Inflammation and host-microbe signaling in the development and progression of colorectal carcinoma

Gut microbiota play an integral role in the postnatal development and maturation of the intestinal epithelium as well as the innate and adaptive immune system. Gut microbes communicate to the host via pattern recognition receptors (PRRs) which regulate intestinal homeostasis during health and disease. My thesis has elucidated the role of gut microflora and PRR-mediated signaling during inflammation, infection and tumor development. I have examined the relevant contributions of host-microbe crosstalk in the regulation of intestinal tumorigenesis (Paper I and II) and innate immune responses to enteric pathogens (Paper III), as well as the transcriptional regulation of gene expression during inflammation and cancer development (Paper IV). In Paper I, the role of microbiota-derived signals in promoting tumor growth in APCMin/+ mice, a mouse model of colorectal cancer (CRC) was examined. Our data showed that germ-free APCMin/+ mice have a reduced tumor load compared to that observed in APCMin/+ mice harboring gut microbiota. Further in-depth characterization studies suggested a role for c-Jun/JNK and myeloid cell-dependent STAT3 activation pathways in the acceleration of tumor growth. Thus, gut microbiota can accelerate tumor growth. In Paper II, the role of PRR-mediated signaling in intestinal tumorigenesis was studied. By introduction of a constitutively active Toll-like-receptor 4 transgene (CD4-TLR4) to the intestinal epithelium of APCMin/+ mice, we found a marked reduction of intestinal tumor burden in CD4-TLR4-APCMin/+ mice. This tumor suppression was likely due to the observed Cox-2 down-regulation and IFNβ induction which resulted in increased apoptosis of tumor cells. These results unravel a previously unrecognized role of TLR4 signaling in modulating the balance between proliferative and apoptotic signals. In Paper III, the regulation of host innate immune responses during Salmonella Typhimurium induced colitis was studied. Our data demonstrated an aggravated colitis in infected mice lacking the innate immune regulator gene - PPAR in the intestinal epithelium. This increased tissue damage correlated with the elevation of lipocalin-2 (Lcn2) expression, which promoted the stabilization of tissue degrading enzyme, matrix metalloproteinase 9 (MMP-9). Interestingly, Lcn2-deficient mice were markedly protected from S. Typhimurium induced colitis. These findings therefore illustrate how enteric pathogens can exploit the host’s mucosal defense mechanisms to disrupt normal host-microbe homeostasis, in order to ensure colonization and survival in the host. In Paper IV, I have examined the significance of histone modifications and chromatinbinding proteins in the transcriptional regulation of T lymphocytes. Our results demonstrate that the bromodomain-containing protein, BRD4, is important in regulating Pol II Ser2-mediated transcriptional elongation in human CD4+ T cells. In conclusion, my thesis work further underscores the significant impact of gut microbiota mediated signaling in the regulation of intestinal homeostasis and tumorigenesis

Intense keV isolated attosecond pulse generation by orthogonally polarized multicycle midinfrared two-color laser field

We theoretically investigate the generation of intense keV attosecond pulses in an orthogonally polarized multicycle midinfrared two-color laser field. It is demonstrated that multiple continuum-like humps, which have a spectral width of about twenty orders of harmonics and an intensity of about one order higher than adjacent normal harmonic peaks, are generated under proper two-color delays, owing to the reduction of the number of electron-ion recollisions and suppression of inter-half-cycle interference effect of multiple electron trajectories when the long wavelength midinfrared driving field is used. Using the semiclassical trajectory model, we have revealed the two-dimensional manipulation of the electron-ion recollision process, which agrees well with the time frequency analysis. By filtering these humps, intense isolated attosecond pulses are directly generated without any phase compensation. Our proposal provides a simple technique to generate intense isolated attosecond pulses with various central photon energies covering the multi-keV spectral regime by using multicycle driving pulses with high pump energy in experiment.Comment: 11 pages,5 figures, research articl

Graph Homomorphism Revisited for Graph Matching

In a variety of emerging applications one needs to decide whether a graph G matches another G p , i.e. , whether G has a topological structure similar to that of G p . The traditional notions of graph homomorphism and isomorphism often fall short of capturing the structural similarity in these applications. This paper studies revisions of these notions, providing a full treatment from complexity to algorithms. (1) We propose p-homomorphism (p -hom) and 1-1 p -hom, which extend graph homomorphism and subgraph isomorphism, respectively, by mapping edges from one graph to paths in another, and by measuring the similarity of nodes . (2) We introduce metrics to measure graph similarity, and several optimization problems for p -hom and 1-1 p -hom. (3) We show that the decision problems for p -hom and 1-1 p -hom are NP-complete even for DAGs, and that the optimization problems are approximation-hard. (4) Nevertheless, we provide approximation algorithms with provable guarantees on match quality. We experimentally verify the effectiveness of the revised notions and the efficiency of our algorithms in Web site matching, using real-life and synthetic data. </jats:p

