Hypoxia-related signature to risk stratify patients for the benefit of immune checkpoint inhibitors therapy in head and neck squamous cell carcinoma: An experimental study.

BACKGROUND: Increasing evidence has shown that hypoxia is a biomarker of tumor proliferation and metastasis. This research aimed to identify a hypoxia-associated gene prognostic index (HAGPI) in head and neck squamous cell carcinoma (HNSCC) and based on HAGPI-defined subgroups to predict prognosis and response to immune checkpoint inhibitors therapy. METHODS: RNA-sequencing transcriptomic data for patients with HNSCC were downloaded from The Cancer Genome Atlas (TCGA). Protein-protein interaction network analysis was performed to select hypoxia-related hub genes. Univariate and multivariate cox regression analyses were used to identify hub genes to develop the HAGPI. Afterward expression data were imported into CIBERSORT to evaluate the relative proportion of 22 immune cells and compared the relative proportions of immune cells between the 2 HAGPI subgroups. The relationship between immunopheno score (IPS) and HAGPI was validated for immune checkpoint inhibitors (ICIs) response in TCGA cohorts. RESULTS: The HAGPI was constructed based on HS3ST1, HK1, PGK1, STC2, SERPINE1, PKLR genes. In high-HAGPI patients, the primary and secondary endpoint events in TCGA and GEO cohorts were significantly lower than low-HAGPI groups (P < .05). HAGPI-high patients exhibited a poorer prognosis than HAGPI-low patients did. The abundance of M2 macrophages and NK cell were significantly enhanced in the high-HAGPI while T cells regulatory and T cells CD8, were markedly elevated in the low-HAGPI. Meanwhile, patients in the low-HAGPI patients had higher levels of immunosuppressant expression and less aggressive phenotypes. Furthermore, IPS analysis showed that the low-HAGPI group with higher IPS represented a more immunogenic phenotype. CONCLUSION: The current study developed and verified a HAPGI model that can be considered as an independent prognostic biomarker and elucidated the tumor immune microenvironment of HNSCC.

Differential changes in mast cells with food reintroduction in children with Eosinophilic Esophagitis.

BACKGROUND: Intraepithelial mast cells (MC) are increased in Eosinophilic Esophagitis (EoE) and reduced with elimination of dietary antigens. Single food reintroduction can identify triggers of eosinophilia however it remains unknown the extent to which specific foods trigger intraepithelial mastocytosis. We hypothesized that specific foods drive different degrees of MC inflammation. METHODS: We previously reported a prospective pediatric EoE cohort treated with a 4-food elimination diet (4FED) with removal of soy, egg, wheat, milk. We retrieved unstained slides in which baseline, 4FED, and post-4FED diet reintroduction time points were available. Slides were stained with tryptase, and intraepithelial MCs were counted. Comparisons were made by stratifying patients by eosinophilia, basal cell hyperplasia (BCH), endoscopic abnormalities, and symptoms. Pearson correlation was assessed for MCs with eosinophilic, endoscopic and BCH severity, symptoms, and a novel mucosal activity score (MAS) combining endoscopic and histologic structural severity. RESULTS: Slides were available from 37 patients with at least 1 food reintroduced. MCs were significantly reduced with 4FED. Wheat led to increased intraepithelial MCs in the upper esophagus and with food-induced eosinophilia, while milk led to significantly increased MCs in the upper and lower esophagus and was significantly associated with patients with food-triggered eosinophilia, endoscopic abnormalities, BCH, and symptoms. MCs best correlated with the MAS during milk reintroduction. CONCLUSION: In children with EoE, MCs are reduced with 4FED. During milk reintroduction, significant increases in MCs were observed with all metrics of inflammation along with moderate correlation with structural mucosal activity that was not seen with other foods. This suggests milk exerts unique effects either directly or indirectly on MCs in the esophagus in EoE patients.

An interpretable two-branch bi-coordinate network based on multi-grained domain knowledge for classification of thyroid nodules in ultrasound images.

Computer-aided diagnosis (CAD) for thyroid nodules has been studied for years, yet there are still reliability and interpretability challenges due to the lack of clinically-relevant evidence. To address this issue, inspired by Thyroid Imaging Reporting and Data System (TI-RADS), we propose a novel interpretable two-branch bi-coordinate network based on multi-grained domain knowledge. First, we transform the two types of domain knowledge provided by TI-RADS, namely region-based and boundary-based knowledge, into labels at multi-grained levels: coarse-grained classification labels, and fine-grained region segmentation masks and boundary localization vectors. We combine these two labels to form the Multi-grained Domain Knowledge Representation (MG-DKR) of TI-RADS. Then we design a Two-branch Bi-coordinate network (TB2C-net) which utilizes two branches to predict MG-DKR from both Cartesian and polar images, and uses an attention-based integration module to integrate the features of the two branches for benign-malignant classification. We validated our method on a large cohort containing 3245 patients (with 3558 nodules and 6466 ultrasound images). Results show that our method achieves competitive performance with AUC of 0.93 and ACC of 0.87 compared with other state-of-the-art methods. Ablation experiment results demonstrate the effectiveness of the TB2C-net and MG-DKR, and the knowledge attention map from the integration module provides the interpretability for benign-malignant classification.

Safety of one 8.5-Fr pigtail catheter for postoperative continuous open gravity drainage after uniportal video-assisted thoracoscopic surgery pneumonectomy.

OBJECTIVES: Uniportal video-assisted thoracoscopic surgery pneumonectomy (U-VATS-P) is feasible and safe from a perioperative standpoint. How to choose the proper chest tube and drainage method is important in enhanced recovery after surgery (ERAS) protocols. In this study, we aimed to assess the safety of one 8.5-Fr (1Fr = 0.333 mm) pigtail catheter for postoperative continuous open gravity drainage after U-VATS-P. METHODS: We retrospectively reviewed a single surgeon's experience with U-VATS-P for lung cancer from May 2016 to September 2022. Patients were managed with one 8.5-Fr pigtail catheter for postoperative continuous open gravity drainage after U-VATS-P. The clinical characteristics and perioperative outcomes of the patients were retrospectively analyzed. RESULTS: In total, 77 patients had one 8.5-Fr pigtail catheter placed for postoperative continuous open gravity drainage after U-VATS-P for lung cancer. The mean age was 60.9±7.39 (40-76) years; The mean FEV1 was 2.1±0.6 (l/s), and the mean FEV1% was 71.2±22.7. The median operative time was 191.38±59.32 min; the mean operative hemorrhage was 109.46±96.56 ml; the mean duration of postoperative chest tube drainage was 6.80±2.33 days; the mean drainage volumes in the first three days after operation were 186.31±50.97, 321.97±52.03, and 216.44±35.67 ml, respectively; and the mean postoperative hospital stay was 7.90±2.58 days. No patient experienced complications resulting from chest tube malfunction. Ten patients experienced minor complications. One patient with nonlife-threatening empyema and bronchopleural fistula required short rehospitalization for anti-inflammatory therapy and reintubation. Three patients with chylothorax were treated with intravenous nutrition. Four patients had atrial fibrillation that was controlled by antiarrhythmic therapy. Two patients had more thoracic hemorrhagic exudation after the operation, which was found in time and was cured effectively, so they were discharged from the hospital uneventfully after early hemostatic therapy and nutritional support. CONCLUSIONS: All patients in this study received early postoperative rehabilitation, and the rate of relevant complications was low. We therefore recommend a single 8.5-Fr pigtail catheter for postoperative continuous open gravity drainage as an effective, safe and reliable drainage method for the management of U-VATS-P.

Efficient extraction of nickel from chloride system using a cleaner extractant: Taking the example of processing nickel-aluminum slag remaining from spent hydroprocessing catalysts.

The efficient recovery of nickel from chloride systems has long presented a challenge in the field. While solvent extraction is a viable approach, conventional extractants have been associated with drawbacks such as a high requirement for chloride ions and substantial consumption of acids and alkalis. In response to these challenges, this investigation developed and synthesized a novel thiazole-based extractant, N, N-Bis(4-thiazolylmethyl)octylamine (NNBT), tailored for the selective extraction of nickel from chloride systems. Findings from the study indicate that the nitrogen atom situated on the benzylamine framework within NNBT can interact synergistically with the chelating thiazole ring, facilitating effective nickel extraction and notably reducing the need for chloride ions. Furthermore, the extractant can be regenerated using deionized water, thereby obviating the necessity for additional consumption of acids and alkalis. Following the validation of NNBT as an environmentally sustainable and efficient nickel extractant within the chloride ion system, it was successfully employed to selectively and effectively extract nickel from the nickel-aluminum slag of spent HDP catalyst. The extracted nickel and aluminum were subsequently processed into electroplated nickel chloride and polyaluminum chloride, respectively, meeting the national standards of China. These outcomes underscore the eco-friendliness and promise of NNBT for nickel extraction from chloride systems.

