Newtonianism and the enthusiasm of Enlightenment

The career of John Jackson (1686-1763), Arian theologian and controversialist, provides a key to unlocking the early reception and quick collapse of a Newtonian natural apologetic originally developed by Samuel Clarke. The importance of friendship and discipleship in eighteenth-century intellectual enquiry is emphasised, and the links between Newton and his followers are traced alongside those of a group of Cambridge Lockeans, led by Jackson’s direct contemporary Daniel Waterland, who proved instrumental in the initial dismantling of Clarke’s brand of Newtonian apologetic. The controversial context of this engagement is shown to have been largely provided by the religiously compromising rise of freethinking, and Tindal’s Christianity as old as the creation (1731) signalled the dangers to proponents of natural religion as an adjunct of Christian apologetic in such a heated atmosphere. Religious division of the sort that resulted paradoxically played into the hands of the freethinkers in the anticlerical atmosphere of the 1730s, and accusations were exchanged between Newtonians and Lockeans accordingly. The dynamic of England’s Enlightenment experience is, then, a complicated one, and, as the career and writings of Jackson and William Whiston demonstrate, it was one which absorbed as well as repudiated ‘enthusiasm’.     

Total systems intervention and human inquiry: The search for a common ground

Total Systems Intervention (TSI) is an approach to intervening in problem situations which has much to offer where complex interacting issues need to be addressed by the complementary use of intervention methodologies. That such an approach has much in common with Action Research (AR) has been recognized, with much recent effort being devoted to the relationship between AR and Critical Systems Thinking (CST), the theoretical endeavor underpinning TSI. This paper further develops this line of debate and relates AR or Human Inquiry (HI) more directly to TSI, using an information systems intervention to enhance the study. The outcome is a demonstration of how TSI implicitly uses techniques informed from the field of Action Research, and how a more thorough synthesis of HI with TSI might serve to improve the overall intervention process.     

波浪载荷下海床土体孔隙水压的瞬态与累积响应机理

室内模型实验和现场观测均已发现了波浪引起的海床孔隙水压力存在瞬态和累积两种响应, 已有工作大多只单独研究其中的一种孔隙水压响应机理.分析得到了波浪诱导残余孔隙水压的理论解答, 并与实验结果进行了比较分析. 在所得理论解的基础上, 进行参量研究, 给出了孔隙水压瞬态和累积响应分析的应用范围. 提出了一种便于工程应用的预测波浪载荷下海床液化势的近似解.     

Narrative constructs in modern clinical case reporting

Modern clinical case reporting takes the form of problem-solution narratives that redescribe symptoms in terms of disease categories. Authored almost always by those who have played a part in the medical assessment of the patient, reports historicise the salient details of an individual's illness as a complex effect of identifiable antecedent causes. Candidate hypotheses linking illness to pathological mechanisms are suggested by the patient’s experience, and by data that emerge from clinical examination and investigation. Observational and interpretive statements from these considerations are fitted into a temporally inflected account of the patient’s medical condition, configured from the vantage point of hindsight. Drawing on established forms of deferred telling, readers are invited to follow a story that drip-feeds a mixture of contingent and non-incidental information into the account, which engenders and frustrates curiosity, creates expectations, and challenges powers of reasoning and pattern recognition. Whereas case reporting once favoured memoir, the sentimental tale and eccentric biography as the means by which its historical narrative was cast, the preferred genres of contemporary case reporting include detective fiction, and puzzle and riddle narratives, formats that conceptualise the medical consultation in narrow problem-solution terms.     

Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.     

A draft genome of Yersinia pestis from victims of the Black Death

Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.     

An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.