Hippocampal replay sequence governed by spontaneous brain-wide dynamics.

Neurons in the hippocampus exhibit spontaneous spiking activity during rest that appears to recapitulate previously experienced events. While this replay activity is frequently linked to memory consolidation and learning, the underlying mechanisms are not well understood. Recent large-scale neural recordings in mice have demonstrated that resting-state spontaneous activity is expressed as quasi-periodic cascades of spiking activity that pervade the forebrain, with each cascade engaging a high proportion of recorded neurons. Hippocampal ripples are known to be coordinated with cortical dynamics; however, less is known about the occurrence of replay activity relative to other brain-wide spontaneous events. Here we analyzed responses across the mouse brain to multiple viewings of natural movies, as well as subsequent patterns of neural activity during rest. We found that hippocampal neurons showed time-selectivity, with individual neurons responding consistently during particular moments of the movie. During rest, the population of time-selective hippocampal neurons showed both forward and time-reversed replay activity that matched the sequence observed in the movie. Importantly, these replay events were strongly time-locked to brain-wide spiking cascades, with forward and time-reversed replay activity associated with distinct cascade types. Thus, intrinsic hippocampal replay activity is temporally structured according to large-scale spontaneous physiology affecting areas throughout the forebrain. These findings shed light on the coordination between hippocampal and cortical circuits thought to be critical for memory consolidation.

The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study.

PURPOSE: Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. METHODS: We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. RESULTS: The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: ß = 0.063, P = 0.034), the genus Butyrivibrio (IVW: ß = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: ß=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: ß=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: ß=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: ß = 0.235, P = 0.03) and the order Clostridiales (IVW: ß = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: ß = 0.953, P = 0.022) and the order Lactobacillales (IVW: ß=-0.806, P = 0.042) were suggestive of an association with PAI-1. CONCLUSION: This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases.

Clinical Assessment of Magnetic Resonance Spectroscopy and Diffusion-Weighted Imaging in Diffuse Glioma: Insights Into Histological Grading and IDH Classification.

PURPOSE: To assess the diagnostic utility of clinical magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in distinguishing between histological grading and isocitrate dehydrogenase (IDH) classification in adult diffuse gliomas. METHODS: A retrospective analysis was conducted on 247 patients diagnosed with adult diffuse glioma. Experienced radiologists evaluated DWI and MRS images. The Kruskal-Wallis test examined differences in DWI and MRS-related parameters across histological grades, while the Mann-Whitney U test assessed molecular classification. Receiver Operating Characteristic (ROC) curves evaluated parameter effectiveness. Survival curves, stratified by histological grade and IDH classification, were constructed using the Kaplan-Meier test. RESULTS: The cohort comprised 141 males and 106 females, with ages ranging from 19 to 85 years. The Kruskal-Wallis test revealed significant differences in ADC mean, Cho/NAA, and Cho/Cr concerning glioma histological grade (P < .01). Subsequent application of Dunn's test showed significant differences in ADC mean among each histological grade (P < .01). Notably, Cho/NAA exhibited a marked distinction between grade 2 and grade 3/4 gliomas (P < .01). The Mann-Whitney U test indicated that only ADC mean showed statistical significance for IDH molecular classification (P < .01). ROC curves were constructed to demonstrate the effectiveness of the specified parameters. Survival curves were also delineated to portray survival outcomes categorized by histological grade and IDH classification. Conclusions: Clinical MRS demonstrates efficacy in glioma histological grading but faces challenges in IDH classification. Clinical DWI's ADC mean parameter shows significant distinctions in both histological grade and IDH classification.

A case of ulcerative colitis complicated by a simple appendiceal opening.

This case report describes the clinical course of a 64-year-old male with intermittent abdominal pain attributed to recurrent ulcers at the appendiceal orifice. Initial investigations in November 2019 revealed chronic gastritis and ulcers at the appendiceal orifice, prompting consideration of ulcerative colitis (UC). The patient responded well to mesalazine therapy, experiencing relief from symptoms and improved colonoscopy findings in May 2020. Despite discontinuing medication, a recurrence of symptoms in August 2021 led to a repeat colonoscopy showing renewed ulcers. Mesalazine was reinstated, resulting in symptom resolution and improved colonoscopy findings by December 2021. However, in May 2023, a subsequent recurrence of abdominal pain and colonoscopy-confirmed mucosal changes at the appendiceal orifice prompted reintroduction of mesalazine. The patient remains under regular monitoring on mesalazine therapy. This case highlights the challenges in managing recurrent appendiceal ulcers and the importance of long-term therapeutic vigilance in suspected UC cases.

Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation.

BACKGROUND: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. RESULTS: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. CONCLUSIONS: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Csn5 inhibits autophagy by regulating the ubiquitination of Atg6 and Tor to mediate the pathogenicity of Magnaporthe oryzae.

Csn5 is subunit 5 of the COP9 signalosome (CSN), but the mechanism by which it strictly controls the pathogenicity of pathogenic fungi through autophagy remains unclear. Here, we found that Csn5 deficiency attenuated pathogenicity and enhanced autophagy in Magnaporthe oryzae. MoCSN5 knockout led to overubiquitination and overdegradation of MoTor (the core protein of the TORC1 complex [target of rapamycin]) thereby promoted autophagy. In addition, we identified MoCsn5 as a new interactor of MoAtg6. Atg6 was found to be ubiquitinated through linkage with lysine 48 (K48) in cells, which is necessary for infection-associated autophagy in pathogenic fungi. K48-ubiquitination of Atg6 enhanced its degradation and thereby inhibited autophagic activity. Our experimental results indicated that MoCsn5 promoted K48-ubiquitination of MoAtg6, which reduced the MoAtg6 protein content and thus inhibited autophagy. Aberrant ubiquitination and autophagy in ΔMocsn5 led to pleiotropic defects in the growth, development, stress resistance, and pathogenicity of M. oryzae. In summary, our study revealed a novel mechanism by which Csn5 regulates autophagy and pathogenicity in rice blast fungus through ubiquitination.

Characterization of the metabolic contributions of cytochrome P450 isoforms to bicyclol using the relative activity factor method.

Bicyclol is a hepatoprotective agent widely used for treating chronic hepatitis and drug-induced liver injuries in clinics. The purpose of the study was to elucidate the contribution of CYP450 enzymes to the metabolism of bicyclol using the relative activity factor approach. After incubation with human liver microsomes and recombinant human liver CYP450 enzymes, the calculated contribution of CYP3A4 and 2C19 to the metabolism of bicyclol was 85.6-90.3% and 9.2-9.7%, respectively. The metabolism was interrupted in the presence of CYP3A4 and 2C19 selective inhibitors. These findings help to predict or avoid metabolic drug-drug interactions or toxicity in clinical applications of bicyclol.

Low expression of KLRB1 predicts poor survival outcomes and is associated with immune infiltration in breast cancer.

