Mining Pure, Strict Epistatic Interactions from High-Dimensional Datasets: Ameliorating the Curse of Dimensionality

Background: The interaction between loci to affect phenotype is called epistasis. It is strict epistasis if no proper subset of the interacting loci exhibits a marginal effect. For many diseases, it is likely that unknown epistatic interactions affect disease susceptibility. A difficulty when mining epistatic interactions from high-dimensional datasets concerns the curse of dimensionality. There are too many combinations of SNPs to perform an exhaustive search. A method that could locate strict epistasis without an exhaustive search can be considered the brass ring of methods for analyzing high-dimensional datasets. Methodology/Findings: A SNP pattern is a Bayesian network representing SNP-disease relationships. The Bayesian score for a SNP pattern is the probability of the data given the pattern, and has been used to learn SNP patterns. We identified a bound for the score of a SNP pattern. The bound provides an upper limit on the Bayesian score of any pattern that could be obtained by expanding a given pattern. We felt that the bound might enable the data to say something about the promise of expanding a 1-SNP pattern even when there are no marginal effects. We tested the bound using simulated datasets and semi-synthetic high-dimensional datasets obtained from GWAS datasets. We found that the bound was able to dramatically reduce the search time for strict epistasis. Using an Alzheimer's dataset, we showed that it is possible to discover an interaction involving the APOE gene based on its score because of its large marginal effect, but that the bound is most effective at discovering interactions without marginal effects. Conclusions/Significance: We conclude that the bound appears to ameliorate the curse of dimensionality in high-dimensional datasets. This is a very consequential result and could be pivotal in our efforts to reveal the dark matter of genetic disease risk from high-dimensional datasets. © 2012 Jiang, Neapolitan

Smart Substation Network Fault Classification Based on a Hybrid Optimization Algorithm

Accurate network fault diagnosis in smart substations is key to strengthening grid security. To solve fault classification problems and enhance classification accuracy, we propose a hybrid optimization algorithm consisting of three parts: anti-noise processing (ANP), an improved separation interval method (ISIM), and a genetic algorithm-particle swarm optimization (GA-PSO) method. ANP cleans out the outliers and noise in the dataset. ISIM uses a support vector machine (SVM) architecture to optimize SVM kernel parameters. Finally, we propose the GA-PSO algorithm, which combines the advantages of both genetic and particle swarm optimization algorithms to optimize the penalty parameter. The experimental results show that our proposed hybrid optimization algorithm enhances the classification accuracy of smart substation network faults and shows stronger performance compared with existing methods

Effect of high heat treatment and β-casein-reduction on the rennet coagulation and ripening of Cheddar and Emmental cheeses manufactured from micellar casein concentrate

Microfiltration (MF) removed 53.60 ‒ 70.29 % of native whey protein from pasteurized skim milk to permeate, and retained micellar casein concentrate (MCC) (89.64 - 93.64 % of casein expressed as percentage of total protein) in the retentate. The objective of this thesis was to formulate cheesemilk of desired composition by using MF and to study how each component affect cheese quality. In this thesis, (1) the influence of temperature, number of diafiltration (DF) steps, composition of DF media as well as type of MF membrane on the composition of MCC was examined; (2) the effect of levels of total casein, β-casein or whey protein in cheesemilk on the qualities of semi-hard cheese (Cheddar or Emmental) made therefrom were evaluated and (3) as casein micelles is more heat stable than whey protein, the heat stability of MCC and its impact on resultant cheesemilk was also analysed. Compared to MF without a DF step, DF with water increased the removal of whey protein and small molecules, such as lactose and soluble salts, from feed milk to permeate and the depletion of solutes present in the serum phase of milk increased with an increasing number of DF steps. The rennet coagulability of cheesemilk in addition to the composition, pH, texture, yield, flowability and colour in resultant cheeses were not affected by the whey protein content of the cheesemilk. However, removing whey protein from milk increased the plasmin activity of the cheesemilk formulated therefrom and also increased the level of primary proteolysis (as measured by urea-PAGE and HPLC) in the resultant Emmental cheeses. Increasing the casein content in cheesemilk led to an increased gel firming rate in milk and an increase in hardness, pH and plasmin activity as well as a decrease in moisture content and primary proteolysis in the resultant Cheddar cheese. Reducing β-casein levels from milk by 4.25 % neither affected the rennet coagulation properties of cheesemilk nor influenced the composition, pH, plasmin activity, primary proteolysis, texture profile, flowability and colour in the resultant Emmental cheese. Depletion of milk whey protein content in milk by either 53.60 % or 70.29 % largely increased milk heat stability as measured by rennet coagulation, plasmin activity and cheese quality. Subjecting MCC with 70.29 % whey protein depletion to 90 °C for 15 s neither impaired the rennet coagulation properties of cheese milk prepared therefrom nor altered the composition, texture profile, meltability and volatile profile of resultant Cheddar cheese. However for whey protein reduced-milk (53.60 %) heated at 120 °C for 15 s, the rennet coagulability and plasmin activity in the resultant cheesemilk were significantly reduced, with the flowability in the resultant Emmental cheese decreased and redness increased. Overall, the results generated from this research will help cheesemakers to formulate cheesemilk of desired composition and milk with superior heat stability by using MF and micellar casein concentrates. This research also generated new knowledge on the interactions between cheesemilk components and processes to which the milk is subjected to and how this influences the quality of semi-hard cheeses produced therefrom

