Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.248
Filtrar
1.
J Environ Manage ; 277: 111325, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949949

RESUMO

Technological progress greatly contributes to the promotion of carbon productivity (CP). This study aims to identify an appropriate mode of technological progress that increases CP. A data envelopment analysis-based method was used to investigate the impacts of four forms of technological progress under two classifications of CP: the progress of neutral technology (NT) and capital-embodied technology (CET) under a technological source and the progress of energy technology (ET) and carbon technology (CT) under an abatement process. We applied dynamic panel data models to deeply analyze the different impacts of the four forms of technological progress on the CPs of Chinese manufacturing industries from 1995 to 2015. Results show that (1) a change in ET contributes more to the promotion of CP than a change in CT; (2) a change in CET promotes CP more than a change in NT; and (3) the indirect effect of a change in CET on CP through a change in ET and the indirect effect of a change in NT on CP through a change in CT are advantageous. These findings provide important policy implications in promoting technological progress and improving Chinese MIs' CPs. Significant policy measures based on theoretical and empirical conclusions are proposed.

2.
Methods Mol Biol ; 2196: 53-62, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32889712

RESUMO

An essential gene is defined as a gene that cannot be completely removed from the genome. Investigation of an essential gene function is limited because its deletion strain cannot be readily created. Here we describe a protocol called plasmid shuffling that can be conveniently employed in yeast to study essential gene functions. The essential gene is first cloned into a YCp-based plasmid with URA3 as a selectable marker and then transformed into host cells. The transformed cells can then be used to delete the chromosomal copy of the essential gene. The gene is then cloned into another YCp-based plasmid with a different selectable marker, and the gene sequence can be altered in vitro. Plasmids carrying the mutated gene sequences are transformed into the above cells, resulting in carrying two plasmids. These cells are grown in medium containing 5-FOA that selects ura3 cells. The 5-FOA-resistant cells are expected to only carry the plasmid containing the mutated essential gene, whose functions can be assessed.

3.
Food Chem ; 338: 127805, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798814

RESUMO

In order to meet the requirements of pesticide residues' detection in complex matrix samples, the magnetic fluorinated multi-wall carbon nanotubes (M-F-MWCNTs) were prepared and applied as new QuEChERS clean-up materials. Combined with GC-MS, an improved QuEChERS method was successfully developed for the detection of organophosphorus pesticide residues. The results showed that the M-F-MWCNTs could effectively remove the interfering substances in Lycium ruthenicum Murr. (L. ruthenicum) samples. The recoveries of 10 tested targets were 74.9% to 113.5% with the relative standard deviations (RSDs) of 3.9-14.7%. The experiment results pointed out that the M-F-MWCNTs were qualified as QuEChERS clean-up materials and expected to be applied to other complex matrix samples and pesticide targets.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 247: 119085, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33161261

RESUMO

Many reports have suggested that near-infrared (NIR) fluorescent probes are one of the most promising molecules for improving the sensitivity of fluorescence sensing and imaging. Herein, gold nanoclusters with excellent near-infrared photoluminescence (PL) were synthesized by a simply hydrothermal treatment of hydrogen tetrachloroaurate(III) trihydrate and glutathione (GSH). The NIR PL of GSH-capped gold nanoclusters (GSH-AuNCs) can be significantly quenched by Fe3+, which follows a dynamic quenching mechanism. However, the NIR PL of the GSH-AuNCs/Fe3+ system can be recovered after the addition of ascorbic acid (AA). The decrease and increase of NIR PL intensities of GSH-AuNCs were linearly correlated with the concentration of Fe3+ and AA, respectively. Therefore, a turn-off-on NIR PL sensing strategy can be constructed for sequential detection of Fe3+ and AA with the linear range of 0.7-180 µM and 0.5-120 µM, respectively. The proposed NIR PL sensor exhibits excellent sensing performance and has been applied to the determination of Fe3+ and AA in real samples with satisfactory results.