Background: KLRB1 is downregulated in various cancer types. Nevertheless, the specific involvement of KLRB1 in the context of breast cancer (BRCA) has not been fully elucidated. This research aimed to explore its clinical value in BRCA. Methods: A dataset comprising 1,109 BRCA samples and 113 healthy samples was retrieved from The Cancer Genome Atlas (TCGA) database to establish the association between KLRB1 expression and pan-cancer. Subsequently, an analysis was executed to explore the link between KLRB1 and BRCA. T-tests and Chi-squared tests were conducted to assess the expression of KLRB1 and its clinical implications in BRCA. The prognosis-predictive value of KLRB1 in BRCA was assessed using the Kaplan-Meier method and Cox regression analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses screened biological pathways to analyze the association between the immune infiltration level and KLRB1 expression in BRCA. Lastly, the conclusion was validated through quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC), and Cell Counting Kit-8 (CCK8) assays. Results: KLRB1 exhibited low expression in patients with BRCA. Furthermore, KLRB1 demonstrated strong diagnostic potential, as indicated by an area under curve (AUC) of 0.712. Kaplan-Meier survival and Cox regression analyses indicated that attenuated expression of KLRB1 was independently linked to unfavorable clinical outcomes. GO and KEGG enrichment analyses were performed on the top 10 genes that exhibited positive and negative correlations with KLRB1. Analysis of genes positively correlated with KLRB1 revealed associations with signaling receptor activator activity, lymphocyte proliferation, mononuclear cell proliferation, leukocyte proliferation, receptor-ligand activity, immunoglobulin binding, and hematopoietic cell lineage signaling pathway. KLRB1 expression exhibited significant correlations with all immune cells. Furthermore, qPCR and IHC outcomes demonstrated that KLRB1 was significantly downregulated in BRCA tissues. CCK8 findings showed a decrease in the proliferation of BRCA MCF7 cells upon knockout of KLRB1. Conclusions: This research investigated the mechanism and potential therapeutic target of the KLRB1 gene in BRCA. By analyzing the expression and function of the KLRB1 gene, the study aims to find its significant role in the onset and progression of BRCA. This research endeavors to offer novel strategies and approaches for treating BRCA.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

[Mechanism of astragaloside â £ combined with Panax notoginseng saponins in regulating angiogenesis to treat cerebral ischemia based on network pharmacology and experimental verification].

Network pharmacology and animal and cell experiments were employed to explore the mechanism of astragaloside Ⅳ(AST Ⅳ) combined with Panax notoginseng saponins(PNS) in regulating angiogenesis to treat cerebral ischemia. The method of network pharmacology was used to predict the possible mechanisms of AST Ⅳ and PNS in treating cerebral ischemia by mediating angiogenesis. In vivo experiment: SD rats were randomized into sham, model, and AST Ⅳ(10 mg·kg~(-1)) + PNS(25 mg·kg~(-1)) groups, and the model of cerebral ischemia was established with middle cerebral artery occlusion(MCAO) method. AST Ⅳ and PNS were administered by gavage twice a day. the Longa method was employed to measure the neurological deficits. The brain tissue was stained with hematoxylin-eosin(HE) to reveal the pathological damage. Immunohistochemical assay was employed to measure the expression of von Willebrand factor(vWF), and immunofluorescence assay to measure the expression of vascular endothelial growth factor A(VEGFA). Western blot was employed to determine the protein levels of vascular endothelial growth factor receptor 2(VEGFR2), VEGFA, phosphorylated phosphatidylinositol 3-kinase(p-PI3K), and phosphorylated protein kinase B(p-AKT) in the brain tissue. In vitro experiment: the primary generation of rat brain microvascular endothelial cells(rBEMCs) was cultured and identified. The third-generation rBMECs were assigned into control, model, AST Ⅳ(50 µmol·L~(-1)) + PNS(30 µmol·L~(-1)), LY294002(PI3K/AKT signaling pathway inhibitor), 740Y-P(PI3K/AKT signaling pathway agonist), AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P groups. Oxygen glucose deprivation/re-oxygenation(OGD/R) was employed to establish the cell model of cerebral ischemia-reperfusion injury. The cell counting kit-8(CCK-8) and scratch assay were employed to examine the survival and migration of rBEMCs, respectively. Matrigel was used to evaluate the tube formation from rBEMCs. The Transwell assay was employed to examine endothelial cell permeability. Western blot was employed to determine the expression of VEGFR2, VEGFA, p-PI3K, and p-AKT in rBEMCs. The results of network pharmacology analysis showed that AST Ⅳ and PNS regulated 21 targets including VEGFA and AKT1 of angiogenesis in cerebral infarction. Most of these 21 targets were involved in the PI3K/AKT signaling pathway. The in vivo experiments showed that compared with the model group, AST Ⅳ + PNS reduced the neurological deficit score(P<0.05) and the cell damage rate in the brain tissue(P<0.05), promoted the expression of vWF and VEGFA(P<0.01) and angiogenesis, and up-regulated the expression of proteins in the PI3K/AKT pathway(P<0.05, P<0.01). The in vitro experiments showed that compared with the model group, the AST Ⅳ + PNS, 740Y-P, AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P improved the survival of rBEMCs after OGD/R, enhanced the migration of rBEMCs, increased the tubes formed by rBEMCs, up-regulated the expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.05, P<0.01). Compared with the LY294002 group, the AST Ⅳ + PNS + LY294002 group showed increased survival rate, migration rate, and number of tubes, up-regulated expression of proteins in the PI3K/AKT pathway, and decreased endothelial cell permeability(P<0.05,P<0.01). Compared with the AST Ⅳ + PNS and 740Y-P groups, the AST Ⅳ + PNS + 740Y-P group presented increased survival rate, migration rate, and number of tubes and up-regulated expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.01). This study indicates that AST Ⅳ and PNS can promote angiogenesis after cerebral ischemia by activating the PI3K/AKT signaling pathway.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Salivary Biomarkers of Primary Sjögren's Syndrome.

