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Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light years1. The nature of their progenitors and their emission mechanism remain open astrophysical questions2. Here we report the detection of the multicomponent FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components, with a significance of 6.5σ. The long (roughly 3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere3,4, as opposed to emission regions located further away from the star, as predicted by some models5.
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In a recent issue of Molecular Cell, Boehm et al. (2018), Blazquez et al. (2018), and Gonatopoulos-Pournatzis et al. (2018) uncover novel mechanisms by which the cell regulates splicing of cryptic splice sites and microexons.
Assuntos
Sítios de Splice de RNA , Transcriptoma , Núcleo Celular , Éxons , Splicing de RNARESUMO
Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.
Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Criança , Humanos , Animais , Feminino , Transtorno do Espectro Autista/etiologia , Cromatina/genética , Processamento Alternativo/genética , Ácido Valproico/efeitos adversos , RNA Mensageiro/metabolismo , Modelos Animais de DoençasRESUMO
Methionine is an essential amino acid critical for cell growth and survival. Preclinical evidence suggests a methionine restricted diet (MRD) sensitizes cancer to radiation therapy (RT), without significant adverse effects. However, this has never been evaluated in humans. The purpose of this pilot study was to evaluate the safety and feasibility of concurrent MRD with standard-of-care definitive RT in adults with any non-skin cancer malignancy. The MRD extended from 2 wk before RT initiation, through 2 wk beyond RT completion. The primary endpoint of safety was assessed as rate of grade 3 or higher acute and late toxicities. Feasibility was assessed with quantitative plasma amino acid panel every 2 wk during the MRD (target plasma methionine 13 µM). Nine patients were accrued over a two-year period, with five able to complete the treatment course. The trial was closed due to slow accrual and subjects' difficulty maintaining the diet. No grade 3 or higher adverse events were observed. Subjects' average methionine level was 18.8 µM during treatment, with average nadir 16.8 µM. These findings suggest the safety of concurrent MRD with RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients.
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Metionina , Humanos , Metionina/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Projetos Piloto , Idoso , Adulto , Neoplasias/radioterapia , Neoplasias/dietoterapia , DietaRESUMO
A recent crystal structure of a ribosome complex undergoing partial translocation in the absence of elongation factor EF-G showed disruption of codon-anticodon pairing and slippage of the reading frame by -1, directly implicating EF-G in preservation of the translational reading frame. Among mutations identified in a random screen for dominant-lethal mutations of EF-G were a cluster of six that map to the tip of domain IV, which has been shown to contact the codon-anticodon duplex in trapped translocation intermediates. In vitro synthesis of a full-length protein using these mutant EF-Gs revealed dramatically increased -1 frameshifting, providing new evidence for a role for domain IV of EF-G in maintaining the reading frame. These mutations also caused decreased rates of mRNA translocation and rotational movement of the head and body domains of the 30S ribosomal subunit during translocation. Our results are in general agreement with recent findings from Rodnina and coworkers based on in vitro translation of an oligopeptide using EF-Gs containing mutations at two positions in domain IV, who found an inverse correlation between the degree of frameshifting and rates of translocation. Four of our six mutations are substitutions at positions that interact with the translocating tRNA, in each case contacting the RNA backbone of the anticodon loop. We suggest that EF-G helps to preserve the translational reading frame by preventing uncoupled movement of the tRNA through these contacts; a further possibility is that these interactions may stabilize a conformation of the anticodon that favors base-pairing with its codon.
