A higher peak heart rate during head-up tilt test predicts the therapeutic efficacy of metoprolol in vasovagal syncope.

BACKGROUND: Although beta blockers, such as metoprolol, have been widely used in the management of vasovagal syncope (VVS), their efficacy remains debated, with larger studies showing limited benefit. Identifying patient-specific characteristics that predict a positive response to metoprolol could optimize its use. This study aims to investigate the key factors that may determine which VVS patients are suitable candidates for metoprolol treatment. METHODS: This retrospective study was conducted at a single center. Patients diagnosed with VVS and treated with metoprolol for a minimum of three months were included. A 50% reduction in syncope symptom score (SS) after three months of metoprolol treatment was used to define metoprolol responders, while those who did not achieve this reduction were classified as non-responders. After a three-month follow-up, patients were divided into two groups: responders and non-responders. Baseline data-including age, gender, comorbidities, laboratory tests, and the type of VVS-were analyzed for each patient. Changes in heart rate (HR) and blood pressure during the head-up tilt test (HUTT) were also evaluated between the two groups. Logistic regression analysis was performed to identify potential predictors of metoprolol response, and receiver operating characteristic (ROC) curve analysis was used to assess the value of these predictors in selecting potential responders. RESULTS: A total of 168 VVS patients were enrolled between January 2016 and December 2020. Of these, 100 patients responded positively to metoprolol, while 68 did not. No significant differences in baseline characteristics or HUTT results were observed between the two groups (p > 0.05). However, responders exhibited a significantly higher peak HR compared to non-responders during the HUTT (120.13 ± 19.33 vs. 106.60 ± 22.32, p < 0.001). The increase in HR was also more pronounced in responders (0.60 ± 0.23 vs. 0.41 ± 0.25, p < 0.001). Additionally, HR variability was significantly greater in responders than in non-responders (16.18 ± 5.51 vs. 12.61 ± 5.50, p < 0.001). CONCLUSION: Higher peak HR, larger increases in HR, and greater HR variability during the HUTT may serve as reliable predictors of a positive response to metoprolol in patients with VVS.

Discovery of potential components characteristic by conjugated enone from the branches and leaves of Croton lauioides with anti-neuroinflammatory activity via regulating the NF-κB pathway.

In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.

Signaling Size: Ankyrin and SOCS Box-Containing ASB E3 Ligases in Action.

Ankyrin repeat and suppressor of cytokine signaling (SOCS) box (Asb) proteins are ubiquitin E3 ligases. The subfamily of six-ankyrin repeat domain-containing Asb proteins (Asb5, Asb9, Asb11, and Asb13) is of specific interest because they display unusual strong evolutionary conservation (e.g., urochordate and human ASB11 are >49% similar at the amino acid level) and mediate compartment size expansion, regulating, for instance, the size of the brain and muscle compartment. Thus, they may be involved in the explanation of the differences in brain size between humans and apes. Mechanistically, many questions remain, but it has become clear that regulation of canonical Notch signaling and also mitochondrial function are important effectors. Here, we review the action and function of six ankyrin repeat domain-containing Asb proteins in physiology and pathophysiology.

Single-Cell Sequencing and Organoids: A Powerful Combination for Modelling Organ Development and Diseases.

The development and function of a particular organ and the pathogenesis of various diseases remain intimately linked to the features of each cell type in the organ. Conventional messenger RNA- or protein-based methodologies often fail to elucidate the contribution of rare cell types, including some subpopulations of stem cells, short-lived progenitors and circulating tumour cells, thus hampering their applications in studies regarding organ development and diseases. The scRNA-seq technique represents a new approach for determining gene expression variability at the single-cell level. Organoids are new preclinical models that recapitulate complete or partial features of their original organ and are thought to be superior to cell models in mimicking the sophisticated spatiotemporal processes of the development and regeneration and diseases. In this review, we highlight recent advances in the field of scRNA-seq, organoids and their current applications and summarize the advantages of using a combination of scRNA-seq and organoid technology to model diseases and organ development.

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.

BACKGROUND: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. METHODS: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. RESULTS: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. CONCLUSION: Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Preparation, Structure-Performance Relationship, and Reaction Network of ZnZSM-5 for Oxidative Dehydrogenation of Ethane with CO2.

