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BACKGROUND: Abdominal perfusion pressure (APP) is a salient feature in the design of a prognostic model for patients with intra-abdominal hypertension (IAH). However, incomplete data significantly limits the size of the beneficiary patient population in clinical practice. Using advanced artificial intelligence methods, we developed a robust mortality prediction model with APP from incomplete data. METHODS: We retrospectively evaluated the patients with IAH from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Incomplete data were filled in using generative adversarial imputation nets (GAIN). Lastly, demographic, clinical, and laboratory findings were combined to build a 7-day mortality prediction model. RESULTS: We included 1354 patients in this study, of which 63 features were extracted. Data imputation with GAIN achieved the best performance. Patients with an APP< 60 mmHg had significantly higher all-cause mortality within 7 to 90 days. The difference remained significant in long-term survival even after propensity score matching (PSM) eliminated other mortality risks between groups. Lastly, the built machine learning model for 7-day modality prediction achieved the best results with an AUC of 0.80 in patients with confirmed IAH outperforming the other four traditional clinical scoring systems. CONCLUSIONS: APP reduction is an important survival predictor affecting the survival prognosis of patients with IAH. We constructed a robust model to predict the 7-day mortality probability of patients with IAH, which is superior to the commonly used clinical scoring systems.
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BACKGROUND: The proposal of Q-markers for traditional Chinese medicine (TCM) represents a novel avenue of research pertaining to the quality control of TCM prescriptions. However, prior exploratory studies on Q-markers with multiple properties consistently neglected the consideration of weights, hampering our ability to accurately gauge the significance of each property and potentially leading to a flawed comprehension of Q-markers. PURPOSE: In this study, a quantitative ternary network strategy was firstly proposed to visually discover the Q-markers from TCM prescriptions, and it has been successfully applied into the quality control study of Bu-Zhong-Yi-Qi-Tang (BZYQT), a classical TCM prescription. METHODS: Firstly, the contents of 34 components in BZYQT, along with the kinetic features of 17 candidate Q-markers in biosamples (plasma and small intestinal contents), were characterized by UPLC-QqQ-MS/MS, and their immunomodulatory activities in macrophages and splenic lymphocytes were also assessed. Next, the obtained data were integrated into three properties: testability, bioavailability, effectiveness, and their weights were calculated using the entropy weight method to further establish a ternary network for quantitatively screening Q-markers. Subsequently, the identified Q-markers of BZYQT were utilized for the holistic quality evaluation of 36 batches of the commercial BZYQT preparation, Bu-Zhong-Yi-Qi-Pill (BZYQP) produced by three manufacturers, through similarity evaluation of the Q-marker-based fingerprint. RESULTS: Nine compounds (hesperidin, astragaloside IV, ononin, 18ß-glycyrrhizic acid, narirutin, calycosin, cimigenoside, astragaloside II, and liquiritin) showing three core properties, including testability, bioavailability, and effectiveness, were screened out as Q-markers of BZYQT based on their rankings in terms of regression area of the ternary network. Employing Q-markers as common peaks, the similarity values of 36 batches BZYQP ranged 0.914-0.998 under HPLC-UVD mode, and 0.631-1.000 under HPLC-ELSD mode, which were less than the similarity values evaluated by the conventional common peaks (HPLC-UVD mode: 0.946-0.990; HPLC-ELSD mode: 0.957-0.997). This observation suggests that the identified Q-markers are more representative as common peaks in chromatographic fingerprints for the holistic quality evaluation of TCM-related products from different manufacturers. CONCLUSION: The quantitative discovery of Q-markers from BZYQT laid an important foundation for holistic quality assessment of its related commercially available products, and our work offering a new strategy for ensuring the consistency and efficacy of TCM prescriptions.
