Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

Host-guest interaction induced room-temperature phosphorescence enhancement of organic dyes: a computational study.

To achieve the effective regulation of organic room temperature phosphorescence (RTP) in supramolecular systems, the elucidation of host-guest interactions in RTP is of vital importance. Herein, we employed two organic dyes (PYCl and PYBr) and their four host-guest complexes with CB[6] and CB[7] and explored the mechanism of host-guest interaction induced RTP enhancement using quantum mechanics/molecular mechanics (QM/MM) approach. For the two organic dyes, we found that the better RTP performance of PYBr than PYCl is attributed to intersystem crossing (ISC) augmentation induced by the heavy atom effect. Binding to CB[6] through host-guest interactions can simultaneously accelerate the radiative decay process by increasing the transition dipole moment of T1 → S0 (µT1→S0), block the nonradiative decay process, and promote the ISC process, eventually leading to a remarkably boosted RTP. Upon complexation, the conversion of S1 from 1(n, π*) to 1(π, π*) is key to µT1→S0 enhancement; reduced reorganization energies reflect the suppression of the nonradiative decay process by restricting the rotation of rings A and B in organic dyes. In addition, the promoted ISC process is due to the activation of more ISC channels between S1 and high-lying triplet states with large spin-orbital coupling constants and small energy gap. The case of CB[7]-type complexes is much different, because of the extremely large cavity size of CB[7] for encapsulation. This work proposes the mechanism of host-guest interaction-induced RTP enhancement of organic dyes, thus laying a solid foundation for the rational design of advanced RTP materials based on supramolecular assemblies.

Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights.

Phenylacetylglutamine (PAGln) is an amino acid derivate that comes from the amino acid phenylalanine. There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases. In this review, we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln. We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases, such as heart failure, coronary heart disease/atherosclerosis, and cardiac arrhythmia. The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors. Besides, other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln. Moreover, since PAGln is produced across different organs including the intestine, liver, and kidney, the cross-talk among multiple organs focused on the function of this uremic toxic metabolite. Finally, the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.

The effects of various auditory takeover requests: A simulated driving study considering the modality of non-driving-related tasks.

With the era of automated driving approaching, designing an effective auditory takeover request (TOR) is critical to ensure automated driving safety. The present study investigated the effects of speech-based (speech and spearcon) and non-speech-based (earcon and auditory icon) TORs on takeover performance and subjective preferences. The potential impact of the non-driving-related task (NDRT) modality on auditory TORs was considered. Thirty-two participants were recruited in the present study and assigned to two groups, with one group performing the visual N-back task and another performing the auditory N-back task during automated driving. They were required to complete four simulated driving blocks corresponding to four auditory TOR types. The earcon TOR was found to be the most suitable for alerting drivers to return to the control loop because of its advantageous takeover time, lane change time, and minimum time to collision. Although participants preferred the speech TOR, it led to relatively poor takeover performance. In addition, the auditory NDRT was found to have a detrimental impact on auditory TORs. When drivers were engaged in the auditory NDRT, the takeover time and lane change time advantages of earcon TORs no longer existed. These findings highlight the importance of considering the influence of auditory NDRTs when designing an auditory takeover interface. The present study also has some practical implications for researchers and designers when designing an auditory takeover system in automated vehicles.

Sensors for Emerging Water Contaminants: Overcoming Roadblocks to Innovation.

Ensuring water quality and safety requires the effective detection of emerging contaminants, which present significant risks to both human health and the environment. Field deployable low-cost sensors provide solutions to detect contaminants at their source and enable large-scale water quality monitoring and management. Unfortunately, the availability and utilization of such sensors remain limited. This Perspective examines current sensing technologies for detecting emerging contaminants and analyzes critical barriers, such as high costs, lack of reliability, difficulties in implementation in real-world settings, and lack of stakeholder involvement in sensor design. These technical and nontechnical barriers severely hinder progression from proof-of-concepts and negatively impact user experience factors such as ease-of-use and actionability using sensing data, ultimately affecting successful translation and widespread adoption of these technologies. We provide examples of specific sensing systems and explore key strategies to address the remaining scientific challenges that must be overcome to translate these technologies into the field such as improving sensitivity, selectivity, robustness, and performance in real-world water environments. Other critical aspects such as tailoring research to meet end-users' requirements, integrating cost considerations and consumer needs into the early prototype design, establishing standardized evaluation and validation protocols, fostering academia-industry collaborations, maximizing data value by establishing data sharing initiatives, and promoting workforce development are also discussed. The Perspective describes a set of guidelines for the development, translation, and implementation of water quality sensors to swiftly and accurately detect, analyze, track, and manage contamination.

