YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells.

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

Safety and efficacy of an anti-human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

Targeted proteomics profiling reveals valuable biomarkers in the diagnosis of primary immune thrombocytopaenia.

The lack of biomarkers for accurate diagnosis and prognosis is a major clinical challenge of primary immune thrombocytopaenia (ITP). Using an Olink proteomics platform with a 92 immune response-related human protein panel, we analysed plasma samples from ITP patients (ITP, n = 40), patients with thrombocytopaenia secondary to other causes (Non-ITP, n = 19) and healthy controls (NC, n = 18), of a discovery cohort as well as a validation cohort (ITP, n = 36; NC, n = 20). A total of 10 differentially expressed proteins (DEPs) were identified in the ITP group compared with the non-ITP and NC groups of the discovery cohort. These include CXCL11, GZMH, ARG1, TGF-ß1, ANGPT1, CXCL12, CD40-L, PDGF subunit B, IL4 and TNFSF14. Furthermore, least absolute shrinkage and selection operator regression analysis showed some of these DEPs, such as CXCL11, TGF-ß1, ARG1 and GZMH to be significant in differentiating between patients with ITP and healthy controls (validation area under the curve = 0.87). The analysis demonstrated that the ITP group has a specific proteomic profile relative to non-ITP and NC groups. In summary, we report for the first time that Olink precision proteomics can specifically detect up-regulated inflammatory proteins as potential diagnostic biomarkers for ITP.

Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach.

Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.

The modulation of lung cancer cell motility by Calponin 3 is achieved through its ability to sense and respond to changes in substrate stiffness.

The influence of extracellular matrix (ECM) stiffness on cell behavior is a well-established phenomenon. Tumor development is associated with the stiffening of the ECM. However, the understanding of the role of biomechanical behavior and mechanotransduction pathways in the oncogenesis of tumor cells remains limited. In this study, we constructed in vitro models using Polydimethylsiloxane substrates to create soft and stiff substrates. We then evaluated the migration of lung cancer cells A549 using video-microscopy and transwell assays. The mechanical properties were assessed through the utilization of atomic force microscopy, Optical Magnetic Twisting Cytometry, and traction force analysis. Additionally, the expression of Calponin 3 (CNN3) was evaluated using reverse transcription­quantitative PCR and immunofluorescence techniques. Our observations indicate that the presence of a stiff substrate enhances A549 motility, as evidenced by increased stiffness and traction force in A549 cells on the stiff substrate. Furthermore, we observed a decrease in CNN3 expression in A549 cells on the stiff substrate. Notably, when CNN3 was overexpressed, it effectively inhibited the migration and invasion of A549 cells on the stiff substrate. The results of our study provide novel perspectives on the mechanisms underlying cancer cell migration in response to substrate mechanical properties.

Cloning and expression of Neurospora crassa cellobiohydrolase II in Pichia pastoris.

A major cellobiohydrolase of Neurospora crassa CBH2 was successfully expressed in Pichia pastoris. The maximum Avicelase activity in shake flask among seven transformants which selected on 4.0 g/L G418 plates was 0.61 U/mL. The optimal pH and temperature for Avicelase activity of the recombinant CBH2 were determined to be 4.8 and 60 °C, respectively. The new CBH2 maintained 63.5 % Avicelase activity in the range of pH 4.0-10.4, and 60.2 % Avicelase activity in the range of 30-90 °C. After incubation at 70-90 °C for 1 h, the Avicelase activity retained 60.5 % of its initial activity. The presence of Zn2+, Ca2+ or Cd2+ enhanced the Avicelase activity of the CBH2, of which Cd2+ at 10 mM causing the highest increase. The recombinant CBH2 was used to enhance the Avicel hydrolysis by improving the exo-exo-synergism between CBH2 and CBH1 in N.crassa cellulase. The enzymatic hydrolysis yield was increased by 38.1 % by adding recombinant CBH2 and CBH1, and the yield was increased by 215.4 % when the temperature is raised to 70 °C. This work provided a CBH2 with broader pH range and better heat resistance, which is a potential enzyme candidate in food, textile, pulp and paper industries, and other industrial fields.

Sacculatane Diterpenoids from the Liverwort Plagiochila nitens Collected in China.

