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- ArticleLipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment.Brohée L, Demine S, Willems J, Arnould T, Colige AC, Deroanne CF.Oncotarget. 2015 May 10;6(13):11264-80.Lipogenesis inhibition was reported to induce apoptosis and repress proliferation of cancer cells while barely affecting normal cells. Lipins exhibit dual function as enzymes catalyzing the dephosphorylation of phosphatidic acid to diacylglycerol and as co-transcriptional regulators. Thus, they are able to regulate lipid homeostasis at several nodal points. Here, we show that lipin-1 is up-regulated in several cancer cell lines and overexpressed in 50 % of high grade prostate cancers. The proliferation of prostate and breast cancer cells, but not of non-tumorigenic cells, was repressed upon lipin-1 knock-down. Lipin-1 depletion also decreased cancer cell migration through RhoA activation. Lipin-1 silencing did not significantly affect global lipid synthesis but enhanced the cellular concentration of phosphatidic acid. In parallel, autophagy was induced while AKT and ribosomal protein S6 phosphorylation were repressed. We also observed a compensatory regulation between lipin-1 and lipin-2 and demonstrated that their co-silencing aggravates the phenotype induced by lipin-1 silencing alone. Most interestingly, lipin-1 depletion or lipins inhibition with propranolol sensitized cancer cells to rapamycin. These data indicate that lipin-1 controls main cellular processes involved in cancer progression and that its targeting, alone or in combination with other treatments, could open new avenues in anticancer therapy.
- ArticleQin N, Ma Z, Wang C, Zhang E, Li Y, Huang M, Chen C, Zhang C, Fan J, Gu Y, Xu X, Yang L, Wei X, Yin R, Jiang Y, Dai J, Jin G, Xu L, Hu Z, Shen H, Ma H.Theranostics. 2020;10(24):11264-11277.Rationale: As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. Methods: A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. Results: A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs (P = 7.61×10-3). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, P = 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, P = 5.95×10-12) and clinically-actionable genes (ER = 2.19, P = 3.44×10-4). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, P = 0.015; PFI: HR = 1.64, P = 0.034). Conclusions: The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.
- ArticleYao H, Shiratsu T.Nanoscale. 2016 Jun 07;8(21):11264-74.Large magneto-optical (MO) responses at the energy of localized surface plasmon resonance (LSPR), namely, surface magnetoplasmons, are demonstrated for the first time in thiolate-protected silver nanoparticles with magnetic circular dichroism (MCD) spectroscopy. The samples examined are decanethiol (DT)-, azobenzenethiol (ABT)-, and ABT/DT mixed-monolayer-protected Ag nanoparticles. ABT-protected Ag nanoparticles are somewhat aggregated and thus exhibit a broad, collective mode of plasmonic absorption, whereas other samples with highly-dispersed nanoparticles show an individual mode of LSPR absorption. In all Ag nanoparticles, a derivative-like MCD signal is observed under an applied magnetic field of 1.6 T, which can be explained in terms of two circular modes of magnetoplasmon caused by the increase (or decrease) in the Lorentz force imparted on the free electrons that oscillate in the left (or right) circular orbits in the nanosphere. For the Ag nanoparticles exhibiting an individual LSPR mode, in particular, simultaneous deconvolution analysis of UV-vis absorption and MCD spectra reveal that (i) the amplitude of the magnetoplasmonic component with lower frequency (ω-), resulting from the reduction in the confinement strength of collective electrons by the Lorentz force, is stronger than that with a higher frequency (ω+); (ii) the accurate shift or cyclotron frequency between two magnetoplasmonic modes (ωc = ω+-ω-) is size-dependent, and presents a very large value with implications for the apparent enhancement of the local magnetic-field in the Ag nanoparticles. These results strongly suggest that the Ag-thiolate layer or Ag-S bonding on the nanoparticle surface plays a significant role in the MO enhancement.