Profiling of m6A methylation in porcine intramuscular adipocytes and unravelling PHKG1 represses porcine intramuscular lipid deposition in an m6A-dependent manner.

Intramuscular fat (IMF) content is mainly determined by intramuscular preadipocyte adipogenesis. Epigenetic modifications are known to have a regulatory effect on IMF. As N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic RNAs. In the present study, we used m6A methylation and RNA sequencing (seq) to identify the m6A-modified RNAs associated with the adipogenic differentiation of intramuscular preadipocytes. Among them, the expression and m6A level of phosphorylase kinase subunit G1 (PHKG1) were found to be significantly changed during adipogenesis. Further studies revealed that knockdown of the methylase METTL3 decreased the m6A methylation of PHKG1 and led to a reduction in PHKG1. Moreover, knockdown of PHKG1 promoted adipogenic differentiation by upregulating the expression of adipogenic genes. In addition, we found that the IMF content in the longissimus thoracis (LT) of Bamei (BM) pigs was greater than that in Large White (LW) pigs, whereas the m6A and PHKG1 expression levels were lower in BM pigs. These findings indicate that the m6A level and expression of PHKG1 were significantly correlated with IMF content and meat quality. In conclusion, this study sheds light on the mechanism by which m6A modification regulates IMF deposition.

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

Ether-Water Co-Solvent Electrolytes Enhanced Vanadium Oxide Cathode Cyclic Behaviors for Zinc Batteries.

Vanadium-based compounds are fantastic cathodes for aqueous zinc metal batteries due to the high specific capacity and excellent rate capability. Nevertheless, the practical application has been hampered by the dissolution of vanadium in traditional aqueous electrolytes owing to the strong polarity of water molecules. Herein, we propose a hybrid electrolyte made of Zn(ClO4)2 salt in tetraethylene glycol dimethyl ether (G4) and H2O solvents to upgrade the cycle life of Zn//K0.486V2O5 battery. The G4 jointly solvates with Zn2+ ions and replaces a portion of the H2O molecules in the Zn2+ solvation sheath. It forms a strong bond with H2O, reducing its activity, and significantly inhibiting vanadium dissolution and water-induced parasitic reaction. Consequently, the optimized electrolyte with H2O and G4 volume ratio of 5 : 5 enhances the cycling stability of Zn//K0.486V2O5 battery, enabling it to reach up to 600 cycles. In addition, the battery demonstrates a satisfactory reversible capacity of 475.7 mAh g-1 and excellent rate performance attributed to the moderate ionic conductivity (28.8 mS cm-1) of the hybrid electrolyte. Last but not least, in the optimized electrolyte, the symmetric Zn//Zn cells deliver a long cycling performance of 400 h, while the asymmetric Zn//Cu cells shows a high average coulombic efficiency of 97.4 %.

Causal relationship between gut microbiota and polycystic ovary syndrome: a literature review and Mendelian randomization study.

Introduction: Numerous studies have suggested an association between gut microbiota and polycystic ovarian syndrome (PCOS). However, the causal relationship between these two factors remains unclear. Methods: A review of observational studies was conducted to compare changes in gut microbiota between PCOS patients and controls. The analysis focused on four levels of classification, namely, phylum, family, genus, and species/genus subgroups. To further investigate the causal relationship, Mendelian randomization (MR) was employed using genome-wide association study (GWAS) data on gut microbiota from the MiBioGen consortium, as well as GWAS data from a large meta-analysis of PCOS. Additionally, a reverse MR was performed, and the results were verified through sensitivity analyses. Results: The present review included 18 observational studies that met the inclusion and exclusion criteria. The abundance of 64 gut microbiota taxa significantly differed between PCOS patients and controls. Using the MR method, eight bacteria were identified as causally associated with PCOS. The protective effects of the genus Sellimonas on PCOS remained significant after applying Bonferroni correction. No significant heterogeneity or horizontal pleiotropy was found in the instrumental variables (IVs). Reverse MR analyses did not reveal a significant causal effect of PCOS on gut microbiota. Conclusion: The differences in gut microbiota between PCOS patients and controls vary across observational studies. However, MR analyses identified specific gut microbiota taxa that are causally related to PCOS. Future studies should investigate the gut microbiota that showed significant results in the MR analyses, as well as the underlying mechanisms of this causal relationship and its potential clinical significance.

