Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families

The gene coding for the amyloid protein, a component of neuritic plaques found in brain tissue from patients with Alzheimer's disease, has been localized to chromosome 21, and neighbouring polymorphic DNA markers segregate with Alzheimer's disease in several large families. These data, and the association of Alzheimer's disease with Down's syndrome, suggest that overproduction of the amyloid protein, or production of an abnormal variant of the protein, may be the underlying pathological change causing Alzheimer's disease. We have identified a restriction fragment length polymorphism of the A4-amyloid gene, and find recombinants in two Alzheimer's disease families between Alzheimer's disease and the A4-amyloid locus. This demonstrates that the gene for plaque core A4-amyloid cannot be the locus of a defect causing Alzheimer's disease in these families. These data indicate that alterations in the plaque core amyloid gene cannot explain the molecular pathology for all cases of Alzheimer's disease.     

Germline mosaicism and Duchenne muscular dystrophy mutations

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3,500 newborn boys. The DMD locus has a high mutation frequency: one third of the cases is thought to result from a new mutation. Linkage studies using probes to detect restriction fragment length polymorphisms and DNA deletion studies have greatly improved DMD carrier detection and prenatal diagnosis. Here we report on two families in which a pERT87 (DXS164) deletion was transmitted to more than one offspring by women who showed no evidence for the mutation in their own somatic (white blood) cells. We also show that the deletion in both siblings in one of the families is identical, indicating that the deletion must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism. This phenomenon may turn out to be a major factor contributing to the induction of DMD mutations, and has important implications for the counselling of DMD families.     

Ten reasons to embrace scientism

A strong version of scientism, such as that of Alex Rosenberg, says, roughly, that natural science reliably delivers rational belief or knowledge, whereas common sense sources of belief, such as moral intuition, memory, and introspection, do not. In this paper I discuss ten reasons that adherents of scientism have or might put forward in defence of scientism. The aim is to show which considerations could plausibly count in favour of scientism and what this implies for the way scientism ought to be formulated. I argue that only three out of these ten reasons potentially hold water and that the evidential weight is, therefore, on their shoulders. These three reasons for embracing scientism are, respectively, particular empirical arguments to the effect that there are good debunking explanations for certain common sense beliefs, that there are incoherences and biases in the doxastic outputs of certain common sense sources of belief, and that beliefs that issue from certain common sense doxastic sources are illusory. From what I argue, it follows that only a version of scientism that is significantly weaker than many versions of scientism that we find in the literature is potentially tenable. I conclude the paper by stating what such a significantly weaker version of scientism could amount to.     

The mass of the missing baryons in the X-ray forest of the warm-hot intergalactic medium

Recent cosmological measurements indicate that baryons comprise about four per cent of the total mass-energy density of the Universe, which is in accord with the predictions arising from studies of the production of the lightest elements. It is also in agreement with the actual number of baryons detected at early times (redshifts z > 2). Close to our own epoch (z < 2), however, the number of baryons detected add up to just over half (approximately 55 per cent) of the number seen at z > 2 (refs 6-11), meaning that about approximately 45 per cent are 'missing'. Here we report a determination of the mass-density of a previously undetected population of baryons, in the warm-hot phase of the intergalactic medium. We show that this mass density is consistent, within the uncertainties, with the mass density of the missing baryons.     

Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments

CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3?ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport.