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Skin grafts of embryos and teratomas formed after the transplantation of ground tissues of embryos (18-20 day and 12-14-day) to neonatal syngeneic recipients were studied; it appeared that their growth was considerably delayed in comparison with analogous transplants in adult recipients. It is supposed that the organism of embryos and neonates has factors controlling the growth of embryonic tissues.
We have mapped quantitative trait loci (QTL) responsible for natural variation in light and hormone response between the Cape Verde Islands (Cvi) and Landsberg erecta (Ler) accessions of Arabidopsis thaliana using recombinant inbred lines (RILs). Hypocotyl length was measured in four light environments: white, blue, red, and far-red light and in the dark. In addition, white light plus gibberellin (GA) and dark plus the brassinosteroid biosynthesis inhibitor brassinazole (BRZ) were used to detect hormone effects. Twelve QTL were identified that map to loci not previously known to affect light response, as well as loci where candidate genes have been identified from known mutations. Some QTL act in all environments while others show genotype-by-environment interaction. A global threshold was established to identify a significant epistatic interaction between two loci that have few main effects of their own. LIGHT1, a major QTL, has been confirmed in a near isogenic line (NIL) and maps to a new locus with effects in all light environments. The erecta mutation can explain the effect of the HYP2 QTL in the blue, BRZ, and dark environments, but not in far-red. LIGHT2, also confirmed in an NIL, has effects in white and red light and shows interaction with GA. The phenotype and map position of LIGHT2 suggest the photoreceptor PHYB as a candidate gene. Natural variation in light and hormone response thus defines both new genes and known genes that control light response in wild accessions.
The mandibular condyle of 5-, 10- or 20-day inbred male rats was transplanted across the interparietal suture of male litter-mates and the transverse dimension of the neurocranium was measured from dry skulls at 25 or 35 days. The width of the neurocranium had increased significantly from days 5 or 10 to 25 in the rats with the transplants, whereas the difference from controls was small or non-existent by 35 days. Histological examination showed that the cartilaginous zone was reduced in the transplants at 25 days but that there were still layers of chondrocytes at 35 days. It is suggested that the rat mandibular condyle is endowed with a tissue-separating, interstitial growth potential that, to some extent, is unrelated to mobility, and essentially effected by chondrocyte hypertrophy.
A set of Drosophila melanogaster was generated, all derived from a common isogenic base stock and each with a single new P element insert on the second or third chromosome. The lines were scored for their body size, measured as thorax length. P inserts were associated with highly significant effects on body size, although the genotypes of the construct and of the control prevented deduction of the direction of mutant effects. In addition to mutant effects on the thorax length of both sexes, there were also highly significant sex-specific effects. Pleiotropic effects of inserts affecting body size on viability and bristle number, as ascertained in a separate study of these lines (Lyman et al., 1996), were weak, Insertional mutagenesis is potentially a powerful tool for investigating the genes involved in size-control in Drosophila, but the technique requires fine tuning for use on polygenic and fitness-related traits.
We investigated the role of pneumolysin's complement-activating activity during Streptococcus pneumoniae bacteremia in a hypocomplementemic, cirrhotic host. Isogenic mutant pneumococcal strains, in which pneumolysin was expressed from a plasmid, were used. These strains included H+C+, expressing wild-type pneumolysin with both cytolytic and complement-activating activity; PLY-, carrying the plasmid without the pneumolysin gene; and, H+C-, expressing pneumolysin with cytolytic activity only. In control rats, intravenous infection with 2.0 x 10(7) CFU of H+C+ per ml of blood resulted in a decrease in bacteremia of 3.5 log units by 18 h postinfection and 55% mortality. By contrast, cirrhotic rats infected similarly with the H+C+ strain demonstrated a 0.2-log-unit increase in bacteremia by 18 h postinfection and 100% mortality. Both control and cirrhotic rats cleared the PLY- strain more effectively from their bloodstreams by 18 h postinfection (6.2 and 5. 6 log unit decreases, respectively). Infection with the PLY- strain also resulted in low mortality (0 and 14%, respectively) for control and cirrhotic rats. When infected with the H+C- strain (without complement-activating activity), both groups cleared the organism from their bloodstreams nearly as well as they did the PLY- strain. Furthermore, the mortality rate for control and cirrhotic rats was identical after infection with the H+C- strain. These studies suggest that pneumolysin production contributes to decreased pneumococcal clearance from the bloodstream and higher mortality in both control and cirrhotic rats. However, pneumolysin's complement-activating activity may uniquely enhance pneumococcal virulence in the hypocomplementemic, cirrhotic host.
Vaccination and competitive exclusion (CE) represent accepted prophylactic measures to control Salmonella infections in chickens. To use the advantages of both the CE technique and vaccination with live Salmonella vaccines the combination of these methods was studied. In three experiments, SPF chickens were pre-treated using combined or unique administration of CE and vaccination with a live Salmonella typhimurium strain on days 1 and 2 of life and challenged with the antibiotic resistant, but otherwise isogenic mutant of this Salmonella typhimurium strain on days 3, 15 or 40 of life. The caecal colonization of both the vaccine and the challenge strain and the antibody response after infection were examined to evaluate the protective effects of the different combinations. The exclusion effect of CE cultures against Salmonella infection could be seen in very young chicks and was still considerable on day 40 of life of the birds. The Salmonella wild-type strain used as vaccine alone also resulted in a substantial protective effect against homologous challenge. The combined administration of competitive exclusion and immunization using the Salmonella wild-type strain as vaccine resulted in a considerable additional protective effect above the level of the respective exclusive application of these prophylactic measures. Administration of the Salmonella vaccine strain prior to or simultaneously with the CE culture produced the best protective effect, because such combinations ensure an adequate persistence of the vaccine strain as prerequisite for the expression of colonization inhibition effects and a strong immune response. The full exploitation of this potential using attenuated live Salmonella vaccines will require the presence of high inhibitory and immunogenic properties in the vaccine strain after attenuation of a selected parent strain. The combination of competitive exclusion and vaccination as a new measure in integrated control programmes against Salmonella infection in poultry could result in a considerable increase of protection in both very young and older chickens.
The W/Wv mouse has a recessively inherited defect in hematopoietic stem cells (HSC) but can be cured of its hematopoietic abnormalities by infusion of marrow from a co-isogeneic, +/+ mouse. The "curative" cell for the W/Wv is thought to be a subcompartment of the HSC that is capable of forming hematopoietic spleen colonies (CFU-S) in irradiated mice. The curative HSC must have a very high proliferative potential and it is known that HSC with variable degrees of proliferative potential are found within the CFU-S compartment. Rabbit antimouse brain serum (RAMBS) was used to treat +/+ marrow and its effect upon CFU-S and upon curative cells was compared with the effect of normal rabbit serum (NRS) or of sham treatment. CFU-S were reduced to 70%-79% of control by NRS and to 8%-9% by RAMBS. Curative cells for the W/Wv were not detectably reduced by NRS; they were reduced by RAMBS, but to only approximately 20%-30% of control. Thus, it appeared to a certain degree that RAMBS spared HSC with a high proliferative potential when compared with its effect on the entire CFU-S compartment.
The global regulatory two-component system CovR/S controls expression of about 15% of the Streptococcus pyogenes (group A streptococcus; GAS) genome. Recently, we found that CovS plays a pivotal role in general stress response of this strictly human pathogen. Therefore, we expected that both CovS and CovR might affect virulence. In this work, mice were inoculated subcutaneously with isogenic nonpolar covR and covS deletion-substitution mutants and the isogenic wild-type strain. The covS mutant behaved like the wild-type parental strain in terms of resulting lesion appearance and invasive disease leading to death. This is in agreement with previous results suggesting that the absence of its cognate sensor kinase does not affect the ability of CovR to become phosphorylated and cause repression of its regulon. However, two different covR deletion-substitution mutants caused significantly less invasive disease and death in the mice than the wild-type parental strain, although the local lesions produced by the covR mutants were more severe and purulent than those resulting from the wild-type GAS strain. Thus, it appears that production of CovR increases the ability of S. pyogenes to cause severe invasive disease in this mouse model and therefore is an important virulence factor for this organism.
Mismatch repair (MMR) deficiency was reported to increase resistance of mammalian cells to killing by several genotoxic substances. However, although MMR-deficient cells are approximately 100-fold more resistant to killing by S(N)1 type methylating agents than MMR-proficient controls, the sensitivity differences reported for the other agents were typically <2-fold. To test whether these differences were linked to factors other than MMR status, we studied the cytotoxicities of mitomycin C, chloroethylcyclohexyl nitrosourea, melphalan, psoralen-UVA, etoposide, camptothecin, ionizing radiation, and cis-dichlorodiaminoplatinum (cisplatin) in a strictly isogenic system. We now report that MMR deficiency reproducibly desensitized cells solely to cisplatin.
1. Forty-five outbred Wistar rats were randomly assigned to three experimental groups: GI, 10 non-diabetic control rats; GII, 10 alloxan-diabetic control rats; GIII, 25 alloxan-diabetic rats which received pancreaticoduodenal transplantation (PDT) from normal Wistar donor rats and were immunosuppressed with cyclosporin A (Cy-A), 10 mg kg body weight-1 day-1, administered intraperitoneally for 30 days. 2. In parallel, 15 alloxan-diabetic inbred Wistar rats received isogeneic PDT from normal Wistar donor rats. 3. Cy-A prevented graft rejection in the 15 surviving animals in group III. These observations were confirmed by clinical and biochemical parameters (body weight, urine output, water and food intake, blood and urinary glucose and plasma insulin) and by histology and immunohistochemistry of the pancreas. 4. However, Cy-A was associated with 60% of the infectious complications in transplanted rats leading to 40% mortality. Pulmonary infections were the main cause of death. There were no side effects of immunosuppression on the pancreas. Infections were not significant in inbred rats submitted to PDT.
In earlier investigations of marrow transfusions into isogeneic, nonirradiated mice, the percentage of donor cells in the recipients' marrow and peripheral blood was found to vary between 16% and 40% following transfusion of 200 million marrow cells. The present experiments demonstrated that the hosts' pluripotential stem cells were elevated to an average of 132% of simultaneously assayed nontransfused controls. The elevation persisted for two months and then returned to normal. The similar magnitude of elevation of pluripotential stem cells and of the percentage of donor cells in the recipients indicates that the seeded stem cells did not replace the hosts' own, but were added to the existing complement of pluripotential cells. Implications for the regulation of stem cell numbers are discussed.
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Intraductal distention of the pancreas with collagenase followed by stationary warm incubation improves the recovery of islets of Langerhans in the rat, but controlled studies are needed for valid comparison with standard isolation methods. We have modified Gotoh's technique of stationary digestion for high-yield isolation in the rat (Stationary). The method is subjected herein to rigorous blinded comparison with the standard chopped tissue (Chopped) technique, based on Lacy et al., as performed in our laboratory for over 10 yr. Islet recovery was determined by a single observe 'blinded' to the method of isolation used, and only intact islets of diameter > or = 100 microns were included. Stationary gave 719 +/- 114 islets per pancreas (mean +/- SD, n = 21 isolations) vs. 487.5 +/- 69 for Chopped (n = 36 isolations), a 47.5% increment in yield (p < 0.0001). In vitro islet perifusion showed no statistical difference in stimulation index (SI) or stimulated area under the curve (SAUC) between the two methods, but Stationary showed a trend towards improved phase II insulin release. In vivo function was assessed by isogeneic transplantation of 2,000 islets beneath the renal capsule of streptozotocin diabetic recipients (65 mg/kg Sigma); Stationary recipients (n = 7) became normoglycemic (< or = 8 mmol/L) by 3.3 +/- 4.8 days vs. 1.6 +/- 1.5 days for Chopped recipients (p = 0.4 ns, mean +/- SEM). IVGTT performed at 1 mo posttransplant gave K-values for Stationary of 2.64 +/- 0.8 vs. 2.62 +/- 0.8 for Chopped (mean +/- SD, p = 0.9 ns, n = 6, unpaired t-test), which were not distinguishable from normal control rats (2.59 +/- 0.8) (p = 0.9 ns, n = 10). Graft function remained stable until graft bearing nephrectomy induced hyperglycemia uniformly within 1 day. Graft histology showed a healthy well-preserved structure on light microscopy, with well-granulated beta cells on EM. Economic costs of rat, collagenase, and Ficoll were 26% ($50.82) lower per recipient for Stationary. We conclude that modified stationary digestion significantly improves islet recovery with excellent in vitro and in vivo function, and is cost effective.
The importance of phase III of the migrating myoelectric complex (MMC) for homeostasis of enteric flora is well documented. The goal of this study was to evaluate in an isogeneic rat model the effect of MMC changes on the self-purging capacity of the jejunal graft. The proximal 25% of the entire jejunoileum of Lewis rats was transplanted orthotopically. Electrodes were then fixed to the graft. Native bowel of five rats and five rats with analogue jejunal segmentation served as controls. Myoelectric recordings were carried out until day 21, when animals were killed for bacteriologic analysis of the segments analyzed myoelectrically and the of neighboring gut. MMCs were observed in all animals during all recordings. Phase III was irregular in transplants because of long-lasting periods of phase III absence alternating with phase III occurring more frequently. The variation coefficient of phase III periodicity calculated for grafts was 48.74, for native bowel 14.79, and for segmented jejunum 22.9. Enteric flora found in all specimens consisted of colonic-like microorganisms. Titers of microorganisms in grafts did not differ from control segments. These findings show that phase III periodicity is severely altered in jejunal grafts. Homeostasis of enteric flora, however, is not influenced by the transplant procedure.
The high copy dTph1 transposon system of Petunia (Solanaceae) is one of the most powerful insertion mutagens in plants, but its activity cannot be controlled in the commonly used mutator strains. We analysed the regulation of dTph1 activity by QTL analysis in recombinant inbred lines of the mutator strain W138 and a wild species (P. integrifolia spp. inflata). Two genetic factors were identified that control dTph1 transposition. One corresponded to the ACT1 locus on chromosome I. A second, previously undescribed locus ACT2 mapped on chromosome V. As a 6-cM introgression in W138, the P. i. inflata act1(S6) allele behaved as a single recessive locus that fully eliminated transposition of all dTph1 elements in all stages of plant development and in a heritable fashion. Weak dTph1 activity was restored in act1S6/ACT2S6 double introgression lines, indicating that the P. i. inflata allele at ACT2 conferred a low level of transposition. Thus, the act1S6 allele is useful for simple and predictable control of transposition of the entire dTph1 family when introgressed into an ultra-high copy W138 mutator strain. We demonstrate the use of the ACT1W138/act1S6 allele pair in a two-element dTph1 transposition system by producing 10,000 unique and fixed dTph1 insertions in a population of 1250 co-isogenic lines. This Petunia system produces the highest per plant insertion number of any known two-element system, providing a powerful and logistically simple tool for transposon mutagenesis of qualitative as well as quantitative traits.
Campylobacter jejuni is a major worldwide cause of enteric illnesses. Adult immunocompetent mice are not susceptible to C. jejuni infection. However, we show here that mice deficient in the adaptor protein myeloid differentiation factor 88 (MyD88), which is required for signaling through most Toll-like receptors, can be stably colonized by C. jejuni but not by isogenic derivatives carrying mutations in known virulence genes. We also found that Nramp1 deficiency increases the mouse susceptibility to C. jejuni infection when administered systemically. These results indicate that MyD88-deficient mice could be a useful model to study C. jejuni colonization and reveal a potential role for Nramp1 in the control of this bacterial pathogen.
The prototype Staphylococcus aureus strain 8325-4 produces high levels of hemolysins and proteases. Recently it has been shown that this property depends on a deficiency of sigma factor B (SigB) activity controlling the activation of regulatory genes such as agr and sarA. SigB deficiency is in turn due to a mutation in the rsbU gene, which is required for posttranslational activation of SigB. The rsbU defect of strain 8325-4 has recently been repaired, and we used this strain (SH1000), along with its isogenic sigB-negative mutant, to investigate the contributions of RsbU and SigB in a murine model of septic arthritis. Intravenous inoculation with the rsbU-repaired isogenic strain SH1000 resulted in significantly more severe arthritis, weight decrease, and mortality compared to those of the parental strain 8325-4 (rsbU-negative) or the isogenic sigB-negative mutant (MJH502). SH1000 also persisted more in kidneys and joints of infected mice. Our data strongly suggest that RsbU and SigB regulate important virulence factors, thereby contributing significantly to the outcome of staphylococcal infection.