The autophagic degradation of cytosolic pools of peroxisomal proteins by a new selective pathway.

Damaged or redundant peroxisomes and their luminal cargoes are removed by pexophagy, a selective autophagy pathway. In yeasts, pexophagy depends mostly on the pexophagy receptors, such as Atg30 for Pichia pastoris and Atg36 for Saccharomyces cerevisiae, the autophagy scaffold proteins, Atg11 and Atg17, and the core autophagy machinery. In P. pastoris, the receptors for peroxisomal matrix proteins containing peroxisomal targeting signals (PTSs) include the PTS1 receptor, Pex5, and the PTS2 receptor and co-receptor, Pex7 and Pex20, respectively. These shuttling receptors are predominantly cytosolic and only partially peroxisomal. It remains unresolved as to whether, when and how the cytosolic pools of peroxisomal receptors, as well as the peroxisomal matrix proteins, are degraded under pexophagy conditions. These cytosolic pools exist both in normal and mutant cells impaired in peroxisome biogenesis. We report here that Pex5 and Pex7, but not Pex20, are degraded by an Atg30-independent, selective autophagy pathway. To enter this selective autophagy pathway, Pex7 required its major PTS2 cargo, Pot1. Similarly, the degradation of Pex5 was inhibited in cells missing abundant PTS1 cargoes, such as alcohol oxidases and Fox2 (hydratase-dehydrogenase-epimerase). Furthermore, in cells deficient in PTS receptors, the cytosolic pools of peroxisomal matrix proteins, such as Pot1 and Fox2, were also removed by Atg30-independent, selective autophagy, under pexophagy conditions. In summary, the cytosolic pools of PTS receptors and their cargoes are degraded via a pexophagy-independent, selective autophagy pathway under pexophagy conditions. These autophagy pathways likely protect cells from futile enzymatic reactions that could potentially cause the accumulation of toxic cytosolic products.Abbreviations: ATG: autophagy related; Cvt: cytoplasm to vacuole targeting; Fox2: hydratase-dehydrogenase-epimerase; PAGE: polyacrylamide gel electrophoresis; Pot1: thiolase; PMP: peroxisomal membrane protein; Pgk1: 3-phosphoglycerate kinase; PTS: peroxisomal targeting signal; RADAR: receptor accumulation and degradation in the absence of recycling; RING: really interesting new gene; SDS: sodium dodecyl sulphate; TCA, trichloroacetic acid; Ub: ubiquitin; UPS: ubiquitin-proteasome system Vid: vacuole import and degradation

MicroRNA Profiling and Head and Neck Cancer

Head and neck/oral cancer (HNOC) is a devastating disease. Despite advances in diagnosis and treatment, mortality rates have not improved significantly over the past three decades. Improvement in patient survival requires a better understanding of the disease progression so that HNOC can be detected early in the disease process and targeted therapeutic interventions can be deployed. Accumulating evidence suggests that microRNAs play important roles in many human cancers. They are pivotal regulators of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, and morphogenesis. MicroRNA expression patterns may become powerful biomarkers for diagnosis and prognosis of HNOC. In addition, microRNA therapy could be a novel strategy for HNOC prevention and therapeutics. Recent advances in microRNA expression profiling have led to a better understanding of the cancer pathogenesis. In this review, we will survey recent technological advances in microRNA profiling and their applications in defining microRNA markers/targets for cancer prediction, diagnostics, treatment, and prognostics. MicroRNA alterations that consistently identified in HNOC will be discussed, such as upregulation of miR-21, miR-31, miR-155, and downregulation of miR-26b, miR-107, miR-133b, miR-138, and miR-139

Toeplitz Operators on Dirichlet-Type Space of Unit Ball

We construct a function u in L2Bn, dV which is unbounded on any neighborhood of each boundary point of Bn such that Toeplitz operator Tu is a Schatten p-class 0<p<∞ operator on Dirichlet-type space DBn, dV. Then, we discuss some algebraic properties of Toeplitz operators with radial symbols on the Dirichlet-type space DBn, dV. We determine when the product of two Toeplitz operators with radial symbols is a Toeplitz operator. We investigate the zero-product problem for several Toeplitz operators with radial symbols. Furthermore, the corresponding commuting problem of Toeplitz operators whose symbols are of the form ξku is studied, where k ∈ Zn, ξ ∈ ∂Bn, and u is a radial function

