Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice

Background: A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoim)Hgumouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hguhad been generated using strict brother × sister mating. CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hgumice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hguinsertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hguonto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hguand wild type controls. Results: Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hguand B6.129P2(CF/3)-CftrTgH(neoim)Hguexhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgufemales were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15-100% of those of the cognate wild type control animals. Conclusion: The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgumice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms

The ter Mutation in the Rat Dnd1 Gene Initiates Gonadal Teratomas and Infertility in Both Genders

A spontaneous mutation leading to the formation of congenital ovarian and testicular tumors was detected in the WKY/Ztm rat strain. The histological evaluation revealed derivatives from all three germ layers, thereby identifying these tumors as teratomas. Teratocarcinogenesis was accompanied by infertility and the underlying mutation was termed ter. Linkage analysis of 58 (WKY-ter×SPRD-Cu3) F2 rats associated the ter mutation with RNO18 (LOD = 3.25). Sequencing of candidate genes detected a point mutation in exon 4 of the dead-end homolog 1 gene (Dnd1), which introduces a premature stop codon assumed to cause a truncation of the Dnd1 protein. Genotyping of the recessive ter mutation revealed a complete penetrance of teratocarcinogenesis and infertility in homozygous ter rats of both genders. Morphologically non-tumorous testes of homozygous ter males were reduced in both size and weight. This testicular malformation was linked to a lack of spermatogenesis using immunohistochemical and histological staining. Our WKY-Dnd1ter/Ztm rat is a novel animal model to investigate gonadal teratocarcinogenesis and the molecular mechanisms involved in germ cell development of both genders

Some Remarks on the Decidability of the Generation Problem in LFG- and PATR-Style Unification Grammars

In this paper, we prove the decidability of the generation problem for those unification grammars which are based on contextfree phrase structure rule skeletons, like e.g. LFG and PATR-II. The result shows a perhaps unexpected asymmetry, since it is valid also for those unification grammars whose parsing problem is undecidable, e.g. grammars which do not satisfy the off-line parsability constraint. The general proof is achieved by showing that the space of the derivations which have to be considered in order to decide the problem for a given input is always restricted to derivations whose length is limited by some fixed upper bound which is determined relative to the "size" of the input

On Inference-Based Procedures for Lexical Disambiguation

In this paper we sketch a decidable inference-based procedure for lexical dismnbiguation which operates on semantic representations of discourse and conceptual knowledge. In contrast to other approaches which use a classical logic for the disambiguating inferences and run into dccidability problems, we argue on the basis of empirical evidence that the underlying inference nmchanism has to be essentially incomplete in order to be (cognitively) adequatc. Since our con- ceptual knowledge can be represented in a rather restricted representation language, it, is then possible to show that the restrictions satisfied by the conceptual knowledge and the inferences ensure in an empirically adequate way the decidability of the problen, although a fifily expressive language is used to represent discourse

A Concept of Derivation for LFG

In this paper a version of LFG will be developed, which has only one level of representation and is equivalent to the modified version of [2], presented in [3]. The structures of this monostratal version are f-structures, augmented by additional information about the derived symbols and their linear order. For these structures it is possible to define an adequate concept of direct derivability by which the derivation process becomes more efficient, as the f-description solution algorithm is directly simulated duriug the derivation of these structures, instead of being postponed. Apart from this it follows from this reducability that LFG as a theory in its present form does not make use of the c-structure information that goes beyond the mere linear order of the derived symbols