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PubMed2002

On the efficiency of composite interval mapping in an outbred population.

Composite interval mapping (CIM) has been successfully applied to the detection of QTL in experimental animals and plants. However, practical analyses based on CIM have been reported mainly for populations derived from cross between inbred lines. There are few studies on QTL analyses with CIM in outbred populations. To evaluate the applicability of CIM to outbred populations is prerequisite for the fine mapping of QTL in industrial animals such as pig and chicken. Some markers are usually not fully informative in outbred populations. In application of CIM to outbred populations, the influence of inclusion of such uninformative markers used as covariates on the efficiency of CIM should be investigated. In this paper a least-squares method for CIM was formalized in an F(2) population derived by crossing two outbred lines. The efficiencies of CIM were evaluated for outbred populations in comparison with simple interval mapping (SIM) for several cases of marker informativeness using simulations. By incorporating markers linked to a tested position as well as those unlinked, CIM showed a higher efficiency to separate two linked QTL over SIM. The efficiency of dissection was enhanced as the marker informativeness was increased. The power of CIM to detect an isolated QTL was improved by excluding markers linked to a tested position from covariates and higher than SIM regardless of marker informativeness. In conclusion, CIM is a useful procedure for the analysis of QTL in outbred populations even under low marker informativeness.

Animals↗
PubMed2003

Upregulation of p55 and p75 receptors mediating TNF-alpha transport across the injured blood-spinal cord barrier.

Tumor necrosis factor (TNF-alpha) is involved in the inflammation and tissue regeneration occurring after spinal cord injury (SCI). This study tests the specific role of p55 and p75 receptors in mediating the transport of TNF-alpha across the blood-spinal cord barrier (BSCB) after SCI by compression. Transcytosis of 125I-TNF-alpha across a monolayer of the cerebral endothelial cells that compose the blood-brain barrier was significantly reduced in the absence of functional p55 and p75 receptors. At 3 d after SCI, double receptor knockout mice had a significantly reduced increase in TNF-alpha uptake from blood to injured lumbar spinal cord as compared with their inbred controls, despite the similar extent of BSCB disruption (measured by 99mTc-albumin). The p75 single receptor knockout mice had a reduced increase in 125I-TNF-alpha uptake, whereas the p55 receptor knockout mice had no significant increase of 125I-TNF-alpha uptake after SCI, suggesting that the p55 receptor plays a major role. Hence, the increased uptake of TNF-alpha 3 d after SCI is not explained by nonspecific barrier disruption but by receptor-mediated upregulation of transport. Quantitative RT-PCR analysis further showed that upregulation of TNF-alpha transport was related to increased expression of mRNA for p55 and p75 receptors. The increase of p55 receptor expression was more robust and seen between 12 h and 1 wk after SCI, whereas the increase of p75 receptor expression occurred later and involved fewer regions. Thus, the differential upregulation of p55 and p75 receptors indicates that permeation of TNF-alpha across the injured BSCB remains a regulated process. Knowledge of receptor-mediated regulation could facilitate effective therapeutic manipulation of BSCB permeation of vascular cytokines important to CNS regeneration.

Animals↗
PubMed2006

Where do we stand now? Mouse early embryo patterning meeting in Freiburg, Germany (2005).

Mechanism underlying mammalian preimplantation development has long been a subject of controversy and the central question has been if any "determinants" play a key role in a manner comparable to the non-mammalian "model" system. During the last decade, this issue has been revived (Pearson, 2002; Rossant and Tam, 2004) by claims that the axes of the mouse blastocyst are anticipated at the egg ("prepatterning model"; Gardner, 1997; Gardner, 2001; Piotrowska et al., 2001; Piotrowska and Zernicka-Goetz, 2001; Zernicka-Goetz, 2005), suggesting that a mechanism comparable to that operating in non-mammals may be at work. However, recent studies by other laboratories do not support these claims ("regulative model"; Alarcon and Marikawa, 2003; Chroscicka et al., 2004; Hiiragi and Solter, 2004; Alarcon and Marikawa, 2005; Louvet-Vallee et al., 2005; Motosugi et al., 2005) and the issue is currently under hot debate (Vogel, 2005). Deepening our knowledge of this issue will not only provide an essential basis for understanding mammalian development, but also directly apply to ongoing clinical practices such as intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD). These practices were originally supported by a classical premise that mammalian preimplantation embryos are highly regulative (Tarkowski, 1959; Tarkowski, 1961; Tarkowski and Wroblewska, 1967; Rossant, 1976), in keeping with the "regulative model". However, if the "prepatterning model" is correct, the latter will require critical reassessment.

Animals↗
PubMed2005

Brain oxytocin correlates with maternal aggression: link to anxiety.

The oxytocinergic system is critically involved in the regulation of maternal behavior, which includes maternal aggression. Because aggression has been linked to anxiety, we investigated the maternal aggression and the role of brain oxytocin in lactating Wistar rats selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) during the 10 min maternal defense test. HAB dams displayed more maternal aggression against a virgin intruder compared with LAB dams, resulting in more defensive behavior and higher anxiety of HAB-defeated virgins. The different levels of aggression were accompanied by opposite oxytocin release patterns within the paraventricular nucleus (PVN; HAB, increase; LAB, decrease). Furthermore, oxytocin release was higher within the central nucleus of the amygdala (CeA) of HAB dams compared with LABs. A direct correlation between the offensive behavior displayed during the maternal defense test and local oxytocin release was found in both the PVN and CeA. Using retrodialysis, blockade of endogenous oxytocin action by infusion of an oxytocin receptor antagonist (des-Gly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT) into the PVN or CeA reduced maternal aggression of HAB dams, whereas infusion of synthetic oxytocin into the PVN tended to increase aggression toward the intruder in LAB dams. There were no significant differences in oxytocin receptor mRNA expression or oxytocin receptor binding between lactating HAB and LAB dams. Therefore, differences in intracerebral release patterns of oxytocin, rather than differences at the level of oxytocin receptors, are critical for the regulation of maternal aggressive behavior.

Aggression↗
PubMed2005

The first steps of transposable elements invasion: parasitic strategy vs. genetic drift.

Transposable elements are often considered as selfish DNA sequences able to invade the genome of their host species. Their evolutive dynamics are complex, due to the interaction between their intrinsic amplification capacity, selection at the host level, transposition regulation, and genetic drift. Here, we propose modeling the first steps of TE invasion, i.e., just after a horizontal transfer, when a single copy is present in the genome of one individual. If the element has a constant transposition rate, it will disappear in most cases: the elements with low-transposition rate are frequently lost through genetic drift, while those with high-transposition rate may amplify, leading to the sterility of their host. Elements whose transposition rate is regulated are able to successfully invade the populations, thanks to an initial transposition burst followed by a strong limitation of their activity. Self-regulation or hybrid dysgenesis may thus represent some genome-invasion parasitic strategies.

Animals↗
PubMed2005

Genome-wide scan in a novel IgA nephropathy model identifies a susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22-23.

Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy (IgAN) on the basis of racial differences in the prevalence and familial aggregation. The ddY mouse is a spontaneous animal model of human IgAN, with a highly variable incidence and extent of glomerular injury as a result of the heterogeneous background, resembling the human situation. It was hypothesized that susceptibility genes for IgAN can be detected by a genome-wide scan using this model. First, serial renal biopsies were performed at 20, 40, and 60 wk of age in 361 ddY mice. The ddY mice were classified into three groups on the basis of the onset of glomerular injury: Early onset at 20 wk (31.9%), late onset at 40 wk (37.9%), and quiescent even at 60 wk (30.2%). The severity of glomerular lesions in both onset groups correlated with the intensity of glomerular IgA deposition but not with serum IgA level. The genome-wide scan with 270 microsatellite markers identified three chromosomal regions on chromosomes 1, 9, and 10, which were significantly associated with the glomerular injuries. Surprisingly, the peak marker D10MIT86 on chromosome 10 is located on the region syntenic to human 6q22-23 with IGAN1, which is the responsible candidate of familial IgAN. In addition, D1MIT16 on chromosome 1 was very closely located at the locus of selectin gene, which is a known candidate of human IgAN. In conclusion, the three-group ddY mouse model can be a useful tool for identifying the susceptibility genes and also to examine their roles in the pathogenesis of IgAN.

Animals↗
PubMed2006

Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis.

Bone marrow-derived cells contribute to glomerular cell turnover and repair, but the cell types involved are unknown. Whether rat mesenchymal stem cells (MSC) can accelerate recovery from damage in rat mesangioproliferative anti-Thy1.1 glomerulonephritis was studied. After injection into the left renal artery on day 2 after disease induction, fluorescently labeled MSC were detected in 20 to 50% of glomeruli and rare intrarenal vessels but not in the tubulointerstitium, in contralateral kidneys, or in medium controls. In control experiments, injected mesangial cells were detected less frequently in glomeruli in comparison with injected MSC. In nephritic outbred Wistar rats, MSC injection led to an approximately 50% reduction of mesangiolysis on days 4 and 6 after disease induction, accompanied by three- to four-fold higher intraglomerular cell proliferation on day 4 and more rapid mesangial reconstitution as detected by alpha-smooth muscle actin expression. Injection of MSC into tail veins or intra-arterial injection of mesangial cells instead of MSC failed to reproduce any of these findings. In inbred Lewis rats, anti-Thy1.1 nephritis followed an aggravated course with transient acute renal failure. Acute renal failure was ameliorated by MSC injection into the left renal artery on day 2 after disease induction. Again, MSC led to more rapid recovery from mesangiolysis, increased glomerular cell proliferation, and reduction of proteinuria by 28%. Double immunostaining of 5-bromo-2'-deoxyuridine-labeled MSC for endothelial, mesangial, or monocyte/macrophage antigens showed that 85 to 95% of MSC that localized in glomeruli on day 6 failed to express these markers. In vitro, MSC secreted high amounts of vascular endothelial growth factor and TGF-beta1 but not PDGF-BB. In conclusion, even low numbers of MSC can markedly accelerate glomerular recovery from mesangiolytic damage possibly related to paracrine growth factor release and not to differentiation into resident glomerular cell types or monocytes/macrophages.

Animals↗
PubMed2026

[Effects and mechanisms of ethanol extract of Salvia miltiorrhiza on liver fibrosis in mice].

To identify clinically advantageous TCMs for anti-hepatic fibrosis and to elucidate the effects and molecular mechanisms of Salvia miltiorrhiza ethanol extract in the intervention of liver fibrosis, this study screened high-frequency anti-hepatic fibrosis TCMs through a review of clinical literature. The S. miltiorrhiza active components, potential targets, and liver fibrosis-related disease targets were obtained using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), the GeneCards database, and other databases. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed on the shared targets between drugs and diseases. Molecular docking was conducted to evaluate the binding affinities between key components and core targets. In animal experiments, male Kunming mice were used to establish a liver fibrosis model induced by carbon tetrachloride(CCl_4). The mice were administered low, medium, and high doses of S. miltiorrhiza ethanol extract by gavage. The liver index, as well as serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels, were measured. Histopathological changes in liver tissue were observed using hematoxylin-eosin(HE) staining and Masson's trichrome staining. Western blot analysis was used to detect the protein expression levels of α-smooth muscle actin(α-SMA), Collagen Ⅰ, and heat shock protein 90 alpha family class A member 1(HSP90AA1) in liver tissue. The results showed that S. miltiorrhiza was the most frequently used TCM in clinical anti-hepatic fibrosis. A total of 65 active components and 135 potential targets were identified, and 109 common targets were obtained by intersecting these with liver fibrosis-related targets. The core targets included tumor protein p53(TP53), serine/threonine protein kinase AKT1(AKT1), Jun proto-oncogene(JUN), signal transducer and activator of transcription 3(STAT3), and HSP90AA1, which were mainly enriched in pathways related to cancer, hepatitis B, and the PI3K-AKT signaling pathway. Molecular docking indicated that the main active components of S. miltiorrhiza bound stably to the core targets, with the strongest binding affinity observed for HSP90AA1. Animal experiments demonstrated that the liver index, serum ALT and AST levels, and the expression of α-SMA, Collagen Ⅰ, and HSP90AA1 in liver tissue were significantly increased in the model group, accompanied by obvious pathological manifestations of fibrosis. Compared with the model group, different dose groups of S. miltiorrhiza ethanol extract reduced the liver index and serum ALT and AST levels to varying degrees, alleviated pathological damage and collagen deposition in liver tissue, and downregulated the protein expression of α-SMA, Collagen Ⅰ, and HSP90AA1. In conclusion, S. miltiorrhiza ethanol extract exerts a significant protective effect on CCl_4-induced liver fibrosis in mice, and its mechanisms may be related to the inhibition of HSP90AA1 expression and the regulation of liver fibrosis-related signaling pathways.

Animals↗
PubMed2005

Effects of norepinephrine and histamine on vascular resistance in isolated perfused mouse liver.

Mice have frequently been used for a variety of physiological studies because of the development of genetic engineering. However, the characteristics of hepatic vessels such as the vascular resistance distribution and the reactivity to various vasoconstrictors are not known in mice. We therefore determined the basal levels of segmental vascular resistances and the effects of histamine and norepinephrine on the vascular resistance distribution of mice. The liver of male non-inbred ddY mice was excised and perfused via the portal vein with 5% bovine albumin-Krebs solution at a constant flow rate. The sinusoidal pressure was measured by the double occlusion pressure and used to determine the presinusoidal (R(pre)) and postsinusoidal (R(post)) resistances. The basal R(post) comprised 53 +/- 1% of the total hepatic vascular resistance. The norepinephrine and histamine increased R(pre) in a greater magnitude than R(post) with liver weight loss. However, the response to histamine was weaker than that to norepinephrine. Moreover, histamine-induced vasoconstriction showed tachyphylaxis. In conclusion, the presinusoidal and postsinusoidal resistances of mouse livers were similar in magnitude. The presinusoidal vessels predominantly contract in response to norepinephrine and histamine in mouse livers.

Animals↗
PubMed2005

Rolipram, a phosphodiesterase 4 inhibitor, stimulates inducible cAMP early repressor expression in osteoblasts.

Phosphodiesterase (PDE) 4 inhibitors have been shown to induce the cAMP-mediated signaling pathway by inhibiting cAMP hydrolysis. This study investigated the effect of a PDE4 inhibitor on the expression of the inducible cAMP early repressor (ICER), which is an endogenous inhibitor of CRE- mediated transcription, in osteoblastic cells. RT-PCR analysis revealed that rolipram, a PDE4 inhibitor, stimulates the ICER mRNA in a dose dependent manner. The induction of ICER mRNA expression by rolipram was suppressed by the inhibitors of protein kinase A (PKA) and p38 MAPK, suggesting the involvement of PKA and p38 MAPK activation in ICER expression by rolipram. It was previously shown that rolipram induced the expression of TNF-related activation-induced cytokine (TRANCE, also known as RANKL, ODF, or OPGL) in osteoblasts. This paper provides evidences that a transcriptional repressor like ICER might modulate TRANCE mRNA expression by rolipram in osteoblasts.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Intrapulmonary TNF gene therapy reverses sepsis-induced suppression of lung antibacterial host defense.

Sepsis syndrome is frequently complicated by the development of nosocomial infections, particularly Gram-negative pneumonia. Although TNF-alpha (TNF) has been shown to mediate many of the pathophysiologic events in sepsis, this cytokine is a critical component of innate immune response within the lung. Therefore, we hypothesized that the transient transgenic expression of TNF within the lung during the postseptic period could augment host immunity against nosocomial pathogens. To test this, mice underwent 26-gauge cecal ligation and puncture (CLP) as a model of abdominal sepsis, followed 24 h later by intratracheal (i.t.) administration of Pseudomonas aeruginosa. In animals undergoing sham surgery followed by bacterial challenge, Pseudomonas were nearly completely cleared from the lungs by 24 h. In contrast, mice undergoing CLP were unable to clear P. aeruginosa and rapidly developed bacteremia. Alveolar macrophages (AM) recovered from mice 24 h after CLP produced significantly less TNF ex vivo, as compared with AM from sham animals. Furthermore, the adenoviral mediated transgenic expression of TNF within the lung increased survival in CLP animals challenged with Pseudomonas from 25% in animals receiving control vector to 91% in animals administered recombinant murine TNF adenoviral vector. Improved survival in recombinant murine TNF adenoviral vector-treated mice was associated with enhanced lung bacterial clearance and proinflammatory cytokine expression, as well as enhanced AM phagocytic activity and cytokine expression when cultured ex vivo. These observations suggest that intrapulmonary immunostimulation with TNF can reverse sepsis-induced impairment in antibacterial host defense.

Adenoviruses, Human↗
PubMed2000

The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19.

c-Abl is a nonreceptor tyrosine kinase that we have recently linked to growth factor receptor signaling. The c-Abl kinase is ubiquitously expressed and localizes to the cytoplasm, plasma membrane, cytoskeleton, and nucleus. Thus, c-Abl may regulate signaling processes in multiple subcellular compartments. Targeted deletion or mutation of c-Abl in mice results in a variety of phenotypes, including splenic and thymic atrophy and lymphopenia. Additionally, lymphocytes isolated from specific compartments of c-Abl mutant mice have reduced responses to a variety of stimuli and an increased susceptibility to apoptosis following growth factor deprivation. Despite these observations, little is known regarding the signaling mechanisms responsible for these phenotypes. We report here that splenic B cells from c-Abl-deficient mice are hyporesponsive to the proliferative effects of B cell Ag receptor (BCR) stimulation. The c-Abl kinase activity and protein levels are elevated in the cytosol following activation of the BCR in B cell lines. We show that c-Abl associates with and phosphorylates the BCR coreceptor CD19, and that c-Abl and CD19 colocalize in lipid membrane rafts. These data suggest a role for c-Abl in the regulation of B cell proliferation downstream of the BCR, possibly through interactions with CD19.

Animals↗
PubMed2000

TGF-beta 1 and IFN-gamma direct macrophage activation by TNF-alpha to osteoclastic or cytocidal phenotype.

TNF-related activation-induced cytokine (TRANCE; also called receptor activator of NF-kappaB ligand (RANKL), osteoclast differentiation factor (ODF), osteoprotegerin ligand (OPGL), and TNFSF11) induces the differentiation of progenitors of the mononuclear phagocyte lineage into osteoclasts in the presence of M-CSF. Surprisingly, in view of its potent ability to induce inflammation and activate macrophage cytocidal function, TNF-alpha has also been found to induce osteoclast-like cells in vitro under similar conditions. This raises questions concerning both the nature of osteoclasts and the mechanism of lineage choice in mononuclear phagocytes. We found that, as with TRANCE, the macrophage deactivator TGF-beta(1) strongly promoted TNF-alpha-induced osteoclast-like cell formation from immature bone marrow macrophages. This was abolished by IFN-gamma. However, TRANCE did not share the ability of TNF-alpha to activate NO production or heighten respiratory burst potential by macrophages, or induce inflammation on s.c. injection into mice. This suggests that TGF-beta(1) promotes osteoclast formation not only by inhibiting cytocidal behavior, but also by actively directing TNF-alpha activation of precursors toward osteoclasts. The osteoclast appears to be an equivalent, alternative destiny for precursors to that of cytocidal macrophage, and may represent an activated variant of scavenger macrophage.

Animals↗
PubMedDate not supplied

[Tanfelam: synthesis, study of ovicidal activity, and acute toxicity].

The papers describes the synthesis of N-(2-piperidinoethyl)-N-tosyl-n-anisidine (Tanfelam) which showed a 100% ovicidal activity when tested by the Harada and Mori methods (in vitro inhibited N.brasiliensis hatching and development test). Tanfelam has been transferred for in-depth tests.

Animals↗
PubMed1975

Cardiac heterotransplantation. Morphological and immunohistological studies.

A vascularized heterograft model using outbred strains of animals was developed by transplanting mouse hearts heterotopically into rats. With this species desparity rapid but not immediate graft rejection was observed, with a predictably narrow range of graft survival times. Morphological and immunohistological studies showed early deposition of fibrinogen and vascular and myocardial inflammation without prominent or consistent localization of either IgG or C3. Later more extensive changes were observed, and deposition of IgG and C3 were more prominent in the grafts. Pretreatment of the recipient with cyclophosphamide alone or cyclophosphamide plus antigen prolonged graft survival; however, no statistically significant difference was noted between these groups. Morphological and immunohistological alterations preceded clinical rejection, and tissue injury appeared to be mediated by humoral and cellular immune mechanisms and by the coagulation system. This model is potentially useful for the study of heterotransplantation.

Animals↗
PubMedDate not supplied

[The influence of calcium channel blockers on the effects of anxiogenic preparations].

The effect of anxiogenic drugs (caffeine, pentilentetrazole, phenilethylamine, strophantine, BAY K 8644) on SHR mice' behavior was studied in the dark-light chamber test. All these drugs have diminished the number of transitions between the chambers. Pretreatment with verapamil, nifedipine, cinnarizine and fendilin have not altered the effect of relevant anxiogenic drugs. Diltiazem prevented the effect of stophantine. It is suggested that the lack of the effect of calcium channel blockers on the action of anxiogens is related to peculiarities of formation of anxiety in this test.

Animals↗
PubMed2000

CFU-S(11) activity does not localize solely with the aorta in the aorta-gonad-mesonephros region.

The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site in the midgestation mouse conceptus and first contains colony-forming units-spleen day 11 (CFU-S(11)) at embryonic day 10 (E10). Because CFU-S(11) activity is present in the AGM region before the onset of hematopoietic stem cell (HSC) activity, CFU-S(11) activity in the complex developing vascular and urogenital regions of the AGM was localized. From E10 onward, CFU-S(11) activity is associated with the aortic vasculature, and is found also in the urogenital ridges (UGRs). Together with data obtained from organ explant cultures, in which up to a 16-fold increase in CFU-S(11) activity was observed, it was determined that CFU-S(11) can be increased autonomously both in vascular sites and in UGRs. Furthermore, CFU-S(11) activity is present in vitelline and umbilical vessels. This, together with the presence of CFU-S(11) in the UGRs 2 days before HSC activity, suggests both temporally and spatially distinct emergent sources of CFU-S(11). (Blood. 2000;96:2902-2904)

Animals↗