Pd(II)-Catalyzed Site-Selective Cross Coupling Reaction: Synthesis of Highly Fluorescent Aryl-Formyl-Chromenes and its Iminoantipyrine Analogues as Selective AChE Inhibitors.

A versatile and efficient chemo selective synthesis of 4-aryl-3-formyl-2H-chromenes (AFC) was undertaken using Pd-catalyzed cross-coupling conditions. The key oxidative transmetalation was successfully applied to a significant range of substitutions on the chromene moiety and aryl ring in Ar(BOH)3, accommodating both electron-rich and electron-deficient groups. These π-extended scaffolds exhibited green-yellow fluorescence with a large Stokes shift and high quantum yield. Measurement of photophysical properties revealed that the compound with methoxy substitution in the chromene ring, 3t, caused a significant bathochromic shift. The AFCs obtained from this method can be transformed into biologically active 4-aryl-3-iminoantipyrine-2H-chromenes (AAC) through functionalization of the formyl chromenes. The AFCs and AACs with methoxy substitutions (3t and 4e) were docked against AChE inhibition, and compound 4e had the lowest binding energy of -11.20 kcal/mol. DFT calculations performed on representative compounds revealed that compound 4e is more reactive than 3t, which is in accordance with the docking studies.

A Frequent Diagnostic Pitfall: Dermatological Clinical Features and Pathological Results in Diagnosing Pagetoid Squamous Cell Carcinoma in situ (Case Series).

Squamous cell carcinoma (SCC) in situ can occur on any skin or mucus surface and is more commonly found in elderly patients on areas of skin that have been sunburnt. Most previous case reports are from dermatologists, with few published reports from pathologists. In this study, three patients underwent pathological routine and auxiliary immunohistochemical (IHC) examination and were ultimately diagnosed with pagetoid SCC in situ - a different diagnosis from the initial clinical assessment. All three patients received a complete resection of the skin mass. After follow-up, as of June 2023, the patients had no tumour recurrence or metastasis. Pagetoid SCC in situ is a particular type of SCC in situ that has no specific features in clinical manifestations, gross diagnosis or histopathological sections. The final diagnosis depends on IHC staining. Pagetoid SCC in situ expresses EMA, CK5/6 and p63 but not CEA, CK8 or S-100, which are expressed in extramammary Paget's disease. Pagetoid SCC in situ is usually only locally invasive, and the main treatment is complete surgical resection. The prognosis is related to human papillomavirus infection, surgical margin closure, disease location, tumour thickness and other factors.

Clinicopathological Analysis of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma of the Spleen: A Case Report.

OBJECTIVE: The present study aims to explore the clinicopathological characteristics of Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (IFDCS; EBV+ IFDCS). CASE REPORT: The case involved a 32-year-old woman who underwent surgical resection of a splenic nodule. Histological examination and immunohistochemistry were performed using cluster of differentiation (CD) markers, and in-situ hybridization was conducted to detect EBV-encoded RNA (EBER). RESULTS: A microscopic analysis revealed neoplastic cells with various morphologies, including round, ovoid, or spindled shapes, dispersed within a prominent lymphoplasmacytic infiltrate. The tumor cells exhibited nuclear atypia, with some resembling Reed-Sternberg cells. The immunohistochemistry demonstrated focal positivity for follicular dendritic cell markers, such as CD21, CD23 and CD35, and focal negativity for other markers, including CD3, CD34, CD20, CD79a, myeloperoxidase and HMB45. Additionally, the EBER staining showed strongly positive results. The patient showed no local recurrence or metastasis during the 13-month follow-up. CONCLUSION: A comprehensive understanding of EBV+IFDCS, including its clinicopathological features and immunohistochemical characteristics, is crucial for accurate diagnosis and differential diagnosis of this rare tumor.

A hyper-knowledge graph system for research on AI ethics cases.

Current studies on the artificial intelligence (AI) ethics focus either on very broad guidelines or on a very special domain. Therefore, the research outcome can hardly be converted into actionable measures or transferred to other domains. Potential correlations between various cases of AI ethics at different granularity levels are unexplored. To overcome these deficiencies, the authors designed a case-oriented ontological model (COOM) and a hyper-knowledge graph system (HKGS) for the research of collected AI ethics cases. COOM describes criteria for modelling cases by attributes from three perspectives: event attributes, relational attributes, and positional attributes on the value chain. Based on it, HKGS stores the correlation between cases as knowledge and allows advanced visual analysis. The correlations between cases and their dynamic changes on value chain can be observed and explored. In HKGS's implementation part, one of the collected ethics cases is used as an example to demonstrate how to generate a hyper-knowledge graph and to visually analyze it. The authors also anticipated how different practitioners of AI ethics, can achieve the desired outputs from HKGS in their diverse scenarios.