5.
J Recept Signal Transduct Res ; : 1-8, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33167774

RESUMO

Atherosclerosis is a chronic disease of arteries, which constitutes the pathological basis of a series of cardiovascular diseases. The inflammatory response of vascular endothelial cells mediated by oxidized low density lipoprotein (ox-LDL) is the early behavior and main signal of atherosclerosis. In this study, the damage model of vascular endothelial cells treated with ox-LDL was used to reproduce the damage process of vascular endothelial cells in the process of atherosclerosis. Cell viability was detected by CCK-8. The release levels of reactive oxygen species, nitric oxide, and superoxide dismutase (SOD) were detected by commercial kits. EdU cell proliferation assay was used to detect cell proliferation, real-time fluorescent quantitative PCR and Western blot were used to detect the expression level of related genes. The results showed we successfully constructed a vascular endothelial injury model by incubating vascular endothelial cells with gradient concentrations of ox-LDL. The incubation of safflor yellow A (SYA) partially restored the loss of viability of vascular endothelial cells mediated by ox-LDL, and SYA could promote the proliferation of injured vascular endothelial cells. In addition, SYA may transmit related signals through the AMPK pathway to protect vascular endothelial cells from ox-LDL-mediated damage. All these results provide a further understanding of the occurrence and development of atherosclerosis, provide a theoretical basis for the use of SYA-related drugs in the treatment of cardiovascular diseases, and provide a reference paradigm for studying the pharmacology, toxicology, and mechanism of action of key active substances in TCM.

6.
J Vis Exp ; (163)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-33044464

RESUMO

Structural studies with tryptophan synthase (TS) bienzyme complex (α2ß2 TS) from Salmonella typhimurium have been performed to better understand its catalytic mechanism, allosteric behavior, and details of the enzymatic transformation of substrate to product in PLP-dependent enzymes. In this work, a novel expression system to produce the isolated α- and isolated ß-subunit allowed the purification of high amounts of pure subunits and α2ß2 StTS complex from the isolated subunits within 2 days. Purification was carried out by affinity chromatography followed by cleavage of the affinity tag, ammonium sulfate precipitation, and size exclusion chromatography (SEC). To better understand the role of key residues at the enzyme ß-site, site-direct mutagenesis was performed in prior structural studies. Another protocol was created to purify the wild type and mutant α2ß2 StTS complexes. A simple, fast and efficient protocol using ammonium sulfate fractionation and SEC allowed purification of α2ß2 StTS complex in a single day. Both purification protocols described in this work have considerable advantages when compared with previous protocols to purify the same complex using PEG 8000 and spermine to crystalize the α2ß2 StTS complex along the purification protocol. Crystallization of wild type and some mutant forms occurs under slightly different conditions, impairing the purification of some mutants using PEG 8000 and spermine. To prepare crystals suitable for x-ray crystallographic studies several efforts were made to optimize crystallization, crystal quality and cryoprotection. The methods presented here should be generally applicable for purification of tryptophan synthase subunits and wild type and mutant α2ß2 StTS complexes.

7.
Elife ; 92020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33054973

RESUMO

Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglia rely on CSF1R signaling for survival. However, a small subset of microglia in mouse brains can survive without CSF1R signaling and reestablish the microglial homeostatic population after CSF1R signaling returns. Using single-cell transcriptomic analysis, we characterized the heterogeneous microglial populations under CSF1R inhibition, including microglia with reduced homeostatic markers and elevated markers of inflammatory chemokines and proliferation. Importantly, MAC2/Lgals3 was upregulated under CSF1R inhibition, and shared striking similarities with microglial progenitors in the yolk sac and immature microglia in early embryos. Lineage-tracing studies revealed that these MAC2+ cells were of microglial origin. MAC2+ microglia were also present in non-treated adult mouse brains and exhibited immature transcriptomic signatures indistinguishable from those that survived CSF1R inhibition, supporting the notion that MAC2+ progenitor-like cells are present among adult microglia.

8.
Elife ; 92020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030428

RESUMO

The internalization of the central nervous system, termed neurulation in vertebrates, is a critical step in embryogenesis. Open questions remain regarding how force propels coordinated tissue movement during the process, and little is known as to how internalization happens in invertebrates. We show that in C. elegans morphogenesis, apical constriction in the retracting pharynx drives involution of the adjacent neuroectoderm. HMR-1/cadherin mediates this process via inter-tissue attachment, as well as cohesion within the neuroectoderm. Our results demonstrate that HMR-1 is capable of mediating embryo-wide reorganization driven by a centrally located force generator, and indicate a non-canonical use of cadherin on the basal side of an epithelium that may apply to vertebrate neurulation. Additionally, we highlight shared morphology and gene expression in tissues driving involution, which suggests that neuroectoderm involution in C. elegans is potentially homologous with vertebrate neurulation and thus may help elucidate the evolutionary origin of the brain.

9.
J Mater Chem B ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33125023

RESUMO

A mitochondrial pH sensing fluorescent probe namely 2-(2-(6-hydroxynaphthalen-2-yl)vinyl)-3-(6-(triphenyl-phosphonio)hexyl)benzothiazol-3-ium bromide (HTBT2) was designed and facilely synthesized via the Knoevenagel condensation reaction. HTBT2 displayed a linear fluorescence enhancement at 612 nm in response to pH changes between 8.70 and 7.20. The pKa value was determined to be 8.04 ± 0.02, which might be ideal for mitochondrial pH (pHmito ∼8.0) detection. HTBT2 also exhibited a remarkable large Stokes shift of 176 nm, which could diminish the interference of excitation light. The results of live cell imaging studies suggested that HTBT2 showed excellent targeting ability for mitochondria. Importantly, it was successfully applied to visualize mitochondrial pH changes in live cells and differentiate the pHmito difference between cancer cell lines and normal cell lines. Our results consistently supported that HTBT2 held practical promise for the investigation of physiological processes related to pHmito changes and clinical potential for cancer cell differentiation.

10.
BMC Gastroenterol ; 20(1): 340, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059618

RESUMO

BACKGROUND: Previous studied revealed that psoriasis and Inflammatory bowel disease (IBD) have highly overlapping epidemiological characteristics, genetic susceptibility loci, disease risk factors, immune mechanisms, and comorbidities. More and more biologics have been used to treat psoriasis and IBD. Interleukin (IL)-17 inhibitors played an important role in the treatment of psoriasis, but induced and aggravated inflammatory bowel disease in some patients. IL-23 inhibitors have shown to be effective to both psoriasis and CD. CASE PRESENTATION: Forty-one year old Chinese male patient who came to the hospital for psoriasis, developed severe gastrointestinal symptoms after using an IL-17 inhibitor, and was diagnosed with Crohn's disease (CD). The patient eventually used an IL-23 inhibitor to relieve both psoriasis and CD. CONCLUSION: IBD patients and psoriasis patients have increased probability of suffering from the other disease. The case that patients had suffered from psoriasis and CD before the use of IL-17 inhibitor is quite rare. This case suggests that physicians need to be careful when treating patients with psoriasis and CD with biologics, and it is necessary to evaluate the gastrointestinal tract.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33105321

RESUMO

The mechanisms of aspirin antithrombotic actions have not been fully elucidated. We re-analyzed the data from the project Aspirin Resistance in Patients with Ischemic Atherothrombotic Diseases from April 2008 to June 2010. A total of 530 subjects were classified into three groups, including 40 patients without aspirin use, 24 patients taking 25-50 mg/d aspirin, and 466 patients taking 75-100 mg/d aspirin over 1 month. By 1:1:1 propensity score matching adjusting 15 primary clinical covariates, 51 patients (n=17 per group) comprised the final sample. Hemostasis-related parameters and high platelet reactivity (HPR) as measured by arachidonic acid (AA)-and adenosine diphosphate (ADP)-induced light transmission aggregometry (LTA) were compared in the three groups. A dose-dependent relationship was observed between aspirin and decreased HPR incidence (PAA < 0.001, PADP < 0.01, respectively), decreased monocyte ratio (P = 0.052), increased antithrombin activity (P < 0.001), and increased platelet distribution width (P < 0.05). Aspirin at 25-50 mg/d is related to the lowest RBC count, whereas 75-100mg/d aspirin showed the highest RBC count among the three groups (4.52 ± 0.35×101/L vs. 4.35 ± 0.57×10/L vs.4.80 ± 0.59×10/L, P = 0.046). Our finding demonstrated that aspirin exerts its antithrombotic effects at least by antiplatelet function, enhancing antithrombin activity and suppressing monocytes in vivo. In addition, three blood cell types, namely RBCs, monocytes, and platelets, are involved in aspirin antithrombotic mechanism. The cellular response to aspirin partially enhances the antithrombotic effects while partially inhibiting the effects.

