ABSTRACT
Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.
Subject(s)
Anticoagulants/therapeutic use , Caspases/metabolism , Heparin/therapeutic use , Macrophages/immunology , Sepsis/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Caspases/genetics , Cell Line , Female , Glucuronidase/genetics , Glucuronidase/metabolism , Glycocalyx/metabolism , HMGB1 Protein/metabolism , Humans , Immunomodulation , Lipopolysaccharides/metabolism , Male , Mice , Mice, Knockout , Middle Aged , Sepsis/mortality , Survival Analysis , Young AdultABSTRACT
It is generally believed that long-duration gamma-ray bursts (GRBs) are associated with massive star core collapse1, whereas short-duration GRBs are associated with mergers of compact star binaries2. However, growing observations3-6 have suggested that oddball GRBs do exist, and several criteria (prompt emission properties, supernova/kilonova associations and host galaxy properties) rather than burst duration only are needed to classify GRBs physically7. A previously reported long-duration burst, GRB 060614 (ref. 3), could be viewed as a short GRB with extended emission if it were observed at a larger distance8 and was associated with a kilonova-like feature9. As a result, it belongs to the type I (compact star merger) GRB category and is probably of binary neutron star (NS) merger origin. Here we report a peculiar long-duration burst, GRB 211211A, whose prompt emission properties in many aspects differ from all known type I GRBs, yet its multiband observations suggest a non-massive-star origin. In particular, substantial excess emission in both optical and near-infrared wavelengths has been discovered (see also ref. 10), which resembles kilonova emission, as observed in some type I GRBs. These observations point towards a new progenitor type of GRBs. A scenario invoking a white dwarf (WD)-NS merger with a post-merger magnetar engine provides a self-consistent interpretation for all the observations, including prompt gamma rays, early X-ray afterglow, as well as the engine-fed11,12 kilonova emission.
Subject(s)
Gamma RaysABSTRACT
Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, a lytic form of cell death. Caspase-11-dependent pyroptosis mediates lethality in endotoxemia, but it is unclear how LPS is delivered into the cytosol for the activation of caspase-11. Here we discovered that hepatocyte-released high mobility group box 1 (HMGB1) was required for caspase-11-dependent pyroptosis and lethality in endotoxemia and bacterial sepsis. Mechanistically, hepatocyte-released HMGB1 bound LPS and targeted its internalization into the lysosomes of macrophages and endothelial cells via the receptor for advanced glycation end-products (RAGE). Subsequently, HMGB1 permeabilized the phospholipid bilayer in the acidic environment of lysosomes. This resulted in LPS leakage into the cytosol and caspase-11 activation. Depletion of hepatocyte HMGB1, inhibition of hepatocyte HMGB1 release, neutralizing extracellular HMGB1, or RAGE deficiency prevented caspase-11-dependent pyroptosis and death in endotoxemia and bacterial sepsis. These findings indicate that HMGB1 interacts with LPS to mediate caspase-11-dependent pyroptosis in lethal sepsis.
Subject(s)
Caspases/immunology , Endotoxins/immunology , HMGB1 Protein/immunology , Pyroptosis/immunology , Sepsis/immunology , Animals , Caspases/genetics , Caspases/metabolism , Cells, Cultured , Endothelial Cells/immunology , Endothelial Cells/metabolism , Endotoxins/metabolism , HEK293 Cells , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Humans , Lipopolysaccharides/immunology , Lipopolysaccharides/metabolism , Macrophages/immunology , Macrophages/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Receptor for Advanced Glycation End Products/immunology , Receptor for Advanced Glycation End Products/metabolism , Sepsis/genetics , Sepsis/metabolism , THP-1 CellsABSTRACT
Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.
