•TOMM40 genotype but not PVRL2 gene was associated with Alzheimer's disease in Chinese older adults, depending on APOE genotype.•TOMM40 could interact with PVRL2 to substantially increase the ...likelihood of Alzheimer's disease.•The TOMM40 GG genotype was associated with low plasma Aβ42 concentration and the Aβ42-to-Aβ40 ratio.
Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73–22.48) for TOMM40GG, 1.47 (0.89–2.42) for PVRL2AA, and 12.87 (3.97–41.73) for having both risk alleles (Pinteraction = 0.0003). Among APOEε3/ε3 carriers, the multiadjusted odds ratio of AD associated with TOMM40AG was 2.90(1.15–7.31). In biomarker subsample, TOMM40GG was significantly associated with lower plasma Aβ42 and the Aβ42-to-Aβ40 ratio (p < 0.05). TOMM40 genotype is differentially associated with AD risk depending on APOE genotype. TOMM40 and PVRL2 genes could interact to substantially increase AD risk, possibly through influencing Aβ metabolism.
A leading edge 5nm CMOS platform technology has been defined and optimized for mobile and HPC applications. This industry-leading 5nm technology features, for the first time, full-fledged EUV, and ...high mobility channel (HMC) finFETs with densest 0.021μm 2 HD SRAM. This true 5nm CMOS platform technology is a full node scaling from our successful 7nm node 4 in offering ~1.84x logic density, 15% speed gain or 30% power reduction. The 5nm platform technology successfully passed qualification 3 with consistently high yielding 256Mb HD/HC SRAM, and large logic test chip consisting of CPU/GPU/SoC blocks. Currently in risk production, this true 5nm platform technology is on schedule for high volume production in 1H 2020.
84 chemical constituents were isolated from the leaves of
Chamaecyparis formosensis. These components include 18 sesquiterpenes, 40 diterpenes, 8 flavones, 7 lignans and 11 miscellaneous compounds. ...Among them 3 sesquiterpenes, 7 diterpenes and one lignan are new compounds, the structures of which were determined by chemical and spectral methods.
Propofol (PPF), a widely used intravenous anesthetic for induction and maintenance of anesthesia during surgeries, was found to possess suppressive effect on host immunity. This study aimed at ...investigating whether PPF plays a modulatory role in the lipopolysaccharide (LPS)-induced inflammatory cytokine expression in a cell line of rat hepatocytes. Morphological observation and viability assay showed that PPF exhibits no cytotoxicity at concentrations up to 300 μM after 48 h incubation. Pretreatment with 100 μM PPF for 24 h prior to LPS stimulation was performed to investigate the modulatory effect on LPS-induced inflammatory gene production. The results of semi-quantitative RT-PCR demonstrated that PPF pretreatment significantly suppressed the LPS-induced toll-like receptor (TLR)-4, CD14, tumor necrosis factor (TNF)-α, and granulocyte–macrophage colony-stimulating factor (GM-CSF) gene expression. Western blotting analysis showed that PPF pretreatment potentiated the LPS-induced TLR-4 downregulation. Flow cytometrical analysis revealed that PPF pretreatment showed no modulatory effect on the LPS-upregulated CD14 expression on hepatocytes. In addition, PPF pretreatment attenuated the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and IκBα, as well as the nuclear translocation of NF-κB primed by LPS. Moreover, addition of PD98059, a MAPK kinase inhibitor, significantly suppressed the LPS-induced NF-κB nuclear translocation and GM-CSF production, suggesting that the PPF-attenuated GM-CSF production in hepatocytes may be attributed to its suppressive effect on MAPK/ERK signaling pathway. In conclusion, PPF as an anesthetic may clinically benefit those patients who are vulnerable to sepsis by alleviating sepsis-related inflammatory response in livers.
To maximize the light yield of the liquid scintillator (LS) for the Jiangmen Underground Neutrino Observatory (JUNO), a 20 t LS sample was produced in a pilot plant at Daya Bay. The optical ...properties of the new LS in various compositions were studied by replacing the gadolinium-loaded LS in one antineutrino detector. The concentrations of the fluor, PPO, and the wavelength shifter, bis-MSB, were increased in 12 steps from 0.5 g/L and <0.01 mg/L to 4 g/L and 13 mg/L, respectively. The numbers of total detected photoelectrons suggest that, with the optically purified solvent, the bis-MSB concentration does not need to be more than 4 mg/L. To bridge the one order of magnitude in the detector size difference between Daya Bay and JUNO, the Daya Bay data were used to tune the parameters of a newly developed optical model. Then, the model and tuned parameters were used in the JUNO simulation. This enabled to determine the optimal composition for the JUNO LS: purified solvent LAB with 2.5 g/L PPO, and 1 to 4 mg/L bis-MSB.
