Hydrogen-Bonded Thiol Undergoes Unconventional Excited-State Intramolecular Proton-Transfer Reactions.

The chapter on the thiol-related hydrogen bond (H-bond) and its excited-state intramolecular proton-transfer (ESIPT) reaction was recently opened where compound 4'-diethylamino-3-mercaptoflavone (3NTF) undergoes ESIPT in both cyclohexane solution and solid, giving a 710 nm tautomer emission with an anomalously large Stokes shift of 12,230 cm-1. Considering the thiol H-bond to be unconventional compared to the conventional Pauling-type -OH or -NH H-bond, it is thus essential and timely to probe its fundamental difference between their ESIPT. However, thiol-associated ESIPT tends to be nonemissive due to the dominant nπ* character of the tautomeric lowest excited state. Herein, based on the 3-mercaptoflavone scaffold and π-elongation concept, a new series of 4'-substituted-7-diethylamino-3-mercaptoflavones, NTFs, was designed and synthesized with varied H-bond strength and 690-720 nm tautomeric emission upon ultraviolet (UV) excitation in cyclohexane. The order of their H-bonding strength was experimentally determined to be N-NTF < O-NTF < H-NTF < F-NTF, while the rate of -SH ESIPT measured by fluorescence upconversion was F-NTF (398 fs)-1 < H-NTF (232 fs)-1 < O-NTF (123 fs)-1 < N-NTF (101 fs)-1 in toluene. Unexpectedly, the strongest H-bonded F-NTF gives the slowest ESIPT, which does not conform to the traditional ESIPT model. The results are rationalized by the trend of carbonyl oxygen basicity rather than -SH acidity. Namely, the thiol acidity relevant to the H-bond strength plays a minor role in the driving force of ESIPT. Instead, the proton-accepting strength governs ESIPT. That is to say, the noncanonical thiol H-bonding system undergoes an unconventional type of ESIPT.

Comparison of Carotid Blood Flow Measured by Ultrasound and Cardiac Output in Patients Undergoing Cardiac Surgery.

BACKGROUND: In general, cerebral blood flow accounts for 10-15% of cardiac output (CO), of which about 75% is delivered through the carotid arteries. Hence, if carotid blood flow (CBF) is constantly proportional to CO with high reproducibility and reliability, it would be of great value to measure CBF as an alternative to CO. The aim of this study was to investigate the direct correlation between CBF and CO. We hypothesized that measurement of CBF could be a good substitute for CO, even under more extreme hemodynamic conditions, for a wider range of critically ill patients. METHODS: Patients aged 65-80 years, undergoing elective cardiac surgery were included in this study. CBF in different cardiac cycles were measured by ultrasound: systolic carotid blood flow (SCF), diastolic carotid blood flow (DCF), and total (systolic and diastolic) carotid blood flow (TCF). CO simultaneously was measured by transesophageal echocardiography. RESULTS: For all patients, the correlation coefficients between SCF and CO, TCF and CO were 0.45 and 0.30, respectively, which were statistically significant, but not between DCF and CO. There was no significant correlation between either SCF, TCF or DCF and CO, when CO was <3.5 L/min. CONCLUSIONS: Systolic carotid blood flow may be used as a better index to replace CO. However, the method of direct measurement of CO is essential when the patient's heart function is poor.

Gold-Catalyzed [3+2]-Annulations of α-Aryl Diazoketones with the Tetrasubstituted Alkenes of Cyclopentadienes: High Stereoselectivity and Enantioselectivity.

This work reports gold-catalyzed [3+2]-annulations of α-diazo ketones with highly substituted cyclopentadienes, affording bicyclic 2,3-dihydrofurans with high regio- and stereoselectivity. The reactions highlights the first success of tetrasubstituted alkenes to undergo [3+2]-annulations with α-diazo carbonyls. The enantioselective annulations are also achieved with high enantioselectivity using chiral forms of gold and phosphoric acid. Our mechanistic analysis supports that cyclopentadienes serve as nucleophiles to attack gold carbenes at the more substituted alkenes, yielding gold enolates that complex with chiral phosphoric acid to enhance the enantioselectivity.

DynaPho: a web platform for inferring the dynamics of time-series phosphoproteomics.

Summary: Large-scale phosphoproteomics studies have improved our understanding of dynamic cellular signaling, but the downstream analysis of phosphoproteomics data is still a bottleneck. We develop DynaPho, a useful web-based tool providing comprehensive and in-depth analyses of time-course phosphoproteomics data, making analysis intuitive and accessible to non-bioinformatics experts. The tool currently implements five analytic modules, which reveal the transition of biological pathways, kinase activity, dynamics of interaction networks and the predicted kinase-substrate associations. These features can assist users in translating their larger-scale time-course phosphoproteomics data into valuable biological discoveries. Availability and implementation: DynaPho is freely available at http://dynapho.jhlab.tw/ . Contact: hsuancheng@ym.edu.tw or yukijuan@ntu.edu.tw . Supplementary information: Supplementary data are available at Bioinformatics online.

Consolidation treatments after chemoradiotherapy in patients with locally advanced inoperable non-small cell lung cancer: a systematic review and network meta-analysis protocol.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) is the standard of care for inoperable locally advanced non-small cell lung cancer. To further improve prognosis, the use of consolidation treatments after CCRT has been explored extensively. Although durvalumab is the only consolidation treatment recommended by national clinical practice guidelines, there have been many studies exploring the effectiveness of other agents. However, until now, no studies have compared all agents systematically, and no studies have provided evidence for the optimal combination of different CCRTs and consolidation treatments regimens. This systematic review will evaluate the comparative clinical efficacy of consolidation therapies after CCRT as well as various combinations of CCRTs and consolidation therapies. METHODS AND ANALYSIS: PubMed, the Cochrane Controlled Register of Trials (CENTRAL), EMBASE and ClinicalTrials.gov will be searched for relevant information. The estimated end date for the search will be 3 February 2022. Each stage of the review, including the study section, data extraction and risk of bias and quality of evidence assessments, will be performed in duplicate. We will include randomised controlled trials that included participants who received CCRT and consolidation treatment in at least one treatment arm. The primary endpoints will be overall survival and progression-free survival. Tumour response, health-related quality of life, disease-free survival and treatment-related toxicity will be presented as secondary outcomes. Both traditional meta-analysis and network meta-analysis (NMA) with the Bayesian approach will be conducted. Subgroup analyses and meta-regression will be completed to investigate heterogeneity, and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required as this study is a meta-analysis based on published studies. The results of this study will be submitted to a peer-reviewed journal for publication. In case of any changes in the protocol, protocol amendments will be updated in PROSPERO and explanations of these modifications will be described in the final report of this review. The results of this systematic review and NMA will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021239433.

How well do integrated 3D models predict alveolar defects after treatment with clear aligners?

OBJECTIVES: To evaluate the accuracy of integrated models (IMs) constructed by pretreatment cone-beam computed tomography (pre-CBCT) in diagnosing alveolar defects after treatment with clear aligners. MATERIALS AND METHODS: Pre-CBCT and posttreatment cone-beam computed tomography (CBCT) scans from 69 patients who completed nonextraction treatment with clear aligners were collected. The IMs comprised anterior teeth in predicted positions and alveolar bone from pre-CBCT scans. The accuracy of the IMs for identifying dehiscences or fenestrations was evaluated by comparing the means of the defect volumes, absolute mean differences, and Pearson correlation coefficients with those measured from post-CBCT scans. Defect prediction accuracy was assessed by sensitivity, specificity, positive predictive values, and negative predictive values. Factors possibly affecting changes in mandibular alveolar defects were analyzed using a mixed linear model. RESULTS: The IM measurements showed mean deviations of 2.82 ± 9.99 mm3 for fenestrations and 3.67 ± 9.93 mm3 for dehiscences. The absolute mean differences were 4.50 ± 9.35 mm3 for fenestrations and 5.17 ± 9.24 mm3 for dehiscences. The specificities of the IMs were higher than 0.8, whereas the sensitivities were both lower (fenestration = 0.41; dehiscence = 0.53). The positive predictive values were unacceptable (fenestration = 0.52; dehiscence = 0.62), and the overall reliability was low (<0.80). Molar distalization and proclination were positively correlated with significant increases in alveolar defects at the mandibular incisors after treatment. CONCLUSIONS: Alveolar defects after clear aligner treatment cannot be simulated accurately by IMs constructed from pre-CBCT. Caution should be taken in the treatment of crowding with proclination and molar distalization for the safety of alveolar bone at the mandibular incisors.

