Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Renoprotective effects of Schoenoplectus tabernaemontani rhizomes aqueous extracts against Adriamycin-induced nephropathy in rats.

In recent years, chronic kidney disease (CKD) has emerged as an increasingly significant issue due to the growing prevalence and high treatment costs. While recorded the positive diuretic effect of Schoenoplectus tabernaemontani, there is a lack of reports on its efficacy in treating CKD. The pharmacological effects and mechanisms of Schoenoplectus tabernaemontani rhizomes aqueous extracts (STE) in CKD were investigated by inducing a rodent model of CKD via injection of Adriamycin (ADR; 7.5 mg/kg) into the tail vein of Wistar rats. In summary, our findings suggest that STE has a beneficial effect on anti-renal fibrosis and can reverse ADR-induced renal injury by suppressing oxidative stress and inflammation. Therefore, STE holds promising potential as a treatment option for CKD.

SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration.

BACKGROUND: Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. METHODS: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. RESULTS: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models. CONCLUSIONS: This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

How does the online innovation community climate affect the user's value co-creation behavior: The mediating role of motivation.

Online Innovation Community (OIC) serves as a virtual space for users to exchange products and services, and share knowledge and information. Previous studies have indicated that community climate is an important factor affecting users' value co-creation behavior, however, the influencing process has not been clearly revealed from the perspective of motivation. In this study, we explored the relationship between online innovation community climate (supportive climate and controlling climate), user motivation and value co-creation behavior (user's participation behavior and user's citizenship behavior) based on the SOR model. The study sample included 29,835 pieces of information from 3,315 users in 14 product sections of the OnePlus Community which were analyzed with Mplus8.1. The findings revealed that: (1) The supportive climate had a positive impact on user's citizenship behavior(ß = 0.042), while the controlling climate exerted a significant positive impact on user's citizenship behavior (ß = 0.078) and user's participation behavior(ß = 0.099); (2) The need for achievement played a suppressing effect between community climate and user's participation behavior, the need for power played a suppressing effect between supportive climate and user's value co-creation behavior, and the need for affiliation played a mediating role between supportive climate and user's citizenship behavior (ß = 0.010) and user's participation behavior(ß = 0.006); (3) Community trust positively moderated the relationship between the need for achievement and user's participation behavior(ß = 0.058) as well as between the need for power and user's participation behavior(ß = 0.043).

Identification and Characterization of PrognosticMacrophage Subpopulations for HumanEsophagealCarcinoma.

AIMS: The aim of the present study was to investigate the relationship between the cellular ecosystem and the progression of esophageal carcinoma (ESCA) based on the evolution of macrophages and to analyze the potential of using macrophages as a new therapeutic approach in ESCA treatment. BACKGROUND: Macrophage-based immunotherapy could be used for treating ESCA patients, but its clinical application is limited by the intra-tumor heterogeneity of macrophages. OBJECTIVE: The objective of this study was to analyze the diversity, differentiation trajectory, and intercellular communication of macrophages in ESCA and its prognostic significance. METHODS: Single-cell RNA sequencing (scRNA-seq) data in the GSE154763 dataset were downloaded from Gene Expression Omnibus (GEO) to identify cell clusters and annotate cell types using the Seurat R package. The scRNA-seq profiles of macrophages were extracted, and cluster analysis was performed to identify macrophage subsets. The differentiation trajectories of macrophage subgroups were visualized employing Monocle2. Finally, ligand-receptor pairs and communication intensity among the classified subgroups were analyzed using CellChat. RESULTS: A total of 8 cell types were identified between ESCA tissues and paracancer tissues. The most abundant macrophages in ESCA tissues were further divided into 5 cell clusters. Compared with the normal tissues, the proportion of HSPA6+ macrophages in ESCA tissues increased the most, and the number of ligand-receptor pairs that mediated the communication of HSPA6+ macrophages with mast cells and monocytes also increased significantly. More importantly, a high proportion of HSPA6+ macrophages was inversely correlated with the survival outcomes for ESCA patients. CONCLUSIONS: This study analyzed the diversity, distribution and differentiation trajectory of macrophages in ESCA tissues at single-cell level and classified a prognostic macrophage subtype (HSPA6+ macrophages) of ESCA, providing a theoretical basis for macrophage-targeted therapy in ESCA.

Research progress of N1-methyladenosine RNA modification in cancer.

