Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways.

Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects: one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound 6a being most effective (IC50 values of 1.23 and 1.37 µM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound 26a (IC50 of 1.56 µM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.

Impact of seasonal changes and environmental conditions on suspended and inhalable microplastics in urban air.

Microplastics (MPs) are ubiquitous environmental pollutants extensively detected in atmospheric environments. Airborne MPs have raised concerns due to their transport and potential health risks of inhalation exposure. However, the factors influencing airborne MPs, particularly their concentrations and shapes suspended in urban air, remain unclear. We investigated MPs in total suspension particles with one-year measurements in Taipei City and identified their features using Nile Red staining combined with fluorescence microscopy and micro-Fourier transform infrared (µFTIR) spectroscopy. This study quantified the mean number concentration of total MPs as approximately 6.0 #/m³. We observed that MP abundance varied seasonally, with higher levels in the warm season than in the cold. A similar trend was noted for polymer types. Fragment-like MPs were the predominant shape, mainly found in polystyrene (PS), polyethylene (PE), and polypropylene (PP), while fibrous MPs, detected mostly as polyethylene terephthalate (PET) and polyamide (PA), were primarily observed at sizes greater than 300 µm. Both fiber and fragment-like MPs were positively associated with particle mass concentration, temperature, ultraviolet (UV) index, and wind speed, but negatively correlated with relative humidity and rainfall. Fibrous MPs were more affected by environmental factors than fragment-like MPs. Meteorological changes significantly influenced suspended MPs more than human activity within the city.

NT-pro-BNP Level is Related to Left Ventricular Remodeling in Patients With Primary Aldosteronism.

AIMS: To assess the relationship between the left ventricular remodeling parameters of cardiac magnetic resonance and NT-pro-BNP in patients with primary aldosteronism (PA). METHODS: Seventy-four PA and 39 essential hypertension patients were prospectively recruited and underwent cardiac magnetic resonance. Plasma NT-pro-BNP was measured before patients underwent cardiac magnetic resonance. Left ventricular remodeling parameters were defined as left ventricular function parameters, T1 mapping parameters, and strain parameters. Differences in continuous variables between two groups were analyzed using Student's t-test or Mann-Whitney U test. Differences in categorical variables between two groups were analyzed by chi-squared test. Spearman's correlation and linear regression were used to analyze the relationships between left ventricular remodeling parameters and plasma NT-Pro-BNP level. P<0.05 was considered as statistically significant. RESULTS: Patients with PA demonstrated higher NT-pro-BNP [86.0 (49.5, 145.5) vs. 45.0 (28.5, 73.5) pg/mL, P=0.001] and Native T1 (1227±41 vs. 1206±43 ms, P=0.015) level than essential hypertension patients. Compared to patients with normal NT-pro-BNP levels, those with abnormal levels demonstrated different left ventricular remodeling parameters. NT-pro-BNP level was independently related to native T1 (ß=0.316, P=0.006), extracellular volume (ß=0.419, P<0.001), short-axis global circumferential strain (ß=0.429, P<0.001), four-chamber global longitudinal strain (ß=0.332, P=0.002), and four-chamber global radial strain (ß=-0.334, P=0.004) in patients after adjusting for baseline characteristics. CONCLUSIONS: NT-pro-BNP level was related to left ventricular remodeling parameters derived from cardiac magnetic resonance in patients with PA. This result implies that clinicians should pay attention to NT-pro-BNP assessment in patients with PA in routine clinical assessment.

Compressible Hollow Microlasers in Organoids for High-Throughput and Real-Time Mechanical Screening.

Mechanical stress within organoids is a pivotal indicator in disease modeling and pharmacokinetics, yet current tools lack the ability to rapidly and dynamically screen these mechanics. Here, we introduce biocompatible and compressible hollow microlasers that realize all-optical assessment of cellular stress within organoids. The laser spectroscopy yields identification of cellular deformation at the nanometer scale, corresponding to tens of pascals stress sensitivity. The compressibility enables the investigation of the isotropic component, which is the fundamental mechanics of multicellular models. By integrating with a microwell array, we demonstrate the high-throughput screening of mechanical cues in tumoroids, establishing a platform for mechano-responsive drug screening. Furthermore, we showcase the monitoring and mapping of dynamic contractile stress within human embryonic stem cell-derived cardiac organoids, revealing the internal mechanical inhomogeneity within a single organoid. This method eliminates time-consuming scanning and sample damage, providing insights into organoid mechanobiology.