12.
Ann Neurol ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016348

RESUMO

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2020.

14.
Kidney Blood Press Res ; : 1-10, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032295

RESUMO

INTRODUCTION: High serum sodium is associated with increased blood pressure (BP) in dialysis patients, which is a risk factor for cardiovascular (CV) disease. However, the interaction between serum sodium and BP and their association with clinical outcomes in peritoneal dialysis (PD) patients is uncertain. METHODS: We analyzed a retrospective cohort of 1,656 incident PD patients from January 2006 to December 2013, who were followed up until December 2018. Cox proportional hazards regression models were used to evaluate the association of serum sodium and BP with all-cause and CV mortality. A priori interaction between serum sodium and systolic BP (SBP) was explored, and a subgroup analysis was performed by stratifying SBP into the following 3 groups: <110, 110-130, and >130 mm Hg. RESULTS: Mean baseline serum sodium was 140.2 ± 3.6 mmol/L, mean SBP was 137 ± 20 mm Hg, and diastolic BP was 85 ± 14 mm Hg. During a median (range) follow-up time of 46.5 (2.6-154.3) months, 507 patients died, 252 of whom died due to CV disease. SBP did not predict all-cause and CV mortality when BP was assessed as a continuous variable. However, SBP >130 or <110 mm Hg was associated with higher risk of all-cause and CV mortality compared with SBP of 110-130 mm Hg. There was a significant interaction between baseline serum sodium and SBP for all-cause mortality (p for interaction = 0.016). In subgroup analysis, among those with SBP >130 mm Hg, the risk of all-cause mortality was elevated in those with serum sodium ≥140 mmol/L (adjusted hazard ratio [aHR] 1.45 [95% confidence interval (CI): 1.07-1.98]), but not for those with serum sodium <140 mmol/L (aHR 1.27 [95% CI: 0.89-1.82]). Conversely, among those with SBP <110 mm Hg, those with serum sodium <140 mmol/L had an elevated risk of mortality (aHR 1.99 [95% CI: 1.31-3.02]), but not those with serum sodium ≥140 mmol/L (aHR 1.15 [95% CI: 0.74-1.79]) (p for interaction = 0.028). CONCLUSION: The association of BP with mortality was modified by serum sodium levels in PD patients. Further studies are needed to evaluate whether individualized BP control based on serum sodium levels contributes to improve patient outcomes.

15.
Huan Jing Ke Xue ; 41(8): 3527-3538, 2020 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124325

RESUMO

Surface ozone (O3) has become the primary air pollutant in Guangzhou. Due to the influences of topography, meteorological conditions, and differences in precursor emissions, there are also large differences in the characteristics, formation mechanisms, and influencing factors of ozone in different areas of the same city. Based on the ground measurement data for October 2015 at four air quality monitoring stations that represent different types of regions in Guangzhou [urban area:Guangzhou Monitoring Center (GMC); upwind suburbs:Huadu Normal School (HNS); downwind suburbs:Panyu Middle School (PMS); Mountain area:Maofengshan (MFS)] and the WRF simulated meteorological data, the changing characteristics, influencing factors, and sensitivity of O3 were studied at each station. The results showed that the diurnal variation of O3 and NOx exhibit unimodal and bimodal characteristics (except for NOx at the MFS station). The peak ozone concentration appeared on Saturday at the GMC, HNS, and MFS stations, and on Thursday at the PMS station. The ozone concentration at the MFS station was the highest (98.61 µg·m-3), whereas that at the GMC station was the lowest (44.83 µg·m-3). The NOx inflection point intervals for O3 at different sites were:GMC:55-90 µg·m-3; PMS:30-60 µg·m-3; MFS:10-20 µg·m-3. The temperature inflection point intervals affecting the rate of O3 formation at different sites were:GMC:28-30℃; HNS:26-28℃; PMS:24-26℃; however, this was not obvious at the MFS station. The relative humidity inflection point intervals were:GMC:55%-65% ; HNS and PMS:60%-70% ; MFS:80%-85%. The wind speed(WS) of the light wind type was proportional to the O3 concentration. The O3 concentration at the PMS site was the highest in the northwest wind direction, and the O3 concentration at the MFS site was the highest in the other wind directions. By analyzing the multivariate linear fitting of impact factors on the O3 concentration, the main controlling factors at each site were:GMC:WS and T; PMS and HNS:T and RH; MFS:RH and WS. The ozone sensitivity at each site was as follows:GMC and HNS had a VOCs-limited regime, MFS had a NOx-limited regime, and PMS had a transition regime.


