N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk.

BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.

H3K4 Trimethylation Mediate Hyperhomocysteinemia Induced Neurodegeneration via Suppressing Histone Acetylation by ANP32A.

Homocysteine (Hcy) is an independent and serious risk factor for dementia, including Alzheimer's disease (AD), but the precise mechanisms are still poorly understood. In the current study, we observed that the permissive histone mark trimethyl histone H3 lysine 4 (H3K4me3) and its methyltransferase KMT2B were significantly elevated in hyperhomocysteinemia (HHcy) rats, with impairment of synaptic plasticity and cognitive function. Further research found that histone methylation inhibited synapse-associated protein expression, by suppressing histone acetylation. Inhibiting H3K4me3 by downregulating KMT2B could effectively restore Hcy-inhibited H3K14ace in N2a cells. Moreover, chromatin immunoprecipitation revealed that Hcy-induced H3K4me3 resulted in ANP32A mRNA and protein overexpression in the hippocampus, which was regulated by increased transcription Factor c-fos and inhibited histone acetylation and synapse-associated protein expression, and downregulating ANP32A could reverse these changes in Hcy-treated N2a cells. Additionally, the knockdown of KMT2B restored histone acetylation and synapse-associated proteins in Hcy-treated primary hippocampal neurons. These data have revealed a novel crosstalk mechanism between KMT2B-H3K4me3-ANP32A-H3K14ace, shedding light on its role in Hcy-related neurogenerative disorders.

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

Deep asymmetric extraction and aggregation for infrared small target detection.

Infrared small target detection is widely applied in military and civilian fields. Due to the small size of infrared targets, textural detail is missing. Common target detection methods extract semantic feature by narrowing down the feature map several times, which may lead to the small targets lost in deep layers and are not effective for infrared small target detection. To solve this problem, we propose a novel network called deep asymmetric extraction and aggregation. The network mainly consists of two processes - the vertical feature extraction and the horizontal feature aggregation, both of which are enhanced by an asymmetric attention mechanism. In the vertical process, the use of asymmetric attention mechanism combined with the reduction of down-sampling makes the small target better retained in the deep layers. Then through the horizontal process, shallow spatial feature and deep semantic feature are aggregated to further highlight the small targets while suppressing background noise. Experiments on the public datasets NUAA-SISRT, NUDT-SISRT and MDvsFA-cGan show that our proposed network outperforms the state-of-the-art methods in terms of detection accuracy and parameter efficiency.

Acyclic Cucurbit[n]urils: Effective Taste Masking Nanocontainers for Cationic Bitter Compounds.

New acyclic cucurbit[n]urils (ACBs) with eight carboxylate groups were synthesized. These hosts are highly soluble in water, and can form stable inclusion complexes with cationic bitter compounds. ACBs are confirmed to be non-toxic and biocompatible. Two-bottle preference (TBP) tests on mice show that all ACBs are tasteless to mammals. ACBs are discovered to mask the bitterness of berberine and denatonium benzoate, but not quinine hydrochloride, due to different binding modes.

Progress in the studies on the role of antisense long chain noncoding RNA in tumor development. / åä¹‰é•¿é“¾éžç¼–ç RNAåœ¨è‚¿ç˜¤å‘ç”Ÿå’Œå‘å±•ä¸­çš„ç ”ç©¶è¿›å±•.

Antisense long chain noncoding RNA (lncRNA) is a new class of RNA molecules. In recent years, antisense lncRNA has been found to play an important role in many life activities including tumorigenesis and development. It has become a hot topic in biological research in recent years. Because of the special structure, many antisense lncRNAs have specific expression in tumor tissues and are closely related to the clinical data of the patients. Thus, antisense lncRNA is a potential tumor molecular marker. Further functional studies have shown that lncRNA can participate in gene regulation by means of miRNA sponge and RBP binding to play an important role in tumor cell cycle, apoptosis, angiogenesis, invasion and metastasis. More studies on the mechanisms of antisense lncRNA in cancer are of great theoretical significance in understanding the etiology and pathogenesis of malignant tumors and RNA language. At the same time, antisense lncRNA is a molecular marker or a potential target for the early diagnosis of malignant tumors. The antisense lncRNA may have a broad clinical application prospect in the evaluation of therapeutic effect, prognosis and even gene therapy.

Knockdown of LncRNA RHPN1-AS1 Inhibits Cell Migration, Invasion and Proliferation in Head and Neck Squamous Cell Carcinoma.

Previous studies have revealed that long non-coding RNAs (lncRNAs) are involved in head and neck squamous cell carcinoma (HNSCC) progression. However, the detailed roles of lncRNA RHPN1-AS1 remain to be elucidated. In this study, by analyzing online RNA-Seq data, we found that RHPN1-AS1 was upregulated in HNSCC tissues and that its expression level was associated with neoplasm histologic grade. High expression of RHPN1-AS1 was also confirmed in HNSCC tissues. Knockdown of RHPN1-AS1 inhibited tumor cell migration, invasion and proliferation in HNSCC. Furthermore, inhibition of RHPN1-AS1 suppressed the expression of epithelial-mesenchymal transition (EMT)-related genes (ß-Catenin, Claudin-1 and Vimentin) in HNSCC cells. Collectively, our results suggest that RHPN1-AS1, acting as an oncogene, may be a potential diagnostic and therapeutic target in HNSCC.

Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

We have previously developed a cocktail of nine small molecules to convert human fetal astrocytes into neurons, but a nine-molecule recipe is difficult for clinical applications. Here, we identify a chemical formula with only three to four small molecules for astrocyte-to-neuron conversion. We demonstrate that modulation of three to four signaling pathways among Notch, glycogen synthase kinase 3, transforming growth factor ß, and bone morphogenetic protein pathways is sufficient to change an astrocyte into a neuron. The chemically converted human neurons can survive >7 months in culture, fire repetitive action potentials, and display robust synaptic burst activities. Interestingly, cortical astrocyte-converted neurons are mostly glutamatergic, while midbrain astrocyte-converted neurons can yield some GABAergic neurons in addition to glutamatergic neurons. When administered in vivo through intracranial or intraperitoneal injection, the four-drug combination can significantly increase adult hippocampal neurogenesis. Together, human fetal astrocytes can be chemically converted into functional neurons using three to four small molecules, bringing us one step forward for developing future drug therapy.

Antioxidant and Anti-inflammatory Capacity of Ferulic Acid Released from Wheat Bran by Solid-state Fermentation of Aspergillus niger.

OBJECTIVE: A strain of Aspergillus niger (A. niger), capable of releasing bound phenolic acids from wheat bran, was isolated. This strain was identified by gene sequence identification. The antioxidant and anti-inflammatory capacity of ferulic acid released from wheat bran by this A. niger strain (FA-WB) were evaluated. METHODS: Molecular identification techniques based on PCR analysis of specific genomic sequences were conducted; antioxidant ability was examined using oxygen radical absorbance capacity (ORAC), cellular antioxidant activity (CAA) assays, and erythrocyte hemolysis assays. RAW264.7 cells were used as a model to detect anti-inflammatory activity. RESULTS: The filamentous fungal isolate was identified to be A. niger. ORAC and CAA assay showed that FA-WB had better antioxidant activity than that of the ferulic acid standard. The erythrocyte hemolysis assay results suggested that FA-WB could attenuate AAPH-induced oxidative stress through inhibition of reactive oxy gen species (ROS) generation. FA-WB could significantly restore the AAPH-induced increase in intracellular antioxidant enzyme activities to normal levels as well as inhibit the intracellular malondialdehyde formation. TNF-a, IL-6, and NO levels indicated that FA-WB can inhibit the inflammation induced by lipopolysaccharide (LPS). CONCLUSION: Ferulic acid released from wheat bran by a new strain of A. niger had good anti-inflammatory activity and better antioxidant ability than standard ferulic acid.

Upregulated Expression of Long Non-Coding RNA, LINC00460, Suppresses Proliferation of Colorectal Cancer.

Through bioinformatics analysis, a novel lncRNA, LINC00460, was implicated in the development of multiple cancers. However, the precise expression pattern, clinical significance and biological function of LINC00460 in colorectal cancer (CRC) remain unknown. Network databases were used to investigate the correlation between LINC00460 and CRC. In situ hybridization was performed to verify the precise expression pattern and clinical significance of LINC00460 in a CRC tissue microarray, which included 92 pairs of CRC and adjacent normal tissues. The effect of LINC00460 on proliferation was evaluated by MTT, colony formation assays and flow cytometry employing SW620 and HCT116 cell lines. Cell migration and matrigel invasion assays were performed to investigate whether LINC00460 is involved in the metastasis of CRC. The expression of LINC00460 was significantly upregulated in CRC tissues and cells, associated with early stage CRC and low disease-free survival. The downregulated of LINC00460 expression increased cell proliferation by regulating the cell cycles of SW620 and HCT116 cells. LINC00460 knockdown did not affect cell migration or invasion in vitro. These findings suggest that LINC00460 may be an interesting target for the development of CRC.

MicroRNA-494 inhibition alleviates acute lung injury through Nrf2 signaling pathway via NQO1 in sepsis-associated acute respiratory distress syndrome.

AIMS: Although therapeutic strategies for acute respiratory distress syndrome (ARDS) have achieved improvements, its mortality remains high. It has been reported that microRNAs (miRs) serve as therapeutic strategies for ARDS, while specific mechanisms of miR-494 remain poorly understood. Thus, the present study aimed to assess the effects of miR-494 on acute lung injury (ALI) in rat models of sepsis-associated ARDS and its regulatory mechanism. METHODS: Following establishment of sepsis-associated ARDS rat models, the ratio of wet to dry weight (W/D) in right lung tissues was detected. Moreover, the expression patterns of miR-494, NQO1 and Nrf2 were evaluated in left lung tissues of rats. The miR-494 was exogenously overexpressed in rats so as to analyze the effects of miR-494 on ALI, inflammatory response and oxidative stress. Meanwhile, the Nrf2 signaling pathway was activated in rats in order to show the regulatory mechanism of miR-494 in ALI. And the target gene of miR-494 was identified by dual-luciferase reporter assay. KEY FINDINGS: The findings firstly revealed upregulated miR-494, and enhanced inflammatory response, oxidative stress and ALI in rat models of sepsis-associated ARDS. Additionally, MiR-494 negatively regulated NQO1 and blocked the Nrf2 signaling pathway. Moreover, ectopic expression of miR-494 promoted inflammatory response, oxidative stress and ALI. However, the activation of Nrf2 signaling pathway reversed these effects of miR-494. SIGNIFICANCE: Our key findings highlight the value of miR-494 inhibition as a therapeutic target for sepsis-associated ARDS, as a result of miR-494 accelerated ALI in rats with sepsis-associated ARDS through NQO1-mediated inactivation of Nrf2 signaling pathway.

Clinical Characteristics, Imaging Findings and Surgical Outcomes of Chiari Malformation Type I in Pediatric and Adult Patients.

A growing number of children and adolescents are being diagnosed as Chiari malformation type I (CM-I) for behavioral disorders, developmental delay, seizures, or abnormal orpharyngeal function. The aim of this study was to compare the clinical characteristics, imaging findings and surgical outcomes of CM-I in pediatric and adult patients. Between January 2014 and June 2017, 84 patients with CM-I underwent surgical treatment in our department. We divided the patients into two groups: pediatric group (n=11, age <18 years) and adult group (n=73, age ≥18 years). Data on clinical characteristics, imaging findings, surgical outcomes, and prognosis were retrospectively reviewed and compared between these two groups. For clinical presentation, scoliosis (36.4%) and developmental delay (36.4%) were more common in pediatric patients, whereas, sensory disturbance (58.9%) and motor weakness (41.1%) were more common in adult patients. Imaging findings showed that the incidence of hydrocephalus and craniovertebral junctional abnormalities was significantly higher in pediatric group than in adult group (P<0.05). Compared to adult group, pediatric group showed a better improvement or resolution of syrinx and tonsillar herniation after surgical treatments (P<0.05). The total Chicago Chiari Outcome Scale (CCOS) score in pediatric patients at the last followup was significantly higher than that in adult patients (P=0.002). In conclusion, the clinical characteristics and imaging findings appeared to be different in pediatric and adult patients with CM-I. The surgical outcomes of pediatric patients were shown to be significantly better than those of adult patients.

Epidermal growth factor receptor genotype in plasma DNA and outcome of chemotherapy in the Chinese patients with advanced non-small cell lung cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The genotype of epidermal growth factor receptor (EGFR) is associated with tyrosine kinase inhibitor and effectiveness of therapy, but its role in cytotoxic chemotherapy is still unknown. Previous studies indicated that certain EGFR mutations were associated with response and progression free survival following platinum based chemotherapy. Our recent studies have identified that EGFR genotypes in the tumour tissues were not associated with response to the first-line chemotherapy in Chinese patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated associations of EGFR genotypes from plasma of patients with advanced NSCLC and response to first-line chemotherapy and prognosis.</p><p><b>METHODS</b>We enrolled 145 advanced NSCLC patients who had received first-line chemotherapy in our department. We examined plasma EGFR genotypes for these patients and associations of EGFR mutations with response to chemotherapy and clinical outcomes.</p><p><b>RESULTS</b>There were 54 patients with known EGFR mutations and 91 cases of wild types. No significant difference was detected in the response rate to first-line chemotherapy between mutation carriers and wild-type patients (37.0% vs. 31.9%). The median survival time and 1-, 2-year survival rates were higher in mutation carriers than wild-types (24 months vs. 18 months, 85.7% vs. 65.7% and 43.7% vs. 25.9%, P = 0.047). Clinical stage (IV vs. IIIb), response to the first-line chemotherapy (partial vs. no) and EGFR genotype were independent prognostic factors.</p><p><b>CONCLUSION</b>Plasma EGFR mutations in the Chinese patients with advanced NSCLC is not a predictor for the response to first-line chemotherapy, but an independent prognostic factor indicating longer survival.</p>

Assessment of personal noise exposure of overhead-traveling crane drivers in steel-rolling mills.

BACKGROUND: Noise is widespread occupational hazard in iron and steel industry. Overhead-traveling cranes are widely used in this industry, but few studies characterized the overhead-traveling crane drivers' noise exposure level so far. In this study, we assessed and characterized personal noise exposure levels of overhead-traveling crane drivers in two steel-rolling mills. METHODS: One hundred and twenty-four overhead-traveling crane drivers, 76 in the cold steel-rolling mill and 48 in the hot steel-rolling mill, were enrolled in the study. Personal noise dosimeters (AIHUA Instruments Model AWA5610e, Hangzhou, China) were used to collect full-shift noise exposure data from all the participants. Crane drivers carried dosimeters with microphones placed near their collars during the work shifts. Work logs had been taken by the drivers simultaneously. Personal noise exposure data were divided into segments based on lines in which they worked. All statistical analyses were done using SPSS 13.0. RESULTS: The average personal noise exposure (L(Aeq.8h)) of overhead-traveling crane drivers in the hot steel-rolling mills ((85.03 +/- 2.25) dB (A)) was higher than that in the cold one ((83.05 +/- 2.93) dB (A), P < 0.001). There were 17 overhead traveling cranes in the hot steel-rolling mill and 24 cranes in the cold one, of which carrying capacities varied from 15 tons to 100 tons. The average noise exposure level based on different lines in the hot and cold steel-rolling mills were (85.2 +/- 2.61) dB (A) and (83.3 +/- 3.10) dB (A) respectively (P = 0.001), which were similar to the average personal noise exposure in both mills. The noise exposure levels were different among different lines (P = 0.021). CONCLUSION: Noise exposure levels, depending upon background noise levels and the noise levels on the ground, are inconstant. As the noise exposure levels are above the 85 dB (A) criteria, these drivers should be involved in the Hearing Conservation Program to protect their hearing.

[Measurement of personal noise exposure in a cold rolling mill].

OBJECTIVE: To measure and evaluate the personal noise exposure of cold rolling mill workers by using noise dosimeter. METHODS: According to job category and work type, all workers were divided into 11 groups. 3 to 5 day shift (8:00 to 16:00) workers from each group were selected as subjects for personal noise exposure measurement. SH-126 dosimeters were worn by each subject and collect noise data by a phone fix at collar. All subjects were asked to take notes about their working activities when they were wearing SH-126 dosimeters. Each worker's L(A)(eq) of 8 hours, geometric mean and range of each group were computed. RESULTS: There were many noise sources in the workshop. Recorded data showed that noise exposure of cold rolling mill was unstable. The varieties of personal noise levels were quite large. Among 53 workers, the highest noise exposure level was 100.0 dB (A), the lowest was 81.2 dB (A); the highest work type was of the foreside welders [94.20 dB (A)], and the lowest was of the straight-cutters [89.02 dB (A)]; quality checkers had the biggest rang [16.3 dB (A)], and primary rolling workers had the lest [2.3 dB (A)]. CONCLUSION: Noise exposure of all the 11 groups were more than 85 dB (A). Noise protection of these workers should be improved. It suggested that measuring personal noise exposure individually with dosimeters might obtain the noise exposure level more integrally in the complicated environment.