Two new compounds from the capitula of Chrysanthemum morifolium cv. Fubaiju.

A new germacrane-type sesquiterpenoid (1) and a new alkamide (2), as well as six known compounds (3-8) were isolated from the capitula of Chrysanthemum morifolium cv. Fubaiju. The new structures were elucidated by comprehensive spectroscopic analysis and quantum chemical calculations. The known structures were characterised via 1D NMR data compared with the already existing literature data. Among the isolates, compound 5 showed inhibitory activity against human lung cancer A549 cells and human hepatoma HepG2 cells with the IC50 values of 19.50 ± 1.23 and 23.24 ± 1.30 µM, respectively, and compound 8 exhibited inhibitory effect on RSV infection with IC50 value of 12.50 ± 1.02 µM.

STAT6/LINC01637 axis regulates tumor growth via autophagy and pharmacological targeting STAT6 as a novel strategy for uveal melanoma.

Compelling evidence has revealed a novel function of the STAT pathway in the pathophysiology of uveal melanoma (UM); however, its regulatory mechanisms remain unclear. Here, we analyzed the clinical prognostic value of STAT family genes in UM patients using bioinformatics approaches and found that high STAT6 expression is associated with poor prognosis. Furthermore, cellular experiments and a nude mouse model demonstrated that STAT6 promotes UM progression through the autophagy pathway both in vivo and in vitro. Next, RIP-PCR revealed that STAT6 protein binds to LINC01637 mRNA, which in turn regulates STAT6 expression to promote UM growth. Finally, molecular docking indicated that STAT6 is a target of Zoledronic Acid, which can delay UM tumorigenicity by inhibiting STAT6 expression. Taken together, our results indicate that the STAT6/LINC01637 axis promotes UM progression via autophagy and may serve as a potential therapeutic target for UM.

Paxbp1 is indispensable for the maintenance of epidermal homeostasis.

The mammalian epidermis is a structurally complex tissue that serves critical barrier functions, safeguarding the organism from the external milieu. The development of the epidermis is governed by sophisticated regulatory processes. However, the precise mechanism maintaining epidermal homeostasis remains incompletely elucidated. Recent studies have identified Paxbp1, an evolutionarily conserved protein, as being involved in the developmental regulation of various cells, tissues, and organs. Nonetheless, its role in skin development has not been explored. Here, we report that the targeted deletion of Paxbp1 in epidermal keratinocytes mediated by Keratin14-Cre leads to severe disruption in skin architecture. Mice deficient in Paxbp1 exhibited a substantially reduced epidermal thickness and pronounced separation at the dermo-epidermal junction upon birth. Mechanistically, we demonstrate that the absence of Paxbp1 hinders cellular proliferation, marked by a halt in cell cycle transition, suppressed gene expression of proliferation, and a compromised DNA replication pathway in basal keratinocytes, resulting in the thinning of the skin epidermis. Moreover, molecules and pathways associated with hemidesmosome assembly were impaired in Paxbp1-deficient keratinocytes, culminating in the detachment of the skin epidermal layer. Therefore, our study highlights an indispensable role of Paxbp1 in the maintenance of epidermal homeostasis.

A nomogram with Ki-67 in the prediction of postoperative recurrence and death for glioma.

This study examined to evaluate the predictive value of a nomogram with Ki-67 in overall and disease-free survival in glioma patients, a total of 76 patients diagnosed with glioma by pathology in Tengzhou Central People's Hospital were enrolled. The baseline data and follow ups were retrospectively collected from medical records. The associations between Ki-67 and survival status were examined using log-rank test, univariate and multivariate Cox proportional hazard regression models. Calibrations were performed to validate the established nomograms. Ki-67 negative group showed of a longer OS survival time and a longer PFS survival time with log-rank test (x2 = 16.101, P < 0.001 and x2 = 16.961, P < 0.001). Age older than 50 years (HR = 2.074, 95% CI 1.097-3.923), abnormal treatment (HR = 2.932, 95% CI 1.343-6.403) and Ki-67 positive (HR = 2.722, 95% CI 1.097-6.755) were the independent predictive factors of death. High grade pathology (HR = 2.453, 95% CI 1.010-5.956) and Ki-67 positive (HR = 2.200, 95% CI 1.043-4.639) were the independent predictive factors of recurrence. The C-index for the nomogram of OS and PFS were 0.745 and 0.723, respectively. The calibration results showed that the nomogram could predict the overall and disease-free 1-year survival of glioma patients. In conclusion, the nomograms with Ki-67 as independent risk factor for OS and PFS could provide clinical consultation in the treatment and follow-up of malignant glioma.