Subject(s)
Colorectal Neoplasms , Metformin , Humans , Valosin Containing Protein/genetics , Valosin Containing Protein/metabolism , Neoplastic Processes , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Fatty Acids/metabolism , Metformin/pharmacology , Carnitine O-Palmitoyltransferase/metabolism , Oxidation-ReductionABSTRACT
In this study, we utilized the Olink Cardiovascular III panel to compare the expression levels of 92 cardiovascular-related proteins between patients with dilated cardiomyopathy combined with heart failure (DCM-HF) (n = 20) and healthy normal people (Normal) (n = 18). The top five most significant proteins, including SPP1, IGFBP7, F11R, CHI3L1, and Plaur, were selected by Olink proteomics. These proteins were further validated using ELISA in plasma samples collected from an additional cohort. ELISA validation confirmed significant increases in SPP1, IGFBP7, F11R, CHI3L1, and Plaur in DCM-HF patients compared to healthy controls. GO and KEGG analysis indicated that NT-pro BNP, SPP1, IGFBP7, F11R, CHI3L1, Plaur, BLM hydrolase, CSTB, Gal-4, CCL15, CDH5, SR-PSOX, and CCL2 were associated with DCM-HF. Correlation analysis revealed that these 13 differentially expressed proteins have strong correlations with clinical indicators such as LVEF and NT-pro BNP, etc. Additionally, in the GEO-DCM data sets, the combined diagnostic value of these five core proteins AUC values of 0.959, 0.773, and 0.803, respectively indicating the predictive value of the five core proteins for DCM-HF. Our findings suggest that these proteins may be useful biomarkers for the diagnosis and prediction of DCM-HF, and further research is prompted to explore their potential as therapeutic targets.
ABSTRACT
Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL-10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL-10 in macrophages of BALF was associated with the levels of asthma-related parameters. The immune-suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL-10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL-10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG.
Subject(s)
Asthma , Bronchoalveolar Lavage Fluid , Interleukin-10 , Oligodeoxyribonucleotides , Humans , Asthma/immunology , Oligodeoxyribonucleotides/pharmacology , Oligodeoxyribonucleotides/immunology , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/cytology , Female , Male , Interleukin-10/metabolism , Adult , Macrophages/immunology , Macrophages/metabolism , Middle Aged , Macrophages, Alveolar/immunology , Cells, Cultured , Th2 Cells/immunologyABSTRACT
The construction of stable and efficient nanocomposites with low addition and light weight has always been the goal pursued in the field of electromagnetic wave (EMW) absorption. In this study, the Co@CNTs nanocomposites with Co nanoparticles (13 nm) nanoconfined in the carbon nanotube (CNT) are successfully synthesized by a simple hydrothermal method and phenolic assisted pyrolysis method. The degree of graphitization of CNTs and the microstructure of Co nanoparticles can be effectively regulated by controlling the calcination temperature. The sample calcined at 700 °C can obtain excellent absorption performance at a low filling capacity of 10 wt.%: the minimum reflection loss (RL) is -41.2 dB and the effective absorption bandwidth (EAB) reaches a maximum width of 14.2 GHz. When the sample thickness is only 2.2 mm, the EAB of <-20 dB reaches 8.3 GHz, which is the maximum EAB of most current Co-based absorbers. In particular, the polarization and ferromagnetic coupling behaviors are elucidated in depth with the aid of electromagnetic field simulations using the High-Frequency Structure Simulator (HFSS). This work provides a new nanoconfinement strategy for constructing the Co@CNTs nanocomposites as lightweight and ultra-broadband absorbing materials for EMW protection and EMW pollution control.