N1-methyladenosine (m1A) is a post-transcriptionally modified RNA molecule that plays a pivotal role in the regulation of various biological functions and activities. Especially in cancer cell invasion, proliferation and cell cycle regulation. Over recent years, there has been a burgeoning interest in investigating the m1A modification of RNA. Most studies have focused on the regulation of m1A in cancer enrichment areas and different regions. This review provides a comprehensive overview of the methodologies employed for the detection of m1A modification. Furthermore, this review delves into the key players in m1A modification, known as the "writers," "erasers," and "readers." m1A modification is modified by the m1A methyltransferases, or writers, such as TRMT6, TRMT61A, TRMT61B, TRMT10C, NML, and, removed by the demethylases, or erasers, including FTO and ALKBH1, ALKBH3. It is recognized by m1A-binding proteins YTHDF1, TYHDF2, TYHDF3, and TYHDC1, also known as "readers". Additionally, we explore the intricate relationship between m1A modification and its regulators and their implications for the development and progression of specific types of cancer, we discuss how m1A modification can potentially facilitate the discovery of novel approaches for cancer diagnosis, treatment, and prognosis. Our summary of m1A methylated adenosine modification detection methods and regulatory mechanisms in various cancers provides useful insights for cancer diagnosis, treatment, and prognosis. Video Abstract.

Recent advances in the potential role of RNA N4-acetylcytidine in cancer progression.

N4-acetylcytidine (ac4C) is a highly conserved chemical modification widely found in eukaryotic and prokaryotic RNA, such as tRNA, rRNA, and mRNA. This modification is significantly associated with various human diseases, especially cancer, and its formation depends on the catalytic activity of N-acetyltransferase 10 (NAT10), the only known protein that produces ac4C. This review discusses the detection techniques and regulatory mechanisms of ac4C and summarizes ac4C correlation with tumor occurrence, development, prognosis, and drug therapy. It also comments on a new biomarker for early tumor diagnosis and prognosis prediction and a new target for tumor therapy. Video Abstract.

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism.

Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer-related mortality worldwide. Nop2/Sun domain family member 5 (NSUN5), a conserved RNA 5-methylcytosine methyltransferase, is conventionally recognized as oncogenic. However, its role in HCC development remains unknown. In this study, we observed a remarkable upregulation of NSUN5 expression in both tumor tissues from patients with HCC, establishing a correlation with unfavorable clinical outcomes. NSUN5 knockdown and overexpression significantly inhibited and promoted HCC cell proliferation, respectively. Additionally, employing a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RIP-seq techniques, we identified zinc finger BED domain-containing protein 3 (ZBED3) as a novel downstream target of NSUN5. Additionally, we found that the overexpression of ZBED3 counteracted the tumor-suppressing effect of NSUN5 knockdown and simultaneously reversed the inhibition of the Wnt/ß-catenin signaling pathway. In summary, we elucidated the oncogenic role of NSUN5 in HCC development and identified the ZBED3/Wnt/ß-catenin signaling pathway as its downstream target. This study provides a novel therapeutic target for further development in HCC treatment.

Highly sensitive detection of glucose at a novel non-enzyme electrochemical sensing based on Mo-doped CoO Nanosheets.

In this work, a Mo doped CoO nanosheet grown on nickel foam (labeled as: Mo-CoO) with defect-rich and improved electron transfer capacity was designed to be used as a novel non-enzyme electrode material. Physical characterizations demonstrated the Mo elements were doped inside of the samples and they were mutually stabilized with each other, resulting in a high structural stability electrochemical catalytical activity even if the content of Mo was low. For non-enzymatic glucose electrochemical sensing, the prepared Mo-CoO-1 showed a remarkable sensitivity of 89.3 mA cm-2 mM-1 , and a low detection limit of 0.43 µM. Density functional theory (DFT) studies revealed that the doped Mo atom exhibited a higher d-band center compared to the Co atom. A stronger p-d orbital hybridization between the glucose and the Mo atoms indicated the enhancement of glucose adsorption and activation. Importantly, Mo-CoO-1 provided a good selectivity and long-term stability, which can be expected to be used in future practical applications.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study.

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

The Impact of Urbanization on Tree Growth and Xylem Anatomical Characteristics.

