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1.
Cancer Med ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017467

RESUMO

BACKGROUND: Brain metastases are one of the most common intracranial neoplasms. Increasing evidence have indicated that systemic immunotherapy may provide long-term benefits for brain metastases. Herein, we presented the results of an immune oncology panel RNA sequencing platform for patients with brain metastases from different primary sites. METHODS: We investigated 25 samples of human brain metastases from lung cancer (n = 12), breast cancer (n = 6), and colorectal cancer (n = 7). Besides, 13 paired samples of adjacent noncancerous brain tissue (10 from patients with lung cancer and 3 from patients with breast cancer) were collected as controls. By comparing the brain metastases and paired samples of adjacent noncancerous brain tissue from 13 patients, we detected three upregulated and six downregulated genes, representing the malignant properties of cancer cells and increased immune infiltration in the microenvironment. Next, we profiled the immune-related genes in brain metastases from three primary cancer types. RESULTS: A group of genes were significantly overexpressed in the microenvironment of brain metastases from lung cancer, covering the checkpoint pathways, lymphocyte infiltration, and TCR-coexpression. Especially, immune checkpoint molecules, PD-L1, PD-L2, and IDO1 were expressed at higher levels in brain metastases from lung cancer than those from the other two cancer types. CONCLUSIONS: This study presents an immune landscape of brain metastases from different cancer types. With high RNA expression levels of PD-1/PD-L1 axis and immune infiltration in brain metastases, it would be worthwhile to explore the efficacy of immune checkpoint blockade for lung cancer patients with intracranial metastases.

2.
Ultrason Sonochem ; 61: 104850, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31698197

RESUMO

As a novel type of carbon materials, graphynes possesses the merits of high carrier mobility and large surface areas, etc. However, to date, the main research of graphynes is focused on theoretical calculation whereas few strategies have been reported for the fabrication of graphynes. In this work, a facile method named ultrasound-promoted synthesis was developed to fabricate γ-graphyne using PhBr6 and CaC2 as the raw materials. The reaction system in argon atmosphere ultrasonically vibrated for 24 h in the ultrasonic bath at a power of 180 W and frequency of 53 kHz. The structure, morphology, and component of the obtained samples were detected by X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, FT-IR spectra, scanning electron microscopy, transmission electron microscopy, and the selected area electron diffraction. The electrochemical and photoelectrochemical measurements indicate that γ-graphyne can be used as superior electrode mateirals in supercapacitor and photoelectrochemical catalysis. From the results of galvanostatic charge/discharge measurements, the γ-graphyne supercapacitor delivers a maximum specific capacitance of 81 F/g at 0.2 A/g and a capacitance retention rate of 87.5% after 5000 cycles at 3 A/g. Moreover, UV-vis light photoelectrochemical response and high carrier density are observed for γ-graphyne. It is also demonstrated that the charge-transfer resistance is low by Tafel slopes and Nyquist plots. This work puts forward a new and facile strategy for the fabrication of γ-graphyne and explores its application in the field of solar energy conversion and storage.

3.
BMC Genomics ; 20(1): 831, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703614

RESUMO

BACKGROUND: Formalin-fixed and paraffin-embedded (FFPE) blocks held in clinical laboratories are an invaluable resource for clinical research, especially in the era of personalized medicine. It is important to accurately quantitate gene expression with degraded and small amounts of total RNA from FFPE materials. RESULTS: High concordance in transcript quantifications were shown between FF and FFPE samples using the same kit. The gene expression using the TaKaRa kit showed a difference with other kits, which may be due to the different principle of rRNA depletion or the amount of input total RNA. For seriously degraded RNA from FFPE samples, libraries could be constructed with as low as 50 ng of total RNA, although there was residual rRNA in the libraries. Data analysis with HISAT demonstrated that the unique mapping ratio, percentage of exons in unique mapping reads and number of detected genes decreased along with the decreasing quality of input RNA. CONCLUSIONS: The method of RNA library construction with rRNA depletion can be used for clinical FFPE samples. For degraded and low-input RNA samples, it is still possible to obtain repeatable RNA expression profiling but with a low unique mapping ratio and high residual rRNA.

4.
EBioMedicine ; 48: 478-490, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31628020

RESUMO

BACKGROUND: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models. METHODS: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models. FINDINGS: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology. INTERPRETATION: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea.