ABSTRACT
Rhodococcus equi (R. equi) is a zoonotic opportunistic pathogen that mainly causes fatal lung and extrapulmonary abscesses in foals and immunocompromised individuals. To date, no commercial vaccine against R. equi exists. We previously screened all potential vaccine candidates from the complete genome of R. equi using a reverse vaccinology approach. Five of these candidates, namely ABC transporter substrate-binding protein (ABC transporter), penicillin-binding protein 2 (PBD2), NlpC/P60 family protein (NlpC/P60), esterase family protein (Esterase), and M23 family metallopeptidase (M23) were selected for the evaluation of immunogenicity and immunoprotective effects in BALB/c mice model challenged with R. equi. The results showed that all five vaccine candidate-immunized mice experienced a significant increase in spleen antigen-specific IFN-γ- and TNF-α-positive CD4 + and CD8 + T lymphocytes and generated robust Th1- and Th2-type immune responses and antibody responses. Two weeks after the R. equi challenge, immunization with the five vaccine candidates reduced the bacterial load in the lungs and improved the pathological damage to the lungs and livers compared with those in the control group. NlpC/P60, Esterase, and M23 were more effective than the ABC transporter and PBD2 in inducing protective immunity against R. equi challenge in mice. In addition, these vaccine candidates have the potential to induce T lymphocyte memory immune responses in mice. In summary, these antigens are effective candidates for the development of protective vaccines against R. equi. The R. equi antigen library has been expanded and provides new ideas for the development of multivalent vaccines.
Subject(s)
Actinomycetales Infections , Bacterial Vaccines , Disease Models, Animal , Immunity, Humoral , Mice, Inbred BALB C , Rhodococcus equi , Animals , Rhodococcus equi/immunology , Rhodococcus equi/genetics , Mice , Bacterial Vaccines/immunology , Bacterial Vaccines/administration & dosage , Actinomycetales Infections/prevention & control , Actinomycetales Infections/immunology , Actinomycetales Infections/microbiology , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Immunity, Cellular , Female , Lung/microbiology , Lung/immunology , Lung/pathology , Bacterial Load , Bacterial Proteins/immunology , Bacterial Proteins/genetics , Interferon-gamma/immunology , Interferon-gamma/metabolismABSTRACT
BACKGROUND: Accurate preoperative prediction of lymph node (LN) involvement is essential for the management of early gastric cancer (EGC). Our objective was to formulate a potent nomogram for predicting LN involvement in EGC by leveraging an innovative predictor of tumor budding. METHODS: We assembled a cohort of EGC patients who underwent radical surgery at two tertiary cancer centers. Tumor budding was stratified by using an optimal cutoff value and integrated with other clinicopathological variables to ascertain the risk factors associated with LN involvement. A nomogram was developed and its predictive performance was assessed by using receiver operating characteristic (ROC) curves and calibration plots. In addition, we conducted decision curve analysis to evaluate its clinical utility. Finally, an external validation was conducted by using an independent cohort. RESULTS: Finally, 307 eligible patients (215 in the primary cohort and 92 in the validation cohort) were included. Tumor budding, categorized by a count of two, exhibited a robust association with LN involvement (OR 14.12, p = 0.012). Other significant risk factors include lymphovascular invasion, depth of tumor invasion, ulceration, and tumor differentiation. Notably, the nomogram demonstrated exceptional discriminative power (area under the ROC curve, 0.872 in the primary cohort and 0.885 in the validation cohort) and precise predictive capabilities. Furthermore, the nomogram showed notable clinical applicability through decision curve analysis, particularly in endoscopic curability C-2, by mitigating the risk of overtreatment. CONCLUSIONS: Tumor budding is a robust predictor of LN involvement in EGC. The incorporation of tumor budding into a nomogram is an effective strategy, thereby informing and enhancing clinical decision-making.
Subject(s)
Lymph Nodes , Lymphatic Metastasis , Nomograms , Stomach Neoplasms , Aged , Female , Humans , Male , Middle Aged , China , Follow-Up Studies , Gastrectomy , Lymph Nodes/pathology , Lymph Nodes/surgery , Neoplasm Invasiveness , Prognosis , Retrospective Studies , Risk Factors , ROC Curve , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Reproducibility of ResultsABSTRACT
A fundamental challenge in quantum thermodynamics is the exploration of inherent dimensional constraints in thermodynamic machines. In the context of two-level systems, the most compact refrigerator necessitates the involvement of three entities, operating under self-contained conditions that preclude the use of external work sources. Here, we build such a smallest refrigerator using a nuclear spin system, where three distinct two-level carbon-13 nuclei in the same molecule are involved to facilitate the refrigeration process. The self-contained feature enables it to operate without relying on net external work, and the unique mechanism sets this refrigerator apart from its classical counterparts. We evaluate its performance under varying conditions and systematically scrutinize the cooling constraints across a spectrum of scenarios, which sheds light on the interplay between quantum information and thermodynamics.
