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1.
J Affect Disord ; 260: 281-286, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521864

RESUMO

BACKGROUND: White matter abnormalities have been implicated in mental disorders including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ); however, the shared and distinct white matter integrity across mental disorders is still unclear. METHODS: A total of 290 participants (MDD = 85, BD = 42, SZ = 68, and healthy controls = 95) were included in the present study. Tract-based spatial statistics were performed to measure fractional anisotropy (FA) and characterize shared and distinguishing white matter changes across mental disorders. RESULTS: We found that decreased FA converged across MDD, BD and SZ in the body and genu of the corpus callosum, bilateral anterior and posterior corona radiata, and right superior corona radiata. By contrast, diagnosis-specific effect was only found in MDD in the anterior portion of anterior corona radiata. LIMITATIONS: The small and imbalanced sample size, and possible confounding effects of medication. CONCLUSIONS: Our findings suggest that abnormally reduced white matter integrity in the interhemispheric and thalamocortical circuit could be consistently involved in the pathogenesis of MDD, BD and SZ.

2.
Oncol Rep ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31661146

RESUMO

Long non­coding RNAs (lncRNAs) are considered to be important regulators in breast cancer. In the present study, the potential mechanisms and functional roles of lncRNA PSMG3­antisense (AS)1 were investigated in vivo and in vitro. The relative expression levels of lncRNA PSMG3­AS1 and microRNA (miR)­143­3p were determined using reverse­transcription quantitative PCR. The protein expression levels of collagen type 1 alpha 1 (COL1A1) and proliferating cell nuclear antigen (PCNA) were obtained using western blot analysis. Bioinformatics analysis was used to identify the relationship between PSMG3­AS1, miR­143­3p and COL1A1. Colony forming and Cell Counting Kit­8 assays were used to detect cell proliferation. Transwell and wound­healing assays were used to determine cell migration. The results of the present study demonstrated that PSMG3­AS1 expression was increased in breast cancer tumor tissues and cell lines, and that of miR­143­3p was decreased. Knockdown of PSMG3­AS1 increased the level of miR­143­3p expression, which led to the mitigation of proliferation and migration capacity in breast carcinoma cells. Additionally, PSMG3­AS1 knockdown was demonstrated to reduce the mRNA and protein expression levels of COL1A1. miR­143­3p mimic transfection reduced proliferation and migration in MDA­MB­231 and MCF­7 cell lines. Furthermore, miR­143­3p inhibition significantly increased the proliferation and migration of breast cancer cells compared with the negative control group. The mRNA and protein expression levels of PCNA were reduced in the MCF­7 cell line when transfected with miR­143­3p mimics and si­PSMG3­AS1. However, PCNA expression was increased in cells transfected with a miR­143­3p inhibitor. In conclusion, the results of the present study identified a novel lncRNA PSMG3­AS1, which serves as a sponge for miR­143­3p in the pathogenesis of breast cancer. PSMG3­AS1 may be used as a potential therapeutic target gene in breast cancer treatment.

3.
Sensors (Basel) ; 19(18)2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31500222

RESUMO

The development of new bioelectronic platforms for direct interactions with oral fluid could open up significant opportunities for healthcare monitoring. A tongue depressor is a widely used medical tool that is inserted into the mouth, where it comes into close contact with saliva. Glucose is a typical salivary biomarker. Herein, we report-for the first time-a tongue depressor-based biosensor for the detection of glucose in both phosphate buffer and real human saliva. Carbon nanotubes (CNTs) are attractive electronic materials, with excellent electrochemical properties. The sensor is constructed by printing CNTs and silver/silver chloride (Ag/AgCl) to form three electrodes in an electrochemical cell: Working, reference, and counter electrodes. The enzyme glucose oxidase (GOD) is immobilized on the working electrode. The glucose detection performance of the sensor is excellent, with a detection range of 7.3 µM to 6 mM. The glucose detection time is about 3 min. The discretion between healthy people's and simulated diabetic patients' salivary samples is clear and easy to tell. We anticipate that the biosensor could open up new opportunities for the monitoring of salivary biomarkers and advance healthcare applications.