Single-cell laser emitting cytometry for label-free nucleolus fingerprinting.

The nucleolus, a recognized biomolecular condensate, serves as the hub for ribosome biogenesis within the cell nucleus. Its quantity and morphology are discernible indicators of cellular functional states. However, precise identification and quantification of nucleoli remain challenging without specific labeling, particularly for suspended cells, tissue-level analysis and high-throughput applications. Here we introduce a single-cell laser emitting cytometry (SLEC) for label-free nucleolus differentiation through light-matter interactions within a Fabry-Perot resonator. The separated gain medium enhances the threshold difference by 36-fold between nucleolus and its surroundings, enabling selective laser emissions at nucleolar area while maintaining lower-order mode. The laser emission image provides insights into structural inhomogeneity, temporal fluid-like dynamics, and pathological application. Lasing spectral fingerprint depicts the quantity and size of nucleoli within a single cell, showcasing the label-free flow cytometry for nucleolus. This approach holds promise for nucleolus-guided cell screening and drug evaluation, advancing the study of diseases such as cancer and neurodegenerative disorders.

Modeling multi-component separation in hydrophobic interaction chromatography with improved parameter-by-parameter estimation method.

Mechanistic models are powerful tools for chromatographic process development and optimization. However, hydrophobic interaction chromatography (HIC) mechanistic models lack an effective and logical parameter estimation method, especially for multi-component system. In this study, a parameter-by-parameter method for multi-component system (called as mPbP-HIC) was derived based on the retention mechanism to estimate the six parameters of the Mollerup isotherm for HIC. The linear parameters (ks,i and keq,i) and nonlinear parameters (ni and qmax,i) of the isotherm can be estimated by the linear regression (LR) and the linear approximation (LA) steps, respectively. The remaining two parameters (kp,i and kkin,i) are obtained by the inverse method (IM). The proposed method was verified with a two-component model system. The results showed that the model could accurately predict the protein elution at a loading of 10 g/L. However, the elution curve fitting was unsatisfactory for high loadings (12 g/L and 14 g/L), which is mainly attributed to the demanding experimental conditions of the LA step and the potential large estimation error of the parameter qmax. Therefore, the inverse method was introduced to further calibrate the parameter qmax, thereby reducing the estimation error and improving the curve fitting. Moreover, the simplified linear approximation (SLA) was proposed by reasonable assumption, which provides the initial guess of qmax without solving any complex matrix and avoids the problem of matrix unsolvable. In the improved mPbP-HIC method, qmax would be initialized by the SLA and finally determined by the inverse method, and this strategy was named as SLA+IM. The experimental validation showed that the improved mPbP-HIC method has a better curve fitting, and the use of SLA+IM reduces the error accumulation effect. In process optimization, the parameters estimated by the improved mPbP-HIC method provided the model with excellent predictive ability and reasonable extrapolation. In conclusion, the SLA+IM strategy makes the improved mPbP-HIC method more rational and can be easily applied to the practical separation of protein mixture, which would accelerate the process development for HIC in downstream of biopharmaceuticals.

Enhancing thermodynamic consistency: Clarification on the application of asymmetric activity model in multi-component chromatographic separation.

The single-component Mollerup model, with over 40 direct applications and 442 citations, is the most widely used activity model for chromatographic mechanistic modeling. Many researchers have extended this formula to multi-component systems by directly adding subscripts, a modification deemed thermodynamically inconsistent (referred to as the reference model). In this work, we rederived the asymmetric activity model for multi-component systems, using the van der Waals equation of state, and termed it the multi-component Mollerup model. In contrast to the reference model, our proposed model accounts for the contributions of all components to the activity. Three numerical experiments were performed to investigate the impact of the three different activity models on the chromatographic modeling. The results indicate that our proposed model represents a thermodynamically consistent generalization of the single-component Mollerup model to multi-component systems. This communication advocates adopting of the multi-component Mollerup model for activity modeling in multi-component chromatographic separation to enhance thermodynamic consistency.

Occurrence and emission characteristics of microplastics in agricultural surface runoff under different natural rainfall and short-term fertilizer application.