Clear aligners for maxillary anterior en masse retraction: a 3D finite element study.

To evaluate tooth behaviours under various maxillary incisor retraction protocols for clear aligner therapy. A three-dimensional finite element model of maxillary dentition was constructed for first premolar extraction. A loading method was developed to mimic the mode of action of clear aligners for incisor en masse retraction. Three protocols with different amounts of retraction and intrusion on incisors were designed. Initial tooth displacements and stresses on periodontal ligaments were analysed with ANSYS software. The central (U1) and lateral (U2) incisors exhibited uncontrolled lingual tipping and extrusion upon 0.25 mm retraction. U1 exhibited translation movement, while U2 underwent less tipping during 0.2 mm retraction and 0.15 mm intrusion. Labial tipping and intrusion of U1 and bodily intrusion of U2 were observed during 0.1 mm of retraction and 0.23 mm of intrusion. With the additional intrusion on incisors, canine showed extrusion movement, and higher stresses on periodontal ligaments were shifted from U2 to canines. Incisors also exhibited different mesial-distal angulation in the three simulations, while posterior teeth all suffered mesial inclination. Incorporating intrusion displacement in clear aligners led to a tendency of lingual root movement during incisor retraction. The complexity of tooth movement should be recognized regarding clear aligner therapy.

Upregulated long-non-coding RNA DLEU2 exon 9 expression was an independent indicator of unfavorable overall survival in patients with esophageal adenocarcinoma.

In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.

MFAP2 promotes epithelial-mesenchymal transition in gastric cancer cells by activating TGF-ß/SMAD2/3 signaling pathway.

INTRODUCTION: Microfibril-associated protein 2 (MFAP2) is an extracellular matrix protein that interacts with fibrillin to modulate the function of microfibrils. MFAP2 has been reported to play a significant role in obesity, diabetes, and osteopenia, and has been shown to be upregulated in head and neck squamous cell carcinoma. However, the molecular function and prognostic value of MFAP2 have never been reported in gastric cancer (GC) or any other tumors. METHODS: The current study investigated the expression patterns, prognostic significance, functional role, and possible mechanisms of MFAP2 in GC. RESULTS: We demonstrated that MFAP2 was overexpressed in GC tissues, and its overexpression was significantly correlated with poor overall and disease-free survival in patients with GC. Moreover, we found that MFAP2 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) phenotype in GC cells. MFAP2 might modulate EMT of GC cells by activating the TGF-ß/SMAD2/3 signaling pathway. CONCLUSION: These findings provide novel evidence that MFAP2 plays a crucial role in the progression of GC. Therefore, MFAP2 may be a promising prognostic marker and a potent anticancer agent.

Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death.

In the current study, we evaluated the potential effect of a novel sphingosine kinase 1 (SphK1) activator, K6PC-5, on oxygen-glucose deprivation (OGD)/reoxygenation-induced damages to myocardial cells. We demonstrated that K6PC-5 increased intracellular sphingosine-1-phosphate (S1P) content and remarkably inhibited OGD/reoxygenation-induced death of myocardial cells (H9c2/HL-1 lines and primary murine myocardiocytes). SphK1 inhibitors, B-5354c and SKI-II, or SphK1-siRNA knockdown not only aggregated OGD/reoxygenation-induced cytotoxicity but also nullified the cytoprotection by K6PC-5. On the other hand, overexpression of SphK1 alleviated H9c2 cell death by OGD/reoxygenation, and K6PC-5-mediated cytoprotection was also enhanced in SphK1 overexpressed cells. Molecularly, OGD/reoxygenation activated the mitochondrial death pathway, evidenced by reactive oxygen species (ROS) production, mitochondrial membrane potential reduction, and p53-cyclophilin D (Cyp-D) association, which were all alleviated by K6PC-5 or overexpression of SphK1, but exacerbated by SphK1 knockdown. Furthermore, OGD/reoxygenation induced prodeath ceramide production in myocardial cells, which was largely suppressed by K6PC-5. In the meantime, adding a cell-permeable short-chain ceramide (C6) mimicked OGD/reoxygenation actions and induced ROS production and the mitochondrial death pathway in myocardial cells. Together, we conclude that K6PC-5 inhibits OGD/reoxygenation-induced myocardial cell death probably through activating SphK1. The results of the study indicate a potential benefit of K6PC-5 on ischemic heart disease.