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1.
J Phys Chem Lett ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593475

RESUMO

Direct visualization of electronic and molecular events during chemical and biochemical reactions will offer unprecedented mechanistic insights. Ultrashort pulses produced by X-ray free electron lasers (XFELs) offer an unprecedented opportunity for direct observations of transient events as short-lived as tens of femtoseconds. This paper presents an in-depth analysis of the serial crystallographic datasets collected by Barends & Schlichting et al. (Science 350, 445, 2015) that probe the ligand photodissociation in carbonmonoxy myoglobin (MbCO), a long-serving hallmark for observing ultrafast dynamics in a biological system. This analysis reveals electron density changes that are caused directly by the formation of high-spin 3d atomic orbitals of the heme iron upon the CO departure and the dynamic behaviors of these newly formed orbitals in a time series within the first few picoseconds. The heme iron is found vibrating at a high frequency and developing a positional modulation that causes the iron to pop out of and recoil back into the heme plane in succession. These findings here provide long-awaited visual validations for previous works using ultrafast spectroscopy and molecular dynamics simulations. This analysis also extracts electron density variations largely in the solvent during the first period of a low frequency oscillation previously detected by coherence spectroscopy. This work demonstrates the power and importance of the analytical methods in detecting and isolating transient, often very weak signals of electronic changes arising from chemical reactions in proteins.

2.
Proc Natl Acad Sci U S A ; 116(40): 19973-19982, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31527275

RESUMO

Signal detection and integration by sensory proteins constitute the critical molecular events as living organisms respond to changes in a complex environment. Many sensory proteins adopt a modular architecture that integrates the perception of distinct chemical or physical signals and the generation of a biological response in the same protein molecule. Currently, how signal perception and integration are achieved in such a modular, often dimeric, framework remains elusive. Here, we report a dynamic crystallography study on the tandem sensor domains of a dual-sensor histidine kinase PPHK (phosphorylation-responsive photosensitive histidine kinase) that operates a molecular logic OR, by which the output kinase activity is modulated by a phosphorylation signal and a light signal. A joint analysis of ∼170 crystallographic datasets probing different signaling states shows remarkable dimer asymmetry as PPHK responds to the input signals and transitions from one state to the other. Supported by mutational data and structural analysis, these direct observations reveal the working mechanics of the molecular logic OR in PPHK, where the light-induced bending of a long signaling helix at the dimer interface is counteracted by the ligand-induced structural changes from a different sensor domain. We propose that the logic OR of PPHK, together with an upstream photoreceptor, implements a "long-pass" red light response distinct from those accomplished by classical phytochromes.

3.
Water Res ; 166: 115076, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31536889

RESUMO

Acidic rare earth element tailings (REEs) wastewater with high nitrogen and low COD is the most serious and yet unsolved environmental issue in the rare earth mining industry. The effective and cheap remediation of NH4+-N and NO3--N from the REEs wastewater is still a huge challenge. This harsh wastewater environment results in the difficulty for common microbes and microalgae to be survived. In this work, a novel highly tolerant co-flocculating microalgae (the combination of Scenedesmus sp. and Parachlorella sp.) was successfully isolated from the rare earth mine effluent through three-year cultivation. The removal efficiency of total inorganic nitrogen (TIN) by the co-flocculating microalgae cultivation was as high as 90.9%, which is 1.9 times than the average removal efficiency (47.9%) of previously-reported microalgae species in the wastewater with COD/N ratio ranging from 0 to 1. Thus, the residual concentrations of NH4+-N and TIN could reach the Emission Standards of Pollutants from Rare Earths Industry (GB 26451-2011). Along with the high N removal performance, other related characteristics of the co-flocculating microalgae were also revealed, such as high tolerance towards high NH4+-N and strong acid, rapid growth and sedimentation, and simultaneous removal of NH4+-N and NO3--N. These algae characteristics were ascribed to the specific co-flocculating community structure covered by extracellular polymeric substances.