Production of Exopolysaccharides from Submerged Culture of Antrodia Camphorata S-29

Antrodia camphorata is a unique mushroom of Taiwan, which has been used as a natural therapeutic ingredient in Traditional Chinese Medicine (TCM) for protection of diverse health related conditions. Polysaccharides produced from A. camphorata have attracted much attention of research due to cytotoxic activity and miscellaneous activities. In this paper, we report on the fermentation conditions species-specific exopolysaccharides (EPS) from A. camphorata in submerged culture. A favorable medium for EPS production was obtained only by single-factor experiment, where Glucose and Yeast-Extracts were identified to be the most suitable carbon and nitrogen sources, with the concentration of 40 g/L and 5.0 g/L respectively. Zinc sulphate was identified to be the best salt source with the concentration of 0.4g/l. Initial pH and inoculum size for mycelial growth and EPS yield were 6.0 and 15% respectively. The maximum EPS production was 0.474 g/L in shake-flask culture, which is higher than the baseline media that was 0.351 g/L. This study provides the baseline information about production conditions for this specific specie which is crucial data to know before any further studies as it determines the properties and quantity of the desired produced specie. Keywords: A. camphorata; Exopolysaccharide; Sub­merged culture

c-Jun NH2-terminal kinase activation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Autophagy is a dynamic catabolic process characterized by the formation of double membrane vacuoles termed autophagosomes. LC3, a homologue of yeast Atg8, takes part in autophagosome formation, but the exact regulation mechanism of LC3 still needs to be elucidated.</p> <p>Methods</p> <p>Ceramide-induced autophagy was determined by detecting LC3 expression with Western blotting and confocal microscopy in human nasopharyngeal carcinoma cell lines CNE2 and SUNE1. The activation of JNK pathway was assessed by Western blotting for phospho-specific forms of JNK and c-Jun. The JNK activity specific inhibitor, SP600125, and siRNA directed against JNK were used to block JNK/c-Jun pathway. ChIP and luciferase reporter analysis were applied to determine whether c-Jun was involved in the regulation of LC3 transcription.</p> <p>Results</p> <p>Ceramide-treated cells exhibited the characteristics of autophagy and JNK pathway activation. Inhibition of JNK pathway could block the ceramide-induced autophagy and the up-regulation of LC3 expression. Transcription factor c-Jun was involved in LC3 transcription regulation in response to ceramide treatment.</p> <p>Conclusions</p> <p>Ceramide could induce autophagy in human nasopharyngeal carcinoma cells, and activation of JNK pathway was involved in ceramide-induced autophagy and LC3 expression.</p

Projecting terrestrial carbon sequestration of the southeastern United States in the 21st century

How terrestrial ecosystems respond to future environmental change in the 21st century is critically important for understanding the feedbacks of terrestrial ecosystems to global climate change. The southeastern United States (SEUS) has been one of the major regions acting as a carbon sink over the past century; yet it is unclear how its terrestrial ecosystems will respond to global environmental change in the 21st century. Applying a process-based ecosystem model (Dynamic Land Ecosystem Model, DLEM) in combination with three projected climate change scenarios (A1B, A2, and B1 from the IPCC report) and changes in atmospheric carbon dioxide, nitrogen deposition, and ozone pollution, we examined the potential changes of carbon storage and fluxes in the terrestrial ecosystems across the SEUS during 2000–2099. Simulation results indicate that SEUS\u27s terrestrial ecosystems will likely continue to sequester carbon in the 21st century, resulting in an increase in total carbon density (i.e., litter, vegetation biomass and soil carbon) from 13.5 kg C/m2 in the 2000s to 16.8 kg C/m2 in the 2090s. The terrestrial gross primary production and net primary production will probably continuously increase, while the net carbon exchange (positive indicates sink and negative indicates source) will slightly decrease. The carbon sequestration is primarily attributed to elevated atmospheric carbon dioxide and nitrogen deposition. Forests, including both deciduous and evergreen, show the largest increase in carbon storage as compared with other biomes, while cropland carbon storage shows a small decrease. The sequestered carbon will be primarily stored in vegetation for deciduous forest and in soil for evergreen forest. The central and eastern SEUS will sequester more carbon, while the western portion of the SEUS will release carbon to the atmosphere. The combined effects of climate and atmospheric changes on carbon fluxes and storage vary among climate models and climate scenarios. The largest increase in carbon storage would occur under the A1B climate scenario simulated by the NCAR climate model. Generally, the A1B scenario would result in more carbon sequestration than A2 and B1 scenarios; and the projected climate condition by the NCAR model would result in more carbon sequestration than other climate models