Bioinspired Artificial Intelligence Applications 2023.

With rapid development of Artificial Intelligence (AI), researchers have found many bioinspired AI applications, such as bioinspired images and speech processing, which can increase accuracy [...].

In Situ Monitoring of the Polymerization Kinetics of Organic Pollutants during Persulfate-Based Advanced Oxidation Processes Using Plasmonic Colorimetry.

Using sulfate radicals to initiate polymer production in persulfate-based advanced oxidation processes (AOPs) is an emerging strategy for organics removal. However, our understanding of this process remains limited due to a dearth of efficient methods for in situ and real time monitoring of polymerization kinetics. This study leverages plasmonic colorimetry to monitor the polymerization kinetics of an array of aromatic pollutants in the presence of sulfate radicals. We observed that the formation of polymer shells on the surfaces of gold nanoparticles (AuNPs) led to an increase and red shift in their localized surface plasmon resonance (LSPR) band as a result of an increased refractive index surrounding the AuNP surfaces. This observation aligns with Mie theory simulations and transmission electron microscopy-electron energy loss spectroscopy characterizations. Our study demonstrated that the polymerization kinetics exhibits a significant reliance on the electrophilicity and quantity of benzene rings, the concentration of aromatic pollutants, and the dosage of oxidants. In addition, we found that changes in LSPR band wavelength fit well into a pseudo-first-order kinetic model, providing a comprehensive and quantitative insight into the polymerization kinetics involving diverse organic compounds. This technique holds the potential for optimizing AOP-based water treatment by facilitating the polymerization of aromatic pollutants.

Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

Theoretical Study of the Photocyclization Reaction-Induced Dual Aggregation-Induced Emission Phenomenon.

Photochromic molecules with aggregation-induced emission (AIE) effects are of great value and prospective in various practical applications. To explore its inherent mechanism, the open isomer ap-BBTE and the closed isomer c-BBTE were chosen to perform the theoretical calculation using the quantum mechanics/molecular mechanics model combined with thermal vibration correlation function formalism. The calculations show that the photocyclization (PC) reaction from ap-BBTE to c-BBTE facilitates an improvement in the AIE effect. It is found that the fluorescence quantum yield (ΦF) enhancement of ap-BBTE is attributed to the restriction of the low-frequency rotational motion of the benzothiophene moiety and the high-frequency stretching vibrations of the C-C bond between the benzothiophene and benzylbis(thiadiazole) vinyl groups after aggregation. For c-BBTE, the increase in ΦF upon aggregation is mainly due to the suppression of the high-frequency stretching vibration of the C-C bond between the benzothiophene and the benzobis(thiadiazole) vinyl groups. In addition, the AIE effect was also enhanced from ap-BBTE to c-BBTE, which is consistent with the experimental phenomenon. The corresponding emission spectrum red-shifted from ap-BBTE to c-BBTE in both dilute solution and the crystalline state due to the improved intramolecular conjugation of c-BBTE. Moreover, the PC reaction from ap-BBTE to c-BBTE easily occurs in an excited state with a low energy barrier transition state by forming a C-C bond between benzothiophene groups effectively in dilute solution. Our calculations provide theoretical guidance for the further rational design of efficient AIE luminogens.

Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

Acoustic-Sensing-Based Attribute-Driven Imbalanced Compensation for Anomalous Sound Detection without Machine Identity.

