A bionic mimosa soft robot based on a multi-responsive PNIPAM-PEGDA hydrogel composition.

Deformation plays a vital role in the survival of natural organisms. One example is that plants deform themselves to face the sun for sufficient sunlight exposure, which allows them to produce nutrients through photosynthesis. Drawing inspiration from nature, researchers have been exploring the development of 3D deformable materials. However, the traditional approach to manufacturing deformable hydrogels relies on complex technology, which limits their potential applications. In this study, we simulate the stress variations observed in the plant tissue to create a 3D structure from a 2D material. Using UV curing technology, we create a single-layer poly(N-isopropylacrylamide) hydrogel sheet with microchannels that exhibit distinct swelling rates when subjected to stimulation. After a two-step curing process, we produce a poly(N-isopropylacrylamide)-polyethylene glycol diacrylatedouble-layer structure that can be manipulated to change its shape by controlling the light and solvent content. Based on the double-layer structure, we fabricate a dual-response driven bionic mimosa robot that can perform a variety of functions. This soft robot can not only reversibly change its shape but also maintain a specific shape without continuous stimulation. Its capacity for reversible deformation, resulting from internal stress, presents promising application prospects in the biomedical and soft robotics domain. This study delivers an insightful framework for the development of programmable soft materials.

Synthesis of α-Hydroxy-1,2,3-Triazole-linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2.

Tumour-derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan-ST inhibitor (or sialidase) or systemic delivery of a non-toxic selective ST inhibitors are being pursued as potential new anti-metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP-Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral a-hydroxy-1,2,3-triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub-types. Our ST inhibitors are non-toxic and show improved synthetic accessibility and drug-likeness compared to earlier nucleoside-based ST inhibitors.

Effects of glycerol monolaurate on estradiol and follicle-stimulating hormones, offspring quality, and mRNA expression of reproductive-related genes of zebrafish (Danio rerio) females.

This study aims to explore whether glycerol monolaurate (GML) can improve reproductive performance of female zebrafish (Danio rerio) and the survival percentage of their offspring. Three kinds of isonitrogenous and isolipid diets, including basal diet (control) and basal diet containing 0.75 g/kg GML (L_GML) and 1.5 g/kg GML (H_GML), were prepared for 4 weeks feeding trial. The results show that GML increased the GSI of female zebrafish. GML also enhanced reproductive performance of female zebrafish. Specifically, GML increased spawning number and hatching rate of female zebrafish. Moreover, GML significantly increased the levels of triglycerides (TG), lauric acid, and estradiol (E2) in the ovary (P < 0.05). Follicle-stimulating hormone (FSH) levels in the ovary and brain also significantly increased in the L_GML group (P < 0.05). Besides, dietary GML regulated the hypothalamus-pituitary-gonad (HPG) axis evidenced by the changed expression levels of HPG axis-related genes in the brain and ovary of the L_GML and H_GML groups compared with the control group. Furthermore, compared with the control group, the expression levels of HPG axis-related genes (kiss2, kiss1r, kiss2r, gnrh3, gnrhr1, gnrhr3, lhß, and esr2b) in the brain of the L_GML group were significantly increased (P < 0.05), and the expression levels of HPG axis-related genes (kiss1, kiss2, kiss2r, gnrh2, gnrh3, gnrhr4, fshß, lhß, esr1, esr2a, and esr2b) in the brain of the H_GML group were significantly increased (P < 0.05). These results suggest that GML may stimulate the expression of gnrh2 and gnrh3 by increasing the expression level of kiss1 and kiss2 genes in the hypothalamus, thus promoting the synthesis of FSH and E2. The expression levels of genes associated with gonadotropin receptors (fshr and lhr) and gonadal steroid hormone synthesis (cyp11a1, cyp17, and cyp19a) in the ovary were also significantly upregulated by dietary GML (P < 0.05). The increasing expression level of cyp19a also may promote the FSH synthesis. Particularly, GML enhanced the richness and diversity and regulated the species composition of intestinal microbiota in female zebrafish. Changes in certain intestinal microorganisms may be related to the expression of certain genes involved in the HPG axis. In addition, L_GML and H_GML both significantly decreased larvae mortality at 96 h post fertilization and their mortality during the first-feeding period (P < 0.05), revealing the enhanced the starvation tolerance of zebrafish larvae. In summary, dietary GML regulated genes related to HPG axis to promote the synthesis of E2 and FSH and altered gut microbiota in female zebrafish, and improved the survival percentage of their offspring.