Assuntos
Escherichia coli/genética , Mudança da Fase de Leitura do Gene Ribossômico , Mutação , Elongação Traducional da Cadeia Peptídica , Fator G para Elongação de Peptídeos/genética , Ribossomos/genética , Anticódon/química , Anticódon/metabolismo , Sítios de Ligação , Códon/química , Códon/metabolismo , Escherichia coli/metabolismo , Histidina/genética , Histidina/metabolismo , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Fator G para Elongação de Peptídeos/química , Fator G para Elongação de Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , RNA Mensageiro , RNA de Transferência , Fases de Leitura , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Ribossomos/metabolismoRESUMO
BACKGROUND AND AIMS: Previous recommendations suggested living donor liver transplantation (LDLT) should not be considered for patients with Model for End-Stage Liver Disease (MELD) > 25 and hepatorenal syndrome (HRS). APPROACH AND RESULTS: Patients who were listed with MELD > 25 from 2008 to 2017 were analyzed with intention-to-treat (ITT) basis retrospectively. Patients who had a potential live donor were analyzed as ITT-LDLT, whereas those who had none belonged to ITT-deceased donor liver transplantation (DDLT) group. ITT-overall survival (OS) was analyzed from the time of listing. Three hundred twenty-five patients were listed (ITT-LDLT n = 212, ITT-DDLT n = 113). The risk of delist/death was lower in the ITT-LDLT group (43.4% vs. 19.8%, P < 0.001), whereas the transplant rate was higher in the ITT-LDLT group (78.3% vs. 52.2%, P < 0.001). The 5-year ITT-OS was superior in the ITT-LDLT group (72.6% vs. 49.5%, P < 0.001) for patients with MELD > 25 and patients with both MELD > 25 and HRS (56% vs. 33.8%, P < 0.001). Waitlist mortality was the highest early after listing, and the distinct alteration of slope at survival curve showed that the benefits of ITT-LDLT occurred within the first month after listing. Perioperative outcomes and 5-year patient survival were comparable for patients with MELD > 25 (88% vs. 85.4%, P = 0.279) and patients with both MELD > 25 and HRS (77% vs. 76.4%, P = 0.701) after LDLT and DDLT, respectively. The LDLT group has a higher rate of renal recovery by 1 month (77.4% vs. 59.1%, P = 0.003) and 3 months (86.1% vs, 74.5%, P = 0.029), whereas the long-term estimated glomerular filtration rate (eGFR) was similar between the 2 groups. ITT-LDLT reduced the hazard of mortality (hazard ratio = 0.387-0.552) across all MELD strata. CONCLUSIONS: The ITT-LDLT reduced waitlist mortality and allowed an earlier access to transplant. LDLT in patients with high MELD/HRS was feasible, and they had similar perioperative outcomes and better renal recovery, whereas the long-term survival and eGFR were comparable with DDLT. LDLT should be considered for patients with high MELD/HRS, and the application of LDLT should not be restricted with a MELD cutoff.
Assuntos
Doença Hepática Terminal , Síndrome Hepatorrenal , Transplante de Fígado , Doadores Vivos/estatística & dados numéricos , China/epidemiologia , Doença Hepática Terminal/epidemiologia , Doença Hepática Terminal/cirurgia , Feminino , Acessibilidade aos Serviços de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Síndrome Hepatorrenal/epidemiologia , Síndrome Hepatorrenal/cirurgia , Humanos , Análise de Intenção de Tratamento , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Período Perioperatório/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Listas de Espera/mortalidadeRESUMO
Optical precision spectroscopy of isotope shifts can be used to test for new forces beyond the standard model, and to determine basic properties of atomic nuclei. We measure isotope shifts on the highly forbidden ^{2}S_{1/2}â^{2}F_{7/2} octupole transition of trapped ^{168,170,172,174,176}Yb ions. When combined with previous measurements in Yb^{+} and very recent measurements in Yb, the data reveal a King plot nonlinearity of up to 240σ. The trends exhibited by experimental data are explained by nuclear density functional theory calculations with the Fayans functional. We also find, with 4.3σ confidence, that there is a second distinct source of nonlinearity, and discuss its possible origin.
