Multi-model analysis of gallbladder cancer reveals the role of OxLDL-absorbing neutrophils in promoting liver invasion.

BACKGROUND: Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs or distant metastasis happened long before the diagnosis, especially the direct liver invasion, which is the most common and unfavorable way of spreading. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), proteomics, and multiplexed immunohistochemistry (mIHC) were performed on GBC across multiple tumor stages to characterize the tumor microenvironment (TME), focusing specifically on the preferential enrichment of neutrophils in GBC liver invasion (GBC-LI). RESULTS: Multi-model Analysis reveals the immunosuppressive TME of GBC-LI that was characterized by the enrichment of neutrophils at the invasive front. We identified the context-dependent transcriptional states of neutrophils, with the Tumor-Modifying state being associated with oxidized low-density lipoprotein (oxLDL) metabolism. In vitro assays showed that the direct cell-cell contact between GBC cells and neutrophils led to the drastic increase in oxLDL uptake of neutrophils, which was primarily mediated by the elevated OLR1 on neutrophils. The oxLDL-absorbing neutrophils displayed a higher potential to promote tumor invasion while demonstrating lower cancer cytotoxicity. Finally, we identified a neutrophil-promoting niche at the invasive front of GBC-LI that constituted of KRT17+ GBC cells, neutrophils, and surrounding fibroblasts, which may help cultivate the oxLDL-absorbing neutrophils. CONCLUSIONS: Our study reveals the existence of a subset of pro-tumoral neutrophils with a unique ability to absorb oxLDL via OLR1, a phenomenon induced through cell-cell contact with KRT17+ GBC cells in GBC-LI.

Targeting leucine-rich PPR motif-containing protein/LRPPRC by 5,7,4'-trimethoxyflavone suppresses esophageal squamous cell carcinoma progression.

JAK2/STAT3/MYC axis is dysregulated in nearly 70 % of human cancers, but targeting this pathway therapeutically remains a big challenge in cancer therapy. In this study, genes associated with JAK2, STAT3, and MYC were analyzed, and potential target genes were selected. Leucine-rich PPR motif-containing protein (LRPPRC) whose function and regulation are not fully understood, emerged as one of top 3 genes in terms of RNA epigenetic modification. Here, we demonstrate LRPPRC may be an independent prognostic indicator besides JAK2, STAT3, and MYC. Mechanistically, LRPPRC impairs N6-methyladenosine (m6A) modification of JAK2, STAT3, and MYC to facilitate nuclear mRNA export and expression. Meanwhile, excess LRPPRC act as a scaffold protein binding to JAK2 and STAT3 to enhance stability of JAK2-STAT3 complex, thereby facilitating JAK2/STAT3/MYC axis activation to promote esophageal squamous cell carcinoma (ESCC) progression. Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.

Intertwisted superhydrophilic and superhydrophobic collagen fibers enabled anti-fouling high-performance separation of emulsion wastewater.

Oil-contaminated wastewater has been one of the most concerned environmental issues. Superwetting materials-enabled remediation of oil contamination in wastewater faces the critical challenge of fouling problems due to the formation of intercepted phase. Herein, high-performance separation of emulsions wastewater was accomplished by developing collagen fibers (CFs)-derived water-oil dual-channels that were comprised of intertwisted superhydrophilic and superhydrophobic CFs. The dual-channels relied on the superhydrophilic CFs to accomplish efficient demulsifying, which played the role as water-channel to enable fast transportation of water, while the superhydrophobic CFs served as the oil-transport channel to permit oil transportation. The mutual repellency between water-channel and oil-channel was essential to guarantee the stability of established dual-channels. The unique dual-channel separation mechanism fundamentally resolved the intercepted phase-caused fouling problem frequently engaged by the superwetting materials that provided single-channel separation capability. Long-lasting (1440 min) anti-fouling separations were achieved by the superwetting CFs-derived dual-channels with separation efficiency high up to 99.99%, and more than 4-fold of stable separation flux as compared with that of superhydrophilic CFs with single-channel separation capability. Our investigations demonstrated a novel strategy by using superwetting CFs to develop water-oil dual-channels for achieving high-performance anti-fouling separation of emulsions wastewater. ENVIRONMENTAL IMPLICATION: Industrial processes discard a large amount of emulsion wastewater, which seriously imperils the aquatic ecosystem. This work demonstrated a conceptual-new strategy to achieve effective remediation of emulsion wastewater via the water-oil dual-channels established by the intertwisted superhydrophilic and superhydrophobic collagen fibers (CFs). The superhydrophilic CFs enabled efficient demulsification of emulsions and played the role of water-channel for the rapid transportation of water, while the superhydrophobic CFs worked as oil-channel to permit the efficient transportation of oil pollutants. Consequently, the long-term (1440 min) anti-fouling high-performance separation of emulsion wastewater was achieved.

