Are We In A Simulation?

Graeme A Forbes asks David Chalmers, Michaela mcSweeney and Darren Bradley about this disturbing possibilit

Why a 10,000-year clock is being built under a mountain – and why 10,000 years is too long

Discussio

In vitro studies on the inhibitory effect of lymphoid cells. II. Antitumor activity of lymphoid cells from spontaneous mammary tumor-bearing mice on the autochthonous primary culture tumor cells

As a step in the elucidation of human cancer immunity we studied antitumor activity of lymphoid cells by conducting a series of cultures using the primary culture of cells from spontaneous mammary cancers from C3H and RIll mice mixed with autochthonous lymphoid cells, and obtained the following results. 1) With 24 mammary tumors obtained from 24 mammary cancer. bearing mice, we prepared 22 suspensions containing sufficient numbers of free tumor cells, and attempted primary culture with them. As a result we were able to attain satisfactory primary culture cells in 18 trials. 2) With each group of the 18 primary culture tumor cells we conducted mixed cultures with autochthonous lymphoid cells (mainly spleen cells) in proportion of 1 : 40, for 48 hours, and counted viable tumor cells after the culture. As a result it was found that in 11 trials the lymphoid cells showed antitumor activity. In the remaining 7 groups of lymphoid cells there could be observed no antitumor activity, but some of them showed tendency to slightly accelerate the growth of tumor cells. 3) On looking at the correlation between the antitumor activity of lymphoid cells and the ratio of tumor weight/body weight, it was revealed that the antitumor activity is greatest when the tumor is around 10% the body weight, and as the tumor grows larger, such antitumor activity disappears. From these results, it may be concluded that even in spontaneous mammary cancer of mouse, autochthonous lymphoid cells exhibit anti. tumor activity on indigenous tumor, and this seems to indicate that cell. mediated immunity has been established.</p

Enduring senses

The meanings of words seem to change over time. But while there is a growing body of literature in linguistics and philosophy about meaning change, there has been little discussion about the metaphysical underpinnings of meaning change. The central aim of this paper is to push this discussion forward by surveying the terrain and advocating for a particular metaphysical picture. In so doing, we hope to clarify various aspects of the nature of meaning change, as well as prompt future philosophical investigation into this topic. More specifically, this paper has two parts. The first, broadly exploratory, part surveys various metaphysical accounts of meaning change. The goal here is to lay out the terrain, thereby highlighting some key choice points. Then, in the second part, after critiquing Prosser’s (Philosophy Phenomenol Res 100(3):657–676, 2020) exdurantism about ‘mental files’, we sketch and defend the enduring senses view of meaning change

Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation

Pathogenic, generally loss-of-function, variants in CACNA1F, encoding the Cav1.4α1 calcium channel, underlie congenital stationary night blindness type 2 (CSNB2), a rare inherited retinal disorder associated with visual disability. To establish the underlying pathomechanism, we investigated 10 clinically derived CACNA1F missense variants located across pore-forming domains, connecting loops, and the carboxy-tail domain of the Cav1.4α subunit. Homology modeling showed that all variants cause steric clashes; informatics analysis correctly predicted pathogenicity for 7/10 variants. In vitro analyses demonstrated that all variants cause a decrease in current, global expression, and protein stability and act through a loss-of-function mechanism and suggested that the mutant Cav1.4α proteins were degraded by the proteasome. We showed that the reduced current for these variants could be significantly increased through treatment with clinical proteasome inhibitors. In addition to facilitating clinical interpretation, these studies suggest that proteasomal inhibition represents an avenue of potential therapeutic intervention for CSNB2

The Growing Block’s past problems

The Growing-Block view of time has some problems with the past. It is committed to the existence of the past, but needs to say something about the difference between the past and present. I argue that we should resist Correia and Rosenkranz’ (Oxford studies in metaphysics, vol 8, pp 333–350, 2013) response to Braddon-Mitchell’s (Analysis 64:199–203, 2004) argument that the Growing-Block leads to scepticism about whether we are present. I consider an approach, similar to Peter Forrest (Analysis 64:358–362, 2004), and show it is not so counter-intuitive as Braddon-Mitchell suggests and further show that it requires no ‘semantic and metaphysical gymnastics’, as Chris Heathwood (Analysis 65:249–251, 2005) has suggested. In doing these things I make the problem of the past on the Growing-Block view a problem in its history, not its present

Xanthine oxidase inhibition for the improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) - Protocol for a randomised double blind placebo-controlled clinical trial

Background: Allopurinol, a xanthine oxidase inhibitor, reduced progression of carotid-intima media thickness and lowered blood pressure in a small clinical trial in people with ischaemic stroke. Xanthine oxidase inhibition for improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) aims to assess the effect of allopurinol treatment on white matter hyperintensity progression and blood pressure after stroke. This paper describes the XILO-FIST protocol. Methods: XILO-FIST is a multicentre randomised double-blind, placebo-controlled, parallel group clinical trial funded by the British Heart Foundation and the Stroke Association. The trial has been adopted by the Scottish Stroke Research Network and the UK Clinical Research Network. The trial is registered in clinicaltrials.gov (registration number NCT02122718). XILO-FIST will randomise 464 participants, aged greater than 50 years, with ischaemic stroke within the past month, on a 1:1 basis, to two years treatment with allopurinol 300 mg twice daily or placebo. Participants will undergo brain magnetic resonance imaging, cognitive assessment, ambulatory blood pressure monitoring and blood sampling at baseline and after two years treatment. The primary outcome will be white matter hyperintensity progression, measured using the Rotterdam progression scale. Secondary outcomes will include change in white matter hyperintensity volume, mean day-time systolic blood pressure and measures of cognitive function. Up to 100 will undergo additional cardiac magnetic resonance imaging in a sub-study of left ventricular mass. Discussion: If white matter hyperintensity progression is reduced, allopurinol could be an effective preventative treatment for patients with ischaemic stroke and clinical endpoint studies would be needed. If allopurinol reduces blood pressure after stroke, then it could be used to help patients reach blood pressure targets

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to dat

The Growing-Block: Just one thing after another?

In this article, we consider two independently appealing theories—the Growing-Block view and Humean Supervenience—and argue that at least one is false. The Growing-Block view is a theory about the nature of time. It says that (a) past and present things exist, while future things do not, and (b) the passage of time consists in new things coming into existence. Humean Supervenience is a theory about the nature of entities like laws, nomological possibility, counterfactuals, dispositions, causation, and chance. It says that none of these entities are fundamental, since if there were, this would entail the existence of irreducible necessary connections between matters of fact. Instead, these entities supervene on a fundamental, nonnomological “Humean mosaic” of property instances at spacetime points. We will further explain and motivate the Growing-Block view and Humean Supervenience in sections 2 and 3, but first, we turn to our master argument