Tragedy and Theodicy: The Role of the Sufferer from Job to Ahab

The character of Job starts in literature, a trope and archetype of the suffering man who potentially gains wisdom through suffering. Job’s characterization informs a comparison to Sophocles’ Oedipus Rex, Shakespeare’s King Lear, Milton’s Paradise Lost, and finally Melville’s Moby-Dick. These versions of Job rally, fight, and rebel against a universe that was once loving and fair towards a more chaotic and nihilistic one. Job’s suffering is on the mark of all tragedy because he not only experiences a downfall, he gains wisdom through universalizing his torment. The Job trope not only stresses the role of suffering, it links theodicy (“the problem of suffering”) with tragedy, in which the Job character experiences a progression from innocence to experience, foolishness to wisdom, blindness towards exaltation. As this trope progresses, author’s like Milton and Melville complicate the role of the sufferer by presenting false Job’s, who experience suffering but learn nothing from it. Scholars like William Empson, Harold Bloom and Stanley Fish provide insight into the theological and literary underpinnings of the Job archetype in literature, which illuminates the connection between theodicy and tragedy

Time-resolved molecular dynamics of single and double hydrogen migration in ethanol

Being the lightest, most mobile atom that exists, hydrogen plays an important role in the chemistry of hydrocarbons, proteins and peptides and most biomolecules. Hydrogen can undergo transfer, exchange and migration processes, having considerable impact on the chemical behavior of these molecules. Although much has been learned about reaction dynamics involving one hydrogen atom, less is known about those processes where two or more hydrogen atoms participate. Here we show that single and double hydrogen migrations occurring in ethanol cations and dications take place within a few hundred fs to ps, using a 3D imaging and laser pump-probe technique. For double hydrogen migration, the hydrogens are not correlated, with the second hydrogen migration promoting the breakup of the C–O bond. The probability of double hydrogen migration is quite significant, suggesting that double hydrogen migration plays a more important role than generally assumed. The conclusions are supported by state-of-the-art molecular dynamics calculationsThis work was funded by the National Science Foundation under award No. 1700551, the MINECO projects FIS2016-77889-R and CTQ2016- 76061-P, ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (SEV-2016-0686) and ‘María de Maeztu’ Programme for Units of Excellence in R&D (MDM-2014-0377). We acknowledge the generous allocation of computer time at the Centro de Computación Científica at the Universidad Autónoma de Madrid (CCC-UAM). S.D.-T. gratefully acknowledges the “Ramón y Cajal” program (RYC-2010-07019) of the Spanish Ministerio de Educación y Cienci

Molecular bacterial load assay, a culture-free biomarker for rapid and accurate quantification of sputum Mycobacterium tuberculosis bacillary load during treatment

A molecular assay to quantify Mycobacterium tuberculosis is described. In vitro, 98% (n = 96) of sputum samples with a known number of bacilli (107 to 102 bacilli) could be enumerated within 0.5 log10. In comparison to culture, the molecular bacterial load (MBL) assay is unaffected by other microorganisms present in the sample, results are obtained more quickly (within 24 h) and are seldom inhibited (0.7% samples), and the MBL assay critically shows the same biphasic decline as observed longitudinally during treatment. As a biomarker of treatment response, the MBL assay responds rapidly, with a mean decline in bacterial load for 111 subjects of 0.99 log10 (95% confidence interval [95% CI], 0.81 to 1.17) after 3 days of chemotherapy. There was a significant association between the rate of bacterial decline during the same 3 days and bacilli ml−1 sputum at day 0 (linear regression, P = 0.0003) and a 3.62 increased odds ratio of relapse for every 1 log10 increase in pretreatment bacterial load (95% CI, 1.53 to 8.59)

‘Caution! The Bread is Poisoned’: The Hong Kong Mass Poisoning of January 1857

This article examines the Hong Kong mass poisoning of 15 January 1857, in which bread from a Chinese bakery that supplied the colonial community was adulterated with arsenic. Even though there is a wealth of printed and manuscript documentation available many vital aspects of the poisoning remain unclear. What kind of incident was it: an act of terrorism and attempted mass murder, a war crime, a criminal conspiracy, an act of commercial sabotage, an accident or even an imagined or imaginary event? Throughout, our focus remains firmly fixed on the central act of the poisoning itself and on what it reveals about the precarious nature of early colonial Hong Kong. Interpretations have swarmed over the available ‘facts'. Equally ironic is what happened to the afterlife of how the event was understood. This article seeks to rescue the Hong Kong poisoning from being a freakish and isolated footnote of only local interest. Accepting this historical verdict would be a mistake as it is of significance not only at a local level, but geopolitically in Britain and across the empire

Reorganisation ofHoxdregulatory landscapes during the evolution of a snake-like body plan

Within land vertebrate species, snakes display extreme variations in their body plan, characterized by the absence of limbs and an elongated morphology. Such a particular interpretation of the basic vertebrate body architecture has often been associated with changes in the function or regulation of Hox genes. Here, we use an interspecies comparative approach to investigate different regulatory aspects at the snake HoxD locus. We report that, unlike in other vertebrates, snake mesoderm-specific enhancers are mostly located within the HoxD cluster itself rather than outside. In addition, despite both the absence of limbs and an altered Hoxd gene regulation in external genitalia, the limb-associated bimodal HoxD chromatin structure is maintained at the snake locus. Finally, we show that snake and mouse orthologous enhancer sequences can display distinct expression specificities. These results show that vertebrate morphological evolution likely involved extensive reorganisation at Hox loci, yet within a generally conserved regulatory framework.Fundação para a Ciência e Tecnologia grant: (PTDB/BEX-BID/0899/2014); Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung grant: (310030B_138662); Claraz Foundation; Université de Genève; Instituto Federal de Educação Ciência e Tecnologia do Espírito Santo

Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients