Ras proteins are small GTPases playing a pivotal role in cell proliferation and di erentiation. Their activation state depends on the competing action of GTPase Activating Proteins (GAP) and Guanine nucleotide Exchange Factors (GEF). A tryptophan residue (Trp1056 in CDC25 Mm -GEF), conserved in all rasspeci®c GEFs identi®ed so far has been previously shown to be essential for GEF activity. Its substitution with glutamic acid results in a catalytically inactive mutant, which is able to e ciently displace wild-type GEF from p21 ras and to originate a stable ras/GEF binary complex due to the reduced a nity of the nucleotide-free ras/ GEF complex for the incoming nucleotide. We show here that this`ras-sequestering property' can be utilized to attenuate ras signal transduction pathways in mouse ®broblasts transformed by oncogenic ras. In fact overexpression of the dominant negative GEF W1056E in stable transfected cells strongly reduces intracellular ras´GTP levels in k-ras transformed ®broblasts. Accordingly, the transfected ®broblasts revert to wild-type phenotype on the basis of morphology, cell cycle and anchorage independent growth. The reversion of the transformed phenotype is accompanied by DNA endoreduplication. The possible use of dominant negative ras-speci®c GEFs as a tool to down-regulate tumor growth is discussed.
To study hollows of living trees as the natural habitat of Cryptococcus neoformans in an endemic area of cryptococcosis in the northeastern Brazilian region, samples of decaying wood were collected inside the hollows, plated on niger seed agar and inoculated into mice and hamsters. Identification of C. neoformans was based on morphological and physiological tests. Canavanine–glycine–bromothymol medium was used to screen the varieties and Crypto Check Iatron Kit to serotype the isolates. For a period of 29 months C. neoformans var. gattii serotype B was isolated repeatedly from the hollow of a pottery tree (Moquilea tomentosa), pointing to the natural occurrence of C. neoformans var. gatti in decaying wood forming hollows in living trees. Evidence for a natural habitat of the variety gattii other than that related to Eucalyptus camaldulensis are discussed.
A line of Munich Miniature Swine (MMS) Troll showing a high incidence of spontaneous benign and malignant cutaneous melanocytic lesions has been developed since 1986. The inheritance of cutaneous melanocytic lesions was studied by establishing the F1‐, F2‐ and reciprocal B1‐generations with one melanoma MMS‐Troll boar and four unaffected German Landrace sows as founders. A total of 176 animals were available, 27 in the F1‐, 111 in the F2‐, 19 in the B1‐DL‐, and 14 in the B1‐Troll‐generation. Benign melanocytic lesions were observed in 42% of F1‐, 18% of F2‐, 11% of B1‐DL‐ and 50% of B1‐Troll‐animals. Malignant melanomas developed in 3.6% of F2‐ and 7.1% of B1‐Troll‐animals, although no animal with white coat colour was affected. A mixed major gene model with arbitrary gene action explained the segregation of benign lesions sufficiently well. For melanomas a mixed major gene model required additional dominant acting suppressor loci to obtain a sufficient fit to the data. An influence of SLA haplotypes on the penetrance of melanocytic lesions was not evident. The association analysis of the white phenotypes strongly indicated that the dominant allele I at the I‐locus suppresses malignant melanocytic lesions. A possible explanation is the lack of melanocytes in the skin of dominant white pigs caused by a mutation of the KIT‐gene, which leads to a failure of melanoblast migration and development.
One hundred and fifty‐four human dwellings in the metropolitan area of Rio de Janeiro, Brazil were studied. A total of 824 samples of indoor dust, outdoor soil and avian droppings were collected. Cryptococcus neoformans var. neoformans was isolated from 20 (13%) dwellings, comprising five (15·6%) of 32 dwellings of patients with AIDS‐associated cryptococcosis; four (8·9%) of 45 dwellings of patients with AIDS but without cryptococcosis; and 11 (14·3%) of 77 dwellings of apparently healthy individuals (P>0·05). The principal factor associated with domiciliar contamination by C. neoformans var. neoformans was the presence of avians in the domestic environment or nearby the home. Cryptococcosis was more frequent among AIDS patients residing in dwellings from which C. neoformans var. neoformans was isolated than among AIDS patients from whose domestic environment the fungus was not demonstrated by the methods used (odds ratio (OR)=2·05). These findings suggest that the distribution of C. neoformans var. neoformans in Rio de Janeiro is not restricted to the classically known biotopes as well as reinforce the possibility of exogenous infection in opportunistic cryptococcosis, including exogenous infection acquired in the domestic environment.
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