An extended depth-first search algorithm for optimal triangulation of Bayesian networks

The junction tree algorithm is currently the most popular algorithm for exact inference on Bayesian networks. To improve the time complexity of the junction tree algorithm, we need to find a triangulation with the optimal total table size. For this purpose, Ottosen and Vomlel have proposed a depth-first search (DFS) algorithm. They also introduced several techniques to improve the DFS algorithm, including dynamic clique maintenance and coalescing map pruning. Nevertheless, the efficiency and scalability of that algorithm leave much room for improvement. First, the dynamic clique maintenance allows to recompute some cliques. Second, in the worst case, the DFS algorithm explores the search space of all elimination orders, which has size n!, where n is the number of variables in the Bayesian network. To mitigate these problems, we propose an extended depth-first search (EDFS) algorithm. The new EDFS algorithm introduces the following two techniques as improvements to the DFS algorithm: (1) a new dynamic clique maintenance algorithm that computes only those cliques that contain a new edge, and (2) a new pruning rule, called pivot clique pruning. The new dynamic clique maintenance algorithm explores a smaller search space and runs faster than the Ottosen and Vomlel approach. This improvement can decrease the overhead cost of the DFS algorithm, and the pivot clique pruning reduces the size of the search space by a factor of O(n2). Our empirical results show that our proposed algorithm finds an optimal triangulation markedly faster than the state-of-the-art algorithm does

Caveolin-3 Null Mice Show a Loss of Caveolae, Changes in the Microdomain Distribution of the Dystrophin-Glycoprotein Complex, and T-tubule Abnormalities

Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in caveolin-3 protein expression, i.e. a caveolin-3 deficiency. Here, we created a caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a caveolin-3 deficiency. We show that these mice lack caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level

Characterization of bovine testis mannose 6-phosphate receptors.

Two Man-6-P receptors (MPR-1, 215 kDa and MPR-2, 41-46 kDa) have been isolated from mammalian tissues. The receptors bind ligands carrying covalently bound Man-6-P and are involved in the targeting of acid hydrolases to lysosomes. MPR-1 and MPR-2 were extracted from bovine testis and purified and separated by the sequential use of affinity chromatography and gel filtration. The aggregation state of bovine testis MPR-2 was determined by cross-linking and gel filtration. MPR-2 exists in membranes as a noncovalently-linked dimer and in solution as oligomeric forms, largely as tetramer. The formation of tetramer is affected by the concentration of the receptor in solution. The order of binding of the oligomeric forms to the immobilized ligand agarose-pentamannosephosphate was tetramer $>$ dimer $>$ monomer. MPR-2 contains intrachain disulfide bonds which are of importance in maintaining ligand binding activity and receptor conformation. Bovine testis MPR-2 is comprised of two isoforms (MPR-2A, 45 kDa, and MPR-2B, 41 kDa). Each isoform was purified to near homogeneity by differential centrifugation and affinity chromatography. The isoforms contain a common polypeptide core, but differ in their carbohydrate content. Treatment with specific endoglycosidases demonstrated that each isoform contains two high mannose and/or hybrid and two complex N-linked oligosaccharide chains. The results obtained from treatment of each isoform with endo-$\beta$-galactosidase and neuraminidases and from the use of lectin affinity chromatography suggest that (1) MPR-2A contains a linear polylactosamine sequence(s) with $\sim$5 lactosamine units on one of the complex chains; (2) MPR-2A contains 5-7 sialic acid residues; and (3) MPR-2B lacks polylactosamine sequences and contains only a small amount of sialic acid. Experiments with immobilized lectins revealed that a majority of the outer branches of the complex chains of MPR-2A terminate with sialic acid and those of MPR-2B with $\beta$-galactose. MPR-2A exhibited a lower affinity than MPR-2B for Man-6-P containing ligands. Treatment of MPR-2A with endo-$\beta$-galactosidase and/or neuraminidase followed by affinity chromatography revealed that polylactosamine and sialic acid residues impair the ability of MPR-2A to bind ligands.Ph.D.Biological ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105232/1/9116237.pdfDescription of 9116237.pdf : Restricted to UM users only

N-cadherin Expression in Breast Cancer: Correlation with an Aggressive Histologic Variant – Invasive Micropapillary Carcinoma