Highlights • Landmark constrained diffeomorphic registration of high-genus surfaces is proposed. • Registration algorithm is based on quasi-conformal theories. • Shape analysis models are proposed ...using the registration. • Proposed models are tested on 27 vestibular system (VS) surfaces. • Shape differences in the posterior canal between normal and AIS group are found.
The present study was designed to assess hemodynamics and myocardial function at 18 h after injury caused by cecal ligation and puncture (CLP) in CD8-knockout mice treated with anti-asialoGM1 ...(CD8KO/alphaAsGM1 mice). Arterial pressure was measured by carotid artery cannulation, and left ventricular pressure-volume measurements were obtained by use of a 1.4-Fr conductance catheter. Blood acid-base balance and indexes of hepatic, renal, and pulmonary injury were also measured. CD8KO/alphaAsGM1 mice exhibited higher mean arterial pressure and increased systemic vascular resistance compared with wild-type mice. Cardiac output was significantly decreased in wild-type, but not CD8KO/alphaAsGM1, mice compared with sham controls. Myocardial function was better preserved in CD8KO/alphaAsGM1 mice as indicated by less impairment of left ventricular pressure development over time, time varying maximum elastance, end-systolic pressure-volume relationship, and preload recruitable stroke work. The impairment in myocardial function was associated with induction of proinflammatory cytokine mRNAs in the hearts of wild-type mice. The hemodynamic derangements in wild-type mice were coupled with significant metabolic acidosis and elevated serum creatinine levels. Overall, this study shows that cardiovascular collapse and shock characterized by hypotension, myocardial depression, low systemic vascular resistance, and metabolic acidosis occurs after CLP in wild-type mice but is attenuated in CD8KO/alphaAsGM1 mice. These observations likely explain, in part, the previously observed survival advantage of CD8KO/alphaAsGM1 mice following CLP.
Phenylmethylphosphoro-L-alaninate prodrugs of antiviral
Z-methylenecyclopropane nucleoside analogues and their inactive
E-isomers were synthesized and evaluated for their antiviral activity against ...HCMV, HSV-1, HSV-2, HHV-6, EBV, VZV, HIV-1 and HBV. The adenine
Z-analogue was a potent inhibitor of all these viruses but it displayed cellular toxicity. The guanine
Z-derivative was active against HCMV, HBV, EBV and VZV and it was not cytotoxic. The 2,6-diaminopurine analogue was the most potent against HIV-1 and HBV and somewhat less against HHV-6, HCMV, EBV and VZV in a non-cytotoxic concentration range. The 2-amino-6-cyclopropylamino and 2-amino-6-methoxypurine prodrugs were also more active than parent analogues against several viruses but with a less favorable cytotoxicity profile. In the
E-series of analogues, adenine derivative was active against HIV-1, HBV and EBV, and it was non-cytotoxic. The guanine analogue exhibited a significant effect only against HBV. The 2,6-diaminopurine
E-analogue was inactive with the exception of a single EBV assay. The 2-amino-6-methoxypurine
Z-methylenecyclopropane nucleoside analogue was an effective inhibitor of HCMV, MCMV and EBV. The 2,6-diaminopurine
Z-prodrug seems to be the best candidate for further development.
Allozyme variation of 11 putative loci in five populations of the rare Myrica adenophora Hance, and four populations of its widespread congeneric species, M. rubra (Lour.) Sieb. & Zucc. was studied. ...Among the 21 alleles studied, no unique allele was detected for M. adenophora, whereas M. rubra had 3 alleles not found in the former species. In terms of genetic diversity, populations of the rare species contained fewer alleles per locus (1.5 versus 1.7), fewer effective number of alleles per locus (1.12 versus 1.20), fewer number of alleles per polymorphic locus (2.14 versus 2.46), lower percentage of polymorphic loci (30.9 versus 40.9), and lower expected heterozygosity (0.106 versus 0.163) than populations of the widespread species. Genetic distances within species average 0.043 for M. adenophora and 0.045 for M. rubra, and between species ranged from 0.052 to 0.177, with a mean of 0.103, which agrees with the very similar gross morphologies of these two species. Intrapopulation differentiation was similar in both species: G(ST) = 0.152 for M. adenophora, and 0.146 for M. rubra, whereas estimated gene flow based on G(ST) values were moderate in these two species (Nm = 1.39 versus 1.46). We inferred that M. rubra and M. adenophora are a progenitor-derivative species pair that emerged before migrating into Taiwan during the last glacial period. We consider the Hengchun population (Chiupeng, Hsuhai, and Chufengpi) and Taitung population (Tienkuan and Lanshan) of M. adenophora which probably arose from two subsets of the genome of M. rubra. Genetic drift was inferred to be one of the forces shaping the observed genetic structure in M. adenophora and M. rubra.
PDF
