Nanosensors Monitor Intracellular GSH Depletion: GSH Triggers Cu(II) for Tumor Imaging and Inhibition.

Glutathione (GSH) is the primary antioxidant in cells, and GSH consumption will break the redox balance in cells. Based on this, a method that uses high concentrations of GSH in the tumor microenvironment to trigger the redox reaction of Cu(II) to generate copper nanoprobes with fluorescence and tumor growth inhibition properties is proposed. The nanoprobe mainly exists in the form of Cu(I) and catalyzes the decomposition of hydrogen peroxide into hydroxyl radicals. At the same time, a simple and controllable carbon micro-nano electrode is used to construct a single-cell sensing platform, which enable the detection of glutathione content in single living cells after Cu(II) treatment, providing an excellent example for detecting single-cell biomolecules.

Flexible Full-Inorganic Ultrathin Films with Stable Circularly Polarized Luminescence Covering the Visible to Near-Infrared Region.

Circularly polarized luminescence (CPL) materials hold significant value in various fields, including information storage, secure communication, three-dimensional displays, biological detection, and optoelectronic devices. Using the Langmuir-Schaeffer (LS) assembly technique, we successfully construct a series of large-area flexible optical ultrathin films. Impressively, the inorganic assembled ultrathin films exhibit excellent CPL optical activity covering the visible to near-infrared (NIR) region, with the luminescence asymmetry factor glum ranging from 0.59 to 0.72. Moreover, such ultrathin films also display outstanding mechanical flexibility, the optical activity of which even after 240 bending cycles shows almost no difference compared to the unbent samples. Owing to the ultra-broadband optical activity and ultra-stable optical activity of such full-inorganic assembled materials on flexible substrates, coupled with their excellent processability and outstanding mechanical flexibility, we anticipate they will find use in many fields such as communication technology and flexible optoelectronics.

Suppression of DNMT1 combined with ATM or ATR inhibitor as a therapeutic combination of acute myeloid leukemia.

The potential treatment option of targeting DNA methyltransferase 1 (DNMT1) has been explored, but further investigation is required to assess the efficacy of combination therapy in acute myeloid leukemia (AML). In this study, bioinformatics and online databases were utilized to select the combined therapeutic targets. The potential kinases associated with DNMT1-related genes in AML were analyzed using the Cancer Genome Atlas (TCGA) database and X2K Appyter (Expression2Kinases) database. In-vitro evaluations were conducted to assess the synergistic effects between DNMT1 and ATR/ATM in five AML cell lines (MOLM-16, NB-4, HEL 92.1.7, HEL, EOL-1). In our study, ATR and ATM are primarily the kinases associated with DNMT1-related genes in AML. We observed a significant upregulation of DNMT1, ATR, and ATM expression in AML tissues and cell lines. The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). A considerable synergistic effect was observed in AML cell lines when combining GSK-368 and AZD-1390, GSK-368 and AZD-6738, or AZD-1390 and AZD-6738, resulting in induced cell apoptosis and inhibited cell growth. DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

Benefit of [18F] FDG PET/CT in the diagnosis and salvage treatment of recurrent nasopharyngeal carcinoma.

PURPOSE: To compare PET/CT, MRI and ultrasonography in detecting recurrence of nasopharyngeal carcinoma and identify their benefit in staging, contouring and overall survival (OS). METHODS: Cohort A included 1453 patients with or without histopathology-confirmed local recurrence, while cohort B consisted of 316 patients with 606 histopathology-confirmed lymph nodes to compare the sensitivities and specificities of PET/CT, MRI and ultrasonography using McNemar test. Cohorts C and D consisted of 273 patients from cohort A and 267 patients from cohort B, respectively, to compare the distribution of PET/CT-based and MRI-based rT-stage and rN-stage and the accuracy of rN-stage using McNemar test. Cohort E included 30 random patients from cohort A to evaluate the changes in contouring with or without PET/CT by related-samples T test or Wilcoxon rank test. The OS of 61 rT3-4N0M0 patients staged by PET/CT plus MRI (cohort F) and 67 MRI-staged rT3-4N0M0 patients (cohort G) who underwent similar salvage treatment were compared by log-rank test and Cox regression. RESULTS: PET/CT had similar specificity to MRI but higher sensitivity (93.9% vs. 79.3%, P < 0.001) in detecting local recurrence. PET/CT, MRI and ultrasonography had comparable specificities, but PET/CT had greater sensitivity than MRI (90.9% vs. 67.6%, P < 0.001) and similar sensitivity to ultrasonography in diagnosing lymph nodes. According to PET/CT, more patients were staged rT3-4 (82.8% vs. 68.1%, P < 0.001) or rN + (89.9% vs. 69.3%, P < 0.001), and the rN-stage was more accurate (90.6% vs. 73.8%, P < 0.001). Accordingly, the contours of local recurrence were more precise (median Dice similarity coefficient 0.41 vs. 0.62, P < 0.001) when aided by PET/CT plus MRI. Patients staged by PET/CT plus MRI had a higher 3-year OS than patients staged by MRI alone (85.5% vs. 60.4%, P = 0.006; adjusted HR = 0.34, P = 0.005). CONCLUSION: PET/CT more accurately detected and staged recurrence of nasopharyngeal carcinoma and accordingly complemented MRI, providing benefit in contouring and OS.

Chiral recognition of tryptophan enantiomer based on the electrode modified by polyaniline adsorption bovine serum albumin complex.

A chiral sensing platform was constructed via adsorptive functionalization of ammonium persulfate doped polyaniline (APS-DPANI) with bovine serum albumin (BSA). The novelty of this work is the construction of such chiral interface with adsorption principle. The material has been characterized by scanning electron microscope, Fourier transform infrared and X-ray photoelectron spectroscopy, and thermogravimetric and water contact angle analyses. It displayed considerable stability in multi-run cyclic voltammetric scanning. Moreover, the superior conductivity of APS-DPANI and the decent binding ability of BSA endowed this sensing platform with an excellent recognition effect for tryptophan (Trp) enantiomers in the differential pulse voltammetry (DPV) test. The recognition was highly reproducible, and the detection limits for L- and D-isomer were 0.071 and 0.0478 mM, respectively.

RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy regarding digestive system, which is the fourth leading factor of cancer-related mortalities in the globe. Prognosis is poor due to diagnosis at advanced disease stage, low rates of surgical resection, and resistance to traditional radiotherapy and chemotherapy. In order to develop novel therapeutic strategies, further elucidation of the molecular mechanisms underlying PC chemoresistance is required. Ribosomal RNA biogenesis has been implicated in tumorigenesis. Small nucleolar RNAs (snoRNAs) is responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which have been identified as potential markers of various cancers. Here, we investigate the U3 snoRNA-associated protein RRP9/U3-55 K along with its role in the development of PC and gemcitabine resistance. METHODS: qRT-PCR, western blot and immunohistochemical staining assays were employed to detect RRP9 expression in human PC tissue samples and cell lines. RRP9-overexpression and siRNA-RRP9 plasmids were constructed to test the effects of RRP9 overexpression and knockdown on cell viability investigated by MTT assay, colony formation, and apoptosis measured by FACS and western blot assays. Immunoprecipitation and immunofluorescence staining were utilized to demonstrate a relationship between RRP9 and IGF2BP1. A subcutaneous xenograft tumor model was elucidated in BALB/c nude mice to examine the RRP9 role in PC in vivo. RESULTS: Significantly elevated RRP9 expression was observed in PC tissues than normal tissues, which was negatively correlated with patient prognosis. We found that RRP9 promoted gemcitabine resistance in PC in vivo and in vitro. Mechanistically, RRP9 activated AKT signaling pathway through interacting with DNA binding region of IGF2BP1 in PC cells, thereby promoting PC progression, and inducing gemcitabine resistance through a reduction in DNA damage and inhibition of apoptosis. Treatment with a combination of the AKT inhibitor MK-2206 and gemcitabine significantly inhibited tumor proliferation induced by overexpression of RRP9 in vitro and in vivo. CONCLUSIONS: Our data reveal that RRP9 has a critical function to induce gemcitabine chemoresistance in PC through the IGF2BP1/AKT signaling pathway activation, which might be a candidate to sensitize PC cells to gemcitabine. Video abstract.