5.
Int J Cancer ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577838

RESUMO

Peritoneal metastasis is a critical feature and clinical challenge in epithelial ovarian cancer (EOC). We previously identified a novel long noncoding RNA (lncRNA, TC0101441) in epithelial ovarian cancer (EOC) using microarrays. However, the impact of TC0101441 on EOC metastasis and prognosis remains unclear. TC0101441 expression in EOC tissues and its correlation with clinicopathological factors and prognosis were examined. A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of TC0101441 in EOC metastasis. We found that TC0101441 levels were elevated in EOC tissues compared with those in normal controls and significantly correlated with an advanced clinical stage and lymph node metastasis. TC0101441 was determined to be an independent prognostic predictor of overall survival (OS) and disease-free survival (DFS). Furthermore, loss-of-function assays showed that TC0101441 promoted the invasive and metastatic capacities of EOC cells both in vitro and in vivo. Mechanistically, the prometastatic effects of TC0101441 were linked to the induction of epithelial-mesenchymal transition (EMT). Importantly, KiSS1 was identified as a downstream target gene of TC0101441 and was downregulated by TC0101441 in EOC cells. After TC0101441 was silenced, the corresponding phenotypes of EOC cell invasion and EMT were reversed by the overexpression of KiSS1. Taken together, our data suggest that TC0101441 functions as a potential promigratory/invasive oncogene by promoting EMT and metastasis in EOC through downregulation of KiSS1, which may represent a novel prognostic marker and therapeutic target in EOC.

6.
Onco Targets Ther ; 12: 7699-7711, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571921

RESUMO

Purpose: Exosomes are key mediators of cellular communication by transporting molecules, including long noncoding RNAs (lncRNAs), and have been regarded as promising non-invasive biomarkers. This study aimed to evaluate the expression pattern and clinical significance of serum exosomal lncRNA antisense hypoxia inducible factor (aHIF) in epithelial ovarian cancer (EOC). Patients and methods: Sixty-two EOC patients in Obstetrics and Gynecology Hospital of Fudan University were enrolled. The expression levels of aHIF in tissues and serum exosomes were examined by RT-qPCR. The origin of serum exosomal aHIF was explored in vitro and in vivo. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic factors of EOC. A prognostic predictive nomogram was formulated in R software. Results: We isolated exosomes, identified exosomal aHIF in the serum of EOC patients. The expression of serum exosomal aHIF was higher in EOC patients and was correlated with the aHIF level in EOC tissues. In vitro and in vivo, the results indicated that serum exosomal aHIF was derived from tumor cells. Kaplan-Meier survival analysis demonstrated that EOC patients with higher serum exosomal aHIF expression had poorer overall survival. Cox multivariate regression model revealed that FIGO stage, residual tumor size, and serum exosomal aHIF level were independent prognostic factors of EOC. Based on the prognostic value of serum exosomal aHIF, we established a nomogram model that showed a good predictive ability for EOC patients. Conclusion: Serum exosomal aHIF is overexpressed in EOC and can serve as a noninvasive predictive biomarker for unfavorable prognosis.

7.
Onco Targets Ther ; 12: 6145-6156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496722

RESUMO

Purpose: The long noncoding RNA LINC00673 has emerged as an important regulator of cancer development and progression. However, the clinical significance and biological roles of LINC00673 in epithelial ovarian cancer (EOC) remain unclear. In this study, we aimed to explore the oncogenic roles and underlying molecular mechanisms of LINC00673 in EOC. Patients and methods: The expression levels of LINC00673 in EOC tissues and cell lines were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Real-time cellular analysis (RTCA), flow cytometry, and transwell assays were conducted to investigate cell proliferation, apoptosis, migration and invasion in vitro. Subcutaneous transplanted tumors were established to explore the oncogenic role of LINC00673 in vivo. Differentially expressed genes were analyzed using transcriptome sequencing. Protein levels were determined by Western blot assays. Results: LINC00673 was upregulated in EOC tissues and cell lines compared to their corresponding normal controls. High expression of LINC00673 was associated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, serous histological subtype, lymph node metastasis and poor prognosis in patients with EOC. LINC00673 was also identified as an independent prognostic factor for EOC. In addition, LINC00673 promoted cell migration, invasion and proliferation and inhibited cell apoptosis in vitro and induced tumor growth in vivo. Mechanistically, opioid growth factor receptor (OGFR) was found to be a potential downstream target gene that mediated the oncogenic effect of LINC00673 in EOC. Conclusion: LINC00673 contributes to EOC proliferation and metastasis and may be a promising prognostic biomarker for EOC patients.