Assuntos
Poluentes Atmosféricos , Ozônio , Poluentes Atmosféricos/análise , Cidades , Monitoramento Ambiental , Ozônio/análise , Estações do Ano
16.
Huan Jing Ke Xue ; 41(10): 4446-4454, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124376

RESUMO

Presently, there are a few studies on the measurement of industrial organic solvents in China. To determine the content and species of volatile organic compounds (VOCs) in industrial organic solvents and to provide the emission factors of organic solvents, the Chinese wood and automotive coatings, which accounted for the largest proportion of production in the world, were investigated. Coating samples were obtained by sampling from companies and buying from markets, and were measured in accordance with the domestic standard testing methods for coatings. The content and composition spectrum of VOCs in the coatings were determined, and the ozone formation potential (OFP) was then calculated. The results showed that for wood coatings, the average content of the VOCs in solvent-based, water-based, and ultra-violet (UV) coatings were 37.28%, 9.88%, and 18.02%, respectively. For automotive coatings, the average content of the VOCs in water-based original equipment manufacturer (OEM) coating, solvent-based OEM coating, water-based refinishing coating, and solvent-based refinishing coating were 15.06%, 59.90%, 11.79%, and 54.50%, respectively. The content of the VOCs in different types of coatings varied substantially. The main components and OFP contributors were alcohols and ethers for water-based coatings, benzene series and esters for solvent-based coatings, and esters, alcohols, and ethers for UV coatings. The average value of the coating samples could meet the current mandatory national standards, but 12% of the solvent-based wood coating samples and 42% of the solvent-based OEM coating samples did not meet the standards. In addition, except for the benzene series of the water-based wood coatings, the contents of harmful substances in other coating samples were up to the standards.


Assuntos
Poluentes Atmosféricos , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , China , Monitoramento Ambiental , Compostos Orgânicos Voláteis/análise , Madeira/química
17.
PLoS One ; 15(9): e0238564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32911499

RESUMO

BACKGROUND: The prevalence of human immunodeficiency virus (HIV) varies markedly among different risk groups in China, spreading fromhigh-risk populations to the general population. Indeed, China is in a critical period of HIV/acquired immunodeficiency syndrome (AIDS) prevention and control; however, data regarding HIV testing, infection and coinfection among infertile couples are lacking. This study aimed to estimate the HIV/AIDS prevalence to identify risk factors among infertile couples in Hunan, China. METHODS: A cross-sectional hospital-based study was conducted to evaluate the prevalence of HIV/other infections (hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium (MG) infections) among 338,432 infertile individuals in Hunan, China, from 2012 to 2018. We calculated linear trends in prevalence using bivariate linear regression. RESULTS: The overall prevalence rates of HIV, chlamydia, gonorrhea, MG, syphilis, and HBV and HCV antibody positivity in this study were 0.04%, 1.73%, 0.05%, 2.60%, 2.15%, 12.01% and 0.56%, respectively. The predominant infection was HBV, followed by MG, syphilis, and chlamydia. Only 1.13% of the participants (382/338432) reported sexually transmitted disease (STD) signs and symptoms suggesting genital tract infection. However, from 2012-2018, the variation in HIV prevalence was not significant (ß = 0.000, PTREND = 0.907). The characteristics of the HIV-infected infertile population have not shifted dramatically, with women accounting for 32.56% of HIV cases in China. Overall, 87.60% of HIV-infected individuals have a relatively low education. In total, 37.98% of HIV-positive patients engage in high-risk behaviors. CONCLUSIONS: This study expands upon existing knowledge of HIV prevalence in the infertile Chinese population. However, much work is needed to achieve popularization of prevention knowledge and change concept. Routine HIV screening is urgently needed for all adults with high-risk behaviors.