4.
Nanotechnology ; 30(46): 464001, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422955

RESUMO

Memristors have been intensively studied in recent years as promising building blocks for next-generation nonvolatile memory, artificial neural networks and brain-inspired computing systems. However, most memristors cannot simultaneously function in extremely low and high temperatures, limiting their use for many harsh environment applications. Here, we demonstrate that the memristors based on high-Curie temperature ferroelectrics can resolve these issues. Excellent synaptic learning and memory functions can be achieved in BiFeO3 (BFO)-based ferroelectric memristors in an ultra-wide temperature range. Correlation between electronic transport and ferroelectric properties is established by the coincidence of resistance and ferroelectricity switch and the direct visualization of local current and domain distributions. The interfacial barrier modification by the reversal of ferroelectric polarization leads to a robust resistance switching behavior. Various synaptic functions including long-term potentiation/depression, consecutive potentiation/depression and spike-timing dependent plasticity have been realized in the BFO ferroelectric memristors over an extremely wide temperature range of -170 °C âˆ¼ 300 °C, which even can be extended to 500 °C due to the robust ferroelectricity of BFO at high temperatures. Our findings illustrate that the BFO ferroelectric memristors are promising candidates for ultra-wide temperature electronic synapse in extreme or harsh environments.

5.
Orthop Surg ; 11(4): 569-577, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31322836

RESUMO

OBJECTIVES: To investigate the knowledge and practices of Chinese doctors in the management of osteoporotic fractures after the Chinese osteoporotic fracture guidelines update and aseries of medical education in 2017. METHODS: This was a cross-sectional survey of doctors in 71 cities across Mainland China. Based on the 2017 Chinese guidelines for the diagnosis and treatment of osteoporotic fractures, a questionnaire was designed and pre-tested for reliability and validity. Doctors were surveyed with the questionnaire after scientific meetings during February 2017 to January 2018 through WeChat or conference digital platforms or in paper form. Descriptive statistics was used to analyze the responses to the questionnaire. RESULTS: Overall, 314 valid questionnaires were confirmed. Regarding diagnosis, 77% agreed that osteoporosis could be diagnosed once an osteoporotic fracture occurred; 83% believed that the bone mineral density criteria for osteoporosis diagnosis would be T ≤ -2.5 SD. For treatment, almost all (99.7%) agreed with anti-osteoporosis treatment being one of the basic principles of osteoporotic fracture treatment; 71.6% considered bisphosphonates as the most commonly used anti-osteoporosis drug; 97% believed that patients who have used anti-osteoporosis drugs should reassess osteoporosis after osteoporotic fractures instead of discontinue; 95% thought that the patients who did not use anti-osteoporosis medications before osteoporotic fracture should be treated with anti-osteoporosis drugs after fracture treatment as early as possible; 89% agreed that the standard use of bisphosphonates after osteoporotic fracture would not affect bone healing adversely; 59% believed the course of bisphosphonates treatment for osteoporosis would be 3-5 years, and 27% considered it to be 1-3 years. The patient follow-up rate was poor: 46% selected follow-up rate <30%; only 20% selected follow-up rate >50%. Only 31% of the hospitals had long-term management programs for osteoporotic fractures. CONCLUSIONS: Doctors generally adhered to the updated Chinese guidelines for osteoporotic fractures; frequent participation in medical education can help doctors to increase their awareness of osteoporosis as well as their acceptance and practice of the guidelines.