Ethylene (C2 H4 ) is a major chemical for the modern society, and new technologies for its production are of strategic importance globally. Recently, oxidative dehydrogenation of ethane (C2 H6 ) using CO2 as a milder oxidant (CO2 -ODH) is proposed as a potential way for C2 H4 production, and development of effective catalysts for the process is drawing wide attention. Here, we report on a facilely prepared ZSM-5 supported Zn system, i. e., ZnZSM-5, which showed great promise in CO2 -ODH. Samples with different Zn loadings were prepared and evaluated, and the highest performance was obtained over 0.05ZnZSM-5 at 700 °C and a CO2 :C2 H6 feeding ratio of 5 : 1. During 340 min TOS, the C2 H6 conversion decreased moderately from 36.2 % to 23.1 %, and the C2 H4 yield stabilized at 21.9 % to 27.9 %. Based on systematic characterization and investigation of reaction conditions, the structure-performance relationship and reaction network were discussed in detail.

Analyzing Phylogenetic Trees with a Tree Lattice Coordinate System and a Graph Polynomial.

Phylogenetic trees are a central tool in many areas of life science and medicine. They demonstrate evolutionary patterns among species, genes, and patterns of ancestry among sets of individuals. The tree shapes and branch lengths of phylogenetic trees encode evolutionary and epidemiological information. To extract information from tree shapes and branch lengths, representation and comparison methods for phylogenetic trees are needed. Representing and comparing tree shapes and branch lengths of phylogenetic trees are challenging, for a tree shape is unlabeled and can be displayed in numerous different forms, and branch lengths of a tree shape are specific to edges whose positions vary with respect to the displayed forms of the tree shape. In this article, we introduce representation and comparison methods for rooted unlabeled phylogenetic trees based on a tree lattice that serves as a coordinate system for rooted binary trees with branch lengths and a graph polynomial that fully characterizes tree shapes. We show that the introduced tree representations and metrics provide distance-based likelihood-free methods for tree clustering, parameter estimation, and model selection and apply the methods to analyze phylogenies reconstructed from virus sequences. [Graph polynomial; likelihood-free inference; phylogenetics; tree lattice; tree metrics.].

Experiment and Computational Study on Pd-Catalyzed Methoxyiminoacyl-Directed γ-Alkoxylation of Alkylamides.

The direct alkoxylation of amides has been accomplished via methoxyiminoacyl (MIA)-mediated Pd-catalyzed C-H functionalization. A diverse array of alkylamide substrates is amenable to this protocol, providing γ-C(sp3)-alkoxylation of alkylamide derivatives with good to high efficiency. Two aspects of the research were completed to explore the reaction mechanism. On the one hand, the result of the kinetic isotopic effect experiment and control experiment indicated that reductive elimination is a rate-limiting step. On the other hand, density functional theory calculations demonstrated that a concerted Sn2 reductive elimination mechanism pathway is prior. Finally, the MIA group could be efficiently hydrogenated and protected in a one-pot procedure, which provides a short synthetic route to γ-methoxy amino acid derivatives.

Doping-induced magnetism and magnetoelectric coupling in one-dimensional NbOCl3 and NbOBr3.

Low-dimensional multiferroic systems with magnetoelectric coupling have attracted considerable attention due to their important applications in high-density low-power storage. Based on the first-principles calculations, we demonstrated that the recently proposed one-dimensional (1D) ferroelectric materials NbOCl3 and NbOBr3 have good stabilities, and found that they can be easily separated from the bulk phase. Due to the flat band near the Fermi level, the itinerant ferromagnetism can be induced over a wide range of electron-doping concentrations, and it leads to the coexistence of ferroelectricity and ferromagnetism in 1D NbOX3 (X = Cl, Br) and finite-length nanochains. More interestingly, there is strong magnetoelectric coupling on finite-length nanochains, which is caused by the spontaneous electrical polarization and redistribution of magnetic carriers. In addition, magnetism also can be introduced by oxygen vacancies. We also analyzed the effects of doping concentration, strain, and length on ferroelectric polarization and magnetism. Our findings provide a way to design and search low-dimensional multiferroics.