Acoustic sensing provides crucial data for anomalous sound detection (ASD) in condition monitoring. However, building a robust acoustic-sensing-based ASD system is challenging due to the unsupervised nature of training data, which only contain normal sound samples. Recent discriminative models based on machine identity (ID) classification have shown excellent ASD performance by leveraging strong prior knowledge like machine ID. However, such strong priors are often unavailable in real-world applications, limiting these models. To address this, we propose utilizing the imbalanced and inconsistent attribute labels from acoustic sensors, such as machine running speed and microphone model, as weak priors to train an attribute classifier. We also introduce an imbalanced compensation strategy to handle extremely imbalanced categories and ensure model trainability. Furthermore, we propose a score fusion method to enhance anomaly detection robustness. The proposed algorithm was applied in our DCASE2023 Challenge Task 2 submission, ranking sixth internationally. By exploiting acoustic sensor data attributes as weak prior knowledge, our approach provides an effective framework for robust ASD when strong priors are absent.

ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.

Increased circulating phenylacetylglutamine concentration elevates the predictive value of cardiovascular event risk in heart failure patients.

BACKGROUND: Phenylacetylglutamine (PAGln)-a newly discovered microbial metabolite produced by phenylalanine metabolism-is reportedly associated with cardiovascular events via adrenergic receptors. Nonetheless, its association with cardiovascular outcomes in heart failure (HF) patients remains unknown. OBJECTIVES: This study aimed to prospectively investigate the prognostic value of PAGln for HF. METHODS: Plasma PAGln levels were quantified by liquid chromatography-tandem mass spectrometry. We first assessed the association between plasma PAGln levels and the incidence of adverse cardiovascular events in 3152 HF patients (including HF with preserved and reduced ejection fraction) over a median follow-up period of 2 years. The primary endpoint was the composite of cardiovascular death or heart transplantation. We then assessed the prognostic role of PAGln in addition to the classic biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP). The correlation between PAGln levels and ß-blocker use was also investigated. RESULTS: In total, 520 cardiovascular deaths or heart transplantations occurred in the HF cohort. Elevated PAGln levels were independently associated with a higher risk of the primary endpoint in a dose-response manner, regardless of HF subtype. Concurrent assessment of PAGln and NT-proBNP levels enhanced risk stratification among HF patients. PAGln further showed prognostic value at low NT-proBNP levels. Additionally, the interaction effects between PAGln and ß-blocker use were not significant. CONCLUSIONS: Plasma PAGln levels are an independent predictor of an increased risk of adverse cardiovascular events in HF. Our work could provide joint and complementary prognostic value to NT-proBNP levels in HF patients.

Imaging of pH distribution inside individual microdroplet by stimulated Raman microscopy.

Aerosol microdroplets as microreactors for many important atmospheric reactions are ubiquitous in the atmosphere. pH largely regulates the chemical processes within them; however, how pH and chemical species spatially distribute within an atmospheric microdroplet is still under intense debate. The challenge is to measure pH distribution within a tiny volume without affecting the chemical species distribution. We demonstrate a method based on stimulated Raman scattering microscopy to visualize the three-dimensional pH distribution inside single microdroplets of varying sizes. We find that the surface of all microdroplets is more acidic, and a monotonic trend of pH decreasing is observed in the 2.9-µm aerosol microdroplet from center to edge, which is well supported by molecular dynamics simulation. However, bigger cloud microdroplet differs from small aerosol for pH distribution. This size-dependent pH distribution in microdroplets can be related to the surface-to-volume ratio. This work presents noncontact measurement and chemical imaging of pH distribution in microdroplets, filling the gap in our understanding of spatial pH in atmospheric aerosol.

Machine learning modeling identifies hypertrophic cardiomyopathy subtypes with genetic signature.

Previous studies have revealed that patients with hypertrophic cardiomyopathy (HCM) exhibit differences in symptom severity and prognosis, indicating potential HCM subtypes among these patients. Here, 793 patients with HCM were recruited at an average follow-up of 32.78 ± 27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features. Furthermore, we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data. Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings. Consequently, two subtypes characterized by different clinical outcomes were identified in HCM. Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course, while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression. Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities. Furthermore, the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction. By employing echocardiography and genetic screening for the 46 genes, HCM can be classified into two subtypes with distinct clinical outcomes.