Enhanced FRER Mechanism in Time-Sensitive Networking for Reliable Edge Computing.

Time-Sensitive Networking (TSN) and edge computing are promising networking technologies for the future of the Industrial Internet. TSN provides a reliable and deterministic low-latency communication service for edge computing. The Frame Replication and Elimination for Reliability (FRER) mechanism is important for improving the network reliability of TSN. It achieves high reliability by transmitting identical frames in parallel on two disjoint paths, while eliminating duplicated frames at the destination node. However, there are two problems with the FRER mechanism. One problem is that it does not consider the path reliability, and the other one is that it is difficult to find two completely disjoint path pairs in some cases. To solve the above problems, this paper proposes a method to find edge-disjoint path pairs considering path reliability for FRER in TSN. The method includes two parts: one is building a reliability model for paths, and the other one is computing a working path and a redundant path with the Edge-Disjoint Path Pairs Selection (EDPPS) algorithm. Theoretical and simulation results show that the proposed method effectively improves path reliability while reducing the delay jitter of frames. Compared with the traditional FRER mechanism, the proposed method reduces delay jitter by 15.6% when the network load is 0.9.

Comprehensive characterization of polyproline tri-helix macrocyclic nanoscaffolds for predictive ligand positioning.

Multivalent ligands hold promise for enhancing avidity and selectivity to simultaneously target multimeric proteins, as well as potentially modulating receptor signaling in pharmaceutical applications. Essential for these manipulations are nanosized scaffolds that precisely control ligand display patterns, which can be achieved by using polyproline oligo-helix macrocyclic nanoscaffolds via selective binding to protein oligomers and cell surface receptors. This work focuses on synthesis and structural characterization of different-sized polyproline tri-helix macrocyclic (PP3M) scaffolds. Through combined analysis of circular dichroism (CD), small- and wide-angle X-ray scattering (SWAXS), electron spin resonance (ESR) spectroscopy, and molecular modeling, a non-coplanar tri-helix loop structure with partially crossover helix ends is elucidated. This structural model aligns well with scanning tunneling microscopy (STM) imaging. The present work enhances the precision of nanoscale organic synthesis, offering prospects for controlled ligand positioning on scaffolds. This advancement paves the way for further applications in nanomedicine through selective protein interaction, manipulation of cell surface receptor functions, and developments of more complex polyproline-based nanostructures.

Effect of Temperature-Dependent Low Oxygen Partial Pressure Annealing on SiC MOS.

Oxygen post annealing is a promising method for improving the quality of the SiC metal oxide semiconductor (MOS) interface without the introduction of foreign atoms. In addition, a low oxygen partial pressure annealing atmosphere would prevent the additional oxidation of SiC, inhibiting the generation of new defects. This work focuses on the effect and mechanism of low oxygen partial pressure annealing at different temperatures (900-1250 °C) in the SiO2/SiC stack. N2 was used as a protective gas to achieve the low oxygen partial pressure annealing atmosphere. X-ray photoelectron spectroscopy (XPS) characterization was carried out to confirm that there are no N atoms at or near the interface. Based on the reduction in interface trap density (Dit) and border trap density (Nbt), low oxygen partial pressure annealing is proven to be an effective method in improving the interface quality. Vacuum annealing results and time of flight secondary ion mass spectrometry (ToF-SIMS) results reveal that the oxygen vacancy (V[O]) filling near the interface is the dominant annealing mechanism. The V[O] near the interface is filled more by O2 in the annealing atmosphere with the increase in temperature.

Bidirectional association between major depressive disorder and dementia: Two population-based cohort studies in Taiwan.

BACKGROUND: Major depressive disorder (MDD) and dementia are both major contributors to the global burden of disease. Despite existing literature on the association between MDD and dementia, there is a lack of a nationwide longitudinal cohort study that considers the competing risk of death. Therefore, this study assessed the bidirectional associations between MDD and dementia over an 11-year period in population-based settings, accounting for death as a competing risk. METHODS: We conducted two population-based retrospective cohort studies in Taiwan. We identified 80,742 patients diagnosed with MDD in 2009-2010 and matched them with patients without MDD by sex, age, and year of diagnosis to assess the relative risk of dementia. We also identified 80,108 patients diagnosed with dementia in 2009-2010 and matched them with patients without dementia by sex, age, and year of diagnosis to assess the relative risk of MDD. All patients were followed until they received a diagnosis of new onset MDD or new onset dementia, their death, or the end of 2019. Cause-specific hazards models were used to estimate adjusted hazard ratios (aHRs). RESULTS: The incidence density (ID) of dementia was higher in patients with MDD than in patients without MDD (7.63 vs. 2.99 per 1000 person-years), with an aHR of 2.71 (95% confidence interval [CI]: 2.55-2.88). The ID of MDD was higher in patients with dementia than in patients without dementia (12.77 vs. 4.69 per 1000 person-years), with an aHR of 2.47 (95% CI: 2.35-2.59). CONCLUSIONS: This population-based study found a bidirectional association between MDD and dementia. Our findings suggest the need to identify dementia in patients with MDD and vice versa.