4.
EBioMedicine ; 47: 543-552, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420302

RESUMO

BACKGROUND: Current fMRI-based classification approaches mostly use functional connectivity or spatial maps as input, instead of exploring the dynamic time courses directly, which does not leverage the full temporal information. METHODS: Motivated by the ability of recurrent neural networks (RNN) in capturing dynamic information of time sequences, we propose a multi-scale RNN model, which enables classification between 558 schizophrenia and 542 healthy controls by using time courses of fMRI independent components (ICs) directly. To increase interpretability, we also propose a leave-one-IC-out looping strategy for estimating the top contributing ICs. FINDINGS: Accuracies of 83·2% and 80·2% were obtained respectively for the multi-site pooling and leave-one-site-out transfer classification. Subsequently, dorsal striatum and cerebellum components contribute the top two group-discriminative time courses, which is true even when adopting different brain atlases to extract time series. INTERPRETATION: This is the first attempt to apply a multi-scale RNN model directly on fMRI time courses for classification of mental disorders, and shows the potential for multi-scale RNN-based neuroimaging classifications. FUND: Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, National Institutes of Health Grants, National Science Foundation.

5.
Neurobiol Learn Mem ; 164: 107047, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325495

RESUMO

Reactivation renders consolidated memory labile again, and the ensuing temporary reconsolidation process is highly susceptible to mnemonic modification. Here, we show that memories in such an unstable state could be influenced by sheer behavioral means, bypassing the need for pharmacological intervention. Across several experiments using a "face-location association" paradigm in which participants experienced a "Learning - New-learning - Final-test" procedure, we demonstrate that reactivated memory traces were hampered when the new learning was strategically administered at between 0-min and 20-min delay. Using fMRI, we further advance our theoretical understanding that this lability can be mechanistically explained by the differential activation in the hippocampal-amygdala memory system implicated by the post-activation new-learning whereas the mnemonic intrusion caused by newly learned memories is efficaciously reconciled by the left inferior frontal gyrus.

6.
Clin Chim Acta ; 497: 67-75, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31276634

RESUMO

BACKGROUND: Asymptomatic hypercholanemia of pregnancy (AHP) is a controversial hypercholanemia, which is difficult to distinguish from intrahepatic cholestasis of pregnancy (ICP). Our aim is to elucidate the characteristics of urinary bile acid (BA) profiling of women with AHP and to find potential biomarkers for the diagnosis and differential diagnosis of AHP. METHODS: We developed a pseudo-targeted approach to perform metabolomics analysis of bile acids (BAs) using ultra-high performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Urinary BAs profiles were compared among AHP women (n = 20), ICP patients (n = 33) and normal controls (n = 35). RESULTS: The profiling of urinary BAs was significantly different among the AHP, ICP and control groups. Compared to the control group, the AHP group had higher levels of four possible sulfated BAs and trihydroxy BAs, including the species of muricholic acid (MCA), cholic acid (CA) and six possible BAs, whereas, 20 possible sulfated BAs, taurochenodeoxycholic acid (TCDCA), tetrahydrocannabinolic acid (THCA), and seven possible BAs were significantly lower in the AHP group than those in the ICP group. Based on the receiver operating characteristic (ROC) analysis, glycocholic acid (GCA) combined with T-ω-MCA were found to be the potential combination biomarker for the diagnosis (area under the curve was 0.960) of AHP, and mono-S, Gtri-S-2 combined with TLCA-S were found to be the potential combination biomarker for the differential diagnosis (area under the curve was 0.990) of AHP and ICP. CONCLUSIONS: The metabolisms of urinary Bas were altered in the AHP group compared with the ICP group and the control group. Urinary BA profiling analysis can serve as an effective tool for the diagnosis of AHP and the differential diagnosis of AHP and ICP.