Hydrophilic molecularly imprinted resin-hexagonal boron nitride composite as a new adsorbent for selective extraction and determination of a carcinoid tumor biomarker in urine.

BACKGROUND: The detection of disease biomarkers in biological samples plays an important role in early diagnosis and treatment of carcinoid tumor. However, due to the complexity of biological samples and the extremely low concentration of disease biomarkers, sample pretreatment is still the bottleneck of achieving accurate quantitative determination. In this work, new hydrophilic molecularly imprinted resin-hexagonal boron nitride (HMIR-h-BN) composites were developed and used as a new solid phase extraction (SPE) adsorbent for selective detection of 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of carcinoid tumor, in urine. RESULTS: Twenty-two types of HMIR-h-BN were successfully synthesized through growing hydrophilic molecularly imprinted resin on surface of activated two-dimensional h-BN nanosheets, and preparation parameters affecting the adsorption performance of HMIR-h-BN were investigated and optimized through adsorption experiments. HMIR-h-BN #19 (the ratio of resorcinol to hexamethylenetetramine: 6:3; the dosage of h-BN: 300 mg; the dosage of dummy template: 0.12 mmol; the imprinting time: 4 h) has demonstrated to be the optimal material for efficient separation and extraction of 5-HIAA. Combined with HPLC-UV, the limit of detection and the limit of quantification of 5-HIAA in real urine samples were 9.4 ng mL-1 and 31.3 ng mL-1, respectively, the coefficient of determination (R2) was 0.9996 in the linear range of 0.1-300 µg mL-1 and the relative recoveries ranged from 86.9 % to 97.7 % with RSD ≤5.1 %. Moreover, after being processed by HMIR-h-BN-SPE, there are no interferences from other peaks at the peak position of 5-HIAA. SIGNIFICANCE: The HMIR-h-BN composite has been demonstrated to be capable of selective extraction of 5-HIAA from urine samples and have a significant purification effect. Based on the established HMIR-h-BN-SPE-HPLC-UV method, accurate quantitative determination of 5-HIAA in urine samples was achieved, which is expected to be applied in the early diagnostic of carcinoid tumor.

Diagnostic and prognostic risk factors analysis for distant metastasis in melanoma: a population-based study.

BACKGROUND: We aimed to develop tools that could predict the occurrence of distant metastases in melanoma and its prognosis based on clinical and pathological characteristics. MATERIALS AND METHODS: We obtained data from the Surveillance, Epidemiology, and End Results (SEER) database of melanoma patients diagnosed between 2010 and 2019. Logistic analyses were performed to identify independent risk factors associated with distant metastasis. Additionally, multivariate Cox analyses were conducted to determine independent prognostic factors for patients with distant metastasis. Two nomograms were established and evaluated with the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Furthermore, we performed a retrospective analysis of melanoma with distant metastasis from our institute between March 2018 and June 2022. RESULTS: Of the total 19 396 melanoma patients, 352 (1.8%) had distant metastases at the time of diagnosis. The following clinical and pathological characteristics were identified as independent risk factors for distant metastasis in melanoma: N stage, tumor size, ulceration, mitosis, primary tumor site, and pathological subtype. Furthermore, tumor size, pathological subtype, and radiotherapy were identified as independent prognostic factors. The results of the training and validation cohorts' ROC curves, calibration, DCA, and Kaplan-Meier survival curves demonstrate the effectiveness of the two nomograms. The retrospective study results from our center supported the results from the SEER database. CONCLUSION: The clinical and pathological characteristics of melanoma can predict a patient's risk of metastasis and prognosis, and the two nomograms are expected to be effective tools to guide therapy decisions.

Bamboo leaf extract treatment alleviates the surface browning of fresh-cut apple by regulating membrane lipid metabolism and antioxidant properties.