The polarized electric field of CdTe/B4C3 heterostructure efficiently promotes its photocatalytic overall water splitting.

Inspired by natural photosynthesis, two-dimensional van der Waals (vdW) heterostructures are considered as promising photocatalysts for solar-driven water splitting and they attract ever-growing interest. A type-II vdW hetero-photocatalyst (CdTe/B4C3) integrating the polarized CdTe into metal-free B4C3 was constructed, which could achieve solar-driven spontaneous overall water splitting at pH = 0-7 and exhibit a high solar-to-hydrogen (STH) efficiency of 19.64%. Our calculation results show that the interlayer interaction between the CdTe and B4C3 monolayers in the heterostructure creates an interfacial electric field enhanced by the intrinsic dipole of polarized CdTe, which accelerates the effective separation of photogenerated carriers and makes the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) take place separately on the B4C3 and CdTe layers. Furthermore, the CdTe/B4C3 heterostructure has decent band edge positions to promote the redox reaction to decompose water due to the significant electrostatic potential difference in the CdTe/B4C3 heterostructure and it could trigger spontaneous redox reaction under light at pH = 0-7. This work is helpful for us to design type-II heterojunction photocatalysts with high efficiency of photogenerated carrier separation for overall water splitting.

Fundamental Limitation on the Detectability of Entanglement.

Entanglement detection is essential in quantum information science and quantum many-body physics. It has been proved that entanglement exists almost surely for a random quantum state, while the realizations of effective entanglement criteria usually consume exponentially many resources with regard to system size or qubit number, and efficient criteria often perform poorly without prior knowledge. This fact implies a fundamental limitation might exist in the detectability of entanglement. In this work, we formalize this limitation as a fundamental trade-off between the efficiency and effectiveness of entanglement criteria via a systematic method to evaluate the detection capability of entanglement criteria theoretically. For a system coupled to an environment, we prove that any entanglement criterion needs exponentially many observables to detect the entanglement effectively when restricted to single-copy operations. Otherwise, the detection capability of the criterion will decay double exponentially. Furthermore, if multicopy joint measurements are allowed, the effectiveness of entanglement detection can be exponentially improved, which implies a quantum advantage in entanglement detection problems. Our results may shed light on why quantum phenomena are difficult to observe in large noisy systems.

Detecting Entanglement in Quantum Many-Body Systems via Permutation Moments.

Multipartite entanglement plays an essential role in both quantum information science and many-body physics. Because of the exponentially large dimension and complex geometric structure of the state space, the detection of entanglement in many-body systems is extremely challenging in reality. Conventional means, like entanglement witness and entropy criterion, either highly depend on the prior knowledge of the studied systems or the detection capability is relatively weak. In this Letter, we propose a framework for designing multipartite entanglement criteria based on permutation moments, which have an effective implementation with either the generalized control-swap quantum circuits or the random unitary techniques. As an example, in the bipartite scenario, we develop an entanglement criterion that can detect bound entanglement and show strong detection capability in the multiqubit Ising model with a long-range XY Hamiltonian. In the multipartite case, the permutation-moment-based criteria can detect entangled states that are not detectable by any criteria extended from the bipartite case. Our framework also shows potential in entanglement quantification and entanglement structure detection.

Pd-Catalyzed γ-Acetoxylation of Alkylamides: Structural Influence of Directing Groups.

Although direct acetoxylation and cyclization of alkylamide have been extensively reported, investigation of the structural influence of directing groups on selectivity is limited. Pd-catalyzed 2-methoxyiminoacyl (MIA) assisted γ-acetoxylation of alkylamides has been developed. Further DFT studies have demonstrated that the directing groups have a significant influence on the reductive elimination step. The strong electron-donating effect of the OMe group in MIA leads to the preferential formation of a five-membered cyclopalladium (OAc-Pd-C) complex, which favors the acetoxylation pathway.

Multicomponent TiO2/Ag/Cu7S4@Se Heterostructures Constructed by an Interface Engineering Strategy for Promoting the Electrocatalytic Nitrogen Reduction Reaction Performance.

