A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.     

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).     

Big data and prediction: Four case studies

Has the rise of data-intensive science, or ‘big data’, revolutionized our ability to predict? Does it imply a new priority for prediction over causal understanding, and a diminished role for theory and human experts? I examine four important cases where prediction is desirable: political elections, the weather, GDP, and the results of interventions suggested by economic experiments. These cases suggest caution. Although big data methods are indeed very useful sometimes, in this paper's cases they improve predictions either limitedly or not at all, and their prospects of doing so in the future are limited too.     

The cyclin-dependent kinase family in the social amoebozoan Dictyostelium discoideum

Cyclin-dependent kinases (Cdk) are a family of serine/threonine protein kinases that regulate eukaryotic cell cycle progression. Their ability to modulate the cell cycle has made them an attractive target for anti-cancer therapies. Cdk protein function has been studied in a variety of Eukaryotes ranging from yeast to humans. In the social amoebozoan Dictyostelium discoideum, several homologues of mammalian Cdks have been identified and characterized. The life cycle of this model organism is comprised of a feeding stage where single cells grow and divide mitotically as they feed on their bacterial food source and a multicellular developmental stage that is induced by starvation. Thus it is a valuable system for studying a variety of cellular and developmental processes. In this review I summarize the current knowledge of the Cdk protein family in Dictyostelium by highlighting the research efforts focused on the characterization of Cdk1, Cdk5, and Cdk8 in this model Eukaryote. Accumulated evidence indicates that each protein performs distinct functions during the Dictyostelium life cycle with Cdk1 being required for growth and Cdk5 and Cdk8 being required for processes that occur during development. Recent studies have shown that Dictyostelium Cdk5 shares attributes with mammalian Cdk5 and that the mammalian Cdk inhibitor roscovitine can be used to inhibit Cdk5 activity in Dictyostelium. Together, these results show that Dictyostelium can be used as a model system for studying Cdk protein function.     

Thomas Harriot’s optics,between experiment and imagination: the case of Mr Bulkeley’s glass

Some time in the late 1590s, the Welsh amateur mathematician John Bulkeley wrote to Thomas Harriot asking his opinion about the properties of a truly gargantuan (but totally imaginary) plano-spherical convex lens, 48 feet in diameter. While Bulkeley’s original letter is lost, Harriot devoted several pages to the optical properties of “Mr Bulkeley his Glasse” in his optical papers (now in British Library MS Add. 6789), paying particular attention to the place of its burning point. Harriot’s calculational methods in these papers are almost unique in Harriot’s optical remains, in that he uses both the sine law of refraction and interpolation from Witelo’s refraction tables in order to analyze the passage of light through the glass. For this and other reasons, it is very likely that Harriot wrote his papers on Bulkeley’s glass very shortly after his discovery of the law and while still working closely with Witelo’s great Optics; the papers represent, perhaps, his very first application of the law. His and Bulkeley’s interest in this giant glass conform to a long English tradition of curiosity about the optical and burning properties of large glasses, which grew more intense in late sixteenth-century England. In particular, Thomas Digges’s bold and widely known assertions about his father’s glasses that could see things several miles distant and could burn objects a half-mile or further away may have attracted Harriot and Bulkeley’s skeptical attention; for Harriot’s analysis of the burning distance and the intensity of Bulkeley’s fantastic lens, it shows that Digges’s claims could never have been true about any real lens (and this, I propose, was what Bulkeley had asked about in his original letter to Harriot). There was also a deeper, mathematical relevance to the problem that may have caught Harriot’s attention. His most recent source on refraction—Giambattista della Porta’s De refractione of 1593—identified a mathematical flaw in Witelo’s cursory suggestion about the optics of a lens (the only place that lenses appear, however fleetingly, in the writings of the thirteenth-century Perspectivist authors). In his early notes on optics, in a copy of Witelo’s optics, Harriot highlighted Witelo’s remarks on the lens and della Porta’s criticism (which he found unsatisfactory). The most significant problem with Witelo’s theorem would disappear as the radius of curvature of the lens approached infinity. Bulkeley’s gigantic glass, then, may have provided Harriot an opportunity to test out Witelo’s claims about a plano-spherical glass, at a time when he was still intensely concerned with the problems and methods of the Perspectivist school.