RESUMO
We measure isotope shifts for five Yb^{+} isotopes with zero nuclear spin on two narrow optical quadrupole transitions ^{2}S_{1/2}â^{2}D_{3/2}, ^{2}S_{1/2}â^{2}D_{5/2} with an accuracy of â¼300 Hz. The corresponding King plot shows a 3×10^{-7} deviation from linearity at the 3σ uncertainty level. Such a nonlinearity can indicate physics beyond the Standard Model (SM) in the form of a new bosonic force carrier, or arise from higher-order nuclear effects within the SM. We identify the quadratic field shift as a possible nuclear contributor to the nonlinearity at the observed scale, and show how the nonlinearity pattern can be used in future, more accurate measurements to separate a new-boson signal from nuclear effects.
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PURPOSE OF REVIEW: Heart failure (HF) remains a significant burden to our healthcare system and a leading cause of hospitalizations. Current reactive strategies to treat and manage HF have failed to reduce hospitalizations and improve survival. The CardioMEMS device has recently been demonstrated to improve quality of life in HF and reduce HF-related hospitalizations. Current HF management strategies are reviewed with a particular emphasis on the current role of the CardioMEMS device. RECENT FINDINGS: The CHAMPION trial is the only randomized trial looking at the CardioMEMS device. Patients managed with targeted pulmonary artery pressures resulted in 28% reduction in the primary end-point of HF-related hospitalization at 6 months (HR 0.72, 95% CI 0.60-0.85, p = 0.0002) and 37% reduction during the entire follow-up period, which averaged 15 months (HR 0.63, 95% CI 0.52-0.77, p < 0.0001). The prospective open-label post-approval study recently presented a 58% reduction in HF hospitalizations per patient year (HR 0.42, 95% CI 0.38-0.47, p < 0.0001). Management of HF using the CardioMEMS device has been shown to reduce HF hospitalizations and improve quality of life regardless of ejection fraction. Patients best suited for this device are those with recurrent congestive symptoms despite optimal medical therapy.
Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Monitorização Hemodinâmica , Artéria Pulmonar , Monitorização Ambulatorial da Pressão Arterial , Cateterismo de Swan-Ganz , Cateteres de Demora , Insuficiência Cardíaca/cirurgia , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
In this Letter, we present a cosmic Bell experiment with polarization-entangled photons, in which measurement settings were determined based on real-time measurements of the wavelength of photons from high-redshift quasars, whose light was emitted billions of years ago; the experiment simultaneously ensures locality. Assuming fair sampling for all detected photons and that the wavelength of the quasar photons had not been selectively altered or previewed between emission and detection, we observe statistically significant violation of Bell's inequality by 9.3 standard deviations, corresponding to an estimated p value of â²7.4×10^{-21}. This experiment pushes back to at least â¼7.8 Gyr ago the most recent time by which any local-realist influences could have exploited the "freedom-of-choice" loophole to engineer the observed Bell violation, excluding any such mechanism from 96% of the space-time volume of the past light cone of our experiment, extending from the big bang to today.
RESUMO
Bell's theorem states that some predictions of quantum mechanics cannot be reproduced by a local-realist theory. That conflict is expressed by Bell's inequality, which is usually derived under the assumption that there are no statistical correlations between the choices of measurement settings and anything else that can causally affect the measurement outcomes. In previous experiments, this "freedom of choice" was addressed by ensuring that selection of measurement settings via conventional "quantum random number generators" was spacelike separated from the entangled particle creation. This, however, left open the possibility that an unknown cause affected both the setting choices and measurement outcomes as recently as mere microseconds before each experimental trial. Here we report on a new experimental test of Bell's inequality that, for the first time, uses distant astronomical sources as "cosmic setting generators." In our tests with polarization-entangled photons, measurement settings were chosen using real-time observations of Milky Way stars while simultaneously ensuring locality. Assuming fair sampling for all detected photons, and that each stellar photon's color was set at emission, we observe statistically significant â³7.31σ and â³11.93σ violations of Bell's inequality with estimated p values of â²1.8×10^{-13} and â²4.0×10^{-33}, respectively, thereby pushing back by â¼600 years the most recent time by which any local-realist influences could have engineered the observed Bell violation.