Upregulation of N-cadherin in epithelial tumor cells has been shown to contribute to the invasive/metastatic phenotype. It remains however to be determined whether N-cadherin is increased in human breast cancers with enhanced malignant potential. We examined a large number of invasive breast cancer specimens (n=114) for N- and E-cadherin. These specimens compared invasive duct carcinomas (IDCs) of varying histologic grades with an aggressive subtype, invasive micropapillary carcinoma of the breast (MPAP), which has a high propensity for lymphatic invasion and lymph node metastasis. Staining scores for N- and E-cadherin were compared between non-MPAP and MPAP IDCs, and between the invasive and ductal carcinoma in situ (DCIS) of each IDC using statistical analysis. We found that N-cadherin was expressed in 76% of MPAP and 52% of non-MPAP carcinomas, and E-cadherin in 57% of MPAP and 36% of non-MPAP tumors. More MPAP (25%) compared to non-MPAP (5%) tumors expressed both cadherins. Of the two cadherins, N-cadherin was significantly associated with MPAP tumors (p=0.033) compared to E-cad (p=0.171). Moreover, in the majority of tumors that were positive for N-cadherin, the staining scores were increased in the IDC relative to intraductal components, and this effect was more dramatic in the MPAP carcinomas. This difference for N-cadherin was greater than the corresponding difference for E-cadherin in the MPAP group (p=0.005), whereas such changes were not significant in the non-MPAP group (p=0.10). Thus, N-cadherin is associated with tumor aggressiveness and metastatic potential and may contribute to tumor progression

N-cadherin Expression in Breast Cancer: Correlation with an Aggressive Histologic Variant – Invasive Micropapillary Carcinoma

Upregulation of N-cadherin in epithelial tumor cells has been shown to contribute to the invasive/metastatic phenotype. It remains however to be determined whether N-cadherin is increased in human breast cancers with enhanced malignant potential. We examined a large number of invasive breast cancer specimens (n=114) for N- and E-cadherin. These specimens compared invasive duct carcinomas (IDCs) of varying histologic grades with an aggressive subtype, invasive micropapillary carcinoma of the breast (MPAP), which has a high propensity for lymphatic invasion and lymph node metastasis. Staining scores for N- and E-cadherin were compared between non-MPAP and MPAP IDCs, and between the invasive and ductal carcinoma in situ (DCIS) of each IDC using statistical analysis. We found that N-cadherin was expressed in 76% of MPAP and 52% of non-MPAP carcinomas, and E-cadherin in 57% of MPAP and 36% of non-MPAP tumors. More MPAP (25%) compared to non-MPAP (5%) tumors expressed both cadherins. Of the two cadherins, N-cadherin was significantly associated with MPAP tumors (p=0.033) compared to E-cad (p=0.171). Moreover, in the majority of tumors that were positive for N-cadherin, the staining scores were increased in the IDC relative to intraductal components, and this effect was more dramatic in the MPAP carcinomas. This difference for N-cadherin was greater than the corresponding difference for E-cadherin in the MPAP group (p=0.005), whereas such changes were not significant in the non-MPAP group (p=0.10). Thus, N-cadherin is associated with tumor aggressiveness and metastatic potential and may contribute to tumor progression

Loss of retinal cadherin facilitates mammary tumor progression and metastasis

The mammary epithelium is thought to be stabilized by cellcell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression. ©2009 American Association for Cancer Research.Fil: Agiostratidou, Georgia. Albert Einstein College of Medicine, NY; Estados UnidosFil: Li, Maomi. Albert Einstein College of Medicine, NY; Estados Unidos. Montefiore Medical Center, NY; Estados UnidosFil: Suyama, Kimita. Albert Einstein College of Medicine, NY; Estados UnidosFil: Badano, Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Laboratorio de Biología Molecular Aplicada; Argentina. Albert Einstein College of Medicine, NY; Estados UnidosFil: Keren, Rinat. Albert Einstein College of Medicine, NY; Estados UnidosFil: Chung, Su. Albert Einstein College of Medicine, NY; Estados UnidosFil: Anzovino, Amy. Albert Einstein College of Medicine, NY; Estados UnidosFil: Hulit, James. Albert Einstein College of Medicine, NY; Estados UnidosFil: Qian, Binzhi. Albert Einstein College of Medicine, NY; Estados UnidosFil: Bouzahzah, Boumediene. Albert Einstein College of Medicine, NY; Estados UnidosFil: Eugenin, Eliseo. Albert Einstein College of Medicine, NY; Estados UnidosFil: Loudig, Olivier. Albert Einstein College of Medicine, NY; Estados UnidosFil: Phillips, Greg R.. Mount Sinai School of Medicine, NY; Estados UnidosFil: Locker, Joseph. Albert Einstein College of Medicine, NY; Estados UnidosFil: Hazan, Rachel B.. Albert Einstein College of Medicine, NY; Estados Unido