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From the analysis of traffic's characteristic of China's urban intersections and considering the constraints of queue length and pedestrians cross the street, a multi-objective programming function is constructed to minimize not only the vehicle average delay but also the mean square value of saturations of car flows of all phases. The constraints are that the queue length is not more than the driveway default length and the pedestrians cross the street phase is long enough. The efficacy coefficient method is used to formulate an evaluation function that covers all objective functions of the original problem. An example of Tianhebei road and Tianshou road intersection validated the model and the evaluation function was optimized by genetic algorithm. The results show that the model can prevent urban isolated intersection which contains short sections overflow effectively. [ABSTRACT FROM AUTHOR]

A field experiment was undertaken in Lake Barre, a shallow estuary within the Louisiana coastal zone, in November 1991 with the primary goal of acquiring a better understanding of time-mean flow and sediment transport in a shallow Louisiana bay on the periphery of a deteriorating marsh. A network of four monitoring stations recorded current velocity and water turbidity at various levels within the water columnwhile water level, wave, salinity, and wind speed and direction datawere acquired at a single station. Results show a response of the water column and the seabed to winds, waves, and tides during the period of study. Variations in velocity profiles, roughness lengths, and to a lesser extent, friction velocities suggest the existence of at least two distinct flow regimes during the periods of study that encompassed four cold fronts. One, characterized by small roughness and weak vertical velocity shear, occurred near the time of cold front passages when winds were northerly. The other, identified by large and frequently variable roughness and vertical velocity shear distributed uniformly through the water column, was predominately associated with tidal flows. The former was attributed to current ripples while the latter appeared to be related to the activity of benthic organisms. A large positive vertical sediment gradient that appeared during the first cold front was attributed to advection of sediment from an area ofrapid degradation upstream. Sediment transport calculations reveal fluxes of sediment from the marsh into the study area during cold front passages, the largest magnitudes associated with the earliest cold fronts. Flux magnitude generally decreased with each succeeding cold front. Quantities of fine-grained sediment moving landward during strong prefrontal events are available for nourishing the marsh and contributes material for upward building of a bayou mouth bar. However, long-term subsidence rates are sufficient to mask the effects of depositi [ABSTRACT FROM AUTHOR]

Background: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. Methods: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. Results: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation. Conclusion: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/β-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract. [ABSTRACT FROM AUTHOR]

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24 h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE. [ABSTRACT FROM AUTHOR]

The invasion ability of glioblastoma (GBM) causes tumor cells to infiltrate the surrounding brain parenchyma and leads to poor outcomes. Transient receptor potential vanilloid 4 (TRPV4) exhibits a remarkable role in cancer cell motility, but the contribution of TRPV4 to glioblastoma metastasis is not fully understood. Here, we reported that TRPV4 expression was significantly elevated in malignant glioma compared to normal brain and low-grade glioma, and TRPV4 expression was negatively correlated with the prognosis of glioma patients. Functionally, stimulation of TRPV4 promoted glioblastoma cell migration and invasion, and repression of TRPV4 hindered the migration and invasion of glioblastoma cells in vitro. Molecularly, TRPV4 strongly colocalized and interacted with skeletal protein-F-actin at cellular protrusions, and TRPV4 regulated the formation of invadopodia and filopodia in glioblastoma cells. Furthermore, the Cdc42/N-wasp axis mediated the effect of TRPV4-regulated cellular protrusions and invasion. Foremost, TRPV4 inhibitor treatment or downregulation of TRPV4 significantly reduced the invasion-growth of subcutaneously and intracranially transplanted glioblastoma in mice. In conclusion, the TRPV4/Cdc42/wasp signaling axis regulates cellular protrusion formation in glioblastoma cells and influences the invasion-growth phenotype of glioblastoma in vivo. TRPV4 may serve as a prognostic factor and specific therapeutic target for GBM patients. [ABSTRACT FROM AUTHOR]

Bone metastasis is common in breast cancer and more effective therapies are required, however, its molecular mechanism is poorly understood. Additionally, the role of the m 6 A reader YTHDF1 in bone metastasis of breast cancer has not been reported. Here, we reveal that the increased expression of YTHDF1 is clinically correlated with breast cancer bone metastases. YTHDF1 promotes migration, invasion, and osteoblast adhesion and induces osteoclast differentiation of cancer cells in vitro and vivo. Mechanically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrate that YTHDF1 translationally enhances EZH2 and CDH11 expression by reading m 6 A-enriched sites of their transcripts. Moreover, adeno-associated virus (AAV) was used to deliver shYTHDF1 (shYTHDF1-AAV) in intratibial injection models, eliciting a significant suppressive effect on breast cancer bone metastatic formation and osteolytic destruction. Overall, we uncovered that YTHDF1 promotes osteolytic bone metastases of breast cancer by inducing EZH2 and CDH11 translation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Prolactinoma was the most common functional pituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptor agonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D 2 receptor (D 2 R) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50 μM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Medium-sized-ring compounds have been recognized as challenging synthetic targets in organic chemistry. Especially, the difficulty of synthesis will be augmented if an E-olefin moiety is embedded. Recently, photo-induced dearomative cycloaddition reactions that proceed via energy transfer mechanism have witnessed significant developments and provided powerful methods for the organic transformations that are not easily realized under thermal conditions. Herein, we report an intramolecular dearomative [5 + 4] cycloaddition of naphthalene-derived vinylcyclopropanes under visible-light irradiation and a proper triplet photosensitizer. The reaction affords dearomatized polycyclic molecules possessing a nine-membered-ring with an E-olefin moiety in good yields (up to 86%) and stereoselectivity (up to 8.8/1 E/Z). Detailed computational studies reveal the origin behind the favorable formation of the thermodynamically less stable isomers. Diverse derivations of the dearomatized products have also been demonstrated., (© 2024. The Author(s).)

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47 + T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions., (© 2024. The Author(s).)

Background: Visceral sarcoma is a rare malignancy with a poor prognosis. However, there is no recommended prognostic staging system for the malignant disease., Method: We analyzed the data of patients diagnosed with primary soft tissue sarcoma (STS) of the abdomen and thoracic visceral organs between 2006 and 2017 at our hospital. Prognostic factors (size, tumor grade, and lymph node metastasis) were analyzed in our cohort (n = 203) and the SEER validation cohort (n = 5826)., Results: Tumor size, grade, and lymph node metastasis were important prognostic factors for visceral sarcoma in both our and the SEER cohorts. Based on these prognostic factors, we established a new staging system for visceral sarcoma, by which patients could be stratified into clinically meaningful and non-overlapping stages in both our cohort and the SEER validation series. Moreover, the area under the curve (AUC) value of the staging system for 5-year survival was 0.84 (95% CI: 0.78-0.89) in our series and 0.80 (95% CI: 0.79-0.81) in SEER series, respectively. In addition, compared with the widely used FIGO staging system for female genital sarcoma, the visceral sarcoma staging system could more effectively and reliably stratify patients into four different prognostic groups., Conclusions: The visceral sarcoma staging system is applicable for STS of the abdomen and thoracic visceral organs and is better than the current FIGO staging system for female genital sarcoma and should be incorporated into the AJCC Cancer Staging Manual., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Chiral cyclobutane presents as a popular motif in natural products and biologically active molecules, and its derivatives have been extensively used as key synthons in organic synthesis. Herein, we report an efficient synthetic method toward enantioenriched cyclobutane derivatives. The reaction proceeds in a cascade fashion involving Ir-catalyzed asymmetric allylic etherification and visible-light induced [2 + 2] cycloaddition. Readily available branched allyl acetates and cinnamyl alcohols are directly used as the substrates under mild reaction conditions, providing a broad range of chiral cyclobutanes in good yields with excellent diastereo- and enantioselectivities (up to 12:1 dr, >99% ee). It is worth noting that all substrates and catalysts were simultaneously added without any separated step in this approach. The gram-scale reaction and diverse transformations of product further enhance the potential utility of this method.

Activation of C-C bonds allows editing of molecular skeletons, but methods for selective activation of nonpolar C-C bonds in the absence of a chelation effect or a driving force derived from opening of a strained ring are scarce. Herein, we report a method for ruthenium-catalyzed activation of nonpolar C-C bonds of pro-aromatic compounds by means of π-coordination-enabled aromatization. This method was effective for cleavage of C-C(alkyl) and C-C(aryl) bonds and for ring-opening of spirocyclic compounds, providing an array of benzene-ring-containing products. The isolation of a methyl ruthenium complex intermediate supports a mechanism involving ruthenium-mediated C-C bond cleavage., (© 2023 Wiley-VCH Verlag GmbH.)

Background: Patients with non-small cell lung cancer (NSCLC) show a low survival rate, owing to the lack of early diagnostic method and high invasiveness. Long non-coding RNA MAPKAPK5-AS1 that regulates tumor genesis and progression through multiple signals, is upregulated and involved in the growth and apoptosis in lung adenocarcinoma (LUAD)., Objective: To investigate whether MAPKAPK5-AS1 affected the malignant progression of NSCLC., Methods: The levels of MAPKAPK5-AS1, miR-490-3p and HMGB2 in lung cancer were first analyzed through StarBase website, and confirmed by a quantitative reverse transcriptase-PCR (qRT-PCR) assay. The biological functions of NSCLC cells were examined by CCK-8, 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays. The potential binding sequences lncRNA-miRNA and miRNA-mRNA were predicted by StarBase software and verified via dual luciferase reporter experiment. The effects of MAPKAPK5-AS1 on tumor growth were evaluated in a xenografted mice model., Results: The expression of MAPKAPK5-AS1 was upregulated in tumor tissues from NSCLC patients. Patients with high expression of MAPKAPK5-AS1 had higher tumor size, advanced TNM stage, higher incidence of lymph node and distant metastasis, and shorter overall survival. Knockdown of MAPKAPK5-AS1 inhibited the proliferation, induced apoptosis and blocked epithelial mesenchymal transformation (EMT) of NSCLC cells. Mechanically, MAPKAPK5-AS1 could upregulate the HMGB2 level in NSCLC cells through competitively binding to miR-490-3p. MiR-490-3p inhibitor reversed the roles of MAPKAPK5-AS1 knockdown on tumor cell proliferation, apoptosis and EMT. Also, HMGB2 knockdown suppressed tumor cell malignant phenotypes. Furthermore, interference of MAPKAPK5-AS1 slowed NSCLC tumor growth in vivo., Conclusion: Knockdown of MAPKAPK5-AS1 inhibited the aggressive tumor phenotypes through miR-490-3p/HMGB2 axis in NSCLC. MAPKAPK5-AS1/miR-490-3p/HMGB2 might be potential biomarkers or therapeutic targets for NSCLC., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

The use of alkylarenes as nucleophile precursors in benzylic addition is challenging because the benzylic hydrogen atoms of these compounds are inert to deprotonation. Herein, we report Rh-catalyzed benzylic addition of alkylarenes to Michael acceptors for the formation of C(sp 3 )-C(sp 3 ) bonds. The catalyst is proposed to activate the aromatic ring via η 6 -coordination, dramatically facilitating deprotonation of the unactivated benzylic C-H bond and addition of the resulting carbanion to the α,β-unsaturated double bond in the absence of bases. Notably, this byproduct-free method provides an access to all-carbon quaternary centers through the development of ligands., (© 2022 Wiley-VCH GmbH.)

Hydroalkylation, the direct addition of a C(sp 3 )-H bond across an olefin, is a desirable strategy to produce valuable, complex structural motifs in functional materials, pharmaceuticals, and natural products. Herein, we report a reliable method for accessing α-branched amines via nickel-catalyzed hydroalkylation reactions. Specifically, by using bis(cyclooctadiene)nickel (Ni(cod) 2 ) together with a phosphine ligand, we achieved a formal C(sp 3 )-H bond insertion reaction between olefins and N-sulfonyl amines without the need for an external hydride source. The amine not only provides the alkyl motif but also delivers hydride to the olefin by means of a nickel-engaged β-hydride elimination/reductive elimination process. This method provides a platform for constructing chiral α-branched amines by using a P-chiral ligand, demonstrating its potential utility in organic synthesis. Notably, a sulfonamidyl boronate complex formed in situ under basic conditions promotes ring-opening of the azanickellacycle reaction intermediate, leading to a significant improvement of the catalytic efficiency., (© 2021. The Author(s).)

Nucleophilic aromatic substitution (S N Ar) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic S N Ar reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical S N Ar conditions. Although the mechanism of S N Ar reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η 5 -cyclohexadienyl complex intermediate with an sp 3 -hybridized carbon bearing both a nucleophile and a leaving group., (© 2021 Wiley-VCH GmbH.)

The technique of maxillectomy has been revised since it was first described in the 1820s. During the past decade, the endoscopic approach has been widely practiced for resecting maxilla. Compared with the traditional approaches, the combined endoscopic and transoral approach has many advantages such as avoiding facial incisions and postoperative scars and better visualization of the surgical margin. However, this technique is complicated to master and possess several challenges. Here, we demonstrate this approach step-by-step to show how to perform a total maxillectomy. We also reported nine cases with malignant tumors originating from the maxilla, and for all of them total maxillectomy was performed with combined endoscopic and transoral approach. Our data showed that the combination of the endoscopic and transoral approach could be used to resect the total maxilla successfully, though the tumor extended to the infratemporal and pterygopalatine fossa should be treated very carefully to avoid its spread in the local area. Furthermore, besides denture, other reconstruction methods should be attempted to improve the postoperative quality of life after the total maxillectomy.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and Southeast Asia. In this study, we found that Leucine rich repeat containing G protein-coupled receptor 5 (Lgr5) was highly expressed in NPC tissues and marked NPC stem cells. Lgr5 high tumors showed differential transcriptional landscape compared to Lgr5 not high tumors. Lgr5 expression was associated with the clinicopathologic features in NPC and was able to regulate the stemness and viability of NPC cell line CNE1 and HNE1. Meanwhile, the migration, invasion and epithelial-mesenchymal transition (EMT) was modulated by Lgr5 via Wnt/β-catenin signaling pathway. Furthermore, Lgr5 could regulate the sensitivity of NPC cells to chemotherapy drugs. Xenografted tumors from Lgr5-overexpressed CNE1 cells showed stronger tumor forming capacity and higher expression level of stem cell markers. Thus, we characterized previously unidentified role of Lgr5 in NPC cells, potential serving as a NPC stem cell biomarker and a therapeutic target against NPC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp 3 C-H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C.

Objective: To explore the effects of high altitude on cognitive flexibility., Methods: Simulated hypoxia at an altitude of 3 600 m was performed in a hypobaric chamber. Twenty-three volunteers without hypoxic experience were selected and the mean age was about 25.1 years. The physiological parameters (heart rate, blood pressure and oxygen saturation) were measured. Task switch paradigm was used to explore the cognitive flexibility in each phase, and the changing anxiety state was evaluated simultaneously., Results: Reaction time (RT) switch cost in hypoxia phase showed a significant increase compared with the baseline; anxiety level in hypoxia phase was higher than the adaptation phase; a remarkable negative correlation between anxiety level and RT switch cost was found in adaptation phase, whereas a positive correlation was found in landing phase., Conclusion: High altitude (3 600 m) affects cognitive flexibility and anxiety state. Anxiety before the hypoxia exposure improves the cognitive flexibility performance, while anxiety after the hypoxia exposure hampers the performance because of the post-hypoxia effect.