Hidden Charge Order and Multiple Electronic Instabilities in EuTe4.

The rare-earth telluride compound EuTe4 exhibits a charge density wave (CDW) and an unconventional thermal hysteresis transition. Herein, we report a comprehensive study of the CDW states in EuTe4 by using low-temperature scanning tunneling microscopy. Two types of charge orders are observed at 4 K, including a newly discovered spindle-shaped pattern and a typical stripe-like pattern. As an exotic charge order, the spindle-shaped CDW is off-axis and barely visible at 77 K, indicating that it is a hidden order developed at low temperature. Based on our first-principles calculations, we reveal the origins of the observed electronic instabilities. The spindle-shaped charge order stems from a subsequent transition based on the stripe-like CDW phase. Our work demonstrates that the competition and cooperation between multiple charge orders can generate exotic quantum phases.

Effects of nitrate- and ammonium- nitrogen on anatomical and physiological responses of Catalpa bungei under full and partial root-zone drought.

Catalpa bungei is a precious timber species distributed in North China where drought often occurs. To clarify adaptive responses of C. bungei to partial- and full- root-zone drought under the influence of nitrogen forms, a two-factor experiment was conducted in which well-watered (WW), partial root-zone drought in horizontal direction (H-PRD) and in vertical direction (V-PRD), and full root-zone drought (FRD) were combined with nitrate-nitrogen (NN) and ammonium-nitrogen (AN) treatments. C. bungei responded to FRD by sharply closing stomata, decreasing gas exchange rate and increasing leaf instantaneous water use efficiency (WUEi). Under FRD condition, the growth of seedlings was severely inhibited and the effect of N forms was covered up by the drastic drought effect. In comparison, stomata conductance and gas exchanges were moderately inhibited by PRDs. WUEi in V-PRD treatment was superior to H-PRD due to the active stomata regulation resulting from a higher ABA level and active transcription of genes in abscisic acid (ABA) signaling pathway under V-PRD. Under both PRDs and FRD, nitrate benefited antioxidant defense, stomata regulation and leaf WUEi. Under V-PRD, WUEi in nitrate treatment was superior to that in ammonium treatment due to active stomata regulation by signaling network of nitric oxide (NO), Ca2+ and ABA. Under FRD, WUEi was higher in nitrate treatment due to the favoring photosynthetic efficiency resulting from active NO signal and antioxidant defense. The interactive effect of water and N forms was significant on wood xylem development. Superoxide dismutase (SOD) and catalase (CAT) largely contributes to stress tolerance and xylem development.

Designing Compatible Ceramic/Polymer Composite Solid-State Electrolyte for Stable Silicon Nanosheet Anodes.

The commercialization of silicon anode for lithium-ion batteries has been hindered by severe structure fracture and continuous interfacial reaction against liquid electrolytes, which can be mitigated by solid-state electrolytes. However, rigid ceramic electrolyte suffers from large electrolyte/electrode interfacial resistance, and polymer electrolyte undergoes poor ionic conductivity, both of which are worsened by volume expansion of silicon. Herein, by dispersing Li1.3Al0.3Ti1.7(PO4)3 (LATP) into poly(vinylidene fluoride)-hexafluoropropylene (PVDF-HFP) and poly(ethylene oxide) (PEO) matrix, the PVDF-HFP/PEO/LATP (PHP-L) solid-state electrolyte with high ionic conductivity (1.40 × 10-3 S cm-1), high tensile strength and flexibility is designed, achieving brilliant compatibility with silicon nanosheets. The chemical interactions between PVDF-HFP and PEO, LATP increase amorphous degree of polymer, accelerating Li+ transfer. Good flexibility of the PHP-L contributes to adaptive structure variation of electrolyte with silicon expansion/shrinkage, ensuring swift interfacial ions transfer. Moreover, the solid membrane with high tensile limits electrode structural degradation and eliminates continuous interfacial growth to form stable 2D solid electrolyte interface (SEI) film, achieving superior cyclic performance to liquid electrolytes. The Si//PHP-L15//LiFePO4 solid-state full-cell exhibits stable lithium storage with 81% capacity retention after 100 cycles. This work demonstrates the effectiveness of composite solid electrolyte in addressing fundamental interfacial and performance challenges of silicon anodes.