Mature astrocytes as source for astrocyte repopulation after deletion in the medial prefrontal cortex: Implications for depression.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.

Clinical evaluation of Giomer and self-etch adhesive compared with nanofilled resin composite and etch-and-rinse adhesive - Results at 8 years.

OBJECTIVE: This study aimed to evaluate the long-term clinical performance of Giomer and a self-etch adhesive system compared with a nanofilled resin composite and etch-and-rinse adhesive system in Class I and Class II restorations. METHOD: The study was designed to be double-blinded with intra-individual control. 48 patients with 54 pairs of cavities (class I or class II) were recruited. Each pair of restorations was placed with either BEAUTIFIL II (BF) and FL-BOND II (FL) or Filtek Z350 (Z350) and Scotchbond Multi-Purpose (SMP). Clinical evaluation was performed at baseline, 6-month, 18-month, 4-year and 8-year after placement according to modified USPHS criteria. Kaplan-Meier survival analysis and log rank tests were performed (SPSS 20.0, IBM Corporation, US) to compare the survival probability of different restorations.A generalized linear mixed model (GLMM) was adopted to assess the performance of the materials. The McNemar test was used to show significant changes for all the evaluation criteria and difference between them. RESULTS: At the eight-year recall, 32 patients with 67 restorations were present. There were twelve restorations in total recorded as failure due to loss of retention, restoration fracture, secondary caries, tooth fracture or endodontic treatment due to pulp necrosis. The survival probabilities and calculated annual failure rate(AFR) of BF and Z350 restorations at 8-year were 87.2 % vs 87.8 % and 1.6 % vs 1.5 % respectively with no significant difference (p > 0.05)between the two materials. Over the recall time range of eight years, decreased possibility of alpha rating was observed for retention, marginal adaptation, marginal staining and surface roughness for both materials (p < 0.05). Decreased possibility of alpha rating was observed for surface staining and secondary caries for Z350 (p < 0.05) and restoration fracture for BF (p < 0.05), respectively. Comparing the two restorative systems over eight years, no significant difference was seen for linear decline of the possibility of alpha rating for any of the criteria evaluated (p > 0.05). CONCLUSION: Giomer material and the self-etch adhesive system had comparable clinical performance with nanofilled resin composite and etch-and-rinse adhesive system over the observation period of eight years.

Spontaneous Particle Ordering, Sorting, and Assembly on Soap Films.

Soap bubbles exhibit abundant fascinating phenomena throughout the entire life of evolution with different fundamental physics governing them. Nevertheless, the complicated dynamics of small objects in soap films are still unrevealed. Here, we report the first observation of spontaneous particle ordering in a complicated galaxy of soap films without any external energy. The balance of interfacial tension at two liquid-gas interfaces is theoretically predicted to govern belted wetted particles (BWPs) traveling along a specified path spontaneously. Such spontaneous particle path-finding is found to depend on the particle size and hydrophilic properties. Spontaneous particle sorting is directly realized via these discrete and distinctive paths for different particles. The deformation of the soap membrane facilitates 1D/2D particle organization along the path. This observation represents the discovery of a new spontaneous order phenomenon in soap film systems and provides a new energy-free approach for particle separation and soft colloidal crystal assembly.

High-Performance Liquid Chromatographic Quantification of the Plant Hormone Abscisic Acid at ppb Levels in Plant Samples after a Single Immunoaffinity Column Cleanup.