- ArticleHuang X, Hou J, Huang S, Feng K, Yue Y, Li H, Huang S, Liang M, Chen G, Wu Z.PeerJ. 2021;9:e11264.BACKGROUND: Myocardial injury is a frequent complication after cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to test the hypothesis that melatonin could attenuate myocardial injury in a rat CPB model.
METHODS: Eighteen male Sprague-Dawley rats were randomly divided into three groups, n = 6 for each group: the sham operation (SO) group, CPB group and melatonin group. Rats in the SO group underwent cannulation without CPB, rats in CPB group intraperitoneal injected an equal volume of vehicle daily for 7 days before being subjected to CPB and rats in melatonin group intraperitoneal injected 20 mg/kg of melatonin solution daily for 7 days before being subjected to CPB. After 120 min for CPB, the expression levels of plasma interleukin (IL) -6, IL-1β, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), creatine kinase (CK) -MB and cardiac troponin T (cTnT) were measured. Reactive oxygen species (ROS) were detected by dihydroethidium (DHE). Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Mitochondrial damage and autophagosomes were detected by electron microscopy. Apoptosis inducing factor (AIF) was detected by immunofluorescence. The expression of B cell lymphoma/leukemia2 associated X (Bax), B cell lymphoma/leukemia 2 (Bcl-2), cytochrome C (Cyto-C), cleaved caspase-9, AKT, p-AKT, signal transducer and activator of transcription 3 (STAT3), p-STAT3, LC3, P62, mechanistic target of rapamycin kinase (mTOR), p-mTOR and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were determined using western blotting.
RESULTS: Melatonin significantly decreased the levels of IL-1β, IL-6, MDA, CK-MB and cTnT and increased the levels of SOD and GSH-Px, all of which were altered by CPB. Melatonin reduced cardiomyocyte superoxide production, the apoptosis index and autophagy in cardiomyocytes induced by CPB. The AKT, STAT3 and mTOR signaling pathways were activated by melatonin during CPB.
CONCLUSION: Melatonin may serve as a cardioprotective factor in CPB by inhibiting oxidative damage, apoptosis and autophagy. The AKT, STAT3 and mTOR signaling pathways were involved in this process. - ArticleTayebi B, Jafarfard MR, Sharif F, Song YS, Har D, Kim DY.Opt Express. 2015 May 04;23(9):11264-71.We present a reduced-phase triple-illumination interferometer (RPTII) as a novel single-shot technique to increase the precision of dual-illumination optical phase unwrapping techniques. The technique employs two measurement ranges to record both low-precision unwrapped and high-precision wrapped phases. To unwrap the high-precision phase, a hierarchical optical phase unwrapping algorithm is used with the low-precision unwrapped phase. The feasibility of this technique is demonstrated by measuring a stepped object with a height 2100 times greater than the wavelength of the source. The phase is reconstructed without applying any numerical unwrapping algorithms, and its noise level is decreased by a factor of ten.
- ArticleXu B, Jiang Q, Zhao A, Jia J, Liu Q, Luo W, Guo C.Chem Commun (Camb). 2015 Jun 30;51(56):11264-7.The conversion of the C[double bond, length as m-dash]O bond of ketones to a C[triple bond, length as m-dash]N bond is described. This conversion is catalyzed by copper salts with ammonium salts as the nitrogen source in the presence of molecular oxygen. A wide variety of ketones can be converted into the corresponding compounds containing a C[triple bond, length as m-dash]N bond. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed.
- ArticleLang K, Su M.Heliyon. 2022 Nov;8(11):e11264.The transverse bending stiffness of a corrugated plate determined using an equivalent orthotropic model based on the Dirichlet boundary conditions and representative volume element method is the upper limit of the real solution, albeit often inaccurate in practice. Based on the Kirchhoff hypothesis, the constitutive relations of corrugated plates were reasonably simplified to propose a new corrugated plate equivalent orthotropic model. The resulting equivalent transverse bending stiffness agreed with the results of the most reasonable simplified expression available. Static response results obtained using the proposed model were more accurate than those obtained using the existing model without a simplified constitutive relation. Furthermore, for dynamic response, the proposed model exhibited improved accuracy when predicting low- and high-order natural frequencies. For the arc-and-tangent corrugated plate, two integral parameter expressions were calculated; the proposed equivalent plate model was verified by comparing the results of a full-scale test of the corrugated metal pipe arch culvert.
