Justification As A Loaded Notion

The problem of skepticism is often understood as a paradox: a valid argument with plausible premises whose conclusion is that we lack justification for perceptual beliefs. Typically, this conclusion is deemed unacceptable, so a theory is offered that posits conditions for justification on which some premise is false. The theory defended here is more general, and explains why the paradox arises in the first place. Like Strawson’s (Introduction to logical theory, Wiley, New York, 1952) “ordinary language” approach to induction, the theory posits something built into the very notion of justification: it is loaded with a bias towards the proposition that we are not massively deceived. Beyond the paradox, remaining skeptical problems consist of metaphysical and practical questions: whether we are massively deceived, or why we should use our loaded notion rather than some other. Such challenges have pro- found epistemological significance, but they are not problems that an a priori theory of justification can solve

The Skeptical Paradox and the Generality of Closure (and other principles)

In this essay I defend a solution to a skeptical paradox. The paradox I focus on concerns epistemic justification (rather than knowledge), and skeptical scenarios that entail that most of our ordinary beliefs about the external world are false. This familiar skeptical paradox hinges on a “closure” principle. The solution is to restrict closure, despite its first appearing as a fully general principle, so that it can no longer give rise to the paradox. This has some extra advantages. First, it suggests a general strategy that provides solutions to other versions of the paradox, not just those that depend on closure. Second, it clarifies the relation between the paradox and other kinds of skeptical problem

Veridicalism and Scepticism

According to veridicalism, your beliefs about the existence of ordinary objects are typically true, and can constitute knowledge, even if you are in some global sceptical scenario. Even if you are a victim of Descartes’ demon, you can still know that there are tables, for example. Accordingly, even if you don’t know whether you are in some such scenario, you still know that there are tables. This refutes the standard sceptical argument. But does it solve the sceptical problem posed by that argument? I argue that it does not, because we do not know substantively more about the external world according to veridicalism than we do according to the sceptical argument. Rather, veridicalism merely reformulates what little knowledge we have. I then draw some general conclusions about the nature of the sceptical problem, the formulation of the standard argument, and the significance of this for some other, non-veridicalist strategies

Isolation, characterization, and substrate properties of the external limiting membrane from the avian embryonic optic tectum

The external limiting membrane of the avian embryonic optic tectum is isolated by mechanically separating the neuronal mesencephalon from the overlying mesenchymal tissue. The preparation consists of a basal lamina which is covered on its neural side by endfeet of neuroepithelial cells and has attached to it on its meningeal side a collageneous stroma, containing blood vessels. The external limiting membrane can be flat-mounted on a piece of nitrocellulose filter as mechanical support. It covers an area between 0.3 and 1 the cm2, depending on the age of me donor embryo. The endfeet can be removed together with all cellular components of the meninges by treatment with 2% Triton-X-100 or with distilled water. The basal lamina itself is approximately 80 nm thick and consists of two laminae rarae and a central lamina densa. Immunohistochemical staining reveals that the basal lamina in the embryo, after isolation and after detergent extraction of the isolated preparation, contains type IV collagen, nidogen, laminin, and low density heparan sulfate proteoglycan as do other basement membranes. Antibodies against the neural cell adhesion molecule (N-CAM), chondroitin sulfate proteoglycan, and fibronectin fail to stain the external limiting membrane, but these proteins were clearly identified in the blood vessel-containing meninges or in the optic tectum. The flat-mounted external limiting membrane preparation was used as substrate to culture several different neural tissues of central and peripheral origin. Explants of neural crest cells, dorsal root ganglia, and sympathetic ganglia can be cultured on the external limiting membrane. All explants grow well on the basal lamina preparations whether the endfeet are attached or detergent-extracted prior to explantation; however, neurite outgrowth from sympathetic ganglia is reduced in the presence of the endfeet. Although the endfoot-lined external limiting membrane represents at least part of the immediate environment encountered by retinal axons as they invade the optic tectum and despite its excellent properties as a substrate for retinal axons in vitro, cues guiding the orientation of axons were not detected in the flat-mounted preparation

Rho-mediated Contractility Exposes a Cryptic Site in Fibronectin and Induces Fibronectin Matrix Assembly

Many factors influence the assembly of fibronectin into an insoluble fibrillar extracellular matrix. Previous work demonstrated that one component in serum that promotes the assembly of fibronectin is lysophosphatidic acid (Zhang, Q., W.J. Checovich, D.M. Peters, R.M. Albrecht, and D.F. Mosher. 1994. J. Cell Biol. 127:1447–1459). Here we show that C3 transferase, an inhibitor of the low molecular weight GTP-binding protein Rho, blocks the binding of fibronectin and the 70-kD NH2-terminal fibronectin fragment to cells and blocks the assembly of fibronectin into matrix induced by serum or lysophosphatidic acid. Microinjection of recombinant, constitutively active Rho into quiescent Swiss 3T3 cells promotes fibronectin matrix assembly by the injected cells. Investigating the mechanism by which Rho promotes fibronectin polymerization, we have used C3 to determine whether integrin activation is involved. Under conditions where C3 decreases fibronectin assembly we have only detected small changes in the state of integrin activation. However, several inhibitors of cellular contractility, that differ in their mode of action, inhibit cell binding of fibronectin and the 70-kD NH2-terminal fibronectin fragment, decrease fibronectin incorporation into the deoxycholate insoluble matrix, and prevent fibronectin's assembly into fibrils on the cell surface. Because Rho stimulates contractility, these results suggest that Rho-mediated contractility promotes assembly of fibronectin into a fibrillar matrix. One mechanism by which contractility could enhance fibronectin assembly is by tension exposing cryptic self-assembly sites within fibronectin that is being stretched. Exploring this possibility, we have found a monoclonal antibody, L8, that stains fibronectin matrices differentially depending on the state of cell contractility. L8 was previously shown to inhibit fibronectin matrix assembly (Chernousov, M.A., A.I. Faerman, M.G. Frid, O.Y. Printseva, and V.E. Koteliansky. 1987. FEBS (Fed. Eur. Biochem. Soc.) Lett. 217:124–128). When it is used to stain normal cultures that are developing tension, it reveals a matrix indistinguishable from that revealed by polyclonal anti-fibronectin antibodies. However, the staining of fibronectin matrices by L8 is reduced relative to the polyclonal antibody when the contractility of cells is inhibited by C3. We have investigated the consequences of mechanically stretching fibronectin in the absence of cells. Applying a 30–35% stretch to immobilized fibronectin induced binding of soluble fibronectin, 70-kD fibronectin fragment, and L8 monoclonal antibody. Together, these results provide evidence that self-assembly sites within fibronectin are exposed by tension