In the context of the intensification of global urbanization, how urbanization (urban heat island effect and air pollution) affects urban tree growth is not fully understood. In this paper, the radial growth and xylem anatomical characteristics of three different tree species (Quercus mongolica, Fraxinus mandshurica, and Pinus sylvestris var. mongolica) in urban and rural areas of Harbin were compared by means of tree-ring anatomy. The results showed that there were significant differences in the growth of both broadleaf trees and conifers between urban and rural areas. The vessel number, cumulative area of vessels, and theoretical hydraulic conductivity of all tree species in rural areas were higher than those in urban areas, indicating that urbanization may have the effect of slowing down growth. However, broadleaf trees in urban areas had higher vessel density and a greater percentage of a conductive area within xylem and theoretical xylem-specific hydraulic conductivity. The thickness of cell walls and cell wall reinforcement index of P. sylvestris var. mongolica were strongly reduced by air pollution, implying that it may be more sensitive to urbanization. Compared to Q. mongolica, F. mandshurica showed less sensitivity to urbanization. Warming and drying climate in Harbin may be an important factor affecting tree growth.

Research progress of additional pathogenic mutations in chronic neutrophilic leukemia.

Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm (MPN). Due to its nonspecific clinical symptoms and lack of specific molecular markers, it was previously difficult to distinguish it from other diseases with increased neutrophils. However, the discovery of the CSF3R mutation in CNL 10 years ago and the update of the diagnostic criteria by the World Health Organization (WHO) in 2016 brought CNL into a new era of molecular diagnosis. Next-generation sequencing (NGS) technology has led to the identification of numerous mutant genes in CNL. While CSF3R is commonly recognized as the driver mutation of CNL, other mutations have also been detected in CNL using NGS, including mutations in other signaling pathway genes (CBL, JAK2, NARS, PTPN11) and chromatin modification genes (ASXL1, SETBP1, EZH2), DNA methylation genes (DNMT3A, TET2), myeloid-related transcription factor genes (RUNX1, GATA2), and splicing and RNA metabolism genes (SRSF2, U2AF1). The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients.

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis.

BACKGROUND: Venetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model. RESULTS: A total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia. CONCLUSIONS: This study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

BBOX1-AS1: A novel oncogenic long non-coding RNA in human cancers.

Long non-coding RNAs (lncRNAs) are transcripts that contain more than 200 nucleotides. Despite the fact that they cannot encode proteins, many studies have identified roles they play in human cancers through diverse mechanisms. BBOX1-AS1, an oncogenic lncRNA, has recently been demonstrated to participate in tumorigenesis and progression of numerous cancers. Experimental evidence has determined that it participates in diverse biological process, including cell proliferation, invasion, migration, and apoptosis. The dysregulation of BBOX1-AS1 exerts its oncogenicity by acting as a competitive endogenous RNA (ceRNA) or by directly impacting downstream molecules and signaling pathways. Here we summarize the current understanding of the biological functions and clinical significance of BBOX1-AS1 for human cancers.

Granger Causal Inference Based on Dual Laplacian Distribution and Its Application to MI-BCI Classification.

Granger causality-based effective brain connectivity provides a powerful tool to probe the neural mechanism for information processing and the potential features for brain computer interfaces. However, in real applications, traditional Granger causality is prone to the influence of outliers, such as inevitable ocular artifacts, resulting in unreasonable brain linkages and the failure to decipher inherent cognition states. In this work, motivated by constructing the sparse causality brain networks under the strong physiological outlier noise conditions, we proposed a dual Laplacian Granger causality analysis (DLap-GCA) by imposing Laplacian distributions on both model parameters and residuals. In essence, the first Laplacian assumption on residuals will resist the influence of outliers in electroencephalogram (EEG) on causality inference, and the second Laplacian assumption on model parameters will sparsely characterize the intrinsic interactions among multiple brain regions. Through simulation study, we quantitatively verified its effectiveness in suppressing the influence of complex outliers, the stable capacity for model estimation, and sparse network inference. The application to motor-imagery (MI) EEG further reveals that our method can effectively capture the inherent hemispheric lateralization of MI tasks with sparse patterns even under strong noise conditions. The MI classification based on the network features derived from the proposed approach shows higher accuracy than other existing traditional approaches, which is attributed to the discriminative network structures being captured in a timely manner by DLap-GCA even under the single-trial online condition. Basically, these results consistently show its robustness to the influence of complex outliers and the capability of characterizing representative brain networks for cognition information processing, which has the potential to offer reliable network structures for both cognitive studies and future brain-computer interface (BCI) realization.