BACKGROUND: The effect of bamboo leaf extract (BLE) on controlling the browning of fresh-cut apple stored at 4 °C was investigated. Browning index, H2 O2 content, O2 - production rate, malondialdehyde (MDA) contents, total phenolic content (TPC) and soluble quinone content (SQC), the activities of polyphenol oxidase (PPO), peroxidase (POD), lipoxygenase (LOX), superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), DPPH (2,2-diphenyl-2-picryl-hydrazyl) and ABTS [2,2-azinobis(3-ethylbenzothiazoline- 6-sulfonic acid)] radical scavenging activities, and the expression of genes related to browning were all investigated. RESULTS: BLE effectively alleviated the surface browning of fresh-cut apple, accompanied by a reduction in SQC, LOX activity, H2 O2 , O2 - production rate and MDA accumulation. Furthermore, BLE treatment enhanced the TPC, enzymatic (SOD, CAT, APX and POD) and non-enzymatic antioxidant activities. Principal component analysis and Pearson correlation analysis found the browning inhibition by BLE is not through the reduction of phenolic substrates and PPO activity. CONCLUSION: BLE controls the browning of fresh-cut apple by increasing the antioxidant capacity to scavenge ROS, which could alleviate oxidative damage and maintain the membrane integrity. © 2023 Society of Chemical Industry.

Noninvasive identification of HER2-low-positive status by MRI-based deep learning radiomics predicts the disease-free survival of patients with breast cancer.

OBJECTIVE: This study aimed to establish a MRI-based deep learning radiomics (DLR) signature to predict the human epidermal growth factor receptor 2 (HER2)-low-positive status and further verified the difference in prognosis by the DLR model. METHODS: A total of 481 patients with breast cancer who underwent preoperative MRI were retrospectively recruited from two institutions. Traditional radiomics features and deep semantic segmentation feature-based radiomics (DSFR) features were extracted from segmented tumors to construct models separately. Then, the DLR model was constructed to assess the HER2 status by averaging the output probabilities of the two models. Finally, a Kaplan‒Meier survival analysis was conducted to explore the disease-free survival (DFS) in patients with HER2-low-positive status. The multivariate Cox proportional hazard model was constructed to further determine the factors associated with DFS. RESULTS: First, the DLR model distinguished between HER2-negative and HER2-overexpressing patients with AUCs of 0.868 and 0.763 in the training and validation cohorts, respectively. Furthermore, the DLR model distinguished between HER2-low-positive and HER2-zero patients with AUCs of 0.855 and 0.750, respectively. Cox regression analysis showed that the prediction score obtained using the DLR model (HR, 0.175; p = 0.024) and lesion size (HR, 1.043; p = 0.009) were significant, independent predictors of DFS. CONCLUSIONS: We successfully constructed a DLR model based on MRI to noninvasively evaluate the HER2 status and further revealed prospects for predicting the DFS of patients with HER2-low-positive status. CLINICAL RELEVANCE STATEMENT: The MRI-based DLR model could noninvasively identify HER2-low-positive status, which is considered a novel prognostic predictor and therapeutic target. KEY POINTS: • The DLR model effectively distinguished the HER2 status of breast cancer patients, especially the HER2-low-positive status. • The DLR model was better than the traditional radiomics model or DSFR model in distinguishing HER2 expression. • The prediction score obtained using the model and lesion size were significant independent predictors of DFS.

Determination of alectinib and its active metabolite in plasma by pipette-tip solid-phase extraction using porous polydopamine graphene oxide adsorbent coupled with high-performance liquid chromatography-ultraviolet detection.

Alectinib is known as an effective targeted drug, which has excellent therapeutic effect on non-small cell lung cancer and can significantly prolong the survival of patients. Therapeutic drug monitoring is necessary due to the photo-instability of alectinib and the individual differences in patients. In this work, a porous polydopamine graphene oxide composite (PDAG) was prepared by a simple surface modification method. A PDAG-based pipette-tip solid-phase extraction (PT-SPE) coupled with HPLC-UV detection was proposed for the separation and detection of alectinib and its active metabolite M4 in plasma. The method was methodologically validated and showed good linearity in the range of 50-5000 ng mL-1 (R2 > 0.9995). The limit of detection (LOD) was 4.8 ng mL-1 and 3.9 ng mL-1 for alectinib and M4, respectively, and the limit of quantitation (LOQ) was 16.1 ng mL-1 and 13.1 ng mL-1, respectively. The intra-day and inter-day precision expressed by coefficient of variation was less than 4.8 %. The recovery of this method ranged from 84.9 % to 103.5 % with a standard deviation of less than 4.3 %. In conclusion, the established method is accurate, stable and inexpensive, and can be used to monitor the levels of alectinib and M4 in plasma, which provide technical and data support for exploring optimal individualized remedial dosing regimens.