Seven new terpenoids, including six sacculatane diterpenoids plagiochilarins A-F (1-6), and one ent-2,3-seco-aromandrane sesquiterpenoid plagiochilarin H (8) with a 6/7/3/5 tetracyclic scaffold, alongside three known compounds, were obtained from the Chinese liverwort Plagiochila nitens Inoue. Plagiochilarin B (2) was unpredictably converted to the more stable artifact 7 under acid catalysis through cyclic ether formation. The reaction mechanism was reasonably deduced and experimentally verified. The structures of these terpenoids were determined by analysis of MS and NMR spectroscopic data and single-crystal X-ray diffraction. The inhibitory effect of all of the isolates was evaluated on the growth of two C. albicans strains, wild strain SC5314 and efflux pump-deficient strain DSY654. However, only plagiochilarin H (8) showed a MIC value of 16 µg/mL against C. albicans DSY654.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

RNAi targeting LMAN1-MCFD2 complex promotes anticoagulation in mice.

Combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) is a rare bleeding disease caused by variants in either lectin mannose binding 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2) gene. Reducing the level of FVIII by inhibiting the LMAN1-MCFD2 complex may become a new anticoagulant approach. We aimed to find a new therapeutic option for anticoagulation by RNA interference (RNAi) targeting LMAN1 and MCFD2. siRNA sequences with cross-homology between mice and humans were designed based on LMAN1 or MCFD2 transcripts in NCBI and were screened with the Dual-Luciferase reporter assay. The optimal siRNAs were chemically modified and conjugated with three N-acetylgalactosamine molecules (GalNAc-siRNA), promoting their targeted delivery to the liver. The expression of LMAN1 and MCFD2 in cell lines or mice was examined by RT-qPCR and western blotting. For the mice administered with siRNA, we assessed their coagulation function by measuring APTT and the activity of FVIII factor. After administration, siRNAs GalNAc-LMAN1 and GalNAc-MCFD2 demonstrated effective and persistent LMAN1 and MCFD2 inhibition. 7 days after injection of 3mg/kg GalNAc-LMAN1, the LMAN1 mRNA levels reduced to 19.97% ± 3.78%. MCFD2 mRNA levels reduced to 32.22% ± 13.14% with injection of 3mg/kg GalNAc-MCFD2. After repeated administration, APTT was prolonged and the FVIII activity was remarkably decreased. The tail bleeding test of mice showed that the amount of bleeding in the treated group did not significantly increase compared with the control group. Our study confirms that therapy with RNAi targeting LMAN1-MCFD2 complex is effective and can be considered a viable option for anticoagulation drugs. However, the benefits and potential risk of bleeding in thrombophilic mice model needs to be evaluated.

Attention network training promotes selective attention of children with low socioeconomic status.

The objectives of this study were to evaluate the difference of selective attention efficiency between children with low and high socioeconomic status (SES) and the promotional effect of attention network training (an attention network test was used as the training task) on selective attention in children with the low SES. A total of 139 10- to 12-year-old children participated in two experiments (71 in Experiment 1 and 68 in Experiment 2). The results suggest that selective attention and switch ability of children with high SES are better than those of children with low SES. After attention network training, selective attention, switch ability, and working memory of low-SES children improved significantly. The findings provide evidence that attention network training could enhance selective attention in low-SES children and that the beneficial training effect could also transfer to switch ability and working memory. The research may provide a promising method to compensate cognitive delay of low-SES children.

Machine-Learning Models Reliably Predict Clinical Outcomes in Medial Patellofemoral Ligament Reconstruction.

PURPOSE: To develop a machine-learning model to predict clinical outcomes after medial patellofemoral ligament reconstruction (MPFLR) and identify the important predictive indicators. METHODS: This study included patients who underwent MPFLR from January 2018 to December 2022. The exclusion criteria were as follows: (1) concurrent bony procedures, (2) history of other knee surgeries, and (3) follow-up period of less than 12 months. Forty-two predictive models were constructed for 7 clinical outcomes (failure to achieve minimum clinically important difference of clinical scores, return to preinjury sports, pivoting sports, and recurrent instability) using 6 machine-learning algorithms (random forest, logistic regression, support vector machine, decision tree, implemented multilayer perceptron, and K-nearest neighbor). The performance of the model was evaluated using metrics such as the area under the receiver operating characteristic curve, accuracy, specificity, and sensitivity. In addition, SHapley Additive exPlanation summary plot was employed to identify the important predictive factors of the best-performing model. RESULTS: A total of 218 patients met criteria. For the best-performing models in predicting failure to achieve the minimum clinically important difference for Lysholm, International Knee Documentation Committee, Kujala, and Tegner scores, the area under the receiver operating characteristic curves and accuracies were 0.884 (good) and 87.3%, 0.859 (good) and 86.2%, 0.969 (excellent) and 97.0%, and 0.760 (fair) and 76.8%, respectively; 0.952 (excellent) and 95.2% for return to preinjury sports; 0.756 (fair) and 75.4% for return to pivoting sports; and 0.943 (excellent) and 94.9% for recurrent instability. Low preoperative Tegner score, shorter time to surgery, and absence of severe trochlear dysplasia were significant predictors for return to preinjury sports, whereas the absence of severe trochlear dysplasia and patellar alta were significant predictors for return to pivoting sports. Older age, female sex, and low preoperative Lysholm score were highly predictive of recurrent instability. CONCLUSIONS: The predictive models developed using machine-learning algorithms can reliably forecast the clinical outcomes of MPFLR, particularly demonstrating excellent performance in predicting recurrent instability. LEVEL OF EVIDENCE: Level III, case-control study.

The correlation of inflammation, tryptophan-kynurenine pathway, and suicide risk in adolescent depression.

Accumulating evidence suggests a role for the tryptophan-kynurenine pathway (TKP) in the psychopathology of major depressive disorder (MDD). Abnormal inflammatory profile and production of TKP neurotoxic metabolites appear more pronounced in MDD with suicidality. Progress in understanding the neurobiology of MDD in adolescents lags significantly behind that in adults due to limited empirical evidence. Aims of this study was to investigate the association between inflammation, TKP, and suicidality in adolescent depression. Seventy-three adolescents with MDD were assessed for serum levels of interleukin (IL)-1ß, IL-6, IL-18, IL-10, tumor necrosis factor-α (TNF-α), tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), and kynurenine acid (KA). Correlations between cytokines and TKP measures were examined. Patients were divided into high- (n = 42) and non-high-suicide-risk groups (n = 31), and serum levels of cytokines and TKP metabolites were compared. Significant negative correlations were found between TRP and IL-8 (r = - 0.27, P < 0.05) and IL-10 (r = - 0.23, P < 0.05), while a significant positive correlation was observed between 3-HK and IL-8 (r = 0.39, P < 0.01) in depressed adolescents. The KYN/TPR (index of indoleamine 2,3-dioxygenase, IDO) was positively correlated with IL-1ß (r = 0.34), IL-6 (r = 0.32), IL-10 (r = 0.38) and TNF-α (r = 0.35) levels (P < 0.01); and 3-HK/KYN (index of kynurenine3-monooxidase, KMO) was positively correlated with IL-8 level (r = 0.31, P < 0.01). Depressed adolescents at high suicide risk exhibited significantly higher levels of IL-1ß (Z = 2.726, P < 0.05), IL-10 (Z = 2.444, P < 0.05), and TNF-α (Z = 2.167, P < 0.05) and lower levels of 3-HK (Z = 2.126, P < 0.05) compared to their non-high suicide risk counterparts. Our findings indicated that serum inflammatory cytokines were robustly associated with IDO and KMO activity, along with significantly decreased serum level of TRP, increased level of 3-HK, and higher suicide risk in adolescent depression.

Simultaneous detection of SO2 and viscosity in drug-induced inflammation in live cells and zebrafish.

The viscosity within cells is a crucial microenvironmental factor, and sulfur dioxide (SO2 ) has essential functions in regulating cellular apoptosis and inflammation. Some evidence has been confirmed that changes in viscosity and overexposure of SO2 within the cell may cause detrimental effects including, but not limited to, respiratory and cardiovascular illnesses, inflammation, fatty liver, and various types of cancer. Therefore, precise monitoring of SO2 and viscosity in biological entities holds immense practical importance. Therefore, in this research, we developed a versatile fluorescent TCF-Cou that enables the dual detection of SO2 and viscosity in the living system. Probe TCF-Cou possessed a response to viscosity and SO2 through red and green emissions. The alteration of SO2 and viscosity levels in live cells and zebrafish were also monitored using probe TCF-Cou. We hope that this fluorescent probe could be a potential tool for revealing the related pathological and physiological processes through monitoring the changes in SO2 and viscosity.

Solid-State Luminescence Turn-On Sensing Using MOF-Confined Reporter-Spacer-Receptor Architectures Facilitated by Quencher Displacement.