8.
ACS Med Chem Lett ; 10(8): 1180-1186, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31413803

RESUMO

Aberration in FGFR4 signaling drives carcinogenesis and progression in a subset of hepatocellular carcinoma (HCC) patients, thereby making FGFR4 an attractive molecular target for this disease. Selective FGFR4 inhibition can be achieved through covalently targeting a poorly conserved cysteine residue in the FGFR4 kinase domain. We report mass spectrometry assays and cocrystal structures of FGFR4 in covalent complex with the clinical candidate BLU554 and with a series of four structurally related inhibitors that define the inherent reactivity and selectivity profile of these molecules. We further reveal the structure of FGFR1 with one of our inhibitors and show that off-target covalent binding can occur through an alternative conformation that supports targeting of a cysteine conserved in all members of the FGFR family. Collectively, we propose that rotational freedom, steric hindrance, and protein dynamics explain the exceptional selectivity profile of BLU554 for targeting FGFR4.

9.
Environ Pollut ; 254(Pt A): 112938, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31404731

RESUMO

In the present study, the competitive adsorption of Cu2+, Pb2+, and Cd2+ by a novel natural adsorbent (i.e., argillaceous limestone) modified with chitosan (C-AL) was investigated. The results demonstrated that both intraparticle diffusion and chemisorption marked significant contributions to the Cu2+ adsorption process by both raw argillaceous limestone (R-AL) and C-AL in mono-metal adsorption systems. Antagonism was found to be the predominant competitive effect for Cu2+, Pb2+ and Cd2+ adsorptions by C-AL in the multi-metal adsorption system. The three-dimensional simulation and FTIR analysis revealed that the presence of Cu2+ suppressed Pb2+ and Cd2+ adsorptions, while the effect of Cd2+ on Cu2+ and Pb2+ adsorptions was insignificant. The spectroscopic analyses evidenced that amide groups in C-AL played a crucial role in metal adsorption. The preferential adsorptions of Pb2+ > Cu2+ > Cd2+ were likely due to the different affinities of the metals to the lone pair of electrons on the N atom from the amide groups and/or the O atoms from the -OH and -COO- groups on C-AL. The interactions between C-AL and metal ions and between various metal species influenced their competitive adsorption behaviors. C-AL exhibited a superior metal adsorption capacity in comparison with that the capacities of other natural adsorbents reported during the last decade, suggesting its potential practical applications.


Assuntos
Cádmio/química , Carbonato de Cálcio/química , Quitosana/química , Cobre/química , Recuperação e Remediação Ambiental/métodos , Chumbo/química , Adsorção , Íons , Metais Pesados/química , Análise Espectral
10.
J Cancer ; 10(8): 1930-1940, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205552

RESUMO

Although accumulating evidence suggests that long non-coding RNAs (lncRNAs) are critical determinants of ovarian cancer development and progression, reports of metastasis-associated lncRNAs are limited. Here, we focused on NONHSAT076754 and explored its expression level, clinical value, biological behavior and molecular basis in epithelial ovarian cancer (EOC) metastasis. The results showed that NONHSAT076754 expression was increased in EOC tissues and cell lines and that this expression was closely related with FIGO stage, high tumor grade and lymph node metastasis. Furthermore, NONHSAT076754 knockdown markedly inhibited EOC cell migration and invasion in vitro. Consistently, the in vivo data from both the bioluminescence imaging and tumor dissection revealed that depletion of NONHSAT076754 reduced EOC metastasis. Mechanically, the pro-metastatic activities of NONHSAT076754 were partially regulated by PTEN and HTATIP2. Further rescue assays validated that knockdown of HTATIP2 remarkably reversed NONHSAT076754 silencer-induced inhibition of EOC cell metastasis. These data indicate that NONHSAT076754 is a vital regulator of EOC metastasis, laying the foundation for lncRNA-based clinical management of EOC aggressiveness and metastasis.

11.
Molecules ; 24(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216742

RESUMO

Ilicicolin H is a broad-spectrum antifungal agent targeting mitochondrial cytochrome bc1 reductase. Unfortunately, ilicicolin H shows reduced activities in vivo. Here, we report our effort on the identification of ilicicolin H biosynthetic gene cluster (BGC) by genomic sequencing a producing strain, Neonectria sp. DH2, and its heterologous production in Aspergillus nidulans. In addition, a shunt product with similar antifungal activities, ilicicolin J, was uncovered. This effort would provide a base for future combinatorial biosynthesis of ilicicolin H analogues. Bioinformatics analysis suggests that the backbone of ilicicolin H is assembled by a polyketide-nonribosomal peptide synthethase (IliA), and then offloaded with a tetramic acid moiety. Similar to tenellin biosynthesis, the tetramic acid is then converted to pyridone by a putative P450, IliC. The decalin portion is most possibly constructed by a S-adenosyl-l-methionine (SAM)-dependent Diels-Alderase (IliD).