High-performance liquid chromatography with ultraviolet detection (HPLC-UV) is a common analysis technique due to its high versatility and simple operation. In the present study, HPLC-UV detection was integrated with immunoaffinity cleanup (IAC) of the sample extracts. The matrix effect was greatly reduced, and the limit of detection was as low as 1 ng/g of free abscisic acid (ABA) in fresh plant tissues. A monoclonal antibody 3F1 (mAb 3F1) was developed to specifically recognize free ABA but not ABA analogues. The mAb 3F1-immobilized immunoaffinity column exhibited a capacity of 850 ng/mL and an elution efficiency of 88.8-105% for standards. The extraction recoveries of the column for ABA ranged from 80.4 to 108.9%. ABA content was detected in various plant samples with IAC-HPLC-UV. The results were verified with ultraperformance liquid chromatography-electrospray tandem mass spectrometry. IAC-HPLC-UV can be a sensitive and cost-efficient method for plant hormone analysis.

Anti-MRSA mechanism of spirostane saponin in Rohdea pachynema F.T.Wang & tang.

ETHNOPHARMACOLOGY RELEVANCE: Rohdea pachynema F.T.Wang & Tang (R. pachynema), is a traditional folk medicine used for the treatment of stomach pain, stomach ulcers, bruises, and skin infections in China. Some of the diseases may relate to microbial infections in traditional applications. However few reports on its antimicrobial properties and bioactive components. AIM OF THE STUDY: To identify its bioactive constituents against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo, and its mechanism. MATERIALS AND METHODS: The anti-MRSA ingredient 6α-O-[ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-quinovopyranosyl]-(25S)-5α-spirostan-3ß-ol (XQS) was obtained from R. pachynema by phytochemical isolation. Subsequently, XQS underwent screening using the broth microdilution method and growth inhibition curves to assess its antibacterial activity. The mechanism of XQS was evaluated by multigeneration induction, biofilm resistance assay, scanning electron microscopy, transmission electron microscopy, and metabolomics. Additionally, a mouse skin infection model was established in vivo. RESULTS: 26 compounds were identified from the R. pachynema, in which anti-MRSA spirostane saponin (XQS) was reported for the first time with a minimum inhibitory concentration (MIC) of 8 µg/mL. XQS might bind to peptidoglycan (PGN) of the cell wall, phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) of the cell membrane, then destroying the cell wall and the cell membrane, resulting in reduced membrane fluidity and membrane depolarization. Furthermore, XQS affected MRSA lipid metabolism, amino acid metabolism, and ABC transporters by metabolomics analysis, which targeted cell walls and membranes causing less susceptibility to drug resistance. Furthermore, XQS (8 mg/kg) recovered skin wounds in mice infected by MRSA effectively, superior to vancomycin (8 mg/kg). CONCLUSIONS: XQS showed anti-MRSA bioactivity in vitro and in vivo, and its mechanism association with cell walls and membranes was reported for the first, which supported the traditional uses of R. pachynema and explained its sensitivity to MRSA.

Abnormal expression of Krüppel-like transcription factors and their potential values in lung cancer.

Lung cancer still is one of the most common malignancy tumors in the world. However, the mechanisms of its occurrence and development have not been fully elucidated. Zinc finger protein family (ZNFs) is the largest transcription factor family in human genome. Recently, the more and more basic and clinical evidences have confirmed that ZNFs/Krüppel-like factors (KLFs) refer to a group of conserved zinc finger-containing transcription factors that are involved in lung cancer progression, with the functions of promotion, inhibition, dual roles and unknown classifications. Based on the recent literature, some of the oncogenic KLFs are promising molecular biomarkers for diagnosis, prognosis or therapeutic targets of lung cancer. Interestingly, a novel computational approach has been proposed by using machine learning on features calculated from primary sequences, the XGBoost-based model with accuracy of 96.4 % is efficient in identifying KLF proteins. This paper reviews the recent some progresses of the oncogenic KLFs with their potential values for diagnosis, prognosis and molecular target in lung cancer.

Bioinformatics and Functional Analysis of OsASMT1 Gene in Response to Abiotic Stress.