- ArticleTakeshita JI, Murakami M, Kamo M, Naito W, Yasutaka T, Imoto S.Sci Rep. 2023 07 12;13(1):11264.Isolation of close contact people and negative test certification are used to manage the spread of new coronavirus infections worldwide. These effectively prevent the spread of infection in advance, but they can lead to a decline in socio-economic activity. Thus, the present study quantified the extent to which isolation and negative test certification respectively reduce the risk of infection. To this end, a discrete-time SEIR model was used as the infectious disease model, and equations for calculating the conditional probability of non-infection status given negative test results on two different days were derived. Then the respective non-infection probabilities with two negative PCR test results, and with one negative PCR test result and one antigen test result, were quantified. By substituting initial parameters of the SEIR model into these probabilities, the present study revealed the following: (1) isolating close contact individuals can reduce by [Formula: see text] the risk of infection during the first 5 days, but five more days are needed to reduce the risk [Formula: see text] more, and seven more days to reduce the risk [Formula: see text] more; and (2) if an individual with a negative PCR test result has a negative antigen test result the next day, then his or her infection probability is between 0.6 and [Formula: see text]. Our results show that 5-day isolation has a proportionally greater effect on risk reduction, compared to longer isolation; and thus, if an isolation period of longer than 5 days is contemplated, both the risk reduction and the negative effects from such increased isolation should be considered. Regarding negative test certification, our results provide those in managerial positions, who must decide whether to accept the risk and hold mass-gathering events, with quantitative information that may be useful in their decision-making.
- ArticleYoshida M, Nakabayashi K, Yang W, Sato-Otsubo A, Tsujimoto SI, Ogata-Kawata H, Kawai T, ... Show More Ishiwata K, Sakamoto M, Okamura K, Yoshida K, Shirai R, Osumi T, Kiyotani C, Shioda Y, Terashima K, Ishimaru S, Yuza Y, Takagi M, Arakawa Y, Imamura T, Hasegawa D, Inoue A, Yoshioka T, Ito S, Tomizawa D, Koh K, Matsumoto K, Kiyokawa N, Ogawa S, Manabe A, Niwa A, Hata K, Yang JJ, Kato M.Cancer Med. 2023 05;12(10):11264-11273.BACKGROUND: Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors.
METHODS: We performed whole-exome sequencing in 14 pediatric patients with SMNs, including three brain tumors.
RESULTS: Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer-predisposing genes (CPGs), which was significantly higher than in the control cohort (p < 0.01). The identified genes with variants were TP53 (n = 2), DICER1 (n = 1), PMS2 (n = 1), and PTCH1 (n = 1). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development.
CONCLUSIONS: We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers. - ArticleMandridis D, Ozdur I, Bagnell M, Delfyett PJ.Opt Express. 2010 May 24;18(11):11264-9.In this work a narrow linewidth (1 kHz) laser source is used to measure the free spectral range of a fiberized Fabry-Perot etalon with sub-Hz accuracy (10(-8)). A previously demonstrated technique based on the Pound-Drever-Hall error signal is improved in accuracy by the use of a narrow linewidth laser swept in frequency via an acousto-optic modulator, or single sideband generation. The sub-Hz (10(-8)) accuracy attained enables the characterization of both the long-term drift and the polarization dependence of the free spectral range of the fiberized etalon.