6.
Surg Endosc ; 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31240477

RESUMO

BACKGROUND: Standard treatment for nonampullary duodenal tumors has not yet been established. In case of tumors originated from the muscularis propria (MP) layer and adherent to the serosa layer, the lesions can not be completely removed by ESD. However, with the development of the endoscopic suture technique, endoscopic full-thickness resection (EFTR) of duodenal subepithelial lesions has become possible. METHODS: We retrospectively analyzed 32 patients with nonampullary duodenal subepithelial lesions who underwent EFTR between February 2012 and January 2017. The suturing method, complications that occurred during and after the operations, perioperative management, tumor characteristics, and pathological findings were analyzed in all patients. RESULTS: The complete resection rate was 100%; all patients successfully received EFTR except for one patient who required conversion to open surgery. Severe abdominal pain was observed after the operation in one patient who then received laparoscopic exploration, and the possibility of delayed perforation was considered. Another patient showed a decline in blood oxygen saturation (SO2) and was transferred to the intensive care unit (ICU) for further management. Delayed bleeding and fistula were not observed. All patients achieved complete remission. CONCLUSION: EFTR is a safe, minimally invasive treatment modality that ensures complete eradication of the duodenal subepithelial lesions.

7.
Adv Exp Med Biol ; 1135: 67-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098811

RESUMO

Cholesterol is a highly asymmetric lipid molecule. As an essential constituent of the cell membrane, cholesterol plays important structural and signaling roles in various biological processes. The first high-resolution crystal structure of a transmembrane protein in complex with cholesterol was a human ß2-adrenergic receptor structure deposited to the Protein Data Bank in 2007. Since then, the number of the cholesterol-bound crystal structures has grown considerably providing an invaluable resource for obtaining insights into the structural characteristics of cholesterol binding. In this work, we examine the spatial and orientation distributions of cholesterol relative to the protein framework in a collection of 73 crystal structures of membrane proteins. To characterize the cholesterol-protein interactions, we apply singular value decomposition to an array of interatomic distances, which allows us to systematically assess the flexibility and variability of cholesterols in transmembrane proteins. Together, this joint analysis reveals the common characteristics among the observed cholesterol structures, thereby offering important guidelines for prediction and modification of potential cholesterol binding sites in transmembrane proteins.


Assuntos
Colesterol/química , Proteínas de Membrana/química , Sítios de Ligação , Membrana Celular , Humanos , Ligação Proteica , Receptores Adrenérgicos beta 2/química
8.
Genome Res ; 29(5): 809-818, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940688

RESUMO

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

9.
Int J Mol Med ; 43(5): 2055-2063, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864739

RESUMO

Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of low­density lipoprotein receptor (LDLR) in a time­ and dose­dependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'­dioctadecyl­3,3,3',3'­tetramethyl­indocarbocyanine perchlorate­labeled LDL (DiI­LDL) uptake in the H2S­treated HepG2 cells. Furthermore, the phosphoinositide 3­kinase (PI3K)/protein kinase B (Akt)­sterol regulatory element binding proteins 2 (SREBP­2) signaling pathway was confirmed to be involved in H2S­regulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiI­LDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/Akt­SREBP­2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Pró-Proteína Convertase 9/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Células Hep G2 , Humanos , Modelos Biológicos , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Lancet ; 393(10173): 758-767, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712878

RESUMO

BACKGROUND: Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. METHODS: In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. FINDINGS: Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. INTERPRETATION: Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. FUNDING: Institute for Genomic Medicine (Columbia University Irving Medical Center).


Assuntos
Cariótipo Anormal/embriologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Aneuploidia , Variações do Número de Cópias de DNA/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Anormalidades Múltiplas/epidemiologia , Amniocentese , Amostra da Vilosidade Coriônica , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma/métodos
11.
Nanoscale ; 11(18): 8744-8751, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-30806411

RESUMO

Memristors have been extensively studied for synaptic simulation and neuromorphic computation. Instead of focusing on implementing specific synaptic learning rules by carefully engineering external programming parameters, researchers recently have paid more attention to taking advantage of the second-order memristor that is more analogous to biologic synapses and modulated not only by external inputs but also by internal mechanisms. However, experimental evidence is still scarce. Here, we explore a BiMnO3 memristor by applying simple spike forms. The filament evolution dynamics, including processes of forming and spontaneous decay, were directly observed by the conductive atomic force microscopy (c-AFM) technique. We propose that the unique conductance state of the BMO memristor is regulated by the oxygen vacancy (VO) dynamic process. We believe this primary result is helpful to improve understanding of the internal mechanisms of the second-order oxide memristor, which exhibits promising application in building selectors, memories and neuromorphic-computing systems.