Simultaneous determination of three biomarkers of non-small cells lung cancer in urine by pipette-tip solid-phase extraction coupled with liquid chromatography tandem mass spectrometry.

Simultaneous determination of multiple biomarkers can improve the effectiveness and accuracy of cancer diagnosis. Cortisol, cortisone, and 4-methoxyphenylacetic acid (4-Me) are metabolic biomarker group with high specificity and sensitivity for the diagnosis of non-small cells lung cancer (NSCLC), and the development of their simultaneous determination method is desired. Herein, a simple, sensitive, and low-cost method involving pipette-tip solid-phase extraction (PT-SPE) using anion exchange adsorbent (MAX) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous determination of three biomarkers (cortisol, cortisone, and 4-Me) in human urine. The sample (0.1 mL), adsorbent (1.5 mg) and organic reagent (3.5 mL) of MAX-PT-SPE are less consumed, and have the advantages of easy access to raw materials, simple assembly, convenient on-site instant extraction, low pollution, and low cost. The limits of detection of the three biomarkers were 0.006-0.024 ng mL-1, the recoveries of three spiked levels (2, 50, and 500 ng mL-1) were 91.0%-99.3%, with the relative standard deviations (RSDs) ≤ 5.9%. Finally, the MAX-PT-SPE-LC-MS/MS method achieved the quantitative analysis of cortisol, cortisone, and 4-Me in urine of different patients of NSCLC. This method is expected to be used in the non-invasive auxiliary diagnosis of NSCLC, and it provides a new strategy for multi-molecular diagnosis and multi-omics combined diagnosis.

Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy.

INTRODUCTION: Targeted protein degradation represents a promising therapeutic approach, while diabetic cardiomyopathy (DCM) arises as a consequence of aberrant insulin secretion and impaired glucose and lipid metabolism in the heart.. OBJECTIVES: Considering that the Toll-like receptor 9 (TLR9) signaling pathway plays a pivotal role in regulating energy metabolism, safeguarding cardiomyocytes, and influencing glucose uptake, the primary objective of this study was to investigate the impact of TLR9 on diabetic cardiomyopathy (DCM) and elucidate its underlying mechanism. METHODS: Mouse model of DCM was established using intraperitoneal injection of STZ, and mice were transfected with adeno-associated virus serotype 9-TLR9 (AAV9-TLR9) to assess the role of TLR9 in DCM. To explore the mechanism of TLR9 in regulating DCM disease progression, we conducted interactome analysis and employed multiple molecular approaches. RESULTS: Our study revealed a significant correlation between TLR9 expression and mouse DCM. TLR9 overexpression markedly mitigated cardiac dysfunction, myocardial fibrosis, oxidative stress, and apoptosis in DCM, while inflammation levels remained relatively unaffected. Mechanistically, TLR9 overexpression positively modulated mitochondrial bioenergetics and activated the AMPK-PGC1a signaling pathway. Furthermore, we identified Triad3A as an interacting protein that facilitated TLR9's proteasomal degradation through K48-linked ubiquitination. Inhibiting Triad3A expression improved cardiac function and pathological changes in DCM by enhancing TLR9 activity. CONCLUSIONS: The findings of this study highlight the critical role of TLR9 in maintaining cardiac function and mitigating pathological alterations in diabetic cardiomyopathy. Triad3A-mediated regulation of TLR9 expression and function has significant implications for understanding the pathogenesis of DCM. Targeting TLR9 and its interactions with Triad3A may hold promise for the development of novel therapeutic strategies for diabetic cardiomyopathy. Further research is warranted to fully explore the therapeutic potential of TLR9 modulation in the context of cardiovascular diseases.

Rapid extraction of osimertinib and its active metabolite in urine by miniaturized centrifugal spin-column extraction using ionic liquid hybrid hierarchical porous adsorbent.