ABSTRACT
Although CAR-T cell therapy has been particularly successful as a treatment for B cell malignancies, effectively treating acute myeloid leukemia with CAR remains a greater challenge. Multiple preclinical studies and clinical trials are underway, including on AML-related surface markers that CAR-T cells can target, such as CD123, CD33, NKG2D, CLL1, CD7, FLT3, Lewis Y and CD70, all of which provide opportunities for developing CAR-T therapies with improved specificity and efficacy. We also explored specific strategies for CAR-T cell treatment of AML, including immune checkpoints, suicide genes, dual targeting, genomic tools and the potential for universal CAR. In addition, CAR-T cell therapy for AML still has certain risks and challenges, including cytokine release syndrome (CRS) and haematotoxicity. Despite these challenges, as a new targeting method for AML treatment, CAR-T cell therapy still has great prospects. Ongoing research aims to further optimize this treatment mode.
Subject(s)
Immunotherapy, Adoptive , Leukemia, Myeloid, Acute , Receptors, Chimeric Antigen , Humans , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/genetics , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/therapeutic use , Animals , Cytokine Release Syndrome/etiologyABSTRACT
Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause destruction of cartilage and bone's extracellular matrix. Bromodomain 4 (BRD4), as a transcriptional and epigenetic regulator, plays a key role in cancer and inflammatory diseases. While, the role of BRD4 in bone destruction in RA has not been extensively reported. Our study aimed to investigate the effect of BRD4 on the bone destruction in RA and, further, its mechanism in the pathogenesis of the disease. In this study, receiving approval from the Ethical Committee of the Affiliated Hospital of Qingdao University, we evaluated synovial tissues from patients with RA and OA for BRD4 expression through advanced techniques such as immunohistochemistry, quantitative real-time PCR (qRT-PCR), and Western blotting. We employed a collagen-induced arthritis (CIA) mouse model to assess the therapeutic efficacy of the BRD4 inhibitor JQ1 on disease progression and bone destruction, supported by detailed clinical scoring and histological examinations. Further, in vitro osteoclastogenesis assays using RAW264.7 macrophages, facilitated by TRAP staining and resorption pit assays, provided insights into the mechanistic effects of JQ1 on osteoclast function. Statistical analysis was rigorously conducted using SPSS, applying Kruskal-Wallis, one-way ANOVA, and Student's t-tests to validate the data. In our study, we found that BRD4 expression significantly increased in the synovial tissues of RA patients and the ankle joints of CIA mice, with JQ1, a BRD4 inhibitor, effectively reducing inflammation, arthritis severity (p < 0.05), and bone erosion. Treatment with JQ1 not only improved bone mass and structural integrity in CIA mice but also downregulated osteoclast-related gene expression and the RANKL/RANK signaling pathway, indicating a suppression of osteolysis. Furthermore, in vitro assays demonstrated that JQ1 markedly inhibited osteoclast differentiation and function, underscoring the pivotal role of BRD4 in osteoclastogenesis and its potential as a target for therapeutic intervention in RA-induced bone destruction. Our study concludes that targeting BRD4 with the inhibitor JQ1 significantly mitigates inflammation and bone destruction in rheumatoid arthritis, suggesting that inhibition of BRD4 may be a potential therapeutic strategy for the treatment of bone destruction in RA.
