Variation at APOE and STH loci and Alzheimer's disease

BACKGROUND: The apolipoprotein E (APOE) and tau proteins play important roles in the pathological development of Alzheimer's disease (AD). Many studies have shown an association between the APOE gene and AD. Association between AD and the newly discovered saitohin (STH) gene, nested within the intron of the tau gene, has been reported. The present study aimed to elucidate the association between APOE and AD, and between STH and AD in our sample. METHODS: The functional polymorphisms, rs429358 and rs7412, in the APOE gene (which together define the ε2, ε3, and ε4 alleles), and the Q7R SNP in the STH gene, were genotyped in 369 patients with AD and 289 healthy European-Americans. The associations between these two genes and AD were analyzed in a case-control design. RESULTS: Consistent with previously reported results, the frequencies of the APOE ε4 allele, ε4/ε4 genotype and ε3/ε4 genotype were significantly higher in AD cases than controls; the ε4/ε4 genotype frequency was significantly higher in early-onset AD (EOAD) than late-onset AD (LOAD); the frequencies of the ε2 allele, ε3 allele, ε3/ε3 genotype and ε2/ε3 genotype were significantly lower in AD cases than controls. Positive likelihood ratios (LRs(+)) of APOE alleles and genotypes increased in a linear trend with the number of ε4 alleles and decreased in a linear trend with the number of ε2 or ε3 alleles. There was no significant difference in the STH allele and genotype frequency distributions between AD cases and controls. CONCLUSION: This study confirmed that the ε4 allele is a dose-response risk factor for AD and the ε4/ε4 genotype was associated with a significantly earlier age of onset. Moreover, we found that the ε2 allele was a dose-response protective factor for AD and the ε3 allele exerted a weaker dose-response protective effect for risk of AD compared with ε2. In a clinical setting, APOE genotyping could offer additional biological evidence of whether a subject may develop AD, but it is not robust enough to serve as an independent screening or predictive test in the diagnosis of AD. STH variation was not significantly associated with AD in our sample

A single-amino-acid substitution in the HA protein changes the replication and pathogenicity of the 2009 pandemic A (H1N1) influenza viruses in vitro and in vivo

BACKGROUND: The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and since then it spread world wide over a short period of time. Although the virus infection is generally associated with mild disease and a relatively low mortality, it is projected that mutations in specific regions of the viral genome, especially within the receptor binding domain of the hemagglutinin (HA) protein could result in more virulent virus stains, leading to a more severe pandemic. RESULTS: Here, we found that a single amino acid substitution of Asp-to-Gly at position 222 in the HA protein of the A (H1N1) virus occurred after two passage propagation in the allantoic cavities of chicken embryonated eggs, and this single residue variation dramatically increased the viral replication ability in MDCK cells and pathogenicity in BALB/c mice. CONCLUSIONS: A substitution of Asp-to-Gly at position 222 in the HA protein was prone to occur under positive selection pressures, and this single amino acid mutation could dramatically increase the virus replication ability in vitro and pathogenicity in vivo. Our finding offers a better understanding of the transmission and evolution of the 2009 pandemic A (H1N1) virus and brings attention to further potentially severe influenza pandemic that may result from cross-host evolution of the influenza viruses

Improved Electrochemical Performance of Surface Coated LiNi0.80Co0.15Al0.05O2 With Polypyrrole

Nickel-rich ternary layered oxide (LiNi0.80Co0.15Al0.05O2, LNCA) cathodes are favored in many fields such as electric vehicles due to its high specific capacity, low cost, and stable structure. However, LNCA cathode material still has the disadvantages of low initial coulombic efficiency, rate capability and poor cycle performance, which greatly restricts its commercial application. To overcome this barrier, a polypyrrole (PPy) layer with high electrical conductivity is designed to coat on the surface of LNCA cathode material. PPy coating layer on the surface of LNCA successfully is realized by means of liquid-phase chemical oxidation polymerization method, and which has been verified by the scanning electron microscopy (SEM), transmission electron microscope (TEM) and fourier transform infrared spectroscopy (FTIR). PPy-coated LNCA (PL-2) exhibits satisfactory electrochemical performances including high reversible capacity and excellent rate capability. Furthermore, the capability is superior to pristine LNCA. So, it provides a new structure of conductive polymer modified cathode materials with good property through a mild modification method

Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere

TRF1 is a key component of the telomere-capping complex and binds double-strand telomeric DNA as homodimers. So far, it is not clear whether TRF1 dimerization coincides with its telomere binding or is actively controlled before it binds the telomere, and in the latter case, how this event might affect its telomere association. We previously found that TRF1 dimerization and its telomere binding can be increased by GNL3L, which is the vertebrate paralogue of nucleostemin (NS). Here, we show that NS and GNL3L bind TRF1 directly but competitively through two separate domains of TRF1. In contrast to GNL3L, NS prevents TRF1 dimerization through a mechanism not determined by its ability to displace TRF1-bound GNL3L. Furthermore, NS is capable of shortening the dynamic association of TRF1 with the telomere in normal and TRF2(ΔBΔM)-induced telomere-damaged cells without affecting the amount of telomere-bound TRF1 proteins in vivo. Importantly, NS displays a protective function against the formation of telomere-dysfunction-induced foci. This work demonstrates that TRF1 dimerization is actively and oppositely regulated by NS and GNL3L extrachromosomally. Changing the relative amount of TRF1 monomers versus dimers in the nucleoplasm might affect the dynamic association of TRF1 with the telomere and the repair of damaged telomeres

A five-collagen-based risk model in lung adenocarcinoma: prognostic significance and immune landscape

As part of the tumor microenvironment (TME), collagen plays a significant role in cancer fibrosis formation. However, the collagen family expression profile and clinical features in lung adenocarcinoma (LUAD) are poorly understood. The objective of the present work was to investigate the expression pattern of genes from the collagen family in LUAD and to develop a predictive signature based on collagen family. The Cancer Genome Atlas (TCGA) samples were used as the training set, and five additional cohort samples obtained from the Gene Expression Omnibus (GEO) database were used as the validation set. A predictive model based on five collagen genes, including COL1A1, COL4A3, COL5A1, COL11A1, and COL22A1, was created by analyzing samples from the TCGA cohort using LASSO Cox analysis and univariate/multivariable Cox regression. Using Collagen-Risk scores, LUAD patients were then divided into high- and low-risk groups. KM survival analysis showed that collagen signature presented a robust prognostic power. GO and KEGG analyses confirmed that collagen signature was associated with extracellular matrix organization, ECM-receptor interaction, PI3K-Akts and AGE-RAGE signaling activation. High-risk patients exhibited a considerable activation of the p53 pathway and cell cycle, according to GSEA analysis. The Collage-Risk model showed unique features in immune cell infiltration and tumor-associated macrophage (TAM) polarization of the TME. Additionally, we deeply revealed the association of collagen signature with immune checkpoints (ICPs), tumor mutation burden (TMB), and tumor purity. We first constructed a reliable prognostic model based on TME principal component—collagen, which would enable clinicians to treat patients with LUAD more individually

Resting-state functional magnetic resonance imaging reveals brain remodeling after Tuina therapy in neuropathic pain model

Tuina, a method of traditional Chinese manual manipulation, is an effective alternative therapy for neuropathic pain (NP), but its analgesic mechanism remains unclear. In this study, we used resting-state functional magnetic resonance imaging (R-fMRI) to explore the analgesic mechanism of Tuina in an NP rat model. After undergoing surgery to induce chronic compression of the dorsal root ganglion (CCD), one group of rats underwent Tuina at the ipsilateral BL40 acupoint once a day for 10 min during the 25 days following surgery while another group did not. Behavioral tests were performed at baseline, on the third day following surgery, and once a week for the next 4 weeks. R-fMRI was performed at baseline and 7 days and 28 days following surgery. Behavioral testing revealed that the Tuina group presented a significant response improvement to mechanical and thermal nociception stimuli compared to the untreated group 2 weeks following CCD surgery. Interestingly, rats submitted to Tuina presented higher measures of spontaneous neuronal activity in basal forebrain region, primary somatosensory cortex barrel field, dentate gyrus, secondary somatosensory cortex, striatum, descending corticofugal pathways, and globus pallidum of the left hemisphere 4 weeks after the CCD surgery compared to rats having undergone CCD only. In addition, on the 28th day, the ALFF signals of the left dentate gyrus, left secondary somatosensory cortex, left striatum, and bilateral primary cingulate cortex were significantly increased while those in the right dentate gyrus and bilateral periaqueductal gray were significantly decreased compared to those on the 7th day. Correlation analysis showed that the ALFF values of the left descending corticofugal pathways and globus pallidum had a positive correlation with mechanical withdrawal threshold and paw withdrawal thermal latency tests. Altogether, these results indicate that NPP induced by CCD surgery affects the plasticity of the cerebral cortex, and that Tuina alleviate pain behavior by promoting cortical remodeling

Genomic Polymorphism of the Pandemic A (H1N1) Influenza Viruses Correlates with Viral Replication, Virulence, and Pathogenicity In Vitro and In Vivo

The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and quickly spread worldwide. Like all influenzas, the H1N1 strain-specific properties of replication, virulence, and pathogenicity are a result of the particular genomic sequence and concerted expression of multiple genes. Thus, specific mutations may support increased virulence and may be useful as biomarkers of potential threat to human health. We performed comparative genomic analysis of ten strains of the 2009 pandemic A (H1N1) influenza viruses to determine whether genotypes associated with clinical phenotypes, which ranged from mild to severe illness and up to lethal. Virus replication capacity was tested for each strain in vitro using cultured epithelial cells, while virulence and pathogenicity were investigated in vivo using the BALB/c mouse model. The results indicated that A/Sichuan/1/2009 strain had significantly higher replication ability and virulence than the other strains, and five unique non-synonymous mutations were identified in important gene-encoding sequences. These mutations led to amino acid substitutions in HA (L32I), PA (A343T), PB1 (K353R and T566A), and PB2 (T471M), and may be critical molecular determinants for replication, virulence, and pathogenicity. Our results suggested that the replication capacity in vitro and virulence in vivo of the 2009 pandemic A (H1N1) viruses were not associated with the clinical phenotypes. This study offers new insights into the transmission and evolution of the 2009 pandemic A (H1N1) virus

Adaption of Seasonal H1N1 Influenza Virus in Mice

The experimental infection of a mouse lung with influenza A virus has proven to be an invaluable model for studying the mechanisms of viral adaptation and virulence. The mouse adaption of human influenza A virus can result in mutations in the HA and other proteins, which is associated with increased virulence in mouse lungs. In this study, a mouse-adapted seasonal H1N1 virus was obtained through serial lung-to-lung passages and had significantly increased virulence and pathogenicity in mice. Genetic analysis indicated that the increased virulence of the mouse-adapted virus was attributed to incremental acquisition of three mutations in the HA protein (T89I, N125T, and D221G). However, the mouse adaption of influenza A virus did not change the specificity and affinity of receptor binding and the pH-dependent membrane fusion of HA, as well as the in vitro replication in MDCK cells. Notably, infection with the mouse adapted virus induced severe lymphopenia and modulated cytokine and chemokine responses in mice. Apparently, mouse adaption of human influenza A virus may change the ability to replicate in mouse lungs, which induces strong immune responses and inflammation in mice. Therefore, our findings may provide new insights into understanding the mechanisms underlying the mouse adaption and pathogenicity of highly virulent influenza viruses