RESUMO
In recent years, there has been a vast increase in structural and functional understanding of VDAC1, but VDAC2 and -3 have been understudied despite having many unique phenotypes. One reason for the paucity of structural and biochemical characterization of the VDAC2 and -3 isoforms stems from the inability of obtaining purified, functional protein. Here we demonstrate the expression, isolation, and basic characterization of zebrafish VDAC2 (zfVDAC2). Further, we resolved the structure of zfVDAC2 at 2.8 Å resolution, revealing a crystallographic dimer. The dimer orientation was confirmed in solution by double electron-electron resonance spectroscopy and by cross-linking experiments disclosing a dimer population of â¼20% in lauryldimethine amine oxide detergent micelles, whereas in lipidic bicelles a higher population of dimeric and higher order oligomers species were observed. The present study allows for a more accurate structural comparison between VDAC2 and its better-studied counterpart VDAC1.
Assuntos
Espectroscopia de Ressonância de Spin Eletrônica/métodos , Multimerização Proteica , Canal de Ânion 2 Dependente de Voltagem/química , Proteínas de Peixe-Zebra/química , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Cisteína/química , Cisteína/genética , Cisteína/metabolismo , Condutividade Elétrica , Eletroforese em Gel de Poliacrilamida , Bicamadas Lipídicas/química , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Conformação Proteica , Estrutura Secundária de Proteína , Homologia de Sequência de Aminoácidos , Eletricidade Estática , Canal de Ânion 2 Dependente de Voltagem/genética , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. The ability of GPIHBP1 to bind LPL depends on the Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in the GPIHBP1 Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the preheparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, whereas wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia.
Assuntos
Homozigoto , Hiperlipoproteinemia Tipo I , Lipase Lipoproteica/metabolismo , Mutação de Sentido Incorreto , Multimerização Proteica/genética , Receptores de Lipoproteínas , Adulto , Substituição de Aminoácidos , Linhagem Celular , Humanos , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/metabolismo , Hiperlipoproteinemia Tipo I/patologia , Lipase Lipoproteica/genética , Masculino , Ligação Proteica/genética , Estrutura Terciária de Proteína , Transporte Proteico/genética , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismoRESUMO
The S447X polymorphism in lipoprotein lipase (LPL), which shortens LPL by two amino acids, is associated with low plasma triglyceride levels and reduced risk for coronary heart disease. S447X carriers have higher LPL levels in the pre- and post-heparin plasma, raising the possibility that the S447X polymorphism leads to higher LPL levels within capillaries. One potential explanation for increased amounts of LPL in capillaries would be more avid binding of S447X-LPL to GPIHBP1 (the protein that binds LPL dimers and shuttles them to the capillary lumen). This explanation seems plausible because sequences within the carboxyl terminus of LPL are known to mediate LPL binding to GPIHBP1. To assess the impact of the S447X polymorphism on LPL binding to GPIHBP1, we compared the ability of internally tagged versions of wild-type LPL (WT-LPL) and S447X-LPL to bind to GPIHBP1 in both cell-based and cell-free binding assays. In the cell-based assay, we compared the binding of WT-LPL and S447X-LPL to GPIHBP1 on the surface of cultured cells. This assay revealed no differences in the binding of WT-LPL and S447X-LPL to GPIHBP1. In the cell-free assay, we compared the binding of internally tagged WT-LPL and S447X-LPL to soluble GPIHBP1 immobilized on agarose beads. Again, no differences in the binding of WT-LPL and S447X-LPL to GPIHBP1 were observed. We conclude that increased binding of S447X-LPL to GPIHBP1 is unlikely to be the explanation for more efficient lipolysis and lower plasma triglyceride levels in S447X carriers.