Land-based microplastics (MPs) are considered the primary source of MPs in aquatic environments, with runoff being a major pathway for their transfer from soil to surface water. However, the transportation characteristics of MPs via agricultural surface runoff remain unclear. In this study, we investigated the occurrence and emission characteristics of MPs in agricultural surface runoff under various short-term fertilizer applications and natural rainfall events using laser direct infrared imaging analysis (LDIR). MPs from fertilizers and soils co-migrated with the agricultural runoff. The abundance and concentration of MPs in runoff were 145.90 ± 22.48-2043.38 ± 89.51 items·L-1 and 39.17 ± 21.94-523.04 ± 47.85 µg·L-1, respectively. Small and low-density MPs, such as polyethylene (PE), chlorinated polyethylene (CPE), and polyurethane (PU) in film/fragment form with 20-50 µm exhibited a higher mobility. No statistical differences were observed in the distribution of runoff MPs with the application of different fertilizers. There was a significant positive relationship between runoff MP abundance and rainfall intensity. The annual emission load in this study area was 116.73 g·hm-2, indicating that the transportation of MPs via agricultural surface runoff cannot be ignored. This study is conducive to understanding the migration behavior of MPs in soil-water environments in a better manner.

Real-world effectiveness and safety of macitentan in patients with pulmonary artery hypertension: a multicenter, retrospective, observational study in China.

BACKGROUND: Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. METHODS: This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3-7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)/B-type natriuretic peptide from baseline to first follow-up visit (months 3-7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. RESULTS: From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. CONCLUSION: This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.

The Prognostic Value of Left Ventricular Entropy From T1 Mapping in Patients With Hypertrophic Cardiomyopathy.

Background: The prognostic value of left ventricular (LV) entropy in hypertrophic cardiomyopathy (HCM) is unclear. Objectives: This study aimed to assess the prognostic value of LV entropy from T1 mapping in HCM. Methods: A total of 748 participants with HCM, who underwent cardiovascular magnetic resonance (CMR), were consecutively enrolled. LV entropy was quantified by native T1 mapping. A competing risk analysis and a Cox proportional hazards regression analysis were performed to identify potential associations of LV entropy with sudden cardiac death (SCD) and cardiovascular death (CVD), respectively. Results: A total of 40 patients with HCM experienced SCD, and 65 experienced CVD during a median follow-up of 43 months. Participants with increased LV entropy (≥4.06) were more likely to experience SCD and CVD (all P < 0.05) in the entire study cohort or the subgroup with low late gadolinium enhancement (LGE) extent (<15%). After adjustment for the European Society of Cardiology predictors and the presence of high LGE extent (≥15%), LV mean entropy was an independent predictor for SCD (HR: 1.03; all P < 0.05) by the multivariable competing risk analysis and CVD (HR: 1.06; 95% CI: 1.03-1.09; P < 0.001) by multivariable Cox regression analysis. Conclusions: LV mean entropy derived from native T1 mapping, reflecting myocardial tissue heterogeneity, was an independent predictor of SCD and CVD in participants with HCM. (Cardiac Magnetic Resonance Imaging Clinical Application Registration Study; ChiCTR1900024094).

Dihydrophenanthropyrans derived from the pseudobulbs of Pholidota chinensis alleviates neutrophilic inflammation by inhibiting MAPKs and calcium.

Five dihydrophenanthropyrans (1-5) were isolated from the pseudobulbs of Pholidota chinensis, among which 1,3-di(4'-hydroxybenzy)-imbricatin (3) was isolated from the nature for the first time. Their structures were elucidated and established through various spectroscopic methods. These compounds exhibited a potent inhibition effect on both N-formyl-methionyl-leucyl-phenylalanine (fMLF)-induced superoxide anion generation and elastase release with IC50 values ranging from 0.23 to 7.63 µM. Furthermore, dihydrophenanthropyrans (1-3) also demonstrated a dose-dependent reactive oxygen species (ROS) scavenging effect. In addition, dihydrophenanthropyrans (2-3) exhibited a dose-dependent reduction in the intracellular Ca2+ concentration ([Ca2+]i) in fMLF-activated human neutrophils. Moreover, dihydrophenanthropyrans (1-3) selectively inhibited the phosphorylation of c-Jun N-terminal kinases (JNKs) and p38, while only dihydrophenanthropyran (1) inhibited the phosphorylation of extracellular signal-regulated kinases (ERKs) in fMLF-activated human neutrophils. Notably, dihydrophenanthropyrans (1-3) did not affect protein kinase B (AKT) activity in these cells. These findings highlight the potent anti-inflammatory capabilities of dihydrophenanthropyrans, manifested through their ability to inhibit superoxide anion generation, suppress elastase release, and selectively modulate key signaling pathways in human neutrophils. This suggests that dihydrophenanthropyrans hold significant promise as therapeutic agents for conditions associated with neutrophil-mediated inflammation.