Objective As primary Sj?gren's syndrome (pSS) primarily affects the salivary glands, saliva can serve as an indicator of the glands' pathophysiology and the disease's status. This study aims to illustrate the salivary proteomic profiles of pSS patients and identify potential candidate biomarkers for diagnosis.Methods The discovery set contained 49 samples (24 from pSS and 25 from age- and gender-matched healthy controls [HCs]) and the validation set included 25 samples (12 from pSS and 13 from HCs). Totally 36 pSS patients and 38 HCs were centrally randomized into the discovery set or to the validation set at a 2:1 ratio. Unstimulated whole saliva samples from pSS patients and HCs were analyzed using a data-independent acquisition (DIA) strategy on a 2D LC?HRMS/MS platform to reveal differential proteins. The crucial proteins were verified using DIA analysis and annotated using gene ontology (GO) and International Pharmaceutical Abstracts (IPA) analysis. A prediction model for SS was established using random forests.Results A total of 1,963 proteins were discovered, and 136 proteins exhibited differential representation in pSS patients. The bioinformatic research indicated that these proteins were primarily linked to immunological functions, metabolism, and inflammation. A panel of 19 protein biomarkers was identified by ranking order based on P-value and random forest algorichm, and was validated as the predictive biomarkers exhibiting good performance with area under the curve (AUC) of 0.817 for discovery set and 0.882 for validation set.Conclusions The candidate protein panel discovered may aid in pSS diagnosis. Salivary proteomic analysis is a promising non-invasive method for prognostic evaluation and early and precise treatments for pSS patients. DIA offers the best time efficiency and data dependability and may be a suitable option for future research on the salivary proteome.

Bottom-Up Construction of Rhombic Lamellar CoNi-MOFs for the Electrochemical Sensing of H2S.

Lamellar metal-organic frameworks (MOFs) have attracted significant attention in the field of electrochemical sensing due to their abundant open active sites and specific electron conductivity. Herein, by employing a bottom-up synthesis strategy, rhombic lamellar heterometallic CoNi-MOFs with varying thicknesses are constructed. This is achieved by using 4-methylpyridine as a capping agent based on the (4,6)-linked Co2(azpy)2(bptc) (azpy = 4,4'-azopyridine, bptc = 3,3',5,5'-biphenyltetracarboxylic acid) structure with a fsc topology and by introducing Ni species simultaneously. To mitigate sulfur deposition on electrodes, the triple pulse amperometry (TPA) method is employed. Among the synthesized lamellar CoNi-MOFs, lamellar CoNi-MOF-3 with the minimum thickness exhibits an optimal electrochemical sensing performance toward hydrogen sulfide, with a sensitivity of 119.3 µA·mM-1·cm-2 in the linear range of 2-2000 µM. This study pioneers a new approach to the controlled construction and electrochemical activity modification of lamellar MOF materials.

Controllable and reusable seesaw circuit based on nicking endonucleases.

Seesaw circuits are essential for molecular computing and biosensing. However, a notable limitation of seesaw circuits lies in the irreversible depletion of components, precluding the attainment of system recovery and rendering nucleic acid circuits non-reusable. We developed a brand-new method for creating controllable and reusable seesaw circuits. By using the nicking endonucleases Nt.BbvCI and Nt.Alwi, we removed "functional components" while keeping the "skeletal components" for recurrent usage. T-inputs were introduced, increasing the signal-to-noise ratio of AND logic from 2.68 to 11.33 and demonstrating compatibility. We identified the logic switching feature and verified that it does not impair circuit performance. We also built intricate logic circuits, such as OR-AND gate, to demonstrate the versatility of our methodology. This controllable reusability extends the applications of nanotechnology and bioengineering, enhancing the practicality and efficiency of these circuits across various domains.

Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Suppresses macrophage capping protein beyond STING activation.

The vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) induces apoptosis in vascular endothelial cells and leads to tumor hemorrhagic necrosis. While DMXAA has been proven to be a potent agonist of murine stimulator of interferon genes (mSTING), it has little effect on human-STING (hSTING). This species selectivity of DMXAA may explain its effectiveness against solid tumors in mice and its failure in clinical trials. However, DMXAA did reduce tumor volume in some patients during clinical trials. These paradoxical results have prompted us to investigate the anti-tumor mechanism of DMXAA beyond STING in the destruction of tumor vasculature in humans. In this study, we demonstrated that DMXAA binds to both human and mouse macrophage capping protein (CapG), with a KD of 5.839 µM for hCapG and a KD of 2.867 µM for mCapG, as determined by surface plasmon resonance (SPR) analysis. Homology modeling and molecular docking analysis of hCapG indicated that the critical residues involved in the hydrogen bond interaction of DMXAA with hCapG were Arg153, Thr151, and GLN141, Asn234. In addition, electrostatic pi-cation interaction occurred between DMXAA and hCapG. Further functional studies revealed that CapG protein plays a crucial role in the effects of DMXAA on human umbilical endothelial vein cell (HUEVC) angiogenesis and migration, as well as the expression of cytoskeletal proteins actin and tubulin, and the invasion of A549 lung adenocarcinoma cells. Our study has originally uncovered a novel cross-species pathway underlying the antitumor vascular disruption of DMXAA extends beyond STING activation. This finding deepens our understanding of the multifaceted actions of flavonoid VDAs in animal models and in clinical settings, and may provide insights for the precise therapy of DMXAA based on the biomarker CapG protein.

PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans.

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

Establishment of a prognosis predictive model for liver cancer based on expression of genes involved in the ubiquitin-proteasome pathway.

BACKGROUND: The ubiquitin-proteasome pathway (UPP) has been proven to play important roles in cancer. AIM: To investigate the prognostic significance of genes involved in the UPP and develop a predictive model for liver cancer based on the expression of these genes. METHODS: In this study, UPP-related E1, E2, E3, deubiquitylating enzyme, and proteasome gene sets were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, aiming to screen the prognostic genes using univariate and multivariate regression analysis and develop a prognosis predictive model based on the Cancer Genome Atlas liver cancer cases. RESULTS: Five genes (including autophagy related 10, proteasome 20S subunit alpha 8, proteasome 20S subunit beta 2, ubiquitin specific peptidase 17 like family member 2, and ubiquitin specific peptidase 8) were proven significantly correlated with prognosis and used to develop a prognosis predictive model for liver cancer. Among training, validation, and Gene Expression Omnibus sets, the overall survival differed significantly between the high-risk and low-risk groups. The expression of the five genes was significantly associated with immunocyte infiltration, tumor stage, and postoperative recurrence. A total of 111 differentially expressed genes (DEGs) were identified between the high-risk and low-risk groups and they were enriched in 20 and 5 gene ontology and KEGG pathways. Cell division cycle 20, Kelch repeat and BTB domain containing 11, and DDB1 and CUL4 associated factor 4 like 2 were the DEGs in the E3 gene set that correlated with survival. CONCLUSION: We have constructed a prognosis predictive model in patients with liver cancer, which contains five genes that associate with immunocyte infiltration, tumor stage, and postoperative recurrence.

Clinical efficacy and safety of erlotinib combined with chemotherapy in the treatment of advanced pancreatic cancer: A meta-analysis.

BACKGROUND: Advanced pancreatic cancer is resistant to chemotherapeutic drugs, resulting in limited treatment efficacy and poor prognosis. Combined administration of the chemotherapeutic gemcitabine and erlotinib is considered a potential first-line treatment for advanced pancreatic cancer. However, their comparative benefits and potential risks remain unclear. AIM: To assess the clinical efficacy and safety of erlotinib combined with other chemotherapy regimens for the treatment of advanced pancreatic cancer. METHODS: Literature on the clinical efficacy and safety of erlotinib combined with chemotherapy for advanced pancreatic cancer was retrieved through an online search. The retrieved literature was subjected to a methodological qualitative assessment and was analyzed using the RevMan 5.3 software. Ten randomized controlled trials involving 2444 patients with advanced pancreatic cancer were included in the meta-analysis. RESULTS: Compared with chemotherapeutic treatment, erlotinib combined with chemotherapy significantly prolonged the progression-free survival time of pancreatic cancer patients [hazard ratio (HR) = 0.78, 95%CI: 0.66-0.92, P = 0.003]. Meanwhile, the overall survival (HR= 0.99, 95%CI: 0.72-1.37, and P = 0.95) and disease control rate (OR = 0.93, 95%CI: 0.45-0.91, P = 0.84) were not significantly favorable. In terms of safety, the erlotinib and chemotherapy combination was associated with a significantly higher risk of diarrhea (OR = 3.59, 95%CI: 1.63-7.90, P < 0.05) and rash (OR = 3.63, 95%CI: 1.64-8.01, P < 0.05) compared with single-agent chemotherapy. Moreover, the risk of vomiting (OR = 1.27, 95%CI: 0.62-2.59, P = 0.51), regurgitation/anorexia (OR = 1.61, 95%CI: 0.25-10.31, P = 0.62), and infection (OR = 0.72, 95%CI: 0.28-1.87, P = 0.50) were not significant in either group. CONCLUSION: Compared with a single chemotherapeutic modality, erlotinib combined with gemcitabine can prolong progression-free survival in pancreatic cancer, but does not improve survival benefit or disease control rate, and can increase the risk of diarrhea and rash.

Early postoperative complications after transverse colostomy closure, a retrospective study.

BACKGROUND: Ostomy is a common surgery usually performed to protect patients from clinical symptoms caused by distal anastomotic leakage after colorectal cancer (CRC) surgery and perforation or to relieve intestinal obstruction. AIM: To analyze the complications after transverse colostomy closure. METHODS: Patients who underwent transverse colostomy closure from Jan 2015 to Jan 2022 were retrospectively enrolled in a single clinical center. The differences between the complication group and the no complication group were compared. Logistic regression analyses were conducted to find independent factors for overall complications or incision infection. RESULTS: A total of 102 patients who underwent transverse colostomy closure were enrolled in the current study. Seventy (68.6%) patients underwent transverse colostomy because of CRC related causes. Postoperative complications occurred in 30 (29.4%) patients and the most frequent complication occurring after transverse colostomy closure was incision infection (46.7%). The complication group had longer hospital stays (P < 0.01). However, no potential risk factors were identified for overall complications and incision infection. CONCLUSION: The most frequent complication occurring after transverse colostomy closure surgery in our center was incision infection. The operation time, interval from transverse colostomy to reversal, and method of anastomosis might have no impact on the postoperative complications. Surgeons should pay more attention to aseptic techniques.