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Articles by L Lu
Total Records ( 18 ) for L Lu
  L Lu , A Khan and W. A. Walker
 

Diarrheal disease is a major cause of morbidity and mortality in infants and children worldwide. Evidence suggests that the interaction of immature human enterocytes with bacteria and their enterotoxins may account for the increased susceptibility of neonates to diarrheal diseases. However, the precise mechanisms that contribute to the excessive response to cholera toxin by the immature gut are largely unknown. Our aim was to characterize the cellular/molecular changes in Gs during gut development. In this study, a colonic human epithelial cell line (T84) was used as representative of a mature enterocyte and a human fetal primary small intestinal cell line (H4) as representative of an immature enterocyte. Using our cell culture model of human intestinal development, we provide consistent evidence that cholera toxin (CT)-mediated Gs activation in fetal enterocytes differs from that of mature enterocytes, and the difference may be related to ADP-ribosylation factor (ARF) interaction with the CT-signaling process. Here we demonstrated that ARF1 may play a critical role in clathrin-mediated CT trafficking through the endoplasmic reticulum and Golgi and that ARF6 may facilitate clathrin-mediated CT endocytosis that leads to enhanced Gs activation by CT. Collectively, these findings support our hypothesis that there is a developmentally regulated intestinal cellular response to bacterial exotoxins involving complex cellular events that accounts for the increased incidence and severity of toxogenic diarrhea during infancy.

  H. A Risch , H Yu , L Lu and M. S. Kidd
 

Carriage of a non–O ABO blood group and colonization by Helicobacter pylori are thought to be risk factors for pancreatic cancer. We examined these associations in a population-based case–control study of 373 case patients and 690 control subjects frequency matched on sex and age. Control subjects were selected by random-digit dialing. Seropositivity for H pylori and its virulence protein CagA was determined by enzyme-linked immunosorbent assay (ELISA). Increased risk of pancreatic cancer was associated with non–O blood group (adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.02 to 1.83, P = .034) and CagA-negative H pylori seropositivity (OR = 1.68, 95% CI = 1.07 to 2.66, P = .025), but no association was observed for CagA seropositivity (OR = 0.77, 95% CI = 0.52 to 1.16). An association between pancreatic cancer risk and CagA-negative H pylori seropositivity was found among individuals with non–O blood type but not among those with O blood type (OR = 2.78, 95% CI = 1.49 to 5.20, P = .0014; OR = 1.28, 95% CI = 0.62 to 2.64, P = .51, respectively). This study demonstrates an association between pancreatic cancer and H pylori colonization, particularly for individuals with non–O blood types.

  A Lionikas , O Carlborg , L Lu , J. L Peirce , R. W Williams , F Yu , G. P Vogler , G. E McClearn and D. A. Blizard
 

The precise locations of attachment points of muscle to bone—the origin and insertion sites—are crucial anatomical and functional characteristics that influence locomotor performance. Mechanisms that control the development of these interactions between muscle, tendon, and bone are currently not well understood. In a subset of BXD recombinant inbred (RI) strains derived from the C57BL/6J and DBA/2J strains, we observed a soleus femoral attachment anomaly (SFAA) that was rare in both parental strains (Lionikas, Glover et al. 2006). The aim of the present study was to assess suitability of SFAA as a model to study the genetic mechanisms underlying variation in musculoskeletal anatomy. We scored the incidence of SFAA in 55 BXD strains (n = 9 to 136, median = 26, phenotyped animals per strain, for a total number of 2367). Seven strains (BXD1, 12, 38, 43, 48, 54, and 56) exhibited a high incidence of unilateral SFAA (47–89%), whereas 23 strains scored 0%. Exploration of the mechanisms underlying SFAA in 2 high incidence strains, BXD1 and BXD38, indicated that SFAA-relevant genes are to be found in both C57BL/6J and DBA/2J regions of the BXD1 genome. However, not all alleles relevant for the expression of the phenotype were shared between the 2 high-incidence BXD strains. In conclusion, the anatomical origin of the soleus muscle in mouse is controlled by a polygenic system. A panel of BXD RI strains is a useful tool in exploring the genetic mechanisms underlying SFAA and improving our understanding of musculoskeletal development.

  L Lu , P Li , C Yang , T Kurth , M Misale , M Skelton , C Moreno , R. J Roman , A. S Greene , H. J Jacob , J Lazar , M Liang and A. W. Cowley
 

Chromosome 13 consomic and congenic rat strains were analyzed to investigate the pattern of genomic pathway utilization involved in protection against salt-sensitive hypertension and renal injury. Introgression of the entire Brown-Norway chromosome 13 (consomic SS-13BN) or nonoverlapping segments of this chromosome (congenic strains, 16 Mbp in D13Rat151–D13Rat197 or 14 Mbp in D13Rat111–D13Got22) into the genome of the Dahl salt-sensitive rat attenuated salt-induced hypertension and proteinuria. mRNA abundance profiles in the renal cortex and the renal medulla from rats receiving 0.4% or 8% NaCl diets revealed two important features of pathway recruitment in these rat strains. First, the two congenic strains shared alterations in several pathways compared with Dahl salt-sensitive rats, despite the fact that the genomic segments introgressed in the two congenic strains did not overlap. Second, even though the genomic segment introgressed in each congenic strain was a part of the chromosome introgressed in the consomic strain, pathways altered in each congenic strain were not simply a subset of those altered in the consomic. Supporting the relevance of the mRNA data, differential expression of oxidative stress-related genes among the four strains of rats was associated with differences in urinary excretion of lipid peroxidation products. The findings suggest that different genetic alterations might converge to influence shared pathways in protection from hypertension, and that, depending on the genomic context, the same genetic alteration might diverge to affect different pathways.

  D. M Gatti , N Zhao , E. J Chesler , B. U Bradford , A. A Shabalin , R Yordanova , L Lu and I. Rusyn
 

Differences in clinical phenotypes between the sexes are well documented and have their roots in differential gene expression. While sex has a major effect on gene expression, transcription is also influenced by complex interactions between individual genetic variation and environmental stimuli. In this study, we sought to understand how genetic variation affects sex-related differences in liver gene expression by performing genetic mapping of genomewide liver mRNA expression data in a genetically defined population of naive male and female mice from C57BL/6J, DBA/2J, B6D2F1, and 37 C57BL/6J x DBA/2J (BXD) recombinant inbred strains. As expected, we found that many genes important to xenobiotic metabolism and other important pathways exhibit sexually dimorphic expression. We also performed gene expression quantitative trait locus mapping in this panel and report that the most significant loci that appear to regulate a larger number of genes than expected by chance are largely sex independent. Importantly, we found that the degree of correlation within gene expression networks differs substantially between the sexes. Finally, we compare our results to a recently released human liver gene expression data set and report on important similarities in sexually dimorphic liver gene expression between mouse and human. This study enhances our understanding of sex differences at the genome level and between species, as well as increasing our knowledge of the molecular underpinnings of sex differences in responses to xenobiotics.

 
 
 
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