7.
Brain Imaging Behav ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278651

RESUMO

Intelligence is a socially and scientifically interesting topic because of its prominence in human behavior, yet there is little clarity on how the neuroimaging and neurobiological correlates of intelligence differ between males and females, with most investigations limited to using either mass-univariate techniques or a single neuroimaging modality. Here we employed connectome-based predictive modeling (CPM) to predict the intelligence quotient (IQ) scores for 166 males and 160 females separately, using resting-state functional connectivity, grey matter cortical thickness or both. The identified multimodal, IQ-predictive imaging features were then compared between genders. CPM showed high out-of-sample prediction accuracy (r > 0.34), and integrating both functional and structural features further improved prediction accuracy by capturing complementary information (r = 0.45). Male IQ demonstrated higher correlations with cortical thickness in the left inferior parietal lobule, and with functional connectivity in left parahippocampus and default mode network, regions previously implicated in spatial cognition and logical thinking. In contrast, female IQ was more correlated with cortical thickness in the right inferior parietal lobule, and with functional connectivity in putamen and cerebellar networks, regions previously implicated in verbal learning and item memory. Results suggest that the intelligence generation of males and females may rely on opposite cerebral lateralized key brain regions and distinct functional networks consistent with their respective superiority in cognitive domains. Promisingly, understanding the neural basis of gender differences underlying intelligence may potentially lead to optimized personal cognitive developmental programs and facilitate advancements in unbiased educational test design.

8.
Open Biol ; 9(7): 180227, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31337279

RESUMO

Non-small cell lung cancer (NSCLC) is considered to be the primary cause of cancer-related mortalities worldwide. Paclitaxel (PTX), either as a monotherapy or in combination with other drugs, is an alternative therapy for advanced NSCLC. However, cancer cell resistance against PTX represents a major clinical problem. This study aimed to investigate the role and underlying mechanism of miR-4262 in PTX-resistant NSCLC. The levels of miR-4262 were analysed by quantitative reverse transcription polymerase chain reaction. A luciferase reporter assay and bioinformatics were used to explore the potential target gene of miR-4262. Regulation of miR-4262 and PTEN expressions in NSCLC was conducted by transfection. PTX-resistant A549 and H1299 cells were established by stepwise screening through increasing the PTX concentration in the cultures. In vivo, tumorigenesis experiments were used to explore the effects of miR-4262 and PTX. Cell proliferation, apoptosis and cell migration were detected using a CCK-8 assay, flow cytometry and Transwell migration assay, respectively. PI3 K/Akt pathway-related proteins were detected by western blot. miR-4262 expression was significantly upregulated in NSCLC tissues and cell lines, and miR-4262 targeted PTEN. In addition, miR-4262 induced PTX chemoresistance by promoting survival and migration in A549/PTX and H1299/PTX cells. Moreover, miR-4262 expression and PI3 K/Akt signalling pathway-related proteins were upregulated and PTEN was downregulated in A549/PTX and H1299/PTX. Our results indicate that miR-4262 enhances PTX resistance in NSCLC cells through targeting PTEN and activating the PI3 K/Akt signalling pathway. The inhibition of miR-4262 expression might be an improved treatment to overcome PTX resistance in NSCLC.