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OBJECTIVES: To investigate the effect of neutral 10-methacryloyloxydecyl dihydrogen phosphate salt (MDP-Na) on the dentin bond strength and remineralization potential of etch-&-rinse adhesive. METHODS: Two experimental etch-&-rinse adhesives were formulated by incorporating 0 wt% (E0) or 20 wt% (E20) neutral MDP-Na into a basic primer. A commercial adhesive, Adper Single Bond 2 (SB, 3 M ESPE), served as the control. Sixty prepared teeth were randomly allocated into three groups (n = 20) and bonded using either one of the experimental adhesives or SB. Following 24 h of water storage, the bonded specimens were sectioned into resin-dentin sticks, with four resin-dentin sticks obtained from each tooth for microtensile bond strength (MTBS) test. Half of the sticks from each group were immediately subjected to tensile loading using a microtensile tester at a crosshead speed of 1 mm/min, while the other half underwent tensile loading after 6-month incubation in artificial saliva (AS). The degree of conversion (DC) of both the control and experimental adhesives (n = 6 in each group) and the adsorption properties of MDP-Na on the dentin organic matrix (n = 5 in each group) were determined using Fourier-transform infrared spectrometry. Furthermore, the effectiveness of neutral MDP-Na in promoting the mineralization of two-dimensional collagen fibrils and the adhesive-dentin interface was explored using transmission electron microscopy and selected-area electron diffraction. Two- and one-way ANOVA was employed to assess the impact of adhesive type and water storage on dentin bond strength and the DC (α = 0.05). RESULTS: The addition of MDP-Na into the primer increased both the short- and long-term MTBS of the experimental adhesives (p = 0.00). No difference was noted in the DC between the control, E0 and E20 groups (p = 0.366). The MDP-Na remained absorbed on the demineralized dentin even after thorough rinsing. The intra- and extra-fibrillar mineralization of the two-dimensional collagen fibril and dentin bond hybrid layer was confirmed by transmission electron microscopy and selected-area electron diffraction when the primer was added with MDP-Na. CONCLUSIONS: The use of neutral MDP-Na results in high-quality hybrid layer that increase the dentin bond strength of etch-&-rinse adhesive and provides the adhesive with remineralizing capability. This approach may represent a suitable bonding strategy for improving the dentin bond strength and durability of etch-&-rinse adhesive.
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Colagem Dentária , Adesivos Dentinários , Dentina , Metacrilatos , Resistência à Tração , Metacrilatos/química , Humanos , Colagem Dentária/métodos , Dentina/ultraestrutura , Dentina/efeitos dos fármacos , Adesivos Dentinários/química , Remineralização Dentária/métodos , Teste de Materiais , Microscopia Eletrônica de Varredura , Condicionamento Ácido do Dente/métodos , Análise do Estresse Dentário , Técnicas In Vitro , Cimentos de Resina/química , Espectroscopia de Infravermelho com Transformada de Fourier , Cimentos Dentários/química , Propriedades de SuperfícieRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored. METHODS: The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery. RESULTS: OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-ß/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-ß/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models. CONCLUSION: Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis.
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Modelos Animais de Doenças , Fibrose Pulmonar Idiopática , Integrina alfaV , Pulmão , Miofibroblastos , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Camundongos , Integrina alfaV/metabolismo , Integrina alfaV/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/genética , Pulmão/metabolismo , Pulmão/patologia , Proteínas Smad/metabolismo , Proteínas Smad/genética , Humanos , Técnicas de Silenciamento de Genes , Masculino , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologiaRESUMO
Background: Persistent cough is one of the most common complications following pulmonary resection, that impairs patients' quality of life and prolongs recovery time. However, a comprehensive review of persistent cough after pulmonary resection (CAP) has not been performed. Methods: A literature search of PubMed/MEDLINE, Web of Science, and Embase database was conducted for persistent-CAP up to June 2023. Subsequent qualitative systematic review focused on definition, risk factors, prevention, and treatment of persistent-CAP. Results: Persistent-CAP stands as a prevalent postoperative complication subsequent to pulmonary resection procedures. with an incidence of 24.4-55.0 %. Although persistent-CAP has a minor impact on survival, this condition is of critical importance because it presents a major hurdle in recovery after surgery. In this review, we proposed a systemic definition for persistent-CAP based on available evidence and our own data. Several assessment tools used to assess severity of persistent-CAP are also introduced. Risk factors associated with persistent-CAP are explored, including surgical approaches, resection extent, surgical site, lymph node dissection, postoperative gastroesophageal acid reflux, tracheal intubation anesthesia, preoperative comorbidity, and sex among others. Surgical and anesthesia preventions targeting risk factors to prevent persistent-CAP are elaborated. A number of studies have shown that a multidisciplinary approach can effectively relieve persistent-CAP. Conclusions: Although the mechanisms underlying persistent-CAP are still unclear, existing studies demonstrated that persistent-CAP is related to surgical and anesthesia factors. Therefore, in the future, prevention and treatment should be developed based on risk factors to overcome the hurdle of persistent-CAP.
