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  • 1
    Publication Date: 2018-01-03
    Description: Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 2
    Publication Date: 2018-11-08
    Description: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1 , CCM2 , and CCM3 , have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Keywords: POPULATION ; RISK ; MELANOMA ; BRCA1 MUTATION CARRIERS ; CONSORTIUM ; TUMOR SUBTYPES
    Abstract: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
    Type of Publication: Journal article published
    PubMed ID: 22976474
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  • 4
    Publication Date: 2018-02-23
    Description: Objective The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR). Design Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library, ClinicalTrials.gov and websites of major cardiovascular congresses. Setting Only randomised trials comparing DES with DCB were included. Participants Patients with ISR in the included trials. Interventions New-generation DES versus DCB. Outcomes The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial infarction, target lesion revascularisation (TLR), target vessel revascularisation (TVR), major adverse cardiac events (MACE) and stent thrombosis were investigated. Results Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results identified that new-generation DES were associated with higher acute luminal gain (–0.31 mm, 95% CI –0.42 to –0.20, P〈0.001) and lower per cent diameter stenosis (risk ratio (RR): 0.28, 95% CI 0.02 to 0.55, P=0.04). DES significantly reduced the risk of TLR (RR: 1.96, 95% CI 1.17 to 3.28, P=0.01) compared with DCB; however, there was no statistical differences for MACE (RR: 1.21, 95% CI 0.67 to 2.17, P=0.53), myocardial infarction (RR: 1.16, 95% CI 0.55 to 2.48, P=0.69) and cardiac death (RR: 1.80, 95% CI 0.60 to 5.39, P=0.29). Conclusions Interventions with new-generation DES appear to be associated with significant reduction in per cent diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction and cardiac death for patients with coronary ISR compared with DCB. Appropriately powered studies with longer term follow-up are warranted to confirm these findings.
    Keywords: Open access, Cardiovascular medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 5
    Publication Date: 2018-09-20
    Description: The relationship between β-diversity and latitude still remains to be a core question in ecology because of the lack of consensus between studies. One hypothesis for the lack of consensus between studies is that spatial scale changes the relationship between latitude and β-diversity. Here, we test this hypothesis using tree data from 15 large-scale forest plots (greater than or equal to 15 ha, diameter at breast height ≥ 1 cm) across a latitudinal gradient (3–30 o ) in the Asia-Pacific region. We found that the observed β-diversity decreased with increasing latitude when sampling local tree communities at small spatial scale (grain size ≤0.1 ha), but the observed β-diversity did not change with latitude when sampling at large spatial scales (greater than or equal to 0.25 ha). Differences in latitudinal β-diversity gradients across spatial scales were caused by pooled species richness (-diversity), which influenced observed β-diversity values at small spatial scales, but not at large spatial scales. Therefore, spatial scale changes the relationship between β-diversity, -diversity and latitude, and improving sample representativeness avoids the -dependence of β-diversity.
    Keywords: biogeography, ecology
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 6
    Publication Date: 2018-12-11
    Description: Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB -, C3 -, C4 -, C5 -, C5aR1 -, C5aR2 -, and C6 -deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1β, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 7
    Publication Date: 2018-09-22
    Description: The development of new membranes with high H 2 separation performance under industrially relevant conditions (high temperatures and pressures) is of primary importance. For instance, these membranes may facilitate the implementation of energy-efficient precombustion CO 2 capture or reduce energy intensity in other industrial processes such as ammonia synthesis. We report a facile synthetic protocol based on interfacial polymerization for the fabrication of supported benzimidazole-linked polymer membranes that display an unprecedented H 2 /CO 2 selectivity (up to 40) at 423 K together with high-pressure resistance and long-term stability (〉800 hours in the presence of water vapor).
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 8
    Publication Date: 2018-03-12
    Description: Molecularly well-defined Ni sites at heterogeneous interfaces were derived from the incorporation of Ni 2+ ions into heteroatom-doped graphene. The molecular Ni sites on graphene were redox-active. However, they showed poor activity toward oxygen evolution reaction (OER) in KOH aqueous solution. We demonstrated for the first time that the presence of Fe 3+ ions in the solution could bond at the vicinity of the Ni sites with a distance of 2.7 Å, generating molecularly sized and heterogeneous Ni-Fe sites anchored on doped graphene. These Ni-Fe sites exhibited markedly improved OER activity. The Pourbaix diagram confirmed the formation of the Ni-Fe sites and revealed that the Ni-Fe sites adsorbed HO – ions with a bridge geometry, which facilitated the OER electrocatalysis.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 9
    Publication Date: 2018-06-28
    Description: A method developed based on the capillary effect and capillary condensation theory was used to synthesize an innovative Fe/C/Pd composite in this study. This composite (Fe@CNTs@Pd) consists of carbon nanotubes (CNTs) with nanoscale zerovalent iron (NZVI) on the inner surface and palladium nanoparticles supported on the outer surface of CNTs. This structure successfully addresses the problems of high iron corrosion rate and lower utilization rate of hydrogen in the application of bimetal nanoparticles for trichloroethylene (TCE) removal. TCE degradation experiments and electrochemical tests were conducted to investigate the material properties and reaction mechanisms of the composite. It is found that the prepared composite material contribute a high level of TCE dechlorination rate and substantially reduced hydrogen production during iron corrosion in water compared with the conventional CNTs-supported bimetal materials (Fe/Pd@CNTs). Hydrogen spillover effect helps the reactivity of Fe@CNTs@Pd for TCE degradation and suppressed the galvanic cell effect, which results in a stronger resistance to corrosion. Although the K obs of Fe@CNTs@Pd was 16.87% lower than that of Fe/Pd@CNTs, the hydrogen production rate of Fe@CNTs@Pd was 10 times slower than that of Fe/Pd@CNTs. Therefore, Fe@CNTs@Pd shows a significant reduction in the corrosion rate at a cost of slightly slower degradation of TCE. In sum, the prepared composites demonstrate important characteristics, including alleviating NZVI agglomeration, maintaining high TCE removal efficiency and reducing the corrosion of NZVI.
    Keywords: nanotechnology, environmental chemistry, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 10
    Publication Date: 2018-07-06
    Description: The crystallization problem is an outstanding challenge in the chemistry of porous covalent organic frameworks (COFs). Their structural characterization has been limited to modeling and solutions based on powder x-ray or electron diffraction data. Single crystals of COFs amenable to x-ray diffraction characterization have not been reported. Here, we developed a general procedure to grow large single crystals of three-dimensional imine-based COFs (COF-300, hydrated form of COF-300, COF-303, LZU-79, and LZU-111). The high quality of the crystals allowed collection of single-crystal x-ray diffraction data of up to 0.83-angstrom resolution, leading to unambiguous solution and precise anisotropic refinement. Characteristics such as degree of interpenetration, arrangement of water guests, the reversed imine connectivity, linker disorder, and uncommon topology were deciphered with atomic precision—aspects impossible to determine without single crystals.
    Keywords: Chemistry, Materials Science
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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