Preoperative lymphocyte to C-reactive protein ratio as a new prognostic indicator in patients with resectable gallbladder cancer.

BACKGROUND: Inflammation is often related to cancer, and several inflammatory scores have been established to predict the prognosis of various types of cancer. Our study aimed to determine the prognostic value of the preoperative lymphocyte to C-reactive protein ratio (LCR) for predicting postoperative outcomes in patients with resectable gallbladder cancer (GBC). METHODS: A retrospective analysis of 104 GBC patients who received curative surgery at Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine from January 2000 to December 2016 was performed. A time-dependent receiver operating characteristic curve was constructed to evaluate the accuracy of different markers. Univariate and multivariate Cox proportional hazard models were used to define factors associated with overall survival. RESULTS: Among the assessed variables, the preoperative LCR showed the highest accuracy in predicting the overall survival of GBC patients (AUC: 0.736). Decreased preoperative LCR was significantly associated with advanced tumor stage, including tumor invasion (P = 0.018), lymph node metastasis (P = 0.011) and TNM stage (P = 0.022). A low preoperative LCR (cutoff threshold = 145.5) was an independent risk factor for overall survival in patients with resectable GBC (P < 0.001). CONCLUSIONS: The preoperative LCR is a novel and valuable prognostic indicator of postoperative survival in patients with resectable GBC.

SiC-functionalized fluorescent aptasensor for determination of Proteus mirabilis.

Aptamer-modified SiC quantum dots (DNA-SiC QDs) as fluorescent aptasensor are described for the determination of Proteus mirabilis. The SiC QDs were synthesized through one-pot hydrothermal method with particle sizes of about 14 nm. The amino-modified aptamers against P. mirabilis were conjugated to the surfaces of SiC QDs for bacteria recognition. The aptamer with an affinity for target protein can bound to P. mirabilis and this causes a decrease in the fluorescence intensity of DNA-SiC QDs. P. mirabilis levels were tested by the aptasensor within 35 min with fluorescence excitation/emission maxima at 320/420 nm. The linear range is from 103 to 108 CFU mL-1 and the limit of detection is 526 CFU mL-1 (S/N = 3). The aptasensor was used for determination of P. mirabilis in pure milk samples and obtained good accuracy (87.6-104.5%) and recovery rates (85-110.2%) were obtained. The detection in simulated forensic identification samples (pure milk, milk powder, blood, and urine) obtained gave satisfactory coincidence rates with the method of bacterial isolation and identification as standard. These results demonstrate that the fluorescent aptasensor is a potential tool for identification of P. mirabilis in forensic food poisoning cases. Graphical abstract Determination of P. mirabilis is based on SiC QDs fluorescence aptasensor. The SiC QDs with plentiful carboxyl groups on the surface can be synthesized via one-pot hydrothermal route. After activated by EDC/NHS, the SiC QDs can bind to aptamer to form fluorescence aptasensors. When the target P. mirabilis exists, the fluorescence of aptasensor will be quenched and the determination of the P. mirabilis based on the fluorescence change can be analyzed.

Bacteria-targeting BSA-stabilized SiC nanoparticles as a fluorescent nanoprobe for forensic identification of saliva.

Forensic saliva identification represents an increasingly useful auxiliary means of crime investigations, particularly in sex crimes. Salivary bacteria detection techniques have been shown to be viable methods for identifying the presence of saliva. A one-pot method is described for the fabrication of bovine serum albumin-stabilized SiC nanoparticles (SiC@BSA NPs). The SiC@BSA NPs were conjugated to antibacterial peptide GH12 to allow for fluorometric detection and imaging of bacteria in saliva. More specifically, the nanoprobe, with fluorescence excitation/emission maxima at 320/410 nm, was used to detect the oral bacteria S. salivarius levels. The detection limit is 25 cfu·mL-1, and the assay can be performed within 40 min. The nanoprobe was also used to detect bacteria in forensic body fluids including blood, urine, and semen. In all cases, positive results were obtained with (mixed) samples containing saliva, while other saliva samples without saliva showed negative results. Fluorescent images of S. salivarius cells were obtained by implementing a high-content image analysis system. These results suggest that this new nanoprobe can be applied to screen for forensic saliva stains. Graphical abstractSchematic representation of the preparation of SiC@BSA-GH12 nanoprobe for fluorometric detection and imaging of S. salivarius in saliva.

The Effect of Virtual Reality Distraction on Pain Relief During Dressing Changes in Children with Chronic Wounds on Lower Limbs.

It has been demonstrated that patients with chronic wounds experience the most pain during dressing changes. Currently, researchers focus mostly on analgesics and appropriate dressing materials to relieve pain during dressing changes of chronic wounds. However, the effect of nonpharmacologic interventions, such as virtual reality distraction, on pain management during dressing changes of pediatric chronic wounds remains poorly understood. To investigate the effect of virtual reality distraction on alleviating pain during dressing changes in children with chronic wounds on their lower limbs. A prospective randomized study. A pediatric center in a tertiary hospital. Sixty-five children, aged from 4 to 16 years, with chronic wounds on their lower limbs. Pain and anxiety scores during dressing changes were recorded by using the Wong-Baker Faces picture scale, visual analogue scale, and pain behavior scale, as well as physiological measurements including pulse rate and oxygen saturation. Time length of dressing change was recorded. Virtual reality distraction significantly relieved pain and anxiety scores during dressing changes and reduced the time length for dressing changes as compared to standard distraction methods. The use of virtual reality as a distraction tool in a pediatric ward offered superior pain reduction to children as compared to standard distractions. This device can potentially improve clinical efficiency by reducing length time for dressing changes.

Thyroid Nodules: Emerging Trends in Detection and Visualization based on Citespace.

BACKGROUND: Thyroid nodule (TN) is a highly prevalent clinical endocrine disease. Many countries have formed guidelines on the prevention and treatment of TN based on extensive research. However, there is a scarcity of TN-related literature based on bibliometrics. OBJECTIVES: This study aimed to evaluate the scientific achievements and progress of TN research from a global perspective by investigating the literature for 20 years through bibliometrics. METHODS: We searched the literature on TN in the core collection of the Web of Science database from 2002 to 2021 and used the Citespace software to analyze the co-authorship, co-citation, and co-occurrence of countries, institutions, authors, keywords, and co-cited literature. RESULTS: We retrieved 12319 documents related to TN. The literature on TN has been growing since 2002. The United States has contributed the largest proportion of TN papers (20.64%), followed by China, Italy, and South Korea. The United States ranked first in terms of centrality (0.38). Haugen BR, Gharib H, and Cibas ES are the top three most cited authors. The papers published in Thyroid were cited most frequently (7952 times). The most prominent keywords were management, cancer, fine needle aspiration, diagnosis, malignant tumor, thyroid cancer, ultrasound, biopsy, benign, surgery, ablation, and cytology. All keywords could be divided into three categories: diagnosis stratification, treatment, and cancer. As far as potential hot spots are concerned, the keywords that have recently burst strongly and are still continuing are: "Association Guideline" (2018-2021), "Radiofrequency Ablation" (2017-2021), "Classification" (2019-2021), and "Data System" (2017-2021). CONCLUSION: Based on the current trends, the number of publications on TN will continue to increase. The United States is the most active contributor to research in this field. Previous literature focused on stratification, cancer, surgery, and ablation, and there were different opinions on the stratification of diagnosis. There were relatively few studies on pathogenesis and treatment using medicine. More focus will be placed on association guidelines, radiofrequency ablation, classification, and data system, which may be the next popular topics in TN research.

