Targeting the IKs Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants.

BACKGROUND: The KCNQ1+KCNE1 (IKs) potassium channel plays a crucial role in cardiac adaptation to stress, in which ß-adrenergic stimulation phosphorylates the IKs channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between IKs channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. METHODS: Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/IKs channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific-induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. RESULTS: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of IKs channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of IKs. We refer to this pattern as the IKs channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the IKs channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell-derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. CONCLUSIONS: Our findings not only elucidate the molecular mechanism of PKA-dependent IKs channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.

Interfacing Neuron-Motor Pathways with Stretchable and Biocompatible Electrode Arrays.

ConspectusIn the field of neuroscience, understanding the complex interactions within the intricate neuron-motor system depends crucially on the use of high-density, physiological multiple electrode arrays (MEAs). In the neuron-motor system, the transmission of biological signals primarily occurs through electrical and chemical signaling. Taking neurons for instance, when a neuron receives external stimuli, it generates an electrical signal known as the action potential. This action potential propagates along the neuron's axon and is transmitted to other neurons via synapses. At the synapse, chemical signals (neurotransmitters) are released, allowing the electrical signal to traverse the synaptic gap and influence the next neuron. MEAs can provide unparalleled insights into neural signal patterns when interfacing with the nerve systems through their excellent spatiotemporal resolution. However, the inherent differences in mechanical and chemical properties between these artificial devices and biological tissues can lead to serious complications after chronic implantation, such as body rejection, infection, tissue damage, or device malfunction. A promising strategy to enhance MEAs' biocompatibility involves minimizing their thickness, which aligns their bending stiffness with that of surrounding tissues, thereby minimizing damage over time. However, this solution has its limits; the resulting ultrathin devices, typically based on plastic films, lack the necessary stretchability, restricting their use to organs that neither stretch nor grow.For practical deployments, devices must exhibit certain levels of stretchability (ranging from 20 to 70%), tailored to the specific requirements of the target organs. In this Account, we outline recent advancements in developing stretchable MEAs that balance stretchability with sufficient electrical conductivity for effective use in physiological research, acting as sensors and stimulators. By concentrating on the neuron-motor pathways, we summarize how the stretchable MEAs meet various application needs and examine their effectiveness. We distinguish between on-skin and implantable uses, given their vastly different requirements. Within each application scope, we highlight cutting-edge technologies, evaluating their strengths and shortcomings. Recognizing that most current devices rely on elastic films with a Young's modulus value between ∼0.5 and 5 MPa, we delve into the potential for softer MEAs, particularly those using multifunctional hydrogels for an optimizing tissue-device interface and address the challenges in adapting such hydrogel-based MEAs for chronic implants. Additionally, transitioning soft MEAs from lab to fab involves connecting them to a rigid adapter and external machinery, highlighting a critical challenge at the soft-rigid interface due to strain concentration, especially in chronic studies subject to unforeseen mechanical strains. We discuss innovative solutions to this integration challenge, being optimistic that the development of durable, biocompatible, stretchable MEAs will significantly advance neuroscience and related fields.

Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

Whole-genome sequence of Sclerotium delphinii, a pathogenic fungus of Dendrobium officinale southern blight.

Dendrobium officinale is a rare and precious medicinal plant. Southern blight is a destructive disease in the artificial cultivation of D. officinale, and one of its pathogens is Sclerotium delphinii. S. delphinii is a phytopathogenic fungus with a wide host range with extremely strong pathogenicity. In this study, S. delphinii was isolated from D. officinale with southern blight. Subsequently, this specific strain underwent thorough whole-genome sequencing using the PacBio Sequel II platform, which employed single-molecule real-time (SMRT) technology. Comprehensive annotations were obtained through functional annotation of protein sequences using various publicly available databases. The genome of S. delphinii measures 73.66 Mb, with an N90 contig size of 2,707,110 bp, and it contains 18,506 putative predictive genes. This study represents the first report on the genome size assembly and annotation of S. delphinii, making it the initial species within the Sclerotium genus to undergo whole-genome sequencing, which can provide solid data and a theoretical basis for further research on the pathogenesis, omics of S. delphinii.

Machine Learning-Assisted Discovery of Propane-Selective Metal-Organic Frameworks.

Machine learning is gaining momentum in the prediction and discovery of materials for specific applications. Given the abundance of metal-organic frameworks (MOFs), computational screening of the existing MOFs for propane/propylene (C3H8/C3H6) separation could be equally important for developing new MOFs. Herein, we report a machine learning-assisted strategy for screening C3H8-selective MOFs from the CoRE MOF database. Among the four algorithms applied in machine learning, the random forest (RF) algorithm displays the highest degree of accuracy. We experimentally verified the identified top-performing MOF (JNU-90) with its benchmark selectivity and separation performance of directly producing C3H6. Considering its excellent hydrolytic stability, JNU-90 shows great promise in the energy-efficient separation of C3H8/C3H6. This work may accelerate the development of MOFs for challenging separations.

Prediction of antimicrobial resistance in Klebsiella pneumoniae using genomic and metagenomic next-generation sequencing data.

OBJECTIVES: Klebsiella pneumoniae is a significant pathogen with increasing resistance and high mortality rates. Conventional antibiotic susceptibility testing methods are time-consuming. Next-generation sequencing has shown promise for predicting antimicrobial resistance (AMR). This study aims to develop prediction models using whole-genome sequencing data and assess their feasibility with metagenomic next-generation sequencing data from clinical samples. METHODS: On the basis of 4170 K. pneumoniae genomes, the main genetic characteristics associated with AMR were identified using a LASSO regression model. Consequently, the prediction model was established, validated and optimized using clinical isolate read simulation sequences. To evaluate the efficacy of the model, clinical specimens were collected. RESULTS: Four predictive models for amikacin, ciprofloxacin, levofloxacin, and piperacillin/tazobactam, initially had positive predictive values (PPVs) of 92%, 98%, 99%, 94%, respectively, when they were originally constructed. When applied to clinical specimens, their PPVs were 96%, 96%, 95%, and 100%, respectively. Meanwhile, there were negative predictive values (NPVs) of 100% for ciprofloxacin and levofloxacin, and 'not applicable' (NA) for amikacin and piperacillin/tazobactam. Our method achieved antibacterial phenotype classification accuracy rates of 95.92% for amikacin, 96.15% for ciprofloxacin, 95.31% for levofloxacin and 100% for piperacillin/tazobactam. The sequence-based prediction antibiotic susceptibility testing (AST) reported results in an average time of 19.5 h, compared with the 67.9 h needed for culture-based AST, resulting in a significant reduction of 48.4 h. CONCLUSIONS: These preliminary results demonstrated that the performance of prediction model for a clinically significant antimicrobial-species pair was comparable to that of phenotypic methods, thereby encouraging the expansion of sequence-based susceptibility prediction and its clinical validation and application.

Association between the C-Reactive Protein-Albumin-Lymphocyte (CALLY) Index and Adverse Clinical Outcomes in CAD Patients after PCI: Findings of a Real-World Study.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel inflammatory biomarker, and its association with the prognosis of coronary artery disease (CAD) after percutaneous coronary intervention (PCI) has not previously been studied. Therefore, this study aimed to investigate the effect of using the CALLY index on adverse outcomes in CAD patients undergoing PCI. Methods: From December 2016 to October 2021, we consecutively enrolled 15,250 CAD patients and performed follow-ups for primary endpoints consisting of all-cause mortality (ACM) and cardiac mortality (CM). The CALLY index was computed using the following formula: (albumin × lymphocyte)/(C-reactive protein (CRP) × 10 4 ). The average duration of the follow-up was 24 months. Results: A total of 3799 CAD patients who had undergone PCI were ultimately enrolled in the present study. The patients were divided into four groups according to the CALLY index quartiles: Q1 ( ≤ 0.69, n = 950), Q2 (0.69-2.44, n = 950), Q3 (2.44-9.52, n = 950), and Q4 ( > 9.52, n = 949). The low-Q1 group had a significantly higher prevalence of ACM (p < 0.001), CM (p < 0.001), major adverse cardiac events (MACEs) (p = 0.002), and major adverse cardiac and cerebrovascular events (MACCEs) (p = 0.002). Kaplan-Meier analysis revealed that a low CALLY index was significantly linked with adverse outcomes. After univariate and multivariate Cox regression analysis, the risk of ACM, CM, MACEs, and MACCEs decreased by 73.7% (adjust hazard risk [HR] = 0.263, 95% CI: 0.147-0.468, p < 0.001), 70.6% (adjust HR = 0.294, 95% CI: 0.150-0.579, p < 0. 001), 37.4% (adjust HR = 0.626, 95% CI: 0.422-0.929, p = 0.010), and 41.5% (adjust HR = 0.585, 95% CI: 0.401-0.856, p = 0.006), respectively, in the Q4 quartiles compared with the Q1 quartiles. Conclusions: This study revealed that a decreased CALLY index was associated with worse prognoses for CAD patients after PCI. The categorization of patients with a decreased CALLY index could provide valuable evidence for the risk stratification of adverse outcomes in CAD patients after PCI. Clinical Trial Registration: The details are available at http://www.chictr.org.cn (Identifier: NCT05174143).

Performance improvement of reflective phosphor film via adjusting the thickness realizing bright and efficient laser lighting.

Phosphor-in-glass-film (PiG-F) has been extensively investigated, showing great potential for use in laser lighting technique. Thickness is apparently a key parameter for PiG-F, affecting the heat dissipation, absorption, and reabsorption, thus determining the luminous efficacy and luminescence saturation threshold (LST). Conventional studies suggest that thinner films often have lower thermal load than that of the thicker ones. Unexpectedly, we found that the Lu3Al5O12:Ce (LuAG:Ce)-based PiG-F with a moderate thickness (78 µm) yielded the optimal LST of 31.9 W (14.2 W·mm-2, rather than 28.0 W (12.3 W·mm-2) for the thinnest one (56 µm). This unexpected result was further verified by thermal simulations. With the high saturation threshold together with a high luminous efficacy (∼296 lm·W-1), an ultrahigh luminous flux of 7178 lm with a luminous exitance of 2930 lm·mm-2 was thus attained. We believe the new, to the best of our knowledge, findings in this study will substantially impact the design principles of phosphors for laser lighting.

Copper(II)-Catalyzed Regioselective H/D Exchange Based on Reversible C-H Activation.

Despite the increasing use of copper in C-H functionalizations, the Cu-catalyzed direct deuteration of C-H bonds remains a significant challenge due to its inherent low reactivity in inverse C-H bond reconstruction. In this paper, a novel strategy had been developed to reverse the copper-catalyzed concerted metalation-deprotonation process by inhibiting the unexpected disproportionation of Cu(II) to Cu(III). Picolinic acid was identified as a powerful ligand for facilitating this H/D exchange with D2O as deuterium source, and its inhibition activity was supported by preliminary control experiments and DFT studies.

Magnetic Resonance Imaging-Based Classification Systems for Informing Better Outcomes of Adenomyosis After Ultrasound-Guided High-Intensity Focused Ultrasound Ablating Surgery.

BACKGROUND: A referenced MRI-based classification associated with focused ultrasound ablation surgery (FUAS) outcomes is lacking in adenomyosis. PURPOSE: To identify an MRI-based classification system for informing the FUAS outcomes. STUDY TYPE: Retrospective. POPULATION: Patients with FUAS for adenomyosis, were divided into a training set (N = 643; 355 with post-FUAS gonadotropin-releasing hormone/levonorgestrel, 288 without post-FUAS therapy) and an external validation set (N = 135; all without post-FUAS therapy). FIELD STRENGTH/SEQUENCE: 1.5 T, turbo spin-echo T2-weighted imaging and single-shot echo-planar diffusion-weighted imaging sequences. ASSESSMENT: Five MRI-based adenomyosis classifications: classification 1 (C1) (diffuse, focal, and mild), C2 (intrinsic, extrinsic, intramural, and indeterminate), C3 (internal, adenomyomas, and external), C4 (six subtypes on areas [internal or external] and volumes [<1/3 or ≥2/3]), and C5 (internal [asymmetric or symmetric], external, intramural, full thickness [asymmetric or symmetric]) for FUAS outcomes (symptom relief and recurrence). STATISTICAL TESTS: The optimal classification was significantly associated with the most subtypes of FUAS outcomes. Relating to the timing of recurrence was measured using Cox regression analysis and median recurrence time was estimated by a Kaplan-Meier curve. A P value <0.05 was considered statistically significant. RESULTS: Dysmenorrhea relief and recurrence were only associated with C2 in training patients undergoing FUAS alone. Compared with other subtypes, the extrinsic subtype of C2 was significantly associated with dysmenorrhea recurrence in the FUAS group. Besides, the median dysmenorrhea recurrence time of extrinsic subtype was significantly shorter than that of other subtypes (42.0 months vs. 50.3 months). In the validation cohort, C2 was confirmed as the optimal system and its extrinsic subtype was confirmed to have a significantly shorter dysmenorrhea recurrence time than other subtypes. DATA CONCLUSION: Classification 2 can inform dysmenorrhea relief and recurrence in patients with adenomyosis undergoing FAUS only. Itsextrinsic subtype was associated with an earlier onset of dysmenorrhea recurrence after treatment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Faecalibacterium prausnitzii as a potential Antiatherosclerotic microbe.

BACKGROUND: The gut microbiota plays a crucial role in coronary artery disease (CAD) development, but limited attention has been given to the role of the microbiota in preventing this disease. This study aimed to identify key biomarkers using metagenomics and untargeted metabolomics and verify their associations with atherosclerosis. METHODS: A total of 371 participants, including individuals with various CAD types and CAD-free controls, were enrolled. Subsequently, significant markers were identified in the stool samples through gut metagenomic sequencing and untargeted metabolomics. In vivo and in vitro experiments were performed to investigate the mechanisms underlying the association between these markers and atherosclerosis. RESULTS: Faecal omics sequencing revealed that individuals with a substantial presence of Faecalibacterium prausnitzii had the lowest incidence of CAD across diverse CAD groups and control subjects. A random forest model confirmed the significant relationship between F. prausnitzii and CAD incidence. Notably, F. prausnitzii emerged as a robust, independent CAD predictor. Furthermore, our findings indicated the potential of the gut microbiota and gut metabolites to predict CAD occurrence and progression, potentially impacting amino acid and vitamin metabolism. F. prausnitzii mitigated inflammation and exhibited an antiatherosclerotic effect on ApoE-/- mice after gavage. This effect was attributed to reduced intestinal LPS synthesis and reinforced mechanical and mucosal barriers, leading to decreased plasma LPS levels and an antiatherosclerotic outcome. CONCLUSIONS: Sequencing of the samples revealed a previously unknown link between specific gut microbiota and atherosclerosis. Treatment with F. prausnitzii may help prevent CAD by inhibiting atherosclerosis.

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

Omics research in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition within the arterial intima, as well as fibrous tissue proliferation and calcification. AS has long been recognized as one of the primary pathological foundations of cardiovascular diseases in humans. Its pathogenesis is intricate and not yet fully elucidated. Studies have shown that AS is associated with oxidative stress, inflammatory response, lipid deposition, and changes in cell phenotype. Unfortunately, there is currently no effective prevention or targeted treatment for AS. The rapid advancement of omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, has opened up novel avenues to elucidate the fundamental pathophysiology and associated mechanisms of AS. Here, we review articles published over the past decade and focus on the current status, challenges, limitations, and prospects of omics in AS research and clinical practice. Emphasizing potential targets based on omics technologies will improve our understanding of this pathological condition and assist in the development of potential therapeutic approaches for AS-related diseases.

H/D Exchange of Aromatic Sulfones via Base Promotion and Silver Catalysis.

Aromatic sulfones are the prevailing scaffolds in pharmaceutical and material sciences. However, compared to their widespread application, the selective deuterium labeling of these structures is restricted due to their electron-deficient properties. This study presents two comprehensive strategies for the deuteration of aromatic sulfones. The base-promoted deuteration uses DMSO-d6 as the deuterium source, resulting in a rapid H/D exchange within 2 h. Meanwhile, a silver-catalyzed protocol offers a much milder option by using economical D2O to furnish the labeled sulfones.

Rational Design and Synthesis of Fe-Doped Co-Based Coordination Polymer Composite Photocatalysts for the Degradation of Norfloxacin and Ciprofloxacin.

The solar light-responsive Fe-doped Co-based coordination polymer (Fe@Co-CP) photocatalyst was synthesized under mild conditions. [Co(4-padpe)(1,3-BDC)]n (Co-CP) was first constructed using mixed ligands through the hydrothermal method. Then, Fe was introduced into the Co-CP framework to achieve the enhanced photocatalytic activity. The optimal Fe@Co-CP-2 exhibited excellent catalytic degradation performance for norfloxacin and ciprofloxacin under sunlight irradiation without auxiliary oxidants, and the degradation rates were 91.25 and 92.66% in 120 min. These excellent photocatalytic properties were ascribed to the generation of the Fe-O bond, which not only enhanced the light absorption intensity but also accelerated the separation efficiency of electrons and holes, and hence significantly improved the photocatalytic property of the composites. Meanwhile, Fe@Co-CP-2 displayed excellent stability and reusability. In addition, the degradation pathways and intermediates of antibiotic molecules were effectively analyzed. The free radical scavenging experiment and ESR results confirmed that •OH, •O2-, and h+ active species were involved in the catalytic degradation reaction; the corresponding mechanisms were deeply investigated. This study provides a fresh approach for constructing Fe-doped Co-CP-based composite materials as photocatalysts for degradation of antibiotic contaminants.

Amino-Functionalized NDI-Based MOFs as Unusual "Turn On" and "Turn Off" Fluorescent Sensors for Phenolic Pollutants with Double Solvent Channel Response and Iodine Adsorbents.

Regulating mixed ligands to change the functional properties of metal-organic frameworks (MOFs) has been an important topic; especially, the structural changes have significant implications for the transformation of sensing response in different solvent channels. Herein, two [Cd (DPNDI) (NH2-BDC)0.5(NO3)]·2.25DMF (1) and [Cd(DPNDI)(NH2-AIPA)]·0.5DMF (2) (DPNDI = N,N-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide, NH2-BDC = 2-amino terephthalic acid, NH2-AIPA = 5-aminoisophthalic acid) were synthesized by the solvothermal method. Structural analysis shows that complex 1 has a two-dimensional planar network structure and complex 2 exhibits a three-dimensional network structure, endowing its potential as an efficient fluorescence sensor for phenolic compound detection under different solvent environments. Both complexes showed high fluorescence quenching sensitivity to phenolics in a water medium. Conversely, complex 1 showed a fluorescence enhancement response to phenolic pollutants in an ethanol system with significantly low detection limits and recyclability. The detection limits were 0.58 µM for TNP, 1.3 µM for DNP, and 2.43 µM for PCP. In addition, the uncoordinated amino groups in the complexes promote them to exhibit excellent iodine adsorption performance. Especially, complex 2 can serve as an adsorbent for iodine in cyclohexane solution with better adsorption efficiency than that of complex 1, and its adsorption capacity can reach 505 mg/g. The mixed ligands regulation strategy of NDI-based MOFs will open up an effective avenue for the conversion of fluorescence signals in dual-solvent channels and play simultaneously important roles in multiple applications.

Electrophysiological characteristics and catheter ablation of ventricular arrhythmias arising from the superior septal left ventricle.

BACKGROUND AND AIMS: Electrophysiological characteristics and radiofrequency catheter ablation (RFCA) of premature ventricular contractions (PVCs) originating from the superior septal left ventricle (SSLV) have not yet been fully characterized. METHODS AND RESULTS: This study included 247 patients who underwent RFCA for PVCs arising from the ventricular outflow tract between February 2020 and August 2022. The successful ablation site was on the SSLV in 37 of the 247 patients. In 12 (32.4%) of those 37 patients, a low amplitude and high frequency spiky potential (SP) was recognized. Five patients showed a narrow QRS duration (86.8 ± 4.6 ms), with a discrete SP observed in PVCs and sinus rhythm, which showed an isoelectric line with the ventricular electrogram at the earliest activation site. Seven patients showed a wide QRS duration (131.6 ± 4.5 ms), with SP observed in PVCs without an isoelectric line with the ventricular electrogram. RFCA was successful at the site of the earliest SP in all 12 patients. The time from SP onset at the successful ablation site to the QRS onset (local activation time) was 30 ± 12 ms, which differed significantly from that for the remaining 25 patients withoutSP(22.1 ± 7.1 ms, P < 0.05). CONCLUSIONS: SPs were recorded in 12 (32.4%) of the 37 patients with PVCs originating from the SSLV. The morphology of the PVCs may show a narrow or wide QRS duration and the target site for successful ablation should be identified by the earliest SP.

NMR-Guided Isolation of Anti-inflammatory Carabranolides from the Fruits of Carpesium abrotanoides L.

Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.

Nuclear proteins and diabetic retinopathy: a review.

Diabetic retinopathy (DR) is an eye disease that causes blindness and vision loss in diabetic. Risk factors for DR include high blood glucose levels and some environmental factors. The pathogenesis is based on inflammation caused by interferon and other nuclear proteins. This review article provides an overview of DR and discusses the role of nuclear proteins in the pathogenesis of the disease. Some core proteins such as MAPK, transcription co-factors, transcription co-activators, and others are part of this review. In addition, some current advanced treatment resulting from the role of nuclear proteins will be analyzes, including epigenetic modifications, the use of methylation, acetylation, and histone modifications. Stem cell technology and the use of nanobiotechnology are proposed as promising approaches for a more effective treatment of DR.

Atrachinenins D-S, novel meroterpenoids with geranyl hydroquinone moiety from Atractylodes chinensis by the LC/MS-based molecular decoy and targeted isolation.

To mine fascinating molecules from the rhizomes of Atractylodes chinensis, the known molecular formula of atrachinenin A was used as a bait to search LC-HRMS data in different subfractions. Sixteen new meroterpenoids, atrachinenins D-S (1-16) including three unprecedented carbon skeletons (1-5) and eleven new oxygen-bridged hybrids (6-16) were obtained by the targeted isolation. Their structures and absolute configurations were elucidated by the spectroscopic data and electronic circular dichroism (ECD) calculations. The isolated compounds were evaluated for their inhibitory activity of NO production and compounds 1, 4, 8, and 13 showed moderate anti-inflammatory activity. The proposed biosynthetic pathways of 1-5 were also discussed.