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Psychological resilience plays an important role in overcoming emotional distress among people receiving maintenance hemodialysis (MHD). This study aimed to investigate how social support and family resilience interact to influence psychological resilience among Chinese people receiving MHD. This was a prospective longitudinal study with three time points: baseline (T1), 3 months (T2), and 6 months (T3) later. A convenience sample of 252 participants (67.1% male; 57.6 ± 13.8 years of age) from Zhejiang Province, China, who completed baseline measures of social support, family resilience, and psychological resilience, were further assessed for psychological resilience at T2 and T3. Polynomial regression (PR) and response surface analysis (RSA) were used to analyze the data. At all time points, and in the case of agreement between social support and family resilience, the combined effect of both variables manifested as a positive linear association with psychological resilience. Instead, at baseline, and in case of disagreement, the same combined effect manifested as a negative linear relationship related to psychological resilience. The findings highlighted the importance of considering the conjoint influence of social support and family resilience when developing interventions to improve the psychological resilience of people receiving MHD.
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Estrogen and related receptors have been shown to have a significant impact on human development, reproduction, metabolism and immune regulation and to play a critical role in tumor development and treatment. Traditionally, the nuclear estrogen receptors (nERs) ERα and ERß have been thought to be involved in mediating the estrogenic effects. However, our group and others have previously demonstrated that the G protein-coupled estrogen receptor (GPER) is the third independent ER, and estrogen signaling mediated by GPER is known to play an important role in normal physiology and a variety of abnormal diseases. Interestingly, recent studies have progressively revealed GPER involvement in the maintenance of the normal immune system, abnormal immune diseases, and inflammatory lesions, which may be of significant clinical value primarily in the immunotherapy of tumors. In this article, we review current advances in GPER-related immunomodulators and provide a theoretical basis and potential clinical targets to ameliorate immune-related diseases and immunotherapy for tumors.
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Neoplasias , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/imunologia , Receptores de Estrogênio/metabolismo , Animais , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Imunoterapia/métodos , Transdução de Sinais , Estrogênios/metabolismoRESUMO
The fabrication of stimulus-responsive supramolecular hydrogels as smart materials has attracted much attention in recent years. However, the multi-stimuli responsiveness often requires complicated chemical synthesis and rational molecular design. Herein, a quadruple-stimuli responsive supramolecular hydrogel was designed through the host-guest interaction between a ß-CD dimer and a methoxy-azobenzene (mAzo) and ferrocene (Fc) grafted poly(acrylic acid) derivative, as well as through the electrostatic interaction of negatively charged carboxyl side groups. Owing to the dynamic properties of the host-guest and electrostatic interactions, reversible sol-gel transition can be triggered by various stimuli, including temperature, light irradiations, pH changes and chemical redox reagents. As a result, the release of rhodamine B loaded in the hydrogel can be accelerated by green light irradiation, oxidizing agents and low pH, demonstrating potential applications in biomedical materials.
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OBJECTIVE: To explore clinical effect of vancomycin calcium sulfate combined with internal fixation on calcaneal beak-like fracture secondary to calcaneal osteomyelitis caused by diabetic foot. METHODS: From April 2018 to October 2021, a retrospective analysis was performed on 5 patients with calcaneal bone osteomyelitis secondary to diabetic foot, including 2 males and 3 females, aged from 48 to 60 years old;diabetes course ranged from 5 to 13 years;the courses of diabetic foot disease ranged from 18 to 52 days;5 patients were grade â ¢ according to Wagner classification. All patients were treated with debridement, vancomycin bone cement implantation, negative pressure aspiration at stageâ , vancomycin calcium sulfate and internal fixation at stageâ ¡for calcaneal beak-like fracture. Surgical incision and fracture healing time were recorded, and the recurrence of osteomyelitis was observed. American Orthopedic Foot Andankle Society (AOFAS) score and exudation at 12 months after operation were evaluated. RESULTS: Five patients were successfully completed operation without lower extremity vascular occlusion, and were followed up for 16 to 36 months. The wound healing time after internal fixation ranged from 16 to 26 days, and healing time of fractures ranged from 16 to 27 weeks. AOFAS score ranged from 65 to 91 at 12 months after operation, and 2 patients got excellent result, 2 good and 1 fair. Among them, 1 patient with skin ulcer on the back of foot caused by scalding at 5 months after operation (non-complication), was recovered after treatment;the wound leakage complication occurred in 2 patients, and were recovered after dressing change. No osteomyelitis or fracture occurred in all patients. CONCLUSION: Vancomycin calcium sulfate with internal fixation in treating calcaneal osteomyelitis secondary to calcaneal osteomyelitis caused by diabetic foot could not only control infection, but also promote fracture healing, and obtain good clinical results.