The study aimed to elucidate the functional characteristics of OsASMT1 gene under copper (Cu) or sodium chloride (NaCl) stress. Bioinformatics scrutiny unveiled that OsASMT1 is situated on chromosome 9. Its protein architecture, comprising dimerization and methyltransferase domains, showed significant similarities to OsASMT2 and OsASMT3. High expression in roots and panicles, along with abiotic stress putative cis-regulatory elements in the promoter, indicated potential stress responsiveness. Real-time quantitative PCR confirmed OsASMT1 induction under Cu and NaCl stress in rice. Surprisingly, yeast expressing OsASMT1 did not exhibit enhanced resistance to abiotic stresses. The results of subcellular localization analysis indicated that OsASMT1 plays a role in the cytoplasm. While OsASMT1 responded to Cu and NaCl stress in rice, its heterologous expression in yeast failed to confer abiotic stress resistance, highlighting the need for further investigation of its functional implications.

Safety-Preserving Lyapunov-Based Model Predictive Rendezvous Control for Heterogeneous Marine Vehicles Subject to External Disturbances.

This article investigates the cooperative rendezvous control problem for perturbed heterogeneous marine systems composed of an autonomous underwater vehicle (AUV) and an autonomous surface vehicle (ASV). A novel Lyapunov-based model predictive control (LMPC) framework is presented to accomplish safe and precise rendezvous under input limitations and external disturbances. First, by incorporating the prescribed performance control (PPC) technique into the LMPC framework, we transform the original ascending state of the AUV into a self-constrained state, which serves as the decision variable of the model predictive control (MPC) optimization problem. Then, PPC-aided auxiliary control laws based on disturbance observers (DOBs) are designed to establish a robust contractive constraint to provide stability margins. Combining the LMPC with the PPC technique makes the original state-constrained problem an equivalent state-constraint-free problem. By addressing the MPC problem for the equivalent unconstrained system, the proposed method preserves the rendezvous safety. With the robust contractive constraint, the proposed safety-preserving LMPC (SP-LMPC) controller can inherit robustness and stability from the robust auxiliary control laws. Furthermore, theoretical analyses are conducted to assess recursive feasibility and closed-loop stability. With comprehensive theoretical support, the proposed method provides a new framework to simultaneously address state constraints and disturbances for highly nonlinear marine systems. Finally, simulations and comparisons are conducted to demonstrate the effectiveness and advantages of the proposed algorithm.

Soybean steroids improve crop abiotic stress tolerance and increase yield.

Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.

Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs.

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.

Quantized Zeroth-Order Gradient Tracking Algorithm for Distributed Nonconvex Optimization Under Polyak- [Formula: see text] ojasiewicz Condition.

This article focuses on distributed nonconvex optimization by exchanging information between agents to minimize the average of local nonconvex cost functions. The communication channel between agents is normally constrained by limited bandwidth, and the gradient information is typically unavailable. To overcome these limitations, we propose a quantized distributed zeroth-order algorithm, which integrates the deterministic gradient estimator, the standard uniform quantizer, and the distributed gradient tracking algorithm. We establish linear convergence to a global optimal point for the proposed algorithm by assuming Polyak- [Formula: see text] ojasiewicz condition for the global cost function and smoothness condition for the local cost functions. Moreover, the proposed algorithm maintains linear convergence at low-data rates with a proper selection of algorithm parameters. Numerical simulations validate the theoretical results.

New RNN Algorithms for Different Time-Variant Matrix Inequalities Solving Under Discrete-Time Framework.

A series of discrete time-variant matrix inequalities is generally regarded as one of the challenging problems in science and engineering fields. As a discrete time-variant problem, the existing solving schemes generally need the theoretical support under the continuous-time framework, and there is no independent solving scheme under the discrete-time framework. The theoretical deficiency of solving scheme greatly limits the theoretical research and practical application of discrete time-variant matrix inequalities. In this article, new discrete-time recurrent neural network (RNN) algorithms are proposed, analyzed, and investigated for solving different time-variant matrix inequalities under the discrete-time framework, including discrete time-variant matrix vector inequality (discrete time-variant MVI), discrete time-variant generalized matrix inequality (discrete time-variant GMI), discrete time-variant generalized-Sylvester matrix inequality (discrete time-variant GSMI), and discrete time-variant complicated-Sylvester matrix inequality (discrete time-variant CSMI), and all solving processes are based on the direct discretization thought. Specifically, first of all, four discrete time-variant matrix inequalities are presented as the target problems of these researches. Second, for solving such problems, we propose corresponding discrete-time recurrent neural network (RNN) (DT-RNN) algorithms (termed DT-RNN-MVI algorithm, DT-RNN-GMI algorithm, DT-RNN-GSMI algorithm, and DT-RNN-CSMI algorithm), which are different from the traditional DT-RNN design thought because second-order Taylor expansion is applied to derive the DT-RNN algorithms. This creative process avoids the intervention of continuous-time framework. Then, theoretical analyses are presented, which show the convergence and precision of the DT-RNN algorithms. Abundant numerical experiments are further carried out, which further confirm the excellent properties of the DT-RNN algorithms.