The electrocatalytic nitrogen reduction reaction (ECNRR) is a sustainable and environmentally friendly method for NH3 synthesis under environmental conditions relative to the Haber-Bosch process; however, its low selectivity (Faradaic efficiency (FE)) and low NH3 yield impede the progress. Herein, benefiting from the application of the interface engineering strategy, a multicomponent TiO2/Ag/Cu7S4@Se-CC heterogeneous electrocatalyst with a unique structure was successfully fabricated, generating a unique sandwich structure by using a Ag layer as an electric bridge intercalated between TiO2 and Cu7S4, in which the optimized catalyst can accelerate the electron transfer efficiency. Moreover, through the electronic structure adjustment, an electron-deficient region was constructed, which can inhibit the H2 adsorption but enhance the N2 adsorption, thereby improving the selectivity and the catalytic activity. Significantly, the FE and NH3 yield of TiO2/Ag/Cu7S4@Se-CC reached 51.05 ± 0.16% and 39.16 ± 2.31 µg h-1 cm-2, in which the FE is among the highest non-precious metal-based NRR electrocatalysts in alkaline electrolytes reported. This study provides insight into the rational design and construction of NRR electrocatalysts for electrocatalytic applications.

Amorphous Boron Carbide on Titanium Dioxide Nanobelt Arrays for High-Efficiency Electrocatalytic NO Reduction to NH3.

Electrocatalytic NO reduction is regarded as an attractive strategy to degrade the NO contaminant into useful NH3 , but the lack of efficient and stable electrocatalysts to facilitate such multiple proton-coupled electron-transfer processes impedes its applications. Here, we report on developing amorphous B2.6 C supported on a TiO2 nanoarray on a Ti plate (a-B2.6 C@TiO2 /Ti) as an NH3 -producing nanocatalyst with appreciable activity and durability toward the NO electroreduction. It shows a yield of 3678.6 µg h-1 cm-2 and a FE of 87.6 %, superior to TiO2 /Ti (563.5 µg h-1 cm-2 , 42.6 %) and a-B2.6 C/Ti (2499.2 µg h-1 cm-2 , 85.6 %). An a-B2.6 C@TiO2 /Ti-based Zn-NO battery achieves a power density of 1.7 mW cm-2 with an NH3 yield of 1125 µg h-1 cm-2 . An in-depth understanding of catalytic mechanisms is gained by theoretical calculations.

ReCGBM: a gradient boosting-based method for predicting human dicer cleavage sites.

BACKGROUND: Human dicer is an enzyme that cleaves pre-miRNAs into miRNAs. Several models have been developed to predict human dicer cleavage sites, including PHDCleav and LBSizeCleav. Given an input sequence, these models can predict whether the sequence contains a cleavage site. However, these models only consider each sequence independently and lack interpretability. Therefore, it is necessary to develop an accurate and explainable predictor, which employs relations between different sequences, to enhance the understanding of the mechanism by which human dicer cleaves pre-miRNA. RESULTS: In this study, we develop an accurate and explainable predictor for human dicer cleavage site - ReCGBM. We design relational features and class features as inputs to a lightGBM model. Computational experiments show that ReCGBM achieves the best performance compared to the existing methods. Further, we find that features in close proximity to the center of pre-miRNA are more important and make a significant contribution to the performance improvement of the developed method. CONCLUSIONS: The results of this study show that ReCGBM is an interpretable and accurate predictor. Besides, the analyses of feature importance show that it might be of particular interest to consider more informative features close to the center of the pre-miRNA in future predictors.

A novel hypoxia gene signature indicates prognosis and immune microenvironments characters in patients with hepatocellular carcinoma.