In situ monitoring of cytoplasmic dopamine levels by noble metals decorated carbon fiber tips.

Dopamine (DA), a catecholamine neurotransmitter, is crucial in brain signal transmission. Monitoring cytoplasmic DA levels can reflect changes in metabolic factors and provide valuable information for researching the mechanisms involved in neurodegenerative diseases. However, the in-situ detection of intracellular DA is constrained by its low contents in small-sized single cells. In this work, we report that noble metal (Au, Pt)-modified carbon fiber micro-nanoelectrodes are capable of real-time detection of DA in single cells with excellent sensitivity, selectivity, and anti-contamination capabilities. Notably, noble metals can be modified on the electrode surface through electrochemical deposition to enhance the conductivity of the electrode and the oxidation current of DA by 50 %. The nanosensors can work stably and continuously in rat adrenal pheochromocytoma cells (PC12) to monitor changes in DA levels upon K+ stimulation. The functionalized carbon fibers based nanosensors will provide excellent prospects for DA analysis in the brains of living animals.

TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

Accumulated Dose Deviation of Rotational and Residual Setup Errors on Nasopharyngeal Carcinoma Using MIM Treated by Helical Tomotherapy.

BACKGROUND: To analyze the relationship between the rotational and residual setup errors and the dose deviation on nasopharyngeal carcinoma (NPC) treated by helical tomotherapy (HT). METHODS: From 25 July 2017 to 20 August 2019, 16 treated NPC patients were enrolled in the study. These patients were scanned with full target range megavoltage computed tomography (MVCT) every other day. Adaptive radiotherapy function application software MIM7.1.3 were used to accumulate the actual dose. The dose deviation with the initial plan dose of the patients' target and organs at risk (OAR) were compared, and the correlation between the dose change and the setup errors (rotational setup errors and neck residual setup error) was analyzed. RESULTS: Translational setup errors increased farther away from the head. Statistically significant difference among 3 groups was achieved in the directions of left-right (P < .001) and anteroposterior (P < .001) by analysis of variance test. Compared with the initial plan dose, the actual accumulated dose of the target area decreased with the actual exposure dose of the OAR increased. However, most of the dosimetric parameters differed by less than 5%. No correlation was found between dose deviation values and the translational setup errors of target. However, sagittal rotational setup errors (pitch) had a positive relationship (P < .05) with the avearge dose of PTVnd (L) (r = 0.885), PTVnd(R) (r = 0.547) PTV1(r = 0.633) and PTV2(r = 0.584). Transverse rotational setup errors (roll) had a positive relationship (P < .05) with the avearge dose of PTVnd(R) (r = 0.593), PTV1(r = 0.505) and PTV2(r = 0.662). CONCLUSIONS: Dose deviation between the actual accumulated and initial plan is not negligible, but most indicators difference is less than 5%, NPC patients treated by HT with MVCT correction setup errors every other day did not need adaptive radiotherapy model unless got rapid tumor shrinkage or weight loss. Moreover, to minimize the dose deviation, more attention should be paid to the reduction of pitch, roll, and residual error of cervical vertebrae during body positioning.

Constructing Chiral Covalent-Organic Frameworks for Circularly Polarized Light Detection.

The use of chiral covalent organic frameworks (COFs) as active elements in photodetectors to directly identify circularly polarized light (CPL) can meet the requirement of integration and miniaturization of the as-fabricated devices. Herein, the design and synthesis of two isoreticular chiral two-dimensional (2D) COFs (CityU-7 and CityU-8) by introducing photosensitive porphyrin-based amines (5,10,15,20-tetrakis(4-aminophenyl)porphyrin) to enhance the optical absorption and chiral aldehyde linkage (2,5-bis((S/R))-2-methylbutoxy)terephthalaldehyde) to engender chirality for direct CPL detection  are  reported. Their crystalline structures  were  confirmed by powder X-ray diffraction, Fourier-transform infrared spectroscopy, and low-dose transition electron microscopy. Employing both chiral COFs as the active layers in photodetectors, left-handed circularly (LHC) and right-handed circularly (RHC) polarized light at 405 nm can be well distinguishable with short response time, high responsivity, and satisfying detectivity. The study provides the first example on the design and synthesis of chiral COFs for direct detection of CPL.

Highly sensitive fluorescent aptasensor based on MoS2 nanosheets for one-step determination of methamphetamine.

In this work, a simple and sensitive fluorescence aptasensor based on MoS2 nanosheets (MoS2-Ns) combined with a fluorophore-labeled aptamer (aptamer-FAM) for MTA determination in one step has been described. The aptamer-FAM can be spontaneously absorbed by the surface of MoS2-Ns to form an aptamer-FAM/MoS2-Ns' sensing platform, resulting in quenching of the fluorescence of aptamer-FAM largely. However, after introducing the target MTA, the fluorescence will be restored depending on the levels of MTA added. Such an above reaction platform possesses a linear correlation of between 5 and 2400 nM, with a detection limit of 2.3 nM (S/N = 3). Moreover, the cross reactivity to ketamine, morphine and cocaine was only slightly significant. Simultaneously, the assay was also successfully applied to recognize MTA in spiked human blood and urine, as well as in the real forensic identification samples obtained from a forensic case about a MTA abuser.

Long non-coding RNA Opa interacting protein 5-antisense RNA 1 promotes mitochondrial autophagy and protects SH-SY5Y cells from 1-methyl-4-phenylpyridine-induced damage by binding to microRNA-137 and upregulating NIX.

Parkinson's disease (PD) is a leading cause of disability. Long noncoding RNA (LncRNA) OIP5-AS1 alleviates the accumulation and toxicity of 1-methyl-4-phenylpyridine (MPP+ )/-induced α-synuclein in human neuroblastoma SH-SY5Y cells, which may be involved in the pathological process of PD. This study explored the neuroprotective effect of lncRNA OIP5-AS1 on MPP+ /-induced SH-SY5Y cell model of PD, so as to provide a theoretical basis for PD treatment. The PD cell model was established (MPP+ group). The overexpression vector oe-OIP5-AS1 was constructed and transfected into MPP+/-induced SH-SY5Y cells, which were further transfected with miR-137 mimic or si-NIX plasmids. The localization of OIP5-AS1 and its binding sites with miR-137 were predicted by subcellular isolation and fluorescence in situ hybridization analysis. The targeting relationships between OIP5-AS1 and miR-137, and miR-137 and NIX were detected by dual-luciferase reporter assays. The mitochondrial membrane potential (Δψm) and total reactive oxygen species (ROS) levels, and expressions of α-synuclein, inflammatory cytokines, and microglia-activated chemokines, cell activity, and apoptosis were assessed. OIP5-AS1 was downregulated in MPP+ cells. After OIP5-AS1 overexpression, miR-137 was downregulated and NIX was upregulated in MPP+ cells, inflammatory factors and chemokines were downregulated. There were target relationships between OIP5-AS1 and miR-137, and miR-137 and NIX. After OIP5-AS1 overexpression, miR-137 overexpression or NIX downregulation inhibited mitochondrial autophagy and ROS levels and aggravated mitochondrial vacuolation; and partially reversed the effect of OIP5-AS1 overexpression on promoting mitochondrial autophagy and protection on MPP+ cells. Collectively, lncRNA OIP5-AS1 promoted NIX expression through competitively binding to miR-137, and promoted mitochondrial autophagy, thus protecting neurons from degeneration which might be seen in patients with PD.