ABSTRACT
OBJECTIVES: The treatment of refractory and recurrent acute myeloid leukaemia (AML) is still a challenge with poor response rates and short survival times. In an attempt to solve this problem, we constructed a tandem bispecific chimeric antigen receptor (CAR) targeting CD123 and C-type lectin-like molecule 1 (CLL-1), two different AML antigens, and verified its cytotoxic effects in vitro. METHODS: We established and cultured K562 cell lines expressing both CD123 and CLL1 antigens. Single-target CAR-T cells specific to CD123 and CLL1 were engineered, alongside tandem CD123/CLL1 bispecific CAR-T cells. Flow cytometry was used to determine cell phenotypes, transfection efficiencies, cytokine release, and CAR-T-cell proliferation, and an lactate dehydrogenase assay was used to detect the cytotoxicity of CD123/CLL-1 bispecific tandem CAR-T cells in vitro. RESULTS: Two types of tandem CAR-T cells exhibited significant killing effects on CLL-1 + CD123+ leukaemia cell lines and primary AML tumour cells. The killing efficiency of tandem CAR-T cells in the case of single antigen expression is comparable to that of single target CAR-T cells. When faced with dual target tumour cells, dual target CAR-T cells significantly surpass single target CAR-T cells. CD123/CLL-1 CAR-T cells in tandem targeted and killed CD123- and CLL-1-positive leukaemia cell lines and released a large number of cytokines. CONCLUSIONS: CD123/CLL-1 CAR-T cells in tandem can simultaneously target CD123 and CLL-1 on AML cells, demonstrating a significant ability to kill single antigens and multi-target tumour cells. This suggests that CD123/CLL-1 CAR-T cells exhibit significant advantages in the expression of multiple antigens in a wide range of target cells, which may help overcome the challenges posed by tumour heterogeneity and evasion mechanisms.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Leukemia, Myeloid, Acute , Receptors, Chimeric Antigen , Humans , Cell Line, Tumor , Cytokines/metabolism , Immunotherapy, Adoptive , Interleukin-3 Receptor alpha Subunit/genetics , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/metabolism , Neoplasm Recurrence, Local , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , T-LymphocytesABSTRACT
BACKGROUND: To nurture a new online community for health behavior change, a fruitful strategy is to recruit "seed users" to create content and encourage participation. PURPOSE: This study evaluated the impact of support from seed users in an online community for smoking cessation among people living with HIV/AIDS and explored the linguistic characteristics of their interactions. METHODS: These secondary analyses examined data from a randomized trial of a smoking cessation intervention for HIV+ smokers delivered via an online health community (OHC). The analytic sample comprised n = 188 participants randomized to the intervention arm who participated in the community. Independent variables were OHC interactions categorized by participant interlocutor type (study participant, seed user) and interaction type (active, passive). The primary outcome was biochemically verified 7-day abstinence from cigarettes measured 3 months post-randomization; 30-day abstinence was examined for robustness. RESULTS: Logistic regression models showed that participants' interactions with seed users were a positive predictor of abstinence but interactions with other study participants were not. Specifically, the odds of abstinence increased as the number of posts received from seed users increased. Exploratory linguistic analyses revealed that seed users wrote longer comments which included more frequent use of "we" and "you" pronouns and that study participants users used more first-person singular pronouns ("I"). CONCLUSIONS: Seeding a community at its inception and nurturing its growth through seed users may be a scalable way to foster behavior change among OHC members. These findings have implications for the design and management of an OHC capable of promoting smoking cessation.
Online health communities (OHCs) are a popular means for people with similar health concerns to exchange information and support. The success of OHCs depends on members' active participation and on the formation of meaningful relationships. Jumpstarting a new OHC with active members (seed users) can promote engagement and foster its growth. Using data from a multisite randomized controlled trial of a web-based smoking cessation intervention developed specifically for people living with HIV/AIDS (PLWH), we examined whether support provided by seed users in the OHC was a stronger predictor of abstinence from smoking compared with support from other tobacco users who are also trying to quit. These secondary analyses focused on 188 urban, predominantly Black PLWH who smoked that were randomized to the intervention arm and participated in the online community. The primary outcome was biochemically verified 7-day abstinence from cigarettes measured 3 months following study enrollment. Receiving support from seed users was a positive predictor of abstinence among smokers in the trial whereas interactions with other study participants did not relate to abstinence. These findings suggest that for a new OHC, seed users can be critical for generating engagement and promoting health behavior change.