Design, synthesis and the evaluation of cholinesterase inhibition and blood-brain permeability of daidzein derivatives or analogs.

In the present study, a series of derivatives and analogs of daidzein were designed and synthesized to investigate cholinesterase inhibition and blood-brain barrier permeability. The enzyme assay showed that most of the compounds containing a tertiary amine group exhibit moderate cholinesterase inhibition, 7-hydroxychromone derivatives (absence of B ring of daidzein scaffold) only have a weaker bioactivity, while those compounds without the tertiary amine group have no bioactivity. Among them compound 15a (4'-N,N-dimethylaminoethoxy-7-methoxyisoflavone) appeared the best inhibitory activity (IC50 : 2.14 ± 0.31 µmol/L) and higher selectivity for AChE over BuChE (Ratio: 7.07). It was selected for the further investigation by UPLC-MS/MS. The results show that CBrain/Serum of compound 15a in mice was more than 2.87 within 240 min. This discovery may provide worthy information for the future development of central nervous drugs including but not limited to cholinesterase inhibitors.

In-Site Grown NiFeOOH Nanosheets Foam Directly as Robust Electrocatalyst for Efficient Urea Oxidation Application.

In this work, a series of morphology-controlled NiFeOOH nanosheets were directly developed through a one-step mild in-situ acid-etching hydrothermal process. Benefiting from the ultrathin interwoven geometric structure and most favorable electron transport structure, the NiFeOOH nanosheets synthesized under 120 °C (denoted as NiFe_120) exhibited the optimal electrochemical performance for urea oxidation reaction (UOR). An overpotential of merely 1.4 V was required to drive the current density of 100 mA cm-2 , and the electrochemical activity remains no change even after 5000 cycles' accelerated degradation test. Moreover, the assembled urea electrolysis set by using the NiFe_120 as bifunctional catalysts presented a reduced potential of 1.573 V at 10 mA cm-2 , which was much lower than that of overall water splitting. We believe this work will lay a foundation for developing high-performance urea oxidation catalysts for the large-scale production of hydrogen and purification of urea-rich sewage.

An adaptive joint CCA-ICA method for ocular artifact removal and its application to emotion classification.

BACKGROUND: The quality of Electroencephalogram (EEG) signals is critical for revealing the neural mechanism of emotions. However, ocular artifacts decreased the signal to noise ratio (SNR) and covered the inherent cognitive component of EEGs, which pose a great challenge in neuroscience research. NEW METHOD: We proposed a novel unsupervised learning algorithm to adaptively remove the ocular artifacts by combining canonical correlation analysis (CCA), independent component analysis (ICA), higher-order statistics, empirical mode decomposition (EMD), and wavelet denoising techniques. Specifically, the combination of CCA and ICA aimed to improve the quality of source separation, while the higher-order statistics further located the source of ocular artifacts. Subsequently, these noised sources were further corrected by EMD and wavelet denoising to improve SNR of EEG signals. RESULTS: We evaluated the performance of our proposed method with simulation studies and real EEG applications. The results of simulation study showed our proposed method could significantly improve the quality of signals under almost all noise conditions compared to four state-of-art methods. Consistently, the experiments of real EEG applications showed that the proposed methods could efficiently restrict the components of ocular artifacts and preserve the inherent information of cognition processing to improve the reliability of related analysis such as power spectral density (PSD) and emotion recognition. COMPARISON WITH EXISTING METHODS: Our proposed model outperforms the comparative methods in EEG recovery, which further improve the application performance such as PSD analysis and emotion recognition. CONCLUSIONS: The superior performance of our proposed method suggests that it is promising for removing ocular artifacts from EEG signals, which offers an efficient EEG preprocessing technology for the development of brain computer interface such as emotion recognition.

Bacteria require phase separation for fitness in the mammalian gut.

Therapeutic manipulation of the gut microbiota holds great potential for human health. The mechanisms bacteria use to colonize the gut therefore present valuable targets for clinical intervention. We now report that bacteria use phase separation to enhance fitness in the mammalian gut. We establish that the intrinsically disordered region (IDR) of the broadly and highly conserved transcription termination factor Rho is necessary and sufficient for phase separation in vivo and in vitro in the human commensal Bacteroides thetaiotaomicron. Phase separation increases transcription termination by Rho in an IDR-dependent manner. Moreover, the IDR is critical for gene regulation in the gut. Our findings expose phase separation as vital for host-commensal bacteria interactions and relevant for novel clinical applications.