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Calcâneo , Pé Diabético , Fixação Interna de Fraturas , Osteomielite , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Osteomielite/cirurgia , Osteomielite/tratamento farmacológico , Osteomielite/etiologia , Pé Diabético/cirurgia , Calcâneo/lesões , Calcâneo/cirurgia , Estudos Retrospectivos , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/complicações , Fraturas Ósseas/cirurgiaRESUMO
BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.
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Cisteína , Eletroforese em Gel de Poliacrilamida , Corantes Fluorescentes , Glutationa , Homocisteína , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Cisteína/análise , Cisteína/química , Glutationa/análise , Glutationa/química , Homocisteína/análise , Homocisteína/química , Animais , Fótons , Imagem Óptica , Arabidopsis/química , Humanos , Ciclização , Peixe-ZebraRESUMO
Traumatic brain injury (TBI) is a global public-health problem. Astrocytes, and their mitochondria, are important factors in the pathogenesis of TBI-induced secondary injury. Mitochondria extracted from healthy tissues and then transplanted have shown promise in models of a variety of diseases. However, the effect on recipient astrocytes is unclear. Here, we isolated primary astrocytes from newborn C57BL/6 mice, one portion of which was used to isolate mitochondria, and another was subjected to stretch injury (SI) followed by transplantation of the isolated mitochondria. After incubation for 12 h, cell viability, mitochondrial dysfunction, calcium overload, redox stress, inflammatory response, and apoptosis were improved. Live-cell imaging showed that the transplanted mitochondria were incorporated into injured astrocytes and fused with their mitochondrial networks, which was in accordance with the changes in the expression levels of markers of mitochondrial dynamics. The astrocytic IKK/NF-κB pathway was decelerated whereas the AMPK/PGC-1α pathway was accelerated by transplantation. Together, these results indicate that exogenous mitochondria from untreated astrocytes can be incorporated into injured astrocytes and fuse with their mitochondrial networks, improving cell viability by ameliorating mitochondrial dysfunction, redox stress, calcium overload, and inflammation.
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Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon's optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3-5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders' cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/genética , Antígeno CTLA-4/uso terapêutico , Linfócitos T CD8-Positivos , Fator de Crescimento Epidérmico , Tomografia Computadorizada por Raios X , Pulmão/patologia , Receptores de Antígenos de Linfócitos T , CitocinasRESUMO
Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta-hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood-brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO-1 by enhancing local ß-hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO-ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.
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Ácido 3-Hidroxibutírico , Barreira Hematoencefálica , Modelos Animais de Doenças , AVC Isquêmico , Proteína da Zônula de Oclusão-1 , Animais , Barreira Hematoencefálica/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Camundongos , AVC Isquêmico/metabolismo , AVC Isquêmico/genética , Proteína da Zônula de Oclusão-1/metabolismo , Proteína da Zônula de Oclusão-1/genética , Epigênese Genética/genética , Masculino , Camundongos Endogâmicos C57BL , Hidroximetilglutaril-CoA Sintase , Transportadores de Ácidos Monocarboxílicos , SimportadoresRESUMO
The phosphorylated noncollagenous proteins (NCPs) play a vital role in manipulating biomineralization, while the mechanism of phosphorylation of NCPs in intrafibrillar mineralization of collagen fibril has not been completely deciphered. Poly(vinylphosphonic acid) (PVPA) and sodium trimetaphosphate (STMP) as templating analogs of NCPs induce hierarchical mineralization in cooperation with indispensable sequestration analogs such as polyacrylic acid (PAA) via polymer-induced liquid-like precursor (PILP) process. Herein, STMP-Ca and PVPA-Ca complexes are proposed to achieve rapid intrafibrillar mineralization through polyelectrolyte-Ca complexes pre-precursor (PCCP) process. This strategy is further verified effectively for remineralization of demineralized dentin matrix both in vitro and in vivo. Although STMP micromolecule fails to stabilize amorphous calcium phosphate (ACP) precursor, STMP-Ca complexes facilely permeate into intrafibrillar interstices and trigger phase transition of ACP to hydroxyapatite within collagen. In contrast, PVPA-stabilized ACP precursors lack liquid-like characteristic and crystallize outside collagen due to rigid conformation of PVPA macromolecule, while PVPA-Ca complexes infiltrate into partial intrafibrillar intervals under electrostatic attraction and osmotic pressure as evidenced by intuitionistic 3D stochastic optical reconstruction microscopy (3D-STORM). The study not only extends the variety and size range of polyelectrolyte for PCCP process but also sheds light on the role of phosphorylation for NCPs in biomineralization.