Query preserving graph compression

It is common to find graphs with millions of nodes and billions of edges in, e.g., social networks. Queries on such graphs are often prohibitively expensive. These motivate us to propose query preserving graph compression, to compress graphs relative to a class Λ of queries of users' choice. We compute a small Gr from a graph G such that (a) for any query Q Ε Λ Q, Q(G) = Q'(Gr), where Q' Ε Λ can be efficiently computed from Q; and (b) any algorithm for computing Q(G) can be directly applied to evaluating Q' on Gr as is. That is, while we cannot lower the complexity of evaluating graph queries, we reduce data graphs while preserving the answers to all the queries in Λ. To verify the effectiveness of this approach, (1) we develop compression strategies for two classes of queries: reachability and graph pattern queries via (bounded) simulation. We show that graphs can be efficiently compressed via a reachability equivalence relation and graph bisimulation, respectively, while reserving query answers. (2) We provide techniques for maintaining compressed graph Gr in response to changes ΔG to the original graph G. We show that the incremental maintenance problems are unbounded for the two lasses of queries, i.e., their costs are not a function of the size of ΔG and changes in Gr. Nevertheless, we develop incremental algorithms that depend only on ΔG and Gr, independent of G, i.e., we do not have to decompress Gr to propagate the changes. (3) Using real-life data, we experimentally verify that our compression techniques could reduce graphs in average by 95% for reachability and 57% for graph pattern matching, and that our incremental maintenance algorithms are efficient.</p

High-density lipoprotein subclass and particle size in coronary heart disease patients with or without diabetes

BACKGROUND: A higher prevalence of coronary heart disease (CHD) in people with diabetes. We investigated the high-density lipoprotein (HDL) subclass profiles and alterations of particle size in CHD patients with diabetes or without diabetes. METHODS: Plasma HDL subclasses were quantified in CHD by 1-dimensional gel electrophoresis coupled with immunodetection. RESULTS: Although the particle size of HDL tend to small, the mean levels of low density lipoprotein cholesterol(LDL-C) and total cholesterol (TC) have achieved normal or desirable for CHD patients with or without diabetes who administered statins therapy. Fasting plasma glucose (FPG), triglyceride (TG), TC, LDL-C concentrations, and HDL(3) (HDL(3b) and (3a)) contents along with Gensini Score were significantly higher; but those of HDL-C, HDL(2b+preβ2), and HDL(2a) were significantly lower in CHD patients with diabetes versus CHD patients without diabetes; The preβ(1)-HDL contents did not differ significantly between these groups. Multivariate regression analysis revealed that Gensini Score was significantly and independently predicted by HDL(2a), and HDL(2b+preβ2). CONCLUSIONS: The abnormality of HDL subpopulations distribution and particle size may contribute to CHD risk in diabetes patients. The HDL subclasses distribution may help in severity of coronary artery and risk stratification, especially in CHD patients with therapeutic LDL, TG and HDL levels

Dissociation of hydrogen molecules on the clean and hydrogen-preadsorbed Be(0001) surface

Using first-principles calculations, we systematically study the potential energy surfaces and dissociation processes for hydrogen molecules on the clean and hydrogen-preadsorbed Be(0001) surfaces. It is found that the most energetically favored dissociation channel for H2 molecules on the clean Be surface is at the surface top site, with the minimum energy barrier of 0.75 eV. It is further found that after dissociation, hydrogen atoms do not like to cluster with each other, as well as to penetrate into subsurface sites. For the hydrogen-preadsorbed Be(0001) surface, the smallest dissociation energy barrier for H2 molecules is found to be 0.50 eV, which is smaller than the dissociation energy barrier on a clean Be(0001) surface. The critical dependence of the dissociation energy barriers for H2 molecules on their horizontal distances from the preadsorbed hydrogen atom is revealed. Our studies well describe the adsorption behaviors of hydrogen on the Be(0001) surface.Comment: 17 pages, 9 figure