Pretreatment synthetic magnetic resonance imaging predicts disease progression in nonmetastatic nasopharyngeal carcinoma after intensity modulation radiation therapy.

BACKGROUND: To investigate the potential of synthetic MRI (SyMRI) in the prognostic assessment of patients with nonmetastatic nasopharyngeal carcinoma (NPC), and the predictive value when combined with diffusion-weighted imaging (DWI) as well as clinical factors. METHODS: Fifty-three NPC patients who underwent SyMRI were prospectively included. 10th Percentile, Mean, Kurtosis, and Skewness of T1, T2, and PD maps and ADC value were obtained from the primary tumor. Cox regression analysis was used for analyzing the association between SyMRI and DWI parameters and progression-free survival (PFS), and then age, sex, staging, and treatment as confounding factors were also included. C-index was obtained by bootstrap. Moreover, significant parameters were used to construct models in predicting 3-year disease progression. ROC curves and leave-one-out cross-validation were used to evaluate the performance and stability. RESULTS: Disease progression occurred in 16 (30.2%) patients at a follow-up of 39.6 (3.5, 48.2) months. T1_Kurtosis, T1_Skewness, T2_10th, PD_Mean, and ADC were correlated with PFS, and T1_Kurtosis (HR: 1.093) and ADC (HR: 1.009) were independent predictors of PFS. The C-index of SyMRI and SyMRI + DWI + Clinic models was 0.687 and 0.779. Moreover, the SyMRI + DWI + Clinic model predicted 3-year disease progression better than DWI or Clinic model (p ≤ 0.008). Interestingly, there was no significant difference between the SyMRI model (AUC: 0.748) and SyMRI + DWI + Clinic model (AUC: 0.846, p = 0.092). CONCLUSION: SyMRI combined with histogram analysis could predict disease progression in NPC patients, and SyMRI + DWI + Clinic model further improved the predictive performance.

High mobility and excellent thermoelectric performance monolayer ZnX2Z4 (X = In, Al, Ga; Z = S, Se, Te) materials.

Recently, two-dimensional (2D) layered polarized ZnIn2S4 nanosheets have been successfully synthesized in experiments. However, the polarized monolayers are unstable in air, which hinders their practical applications. Therefore, in this work, we proposed a new family of nonpolarized monolayers (ß2-phase) ZnX2Z4 (X = In, Al, and Ga; Z = S, Se, and Te) by first-principles. It is confirmed that the energies of ß2-phase ZnX2Z4 are lower than those of the polarized and ß-phase ZnX2Z4 monolayers. Moreover, these ZnX2Z4 monolayers have not only desirable indirect band gaps but also high electron mobility (up to 103 cm2 V-1 s-1), revealing a fascinating visible light absorption range. Furthermore, ß2-phase ZnX2Te4 (X = In, Al, and Ga) has ultra-low lattice thermal conductivity and high ZT value (up to 0.89), suggesting that these monolayers can be good candidates for thermoelectric materials. These new 2D ternary monolayers not only effectively broaden the family of 2D materials but also provide promising candidates for optoelectronic and thermoelectric materials.

Histogram analysis of synthetic magnetic resonance imaging: Correlations with histopathological factors in head and neck squamous cell carcinoma.