Effector Protein Serine Carboxypeptidase FgSCP Is Essential for Full Virulence in F. graminearum and Is Involved in Modulating Plant Immune Responses.

Fusarium head blight (FHB) caused by Fusarium graminearum is a significant pathogen affecting wheat crops. During the infection process, effector proteins are secreted to modulate plant immunity and promote infection. The toxin deoxynivalenol (DON) is produced in infected wheat grains, posing a threat to human and animal health. Serine carboxypeptidases (SCPs) belong to the α/ß hydrolase family of proteases and are widely distributed in plant and fungal vacuoles as well as animal lysosomes. Research on SCPs mainly focuses on the isolation, purification of a small number of fungi as well as their study in plants.However, their functions in F. graminearum, a fungal pathogen, remain relatively unknown. In this study, the biological functions of the FgSCP gene in F. graminearum were investigated. The study revealed that mutations in FgSCP affected nutritional growth, sexual reproduction, and stress tolerance of F. graminearum. Furthermore, the deletion of FgSCP resulted in reduced pathogenicity and hindered the biosynthesis of DON. The upregulation of FgSCP expression three days after infection indicated its involvement in host invasion, possibly acting as a "smokescreen" to deceive the host and suppress the expression of host defensive genes. Subsequently, we confirmed the secretion ability of FgSCP and its ability to inhibit the cell death induced by INF1 in Nicotiana. benthamiana cells, indicating its potential role as an effector protein in suppressing plant immune responses and promoting infection. In summary, we have identified FgSCP as an essential effector protein in F. graminearum, playing critical roles in growth, virulence, secondary metabolism, and host invasion.

A Novel Role of Uricosuric Agent Benzbromarone in BK Channel Activation and Reduction of Airway Smooth Muscle Contraction.

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 µM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing ß1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 µM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies. SIGNIFICANCE STATEMENT: We describe a novel role of uricosuric agent benzbromarone in big potassium (BK) channel activation and relaxation of airway smooth muscle contraction. In this study, we find that benzbromarone is an activator of the large-conductance Ca2+- and voltage-activated K+ channel (BK channel), which serves numerous cellular functions, including control of smooth muscle contraction. Pharmacological activation of BK channel by the FDA-approved drug benzbromarone may hold repurposing potential for treatment of asthma and pulmonary arterial hypertension or BK channelopathies.

Identifying circRNA-miRNA-mRNA Regulatory Networks in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and severe side effect of first-line chemotherapeutic agents. The association between circular RNAs (circRNAs) and CIPN remains unclear. In this study, CIPN models were constructed with Taxol, while 134 differentially expressed circRNAs, 353 differentially expressed long non-coding RNAs, and 86 differentially expressed messenger RNAs (mRNAs) were identified utilizing RNA sequencing. CircRNA-targeted microRNAs (miRNAs) were predicted using miRanda, and miRNA-targeted mRNAs were predicted using TargetScan and miRDB. The intersection of sequencing and mRNA prediction results was selected to establish the circRNA-miRNA-mRNA networks, which include 15 circRNAs, 18 miRNAs, and 11 mRNAs. Functional enrichment pathway analyses and immune infiltration analyses revealed that differentially expressed mRNAs were enriched in the immune system, especially in T cells, monocytes, and macrophages. Cdh1, Satb2, Fas, P2ry2, and Zfhx2 were further identified as hub genes and validated by RT-qPCR, correlating with macrophages, plasmacytoid dendritic cells, and central memory CD4 T cells in CIPN. Additionally, we predicted the associated diseases, 36 potential transcription factors (TFs), and 30 putative drugs for hub genes using the DisGeNET, TRRUST, and DGIdb databases, respectively. Our results indicated the crucial role of circRNAs, and the immune microenvironment played in CIPN, providing novel insights for further research.

Genome-wide identification, phylogenetic and expression pattern analysis of HSF family genes in the Rye (Secale cereale L.).

BACKGROUND: Heat shock factor (HSF), a typical class of transcription factors in plants, has played an essential role in plant growth and developmental stages, signal transduction, and response to biotic and abiotic stresses. The HSF genes families has been identified and characterized in many species through leveraging whole genome sequencing (WGS). However, the identification and systematic analysis of HSF family genes in Rye is limited. RESULTS: In this study, 31 HSF genes were identified in Rye, which were unevenly distributed on seven chromosomes. Based on the homology of A. thaliana, we analyzed the number of conserved domains and gene structures of ScHSF genes that were classified into seven subfamilies. To better understand the developmental mechanisms of ScHSF family during evolution, we selected one monocotyledon (Arabidopsis thaliana) and five (Triticum aestivum L., Hordeum vulgare L., Oryza sativa L., Zea mays L., and Aegilops tauschii Coss.) specific representative dicotyledons associated with Rye for comparative homology mapping. The results showed that fragment replication events modulated the expansion of the ScHSF genes family. In addition, interactions between ScHSF proteins and promoters containing hormone- and stress-responsive cis-acting elements suggest that the regulation of ScHSF expression was complex. A total of 15 representative genes were targeted from seven subfamilies to characterize their gene expression responses in different tissues, fruit developmental stages, three hormones, and six different abiotic stresses. CONCLUSIONS: This study demonstrated that ScHSF genes, especially ScHSF1 and ScHSF3, played a key role in Rye development and its response to various hormones and abiotic stresses. These results provided new insights into the evolution of HSF genes in Rye, which could help the success of molecular breeding in Rye.

Identification of MKI67, TPR , and TCHH Mutations as Prognostic Biomarkers for Patients With Defective Mismatch Repair Colon Cancer Stage II/III.

BACKGROUND: Stage II/III disease is the most predominant form of colorectal cancer, accounting for approximately 70% of cases. Furthermore, approximately 15% to 20% of patients with stage II/III disease have deficient mismatch repair or microsatellite instability-high colorectal cancer. However, there are no identified significant prognostic biomarkers for this disease. OBJECTIVE: To identify prognostic markers for patients with deficient mismatch repair/microsatellite instability-high colon cancer stage II/III. DESIGN: Retrospective study design. SETTING: The study was conducted at a high-volume colorectal center, the Cancer Hospital, Chinese Academy of Medical Sciences. PATIENTS: Patients diagnosed with stage II/III deficient mismatch repair/microsatellite instability-high colon cancer who underwent curative surgery at the Cancer Hospital at the Chinese Academy of Medical Sciences between July 2015 and November 2018 were included. MAIN OUTCOME MEASURES: The primary outcome measure was the influence of differentially mutated genes on progression-free survival. RESULTS: The retrospective deficient mismatch repair/microsatellite instability-high cohort involved 32 patients and The Cancer Genome Atlas-microsatellite instability-high cohort involved 45 patients. Patients with deficient mismatch repair/microsatellite instability-high colon cancer had higher mutational frequencies of MKI67 , TPR , and TCHH than patients with microsatellite stable colon cancer. MKI67 , TPR , TCHH , and gene combination were significantly correlated with prognosis. The biomarker mutation-type colon cancer group had a higher risk of recurrence or death than did the wild-type group. Moreover, biomarker mutation-type tumors had more mutations in the DNA damage repair pathway and tumor mutational burden than did biomarker wild-type tumors. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: MKI67 , TPR , and TCHH may serve as potential diagnostic and prognostic biomarkers for deficient mismatch repair/microsatellite instability-high colon cancer stage II/III. IDENTIFICACIN DE MUTACIONES MKI, TPR Y TCHH COMO BIOMARCADORES PRONSTICOS PARA PACIENTES CON CNCER DE COLON EN ETAPA II/III CON DEFICIENCIA EN LA REPARACION DE ERRORES DE EMPAREJAMIENTO: ANTECEDENTES:La enfermedad en estadio II/III es la forma más predominante de cáncer colorrectal y representa aproximadamente el 70% de los casos. Además, aproximadamente entre el 15% y el 20% de los pacientes con enfermedad en estadio II/III tienen reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta. Sin embargo, no se han identificado biomarcadores pronósticos significativos para esta enfermedad.OBJETIVO:Este estudio tuvo como objetivo identificar marcadores pronósticos para pacientes con cáncer de colon con reparación deficiente de errores de emparejamiento/inestabilidad microsatelital alta en estadio II/III.DISEÑO:Diseño de estudio retrospectivo.ESCENARIO:El estudio se realizó en un centro colorrectal de alto volumen, el Hospital del Cáncer de la Academia China de Ciencias Médicas.PACIENTES:Pacientes diagnosticados con cáncer de colon en estadio II/III con reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta que se sometieron a cirugía curativa en el Hospital del Cáncer de la Academia China de Ciencias Médicas entre julio de 2015 y noviembre de 2018.MEDIDAS DE RESULTADO PRINCIPALES:La medida de resultado primaria fue la influencia de los genes con mutaciones diferenciales en la supervivencia libre de progresión.RESULTADOS:La cohorte retrospectiva de reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta y la cohorte de inestabilidad microsatelital alta del Atlas del Genoma del Cáncer involucraron a 32 y 45 pacientes, respectivamente. Los pacientes con de reparación deficiente de errores de emparejamiento/inestabilidad microsatélital alta tuvieron frecuencias mutacionales más altas de MKI67 , TPR y TCHH que los pacientes estables de microsatélites. MKI67 , TPR , TCHH , y la combinación de genes se correlacionaron significativamente con el pronóstico. El grupo de cáncer de colon de tipo mutación de biomarcador tenía un mayor riesgo de recurrencia o muerte que el grupo de mutación salvaje. Además, los tumores de tipo mutación de biomarcadores tenían más mutaciones en la vía de reparación del daño del ADN y la carga mutacional del tumor que los tumores de tipo salvaje de biomarcadores.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva.CONCLUSIONES:MKI67 , TPR , y TCHH pueden servir como posibles biomarcadores de diagnóstico y pronóstico para cáncer de colon en estadio II/III con reparación deficiente de errores de emparejamiento/inestabilidad microsatélital alta. (Traducción-Dr. Jorge Silva Velazco ).

Improved YOLOv7-Based Algorithm for Detecting Foreign Objects on the Roof of a Subway Vehicle.

Subway vehicle roofs must be inspected when entering and exiting the depot to ensure safe subway vehicle operations. This paper presents an improved method for detecting foreign objects on subway vehicle roofs based on the YOLOv7 algorithm. First, we capture images of foreign objects using a line-scan camera at the depot entrance and exit, creating a dataset of foreign roof objects. Subsequently, we address the shortcomings of the YOLOv7 algorithm by introducing the Ghost module, an improved weighted bidirectional feature pyramid network (WBiFPN), and the Wise intersection over union (WIoU) bounding-box regression loss function. These enhancements are incorporated to build the subway vehicle roof foreign object detection model based on the improved YOLOv7, which we refer to as YOLOv7-GBW. The experimental results demonstrate the practicality and usability of the proposed method. The analysis of the experimental results indicates that the YOLOv7-GBW algorithm achieves a detection accuracy of 90.29% at a speed of 54.3 frames per second (fps) with a parameter count of 15.51 million. The improved YOLOv7 model outperforms mainstream detection algorithms in terms of detection accuracy, speed, and parameter count. This finding confirms that the proposed method meets the requirements for detecting foreign objects on subway vehicle roofs.

Genetic alteration of Chinese patients with rectal mucosal melanoma.

BACKGROUND: Rectal mucosal melanoma (RMM) is a rare and highly aggressive disease with a poor prognosis. Due to the rarity of RMM, there are few studies focusing on its genetic mechanism. This retrospective study aimed to analyze the genetic spectrum and prognosis of RMM in China and lay a foundation for targeted therapy. METHODS: 36 patients with primary RMM from Peking University Cancer Hospital were enrolled in this study. The Next-generation sequencing (NGS) data of the tumor samples were fitted into the TruSight™ Oncology 500 (TSO500) Docker pipeline to detect genomic variants. Then, the univariate and multivariate Cox hazard analysis were performed to evaluate the correlations of the variants with the overall survival (OS), along with Kaplan-Meier and log-rank test to determine their significance. RESULTS: BRAF mutations, NRG1 deletions and mitotic index were significant prognostic factors in the univariate analysis. In multivariable analysis of the OS-related prognostic factors in primary RMM patients, it revealed 2 significant alterations: BRAF mutations [HR 7.732 (95%CI: 1.735-34.456), P = 0.007] and NRG1 deletions [HR 14.976 (95%CI: 2.305-97.300), P = 0.005]. CONCLUSIONS: This is the first study to show genetic alterations exclusively to Chinese patients with RMM. We confirmed genetic alterations of RMM differ from cutaneous melanoma (CM). Our study indicates that BRAF and NRG1 were correlated with a poor prognostic of RMM and may be potential therapeutic targets for RMM treatment.

miR-199b-5p enhances the proliferation of medullary thymic epithelial cells via regulating Wnt signaling by targeting Fzd6.

Thymic epithelial cells (TECs) are essential regulators of T-cell development and selection. miRNAs play critical roles in regulating TEC proliferation during the process of thymic aging. Our previous studies revealed that miR-199b-5p was upregulated in TECs from 1- to 3-month-old mice. But its function and potential mechanism are not clear. We hypothesized that miR-199b-5p may play an important role in age-related thymus involution via targeting some genes. To confirm it, the murine thymic epithelial cell line 1 (MTEC1) cells were used. Our results showed that overexpression of miR-199b-5p can enhance MTEC1 cell proliferation. On the contrary, repression of miR-199b-5p can inhibit MTEC1 cell proliferation. Meanwhile, it was confirmed that frizzled receptor 6 (Fzd6) is the direct target gene of miR-199b-5p. Furthermore, overexpression of miR-199b-5p can upregulate the expressions of ß-catenin, Tcf7, Wnt4, and C-myc to activate Wnt signaling and cell cycle signaling. Silence of Fzd6 and co-transfection with siFzd6 and miR-199b-5p mimic/inhibitor confirmed that the biological function of miR-199b-5p is indeed by targeting Fzd6 in medullary TECs. Overall, miR-199b-5p is an important regulator in medullary TEC proliferation through targeting Fzd6 to activate Wnt signaling and cell cycle signaling. Our data indicate that miR-199b-5p may block the process of thymic aging and be a potential therapeutic target for thymus involution.

Electronic States and Magnetic Response of MnBi2Te4 by Scanning Tunneling Microscopy and Spectroscopy.

Exotic quantum phenomena have been demonstrated in recently discovered intrinsic magnetic topological insulator MnBi2Te4. At its two-dimensional limit, the quantum anomalous Hall effect and axion insulator state were observed in odd and even layers of MnBi2Te4, respectively. Here, we employ low-temperature scanning tunneling microscopy to study the electronic properties of MnBi2Te4. The quasiparticle interference patterns indicate that the electronic structures on the topmost layer of MnBi2Te4 are different from those of the expected out-of-plane A-type antiferromagnetic phase. The topological surface states may be embedded in deeper layers beneath the topmost surface. Such novel electronic structure is presumably related to the modification of crystalline structure during sample cleaving and reorientation of the magnetic moment of Mn atoms near the surface. Mn dopants substituted at the Bi site on the second atomic layer are observed. The electronic structures fluctuate at atomic scale on the surface, which can affect the magnetism of MnBi2Te4.

Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases.

Ferroptosis is a newly recognized type of cell death that is different from traditional forms of cell death, such as apoptosis, autophagy, and necrosis. It is caused by the accumulation of intracellular iron, promoting lipid peroxidation and leading to cell death. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. An increased concentration of iron in the central nervous system has been associated with oxidative stress, lipid peroxidation of proteins, and cell death. The hippocampus is an important brain region for learning, memory, and emotional responses, and is also a sensitive part of the brain to the dysfunctional homeostasis of transition metals. Damage of hippocampal structure and function are intimately involved in the pathogenic mechanisms underlying neurodegenerative diseases. Currently, ferroptosis is playing an increasingly important role in treatment areas of central nervous system diseases. Thus, we provide an overview of ferroptosis regulatory mechanisms, such as lipid metabolism, glutathione metabolism, and iron metabolism in this review. We also highlight the role of ferroptosis in hippocampal-related diseases and investigate a theoretical basis for further research on the role of ferroptosis in nervous system disease treatment.