KIF18B: an important role in signaling pathways and a potential resistant target in tumor development.

KIF18B is a key member of the kinesin-8 family, involved in regulating various physiological processes such as microtubule length, spindle assembly, and chromosome alignment. This article briefly introduces the structure and physiological functions of KIF18B, examines its role in malignant tumors, and the associated carcinogenic signaling pathways such as PI3K/AKT, Wnt/ß-catenin, and mTOR pathways. Research indicates that the upregulation of KIF18B enhances tumor malignancy and resistance to radiotherapy and chemotherapy. KIF18B could become a new target for anticancer drugs, offering significant potential for the treatment of malignant tumors and reducing chemotherapy resistance.

Effect of compound surface modification of shot peening and DLC coating on surface integrity and fatigue properties of gear steel 16Cr3NiWMoVNbE.

We conducted a study on the surface compound modification of shot peening and pure carbon DLC coating to simultaneously meet the requirements of wear resistance and fatigue resistance of spline structure. The effects of surface compound modification were investigated on the surface morphology, residual stress profile, microstructure, and nano-indentation hardness of 16Cr3NiWMovNbE gear steel, and conducted a comparative study on fatigue performance. The results show that the surface compound modification inherits the surface morphology and compressive residual stress gradient of shot peening, while the surface residual stress is slightly smaller than that of shot peening. In addition, surface compound modification still reflects the characteristics of high hardness and high fracture resistance of DLC coatings. Under the bending load based on spline tooth root, compared to the original specimen, the fatigue life after shot peening, pure carbon DLC coating, and surface compound modification is increased by 3.68, 2.35, and 3.36 respectively. Although the compound modified surface still maintains the shot peening morphology with a increasing surface roughness and stress concentration coefficient, the 100 µm-depth compressive residual stress profile and the subgrain refinement layer introduced, as well as the hard surface layer with good load-bearing capacity, have played the role of fatigue strengthening.

Retrospective analysis of a novel grading system for evaluating the long-term benefit of revascularization on carotid artery stenosis.

OBJECTIVE: To estimate revascularization benefit for carotid artery stenosis, with a novel grading system containing symptoms, stenosis, plaque, and collaterals collateral compensation (SSPC grading system). METHODS: A retrospective multicenter study examined 945 consecutive patients diagnosed with carotid stenosis from January 2013 to December 2017. The cohort was classified into two groups: the revascularization group and the best medical therapy (BMT) group. Demographic, clinical, and lesion characteristics of all patients were recorded and five-year non-procedural stroke survival was calculated using Kaplan-Meier curve analyses. RESULTS: Of the 945 patients, 514 underwent carotid revascularization (483 for carotid endarterectomy [CEA] and 31 for transfemoral-carotid artery stenting [TF-CAS]) and 431 patients were treated with BMT. Patients in the revascularization group had a significantly higher proportion of preprocedural stroke/transient ischemic attack (TIA) and grades of stenosis. Of the patients in the revascularization group, 3.1% were classified as SSPC I, 10.3% as SSPC II, 41.4% as SSPC III, and 45.1% as SSPC IV. Meanwhile, 17.9% were classified as SSPC I, 19.7% as SSPC II, 49.2% as class III, and 13.2% had class IV in the BMT group. Procedural stroke developed in 13 patients (2.5%) following revascularization (10 of them were non-disabling). The overall rate of freedom from any non-procedural stroke was 94.1±1.1% in the revascularization group and 89.5±1.6% in the BMT group (P=0.01). Subgroup analysis was conducted for asymptomatic carotid stenosis (ACS) and carotid near-occlusion (CNO) patients. Non-significance was noted in the rate of freedom from any non-procedural stroke between revascularization and BMT in both ACS and CNO subgroups (P=0.09 and 0.12, respectively). Of note, in ACS patients graded as SSPC III, a significant difference in stroke survival was found between the revascularization and BMT group (96.0±2.0% vs. 89.1±2.4%, P=0.04). Meanwhile, in symptomatic CNO patients, similar results were found regarding SSPC classification (94.8±3.6% vs. 63.8±14.9%, P=0.01). CONCLUSIONS: The SSPC grading system stratifies the patients with carotid artery stenosis and predicts the long-term benefits of revascularization. Meanwhile, potential revascularization benefits could be better attained via SSPC classes in specific patients with ACS and CNO.

Endoscopic dacryocystorhinostomy in acute dacryocystitis: a multicenter study in China.

AIM: To report the clinical profile, endoscopic dacryocystorhinostomy (En-DCR) management, and acute dacryocystitis (AD) outcomes in China. METHODS: Clinical data of 554 adult AD patients (554 eyes) who presented in 7 tertiary eye care centers for 10y from Jan 2010 to Mar 2020 were retrospectively analyzed. Clinical profile, En-DCR management, and outcomes of all cases were recorded. The anatomical and functional success were evaluated for 12mo post-operation. RESULTS: The analysis included 149 males and 368 females with a median age of 55.2y (range: 18-84y). There were 459 eyes with a history of epiphora or purulent secretion. The time between a symptom of lacrimal duct obstruction and acute onset was 1 to 540 (66.1±58.2)mo. Fifty-nine eyes had a history of the previous acute attack. Seventy-four eyes developed a cutaneous fistula, while 11 eyes had post septal cellulitis pre-operation. En-DCR with an anatomical success of 91.7% and functional success of 90.1%. The success rate of the patients with a history of acute episodes and the preoperative fistula was lower than the overall success rates. CONCLUSION: En-DCR can be performed during an acute episode in AD with a success rate of over 90%.

Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein.

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.

Four-step electron transfer coupled spin transition in a cyano-bridged [Fe2Co2] square complex.

The design of molecular functional materials with multi-step magnetic transitions has attracted considerable attention. However, the development of such materials is still infrequent and challenging. Here, a cyano-bridged square Prussian blue complex that exhibits a thermally induced four-step electron transfer coupled spin transition (ETCST) is reported. The magnetic and spectroscopic analyses confirm this multi-step transition. Variable-temperature infrared spectrum suggested the electronic structures in each phase and a four-step transition model is proposed.

Pegaharolines A - I, structurally novel indole alkaloids with anti-HSV-2 virus activities from Peganum harmala L. seeds.

Leading by the antiviral activities against HSV-2 virus, bioactivity-guided the fraction of crude alkaloids from seeds of Peganum harmala led to the isolation of nine structurally novel indole alkaloids, pegaharolines A - I (1-9), and 11 known ones (10-20). Compound 3 was an unusual 6/5/5/5 spirotetracyclic indole-derived alkaloids featuring a classic bicyclic indole unit fused with an additional pyrrolizine ring via a spiral atom (C-3). Compound 4 was determined as a novel indole alkaloid, characterized with a rare hexacyclic 6/5/6/5-6/6 ring system, by a single-crystal X-ray diffraction. Compounds 5 and 6 were peculiar indole dimers featuring with the rare carbon skeleton of an octacyclic scaffold. Compounds 1-6 were six racemates. Most compounds exhibited different levels of antiviral activities against HSV-2. Especially, the anti-HSV-2 activity of compound 1 (IC50 = 0.90 ±â€¯0.10 µM) was much better than that of the positive control (acyclovir, IC50 = 1.12 ±â€¯0.15 µM). In this study, the discovery of anti-HSV-2 components from the seeds of P. harmala, could benefit development and utilization of this plant in antiviral medicinal products.

Spinal PTP1B Regulated NMDA Receptor-mediated Nociceptive Transmission and Peripheral Inflammation-induced Pain Sensitization.

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of several pain-related substrates in spinal cord dorsal horn and are critically involved in the modification of pain transmission. The current study demonstrated that protein tyrosine phosphatase 1B (PTP1B), a unique endoplasmic reticulum-resident member of PTP family, displayed an activity-dependent increase in its protein expression and synaptic localization in spinal dorsal horn of adult male rats. PTP1B interacted with the Src Homology 3 (SH3) domain of Synapse-Associated Protein 102 (SAP102), one of the postsynaptic scaffolding proteins that anchored PTP1B at postsynaptic sites. The SAP102-tethered PTP1B augmented the synaptic transmission mediated specifically by GluN2B subunit-containing N-methyl-D-aspartate subtype glutamate receptors. Interference with PTP1B activity or disruption of its interaction with SAP102 attenuated GluN2B-mediated nociceptive transmission and ameliorated pain sensitization induced by intraplantar injection of Complete Freund's Adjuvant. These data suggested that the activity-dependent synaptic redistribution of PTP1B served as an important mechanism regulating GluN2B receptor activity and that manipulation of PTP1B synaptic targeting might represent an effective approach for the treatment of chronic inflammatory pain.

Prognosis impact of multiple novel lymphocyte-based inflammatory indices in patients with initially diagnosed coronary artery disease.

