We have generated Cbfa1-deficient mice. Homozygous mutants die of respiratory failure shortly after birth. Analysis of their skeletons revealed an absence of osteoblasts and bone. Heterozygous mice showed specific skeletal abnormalities that are characteristic of the human heritable skeletal disorder, cleidocranial dysplasia (CCD). These defects are also observed in a mouse Ccd mutant for this disease. The Cbfa1 gene was shown to be deleted in the Ccd mutation. Analysis of embryonic Cbfa1 expression using a lacZ reporter gene revealed strong expression at sites of bone formation prior to the earliest stages of ossification. Thus, the Cbfa1 gene is essential for osteoblast differentiation and bone formation, and the Cbfa1 heterozygous mouse is a paradigm for a human skeletal disorder.
Objective:To evaluate short-term outcomes of a new treatment for perforated diverticulitis with purulent peritonitis in a randomized controlled trial.Background:Perforated diverticulitis with purulent peritonitis (Hinchey III) has traditionally been treated with surgery including colon resection and stoma (Hartmann procedure) with considerable postoperative morbidity and mortality. Laparoscopic lavage has been suggested as a less invasive surgical treatment.Methods:Laparoscopic lavage was compared with colon resection and stoma in a randomized controlled multicenter trial, DILALA (ISRCTN82208287). Initial diagnostic laparoscopy showing Hinchey III was followed by randomization. Clinical data was collected up to 12 weeks postoperatively.Results: Eighty-three patients were randomized, out of whom 39 patients in laparoscopic lavage and 36 patients in the Hartmann procedure groups were available for analysis. Morbidity and mortality after laparoscopic lavage did not differ when compared with the Hartmann procedure. Laparoscopic lavage resulted in shorter operating time, shorter time in the recovery unit, and shorter hospital stay.Conclusions:In this trial, laparoscopic lavage as treatment for patients with perforated diverticulitis Hinchey III was feasible and safe in the short-term.
The ubiquitous Ca(2+)-binding protein calmodulin (CaM) is a key protein in Ca2+ homeostasis and activation of eukaryotic cells. CaM is the molecular link between free Ca2+ in the cell and the inhibition, or activation, of numerous enzymes. Many nuclear functions are under Ca2+/CaM control, and some transcriptional activators are known to be Ca2+ modulated indirectly through Ca2+/CaM-dependent protein kinases. But Ca2+/CaM has not yet been found to directly modulate any transcription factor or other DNA-binding protein. Transcription factors of the basic-helix-loop-helix (bHLH) group are important regulators in numerous systems. Here we report that binding of Ca(2+)-loaded CaM to the bHLH domains of several bHLH proteins directly inhibits their DNA binding. Other bHLH proteins are either less sensitive or resistant. Ca2+ ionophore selectively inhibits transcriptional activation by Ca2+/CaM-sensitive bHLH proteins in vivo, implying that Ca2+ can directly influence transcription through differential CaM inhibition of bHLH domains.
An electrophoretic mobility shift assay was used to characterize interactions of nuclear proteins with a DNA segment in the enhancer element of the leukemogenic murine retrovirus SL3-3. Mutation of a DNA sequence of the 5'-TGTGG-3' type decreased transcription in vivo specifically in T-lymphocyte cell lines. Extracts of nuclei from different T-lymphocyte cell lines or cells from lymphoid organs resulted in much higher amounts of complexes in vitro with this DNA sequence than did extracts from other cell lines or organs tested. Differences were also found in the sets of complexes obtained with extracts from the different types of cells. The DNA sequence specificities of the different SL3-3 enhancer factor 1 (SEFI) protein complexes were found to be distinct from those of several other previously identified DNA motifs of the TGTGG type because of differences in several nucleotides critical for binding and because these other DNA motifs could not compete with the identified DNA sequence for binding of SEF1. Limited treatment with several different proteases cleaved the SEF1 proteins such that their DNA-binding domain(s) remained and created complexes with decreased and nondistinguishable electrophoretic mobility shifts and with new properties. These results indicate that the SEF1 proteins have a structure with a flexible and relatively vulnerable hinge region linking a DNA-binding domain(s) to a more variable domain(s) with other functions. We suggest that the binding of SEFI is an essential factor for the T-cell tropism of SL3-3 and the ability of this virus to cause T-cell lymphomas.Regulatory elements, denoted enhancers, that can potentiate transcription from a variety of promoters in a relatively distance-and orientation-independent manner were originally defined in viruses and subsequently also identified for chromosomal genes (for reviews, see references 8, 19, 31, and 61). Results of competition experiments in vitro (57,62,75) and in vivo (45, 59) have shown that specific trans-acting factors are involved in enhancer function. The enhancer activity of simian virus 40 (SV40) has been shown to result from the integrated function of multiple sequence elements (79) which bind such factors (76). Results of studies of several other enhancers both in vivo and in vitro have supported the notion of a modular organization of enhancers based upon shorter sequence elements (79). Homologies between such sequence elements have also been found for enhancers with very different cell type specificities. The first noted and most commonly found homology between enhancers is an element with 5'-TGTGG-3' as its most conserved sequence feature (23,31,40,53,72,73).Enhancers have been shown to display several distinct properties that are indicative of a high degree of flexibility. (i) They can function when separated from the promoter by a long distance of DNA. (ii) They can, without displaying symmetry in their DNA sequences, function irrespective of their orientations relative to the promoter. (iii) Their sequence motifs can be re...
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