Assuntos
Proteínas Imobilizadas/metabolismo , Lipase Lipoproteica/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Lipoproteínas/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Triglicerídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Bioensaio , Células CHO , Cricetulus , Expressão Gênica , Humanos , Proteínas Imobilizadas/genética , Metabolismo dos Lipídeos , Lipase Lipoproteica/genética , Dados de Sequência Molecular , Ligação Proteica , Transporte Proteico , Receptores de Lipoproteínas/genética , Proteínas Recombinantes de Fusão/genéticaRESUMO
Lipoprotein lipase (LPL) has been highly conserved through vertebrate evolution, making it challenging to generate useful antibodies. Some polyclonal antibodies against LPL have turned out to be nonspecific, and the available monoclonal antibodies (Mabs) against LPL, all of which bind to LPL's carboxyl terminus, have drawbacks for some purposes. We report a new LPL-specific monoclonal antibody, Mab 4-1a, which binds to the amino terminus of LPL (residues 5-25). Mab 4-1a binds human and bovine LPL avidly; it does not inhibit LPL catalytic activity nor does it interfere with the binding of LPL to heparin. Mab 4-1a does not bind to human hepatic lipase. Mab 4-1a binds to GPIHBP1-bound LPL and does not interfere with the ability of the LPL-GPIHBP1 complex to bind triglyceride-rich lipoproteins. Mab 4-1a will be a useful reagent for both biochemists and clinical laboratories.
Assuntos
Anticorpos Monoclonais/metabolismo , Lipase Lipoproteica/metabolismo , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/isolamento & purificação , Afinidade de Anticorpos , Especificidade de Anticorpos , Células CHO , Bovinos , Cricetulus , Expressão Gênica , Heparina/metabolismo , Humanos , Lipase/metabolismo , Lipase Lipoproteica/genética , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Transporte Proteico , Receptores de Lipoproteínas/genética , TransfecçãoRESUMO
BACKGROUND AND AIMS: The prognostic role of noninvasive assessments of liver fibrosis has been evolving. Our aim was to investigate the prognostic value of liver stiffness measurement (LSM) with transient elastography and serum-based Hui index to predict hepatic events and deaths in chronic hepatitis B (CHB) patients. METHODS: The main prospective cohort included 1555 consecutive CHB patients referred for transient elastography examination; a subgroup of 980 patients underwent follow-up assessments at least 3 years later formed the serial cohort. Cox proportional hazard model was performed to determine the relationship of LSM, Hui index and other clinical variables with hepatic events and deaths. RESULTS: During a mean follow-up of 69 ± 9 months, 119 patients (7.6%) developed hepatic events or deaths. Hepatic event-free survival was significantly decreased with increasing stages of LSM and Hui index. The 5-year cumulative probability of hepatic event-free survival of patients of Stage 1-7 of LSM were 99.3%, 98.8%, 95.7%, 90.9%, 89.6%, 74.6%, and 50.0%, respectively; that of Stage 1 to 3 of Hui index were 98.2%, 93.1%, and 77.5%, respectively. Independent predictors of hepatic event-free survival were age, baseline LSM, and follow-up Hui index. Serum ALT and body mass index affected the accuracy of prediction by LSM. Patients remained early stages of LSM or Hui index at follow-up visit had better survival compared to those remained at late stages. CONCLUSION: Baseline and change in noninvasive parameters of liver fibrosis, LSM and Hui index, are accurate to predict hepatic event-free survival in CHB patients.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hepatite B Crônica/complicações , Hepatite B Crônica/mortalidade , Cirrose Hepática/diagnóstico , Transaminases/sangue , Adulto , Fatores Etários , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores de TIE , Índice de Gravidade de DoençaRESUMO
In this paper, vertically aligned Pt nanowire arrays (PtNWA) with different lengths and surface roughnesses were fabricated and their electrochemical performance toward hydrogen peroxide (H2O2) detection was studied. The nanowire arrays were synthesized by electroplating Pt in nanopores of anodic aluminum oxide (AAO) template. Different parameters, such as current density and deposition time, were precisely controlled to synthesize nanowires with different surface roughnesses and various lengths from 3 µm to 12 µm. The PtNWA electrodes showed better performance than the conventional electrodes modified by Pt nanowires randomly dispersed on the electrode surface. The results indicate that both the length and surface roughness can affect the sensing performance of vertically aligned Pt nanowire array electrodes. Generally, longer nanowires with rougher surfaces showed better electrochemical sensing performance. The 12 µm rough surface PtNWA presented the largest sensitivity (654 µA·mM⻹·cm⻲) among all the nanowires studied, and showed a limit of detection of 2.4 µM. The 12 µm rough surface PtNWA electrode also showed good anti-interference property from chemicals that are typically present in the biological samples such as ascorbic, uric acid, citric acid, and glucose. The sensing performance in real samples (river water) was tested and good recovery was observed. These Nafion-free, vertically aligned Pt nanowires with surface roughness control show great promise as versatile electrochemical sensors and biosensors.