Osimertinib (OSIM) is widely used as a mainstream drug for the treatment of non-small cell lung cancer (NSCLC). However, the lack of a rapid extraction and detection method for OSIM and its metabolite, AZ-5104, has limited clinical drug metabolism and drug resistance research because the drug is unstable. In this study, a new ionic liquid hybrid hierarchical porous material (IL-HHPM) was synthesized with hierarchical porous structures, including micropores (1.6-2.0 nm), mesopores (2.0-50.0 nm), macropores (50.0-148.7 nm), and multiple functional groups via a one-step hydrothermal method using silanized ionic liquids (IL) as functionalized hybrid monomer. The IL-HHPM has the advantages of a high specific surface area (437.4 ± 4.6 m2 g-1), sizable pore volume (0.74 cm3 g-1), and fast mass transfer, additionally, the IL-HHPM adsorbed OSIM and AZ-5104 via π-π interactions and hydrogen bonding. OSIM and AZ-5104 were rapidly extracted and measured in human urine using rapid and miniaturized centrifugal spin-column extraction (MCSCE), which was based on the IL-HHPM. The optimized factors for the extraction recoveries of OSIM and AZ-5104 were adsorbent dosage (8.0 mg), sample volume (0.5 mL), and operation time (9.0 min), and markedly reduced the adsorbent dosage and operation time. The IL-HHPM-MCSCE-HPLC method displayed good linearity (0.02-5.00 µg mL-1, r ≥ 0.9997), satisfying accuracy (spiked recoveries of 87.7%-100.0%), and good precision (RSDs ≤ 7.0%). The developed method is rapid, sensitive, and reproducible for the simultaneous determination of trace level of OSIM and AZ-5104 in human urine.

Improving Tumor Classification by Reusing Self-predicted Segmentation of Medical Images as Guiding Knowledge.

Differential diagnosis of tumors is important for computer-aided diagnosis. In computer-aided diagnosis systems, expert knowledge of lesion segmentation masks is limited as it is only used during preprocessing or as supervision to guide feature extraction. To improve the utilization of lesion segmentation masks, this study proposes a simple and effective multitask learning network that improves medical image classification using self-predicted segmentation as guiding knowledge; we call this network RS 2-net. In RS 2-net, the predicted segmentation probability map obtained from the initial segmentation inference is added to the original image to form a new input, which is then reinput to the network for the final classification inference. We validated the proposed RS 2-net using three datasets: the pNENs-Grade dataset, which tested the prediction of pancreatic neuroendocrine neoplasm grading, and the HCC-MVI dataset, which tested the prediction of microvascular invasion of hepatocellular carcinoma, and ISIC 2017 public skin lesion dataset. The experimental results indicate that the proposed strategy of reusing self-predicted segmentation is effective, and RS 2-net outperforms other popular networks and existing state-of-the-art studies. Interpretive analytics based on feature visualization demonstrates that the improved classification performance of our reuse strategy is due to the semantic information that can be acquired in advance in a shallow network.

Discovery of HyT-Based Degraders of CDK9-Cyclin T1 Complex.

Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362 µM against CDK9 and 0.680 µM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.

Genome-Wide Identification and Analysis of R2R3-MYB Genes Response to Saline-Alkali Stress in Quinoa.

Soil saline-alkalization inhibits plant growth and development and seriously affects crop yields. Over their long-term evolution, plants have formed complex stress response systems to maintain species continuity. R2R3-MYB transcription factors are one of the largest transcription factor families in plants, widely involved in plant growth and development, metabolism, and stress response. Quinoa (Chenopodium quinoa Willd.), as a crop with high nutritional value, is tolerant to various biotic and abiotic stress. In this study, we identified 65 R2R3-MYB genes in quinoa, which are divided into 26 subfamilies. In addition, we analyzed the evolutionary relationships, protein physicochemical properties, conserved domains and motifs, gene structure, and cis-regulatory elements of CqR2R3-MYB family members. To investigate the roles of CqR2R3-MYB transcription factors in abiotic stress response, we performed transcriptome analysis to figure out the expression file of CqR2R3-MYB genes under saline-alkali stress. The results indicate that the expression of the six CqMYB2R genes was altered significantly in quinoa leaves that had undergone saline-alkali stress. Subcellular localization and transcriptional activation activity analysis revealed that CqMYB2R09, CqMYB2R16, CqMYB2R25, and CqMYB2R62, whose Arabidopsis homologues are involved in salt stress response, are localized in the nucleus and exhibit transcriptional activation activity. Our study provides basic information and effective clues for further functional investigation of CqR2R3-MYB transcription factors in quinoa.