9.
J Alzheimers Dis ; 70(3): 747-756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256131

RESUMO

BACKGROUND: The Mild Behavioral Impairment Checklist (MBI-C), a screening scale for neuropsychiatric symptom evaluation, facilitates Alzheimer's disease (AD) screening. However, its validity and reliability for use as an AD screening tool have not been determined. OBJECTIVE: To develop an AD screening scale suitable for the Chinese population. METHODS: The MBI-C was translated into Chinese and back-translated with the original author's consent. Forty-six AD patients, attending the Xuanwu hospital memory clinic, and 50 sex- and education-matched controls from the community underwent a full neuropsychological evaluation, including MBI-C assessment. Among them, 15 AD patients were evaluated repeatedly, and eight were evaluated simultaneously by two different clinicians, to assess MBI-C reliability. RESULTS: The MBI-C demonstrated good internal consistency reliability, test-retest reliability, and inter-rater reliability. Its optimal cutoff point was 6/7 for identifying AD dementia, with a sensitivity of 86.96% and specificity of 86.00%, and its detection rate for moderate-severe AD dementia was higher than that of the Neuropsychiatric Inventory Questionnaire (NPI-Q). Pearson's correlation coefficients ranged from 0.702 to 0.831, indicating content validity. Seven factors were extracted during principal component analysis, with a cumulative contribution of 70.55%. Moreover, the Pearson's correlation coefficient was 0.758, indicating its criterion validity. The MBI-C could also distinguish AD dementia severity. MBI-C scores were significantly negatively correlated with MMSE and MoCA scores, and positively correlated with ADL scores. CONCLUSION: This study showed that the Chinese version of MBI-C has high reliability and validity, and could replace the NPI-Q for AD dementia screening in the Chinese population.

10.
Cancer Lett ; 460: 65-74, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31233836

RESUMO

Pds5b (precocious dissociation of sisters 5B) is involved in both tumorigenesis and cancer progression; however, the functions and molecular mechanisms of Pds5b in pancreatic cancer (PC) are unknown. Several approaches were conducted to investigate the molecular basis of Pds5b-related PC progression, including transfection, MTT, FACS, western blotting, wound healing assay, transwell chamber invasion assay, and immunohistochemical methods. Pds5b overexpression inhibited cell growth and induced apoptosis, whereas the inhibition of Pds5b promoted growth of PC cells. Moreover, Pds5b overexpression inhibited cell migration and invasion, while the downregulation of Pds5b enhanced cell motility. Furthermore, reduced Pds5b expression was associated with survival in PC patients. Mechanistically, Pds5b positively regulated the expression of Ptch2 to influence the Sonic hedgehog signaling pathway. Consistently, Ptch2 downregulation enhanced cell growth, migration, and invasion, while inhibiting cell apoptosis. Notably, the downregulation of Ptch2 abolished Pds5b-mediated anti-tumor activity in PC cells. Strikingly, Pds5b expression was positively associated with levels of Ptch2 in PC patient samples, suggesting that the Pds5b/Ptch2 axis regulates cell proliferation and invasion in PC cells. Our findings indicate that targeting Pds5b and Ptch2 may represent a novel therapeutic approach for PC.

11.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117168, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31226612

RESUMO

Barbituric acid derivatives with typical aggregation induced emission (AIE) are reported. Their emission wavelengths varied with water fraction of their solution. UV-visible absorption spectroscopy and theoretical calculations revealed the intramolecular charge transfer (ICT) possibility from donor to acceptor and the mechanism was confirmed as a restriction of intramolecular motion (RIM). The AIE properties were affected by the different substituents on barbituric acid. When the molecular volume increased, the AIE effect decreased. Fluorescent quenching mechanism was applied to detect nitroaromatic explosives. For 2,4,6-trinitrophenol (PA), one of the derivatives 5-(4-diphenylamino styrene)-1,3-diphenyl-barbituric acid in THF/H2O mixture (1:9, v/v), showed amplified fluorescence quenching with a maximum Stern-Volmer quenching constant of 4.1 × 104 M-1. The solid phase paper test based on 5-(4-diphenylamino styrene)-1,3-diphenyl-barbituric acid also showed a superior sensitivity toward PA both in vapor and solution.

12.
Anal Bioanal Chem ; 411(21): 5499-5507, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179529

RESUMO

Anti-Müllerian hormone (AMH) is a biomarker for the assessment of female fertility. The accurate measurement of the concentration of AMH is relevant for the success of assisted reproductive therapies and diagnosis of clinical cases. In this study, we show that cytokines such as fetal liver tyrosine kinase 3 ligand (Flt3L), CC subtype chemokine ligand 20 (CCL20), granulocyte-macrophage colony-stimulating factor (GM-CSF), and ß2-microglobulin (ß2M) significantly enhance the immune response against AMH. Two anti-AMH monoclonal antibodies (mAbs) with high affinity were selected by biolayer interferometry (BLI) technology for application in a fully automated magnetic chemiluminescence immunoassay (CLIA). This robust and rapid assay can efficiently detect AMH in the range of 0.125~20 ng mL-1 with a detection limit of 0.099 ng mL-1. This immunoassay showed high specificity with no cross-reaction with structurally related proteins and some of the other members of the TGF-ß super family, such as inhibin A, activin A, follicle-stimulating hormone, and luteinizing hormone. The average recovery rates of three different batches were 100.19%, 102.72%, and 103.59%, respectively, with coefficients of variation of less than 12%. The developed assay was applied in the detection of AMH in 69 serum samples from randomly selected patients. Our data showed a high correlation with those obtained using commercially available ELISA kits (correlation coefficient, 0.9831). Hence, we suggest that this immunoassay could find application in the development of POCT for the diagnosis of AMH in clinical samples. Graphical abstract.


Assuntos
Hormônio Antimülleriano/metabolismo , Imunoensaio/métodos , Interferometria/métodos , Hormônio Antimülleriano/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/imunologia , Calibragem , Citocinas/metabolismo , Feminino , Humanos
13.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
14.
Hepatology ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095752

RESUMO

Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy-induced liver pathogenesis and tumorigenesis was investigated by using liver-specific autophagy related 5 knockout (L-ATG5 KO) mice, L-ATG5/mTOR, and L-ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L-ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L-ATG5 KO mice. Moreover, more than 50% of L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L-ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L-ATG5/mTOR DKO and L-ATG5/Raptor DKO had developed liver tumors. Mechanistically, L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45-related factor 2 activation but had increased Akt activation compared with L-ATG5 KO mice. Conclusion: Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.

15.
Int J Nanomedicine ; 14: 3027-3041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118620

RESUMO

Background: In the discovery of DNA intercalators, ß-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-ß-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity. Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models. Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 µmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice. Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral ß-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.


Assuntos
Carbolinas/farmacologia , Nanopartículas/química , Neoplasias/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Creatinina/sangue , DNA/metabolismo , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura
16.
BMC Bioinformatics ; 20(1): 219, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039742

RESUMO

BACKGROUND: Data from genome-wide association studies (GWASs) have been used to estimate the heritability of human complex traits in recent years. Existing methods are based on the linear mixed model, with the assumption that the genetic effects are random variables, which is opposite to the fixed effect assumption embedded in the framework of quantitative genetics theory. Moreover, heritability estimators provided by existing methods may have large standard errors, which calls for the development of reliable and accurate methods to estimate heritability. RESULTS: In this paper, we first investigate the influences of the fixed and random effect assumption on heritability estimation, and prove that these two assumptions are equivalent under mild conditions in the theoretical aspect. Second, we propose a two-stage strategy by first performing sparse regularization via cross-validated elastic net, and then applying variance estimation methods to construct reliable heritability estimations. Results on both simulated data and real data show that our strategy achieves a considerable reduction in the standard error while reserving the accuracy. CONCLUSIONS: The proposed strategy allows for a reliable and accurate heritability estimation using GWAS data. It shows the promising future that reliable estimations can still be obtained with even a relatively restricted sample size, and should be especially useful for large-scale heritability analyses in the genomics era.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Modelos Genéticos , Humanos
17.
Sensors (Basel) ; 19(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137654

RESUMO

An underdetermined direction of arrival (DOA) estimation method of wideband linear frequency modulated (LFM) signals is proposed without grid mismatch. According to the concentration property of LFM signal in the fractional Fourier (FRF) domain, the received sparse model of wideband signals with time-variant steering vector is firstly derived based on a coprime array. Afterwards, by interpolating virtual sensors, a virtual extended uniform linear array (ULA) is constructed with more degrees of freedom, and its covariance matrix in the FRF domain is recovered by employing sparse matrix reconstruction. Meanwhile, in order to avoid the grid mismatch problem, the modified atomic norm minimization is used to retrieve the covariance matrix with the consecutive basis. Different from the existing methods that approximately assume the frequency and the steering vector of the wideband signals are time-invariant in every narrowband frequency bin, the proposed method not only can directly solve more DOAs of LFM signals than the number of physical sensors with time-variant frequency and steering vector, but also obtain higher resolution and more accurate DOA estimation performance by the gridless sparse reconstruction. Simulation results demonstrate the effectiveness of the proposed method.