4D Printed Soft Microactuator for Particle Manipulation via Surrounding Medium Variation.

Soft actuators have assumed vital roles in a diverse number of research and application fields, driving innovation and transformative advancements. Using 3D molding of smart materials and combining these materials through structural design strategies, a single soft actuator can achieve multiple functions. However, it is still challenging to realize soft actuators that possess high environmental adaptability while capable of different tasks. Here, the response threshold of a soft actuator is modulated by precisely tuning the ratio of stimulus-responsive groups in hydrogels. By combining a heterogeneous bilayer membrane structure and in situ multimaterial printing, the obtained soft actuator deformed in response to changes in the surrounding medium. The response medium is suitable for both biotic and abiotic environments, and the response rate is fast. By changing the surrounding medium, the precise capture, manipulation, and release of micron-sized particles of different diameters in 3D are realized. In addition, static capture of a single red blood cell is realized using biologically responsive medium changes. Finally, the experimental results are well predicted using finite element analysis. It is believed that with further optimization of the structure size and autonomous navigation platform, the proposed soft microactuator has significant potential to function as an easy-to-manipulate multifunctional robot.

HOXA-AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1-HDAC1/2 Deacetylase Complex to cccDNA Minichromosome.

Persistent transcription of HBV covalently closed circular DNA (cccDNA) is critical for chronic HBV infection. Silencing cccDNA transcription through epigenetic mechanisms offers an effective strategy to control HBV. Long non-coding RNAs (lncRNAs), as important epigenetic regulators, have an unclear role in cccDNA transcription regulation. In this study, lncRNA sequencing (lncRNA seq) is conducted on five pairs of HBV-positive and HBV-negative liver tissue. Through analysis, HOXA-AS2 (HOXA cluster antisense RNA 2) is identified as a significantly upregulated lncRNA in HBV-infected livers. Further experiments demonstrate that HBV DNA polymerase (DNA pol) induces HOXA-AS2 after establishing persistent high-level HBV replication. Functional studies reveal that HOXA-AS2 physically binds to cccDNA and significantly inhibits its transcription. Mechanistically, HOXA-AS2 recruits the MTA1-HDAC1/2 deacetylase complex to cccDNA minichromosome by physically interacting with metastasis associated 1 (MTA1) subunit, resulting in reduced acetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac) associated with cccDNA and subsequently suppressing cccDNA transcription. Altogether, the study reveals a mechanism to self-limit HBV replication, wherein the upregulation of lncRNA HOXA-AS2, induced by HBV DNA pol, can epigenetically suppress cccDNA transcription.

Active components of Dengzhan Shengmai ameliorate cognitive impairment by facilitating hippocampal long-term potentiation via the NMDA receptor-mediated Ca2+/CaMKII pathway.

Image 1.

Schisandrin B from Schisandra chinensis alleviated pain via glycine receptors, Nav1.7 channels and Cav2.2 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.

Evaluation of hepatic functional reserve of hepatocellular carcinoma (≤ 5 cm) by liver shear wave velocity combined with multiple parameters.

Background: Normal hepatic functional reserve is the key to avoiding liver failure after liver surgery. This study investigated the assessment of hepatic functional reserve using liver shear wave velocity (LSWV) combined with biochemical indicators, tumor volume, and portal vein diameter. Methods: In this single-center prospective study, a total of 123 patients with hepatocellular carcinoma (HCC) were divided into a test group (n=92) and a validation group (n=31). All patients were Child-Pugh grade A. The indocyanine green retention rate at 15 min (ICG-R15), liver shear wave velocity (LSWV), portal vein diameter (Dpv), alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GGT), albumin (ALB), prothrombin time (PT), and also liver tumor volume (maximum diameter ≤5 cm) were measured. In the test group, multiple parameters were used to evaluate hepatic functional reserve, and the multiparametric model was established. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance of the multiparametric model. In the validation group, the predictive effectiveness of the multiparametric model was analyzed using consistency tests. Results: It was revealed that LSWV, ALB, and PT were statistically significant in evaluation of the hepatic functional reserve (P<0.05). The multiparametric model was formulated as follows: Y= -18.954 + 9.726*LSWV-0.397*ALB+2.063*PT. The value of the area under the curve (AUC) for the multiparametric model was 0.913 (95% confidence interval (CI): 0.835-0.962, P< 0.01), with a cutoff value of 16.656 (sensitivity, 0.763; specificity, 0.926). The Kappa value of consistency testing was 0.655 (P<0.01). Conclusion: LSWV combined with ALB and PT exhibited a high predictive effectiveness for the assessment of hepatic functional reserve, assisting the clinical diagnosis and management of liver diseases.

Exploring the Impact of Leader Bottom-Line Mentality on Subordinate Learning from Work Failures: A Social Information Processing Perspective.

Learning from work failures is not only beneficial for individual development but also crucial for improving organizational performance and achieving sustainable development. We hypothesize that leader bottom-line mentality, which is commonly used by leaders to prevent profit and performance losses, may reduce subordinates learning from work failures. Drawing on social information processing theory, this paper examines how and when leader bottom-line mentality negatively affects subordinates learning from work failures. We tested our hypotheses through a three-wave survey of 245 employees from several high-tech companies in China. For data analysis, we used SPSS 26.0 and Mplus 8.0 to test the theoretical model and research hypotheses. The results indicated that leader bottom-line mentality has a negative indirect effect on subordinates learning from work failures through the mediating role of subordinates' psychological availability. In addition, subordinate self-compassion can mitigate this negative mediating mechanism. The present study has several theoretical and practical implications for the current literature.

Multiply restimulated human cord blood-derived Tregs maintain stabilized phenotype and suppressive function and predict their therapeutic effects on autoimmune diabetes.

BACKGROUND: Regulatory T cells (Tregs) are involved in the maintenance of immune homeostasis and immune regulation. Clinical trials on the adoptive transfer of Tregs have been ongoing for > 10 years. However, many unresolved issues remain in the production of readymade Treg products and selection of patients. Hence, this study aimed to develop a method to expand off-the-shelf Tregs derived from umbilical cord blood (UCB-Tregs) in vitro without changing their phenotype and inhibitory function. In addition, the study intended to design an approach to precisely select patients who are more likely to benefit from the adoptive Treg transfer therapy. METHODS: UCB-Tregs were isolated and cultured in a medium containing human recombinant IL-2 and rapamycin and then multiply restimulated with human T-activator CD3/CD28 dynabeads. The phenotype and suppressive capacity of Tregs were assessed on days 18 and 42. The relationship between the suppressive function of UCB-Tregs in vitro and clinical indicators was analyzed, and the ability of the in vitro suppressive capacity to predict the in vivo therapeutic effects was evaluated. RESULTS: UCB-Tregs expanded 123-fold and 5,981-fold at 18 and 42 days, respectively. The suppressive function of UCB-Tregs on the proliferation of immune cells at 42 days was not significantly different compared with that of UCB-Tregs obtained at 18 days. The suppression rate of UCB-Tregs to PBMCs was negatively correlated with the course of diabetes. Moreover, the high-suppression group exhibited a better treatment response than the low-suppression group during the 12-month follow-up period. CONCLUSIONS: Multiply restimulated UCB-Tregs expanded at a large scale without any alterations in their classical phenotypic features and inhibitory functions. The suppressive function of Tregs in vitro was negatively correlated with the disease duration. The present study revealed the possibility of predicting the in vivo therapeutic effects via the in vitro inhibition assay. Thus, these findings provided a method to obtain off-the-shelf Treg products and facilitated the selection of patients who are likely to respond to the treatment, thereby moving toward the goal of precision treatment.

Stiffness-tunable substrate fabrication by DMDbased optical projection lithography for cancer cell invasion studies.

OBJECTIVE: Cancer cell invasion is a critical cause of fatality in cancer patients. Physiologically relevant tumor models play a key role in revealing the mechanisms underlying the invasive behavior of cancer cells. However, most existing models only consider interactions between cells and extracellular matrix (ECM) components while neglecting the role of matrix stiffness in tumor invasion. Here, we propose an effective approach that can construct stiffness-tunable substrates using digital mirror device (DMD)-based optical projection lithography to explore the invasion behavior of cancer cells. The printability, mechanical properties, and cell viability of three-dimensional (3D) models can be tuned by the concentration of prepolymer and the exposure time. The invasion trajectories of gastric cancer cells in tumor models of different stiffness were automatically detected and tracked in real-time using a deep learning algorithm. The results show that tumor models of different mechanical stiffness can yield distinct regulatory effects. Moreover, owing to the biophysical characteristics of the 3D in vitro model, different cellular substructures of cancer cells were induced. The proposed tunable substrate construction method can be used to build various microstructures to achieve simulation of cancer invasion and antitumor screening, which has great potential in promoting personalized therapy.

Electroacupuncture attenuates middle cerebral artery occlusion-induced learning and memory impairment by regulating microglial polarization in hippocampus.

BACKGROUND: As a traditional medical therapy, electroacupuncture (EA) has been demonstrated to have beneficial effects on ischemic stroke-induced cognitive impairment. However, the underlying mechanism is largely unclear. METHODS: Adult rats received occlusion of the middle cerebral artery and reperfusion (MCAO/R) to establish the ischemic stroke model. Morris water maze test was performed following EA stimulation at the GV20, PC6, and KI1 acupoints in rats to test the learning and memory ability. Western blot, immunofluorescent staining, and enzyme-linked immunosorbent assay were conducted to assess the cellular and molecular mechanisms. RESULTS: EA stimulation attenuated neurological deficits. In the Morris water maze test, EA treatment ameliorated the MCAO/R-induced learning and memory impairment. Moreover, we observed that MCAO/R induced microglial activation and polarization in the ischemic hippocampus, whereas, EA treatment dampened microglial activation and inhibited M1 microglial polarization but enhanced M2 microglial polarization. EA treatment inhibited the increased expression of proinflammatory cytokines and enhanced the increased expression of anti-inflammatory cytokines. Finally, we found that EA treatment dampened microglial p38 mitogen-activated protein kinase (MAPK) phosphorylation. CONCLUSION: Collectively, our data suggested that EA treatment ameliorated cognitive impairment induced by MCAO/R and the underlying mechanism may be p38-mediated microglia polarization and neuroinflammation.

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism.

We developed the Stem Cell Educator therapy among multiple clinical trials based on the immune modulations of multipotent cord blood-derived stem cells (CB-SCs) on different compartments of immune cells, such as T cells and monocytes/macrophages, in type 1 diabetes and other autoimmune diseases. However, the effects of CB-SCs on the B cells remained unclear. To better understand the molecular mechanisms underlying the immune education of CB-SCs, we explored the modulations of CB-SCs on human B cells. CB-SCs were isolated from human cord blood units and confirmed by flow cytometry with different markers for their purity. B cells were purified by using anti-CD19 immunomagnetic beads from human peripheral blood mononuclear cells (PBMCs). Next, the activated B cells were treated in the presence or absence of coculture with CB-SCs for 7 days before undergoing flow cytometry analysis of phenotypic changes with different markers. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized to evaluate the levels of galectin expressions on CB-SCs with or without treatment of activated B cells in order to find the key galectin that was contributing to the B-cell modulation. Flow cytometry demonstrated that the proliferation of activated B cells was markedly suppressed in the presence of CB-SCs, leading to the downregulation of immunoglobulin production from the activated B cells. Phenotypic analysis revealed that treatment with CB-SCs increased the percentage of IgD+CD27- naïve B cells, but decreased the percentage of IgD-CD27+ switched B cells. The transwell assay showed that the immune suppression of CB-SCs on B cells was dependent on the galectin-9 molecule, as confirmed by the blocking experiment with the anti-galectin-9 monoclonal antibody. Mechanistic studies demonstrated that both calcium levels of cytoplasm and mitochondria were downregulated after the treatment with CB-SCs, causing the decline in mitochondrial membrane potential in the activated B cells. Western blot exhibited that the levels of phosphorylated Akt and Erk1/2 signaling proteins in the activated B cells were also markedly reduced in the presence of CB-SCs. CB-SCs displayed multiple immune modulations on B cells through the galectin-9-mediated mechanism and calcium flux/Akt/Erk1/2 signaling pathways. The data advance our current understanding of the molecular mechanisms underlying the Stem Cell Educator therapy to treat autoimmune diseases in clinics.

Nanomechanical Analysis of Living Small Extracellular Vesicles to Identify Gastric Cancer Cell Malignancy Based on a Biomimetic Peritoneum.

Gastric cancer is one of the most prevalent digestive malignancies. The lack of effective in vitro peritoneal models has hindered the exploration of the potential mechanisms behind gastric cancer's peritoneal metastasis. An accumulating body of research indicates that small extracellular vesicles (sEVs) play an indispensable role in peritoneal metastasis of gastric cancer cells. In this study, a biomimetic peritoneum was constructed. The biomimetic model is similar to real peritoneum in internal microstructure, composition, and primary function, and it enables the recurrence of peritoneal metastasis process in vitro. Based on this model, the association between the mechanical properties of sEVs and the invasiveness of gastric cancer was identified. By performing nanomechanical analysis on sEVs, we found that the Young's modulus of sEVs can be utilized to differentiate between malignant clinical samples (ascites) and nonmalignant clinical samples (peritoneal lavage). Furthermore, patients' ascites-derived sEVs were verified to stimulate the mesothelial-to-mesenchymal transition, thereby promoting peritoneal metastasis. In summary, nanomechanical analysis of living sEVs could be utilized for the noninvasive diagnosis of malignant degree and peritoneal metastasis of gastric cancer. This finding is expected to contribute future treatments.

Crosstalk Between circRNA and Tumor Microenvironment of Hepatocellular Carcinoma: Mechanism, Function and Applications.

Hepatocellular carcinoma (HCC) is one of the most common aggressive tumors in the world. Despite the availability of various treatments, its prognosis remains poor due to the lack of specific diagnostic indicators and the high heterogeneity of HCC cases. CircRNAs are noncoding RNAs with stable and highly specific expression. Extensive research evidence suggests that circRNAs mediate the pathogenesis and progression of HCC through acting as miRNA sponges, protein modulators, and translation templates. Tumor microenvironment (TME) has become a hotspot of immune-related research in recent years due to its effects on metabolism, secretion and immunity of HCC. Accordingly, understanding the role played by circRNAs in TME is important for the study of HCC. This review will discuss the crosstalk between circRNAs and TME in HCC. In addition, we will discuss the current deficiencies and controversies in research on circRNAs and predict future research directions.

Adverse effects of gestational diabetes mellitus on fetal monocytes revealed by single-cell RNA sequencing.

Gestational diabetes mellitus (GDM), the most prevalent metabolic disorder during pregnancy, has long-term risks of metabolic diseases in offspring. However, the underlying mechanisms remain unclear. Here, we analyzed single-cell transcriptional data of cord blood mononuclear cells (CBMCs) from fetuses of healthy and GDM mothers, peripheral blood mononuclear cells from children and adolescents, and coronary plaques myeloid cells from atherosclerosis. Our results demonstrated that monocytes in cord blood were characterized with down-regulated proinflammatory-related pathways and up-regulated proliferation-related pathways. And monocytes in cord blood from GDM mothers were featured with expanded CXCL8+IL1B+ subclusters, enhanced crosstalk with neutrophil granulocytes and augmented adhesive and phagocytic abilities. Interestingly, CXCL8+IL1B+ monocytes influenced by GDM had transcriptome similarity with those of coronary plaques myeloid cells from individuals with atherosclerotic cardiovascular disease. Collectively, our data reveal adverse impact of maternal GDM environment on fetal monocytes and propose potential mechanisms between maternal GDM and offspring atherosclerosis.

Predictive value of HTS grade in patients with intrahepatic cholangiocarcinoma undergoing radical resection: a multicenter study from China.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor with a poor prognosis. This study aimed to investigate whether Hemoglobin, Albumin, Lymphocytes, and Platelets (HALP) score and Tumor Burden Score (TBS) serves as independent influencing factors following radical resection in patients with ICC. Furthermore, we sought to evaluate the predictive capacity of the combined HALP and TBS grade, referred to as HTS grade, and to develop a prognostic prediction model. METHODS: Clinical data for ICC patients who underwent radical resection were retrospectively analyzed. Univariate and multivariate Cox regression analyses were first used to find influencing factors of prognosis for ICC. Receiver operating characteristic (ROC) curves were then used to find the optimal cut-off values for HALP score and TBS and to compare the predictive ability of HALP, TBS, and HTS grade using the area under these curves (AUC). Nomogram prediction models were constructed and validated based on the results of the multivariate analysis. RESULTS: Among 423 patients, 234 (55.3%) were male and 202 (47.8) were aged ≥ 60 years. The cut-off value of HALP was found to be 37.1 and for TBS to be 6.3. Our univariate results showed that HALP, TBS, and HTS grade were prognostic factors of ICC patients (all P < 0.05), and ROC results showed that HTS had the best predictive value. The Kaplan-Meier curve showed that the prognosis of ICC patients was worse with increasing HTS grade. Additionally, multivariate regression analysis showed that HTS grade, carbohydrate antigen 19-9 (CA19-9), tumor differentiation, and vascular invasion were independent influencing factors for Overall survival (OS) and that HTS grade, CA19-9, CEA, vascular invasion and lymph node invasion were independent influencing factors for recurrence-free survival (RFS) (all P < 0.05). In the first, second, and third years of the training group, the AUCs for OS were 0.867, 0.902, and 0.881, and the AUCs for RFS were 0.849, 0.841, and 0.899, respectively. In the first, second, and third years of the validation group, the AUCs for OS were 0.727, 0.771, and 0.763, and the AUCs for RFS were 0.733, 0.746, and 0.801, respectively. Through the examination of calibration curves and using decision curve analysis (DCA), nomograms based on HTS grade showed excellent predictive performance. CONCLUSIONS: Our nomograms based on HTS grade had excellent predictive effects and may thus be able to help clinicians provide individualized clinical decision for ICC patients.

Ion Transport and Inhibitor Binding by Human NHE1: Insights from Molecular Dynamics Simulations and Free Energy Calculations.

The human Na+/H+ exchanger (NHE1) plays a crucial role in maintaining intracellular pH by regulating the electroneutral exchange of a single intracellular H+ for one extracellular Na+ across the plasma membrane. Understanding the molecular mechanisms governing ion transport and the binding of inhibitors is of importance in the development of anticancer therapeutics targeting NHE1. In this context, we performed molecular dynamics (MD) simulations based on the recent cryo-electron microscopy (cryo-EM) structures of outward- and inward-facing conformations of NHE1. These simulations allowed us to explore the dynamics of the protein, examine the ion-translocation pore, and confirm that Asp267 is the ion-binding residue. Our free energy calculations did not show a significant difference between Na+ and K+ binding at the ion-binding site. Consequently, Na+ over K+ selectivity cannot be solely explained by differences in ion binding. Our MD simulations involving NHE1 inhibitors (cariporide and amiloride analogues) maintained stable interactions with Asp267 and Glu346. Our study highlights the importance of the salt bridge between the positively charged acylguanidine moiety and Asp267, which appears to play a role in the competitive inhibitory mechanism for this class of inhibitors. Our computational study provides a detailed mechanistic interpretation of experimental data and serves the basis of future structure-based inhibitor design.

Global trends and development of acupuncture for stroke: A review and bibliometric analysis.

The objective of this review is to elaborate on the status, hotspots, and trends of researches on acupuncture for stroke over the past 26 years. Publications about acupuncture for stroke were downloaded from the Web of Science Core Collection, and these papers were published up to December 31, 2022. A bibliometric analysis of acupuncture for stroke was conducted by CiteSpace (6.2.R4) and VOSviewer (1.6.17). In this study, VOSviewer was used for visual analysis of countries, institutions, authors, journals, keywords, and co-cited references. CiteSpace was used to draw a keyword burst map and a co-cited reference burst map. A total of 534 papers were obtained from the Web of Science Core Collection. The number of papers per year showed a rapid upward trend. The most productive country and institution in this field were China (452) and the Fujian University of Traditional Chinese Medicine (43), respectively. Tao Jing had the highest number of articles (34), and EZ Longa was the most popular author (129 co-citations). Neural Regeneration Research (51) was the most productive journal, and Stroke (1346) was the most co-cited journal. An paper written by EZ Longa was the most influential reference, with the highest citation count. The hotspots and frontiers of this area of research were focused on the mechanisms of acupuncture, especially its neural regenerative or neuroprotective effects. This study used CiteSpace and VOSviewer for bibliometric analysis to provide researchers with information on the research status, hotspots, and trends in acupuncture for stroke research over the past 26 years.

Identification of the genetic characteristics of copy number variations in experimental specific pathogen-free ducks using whole-genome resequencing.

BACKGROUND: Specific pathogen-free ducks are a valuable laboratory resource for waterfowl disease research and poultry vaccine development. High throughput sequencing allows the systematic identification of structural variants in genomes. Copy number variation (CNV) can explain the variation of important duck genetic traits. Herein, the genome-wide CNVs of the three experimental duck species in China (Jinding ducks (JD), Shaoxing ducks (SX), and Fujian Shanma ducks (SM)) were characterized using resequencing to determine their genetic characteristics and selection signatures. RESULTS: We obtained 4,810 CNV regions (CNVRs) by merging 73,012 CNVs, covering 4.2% of the duck genome. Functional analysis revealed that the shared CNVR-harbored genes were significantly enriched for 31 gene ontology terms and 16 Kyoto Encyclopedia of Genes and Genomes pathways (e.g., olfactory transduction and immune system). Based on the genome-wide fixation index for each CNVR, growth (SPAG17 and PTH1R), disease resistance (CATHL3 and DMBT1), and thermoregulation (TRPC4 and SLIT3) candidate genes were identified in strongly selected signatures specific to JD, SM, and SX, respectively. CONCLUSIONS: In conclusion, we investigated the genome-wide distribution of experimental duck CNVs, providing a reference to establish the genetic basis of different phenotypic traits, thus contributing to the management of experimental animal genetic resources.