BACKGROUND: This study aimed to evaluate six novel lymphocyte-based inflammatory markers (neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio, platelet-lymphocyte ratio [PLR], systemic immune inflammation index [SII], systemic inflammatory response index, and systemic immune inflammation response index [SIIRI]) in patients with newly diagnosed coronary artery disease [CAD]. METHODS: A total of 959 patients newly diagnosed with CAD and underwent diagnostic coronary angiography were enrolled in this study and followed for major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The best cutoff value was used to compare the six indicators. Cox risk regression analysis evaluated the relationship between novel lymphocyte-based inflammatory markers and MACEs in newly diagnosed CAD patients. RESULTS: During a mean follow-up period of 33.3 ± 9.9 months, 229 (23.9%) MACEs were identified. Multivariate Cox regression analysis showed that only SIIRI (hazard ratio [HR]: 5.853; 95% confidence interval [CI]: 4.092-8.371; p < .001) and PLR (HR: 1.725; 95% CI: 1.214-2.452; p = .002) were independent predictors of MACEs. Nevertheless, following the adjustment for covariates, only the SIIRI was found to be a significant predictor MACEs and its corresponding specific endpoint occurrences. The predictive ability of the model was improved when six different inflammatory markers were added to the basic model established by traditional risk factors, namely, the C-index increased, and the SIIRI increased most significantly (AUC: 0.778; 95% CI: 0.743-0.812; p < .001). However, among the six novel inflammatory markers, only SIIRI had improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI: 0.187; 95% CI: 0.115-0.259, p < .001. IDI: 0.135; 95% CI: 0.111-0.159, p < .001), which was superior to the basic model established by traditional risk factors. CONCLUSIONS: SIIRI is independent predictor of MACEs in newly diagnosed CAD patients. SIIRI was superior to other measures in predicting MACEs. The combination of SIIRI and traditional risk factors can more accurately predict MACEs.

Implication of CXCR2-Src axis in the angiogenic and osteogenic effects of FP-TEB.

Application of tissue-engineered bones (TEBs) is hindered by challenges associated with incorporated viable cells. Previously, we employed freeze-drying techniques on TEBs to devitalize mesenchymal stem cells (MSCs) while preserving functional proteins, yielding functional proteins-based TEBs (FP-TEBs). Here, we aimed to elucidate their in vivo angiogenic and osteogenic capabilities and the mechanisms. qPCR arrays were employed to evaluate chemokines and receptors governing EC migration. Identified C-X-C chemokine receptors (CXCRs) were substantiated using shRNAs, and the pivotal role of CXCR2 was validated via conditional knockout mice. Finally, signaling molecules downstream of CXCR2 were identified. Additionally, Src, MAP4K4, and p38 MAPK were identified indispensable for CXCR2 function. Further investigations revealed that regulation of p38 MAPK by Src was mediated by MAP4K4. In conclusion, FP-TEBs promoted EC migration, angiogenesis, and osteogenesis via the CXCR2-Src-Map4k4-p38 MAPK axis.

Two 2D spin-crossover coordination polymers constructed by [Pd(SCN)4]2- building blocks.

Two new two-dimensional (2D) coordination polymers, [FeII(L)2{PdII(SCN)4}] (L1 = 2-methoxypyrazine, 1; and L2 = (E)-3-(phenyldiazenyl)pyridine, 2), were successfully constructed by using square-planar [Pd(SCN)4]2- building blocks. Complex 1 exhibits complete and one-step spin-crossover (SCO) behavior, while 2 exhibits incomplete and two-step SCO behavior. Further structural insight into this synergy reveals that the flat/flexing [Fe{Pd(SCN)4}]∞ sheets in 1 and 2 are stabilized by interlayered/intralayered supramolecular interactions.

Using 3D point cloud and graph-based neural networks to improve the estimation of pulmonary function tests from chest CT.

Pulmonary function tests (PFTs) are important clinical metrics to measure the severity of interstitial lung disease for systemic sclerosis patients. However, PFTs cannot always be performed by spirometry if there is a risk of disease transmission or other contraindications. In addition, it is unclear how lung function is affected by changes in lung vessels. Therefore, convolution neural networks (CNNs) were previously proposed to estimate PFTs from chest CT scans (CNN-CT) and extracted vessels (CNN-Vessel). Due to GPU memory constraints, however, these networks used down-sampled images, which causes a loss of information on small vessels. Previous literature has indicated that detailed vessel information from CT scans can be helpful for PFT estimation. Therefore, this paper proposes to use a point cloud neural network (PNN-Vessel) and graph neural network (GNN-Vessel) to estimate PFTs from point cloud and graph-based representations of pulmonary vessel centerlines, respectively. After that, we combine different networks and perform multiple variable step-wise regression analysis to explore if vessel-based networks can contribute to the PFT estimation, in addition to CNN-CT. Results showed that both PNN-Vessel and GNN-Vessel outperformed CNN-Vessel, by 14% and 4%, respectively, when averaged across the intra-class correlation coefficient (ICC) scores of four PFTs metrics. In addition, compared to CNN-Vessel, PNN-Vessel used 30% of training time (1.1 h) and 7% parameters (2.1 M) and GNN-Vessel used only 7% training time (0.25 h) and 0.7% parameters (0.2 M). We combined CNN-CT, PNN-Vessel and GNN-Vessel with the weights obtained from multiple variable regression methods, which achieved the best PFT estimation accuracy (ICC of 0.748, 0.742, 0.836 and 0.835 for the four PFT measures respectively). The results verified that more detailed vessel information could provide further explanation for PFT estimation from anatomical imaging.

Value of Combined Optical Coherence Tomography and Optical Flow Ratio Measurements After Percutaneous Coronary Intervention.

BACKGROUND: Optical flow ratio (OFR) is a novel computational fractional flow reserve derived from optical coherence tomography (OCT). However, the impact of combining post-stenting morphology (OCT) and physiology (OFR) remains largely unknown. METHODS: OCT and OFR were analysed at an independent core laboratory. Target lesion failure (TLF) was defined as the composite of cardiac death, target lesion myocardial infarction, and target lesion revascularisation. Suboptimal stent deployment was identified with at least 1 TLF-related OCT or OFR characteristic. RESULTS: A total of 448 patients with acute coronary syndrome (459 vessels) were assessed. Stent expansion < 80%, minimal stent area < 4.5 mm2, and stent edge lipid-rich plaque and OFR < 0.90 were independent predictors of TLF (all P < 0.001). Patients with OCT-suboptimal (adjusted hazard ratio [aHR] 7.88, 95% CI 2.73-22.72,-P < 0.001) or OFR-suboptimal (aHR 5.78, 95% CI 2.54-13.14; P < 0.001) stent deployment showed significantly higher risk of TLF compared with those with optimal stent deployment, with a significant interaction (Pinteraction < 0.001). OCT and OFR both-suboptimal stent deployment was confirmed as an independent predictor of TLF (aHR 9.39, 95% CI 4.25-20.76; P < 0.001). CONCLUSIONS: Combined OCT and OFR conferred an optimal reclassification of stent deployment, which may aid in decision making regarding a tailored PCI strategy for optimal stent deployment.

Coronary artery calcification and cardiovascular outcome as assessed by intravascular OCT and artificial intelligence.

Coronary artery calcification (CAC) is a marker of atherosclerosis and is thought to be associated with worse clinical outcomes. However, evidence from large-scale high-resolution imaging data is lacking. We proposed a novel deep learning method that can automatically identify and quantify CAC in massive intravascular OCT data trained using efficiently generated sparse labels. 1,106,291 OCT images from 1,048 patients were collected and utilized to train and evaluate the method. The Dice similarity coefficient for CAC segmentation and the accuracy for CAC classification are 0.693 and 0.932, respectively, close to human-level performance. Applying the method to 1259 ST-segment elevated myocardial infarction patients imaged with OCT, we found that patients with a greater extent and more severe calcification in the culprit vessels were significantly more likely to have major adverse cardiovascular and cerebrovascular events (MACCE) (p < 0.05), while the CAC in non-culprit vessels did not differ significantly between MACCE and non-MACCE groups.

Dual-polarized transmissive metasurfaces for near-unitary-NA analog spatial computing empowered by impedance matching and mismatching.

In recent years, due to the increasing requirement for real-time and massive data processing, optical analog computation has arisen as a promising alternative to digital computation. Optical spatial differentiation plays a fundamentally important role in various emerging technologies, including augmented reality, autonomous driving, and object recognition. However, previous demonstrations encountered several limitations, such as the dependence on polarization states and a typically limited numerical aperture (NA) of about 0.5, especially in the transmission mode. Here, a new, to our knowledge, design strategy based on the evolution between impedance matching and mismatching in a metasurface is proposed to fill this gap, which can perform dual-polarized second-order derivative for image processing. Our scheme enables high transmission under dual polarization over an 85° incident angle range (NA = 0.996), resulting in more than twofold spatial resolution. Our work paves the way for polarization-insensitive high-resolution signal and image processing in the terahertz region.