- ArticleAlshareef NO, Otterbach SL, Allu AD, Woo YH, de Werk T, Kamranfar I, Mueller-Roeber B, Tester M, Balazadeh S, Schmöckel SM.Sci Rep. 2022 07 04;12(1):11264.Pre-exposing (priming) plants to mild, non-lethal elevated temperature improves their tolerance to a later higher-temperature stress (triggering stimulus), which is of great ecological importance. 'Thermomemory' is maintaining this tolerance for an extended period of time. NAM/ATAF1/2/CUC2 (NAC) proteins are plant-specific transcription factors (TFs) that modulate responses to abiotic stresses, including heat stress (HS). Here, we investigated the potential role of NACs for thermomemory. We determined the expression of 104 Arabidopsis NAC genes after priming and triggering heat stimuli, and found ATAF1 expression is strongly induced right after priming and declines below control levels thereafter during thermorecovery. Knockout mutants of ATAF1 show better thermomemory than wild type, revealing a negative regulatory role. Differential expression analyses of RNA-seq data from ATAF1 overexpressor, ataf1 mutant and wild-type plants after heat priming revealed five genes that might be priming-associated direct targets of ATAF1: AT2G31260 (ATG9), AT2G41640 (GT61), AT3G44990 (XTH31), AT4G27720 and AT3G23540. Based on co-expression analyses applied to the aforementioned RNA-seq profiles, we identified ANAC055 to be transcriptionally co-regulated with ATAF1. Like ataf1, anac055 mutants show improved thermomemory, revealing a potential co-control of both NAC TFs over thermomemory. Our data reveals a core importance of two NAC transcription factors, ATAF1 and ANAC055, for thermomemory.
- ArticleYao HW, Ling P, Tung YY, Hsu SM, Chen SH.J Virol. 2014 Oct;88(19):11264-70.UNLABELLED: Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ.
IMPORTANCE: Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain. - ArticleSilvers WC, Payne AS, McCarley RL.Chem Commun (Camb). 2011 Oct 28;47(40):11264-6.A new quinone propionic acid-cloaked rhodamine fluorophore has its fluorescence revealed (de-cloaked) upon activation by human NAD(P)H:quinone oxidoreductase 1 (hNQO1), an upregulated enzyme in cancer cells and tumors.
- ArticleKhine WWT, Haldar S, De Loi S, Lee YK.Sci Rep. 2021 05 28;11(1):11264.Short-term changes in dietary intake can induce changes in gut microbiome. While various dietary polyphenols have been shown to modulate gut microflora, the acute influence of polyphenol-rich mixed spices has not been explored in a controlled setting. We investigated the effects of a single serving of mixed spices Indian curry consumption, in two separate doses, on the gut microbiome in 15 healthy, Singaporean Chinese males, with age and BMI of 23.5 ± 2.4 years and 22.9 ± 2.2 kg/m2 respectively. We found that a low-polyphenol, no spices Dose 0 Control (D0C) meal led to an increase in Bacteroides and a decrease in Bifidobacterium. In comparison to D0C, there was significant suppression of Bacteroides (p < 0.05) and an increase in Bifidobacterium (p < 0.05) with increasing doses of curry meal Dose 1 Curry (D1C) and Dose 2 Curry (D2C) containing 6 g and 12 g mixed spices respectively. Significant correlations were also found between bacterial changes and plasma phenolic acids. No differences between treatments were observed in the alpha-diversity of the gut microflora. This study has shown that a single serving of mixed spices can significantly modify/restore certain commensal microbes, particularly in people who do not regularly consume these spices.