Subject(s)
Acquired Immunodeficiency Syndrome , Smoking Cessation , Humans , Smokers , Behavior TherapyABSTRACT
A novel approach to the dearomative allylboration of ketones with benzo[b]thiophenylmethyl boronic acids has been developed. By leveraging the inherent reactivity of the boronic acid unit, this process occurs under mild reaction conditions without the need for a catalyst, leading to the efficient formation of homoallylic tertiary alcohols accompanied by the construction of three-dimensional sulfur-containing alicyclic scaffolds in high yields with excellent stereoselectivities.
ABSTRACT
Electrocatalytic CO2 reduction reaction (CO2RR) to ethanol has been widely researched for potential commercial application. However, it still faces limited selectivity at a large current density. Herein, Mo4+-doped CuS nanosheet-assembled hollow spheres are constructed to address this issue. Mo4+ ion doping modifies the local electronic environments and diversifies the binding sites of CuS, which increases the coverage of linear *COL and produces bridge *COB for subsequent *COL-*COH coupling toward ethanol production. The optimal Mo9.0%-CuS can electrocatalyze CO2 to ethanol with a faradaic efficiency of 67.5% and a partial current density of 186.5 mA cm-2 at -0.6 V in a flow cell. This work clarifies that doping high valence transition metal ions into Cu-based sulfides can regulate the coverage and configuration of related intermediates for ethanol production during the CO2RR in a flow cell.
ABSTRACT
Enzyme immobilization within metal-organic frameworks (MOFs) is a promising solution to avoid denaturation and thereby utilize the desirable properties of enzymes outside of their native environments. The biomimetic mineralization strategy employs biomacromolecules as nucleation agents to promote the crystallization of MOFs in water at room temperature, thus overcoming pore size limitations presented by traditional postassembly encapsulation. Most biomimetic crystallization studies reported to date have employed zeolitic imidazole frameworks (ZIFs). Herein, we expand the library of MOFs suitable for biomimetic mineralization to include zinc(II) MOFs incorporating functionalized terephthalic acid linkers and study the catalytic performance of the enzyme@MOFs. Amine functionalization of terephthalic acids is shown to accelerate the formation of crystalline MOFs enabling new enzyme@MOFs to be synthesized. The structure and morphology of the enzyme@MOFs were characterized by PXRD, FTIR, and SEM-EDX, and the catalytic potential was evaluated. Increasing the linker length while retaining the amino moiety gave rise to a family of linkers; however, MOFs generated with the 2,2'-aminoterephthalic acid linker displayed the best catalytic performance. Our data also illustrate that the pH of the reaction mixture affects the crystal structure of the MOF and that this structural transformation impacts the catalytic performance of the enzyme@MOF.
Subject(s)
Carboxylic Acids , Crystallization , Metal-Organic Frameworks , Temperature , Water , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/chemical synthesis , Carboxylic Acids/chemistry , Water/chemistry , Phthalic Acids/chemistry , Biomimetic Materials/chemistry , Biomimetic Materials/chemical synthesis , Molecular Structure , Zinc/chemistry , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolism , Amines/chemistry , CatalysisABSTRACT
BACKGROUND AND AIM: The study aims to introduce a novel indicator, effective withdrawal time (WTS), which measures the time spent actively searching for suspicious lesions during colonoscopy and to compare WTS and the conventional withdrawal time (WT). METHODS: Colonoscopy video data from 472 patients across two hospitals were retrospectively analyzed. WTS was computed through a combination of artificial intelligence (AI) and manual verification. The results obtained through WTS were compared with those generated by the AI system. Patients were categorized into four groups based on the presence of polyps and whether resections or biopsies were performed. Bland Altman plots were utilized to compare AI-computed WTS with manually verified WTS. Scatterplots were used to illustrate WTS within the four groups, among different hospitals, and across various physicians. A parallel box plot was employed to depict the proportions of WTS relative to WT within each of the four groups. RESULTS: The study included 472 patients, with a median age of 55 years, and 57.8% were male. A significant correlation with manually verified WTS (r = 0.918) was observed in AI-computed WTS. Significant differences in WTS/WT among the four groups were revealed by the parallel box plot (P < 0.001). The group with no detected polyps had the highest WTS/WT, with a median of 0.69 (interquartile range: 0.40, 0.97). WTS patterns were found to be varied between the two hospitals and among senior and junior physicians. CONCLUSIONS: A promising alternative to traditional WT for quality control and training assessment in colonoscopy is offered by AI-assisted computation of WTS.