Features and Risk Factors for Paraneoplastic Autoimmune Multiorgan Syndrome in 145 Chinese Patients.

Paraneoplastic autoimmune multiorgan syndrome is a complex and deadly disease. We retrospectively reviewed the clinical features and risk factors for paraneoplastic autoimmune multiorgan syndrome in 145 Chinese patients. The most common neoplasm was Castleman disease (56%), and patients with Castleman disease tended to be younger (≤ 42 years old: 83% vs. 29%) and to have a greater proportions of lichen planus-like lesions (47% vs. 27%) and bronchiolitis obliterans (49% vs. 29%), compared to other neoplasm-associated patients. Among all 145 patients in the study, the survival rates were 84% at 1 year, 65% at 3 years, and 54% at 5 years. Kaplan-Meier curve analysis revealed that mortality was associated with older age (> 42 years), neoplasm type, labial lesions, and larger skin lesion area (> 17.5% of the body surface area). However, only older age and larger skin lesion area were independent factors associated with mortality in multivariate analysis. We suggest that patients with Castleman disease and paraneoplastic autoimmune multiorgan syndrome have many unique characteristics and the underlying risk factors for death require further exploration.

Concurrent Selective Lymph Node Radiotherapy and S-1 Plus Cisplatin for Esophageal Squamous Cell Carcinoma: A Phase II Study.

BACKGROUND: The efficacy, toxicity, and patterns of failure of esophageal squamous cell carcinoma (ESCC) treated with selective lymph node (SLN) conventional fraction radiotherapy (CFRT) and S-1 plus cisplatin (CDDP) were evaluated. PATIENTS AND METHODS: 67 Patients with clinical stage II-IVa ESCC were enrolled. The total dose of SLN CFRT was 60 Gy in 30 fractions over 6 weeks. The first course of radiation covered the primary and metastatic regional tumors and high-risk lymph nodal regions, given at 2 Gy/fraction for a dose of 40 Gy. In the second course, CFRT was delivered to the boost volume for an additional 20 Gy in 10 days, using 2 Gy/fraction. Two cycles of chemotherapy were given at the beginning of radiotherapy. CDDP at 25 mg/m2/day was given on days 1-3 and days 22-24, and S-1 at 80 mg/m2/day on days 1-14 and days 22-35. Patients achieving objective response after concurrent chemoradiotherapy underwent two additional cycles of chemotherapy. RESULTS: The objective response rate (ORR) was 82.5%. Grade 3 or 4 toxicities included leukopenia (23.8%), neutropenia (14.3%), thrombocytopenia (14.3%), hemoglobin (4.8%), gastrointestinal (12.7%), skin (1.6%), and esophagus fistula (1.6%). One patient died of severe pneumonia, and two died of late toxicity because of esophagus fistula. With median follow-up of 32 months, the overall survival (OS) and progression-free survival (PFS) at 1 year and 2 years were 81.0% and 73.0%, and 63.5% and 49.2%, respectively. CONCLUSIONS: SLN RT concurrent with S-1 plus CDDP may represent a better strategy for treatment of ESCC patients.

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission.

Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1ß), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABAARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

Role of melatonin in sleep deprivation-induced intestinal barrier dysfunction in mice.

Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress.

Chemical conversion of nicotinamide into type I positive allosteric modulator of α7 nAChRs.

Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa-8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus oocytes in two-electrode voltage clamp assay. The compound 8ai was a potent and efficacious PAM with an EC50 = 3.34 ±â€¯1.13 µM and the maximum activation effect of α7 current over 1474 ±â€¯246% in the presence of acetylcholine (100 µM). It is highly specific to α7 nAChR over other subtypes of nAChR and 5-HT3A receptors. The structure-activity relationship analysis identified a key skeleton of nicotinamide nucleus critical for biological activity. Taken together, the 8ai as a type I PAM of α7 nAChR may be beneficial for improvement of cognitive deficit.

Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aß deposition.

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-ß1-42 peptides (Aß1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aß1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3ß (pSer9-GSK3ß) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aß1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3ß and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aß1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3ß and IDE.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1ß3γ2 and α5ß3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.