12.
Int J Mol Med ; 43(3): 1321-1330, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664197

RESUMO

Fibroblast growth factor (FGF)­21, a member of the family of FGFs, exhibits protective effects against myocardial ischemia and ischemia/reperfusion injury; it is also an enhancer of autophagy. However, the mechanisms underlying the protective role of FGF­21 against cardiomyocyte hypoxia/reoxygenation (H/R) injury remain unclear. The present study aimed to investigate the effect of FGF­21 on H9c2 cardiomyocyte injury induced by H/R and the mechanism associated with changes in autophagy. Cultured H9c2 cardiomyocytes subjected to hypoxia were treated with a vehicle or FGF­21 during reoxygenation. The viability of H9c2 rat cardiomyocytes was measured using Cell Counting Kit­8 and trypan blue exclusion assays. The contents of creatine kinase (CK) and creatine kinase isoenzymes (CK­MB), cardiac troponin I (cTnT), cardiac troponin T (cTnI) and lactate dehydrogenase (LDH) in culture medium were detected with a CK, CK­MB, cTnT, cTnI and LDH assay kits. The protein levels were examined by western blot analysis. Autophagic flux was detected by Ad­mCherry­GFP­LC3B autophagy fluorescent adenovirus reagent. The results indicated that FGF­21 alleviated H/R­induced H9c2 myocardial cell injury and enhanced autophagic flux during H/R, and that this effect was antagonized by co­treatment with 3­methyladenine, an autophagy inhibitor. Furthermore, FGF­21 increased the expression levels of Beclin­1 and Vps34 proteins, but not of mechanistic target of rapamycin. These data indicate that FGF­21 treatment limited H/R injury in H9c2 cardiomyocytes by promoting autophagic flux through upregulation of the expression levels of Beclin­1 and Vps34 proteins.


Assuntos
Autofagia , Fatores de Crescimento de Fibroblastos/metabolismo , Hipóxia/metabolismo , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , Animais , Biomarcadores , Linhagem Celular , Sobrevivência Celular , Citoproteção , Fatores de Crescimento de Fibroblastos/farmacologia , Genes Reporter , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Transdução de Sinais
13.
Clin Chim Acta ; 491: 97-102, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30695687

RESUMO

Tissue factor pathway inhibitor (TFPI) reduces the development of atherosclerosis by regulating tissue factor (TF) mediated coagulation pathway. In this review, we focus on recent findings on the inhibitory effects of TFPI on endothelial cell activation, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory cell recruitment and extracellular matrix which are associated with the development of atherosclerosis. Meanwhile, we are also concerned about the impact of TFPI levels and genetic polymorphisms on clinical atherogenesis. This article aims to explain the mechanism in inhibiting the development of atherosclerosis and clinical effects of TFPI, and provide new ideas for the clinical researches and mechanism studies of atherothrombosis.


Assuntos
Aterosclerose/metabolismo , Lipoproteínas/metabolismo , Aterosclerose/patologia , Humanos , Lipoproteínas/química
14.
Clin Chim Acta ; 490: 34-38, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30571947

RESUMO

Endothelial cells are the main components of the heart, blood vessels, and lymphatic vessels, which play an important role in regulating the physiological functions of the cardiovascular system. Endothelial dysfunction is involved in a variety of acute and chronic cardiovascular diseases. As a special type of epithelial-mesenchymal transition (EMT), endothelium to mesenchymal transition (EndMT) regulates the transformation of endothelial cells into mesenchymal cells accompanied by changes in the expression of various transcription factors and cytokines, which is closely related to vascular endothelial injury, vascular remodeling, myocardial fibrosis and valvar disease. Endothelial cells undergoing EndMT lose their endothelial characteristics and undergo a transition toward a more mesenchymal-like phenotype. However, the molecular mechanism of EndMT remains unclear. EndMT, as a type of endothelial dysfunction, can cause vascular remodeling which is a major determinant of atherosclerotic luminal area. Therefore, exploring the important signaling pathways in the process of EndMT may provide novel therapeutic strategies for treating atherosclerotic diseases.