Subject(s)
Artificial Intelligence , Colonoscopy , Humans , Colonoscopy/methods , Male , Middle Aged , Female , Retrospective Studies , Time Factors , Colonic Polyps/diagnosis , Colonic Polyps/pathology , Colonic Polyps/diagnostic imaging , Aged , Adult , Video RecordingABSTRACT
OPINION STATEMENT: In addressing Gestational Trophoblastic Neoplasia (GTN), it is imperative to acknowledge the evolving landscape of treatment options, especially in light of the challenges posed by traditional methods. While historically, surgical interventions, radiation therapy, and chemotherapeutic agents have been the mainstays, the emergence of resistance and high-risk scenarios necessitates a reevaluation of our therapeutic approaches. Our review highlights the promising advancements in immunotherapy and molecular targeted therapy as viable alternatives for GTN management. The introduction of immune checkpoint inhibitors and kinase inhibitors offers a paradigm shift, particularly for patients resistant to conventional chemotherapy regimens. These novel therapies not only exhibit efficacy but also demonstrate manageable toxicity profiles, particularly in high-risk cases. However, integrating these innovative treatments into established international guidelines presents a formidable task. As we move forward, it is imperative that future research not only prioritizes fertility preservation but also rigorously evaluates long-term toxicity implications. International collaboration becomes pivotal in addressing the nuances of this rare and complex disease. In conclusion, our review underscores the need for a nuanced approach to GTN treatment, one that prioritizes reduced toxicity and improved quality of life. By embracing the advancements in immunotherapy and molecular targeted therapy, we can pave the way for more effective and patient-centered care in the management of GTN.
Subject(s)
Disease Management , Gestational Trophoblastic Disease , Immunotherapy , Molecular Targeted Therapy , Humans , Female , Gestational Trophoblastic Disease/therapy , Gestational Trophoblastic Disease/drug therapy , Molecular Targeted Therapy/methods , Pregnancy , Immunotherapy/methods , Combined Modality Therapy/methods , Combined Modality Therapy/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment OutcomeABSTRACT
The recombination of photogenerated carrier leads to inefficient Fe2+ regeneration, which limits the extensive application of heterogeneous photo-Fenton. Here, a novel Fe@Fe2O3/BiOBr catalyst with Z-scheme heterojunction structure is designed, and the establishment of the Z-scheme heterojunction facilitates the separation and transfer of photogenerated carrier and maintains the superior redox capability of the system. As-prepared Fe@Fe2O3/BiOBr catalyst exhibits outstanding catalytic performance and stability, especially for the optimum composite FFB-3, its degradation efficiency of tetracycline (TC) achieves 98.22% and the mineralization degree reaches 59.48% within 90 min under natural pH. The preeminent catalytic efficiency benefited from the synergistic of heterogeneous photo-Fenton and Z-scheme carriers transfer mechanism, where Fe2+ regeneration was achieved by photogenerated electrons, and increased hydroxyl radicals were produced with the participation of H2O2 in-situ generated. The results of free-radical scavenging experiment and ESR illustrated that â¢OH, â¢O2-, 1O2 and h+ were active species participating in TC degradation. Furthermore, the TC degradation paths were proposed according to LC-MS, and the toxicity evaluation result showed that the toxicity of TC solutions was markedly decreased after degradation. This study provides an innovative strategy for heterogeneous photo-Fenton degradation of antibiotic contaminations by constructing Z-scheme heterojunctions.