Bootstrapping and Persuasive Argumentation.

That bootstrapping and Moorean reasoning fail to instantiate persuasive argumentation is an often informally presented but not systematically developed view. In this paper, I will argue that this unpersuasiveness is not determined by principles of justification transmission but by two straightforward principles of rationality, understood as a concept of internal coherence. First, it is rational for S to believe the conclusion of an argument because of the argument, only if S believes sufficiently many premises of the argument.

The Value of Knowledge and Other Epistemic Standings: A Case for Epistemic Pluralism.

In epistemology, the concept of knowledge is of distinctive interest. This fact is also reflected in the discussion of epistemic value, which focuses to a large extend on the value problem of knowledge. This discussion suggests that knowledge has an outstanding value among epistemic standings because its value exceeds the value of its constitutive parts.

Skeptical Arguments and Deep Disagreement.

This paper provides a reinterpretation of some of the most influential skeptical arguments, Agrippa's trilemma, meta-regress arguments, and Cartesian external world skepticism. These skeptical arguments are reasonably regarded as unsound arguments about the extent of our knowledge. However, reinterpretations of these arguments tell us something significant about the preconditions and limits of persuasive argumentation.

Rationally irresolvable disagreement.

The discussion about deep disagreement has gained significant momentum in the last several years. This discussion often relies on the intuition that deep disagreement is, in some sense, rationally irresolvable. In this paper, I will provide a theory of rationally irresolvable disagreement.

Précis on Knowing and Checking: an Epistemological Investigation.

In this Précis, I provide an overview of my (Melchior 2019), which is subject to a book symposium organized by the University of Maribor. This volume in contains contributions by Peter Baumann, Kelly Becker, Marian David, Nenad Miščević, Robert Weston Siscoe, and Danilo Šuster along with my replies.

Replies to the Critics of Knowing and Checking: an Epistemological Investigation.

This paper replies to the comments made in by Peter Baumann, Kelly Becker, Marian David, Nenad Miščević, Wes Siscoe, and Danilo Šuster on my (Routledge 2019), hereinafter abbreviated as KC. These papers resulted from a workshop organized by the department of philosophy of the University of Maribor. I am very thankful to the organizers of the workshop and to the authors for their comments.

A modal theory of discrimination.

Discrimination is a central epistemic capacity but typically, theories of discrimination only use discrimination as a vehicle for analyzing knowledge. This paper aims at developing a self-contained theory of discrimination. Internalist theories of discrimination fail since there is no compelling correlation between discriminatory capacities and experiences.

The persuasiveness puzzle about bootstrapping.

This paper aims at resolving a puzzle about the persuasiveness of bootstrapping. On the one hand, bootstrapping is not a persuasive method of settling questions about the reliability of a source. On the other hand, our beliefs that our sense apparatus is reliable is based on other empirically formed beliefs, that is, they are acquired via a presumably complex bootstrapping process.

Sensitivity has Multiple Heterogeneity Problems: a Reply to Wallbridge.

In this paper, I defend the heterogeneity problem for sensitivity accounts of knowledge against an objection that has been recently proposed by Wallbridge in (2016b). I argue in (Melchior in , (4), 479-496, 2015) that sensitivity accounts of knowledge face a heterogeneity problem when it comes to higher-level knowledge about the truth of one's own beliefs. Beliefs in weaker higher-level propositions are insensitive, but beliefs in stronger higher-level propositions are sensitive.

Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-beta peptide.

Brain plaque deposits of amyloid-beta peptide (Abeta) is a pathological hallmark of Alzheimer's disease (AD) and apolipoprotein E (apoE) is thought to be involved in its deposition. One hypothesis for the role of apoE in the pathogenesis of AD is that apoE may be involved in deposition or clearance of Abeta by direct protein-to-protein interaction. Lipidated apoE4 bound preferentially to an intermediate aggregated form of Abeta and formed two- to three-fold more binding complexes than isoforms apoE2 or apoE3.

Regional organisation of brain activity during paradoxical sleep (PS).

Human brain function is regionally organised during paradoxical sleep (PS) in a very different way than during wakefulness or slow wave sleep. The important activity in the pons and in the limbic/paralimbic areas constitutes the key feature of the functional neuroanatomy of PS, together with a relative quiescence of prefrontal and parietal associative cortices. Two questions are still outstanding.

Remodeling of the HDL in NIDDM: a fundamental role for cholesteryl ester transfer protein.

When the Ay gene is expressed in KK mice, the yellow offspring (KKAy mice) become obese, insulin resistant, hyperglycemic, and severely hypertriglyceridemic, yet they maintain extraordinarily high plasma high-density lipoprotein (HDL) levels. Mice lack the ability to redistribute neutral lipids among circulating lipoproteins, a process catalyzed in humans by cholesteryl ester transfer protein (CETP). To test the hypothesis that it is the absence of CETP that allows these hypertriglyceridemic mice to maintain high plasma HDL levels, simian CETP was expressed in the KKAy mouse.

Centripetal cholesterol flux from extrahepatic organs to the liver is independent of the concentration of high density lipoprotein-cholesterol in plasma.

High density lipoproteins (HDLs) play a role in two processes that include the amelioration of atheroma formation and the centripetal flow of cholesterol from the extrahepatic organs to the liver. This study tests the hypothesis that the flow of sterol from the peripheral organs to the liver is dependent upon circulating HDL concentrations. Transgenic C57BL/6 mice were used that expressed variable amounts of simian cholesteryl ester-transfer protein (CETP).

Kinetics and inhibition of lipid exchange catalyzed by plasma cholesteryl ester transfer protein (lipid transfer protein).

The cholesteryl ester transfer protein-catalyzed cholesteryl ester transfer is inhibited by two compounds identified by a large-scale screening of cholesterol backbone-containing molecules. Kinetic analysis shows that U-95,594, an amino steroid, inhibits competitively the cholesteryl ester transfer protein-catalyzed transfer of both cholesteryl esters and triglycerides, as well from high-density lipoproteins as from synthetic microemulsions. In contrast, U-617, an organomercurial derivative of cholesterol, inhibits competitively the transfer of cholesteryl ester from either donor but is without any effect on triglyceride transfer.

Evidence that cynomolgus monkey cholesteryl ester transfer protein has two neutral lipid binding sites.

Two inhibitors of cynomolgus monkey cholesteryl ester transfer protein were evaluated. One, a monoclonal antibody made against purified cynomolgus monkey cholesteryl ester transfer protein, was capable of severely inhibiting triglyceride transfer, but had a variable effect on cholesteryl ester transfer. At low antibody to antigen ratios, there was what appeared to be a stoichiometric inhibition of cholesteryl ester transfer, but at high antibody to antigen ratios the inhibition of cholesteryl ester transfer was completely relieved, even though triglyceride transfer remained blocked.

Method for measuring the activities of cholesteryl ester transfer protein (lipid transfer protein).

A continuous recording fluorescence assay was developed for cholesteryl ester transfer protein (CETP). The assay measures the increase in fluorescence accompanying the relocation of fluorescent lipids, cholesteryl esters and triglycerides, from a donor emulsion to an acceptor emulsion. In the absence of CETP, the quantum yields of the fluorescent lipids is low because their high concentrations in the donor emulsions result in self-quenching.

Cholesteryl ester transfer protein's role in high-density lipoprotein metabolism Insights from studies with transgenic mice.

A substantial percentage of people who develop coronary artery atherosclerosis have plasma cholesterol levels in the "desirable" range. The principal lipid abnormality in most of these individuals is a low plasma high-density lipoprotein (HDL) level (HDL cholesterol levels of 35 mg/dL or less). As a result, low HDL levels are not only recognized as a risk factor for the disease, but are considered the single best predictor of an individual's likelihood of developing coronary heart disease.

The effect of population density on the development of experimental atherosclerosis in female mice.

The effect of cage population density on plasma lipids and the development of atherosclerosis was examined in female C57BL/6 mice. Mice were housed at a density of one, two or five animals per cage and fed an atherogenic diet for 28 weeks. Subsequently, the animals were bled, sacrificed, the hearts removed and the extent of fatty lesion development in the aorta examined and quantified.

Co-expression of cholesteryl ester transfer protein and defective apolipoprotein E in transgenic mice alters plasma cholesterol distribution. Implications for the pathogenesis of type III hyperlipoproteinemia.

Despite the definite etiologic link between apolipoprotein (apo) E mutations and type III hyperlipoproteinemia (HLP), it is not clear what additional factors are involved in the development of florid hyperlipidemia and how to explain the wide variability in the expression of the hyperlipidemic phenotype in carriers of receptor binding-defective apoE variants. The present study was designed to determine whether the overexpression of cholesteryl ester transfer protein (CETP), a plasma protein that transfers cholesteryl esters from the high density lipoproteins (HDL) to the very low density lipoproteins (VLDL) and whose activity is increased in hyperlipidemic states, plays a role in the development of hyperlipidemia and beta-VLDL accumulation in type III HLP. We produced double-transgenic mice that co-expressed high levels of simian CETP and either high or low levels of a human receptor binding-defective apoE variant, apoE(Cys-142).

The development of fatty liver is accelerated in transgenic mice expressing cynomolgus monkey cholesteryl ester transfer protein.

Expression of cynomolgus monkey cholesteryl ester transfer protein (CETP) in C57BL/6 mice has been shown to have a profound effect on the lipoprotein profile in those animals. The objective of this study was to examine the effect of CETP expression on the hepatic lipids of the CETP transgenic mice. The triglyceride, cholesterol and phospholipid composition of livers from 6- and 12-month-old transgenic mice were evaluated and compared with those of age-matched C57BL/6 mice.

Purification of human cholesteryl ester transfer protein by affinity chromatography on immobilized triazine dyes.

Human cholesteryl ester transfer protein was purified from lipoprotein-depleted serum or plasma in a three-step procedure utilizing commercially available triazine dyes immobilized on agarose. The method used consisted of successive chromatography steps on Reactive Red 120 agarose (Procion Red H-E3B, Cibachron Brilliant Red 4G-E), CM Sepharose, and Reactive Yellow 86 agarose (Procion Yellow M-8G). Upon analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the resultant protein preparation displayed two bands of variable intensity.

Apolipoprotein A-I metabolism in cholesteryl ester transfer protein transgenic mice. Insights into the mechanisms responsible for low plasma high density lipoprotein levels.

Expression of simian cholesteryl ester transfer protein (CETP) in C57BL/6 mice causes the animals' high density lipoprotein (HDL) levels to decrease. The purpose of these studies was to determine how CETP expression caused that reduction. Chemical analysis showed that the HDL of the CETP transgenic mice had about twice as much triglyceride and only about 60% as much cholesteryl ester as the HDL from the C57BL/6 mice.

Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein.

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of neutral lipids among the lipoprotein. Because the principal core lipid of very-low-density lipoprotein (VLDL) is triglyceride and that of high-density lipoprotein (HDL) is cholesterol ester, CETP mediates a 'heteroexchange' of cholesterol ester for triglyceride between those lipoproteins. As a result, animals that express CETP tend to have higher VLDL and low-density lipoprotein (LDL) cholesterol levels, whereas those with no CETP activity tend to have high HDL cholesterol levels.

Lipoprotein profile characterization of the KKA(y) mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing agent pioglitazone.

The purpose of this study was to characterize the lipoprotein profile in the KKA(y) mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing drug pioglitazone. Analysis of the plasma from untreated KKA(y) mice showed that they were severely hyperglycemic, severely hypertriglyceridemic, and moderately hypercholesterolemic. Agarose column chromatographic analysis showed that essentially all of the triglyceride eluted with very low density lipoprotein, and the majority of the cholesterol eluted with high density lipoprotein.