Assuntos
Técnicas Eletroquímicas/instrumentação , Polímeros de Fluorcarboneto/química , Nanofios/química , Carbono/química , Eletrodos , Vidro/química , Peróxido de Hidrogênio/análise , Nanofios/ultraestrutura , Platina , Espectrometria por Raios X , Propriedades de Superfície , Água/químicaRESUMO
BACKGROUND & AIMS: CU-HCC score is accurate to predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. However, diagnosis of cirrhosis may be incorrect based on ultrasonography, leading to some errors in HCC prediction. This study aimed to evaluate the accuracy of LSM-HCC score, refined from CU-HCC score with liver stiffness measurement (LSM) using transient elastography to predict HCC. METHODS: A prospective cohort study of 1555 consecutive CHB patients referred for transient elastography examination; 1035 and 520 patients randomly assigned to training and validation cohorts, respectively. Clinical cirrhosis of CU-HCC score was substituted by LSM and analyzed with multivariable Cox regression analysis with other parameters. RESULTS: During a mean follow-up of 69 months, 38 patients (3.7%) in the training cohort and 17 patients (3.4%) in the validation cohort developed HCC. A new LSM-HCC score composed of LSM, age, serum albumin and hepatitis B virus (HBV) DNA levels were derived, which ranges from 0 to 30. Areas under receiver operating characteristic curves of LSM-HCC score were higher than those of CU-HCC score (0.83-0.89 vs. 0.75-0.81). By applying the cutoff value of 11, the score excluded future HCC with high negative predictive value (99.4%-100%) at 5 years. CONCLUSIONS: LSM-HCC score constructed from LSM, age, serum albumin and HBV DNA level is accurate to predict HCC in CHB patients.
Assuntos
Carcinoma Hepatocelular/etiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/fisiopatologia , Neoplasias Hepáticas/etiologia , Adulto , Idoso , Estudos de Coortes , DNA Viral/sangue , Técnicas de Imagem por Elasticidade , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores de TempoRESUMO
Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies. Here we identify new conserved and druggable analgesic targets using tissue-specific functional genomic screening of candidate "pain" genes in the fly. From these efforts we describe 23 new pain genes for further consideration. This included Acsl, a fatty acid-metabolizing enzyme and mammalian orthologs are involved in arachidonic acid metabolism. Acsl knockdown and mutant larvae showed delayed nocifensive responses to localized and global noxious heat. Mechanistically, knockdown of Acsl reduced dendritic branching of nociceptive neurons. Surprisingly, the pain phenotype in these animals could be rescued through dietary intervention with vitamin B5, highlighting the interplay between genetics, metabolism and nutrient environment to establish sensory perception thresholds. Together, our functional genomic screening within the sensory nociceptor has identified new nociception genes that provide a better understanding of pain biology and can help guide the development of new painkillers.
RESUMO
A 57-year-old woman with good past health was admitted to the accident and emergency department at an outside hospital for sudden onset chest pain. Electrocardiogram revealed ST-segment elevation at inferior leads.