Geospatial artificial intelligence for estimating daytime and nighttime nitrogen dioxide concentration variations in Taiwan: A spatial prediction model.

Nitrogen dioxide (NO2) is a major air pollutant primarily emitted from traffic and industrial activities, posing health risks. However, current air pollution models often underestimate exposure risks by neglecting the bimodal pattern of NO2 levels throughout the day. This study aimed to address this gap by developing ensemble mixed spatial models (EMSM) using geo-artificial intelligence (Geo-AI) to examine the spatial and temporal variations of NO2 concentrations at a high resolution of 50m. These EMSMs integrated spatial modelling methods, including kriging, land use regression, machine learning, and ensemble learning. The models utilized 26 years of observed NO2 measurements, meteorological parameters, geospatial layers, and social and season-dependent variables as representative of emission sources. Separate models were developed for daytime and nighttime periods, which achieved high reliability with adjusted R2 values of 0.92 and 0.93, respectively. The study revealed that mean NO2 concentrations were significantly higher at nighttime (9.60 ppb) compared to daytime (5.61 ppb). Additionally, winter exhibited the highest NO2 levels regardless of time period. The developed EMSMs were utilized to generate maps illustrating NO2 levels pre and during COVID restrictions in Taiwan. These findings could aid epidemiological research on exposure risks and support policy-making and environmental planning initiatives.

A Wearable Thin-Film Hydrogel Laser for Functional Sensing on Skin.

Flexible photonics offers the possibility of realizing wearable sensors by bridging the advantages of flexible materials and photonic sensing elements. Recently, optical resonators have emerged as a tool to improve their oversensitivity by integrating with flexible photonic sensors. However, direct monitoring of multiple psychological information on human skin remains challenging due to the subtle biological signals and complex tissue interface. To tackle the current challenges, here, we developed a functional thin film laser formed by encapsulating liquid crystal droplet lasers in a flexible hydrogel for monitoring metabolites in human sweat (lactate, glucose, and urea). The three-dimensional cross-linked hydrophilic polymer serves as the adhesive layer to allow small molecules to penetrate from human tissue to generate strong light--matter interactions on the interface of whispering gallery modes resonators. Both the hydrogel and cholesteric liquid crystal microdroplets were modified specifically to achieve high sensitivity and selectivity. As a proof of concept, wavelength-multiplexed sensing and a prototype were demonstrated on human skin to detect human metabolites from perspiration. These results present a significant advance in the fabrication and potential guidance for wearable and functional microlasers in healthcare.

Therapeutic value of patent foramen ovale closure for drug-resistant epilepsy: A case series report.

OBJECTIVE: Closure surgery of patent foramen ovale (PFO) has been found to effectively control cryptogenic stroke and migraine, but it is uncertain whether PFO closure could also alleviate epileptic seizures. This study aims to observe the therapeutic effect of PFO closure on epileptic seizures. METHODS: Since July 11th, 2017, in the neurology department of West China Hospital, Sichuan University, Chengdu, we have been regularly monitoring patients with epilepsy who have undergone PFO closure. The patient's clinical information, such as frequency, duration, and severity of seizures, before and after surgery was recorded in detail as well as postoperative safety events. RESULTS: Of the 31 epilepsy patients who confirmed PFO observed (27 cases were drug-resistant epilepsy, 87.10%), average age of surgery was 23.74 years, and 12 cases were female (38.71%). After one-year follow-up, 26 patients (83.87%) achieved remission of seizure frequency, and 22 of whom (70.97%) experienced a remission of more than 50%. Additionally, compared to before surgery, 22 cases (70.97%) reported a decrease in the average seizure duration, and 20 cases (64.52%) reported a reduction in seizure severity. In the seizure indicators of frequency, average duration and severity, significant differences were identified between preoperative and postoperative comparisons with all test p values were <0.05. Furthermore, no serious safety events were reported except for one patient who briefly reported chest pain, and all patients expressed effective PFO closure. SIGNIFICANCE: The PFO closure has been shown for the first time to result in a significant reduction in the frequency, duration, and severity of seizures. Patients with drug-resistant epilepsy and PFO with a large shunt are ideal candidates for undergoing PFO closure. PLAIN LANGUAGE SUMMARY: Since PFO closure was found to have a good therapeutic effect on cryptogenic stroke and migraine, it has become a credible complementary therapy for the treatment of neurological diseases, and drug-resistant epilepsy with PFO is expected to become the next target disease that PFO closure could significantly improve.

A comprehensive examination of temporal-seasonal variations of PM1.0 and PM2.5 in taiwan before and during the COVID-19 lockdown.

COVID-19 has been a significant global concern due to its contagious nature. In May 2021, Taiwan experienced a severe outbreak, leading the government to enforce strict Pandemic Alert Level 3 restrictions in order to curtail its spread. Although previous studies in Taiwan have examined the effects of these measures on air quality, further research is required to compare different time periods and assess the health implications of reducing particulate matter during the Level 3 lockdown. Herein, we analyzed the mass concentrations, chemical compositions, seasonal variations, sources, and potential health risks of PM1.0 and PM2.5 in Central Taiwan before and during the Level 3 lockdown. As a result, coal-fired boilers (47%) and traffic emissions (53%) were identified as the predominant sources of polycyclic aromatic hydrocarbons (PAHs) in PM1.0, while in PM2.5, the dominant sources of PAHs were coal-fired boilers (28%), traffic emissions (50%), and iron and steel sinter plants (22.1%). Before the pandemic, a greater value of 20.9 ± 6.92 µg/m3 was observed for PM2.5, which decreased to 15.3 ± 2.51 µg/m3 during the pandemic due to a reduction in industrial and anthropogenic emissions. Additionally, prior to the pandemic, PM1.0 had a contribution rate of 79% to PM2.5, which changed to 89% during the pandemic. Similarly, BaPeq values in PM2.5 exhibited a comparable trend, with PM1.0 contributing 86% and 65% respectively. In both periods, the OC/EC ratios for PM1.0 and PM2.5 were above 2, due to secondary organic compounds. The incremental lifetime cancer risk (ILCR) of PAHs in PM2.5 decreased by 4.03 × 10-5 during the pandemic, with PM1.0 contributing 73% due to reduced anthropogenic activities.

Light-Chain Cardiac Amyloidosis: Cardiac Magnetic Resonance for Assessing Response to Chemotherapy.

OBJECTIVE: Cardiac magnetic resonance (CMR) is a diagnostic tool that provides precise and reproducible information about cardiac structure, function, and tissue characterization, aiding in the monitoring of chemotherapy response in patients with light-chain cardiac amyloidosis (AL-CA). This study aimed to evaluate the feasibility of CMR in monitoring responses to chemotherapy in patients with AL-CA. MATERIALS AND METHODS: In this prospective study, we enrolled 111 patients with AL-CA (50.5% male; median age, 54 [interquartile range, 49-63] years). Patients underwent longitudinal monitoring using biomarkers and CMR imaging. At follow-up after chemotherapy, patients were categorized into superior and inferior response groups based on their hematological and cardiac laboratory responses to chemotherapy. Changes in CMR findings across therapies and differences between response groups were analyzed. RESULTS: Following chemotherapy (before vs. after), there were significant increases in myocardial T2 (43.6 ± 3.5 ms vs. 44.6 ± 4.1 ms; P = 0.008), recovery in right ventricular (RV) longitudinal strain (median of -9.6% vs. -11.7%; P = 0.031), and decrease in RV extracellular volume fraction (ECV) (median of 53.9% vs. 51.6%; P = 0.048). These changes were more pronounced in the superior-response group. Patients with superior cardiac laboratory response showed significantly greater reductions in RV ECV (-2.9% [interquartile range, -8.7%-1.1%] vs. 1.7% [-5.5%-7.1%]; P = 0.017) and left ventricular ECV (-2.0% [-6.0%-1.3%] vs. 2.0% [-3.0%-5.0%]; P = 0.01) compared with those with inferior response. CONCLUSION: Cardiac amyloid deposition can regress following chemotherapy in patients with AL-CA, particularly showing more prominent regression, possibly earlier, in the RV. CMR emerges as an effective tool for monitoring associated tissue characteristics and ventricular functional recovery in patients with AL-CA undergoing chemotherapy, thereby supporting its utility in treatment response assessment.