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Fosfatos de Cálcio , Colágeno Tipo I , Polivinil , Fosfatos de Cálcio/química , Polivinil/química , Colágeno Tipo I/química , Colágeno Tipo I/metabolismo , Polifosfatos/química , Animais , Resinas Acrílicas/química , Dentina/química , Dentina/metabolismo , Fosforilação , Humanos , Compostos de Vinila , OrganofosfonatosRESUMO
Luminescent metal-organic gels (LMOGs) have gained much attention due to their crucial role in visual recognition and information encryption. However, it is still a challenge to simplify the design of ligands and enrich the stimuli responses in LMOGs simultaneously. Herein, although a single pyridine ligand cannot form gel alone, after coordination with metal ions, two kinds of LMOGs have been obtained with pyridine-metal complexes, where metal ions can act as cogelators and regulate luminescence of the pyridine-functionalized cyanostilbene ligand at the same time. The effects of metal types on the fluorescence emission color, the fluorescence quantum yield, the fibril network, and the assembly mode of the gel have been investigated systematically. In addition, two competitive ligands were used to regulate the fluorescence and phase transition of the gel. Finally, the logic gates and the information encryption and decryption have been successfully constructed. This kind of material is expected to be applied to fluorescence display, advanced information encryption, high-tech anticounterfeit, and so forth.
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Objectives: CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown. Methods: A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity. Results: In comparison with CD4+ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4+ T cells expressed CD39. Most GC-infiltrating CD39+CD4+ T cells exhibited CD45RA-CCR7- effector-memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39-CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival. Conclusion: Our study demonstrates that CD39 expression defines GC-infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.
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Continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants urges the development of new vaccines. We assessed the safety and immunogenicity of SYS6006.32, a bivalent vaccine (XBB.1.5/BQ.1), in healthy adults who had received SARS-CoV-2 primary vaccination. In a randomised, double-blinded, active-controlled trial, 200 participants were randomised to receive one dose of SYS6006.32 (N = 100) or a prototype-based, monovalent control vaccine SYS6006 (N = 100). Adverse events (AEs) were collected through the study. Immunogenicity was assessed by live-virus neutralising antibody (Nab) and pseudovirus Nab. 61 (61.0 %) and 60 (60.0 %) participants reported AE in the SYS6006.32 and SYS6006 groups, respectively. Most AEs were grade 1 or 2. Pain and fever were the most common injection-site and systemic AEs, respectively. No serious AEs were observed. SYS6006.32 heterologous boosting induced robust Nab responses against BA.5, XBB.1.5 and EG.5 with live-virus Nab geometric mean titres (GMTs) increased by 17.1-, 34.0-, and 48.0-fold, and pseudovirus Nab GMTs increased by 12.2-, 32.0-, and 35.1-fold, respectively, 14 days after vaccination. SYS6006.32 demonstrated a superior immunogenicity to SYS6006. SYS6006.32 also induced robust pseudovirus Nab responses against XBB.1.16, XBB.2.3, and BA.2.86, with GMTs 3- to 6-fold higher than those induced by SYS6006. In conclusion, SYS6006.32 showed good safety profile and superior immunogenicity to the monovalent vaccine SYS6006.
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Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , Vacinas de mRNA , COVID-19/prevenção & controle , Anticorpos Bloqueadores , China , Imunogenicidade da Vacina , Anticorpos Antivirais , Anticorpos Neutralizantes , Método Duplo-CegoRESUMO
The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.