Structural basis of interleukin-17B receptor in complex with a neutralizing antibody for guiding humanization and affinity maturation.

Upregulation of interleukin-17 receptor B (IL-17RB) is known to be oncogenic, while other IL-17 receptors and ligands are generally involved in pro-inflammatory pathways. We identify a mouse neutralizing monoclonal antibody (mAb) D9, which blocks the IL-17RB/IL-17B pathway and inhibits pancreatic tumorigenesis in an orthotopic mouse model. The X-ray crystal structure of the IL-17RB ectodomain in complex with its neutralizing antibody D9 shows that D9 binds to a predicted ligand binding interface and engages with the A'-A loop of IL-17RB fibronectin III domain 1 in a unique conformational state. This structure also provides important paratope information to guide the design of antibody humanization and affinity maturation of D9, resulting in a humanized 1B12 antibody with marginal affinity loss and effective neutralization of IL-17B/IL-17RB signaling to impede tumorigenesis in a mouse xenograft model.

Fixed complex electrograms during sinus rhythm and local pacing: potential ablation targets for persistent atrial fibrillation.

In atrial fibrillation (AF) patients, complex electrograms during sinus rhythm (C-EGMs) could be pathological or not. We aimed to demonstrate whether local pacing was helpful to discern pathological C-EGMs. 126 persistent AF patients and 27 patients with left-side accessory pathway (LAP) underwent left atrial mapping during sinus rhythm. If C-EGMs were detected, local pacing was performed. If the electrograms turned normal, we defined them as non-fixed C-EGMs, otherwise as fixed C-EGMs. No difference was detected in the incidence and proportion of non-fixed C-EGMs between AF patients and LAP patients (101/126 vs. 19/27, P = 0.26; 9.1 ± 6.0% vs. 7.7 ± 5.7%, P = 0.28). However, the incidence and proportion of fixed C-EGMs were higher in persistent AF patients (87/126 vs. 1/27, P < 0.01; 4.3 ± 3.4% vs. 0.1 ± 0.5%, P < 0.01). Compared with non-fixed C-EGMs, fixed C-EGMs had lower amplitudes, longer electrogram durations and longer Stimuli-P wave internals. All AF patients received circumferential pulmonary vein isolation. Among AF patients with fixed C-EGMs, 45 patients received fixed C-EGMs ablation and 42 patients underwent linear ablation. Compared with linear ablation, fixed C-EGMs ablation reduced recurrence (HR: 0.43; 95% CI 0.21-0.81; P = 0.011). Among patients without fixed C-EGMs ablation, the proportion of fixed C-EGMs was an independent predictor of ablation outcomes (HR for per percent: 1.13, 95% CI 1.01-1.28, P = 0.038). C-EGMs could be classified into fixed and non-fixed C-EGMs through local pacing. Fixed rather than non-fixed C-EGMs might indicate abnormal atrial substrates and fixed C-EGMs ablation improve outcomes of persistent AF ablation.

Relationship between the time point of left atrial size change and the outcomes of radiofrequency catheter ablation.

PURPOSE: The change in the left atrial anteroposterior diameter (LAD) after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) has become an independent factor in predicting the postoperative curative effect; however, whether the specific time point of this change is related to the postoperative curative effect is unclear. The purpose of this study was to explore the correlation between the specific time point of LAD change and the recurrence of AF 1 year after RFCA. METHODS: Patients with AF who underwent RFCA in our hospital from July 2016 to May 2020 were enrolled in the study. The patients were divided into four groups according to the time point when the LAD decreased by 10% after RFCA: group A, first month after RFCA; group B, second month after RFCA; group C, third month after RFCA; group D, unchanged or changed > 3 months after RFCA. RESULTS: In the multivariable Cox analyses, the duration of AF, LAD, and persistent AF were independent risk factors for the recurrence of AF. The recurrence rate of AF 1 year after RFCA were significantly lower in groups A (odds ratio [OR], 0.160; 95% confidence interval [CI]: 0.073-0.352; P < 0.001) and C (OR, 0.388; 95% CI: 0.156-0.963; P = 0.041) than in the control group. CONCLUSIONS: Reduction of LAD within 3 months after operation predicts the success rate of RFCA, with reduction within 1 month after operation having a higher success rate. This indicates the necessity of treatment in patients with AF who do not experience an early reduction in the LAD after RFCA.

Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices.

The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.

Left Atrial Appendage Morphology and Local Thrombogenesis-Related Blood Parameters in Patients With Atrial Fibrillation.

Background Left atrial appendage (LAA) morphology predicts stroke risk in patients with atrial fibrillation. However, it is not precisely understood how LAA morphology influences stroke risk. The present study aimed to investigate the relationship between LAA morphology and local thrombogenesis-related blood parameters in LAA. Methods and Results We enrolled 205 patients undergoing catheter ablation of atrial fibrillation. The prevalence of chicken wing-, cactus-, windsock-, and cauliflower-type LAAs were 23.9%, 32.7%, 29.3%, and 14.1%, respectively. Blood samples were collected from the femoral vein, left atrium, and LAA in each patient. The levels of blood parameters were tested for each blood sample. The cauliflower-type LAA was associated with elevated platelet P-selectin expression, and interleukin-6 levels and with lower NO levels in LAA blood samples (P<0.05) independent of LAA flow velocity and LAA volume. LAA flow velocity, which was lowest in the cauliflower-type LAA, was the only independent predictor of von Willebrand factor antigen and plasminogen activator inhibitor-1 levels in LAA blood samples. In femoral vein blood samples, no significant difference was detected in the above blood parameters among the four LAA morphological types. In all blood samples, the levels of thrombin-antithrombin complex, D-dimer, fibrinogen, and tissue plasminogen activator were comparable among the four LAA morphological types. Conclusions In patients with atrial fibrillation, LAA morphological types might be associated with local platelet activity, fibrinolysis function, endothelial dysfunction, and inflammation.

Preparation and conformational analysis of polyproline tri-helix macrocycle nanoscaffolds of varied sizes.

Ligand patterns at the nanoscale are essential in modulating biological recognition and signaling through binding to receptor oligomers. Biocompatible nanoscaffolds that allow precise control of multiple ligand presentation would be of great use in manipulating cellular processes and understanding membrane receptor biology. We have previously developed tri-helix and tetra-helix macrocycle scaffolds based on the Pro9 peptide helix to control ligand arrangements that can selectively target receptor oligomers. A better understanding of the structure of these macromolecules would significantly reduce the difficulty in designing matching ligand positions for target receptors. In this work, we expand the arsenal of ligand patterns by preparing polyproline tri-helix macrocycle scaffolds of different sizes. These synthetic nanoscaffolds composed of peptide helices ranging from Pro6 to Pro12 also allowed us to systematically investigate their properties. With a combination of circular dichroism spectroscopy and ion mobility spectrometry-mass spectrometry (IMS-MS), the measurement for varied sizes of these scaffolds indicated the connecting dihedral angle between both ends of the helix affects the strain in the cyclic scaffold. The experimental collision cross section obtained from IMS-MS favors a propeller model for the helix arrangements. The results not only contribute conformational insights for the polyproline tri-helix system, but also provide precious information for the future design and synthesis of cyclic nanostructures based on peptide helices.

Synthesis of Asymmetric N-Glycans as Common Core Substrates for Structural Diversification through Selective Enzymatic Glycosylation.

N-glycans on the cell surface provide distinct signatures that are recognized by different glycan-binding proteins (GBPs) and pathogens. Most glycans in humans are asymmetric and isomeric, yet their biological functions are not well understood due to their lack of availability for studies. In this work, we have developed an improved strategy for asymmetric N-glycan assembly and diversification using designed common core substrates prepared chemically for selective enzymatic fucosylation and sialylation. The resulting 26 well-defined glycans that carry the sialic acid residue on different antennae were used in a microarray as a representative application to profile the binding specificity of hemagglutinin (HA) from the avian influenza virus (H5N2). We found distinct binding affinity for the Neu5Ac-Gal epitope linked to the N-acetylglucosamine (GlcNAc) of different branches and only a minor effect in binding for the terminal galactose on different branches. Overall, the microarray analysis showed branch-biased and context-based recognition patterns.

Two-temperature Collisional-radiative Modeling of Partially Ionized O2-Ar Mixtures over 8000-10,000 K Behind Reflected Shock Waves.