PURPOSE: To analyse the association between histogram parameters derived from synthetic MRI (SyMRI) and different histopathological factors in head and neck squamous cell carcinoma (HNSCC). METHOD: Sixty-one patients with histologically proven primary HNSCC were prospectively enrolled. The correlations between histogram parameters of SyMRI (T1, T2 and proton density (PD) maps) and histopathological factors were analysed using Spearman analysis. The Mann-Whitney U test or Student's t test was utilized to differentiate histological grades and human papillomavirus (HPV) status. The ROC curves and leave-one-out cross-validation (LOOCV) were used to evaluate the differentiation performance. Bootstrapping was applied to avoid overfitting. RESULTS: Several histogram parameters were associated with histological grade: T1 map (r = 0.291) and PD map (r = 0.294 - 0.382/-0.343), and PD_75th Percentile showed the highest differentiation performance (AUC: 0.721 (ROC) and 0.719 (LOOCV)). Moderately negative correlations were found between p16 status and the histogram parameters: T1 map (r = -0.587 - -0.390), T2 map (r = -0.649 - -0.357) and PD map (r = -0.537 - -0.338). In differentiating HPV infection, Entropy was the most discriminative parameter in each map and T2_Entropy showed the highest diagnostic performance (AUC: 0.851 [ROC] and 0.851 [LOOCV]). Additionally, several histogram parameters were correlated with Ki-67 (r = -0.379/-0.397), epidermal growth factor receptor (EGFR) (r = 0.318/0.322) status and p53 (r = 0.452 - 0.665/-0.607) status. CONCLUSIONS: Histogram parameters derived from SyMRI may serve as a potential biomarker for discriminating relevant histopathological features, including histological differentiation grade, HPV infection, Ki-67, EGFR and p53 statuses.

Genetic Profile and Clinical Characteristics of Brugada Syndrome in the Chinese Population.

BACKGROUND: Brugada syndrome (BrS) is an inheritable arrhythmia syndrome that can lead to sudden cardiac death in patients while the heart structure is normal. However, the genetic background of more than 65% of BrS probands remains unclear. OBJECTIVES: The purpose of this study is to report the variant spectrum in a Chinese cohort with suspected BrS and to analyze their distinct clinical and electrocardiographic features. METHODS: Patients with suspected BrS from Tongji Hospital between 2008 and 2021 were analyzed retrospectively. RESULTS: A total of 79 probands were included in this study. Patients with type 1 BrS electrocardiogram (ECG) had a prolonged QRS duration compared to patients with type 2/3 BrS ECG. Of them, 59 probands underwent genetic testing. Twenty-five patients (42.37%) showed abnormal genetic testing results, and eight of them (13.56%) carried pathogenic/likely pathogenic (P/LP) mutations. Mutation carriers presented much more prominent depolarization and repolarization abnormalities than non-carriers, including a prolonged P-wave duration, QRS duration, QTc interval, decreased QRS amplitude, and deviation of the electrocardiographic axes (T-wave axis and R-wave axis). Furthermore, our study identified four novel P/LP mutations: Q3508X in TTN, A990G in KCNH2, G1220E, and D372H (in a representative pedigree) in SCN5A. CONCLUSIONS: Our study showed the variant spectrum of a suspected Chinese BrS cohort, and we identified four novel P/LP mutations in TTN, KCNH2, and SCN5A.

Suppression of reversible photocyclization reaction induced fluorescence enhancement: a theoretical study.

Aggregation-induced emission (AIE) materials with photocyclization (PC) reactions exhibit rich photophysical and photochemical activities. Understanding the mechanism behind is essential to the design of effective AIE materials. Herein, we employ a polarizable continuum model (PCM) and the hybrid quantum mechanics and molecular mechanics (QM/MM) approach, to study the luminescent properties of PC-typed AIEgens, SIP-2 and DPI, in both solution and crystalline states. The calculated results indicate that the fluorescence quantum yields (ΦF) of SIP-2 and DPI under different environments are mainly related to the competition between the PC reaction and aggregation induced restriction of phenyl ring rotational motions. In solution, SIP-2 and DPI undergo PC reactions to form a C-C bond between the phenyl rings A and B, which provides an important non-radiative decay channel and dramatically reduces the fluorescence intensity. Upon aggregation, the restricted rotational motion of rings A and B blocks the PC reaction and reduces the reorganization energy, which lowers the non-radiative decay rate constant (kIC) and benefits the ΦF. This is consistent with the experimental phenomenon that both SIP-2 and DPI exhibit the AIE effect. In addition, the introduction of the rigid spiro backbone of SIP-2 increases the steric effect, further limiting the phenyl ring rotation and PC reaction, resulting in an increase in the fluorescence intensity. Our calculations not only show the detailed mechanism of PC-typed AIEgens but also provide theoretical guidance for the further rational design of efficient AIEgens.