Assuntos
Aterosclerose/patologia , Transição Epitelial-Mesenquimal , Remodelação Vascular , Aterosclerose/complicações , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Humanos , Neovascularização Patológica/complicações , Fator de Crescimento Transformador beta/metabolismo
15.
N Engl J Med ; 380(2): 142-151, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30586318

RESUMO

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).


Assuntos
Exoma , Predisposição Genética para Doença , Mutação , Insuficiência Renal Crônica/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Estudos de Coortes , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etnologia , Adulto Jovem
16.
Medicine (Baltimore) ; 97(48): e13411, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508943

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer-related deaths worldwide. Early diagnosis of HCC remains a great challenge in clinic. Novel and effective biomarkers are in urgent need in early diagnosis of HCC.Serum levels of neurotrophin-receptor-interacting melanoma antigen-encoding gene homolog (NRAGE) were measured for 107 patients with HCC, 98 patients with benign liver diseases, and 89 healthy controls using quantitative real-time polymerase chain reaction. Receiver operating characteristic curve was applied to evaluate the diagnostic capacity of serum NRAGE in HCC.NRAGE expression was significantly higher in patients with HCC than in controls (all, P < .05). Moreover, its expression was tightly correlated with TNM stage (P = .004). NRAGE could distinguish patients with HCC from healthy controls with the area under the curve (AUC) of 0.874, yielding a sensitivity of 81.3% and a specificity of 78.7%. Additionally, in differentiation between benign liver diseases and HCC, the AUC value of NRAGE was 0.726, with a sensitivity of 63.6% and a specificity of 73.5%. Meanwhile, alpha-fetoprotein also could distinguish patients with HCC from benign liver disease cases, with an AUC of 0.677, a sensitivity of 64.4%, and a specificity of 60.2%.NRAGE could be a potential biomarker for HCC early diagnosis.

17.
Gastroenterol Res Pract ; 2018: 1275486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510570

RESUMO

Background: Baicalin (BA) has been shown to have anti-inflammatory and antioxidant activity. Zinc is a nutrient element. Objective: This study is aimed at investigating the antichronic gastric ulcer activity of Zn-Baicalin complex (BA-Zn) and its related mechanisms in an acetic acid-induced gastric ulcer rat model. Results: The severely ulcerated gastric mucosa of model rats had lower GSH-Px (52.21 ± 7.13) and SOD (7.03 ± 0.10) activity, and higher MDA (2.39 ± 0.03) content compared to sham rats. BA-Zn reduced the gastric ulcer index in a dose-dependent manner, significantly increased SOD activity and GSH-Px level, and reduced the MDA content and IL-8 and TNF-α levels in the gastric mucosa. BA-Zn (6.5 and 13 mg/kg) exerted a greater antiulcerogenic effect than both BA and zinc-gluconate, leading to a reduced ulcer index (18.43 ± 1.11, 15.00 ± 1.44), decreased MDA content (1.33 ± 0.07, 0.63 ± 0.01), and increased SOD activity (17.62 ± 0.11, 20.12 ± 0.32) and GSH-Px levels (102.12 ± 9.11, 120.25 ± 9.07). In addition, our results from Western blot suggested that BA-Zn (6.5 and 13 mg/kg) has a greater antiulcerogenic effect than both BA and zinc-gluconate. Conclusion: The BA-Zn complex possesses greater antichronic gastric ulcer properties compared to BA and zinc-gluconate due to its ability of oxidation resistance and anti-inflammatory effects.