Genetic Analysis of a Mosaic Fra(16)(q22)/Del(16)(q22) Karyotype in a Primary Infertile Woman.

Purpose: Fragile sites are specific chromosomal regions showing gaps, poor staining, contractions, or even breaks in the chromosomes. These spontaneous and heritable fragile sites are prone to structural variations which can lead to adverse reproductive outcomes. This paper aims to present a specific case study of a female patient, with a mosaic karyotype involving chromosome 16q22 fragile site which is very rare in clinic and her experience of infertility. Case Presentation: A 37-year-old woman is diagnosed with ten-year primary infertility. She worked in a factory, and she was occasionally exposed to paint. She underwent two cycles of follicular monitoring with intrauterine insemination (IUI) using her husband's sperm six years ago but failed. Most of her prepregnancy tests were normal, except a not smooth right fallopian tube. Her G-band karyotype of peripheral blood lymphocytes was mos 46, XX, del(16)(q22)[40]/46, XX, fra(16)(q22)[29]/46, XX, fra(16)tr(16)(q22)[3]/46, XX[28] which inherited from her mother. The SCE assay detected a significantly higher frequency of SCEs in the 16q region of the patient's chromosomes compared to her mother and a healthy control. However, the average SCEs per chromosome were quite close. Moreover, copy number variation (CNV) sequencing showed no deletion nor duplication at 16q22. Conclusion: Infertility cannot be completely attributed to the fragile site on chromosome 16q22. Assisted reproductive technology combined with preimplantation genetic testing may help in achieving a healthy live birth.

Synthesis of N-H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent.

Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield. This method presents a promising avenue for synthesizing aziridines from a wide range of alkenes, featuring the benefits of straightforward operation, mild reaction conditions, extensive substrate compatibility, and scalability.

Extracellular ATP is a homeostatic messenger that mediates cell‒cell communication in physiological processes and psychiatric diseases.

Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP is generated to meet the high-energy demands. Meantime, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell‒cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological aspects, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a "destabilizing" effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. This review summarizes advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues resulting from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

RNA-seq analysis-based study on the effects of gestational diabetes mellitus on macrosomia.

Background: Both the mother and the infant are negatively impacted by macrosomia. Macrosomia is three times as common in hyperglycemic mothers as in normal mothers. This study sought to determine why hyperglycemic mothers experienced higher macrosomia. Methods: Hematoxylin and Eosin staining was used to detect the placental structure of normal mother(NN), mothers who gave birth to macrosomia(NM), and mothers who gave birth to macrosomia and had hyperglycemia (DM). The gene expressions of different groups were detected by RNA-seq. The differentially expressed genes (DEGs) were screened with DESeq2 R software and verified by qRT-PCR. The STRING database was used to build protein-protein interaction networks of DEGs. The Cytoscape was used to screen the Hub genes of the different group. Results: The NN group's placental weight differed significantly from that of the other groups. The structure of NN group's placenta is different from that of the other group, too. 614 and 3207 DEGs of NM and DM, respectively, were examined in comparison to the NN group. Additionally, 394 DEGs of DM were examined in comparison to NM. qRT-PCR verified the results of RNA-seq. Nucleolar stress appears to be an important factor in macrosomia, according on the results of KEGG and GO analyses. The results revealed 74 overlapped DEGs that acted as links between hyperglycemia and macrosomia, and 10 of these, known as Hub genes, were key players in this process. Additionally, this analysis believes that due of their close connections, non-overlapping Hubs shouldn't be discounted. Conclusion: In diabetic mother, ten Hub genes (RPL36, RPS29, RPL8 and so on) are key factors in the increased macrosomia in hyperglycemia. Hyperglycemia and macrosomia are linked by 74 overlapping DEGs. Additionally, this approach contends that non-overlapping Hubs shouldn't be ignored because of their tight relationships.