We report on a large Dutch family with a syndrome characterized by severe hand and/or foot anomalies, and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal-duct atresia, nail dysplasia, hypohydrosis, hypodontia, and cleft palate with or without bifid uvula. This combination of symptoms has not been reported previously, although there is overlap with the ulnar mammary syndrome (UMS) and with ectrodactyly, ectodermal dysplasia, and clefting syndrome. Allelism with UMS and other related syndromes was excluded by linkage studies with markers from the relevant chromosomal regions. A genomewide screening with polymorphic markers allowed the localization of the genetic defect to the subtelomeric region of chromosome 3q. Haplotype analysis reduced the critical region to a 3-cM interval of chromosome 3q27. This chromosomal segment has not been implicated previously in disorders with defective development of limbs and/or mammary tissue. Therefore, we propose to call this apparently new disorder "limb mammary syndrome" (LMS). The SOX2 gene at 3q27 might be considered an excellent candidate gene for LMS because the corresponding protein stimulates expression of FGF4, an important signaling molecule during limb outgrowth and development. However, no mutations were found in the SOX2 open reading frame, thus excluding its involvement in LMS.
Gain of chromosome 17q material is the most frequent genetic abnormality in neuroblastomas. The common region of gain is at least 375 cR large, which has precluded the identi®cation of genes with a role in neuroblastoma pathogenesis. Neuroblastoma also frequently show ampli®cation of the N-myc oncogene, which correlates closely with 17q gain. Both events are strong predictors of unfavorable prognosis. To identify genes that are part of the N-myc downstream pathway, we constructed SAGE libraries of an N-myc transfected and a control cell line. This identi®ed the chromosome 17q genes nm23-H1 and nm23-H2 as being 6 ± 10 times induced in the N-myc expressing cells. Northern and Western blot analysis con®rmed this up-regulation. Time-course experiment shows that both genes are induced within 4 h after N-myc is switched on. Furthermore, we demonstrate also that c-myc can upregulate nm23-H1 and nm23-H2 expression. Neuroblastoma tumor and cell line panels reveal a striking correlation between N-myc ampli®cation and mRNA and protein expression of both nm23 genes. We show that the nm23 genes are located at the edge of the common region of chromosome 17q gain previously described in neuroblastoma cell lines. Our ®ndings suggest that nm23-H1 and nm23-H2 expression is increased by 17q gain in neuroblastoma and can be further up-regulated by myc overexpression. These observations suggest a major role for nm23-H1 and nm23-H2 in tumorigenesis of unfavorable neuroblastomas.
The cholate-resistant Lactococcus lactis strain C41-2, derived from wild-type L. lactis MG1363 through selection for growth on cholate-containing medium, displayed a reduced accumulation of cholate due to an enhanced active efflux. However, L. lactis C41-2 was not cross resistant to deoxycholate or cationic drugs, such as ethidium and rhodamine 6G, which are typical substrates of the multidrug transporters LmrP and LmrA in L. lactis MG1363. The cholate efflux activity in L. lactis C41-2 was not affected by the presence of valinomycin plus nigericin, which dissipated the proton motive force. In contrast, cholate efflux in L. lactis C41-2 was inhibited by ortho-vanadate, an inhibitor of P-type ATPases and ATP-binding cassette transporters. Besides ATP-dependent drug extrusion by LmrA, two other ATP-dependent efflux activities have previously been detected in L. lactis, one for the artificial pH probe 2,7-bis-(2-carboxyethyl)-5(and 6)-carboxyfluorescein (BCECF) and the other for the artificial pH probe N-(fluorescein thio-ureanyl)-glutamate (FTUG). Surprisingly, the efflux rate of BCECF, but not that of FTUG, was significantly enhanced in L. lactis C41-2. Further experiments with L. lactis C41-2 cells and inside out membrane vesicles revealed that cholate and BCECF inhibit the transport of each other. These data demonstrate the role of an ATP-dependent multispecific organic anion transporter in cholate resistance in L. lactis.Primary bile salts, such as glyco-and taurocholate and glycoand taurochenodeoxycholate, are synthesized from cholesterol in the liver. The steroid nucleus is conjugated with an amide bond at the carboxyl C-24 position to one of two amino acids, glycine or taurine. Following synthesis, the bile salts are secreted into bile and enter the lumen of the small intestine, where they facilitate absorption of fat-soluble vitamins, lipids, and cholesterol. Most of these bile salts are absorbed from the small intestine, returned to the liver via the portal circulation, and resecreted into bile (13,25). The remaining part of the bile salts is deconjugated by the action of bile salt hydrolases present in intestinal bacteria, with the formation of the corresponding free bile acids, such as cholate and chenodeoxycholate (6). The free bile acids are further metabolized by some members of the intestinal bacteria into secondary bile acids, such as deoxycholate and lithocholate (8).Free bile acids are obviously toxic for living cells because they have the ability to disaggregate the ordered structure of biological membranes. With bile salts and free bile acids flowing in large amounts through the digestive tract, the bacterial members of the gastrointestinal microflora must have evolved the ability to survive under these toxic conditions. Although evidence has been obtained for the presence of proton motive force-dependent bile salt transporters in gram-negative bacteria (11,18,20,34), these systems have not yet been studied in detail in gram-positive bacteria. In this paper, the gram-positive bacterium Lactococ...
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