Research on decoupling control for the longitudinal and lateral dynamics of a tractor considering steering delay.

To enhance the efficiency of tractor operation, the longitudinal and lateral dynamic control of a self-driving tractor is studied in this paper, and a control system that decouples control of the longitudinal and lateral movement of the tractor is proposed. The trajectory controller calculates the desired speed and desired yaw rate signals of each subsystem, and a PID controller regulates the longitudinal speed of the tractor. A pure pursuit algorithm calculates the desired front wheel angle of the tractor. To decrease the system time delay in the automatic steering system, an automatic steering scheme based on improved Smith predictive control is proposed. Through decoupling control of the longitudinal and lateral controllers, the tractor's path tracking performance is assured.

AKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis.

Ceramide synthases (CerSs) catalyze the formation of ceramides from sphingoid bases and acyl-CoA substrates. Increasing evidence suggests that cancer cells generally exhibit altered sphingolipid metabolism in the tumorigenesis of multiple cancers. However, there is no evidence that CerSs are associated with pancreatic ductal carcinoma (PDAC). In the present study, we examined CerS expression in clinical tissue and conducted data mining to investigate the clinical significance of CerSs in the TCGA-PAAD database. We found that high CerS6 expression positively correlated with progression and predicted worse prognosis in PDAC patients, establishing CerS6 as a potential biomarker for PDAC. Furthermore, CerS6 promoted cell proliferation, colony formation and invasion by producing C16-ceramide and was required for tumor formation. Mechanistically, AKT1 interacted with and phosphorylated FOXP3 at S418, which decreased the binding of FOXP3 to the CERS6 promoter and in turn induced CerS6 expression by reconstituting an activated state on the CERS6 promoter. The AKT1/FOXP3 axis mediated the CerS6 expression and promoted p53 mutant pancreatic tumorigenesis by producing excessive C16-ceramide, which induced the accumulation of mutant p53. Thus, our study explores the relationship between PI3K/AKT signaling and sphingolipid metabolism, revealing an oncogenic role for CerS6, which may represent a potential target for PDAC treatment.

DGCR5 Promotes Gallbladder Cancer by Sponging MiR-3619-5p via MEK/ERK1/2 and JNK/p38 MAPK Pathways.

Gallbladder cancer (GBC) is a highly aggressive malignant cancer with poor prognosis. Long noncoding RNA (lncRNA) DiGeorge syndrome critical region gene (DGCR5) has been reported to participate in various types of cancers, but its role in GBC remains largely unknown. This study aimed to explore the functions and mechanisms of DGCR5 in GBC. Here, we found that DGCR5 was upregulated in GBC tissues and cell lines. Through functional experiments, it was demonstrated that silence of DGCR5 significantly suppressed the cell proliferation, migration, invasion, and induced apoptosis and cell cycle arrest in GBC cells. In addition, miR-3619-5p was predicted and further verified as the target of DGCR5. Moreover, miR-3619-5p was observed downregulated in GBC tissues and cell lines, and miR-3619-5p mimics repressed the GBC cell proliferation, migration, invasion and could be rescued by DGCR5 overexpression. Mechanistically, it was found that DGCR5 knockdown and miR-3619-5p mimics inactivated the MEK/ERK1/2 and JNK/p38 MAPK pathways. In addition, rescue experiments indicated that inhibition of MEK/ERK1/2 and JNK/p38 MAPK pathways could reverse the effects of DGCR5 overexpression on cell proliferation, migration and invasion. Finally, xenograft model assay was used to validate that knockdown of DGCR5 suppressed GBC via regulating MEK/ERK1/2 and JNK/p38 MAPK pathways in vivo. Taken together, it was uncovered in our study that DGCR5 exerts an oncogenic role by sponging miR-3619-5p and activating MEK/ERK1/2 and JNK/p38 MAPK pathways in GBC progression.