Facing glycosphingolipid–Shiga toxin interaction: dire straits for endothelial cells of the human vasculature

The two major Shiga toxin (Stx) types, Stx1 and Stx2, produced by enterohemorrhagic Escherichia coli (EHEC) in particular injure renal and cerebral microvascular endothelial cells after transfer from the human intestine into the circulation. Stxs are AB₅ toxins composed of an enzymatically active A subunit and the pentameric B subunit, which preferentially binds to the glycosphingolipid globotriaosylceramide (Gb3Cer/CD77). This review summarizes the current knowledge on Stx-caused cellular injury and the structural diversity of Stx receptors as well as the initial molecular interaction of Stxs with the human endothelium of different vascular beds. The varying lipoforms of Stx receptors and their spatial organization in lipid rafts suggest a central role in different modes of receptor-mediated endocytosis and intracellular destiny of the toxins. The design and development of tailored Stx neutralizers targeting the oligosaccharide–toxin recognition event has become a very real prospect to ameliorate or prevent life-threatening renal and neurological complications.     

Preludes to dark energy: zero-point energy and vacuum speculations

According to modern physics and cosmology, the universe expands at an increasing rate as the result of a “dark energy” that characterizes empty space. Although dark energy is a modern concept, some elements in it can be traced back to the early part of the twentieth century. I examine the origin of the idea of zero-point energy, and in particular how it appeared in a cosmological context in a hypothesis proposed by Walther Nernst in 1916. The hypothesis of a zero-point vacuum energy attracted some attention in the 1920s, but without attempts to relate it to the cosmological constant that was discussed by Georges Lemaître in particular. Only in the late 1960s, was it recognized that there is a connection between the cosmological constant and the quantum vacuum. As seen in retrospect, many of the steps that eventually led to the insight of a kind of dark energy occurred isolated and uncoordinated.     

The Context of Discovery: Lemaître and the Origin of the Primeval-Atom Universe

In spite of the paradigmatic status of the Big Bang model of the universe, the genesis of this idea has never been examined in detail. This paper investigates how the Belgian physicist and cosmologist Georges Lemaître in 1931 arrived at the hypothesis that the universe had begun in a Big Bang, or what he called a ‘primeval atom’. Four years earlier, he had suggested a closed expanding model in which the universe slowly inflated from an equilibrium Einstein state, but in 1931 he advocated an abrupt beginning from an initial, superdense concentration of nuclear matter. Why did Lemaître believe that the universe had a definite beginning a finite time ago? It turns out that the law of increase of entropy was one motivation, and that the existence of long-lived radioactive substances was another. Contrary to what is often stated, he most likely had the idea of an exploding universe before 1931. Among his chief inspirations to think about the origin of the universe, we draw attention to his persistent fascination of light as the primeval state of the world. Although this idea was originally seen in a theological perspective, religion played no direct role in Lemaître's hypothesis of 1931.     

Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction

Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells.     

An anthropic myth: Fred Hoyle’s carbon-12 resonance level

The case of Fred Hoyle’s prediction of a resonance state in carbon-12, unknown in 1953 when it was predicted, is often mentioned as an example of anthropic prediction. However, an investigation of the historical circumstances of the prediction and its subsequent experimental confirmation shows that Hoyle and his contemporaries did not associate the level in the carbon nucleus with life. Only in the 1980s, after the emergence of the anthropic principle, did it become common to see Hoyle’s prediction as anthropically significant. At about the same time mythical accounts of the prediction and its history began to abound. Not only has the anthropic myth no basis in historical fact, it is also doubtful if the excited levels in carbon-12 and other atomic nuclei can be used as an argument for the predictive power of the anthropic principle.     

Cosmologies with varying speed of light: A historical perspective

The possibility that natural laws and constants may not be true constants, but vary over cosmic periods of time, has recently attracted much attention. In this paper, I provide some historical background to the issue and consider, in the form of a historical review, some of the more spectacular developments within recent years. The focus of the paper is on the hypothesis of a varying speed of light, which appeared shortly after the announcement of the expanding universe. After a brief account of the history of this hypothesis, I consider in more details the varying c theories that have appeared during the last decade and were originally introduced as an alternative to the inflationary model. These so-called varying speed of light (VSL) theories have been surprisingly popular and created a flood of physics and cosmology papers. However, they have also been severely criticized from conceptual points of view and their status is as yet uncertain. Although a research programme in development, a historical perspective on VSL cosmology may not be out of place.