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      Reply to My Critics: A Response to Reviews of Darwin's Black Box: The Biochemical Challenge to Evolution

      Biology & Philosophy
      Springer Nature

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          Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency.

          Plasmin(ogen) is an extracellular serine protease implicated in the activation of latent growth factors and procollagenase, degradation of extracellular matrix components, and fibrin clearance. Plasminogen (Plg) deficiency in mice results in high mortality, wasting, spontaneous gastrointestinal ulceration, rectal prolapse, and severe thrombosis. Furthermore, Plg-deficient mice display delayed wound healing following skin injury, a defect partly related to impaired keratinocyte migration. We generated mice deficient in Plg and fibrinogen (Fib) and show that removal of fibrin(ogen) from the extracellular environment alleviates the diverse spontaneous pathologies previously associated with Plg deficiency and corrects healing times. Mice deficient in Plg and Fib are phenotypically indistinguishable from Fib-deficient mice. These data suggest that the fundamental and possibly only essential physiological role of Plg is fibrinolysis.
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            Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction.

            Plasminogen (Plg)-deficient mice were generated to define the physiological roles of this key fibrinolytic protein and its proteolytic derivatives, plasmin and angiostatin, in development, hemostasis, and reproduction. Plg-/- mice complete embryonic development, survive to adulthood, and are fertile. There is no evidence of fetal loss of Plg-/- mice based on the Mendelian pattern of transmission of the mutant Plg allele. Furthermore, embryonic development continues to term in the absence of endogenous, sibling-derived, or maternal Plg. However, Plg-/- mice are predisposed to severe thrombosis, and young animals developed multiple spontaneous thrombotic lesions in liver, stomach, colon, rectum, lung, pancreas, and other tissues. Fibrin deposition in the liver was a uniform finding in 5- to 21-week-old mice, and ulcerated lesions in the gastrointestinal tract and rectal tissue were common. A remarkable finding, considering the well-established linkage between plasmin and the proteolytic activation of plasminogen activators, was that the level of active urokinase-type plasminogen activator in urine was unaffected in Plg-/- mice. Therefore, Plg plays a pivotal role in fibrinolysis and hemostasis but is not essential for urokinase proenzyme activation, development, or growth to sexual maturity.
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              Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice.

              To explore the role of the key coagulation factor, fibrinogen, in development, hemostasis, wound repair, and disease pathogenesis, we disrupted the fibrinogen A alpha chain gene in mice. Homozygous, A alpha chain-deficient (A alpha-/-) mice are born normal in appearance, and there is no evidence of fetal loss of these animals based on the Mendelian pattern of transmission of the mutant A alpha chain allele. All of the component chains of fibrinogen (A alpha, B beta, and gamma) are immunologically undetectable in the circulation of both neonatal and adult A alpha-/- mice, and blood samples fail to either clot or support platelet aggregation in vitro. Overt bleeding events develop shortly after birth in approximately 30% of A alpha-/- mice, most frequently in the peritoneal cavity, skin, and soft tissues around joints. Remarkably, most newborns displaying signs of bleeding ultimately control the loss of blood, clear the affected tissues, and survive the neonatal period. Juveniles and young adult A alpha-/- mice are predisposed to spontaneous fatal abdominal hemorrhage, but long-term survival is variable and highly dependent on genetic background. The periodic rupture of ovarian follicles in breeding-age A alpha-/- females does not appear to significantly diminish life expectancy relative to males; however, pregnancy uniformly results in fatal uterine bleeding around the tenth day of gestation. Microscopic analysis of spontaneous lesions found in A alpha-/- mice suggests that fibrin(ogen) plays a fundamental role in the organization of cells at sites of injury.
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                Author and article information

                Journal
                Biology & Philosophy
                Biol Philos
                Springer Nature
                0169-3867
                1572-8404
                November 2001
                November 2001
                : 16
                : 5
                : 683-707
                Article
                10.1023/A:1012268700496
                fce24d4c-05c7-4ba6-b92c-b8af62e83b64
                © 2001

                http://www.springer.com/tdm

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