18.
J Am Chem Soc ; 141(20): 8372-8380, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31060356

RESUMO

Structurally complex and bioactive ent-kaurane diterpenoids have well-characterized biological functions and have drawn widespread attention from chemists for many decades. However, construction of highly oxidized forms of such diterpenoids still presents considerable challenges to synthetic chemists. Herein, we report the first total syntheses of C19 oxygenated spiro-lactone ent-kauranoids, including longirabdiol, longirabdolactone, and effusin. A concise synthesis of the common intermediate used for all three syntheses was enabled via three free-radical-based reactions: (1) a newly devised tandem decarboxylative cyclization/alkenylation sequence that forges the cis-19, 6-lactone concomitantly with vicinal alkenylation, (2) a Ni-catalyzed decarboxylative Giese reaction that constructs C10 quaternary center stereoselectively, and (3) a vinyl radical cyclization that generates a rigid bicyclo[3.2.1]octane. A series of late-stage oxidations from the common intermediate then provided each of the natural products in turn. Further biological evaluation of these synthetic natural products reveals broad anticancer activities.

19.
J Pharm Biomed Anal ; 173: 176-182, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31146173

RESUMO

Gansui-Gancao is one of the "eighteen incompatible herb pairs" which was recorded 2000 years ago according to TCM (Traditional Chinese Medicine) theory for their toxicity when using together. Nevertheless, Gansuibanxia decoction contained the herb pair have satisfactory effect on the treatment of cancerous ascites, pericardial effusion, etc. The present study aimed to investigate the mechanism of the incompatibility of Gansui-Gancao and the compatibility of Gansuibanxia decoction using UHPLC-FT-ICR-MS in a metabonomic perspective. Rats were divided into four groups administrated with different herb combination extracts for successive 14 days. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to plot the metabolic state and screen the potential biomarkers in plasma. A total of 20 biomarkers contributed to the separation of Gansui-Gancao group and control group were tentatively identified mainly involved in 7 metabolic pathways related to hepatotoxicity and nephrotoxicity. The contents of these biomarkers were adjusted to normal levels in Gansuibanxia decoction group. Thus, the results of our study reveled the mechanism of the incompatibility of Gansui-Gancao and the compatibility of Gansuibanxia decoction in a metabonomic perspective and it's valuable for better understanding the "eighteen incompatible madicaments" of TCM theory.

20.
J Chem Phys ; 150(14): 144702, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-30981268

RESUMO

The atomistic stress state at a metal grain boundary is an intrinsic attribute which affects many physical and mechanical properties of the metal. While the virial stress is an accepted measure of the atomistic stress in molecular dynamics simulations, an equivalent definition is not well-established for quantum-mechanical density functional theory (DFT) calculations. Here, we introduce a numerical technique, termed the sequential atom removal (SAR) approach, to reconstruct the atomic stresses near a symmetrical-tilt Σ5(310)[001] Cu grain boundary. In the SAR approach, individual atoms near the boundary are sequentially removed to compute the pair (reaction) force between atoms, while correcting for changes to the local electron density caused by atom removal. We show that this SAR approach accurately reproduces the spatially-varying virial stresses at a grain boundary governed by an embedded atom method potential. The SAR approach is subsequently used to extract the atomistic stresses of the grain boundary from DFT calculations, from which we reconstruct a continuum-equivalent grain boundary traction distribution as a quantitative descriptor of the grain boundary atomic structure.

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