Assuntos
Infecções por HIV/complicações , Infertilidade/complicações , Adulto , China/epidemiologia , Doenças Transmissíveis/complicações , Doenças Transmissíveis/epidemiologia , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Humanos , Infertilidade/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
18.
Diabetes Res Clin Pract ; 169: 108418, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32891692

RESUMO

AIMS: Studies have shown that destruction of the intestinal barrier in type 2 diabetes (T2D) leads to increased absorption of macromolecules from intestinal. We previously exhibited that short-chain fatty acids (SCFAs) and bile acids (BAs) were significantly decreased in faeces of T2D patients. In the current study, we extended these findings by focusing on the interactions between intestinal barrier and clinical characteristics, gut microbiota, SCFAs and BAs. METHODS: 65 T2D patients and 35 healthy controls were recruited, targeted metabolomics was used to evaluate the SCFAs and BAs in their serum samples. The serum zonula occludens-1 (ZO-1) was measured by ELISA to evaluate intestinal barrier. RESULTS: Compared with the healthy controls, the serum concentrations of total SCFA, acetate and propionate were significantly increased in the T2D patients, and certain BAs were also significantly increased. In addition, the higher levels of serum ZO-1 suggested a "leaky gut" in T2D patients. The ZO-1 was comprehensively correlated with clinical characteristics, gut microbiota, SCFAs and BAs. CONCLUSION: SCFAs and BAs were excessively absorbed from the intestinal through the leaky gut, leading to higher levels of circulating SCFAs and BAs in T2D patients, and that the leaky gut might be caused by the disordered gut microbiota.

19.
Contemp Clin Trials ; 98: 106148, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32949732

RESUMO

A 2-in-1 adaptive Phase 2/3 design was proposed by Chen et al. The 2-in-1 design improves the overall clinical trial development efficiency by 1) building in an early and informative decision-making; 2) allowing the flexible endpoint-usage at the decision and the final analysis; 3) potential registration path forward in either Phase 2 or Phase 3. The original paper illustrates a general idea. In this paper, we extend this design to fit more common scenarios. The type I error control in the extended 2-in-1 adaptive Phase 2/3 designs is investigated in both simulation and theoretical ways.

20.
Nucleic Acids Res ; 48(20): 11695-11705, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-32986831

RESUMO

Nucleotide excision repair (NER) removes various DNA lesions caused by UV light and chemical carcinogens. The DNA helicase XPB plays a key role in DNA opening and coordinating damage incision by nucleases during NER, but the underlying mechanisms remain unclear. Here, we report crystal structures of XPB from Sulfurisphaera tokodaii (St) bound to the nuclease Bax1 and their complex with a bubble DNA having one arm unwound in the crystal. StXPB and Bax1 together spirally encircle 10 base pairs of duplex DNA at the double-/single-stranded (ds-ss) junction. Furthermore, StXPB has its ThM motif intruding between the two DNA strands and gripping the 3'-overhang while Bax1 interacts with the 5'-overhang. This ternary complex likely reflects the state of repair bubble extension by the XPB and nuclease machine. ATP binding and hydrolysis by StXPB could lead to a spiral translocation along dsDNA and DNA strand separation by the ThM motif, revealing an unconventional DNA unwinding mechanism. Interestingly, the DNA is kept away from the nuclease domain of Bax1, potentially preventing DNA incision by Bax1 during repair bubble extension.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA