTS: In the preparation protocol of novel frozen human platelets, the operation of centrifugation to remove supernatant was adjusted to before the procedure of platelets freezing, and the effect of centrifugation on platelets was minimal when the centrifugation condition was 800×g for 8 min. In addition, platelets incubated with DMSO for 30 min before centrifugation exhibited better quality after freezing and thawing. The indexes of novel frozen human platelets prepared with this protocol remained stable after long-term cryopreservation. CONCLUSION: The preparation technique of novel frozen human platelets was established and the protocol was formulated. It was also confirmed that the quality of frozen platelets could be improved by incubating platelets with DMSO for 30 min and then centrifuging them at 800×g for 8 min in the preparation of novel frozen human platelets.

Asunto(s)

Plaquetas , Criopreservación , Humanos , Conservación de la Sangre/métodos , Plasma Rico en Plaquetas , Centrifugación , Dimetilsulfóxido , Congelación , Activación Plaquetaria

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BACKGROUND: A new chemiluminescence assay, the Anti-TP-Ⅱ assay, is going to be commercially available in clinical laboratories in China and other countries. This study examined the performance of the new assay for the detection of TP infection and compared it with that of the Anti-TP assay by using large amounts of clinical samples. METHODS: The precision, accuracy, anti-interference ability, and the clinical sensitivity and specificity of the Anti-TP-Ⅱ assay were evaluated. In addition, compared with those of the Anti-TP assay, the false positive and false negative rates of the Anti-TP-Ⅱ assay were evaluated for 2,436 clinical routine samples and 711 preselected Anti-TP assay reactive samples. Discrepancy of the samples was investigated with the recomLinec Treponema IgM/IgG kit or the Elecsys syphilis assay. RESULTS: The precision, accuracy, and anti-interference ability of the Anti-TP-Ⅱ assay met the national standard of China, and there was an overall agreement of 96.75% (Kappa = 0.91) between the two assays. The sensitivity and specificity of the Anti-TP-Ⅱ assay were 100% (95% CI: 94.13% to 100%) and 99.92% (95% CI: 99.70% to 99.99%), respectively. Compared with the Anti-TP assay, the Anti-TP-Ⅱ assay significantly reduced the number of borderline samples and the false positive rate. CONCLUSIONS: Considering its excellent performance, the Anti-TP-Ⅱ assay is a good screening test for high-throughput laboratories and can replace the previous generation of reagents, the Anti-TP assay, with a superior specificity.

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Anticuerpos Antibacterianos , Mediciones Luminiscentes , Sensibilidad y Especificidad , Sífilis , Treponema pallidum , Humanos , Mediciones Luminiscentes/métodos , Treponema pallidum/inmunología , Sífilis/diagnóstico , Sífilis/microbiología , Sífilis/inmunología , Sífilis/sangre , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Reproducibilidad de los Resultados , Serodiagnóstico de la Sífilis/métodos , China , Reacciones Falso Positivas , Masculino , Femenino , Reacciones Falso Negativas

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Background: Coronary artery calcification (CAC) is in almost all patients with coronary artery disease and requires more effective therapies. We aim to explore the effects of phosphoglycerate dehydrogenase (PHGDH) on CAC. Methods: We identified the differentially expressed genes through bioinformatic analysis and selected PHGDH for further verification. Human coronary artery smooth muscle cells (HCASMCs) cultured with calcifying medium were used as models of CAC in vitro. Erastin was administered to induce ferroptosis. We determined the cell viability by the cell count kit-8 assay. The alkaline phosphatase activity, calcium content, and the expression of glutathione were evaluated by the corresponding detection kits. The calcification level was detected by alizarin red staining. Then we performed Western blot to examine the expression of runt-related transcription factor 2, bone morphogenetic protein 2, cyclooxygenase 2, glutathione peroxidase 4, P53, and solute carrier family 7a member 11 (SLC7A11). Results: We acquired 201 differentially expressed genes and selected PHGDH to verify. In calcifying medium-induced HCASMCs, PHGDH overexpression increased the cell viability and decreased the alkaline phosphatase activity, calcium content, calcification level, and the expression of bone morphogenetic protein 2 and runt-related transcription factor 2. Additionally, we found higher levels of glutathione, glutathione peroxidase 4, and SLC7A11 and lower levels of cyclooxygenase 2 and P53 after up-regulating PHGDH. Erastin reversed the effects of PHGDH on calcification of HCASMCs. Conclusion: PHGDH overexpression suppresses the calcification level of HCASMCs by inhibiting ferroptosis through the P53/SLC7A11 signaling pathway, suggesting PHGDH as a promising therapeutic target of CAC.

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Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.

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Ferroptosis , Peroxidación de Lípido , Macrófagos , Fagocitosis , Fosfolípidos , Fosfolípidos/metabolismo , Macrófagos/metabolismo , Animales , Ratones , Humanos , Receptor Toll-Like 2/metabolismo , Microambiente Tumoral , Línea Celular Tumoral , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neoplasias/patología , Células RAW 264.7

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Diabetic infected bone defects (DIBD) with abnormal immune metabolism are prone to the hard-to-treat bacterial infections and delayed bone regeneration, which present significant challenges in clinic. Control of immune metabolism is believed to be important in regulating fundamental immunological processes. Here, we developed a macrophage metabolic reprogramming hydrogel composed of modified silk fibroin (Silk-6) and poly-l-lysine (ε-PL) and further integrated with M2 Macrophage-derived Exo (M2-Exo), named Silk-6/ε-PL@Exo. This degradable hydrogel showed a broad-spectrum antibacterial performance against both Gram-positive and -negative bacteria. More importantly, the release of M2-Exo from Silk-6/ε-PL@Exo could target M1 macrophages, modulating the activity of the key enzyme hexokinase II (HK2) to control the inflammation-related NF-κB pathway, alleviate lactate accumulation, and inhibit glycolysis to normalize the cycle, thereby promoting M1-to-M2 balance. Using a rat model of DIBD, Silk-6/ε-PL@Exo hydrogel promoted infection control, balanced immune responses and accelerated the bone defect healing. Overall, this study demonstrates that this Silk-6/ε-PL @Exo is a promising filler biomaterial with multi-function to treat DIBD and emphasizes the importance of metabolic reprogramming in bone regeneration.

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Regeneración Ósea , Exosomas , Fibroínas , Hidrogeles , Macrófagos , Animales , Hidrogeles/química , Ratas , Regeneración Ósea/efectos de los fármacos , Exosomas/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Fibroínas/química , Fibroínas/farmacología , Ratones , Seda/química , Diabetes Mellitus Experimental , Células RAW 264.7 , Masculino , Antibacterianos/farmacología , Antibacterianos/química , Ratas Sprague-Dawley , FN-kappa B/metabolismo , Reprogramación Metabólica

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Macrophage metabolism dysregulation, which is exacerbated by persistent stimulation in infectious and inflammatory diseases, such as diabetic infectious bone defects (DIBD), eventually leads to the failure of bone repair. Here, we have developed an injectable, macrophage-modulated GAPDH-Silence drug delivery system. This microsphere comprises chondroitin sulfate methacrylate (CM) and methacrylated gelatin (GM), while the dimethyl fumarate (DMF)-loaded liposome (D-lip) is encapsulated within the microsphere (CM@GM), named D-lip/CM@GM. Triggered by the over-expressed collagenase in DIBD, the microspheres degrade and release the encapsulated D-lip. D-lip could modulate metabolism by inhibiting GAPDH, which suppresses the over-activation of glycolysis, thus preventing the inflammatory response of macrophages in vitro. While beneficial for macrophages, D-lip/CM@GM is harmful to bacteria. GAPDH, while crucial for glycolysis of staphylococcal species (S. aureus), can be effectively countered by D-lip/CM@GM. We are utilizing existing drugs in innovative ways to target central metabolism for effective eradication of bacteria. In the DIBD model, our results confirmed that the D-lip/CM@GM enhanced bacteria clearance and reprogrammed dysregulated metabolism, thereby significantly improving bone regeneration. In conclusion, this GAPDH-Silence microsphere system may provide a viable strategy to promote diabetic infection bone regeneration.

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Regeneración Ósea , Macrófagos , Microesferas , Staphylococcus aureus , Animales , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Regeneración Ósea/efectos de los fármacos , Células RAW 264.7 , Staphylococcus aureus/efectos de los fármacos , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Masculino , Glucólisis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Complicaciones de la Diabetes/tratamiento farmacológico , Liposomas/química , Antibacterianos/farmacología

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Purpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.

Asunto(s)

Adyuvantes Inmunológicos , Inmunidad Celular , Ratones Endogámicos C57BL , Nanopartículas , Vacunas de Subunidad , Animales , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Nanopartículas/química , Adyuvantes Inmunológicos/administración & dosificación , Femenino , Vacunas de ARNm , Ratones , Herpesvirus Humano 3/inmunología , Anticuerpos Antivirales/sangre , Inmunización Secundaria/métodos , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/administración & dosificación , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/administración & dosificación , Liposomas

RESUMEN

Background: Side branch (SB) occlusion after main vessel stenting is the main complication in treating coronary bifurcation lesions by provisional stenting. The Jailed Wire Technique (JWT), recommended by the European Bifurcation Club, is a standard technique to deal with this issue. The Jailed Balloon Technique (JBT) has been found to be more effective than the JWT in clinical practice by some interventionists, but it has not been widely accepted. In this meta-analysis, we compared the efficacy and safety of JBT and JWT. Methods: The literature comparing JBT and JWT was systematically reviewed. Stata/MP 17.0 was used to perform a meta-analysis. The primary endpoints were major adverse cardiac events (MACE), cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR). The secondary endpoints were SB occlusion and SB dissection. Aggregated odds ratios and 95% confidence intervals were calculated. A sensitivity analysis was conducted if I 2 was > 50% or p < 0.01. Results: Thirteen studies involving 1789 patients were enrolled. JBT was found to have a significantly lower incidence of MACE, SB occlusion and dissection. The incidence of cardiac death, MI and TLR were also lower in the JBT group, though the differences were not significant. Conclusions: JBT prevents SB occlusion more effectively and does not increase immediate or long-term complications. JBT, or its modified versions, can be used to treat SBs with a high risk of occlusion.