- ArticleDul MC, Ferrando-Soria J, Pardo E, Lescouëzec R, Journaux Y, Ruiz-García R, Cano J, Julve M, Lloret F, Fabelo O, Pasán J, Ruiz-Pérez C.Inorg Chem. 2010 Dec 20;49(24):11264-6.Two new heterometallic Ni(II)(n)Cu(II)((9-n)) complexes [n = 1 (2) and 2 (3)] have been synthesized following a multicomponent self-assembly process from a n:(3 - n):2:6 stoichiometric mixture of Ni(2+), Cu(2+), L(6-), and [CuL'](2+), where L and L' are the bridging and blocking ligands 1,3,5-benzenetris(oxamate) and N,N,N',N'',N''-pentamethyldiethylenetriamine, respectively. Complexes 2 and 3 possess a unique cyclindrical architecture formed by three oxamato-bridged trinuclear linear units connected through two 1,3,5-substituted benzenetris(amidate) bridges, giving a triangular metallacyclophane core. They behave as a ferromagnetically coupled trimer of two (2)/one (3) S = (1)/(2) Cu(II)(3) plus one (2)/two (3) S = 0 Ni(II)Cu(II)(2) linear units with overall S = 1 Ni(II)Cu(II)(8) (2) and S = (1)/(2) Ni(II)(2)Cu(II)(7) (3) ground states.
- ArticleFrank RA, Komiyama NH, Ryan TJ, Zhu F, O'Dell TJ, Grant SG.Nat Commun. 2016 04 27;7:11264.How neuronal proteomes self-organize is poorly understood because of their inherent molecular and cellular complexity. Here, focusing on mammalian synapses we use blue-native PAGE and 'gene-tagging' of GluN1 to report the first biochemical purification of endogenous NMDA receptors (NMDARs) directly from adult mouse brain. We show that NMDARs partition between two discrete populations of receptor complexes and ∼1.5 MDa supercomplexes. We tested the assembly mechanism with six mouse mutants, which indicates a tripartite requirement of GluN2B, PSD93 and PSD95 gate the incorporation of receptors into ∼1.5 MDa supercomplexes, independent of either canonical PDZ-ligands or GluN2A. Supporting the essential role of GluN2B, quantitative gene-tagging revealed a fourfold molar excess of GluN2B over GluN2A in adult forebrain. NMDAR supercomplexes are assembled late in postnatal development and triggered by synapse maturation involving epigenetic and activity-dependent mechanisms. Finally, screening the quaternary organization of 60 native proteins identified numerous discrete supercomplexes that populate the mammalian synapse.
- ArticleHamchand R, Hanley D, Prum RO, Brückner C.Sci Rep. 2020 07 09;10(1):11264.To date, only two pigments have been identified in avian eggshells: rusty-brown protoporphyrin IX and blue-green biliverdin IXα. Most avian eggshell colours can be produced by a mixture of these two tetrapyrrolic pigments. However, tinamou (Tinamidae) eggshells display colours not easily rationalised by combination of these two pigments alone, suggesting the presence of other pigments. Here, through extraction, derivatization, spectroscopy, chromatography, and mass spectrometry, we identify two novel eggshell pigments: yellow-brown tetrapyrrolic bilirubin from the guacamole-green eggshells of Eudromia elegans, and red-orange tripyrrolic uroerythrin from the purplish-brown eggshells of Nothura maculosa. Both pigments are known porphyrin catabolites and are found in the eggshells in conjunction with biliverdin IXα. A colour mixing model using the new pigments and biliverdin reproduces the respective eggshell colours. These discoveries expand our understanding of how eggshell colour diversity is achieved. We suggest that the ability of these pigments to photo-degrade may have an adaptive value for the tinamous.
- ArticleRashid H, Bakht K, Arslan A, Ahmad A.Cureus. 2020 Oct 30;12(10):e11264.Introduction Dysphagia is highly prevalent in patients with a history of recurrent acid peptic disease. Endoscopy is the mainstay of diagnostic workup of these patients to reach underlying cause and appropriate subsequent treatment. The objective of the study was to determine the frequency of various types of endoscopic findings in patients with dysphagia and the association of these findings with gender, age and duration of symptoms. Methods This cross-sectional study was carried out in the Department of Gastroenterology of a tertiary care hospital in Rawalpindi, Pakistan. A total of 137 patients who presented with a history of dysphagia for at least two weeks were enrolled in the study. Duration of symptoms was noted, and all patients underwent upper gastrointestinal endoscopy to find out the cause of dysphagia. Tissue biopsies were obtained, and further histopathological examination was performed to correlate the findings with symptoms of dysphagia. Results A total of 137 patients were enrolled for six months. The mean age of the patients was 56.9 ± 17.44 years, and the mean duration of symptoms was 15.96 ± 12.31 weeks. There were 65 (47.4%) males and 72 (52.6%) females in the study. Majority of them, 123 (89.8%), presented with a short duration of symptoms that varied between 2-24 weeks and were mainly middle-aged (31-60 years) and old-aged (61-80 years). The most commonly observed endoscopic findings were esophageal stricture in 25 (18.2%), achalasia cardia in 20 (14.6%), esophageal mass in 12 (8.8%) and reflux esophagitis in 7 (5%) patients. No association was seen between age, gender and duration of symptoms and findings on the endoscopy. Conclusion Dysphagia is associated with many endoscopic findings that are not related to demographic variables and must be evaluated earlier to reduce further morbidity and mortality.
- ArticleAsbach B, Meier JP, Pfeifer M, Köstler J, Wagner R.Sci Rep. 2018 07 26;8(1):11264.The partially protective phenotype observed in HIV-infected long-term-non-progressors is often associated with certain HLA alleles, thus indicating that cytotoxic T lymphocyte (CTL) responses play a crucial role in combating virus replication. However, both the vast variability of HIV and the HLA diversity impose a challenge on elicitation of broad and effective CTL responses. Therefore, we conceived an algorithm for the enrichment of CD8+ T cell epitopes in HIV's Gag protein, respecting functional preservation to enable cross-presentation. Experimentally identified epitopes were compared to a Gag reference sequence. Amino-acid-substitutions (AAS) were assessed for their impact on Gag's budding-function using a trained classifier that considers structural models and sequence conservation. Experimental assessment of Gag-variants harboring selected AAS demonstrated an apparent classifier-precision of 100%. Compatible epitopes were assigned an immunological score that incorporates features such as conservation or HLA-association in a user-defined weighted manner. Using a genetic algorithm, the epitopes were incorporated in an iterative manner into novel T-cell-epitope-enriched Gag sequences (TeeGag). Computational evaluation showed that these antigen candidates harbor a higher fraction of epitopes with higher score as compared to natural Gag isolates and other artificial antigen designs. Thus, these designer sequences qualify as next-generation antigen candidates for induction of broader CTL responses.
- ArticleYu C, Boon D, McDonald SL, Myers TG, Tomioka K, Nguyen H, Engle RE, Govindarajan S, Emerson SU, Purcell RH.J Virol. 2010 Nov;84(21):11264-78.The chimpanzee is the only animal model for investigating the pathogenesis of viral hepatitis types A through E in humans. Studies of the host response, including microarray analyses, have relied on the close relationship between these two primate species: chimpanzee samples are commonly tested with human-based reagents. In this study, the host responses to two dissimilar viruses, hepatitis E virus (HEV) and hepatitis C virus (HCV), were compared in multiple experimentally infected chimpanzees. Affymetrix U133+2.0 human microarray chips were used to assess the entire transcriptome in serial liver biopsies obtained over the course of the infections. Respecting the limitations of microarray probes designed for human target transcripts to effectively assay chimpanzee transcripts, we conducted probe-level analysis of the microarray data in conjunction with a custom mapping of the probe sequences to the most recent human and chimpanzee genome sequences. Time points for statistical comparison were chosen based on independently measured viremia levels. Regardless of the viral infection, the alignment of differentially expressed genes to the human genome sequence resulted in a larger number of genes being identified when compared with alignment to the chimpanzee genome sequence. This probably reflects the lesser refinement of gene annotation for chimpanzees. In general, the two viruses demonstrated very distinct temporal changes in host response genes, although both RNA viruses induced genes that were involved in many of the same biological systems, including interferon-induced genes. The host response to HCV infection was more robust in the magnitude and number of differentially expressed genes compared to HEV infection.