The collisional excitation kinetics of atomic oxygen was studied behind reflected shock waves using tunable diode laser absorption spectroscopy. A test gas mixture of 1% O2/Ar was shock-heated to temperatures between 8000 and 10,000 K and pressures between 0.15 and 1 atm. The time evolution of the atomic oxygen population in the 3 s 5S0 state was monitored by laser absorption at 777.2 nm. The measured O(3 s 5S0) population revealed multistage behavior that was not observed in previous measurements over a temperature range of 5300-7200 K. To interpret the multistage behavior, a three-level collisional-radiative model for atomic oxygen excitation kinetics was developed. The model utilized two independent temperatures, that is, heavy particle translational temperature Ttr and electron translational temperature Te, to describe the fundamental rate constants of atomic oxygen excitation because of collisions with heavy particles and electrons, respectively. The heavy particle excitation rate was inferred from the early stage of the measurement to be k(3P →5S0) = 3.4 × 10-27 (T/K)0.5(1.061 × 105 + 2 (T/K)) exp(-1.061 × 105 K/T) ± 50% m3 s-1. The electron impact excitation rate constant of oxygen, electron impact, and heavy particle impact ionization rate constants of Argon were modified in the model to match the experimental population time histories. The modified rate parameters are also reported for the temperature range explored in the current study.

Reactivity of NO2 with Porous and Conductive Copper Azobispyridine Metallopolymers.

We report the reactivity of copper azobispyridine (abpy) metallopolymers with nitrogen dioxide (NO2). The porous and conductive [Cu(abpy)]n mixed-valence metallopolymers undergo a redox reaction with NO2, resulting in the disproportionation of NO2 gas. Solid- and gas-phase vibrational spectroscopy and X-ray analysis of the reaction products of the NO2-dosed metallopolymer show evidence of nitrate ions and nitric oxide gas. Exposure to NO2 results in complete loss of porosity and a decrease in the room-temperature conductivity of the metallopolymer by four orders of magnitude with the loss of mixed-valence character. Notably, the porous and conductive [Cu(abpy)]n metallopolymers can be reformed by reducing the Cu-nitrate species.

Selective targeting of DC-SIGN by controlling the oligomannose pattern on a polyproline tetra-helix macrocycle scaffold.

DC-SIGN and langerin receptors both bind to oligomannose but lead to opposite effects upon encountering HIV. Because selective targeting of DC-SIGN can lead to anti-viral effects, we developed a glycoconjugate, which provides over 4800-fold selectivity for DC-SIGN over langerin, by controlling the oligomannose pattern on a polyproline tetra-helix macrocycle scaffold.

Polyproline Tri-Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions.

Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sites arrangement. The GalNAc pattern selectivity is also observed on intact asialoglycoprotein receptor oligomer on human hepatoma cells showing the pattern-selective interaction can be achieved not only on isolated protein oligomers but also the receptors arranged on the cell surface. As the scaffold design allows convenient creation of versatile ligand patterns, it can be expected as a promising tool to probe the arrangement of receptors on the cell surface and as nanomedicine to manipulate signaling or cell recognition.

Acute rhinosinusitis among pediatric patients with allergic rhinitis: A nationwide, population-based cohort study.

BACKGROUND: While chronic rhinosinusitis is a common complication of allergic rhinitis, the link between acute rhinosinusitis and allergic rhinitis is unclear. The aim of this study was to evaluate the risk of incident acute rhinosinusitis among pediatric patients with allergic rhinitis, using a nationwide, population-based health claims research database. METHODS: Newly diagnosed allergic rhinitis patients aged 5-18 years were identified from the health claim records of the Longitudinal Health Insurance Database 2000 of Taiwan's National Health Insurance Research Database. A comparison cohort was assembled by randomly selecting patients from the same database with frequency matching by sex, age group, and index year. All patients were followed until a diagnosis of acute rhinosinusitis or the end of the follow-up period. Cox proportional hazards model was used to assess the association between allergic rhinitis and acute rhinosinusitis. RESULTS: Of the 43,588 pediatric patients included in this study, 55.4% were male and 43.9% were between the ages of 5.0-7.9 years. The risk of acute rhinosinusitis was significantly higher in pediatric patients with allergic rhinitis compared to those without the condition (adjusted hazard ratio = 3.03, 95% confidence interval = 2.89-3.18). Similar hazard ratios were observed between male and female pediatric patients. CONCLUSIONS: This secondary cohort study using a nationwide, population-based health claim data of the Taiwan's NHIRD showed that allergic rhinitis was significantly associated with a higher risk of acute rhinosinusitis among pediatric patients.