A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10-19 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC

Multivariate small sample tests for two-way designs with applications to industrial statistics

In this paper, we present a novel nonparametric approach for multivariate analysis of two-way crossed factorial design based on NonParametric Combination applied to Synchronized Permutation tests. This nonparametric hypothesis testing procedure not only allows to overcome the shortcomings of MANOVA test like violation of assumptions such as multivariate normality or covariance homogeneity, but, in an extensive simulation study, reveals to be a powerful instrument both in case of small sample size and many response variables. We contextualize its application in the field of industrial experiments and we assume a linear additive model for the data set analysis. Indeed, the linear additive model interpretation well adapts to the industrial production environment because of the way control of production machineries is implemented. The case of small sample size reflects the frequent needs of practitioners in the industrial environment where there are constraints or limited resources for the experimental design. Furthermore, an increase in rejection rate can be observed under alternative hypothesis when the number of response variables increases with fixed number of observed units. This could lead to a strategical benefit considering that in many real problems it could be easier to collect more information on a single experimental unit than adding a new unit to the experimental design. An application to industrial thermoforming processes is useful to illustrate and highlight the benefits of the adoption of the herein presented nonparametric approach

Effect in supralethally irradiated rats of granulocyte colony- stimulating factor and lisofylline on hematopoietic reconstitution by syngeneic bone marrow or whole organ passenger leukocytes

We have previously shown the existence of migratory hematopoietic stem cells in adult solid organs. This study demonstrates that granulocyte colony- stimulating factor (G-CSF) and lisofylline, a phosphatidic acid inhibitor that suppresses hematopoiesis-inhibiting cytokines, can enhance the engraftment of organ-based hematopoietic stem cells. When syngeneic heart grafts or liver nonparenchymal cells were transplanted into lethally irradiated (9.5 Gy) Lewis rats, complete hematopoietic reconstitution and animal survival were significantly improved by treating the recipient with G- CSF or, to a lesser extent, with lisofylline. Pretreatment of hepatic nonparenchymal cell donors with G-CSF, but not lisofylline, also resulted in striking improvement of recipient survival which was associated with an augmented subpopulation of donor stem cells. The results suggest that these drugs can be used to enhance the chimerism that we postulate to be the basis of organ allograft acceptance

Geometric and dynamic perspectives on phase-coherent and noncoherent chaos

Statistically distinguishing between phase-coherent and noncoherent chaotic dynamics from time series is a contemporary problem in nonlinear sciences. In this work, we propose different measures based on recurrence properties of recorded trajectories, which characterize the underlying systems from both geometric and dynamic viewpoints. The potentials of the individual measures for discriminating phase-coherent and noncoherent chaotic oscillations are discussed. A detailed numerical analysis is performed for the chaotic R\"ossler system, which displays both types of chaos as one control parameter is varied, and the Mackey-Glass system as an example of a time-delay system with noncoherent chaos. Our results demonstrate that especially geometric measures from recurrence network analysis are well suited for tracing transitions between spiral- and screw-type chaos, a common route from phase-coherent to noncoherent chaos also found in other nonlinear oscillators. A detailed explanation of the observed behavior in terms of attractor geometry is given.Comment: 12 pages, 13 figure

Testing for equivalence: an intersection-union permutation solution

The notion of testing for equivalence of two treatments is widely used in clinical trials, pharmaceutical experiments,bioequivalence and quality control. It is essentially approached within the intersection-union (IU) principle. According to this principle the null hypothesis is stated as the set of effects lying outside a suitably established interval and the alternative as the set of effects lying inside that interval. The solutions provided in the literature are mostly based on likelihood techniques, which in turn are rather difficult to handle, except for cases lying within the regular exponential family and the invariance principle. The main goal of present paper is to go beyond most of the limitations of likelihood based methods, i.e. to work in a nonparametric setting within the permutation frame. To obtain practical solutions, a new IU permutation test is presented and discussed. A simple simulation study for evaluating its main properties, and three application examples are also presented.Comment: 21 pages, 2 figure

Bayesian Nonstationary Spatial Modeling for Very Large Datasets

With the proliferation of modern high-resolution measuring instruments mounted on satellites, planes, ground-based vehicles and monitoring stations, a need has arisen for statistical methods suitable for the analysis of large spatial datasets observed on large spatial domains. Statistical analyses of such datasets provide two main challenges: First, traditional spatial-statistical techniques are often unable to handle large numbers of observations in a computationally feasible way. Second, for large and heterogeneous spatial domains, it is often not appropriate to assume that a process of interest is stationary over the entire domain. We address the first challenge by using a model combining a low-rank component, which allows for flexible modeling of medium-to-long-range dependence via a set of spatial basis functions, with a tapered remainder component, which allows for modeling of local dependence using a compactly supported covariance function. Addressing the second challenge, we propose two extensions to this model that result in increased flexibility: First, the model is parameterized based on a nonstationary Matern covariance, where the parameters vary smoothly across space. Second, in our fully Bayesian model, all components and parameters are considered random, including the number, locations, and shapes of the basis functions used in the low-rank component. Using simulated data and a real-world dataset of high-resolution soil measurements, we show that both extensions can result in substantial improvements over the current state-of-the-art.Comment: 16 pages, 2 color figure

An agent-based model for mRNA export through the nuclear pore complex.

mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood. The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known. It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the nuclear pore complex. Using previously published biophysical and biochemical parameters of mRNA export, we implemented a three-dimensional, coarse-grained, agent-based model of mRNA export in the nanosecond regime to gain insight into these issues. On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA and that there is a rate-limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel. Of note, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport. This has implications for future experimental design to study mRNA transport dynamics

Determining Factors Influencing Nuclear Envelope and Nuclear Pore Complex Structure.

The cell’s nuclear envelope (NE) has pores that are stabilized by nuclear pore complexes (NPC), large proteinaceous structures whose function is to mediate transport between the nucleus and cytoplasm. Although the transport process is well studied, the mechanism of NPC assembly from its protein constituents (nucleoporins) is less understood. To investigate NPC biogenesis, I investigated mutants that result in defective NPCs in Saccharomyces cerevisiae. First, I examined mutants in the GPI anchor pathway (gpi1) that resulted in mislocalized nucleoporins by testing two models: gpi1 mutants cause either misregulation of N-linked glycosylation or alter membrane properties. To test the models, I combined gpi1 mutants with a nucleoporin mutant that is susceptible to disruption of glycosylation or with mutants in membrane bending proteins. Select double mutant of each class rescued the growth phenotype of the single mutants. These results indicate that both of the models play a role in NPC assembly. Secondly, we found the proteasome, a complex responsible for degrading proteins is involved in NPC assembly. In order to further investigate interactions between the NPC and the proteasome, I combined the proteasomal mutant with 3 classes of nuclear pore assembly (npa) mutants to test for synergistic interactions. Positive interactions were observed as the proteasome mutant rescued a temperature sensitive npa mutant providing further evidence for the role of the proteasome in NPC assembl