Assuntos
Antifúngicos/farmacologia , Ascomicetos/genética , Ascomicetos/metabolismo , Benzaldeídos/farmacologia , Vias Biossintéticas/genética , Genes Fúngicos , Família Multigênica , Antifúngicos/química , Antifúngicos/metabolismo , Benzaldeídos/química , Benzaldeídos/metabolismo , Cromatografia Líquida de Alta Pressão , Regulação Fúngica da Expressão Gênica , Estrutura Molecular
12.
An Acad Bras Cienc ; 91(2): e20180637, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31241702

RESUMO

Desmodium caudatum (Thunb.) DC, is an ever-green plant widely used in the central and southern China with great economic value for their medical values on fever, dysentery, gastroenteritis, rectal prolapse, snake bites, mastitis, and boils carbuncle. Despite its extensive uses as a traditional Chinese medicine, no systematic research on the identification of Desmodium caudatum has been reported. In this study, traditional pharmacognostical identification including the botanical origin and morphological characters, medicinal material characters, microscopic characters, physicochemical parameters determination and phytochemical screening, and DNA barcoding analysis were employed to establish an accurate and effective identification system of Desmodium caudatum. In addition, the molecular pharmacognosy study was adopted in order to identify the samples more accurately. The ITS loci of the nuclear genome and psbA-trnH loci of the chloroplast genome were selected and evaluated, which were the most variable loci. The study will be beneficial to the development of the quality standard and the identification of species.


Assuntos
DNA de Plantas/genética , Fabaceae/química , Fabaceae/genética , Código de Barras de DNA Taxonômico , Fabaceae/classificação , Farmacognosia , Análise de Sequência de DNA
13.
Nutr Cancer ; 71(6): 908-921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31044620

RESUMO

To evaluate the relationship between obesity, analyzed by different indicators, and lung cancer incidence, literature search was conducted in the PubMed, Web of Science, EBSCO, Ovid, and China National Knowledge Infrastructure databases for articles published until December 2018. Twenty-eight prospective cohort studies were identified, with 28 784,269 participants and 127,161 lung cancer cases were included in the analysis. The combined relative risks (RRs) with 95% CIs for the highest versus normal category of body mass index (BMI) were RR = 0.77 (95% CI: 0.72-0.82), but the inverse association disappeared for never smokers or small cell carcinoma after stratifying the smoking status or histological cancer types, respectively. Further analysis considered lag time and excluded the effects of preclinical cancer, there is no statistically significant inverse association between BMI and lung cancer risk, RR = 0.89 (95% CI: 0.66-1.19). In contrast, the combined RRs with 95% CIs for the highest versus lowest category of waist circumference (WC) were RR = 1.26 (95% CI: 1.14-1.39). Therefore, due to multiple confounders existed, BMI might not be an appropriate indicator for obesity when study lung cancer risk. The significantly positive relationship between WC and lung cancer risk indicated there might have an etiological connection between central obesity and lung cancer development.

14.
J Nat Prod ; 82(4): 947-957, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30920218

RESUMO

Eight new dimeric sorbicillinoids (1-3, 5-9) and 12 new monomeric sorbicillinoids (10-20, 25), along with five known analogues (4 and 21-24), were isolated from the marine-derived fungus Trichoderma reesei 4670. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-ESIMS, and ECD) and X-ray crystallography. Compound 1, containing a pyrrolidin-2-one moiety, is reported for the first time in the sorbicillinoid family. Compounds 8 and 9 are the first examples of bisorbicillinoids possessing a benzofuro[2,3- h]chromene scaffold from a natural source. Compounds 3-11, 13-16, 18, 21, 22, 24, and 25 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC50 values in the range from 0.94 to 38 µM. Structure-activity relationships of the sorbicillinoids were discussed.