18.
Phys Chem Chem Phys ; 20(46): 29051-29060, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30427339

RESUMO

We present results of combined experimental photoelectron spectroscopy and theoretical modeling studies of solvated dicarboxylate species (-O2C(CH2)2CO2-) in complex with Na+ and K+ metal cations. These ternary clusters serve as simple models for the investigation of aqueous ion/solute specific effects that play an important role in biological systems. The experimental characterization of these systems was performed in the presence of up to six solvating waters. In both Na+ and K+ cases, we observe the presence of one major broad band that gradually shifts to higher electron binding energy (EBE) with an increasing number of waters. In the Na+ case further detailed analysis of experimental spectra was performed using ab initio calculations. In particular, we have identified the structures of the lowest energy clusters whose EBE values match well the major band in the experimental spectra. Our results show that evolution of an aqueous solvation shell emphasizes the coordination of the negatively charged carboxylate groups accompanied by simultaneous interaction with metal cations. Calculations also indicate that in the solvation range investigated experimentally (up to 6 waters), Na+ retains direct contact with the dicarboxylate species, i.e. a contact ion-pair (CIP) complex. Preliminary modeling studies show evidence of an alternative solvent separated ion-pair complex once the solvation range approaches 8 waters, however its energy still remains above that of (∼7-8 kcal/ mol-1) the CIP complex. At a higher number of waters (n = 3 for Na+ and n = 5 for K+), the experimental spectra also show the development of a weak low energy band. Its origin cannot be precisely identified. Our calculations in the Na+ case point out the existence of a quaternary complex consisting of Na+, H2O, OH- and a singly protonated dicarboxylate anion (HO2C(CH)2CO2-). Such a complex appears to be stabilized in the solvation range corresponding to the appearance of the low EBE band and does match its peak, even though the energy of such a complex is fairly high compared to the ternary structure.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30450611

RESUMO

RATIONALE: In situ trace element analysis of melt inclusions by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) provides important geochemistry information. However, the precision and accuracy of this technique are affected by many factors, such as matrix effect, laser conditions, and calibration method. In addition, many previous LA-ICP-MS studies ablated entire melt inclusions along with their host minerals and obtained trace element composition by deconvoluting the mixed ablation signal, which may induce much uncertainty. METHODS: A 193 nm ArF laser ablation system combined with inductively coupled plasma-sector field-mass spectrometry (ICP-SF-MS) was used to investigate matrix effect, laser conditions, choice of external calibration standards, and data reduction strategy for in situ analysis of 36 major and trace elements in six common silicate reference glasses. The validity of the protocol present here was demonstrated by measuring trace elements in olivine-hosted melt inclusions. Instead of ablating entire melt inclusions along with their host minerals, melt inclusions were polished to the surface to avoid laser ablating the mineral host. RESULTS: The calibration lines calculated from the calibration standards should cross the coordinate origin, especially for low-concentration elements (<10 ppm). As the laser crater size increased from 17 to 33 µm, the precision was improved from <20% to <8% (2RSD), and accuracy was improved from ±20% to better than ±10%. Most measured trace elements in Dali melt inclusions are consistent with those in their host rocks. For mobile elements (Ba, Sr, Pb), melt inclusions display much smaller variations than their host rocks. CONCLUSIONS: A simple but accurate approach for in situ analysis of trace elements in melt inclusions by LA-ICP-SF-MS has been established, which should greatly facilitate the wider application of in situ trace element geochemistry to melt inclusion studies.

20.
Ann Intern Med ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30476936

RESUMO

Background: Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists. Objective: To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Design: Secondary analysis of genetic data. Setting: A tertiary care academic medical center. Patients: A convenience sample of exome sequence data from 7974 self-declared healthy adults. Measurements: Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders. Results: Of all participants, 23.3% carried a candidate pathogenic variant, the majority of which were attributable to previously reported variants that have implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned. Limitation: Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses. Conclusion: Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.

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