The reporter-spacer-receptor (RSR) approach is prevalent to develop molecular turn-on sensors. However, the fluorescent RSR sensors barely operate in solid state, which hinders their fabrication into devices for practical applications. Herein, we present a novel strategy to achieve solid-state luminescence turn-on sensing by assembling RSR architectures within MOF frameworks. Unlike the regular RSR systems, the framework-confined fluorophore and receptor are well arranged and separated even in the solid state. This concept is illustrated by a multicomponent MOF (Fc@NU-1000), which contains organic linkers with a highly luminescent pyrene core as the reporter, Zr6 nodes with unsaturated sites as the receptor, and the incorporated Fc molecules as the quencher. The separate incorporation of pyrene core and Fc in the multicomponent MOF favors an efficient pseudointramolecular photoinduced electron transfer (PET) process, resulting in significant luminescence quenching. Interestingly, such PET process can be blocked via the quencher displacement initiated by the phosphate analyte, therefore recovering the solid-state luminescence of MOF microcrystals. We found that Fc@NU-1000 is shown as a sensitive solid-state luminescence turn-on probe for phosphate with the naked-eye response at a low content. What's more, this study is the first example of confining a quencher displacement-based RSR system in the MOF framework for solid-state luminescence turn-on sensing, thus also providing new opportunities for MOF materials to develop luminescence turn-on sensors.

Effect of itaconic acid production on Neurospora crassa in consolidated bioprocessing of cellulose.

A system for itaconic acid synthesis from cellulose by Neurospora crassa was established, resulting in the highest yield of itaconic acid was 354.08 + 35.99 mg/L. Meanwhile, cellulase activity increased significantly, without any strain modifications for improved cellulase production. Multi-omics analyses showed that itaconic acid synthesis reduced energy production, leading to decreases in trehalose, cell wall, fatty acids synthesis and downregulations in MAPK signaling pathway, cell cycle and meiosis. More importantly, the low-energy environment enhanced the energy-efficient cellobionic acid/gluconic acid pathway, and the cellulase composition also changed significantly, manifested as the up-regulation of LPMOs and the down-regulation of ß-glucosidases. Enhancing LPMOs-cellobionic acid/gluconic acid system has the potential to reduce energy consumption of the consolidated bioprocessing. These findings offer an overview of resource allocations by N. crassa in response to itaconic acid synthesis and highlight a series of intriguing connections between itaconic acid synthesis and cellulase synthesis in consolidated bioprocessing.

Association between air temperature and emergency admission for esophagogastric variceal bleeding: a case-crossover study in Beijing, China.

BACKGROUND AND AIMS: Studies concerning the impact of air temperature on esophagogastric variceal bleeding (EGVB) have yielded conflicting results. Our study aimed to evaluate the correlation between air temperature and EGVB. METHODS: A time-stratified case-crossover study design was performed. Patients received emergency gastroscopic hemostasis for upper gastrointestinal bleeding between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital were enrolled. Conditional logistic regression analysis was applied to determine the association between air temperature and EGVB for different lag structures. RESULTS: A total of 4204 cirrhotic patients diagnosed with EGVB and received emergency gastroscopic hemostasis were enrolled. The mean number of daily EGVB cases peaked in October (2.65 ± 1.69) and fell to the lowest level in July (1.86 ± 1.38), and was 2.38 ± 1.58 in spring, 2.00 ± 1.46 in summer, 2.37 ± 1.58 in autumn, and 2.45 ± 1.58 in winter, respectively (P < 0.0001). In conditional logistic regression analysis, no significant correlations between air temperature and EGVB were observed and no significant difference were found when stratified by age, sex, etiology, liver cancer status, and grade of varices. CONCLUSION: Emergency admission for EGVB showed significant monthly and seasonal fluctuations, while in conditional logistic regression analysis, no association between minimum temperature and emergency admission for EGVB were observed.

Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics.

Nitric oxide (NO) may be beneficial to overcoming drug resistance resulting from mutation of mTOR kinases and bypass mechanisms. In this study, a novel structural series of hybrids of mTOR inhibitor and NO donor were designed and synthesized via structure-based drug design (SBDD). Throughout the 20 target compounds, half of the compounds (13a, 13b, 19a-19d, 19f-19j) demonstrated attractive mTOR inhibitory activity with IC50 at single-digit nanomolar level. In particular, 19f exerted superior anti-proliferative activity against HepG2, MCF-7, HL-60 cells (HepG2, IC50 = 0.24 µM; MCF-7, IC50 = 0.88 µM; HL-60, IC50 = 0.02 µM) to that of the clinical investigated mTOR inhibitor MLN0128, and show mild cytotoxicity against normal cells with IC50 over 10 µM. 19a, with the most potent mTOR inhibitory activity in this series (IC50 = 3.31 nM), also displayed attractive cellular potency. In addition, 19f treatment in HL-60 reduces the levels of Phos-Akt and Phos-S6 in a dose-dependent manner, and releases NO in cells. In summary, 19f deserves further development as a novel mTOR-based multi-target anti-cancer agent.

A Ratiometric Fluorescence Biosensor for Detection of Alkaline Phosphatase Via an Advanced Chemometric Model.