15.
Nutr Metab (Lond) ; 16: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873215

RESUMO

Objective: To investigate the influences of exercise on the levels of chemerin and its receptor chemokine-like receptor (CMKLR1) in the peripheral metabolic organs of obesity and diabetes rats, and whether the mechanism is related to peroxisome proliferator activated receptor γ (PPARγ), a key modulator of glycolipid metabolism. Methods: Obesity rats induced by 8-week high fat diet (HFD) were randomly divided into obesity group (OB) and exercised obesity group (EOB) with 8 rats each group, and 40 diabetes rats established by 8-week HFD plus low dose of streptozotocin were randomly divided into 4 groups: diabetes group (DM), exercised diabetes group (EDM), exercised diabetes plus PPARγ agonist pioglitazone group (EDP), and exercised diabetes plus PPARγ antagonist GW9662 group (EDG). The rats in EOB, EDM, EDG and EDP groups participated in a 4-week moderate-intensity aerobic exercise on a treadmill with gradually increasing intensity, once a day and 6 days/week, and 30 min before each exercise EDP and EDG were administrated to the rats in EDP and EDG groups, respectively. Before and after 4-week exercise, glycolipid metabolism indexes, serum chemerin and the levels of chemerin and CMKLR1 in metabolic organs such as liver and gastrocnemius were investigated (not detecting adipose for no available perirenal adipose from DM rats). Results: (1) In addition to serum chemerin, the levels of chemerin and CMKLR1 in the liver and gastrocnemius of EOB and EDM rats were declined, accompanied with the improved glycolipid metabolism. (2) The decreased chemerin/CMKLR1 in the EDM rats were reversed by PPARγ antagonist GW9662 and further strengthened by PPARγ agonist pioglitazones. Conclusions: Besides serum chemerin, the levels of chemerin/CMKLR1 in the metabolic organs of obesity and diabetes rats were alleviated by exercise, which were likely to be associated with the improvement of glycolipid metabolism. Exercise-induced decrements of chemerin/CMKLR1 in the diabetes rats were mediated by PPARγ.

16.
Reprod Sci ; 26(12): 1590-1602, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30808247

RESUMO

OBJECTIVE: The transfer of long noncoding RNAs (lncRNAs) via exosomes to modulate recipient cells represents an important mechanism for disease progression. Antisense hypoxia-inducible factor (aHIF) is a well-known angiogenesis-related lncRNA. Here, we aimed to investigate the clinical implications of aHIF and exosomal aHIF in endometriosis and the involvement of exosome-shuttled aHIF in endometriosis angiogenesis. STUDY DESIGN: The distribution and expression of aHIF in ectopic, eutopic, and normal endometria was evaluated. Serum exosomal aHIF levels in patients with endometriosis were tested. The correlation between serum exosomal aHIF and aHIF expression in ectopic endometria was analyzed. Endometriotic cyst stromal cells (ECSCs)-derived exosomes were characterized. The internalization of exosomes by human umbilical vein endothelial cells (HUVECs) was observed. A series of in vitro assays were conducted to investigate the roles and mechanisms of exosomal aHIF in endometriosis angiogenesis. RESULTS: Clinically, aHIF was highly expressed in ectopic endometria and serum exosomes in patients with endometriosis. Serum exosomal aHIF was significantly correlated to aHIF expression in matched ectopic endometria. In vitro, PKH67-labeled exosomes derived from aHIF high expression ECSCs were effectively internalized by recipient HUVECs. Notably, exosome-shuttled aHIF was transferred from ECSCs to HUVECs, which in turn elicited proangiogenic behavior in HUVECs by activating vascular endothelial growth factor (VEGF)-A, VEGF-D, and basic fibroblast growth factor, thereby facilitating endometriosis angiogenesis. CONCLUSION: Our study illustrates a potential cell-cell communication between ECSCs and HUVECs in an ectopic environment, provides a novel mechanistic model explaining how ECSCs induce angiogenesis from the perspective of the "exosomal transfer of aHIF," and highlights the clinical value of circulating exosomal aHIF in endometriosis.

17.
Hum Mutat ; 40(6): 801-815, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30763456

RESUMO

Autism spectrum disorder (ASD) is a childhood neuropsychiatric disorder with a complex genetic architecture. The diagnostic potential of a targeted panel of ASD genes has only been evaluated in small cohorts to date and is especially understudied in the Chinese population. Here, we designed a capture panel with 358 genes (111 syndromic and 247 nonsyndromic) for ASD and sequenced a Chinese cohort of 539 cases evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) as well as 512 controls. ASD cases were found to carry significantly more ultra-rare functional variants than controls. A subset of 78 syndromic and 54 nonsyndromic genes was the most significantly associated and should be given high priority in the future screening of ASD patients. Pathogenic and likely pathogenic variants were detected in 9.5% of cases. Variants in SHANK3 and SHANK2 were the most frequent, especially in females, and occurred in 1.2% of cases. Duplications of 15q11-13 were detected in 0.8% of cases. Variants in CNTNAP2 and MEF2C were correlated with epilepsy/tics in cases. Our findings reveal the diagnostic potential of ASD genetic panel testing and new insights regarding the variant spectrum. Genotype-phenotype correlations may facilitate the diagnosis and management of ASD.

18.
J Vis Exp ; (143)2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30663664

RESUMO

The mammalian brain exhibits marked symmetry across the sagittal plane. However, detailed description of neural dynamics in symmetric brain regions in adult mammalian animals remains elusive. In this study, we describe an experimental procedure for measuring calcium dynamics through dual optical windows above bilateral primary somatosensory corticies (S1) in Thy1-GCaMP6s transgenic mice using 2-photon (2P) microscopy. This method enables recordings and quantifications of neural activity in bilateral mouse brain regions one at a time in the same experiment for a prolonged period in vivo. Key aspects of this method, which can be completed within an hour, include minimally invasive surgery procedures for creating dual optical windows, and the use of 2P imaging. Although we only demonstrate the technique in the S1 area, the method can be applied to other regions of the living brain facilitating the elucidation of structural and functional complexities of brain neural networks.


Assuntos
Encéfalo/diagnóstico por imagem , Córtex Somatossensorial/diagnóstico por imagem , Antígenos Thy-1/genética , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos
19.
Behav Brain Res ; 364: 447-456, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29113873

RESUMO

Diabetes could negatively affect the structures and functions of the brain, especially could cause the hippocampal dysfunction, however, the potential metabolic mechanism is unclear. The aim of this study was to investigate the changes of glucose metabolism in hippocampus of diabetes mellitus rats and the regulation of aerobic exercise, and to analyze the possible mechanisms. A rat model of type 2 diabetes mellitus was established by high-fat diet feeding in combination with STZ intraperitoneal injection, then 4 weeks of aerobic exercise was conducted. The glucose metabolites and key enzymes involved in glucose metabolism in hippocampus were respectively detected by GC/MS based metabolomics and western blot. Metabolomics results showed that compared with control rats, the level of citric acid was significantly decreased, while the levels of lactic acid, ribose 5-phosphate, xylulose 5-phosphate and glucitol were significantly increased in the diabetic rat. Compared with diabetic rats, the level of citric acid was significantly increased, while the lactic acid, ribose 5-phosphate and xylulose 5-phosphate were significantly decreased in the diabetic exercise rats. Western blot results showed that lower level of citrate synthase and oxoglutarate dehydrogenase, higher level of aldose reductase and glucose 6-phosphatedehydrogenase were found in the diabetic rats when compared to control rats. After 4 weeks of aerobic exercise, citrate synthase was upregulated and glucose 6-phosphatedehydrogenase was downregulated in the diabetic rats. These results suggest that diabetes could cause abnormal glucose metabolism, and aerobic exercise plays an important role in regulating diabetes-induced disorder of glucose metabolism in the hippocampus.

20.
Onco Targets Ther ; 11: 9101-9110, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30588022

RESUMO

Purpose: Hypoxia is a key stress that triggers apoptosis in various tumors, including epithelial ovarian cancer (EOC). Previous researches identified a hypoxia-upregulated lncRNA named "a natural antisense transcript of hypoxia-inducible factor 1 (aHIF)" in some tumors. However, the contribution of aHIF to EOC remains unclear. Here, we aimed to investigate the expression, function, and underlying mechanisms of aHIF in EOC progression under hypoxia. Materials and methods: Expression levels of aHIF in EOC tissues were tested. In vitro and in vivo assays were conducted to explore the function and mechanism of aHIF in hypoxia-induced EOC progression. Results: aHIF levels were increased in EOC tissues and were upregulated by hypoxia in EOC cells. Functional data revealed that aHIF knockdown accelerated cell apoptosis under hypoxia and inhibited EOC tumorigenesis and tumor growth in vivo. Additionally, aHIF overexpression inhibited cell apoptosis and enhanced cell proliferation under hypoxia in EOC. Mechanistically, the dysregulation of certain key mitochondrial apoptosis pathway-related genes, including Bcl-2, Bax, Caspase-7, and Caspase-9, may partially explain aHIF-regulated EOC apoptosis and growth under hypoxia. Conclusion: These data provide the first convincing evidence that aHIF may inhibit EOC apoptosis and thereby promote tumor growth through activation of the mitochondrial apoptosis pathway under hypoxia. Our findings help clarify the role of lncRNA in hypoxia-induced EOC progression.

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