Due to the lack of a suitable gene signature, it is difficult to assess the hypoxic exposure of HCC tissues. The clinical value of assessing hypoxia in HCC is short of tissue-level evidence. We tried to establish a robust and HCC-suitable hypoxia signature using microarray analysis and a robust rank aggregation algorithm. Based on the hypoxia signature, we obtained a hypoxia-associated HCC subtypes system using unsupervised hierarchical clustering and a hypoxia score system was provided using gene set variation analysis. A novel signature containing 21 stable hypoxia-related genes was constructed to effectively indicate the exposure of hypoxia in HCC tissues. The signature was validated by qRT-PCR and compared with other published hypoxia signatures in multiple large-size HCC cohorts. The subtype of HCC derived from this signature had different prognosis and other clinical characteristics. The hypoxia score obtained from the signature could be used to indicate clinical characteristics and predict prognoses of HCC patients. Moreover, we reveal a landscape of immune microenvironments in patients with different hypoxia score. In conclusion, we identified a novel HCC-suitable 21-gene hypoxia signature that could be used to estimate the hypoxia exposure in HCC tissues and indicated prognosis and a series of important clinical features in HCCs. It may enable the development of personalized counselling or treatment strategies for HCC patients with different levels of hypoxia exposure.

Oncogenic Mutations in Armadillo Repeats 5 and 6 of ß-Catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes.

BACKGROUND & AIMS: The ß-catenin signaling pathway is one of the most commonly deregulated pathways in cancer cells. Amino acid substitutions within armadillo repeats 5 and 6 (K335, W383, and N387) of ß-catenin are found in several tumor types, including liver tumors. We investigated the mechanisms by which these substitutions increase signaling and the effects on liver carcinogenesis in mice. METHODS: Plasmids encoding tagged full-length ß-catenin (CTNNB1) or ß-catenin with the K335I or N387K substitutions, along with MET, were injected into tails of FVB/N mice. Tumor growth was monitored, and livers were collected and analyzed by histology, immunohistochemistry, and quantitative reverse-transcription polymerase chain reaction. Tagged full-length and mutant forms of ß-catenin were expressed in HEK293, HCT116, and SNU449 cells, which were analyzed by immunoblots and immunoprecipitation. A panel of ß-catenin variants and cell lines with knock-in mutations were analyzed for differences in N-terminal phosphorylation, half-life, and association with other proteins in the signaling pathway. RESULTS: Mice injected with plasmids encoding K335I or N387K ß-catenin and MET developed larger, more advanced tumors than mice injected with plasmids encoding WT ß-catenin and MET. K335I and N387K ß-catenin bound APC with lower affinity than WT ß-catenin but still interacted with scaffold protein AXIN1 and in the nucleus with TCF7L2. This interaction resulted in increased transcription of genes regulated by ß-catenin. Studies of protein structures supported the observed changes in relative binding affinities. CONCLUSION: Expression of ß-catenin with mutations in armadillo repeats 5 and 6, along with MET, promotes formation of liver tumors in mice. In contrast to N-terminal mutations in ß-catenin that directly impair its phosphorylation by GSK3 or binding to BTRC, the K335I or N387K substitutions increase signaling via reduced binding to APC. However, these mutant forms of ß-catenin still interact with the TCF family of transcription factors in the nucleus. These findings show how these amino acid substitutions increase ß-catenin signaling in cancer cells.

MIA-Directed 2-Pyridione-Enabled Selective Ortho-C-H Arylation of Phenylalanine: A Mechanistic Study.

The 2-methoxyiminoacyl-mediated arylation of substituted phenylalanines has been examined. Selective monoarylation at the ortho position was achieved using pyridone ligands which decelerate the arylation process. Density functional theory (DFT) study of a continuous C-H arylation process that included the first and second arylation stage was performed. The computational result shows that the introduction of a pyridone ligand obviously disfavors the second arylation stage, which directly contributes to the selectivity between the mono/diarylated products. Furthermore, results of the kinetic isotope effect and a control experiment are agreed with DFT study.

Occlusion-capable optical-see-through near-eye display using a single digital micromirror device.

Occlusion of a real scene by displayed virtual images mitigates incorrect depth cues and enhances image visibility in augmented reality applications. In this Letter, we propose a novel optical scheme for the occlusion-capable optical-see-through near-eye display. The proposed scheme uses only a single spatial light modulator, as the real-scene mask and virtual image display simultaneously. A polarization-based double-pass configuration is also combined, enabling a compact implementation. The proposed scheme is verified by optical experiments which demonstrate a 60 Hz red-green-blue video display with a 4-bit depth for each color channel and per-pixel dynamic occlusion of a 90.6% maximum occlusion ratio.