In this paper, a ratiometric fluorescence biosensor was introduced for alkaline phosphatase (ALP) detection based on 2-aminopurine (2-Amp) and thioflavin T (ThT)-G-quadruplex system. We designed a special DNA (5'-AGGGTTAGGGTTAGGGTTAGGGAAA/i2-Amp/AAAA-PO4-3', AP) modified with a phosphate moiety at the 3'-end, G-quadruplex at the 5'-end, and a fluorophore (2-Amp) in the middle. In the absence of ALP, the G-rich AP strand could be prone to fold into G-quadruplex structures in the presence of K+. Then, ThT combined with G-quandruplex, resulting in the enhancement of fluorescence emission peak at 485 nm. However, ALP-mediated hydrolysis of the 3'-phosphoryl end promoted the cleavage of AP by the exonuclease I (Exo I), releasing 2-Amp which displayed a strong fluorescence emission peak at 365 nm. Moreover, the quantitative fluorescence model (QFM) was derived for the analysis of the fluorescence measurements obtained by the proposed ratiometric fluorescent biosensor. With the aid of the advanced model, the proposed ratiometric fluorescent biosensor possessed satisfactory results for the detection of ALP in the human serum samples, with accuracy comparable to that of the reference method-the commercial ALP assay kit. Under the optimized experimental conditions, this method exhibited good selectivity and higher sensitivity, and the detection limit was found to be as low as 0.017 U/L. Therefore, it is reasonable to expect that the method had a great potential to detect ALP quantitatively in clinical diagnosis.

Preoperative frailty assessment could be a predictive factor for the prognosis of elderly patients undergoing coronary artery bypass grafting: a retrospective case-control study.

BACKGROUND: Frailty has been considered to be associated with major mortality and increased length of stay after cardiac surgery. This study aimed to explore the predictive potential of frailty assessment in the prognosis of elderly patients undergoing bypass surgery. METHODS: This study assessed the preoperative frailty according to the Fried's frailty phenotype, and included 150 frail and 150 non-frail elderly patients (≥ 65 y) who underwent bypass surgery. The present study evaluated the prognosis of elderly patients based on sequential organ failure assessment (SOFA) score, and collected clinical indicators to construct logistic regression models with the prognosis as the dependent variable, to explore the potential predictive ability of preoperative frailty. Moreover, this study focused on the complications and analyzed the relationship between preoperative frailty and postoperative complications. RESULTS: In the present study, 244 patients were divided into the favorable prognosis group and 56 patients were divided into the unfavorable prognosis group. Logistic regression analysis showed that increased myoglobin and high cardiac function classification were independent risk factors for unfavorable prognosis in elderly patients undergoing bypass surgery. The discrimination of the clinical prediction model was determined by the receiver operating characteristic (ROC) curve, and the area under curve (AUC) was 0.928. After adding preoperative frailty assessment, the AUC was improved to 0.939. This study found a significant correlation between preoperative frailty and postoperative complications, mainly in the circulatory system. CONCLUSION: Preoperative frailty assessment could be a predictive factor for the prognosis of elderly patients undergoing coronary artery bypass grafting. According to our study, frailty assessment and appropriate intervention before bypass surgery may be beneficial to the enhanced recovery after cardiac surgery. TRIAL REGISTRATION: The clinical study was approved by the Medical Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (2021-SR-393). All patients signed an informed consent form.

Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook.

The discovery of a near-infrared (NIR, 650-900 nm) fluorescent chromophore hemicyanine dye with high structural tailorability is of great significance in the field of detection, bioimaging, and medical therapeutic applications. It exhibits many outstanding advantages including absorption and emission in the NIR region, tunable spectral properties, high photostability as well as a large Stokes shift. These properties are superior to those of conventional fluorogens, such as coumarin, fluorescein, naphthalimides, rhodamine, and cyanine. Researchers have made remarkable progress in developing activity-based multifunctional fluorescent probes based on hemicyanine skeletons for monitoring vital biomolecules in living systems through the output of fluorescence/photoacoustic signals, and integration of diagnosis and treatment of diseases using chemotherapy or photothermal/photodynamic therapy or combination therapy. These achievements prompted researchers to develop more smart fluorescent probes using a hemicyanine fluorogen as a template. In this review, we begin by describing the brief history of the discovery of hemicyanine dyes, synthetic approaches, and design strategies for activity-based functional fluorescent probes. Then, many selected hemicyanine-based probes that can detect ions, small biomolecules, overexpressed enzymes and diagnostic reagents for diseases are systematically highlighted. Finally, potential drawbacks and the outlook for future investigation and clinical medicine transformation of hemicyanine-based activatable functional probes are also discussed.