The future of social is personal: the potential of the personal data store

This chapter argues that technical architectures that facilitate the longitudinal, decentralised and individual-centric personal collection and curation of data will be an important, but partial, response to the pressing problem of the autonomy of the data subject, and the asymmetry of power between the subject and large scale service providers/data consumers. Towards framing the scope and role of such Personal Data Stores (PDSes), the legalistic notion of personal data is examined, and it is argued that a more inclusive, intuitive notion expresses more accurately what individuals require in order to preserve their autonomy in a data-driven world of large aggregators. Six challenges towards realising the PDS vision are set out: the requirement to store data for long periods; the difficulties of managing data for individuals; the need to reconsider the regulatory basis for third-party access to data; the need to comply with international data handling standards; the need to integrate privacy-enhancing technologies; and the need to future-proof data gathering against the evolution of social norms. The open experimental PDS platform INDX is introduced and described, as a means of beginning to address at least some of these six challenges

Phi-values in protein folding kinetics have energetic and structural components

Phi-values are experimental measures of how the kinetics of protein folding is changed by single-site mutations. Phi-values measure energetic quantities, but are often interpreted in terms of the structures of the transition state ensemble. Here we describe a simple analytical model of the folding kinetics in terms of the formation of protein substructures. The model shows that Phi-values have both structural and energetic components. In addition, it provides a natural and general interpretation of "nonclassical" Phi-values (i.e., less than zero, or greater than one). The model reproduces the Phi-values for 20 single-residue mutations in the alpha-helix of the protein CI2, including several nonclassical Phi-values, in good agreement with experiments.Comment: 15 pages, 3 figures, 1 tabl

Mirror Symmetry and Other Miracles in Superstring Theory

The dominance of string theory in the research landscape of quantum gravity physics (despite any direct experimental evidence) can, I think, be justified in a variety of ways. Here I focus on an argument from mathematical fertility, broadly similar to Hilary Putnam's 'no miracles argument' that, I argue, many string theorists in fact espouse. String theory leads to many surprising, useful, and well-confirmed mathematical 'predictions' - here I focus on mirror symmetry. These predictions are made on the basis of general physical principles entering into string theory. The success of the mathematical predictions are then seen as evidence for framework that generated them. I attempt to defend this argument, but there are nonetheless some serious objections to be faced. These objections can only be evaded at a high (philosophical) price.Comment: For submission to a Foundations of Physics special issue on "Forty Years Of String Theory: Reflecting On the Foundations" (edited by G. `t Hooft, E. Verlinde, D. Dieks and S. de Haro)

An Assessment of H1N1 Influenza-Associated Acute Respiratory Distress Syndrome Severity after Adjustment for Treatment Characteristics

Pandemic influenza caused significant increases in healthcare utilization across several continents including the use of high-intensity rescue therapies like extracorporeal membrane oxygenation (ECMO) or high-frequency oscillatory ventilation (HFOV). The severity of illness observed with pandemic influenza in 2009 strained healthcare resources. Because lung injury in ARDS can be influenced by daily management and multiple organ failure, we performed a retrospective cohort study to understand the severity of H1N1 associated ARDS after adjustment for treatment. Sixty subjects were identified in our hospital with ARDS from “direct injury” within 24 hours of ICU admission over a three month period. Twenty-three subjects (38.3%) were positive for H1N1 within 72 hours of hospitalization. These cases of H1N1-associated ARDS were compared to non-H1N1 associated ARDS patients. Subjects with H1N1-associated ARDS were younger and more likely to have a higher body mass index (BMI), present more rapidly and have worse oxygenation. Severity of illness (SOFA score) was directly related to worse oxygenation. Management was similar between the two groups on the day of admission and subsequent five days with respect to tidal volumes used, fluid balance and transfusion practices. There was, however, more frequent use of “rescue” therapy like prone ventilation, HFOV or ECMO in H1N1 patients. First morning set tidal volumes and BMI were significantly associated with increased severity of lung injury (Lung injury score, LIS) at presentation and over time while prior prescription of statins was protective. After assessment of the effect of these co-interventions LIS was significantly higher in H1N1 patients. Patients with pandemic influenza-associated ARDS had higher LIS both at presentation and over the course of the first six days of treatment when compared to non-H1N1 associated ARDS controls. The difference in LIS persisted over the duration of observation in patients with H1N1 possibly explaining the increased duration of mechanical ventilation

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat

Background: The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient’s failure to respond correlated with baseline polymorphisms at SP1 residues 6-8. Results: In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance and SP1-V7M and T8Δ mutations conferred intermediate levels of BVM resistance. Conclusions: Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.Publisher PDFPeer reviewe

Thermochronologic constraints on the late Cenozoic exhumation history of the Gurla Mandhata metamorphic core complex, Southwestern Tibet

This is the publisher's version, also available electronically from http://onlinelibrary.wiley.com/doi/10.1002/2013TC003302/abstractHow the Tibetan plateau is geodynamically linked to the Himalayas is a topic receiving considerable attention. The Karakoram fault plays key roles in describing the structural relationship between southern Tibet and the Himalayas. In particular, considerable debate exists at the southeastern end of the Karakoram fault, where its role is interpreted in two different ways. One interpretation states that slip along the dextral Karakoram fault extends eastward along the Indus-Yalu suture zone, bypassing the Himalayas. The other interprets that fault slip is fed southward into the Himalayan thrust belt along the Gurla Mandhata detachment (GMD). To evaluate these competing models, the late Miocene history of the GMD was reconstructed from thermokinematic modeling of zircon (U-Th)/He data. Three east-west transects reveal rapid cooling of the GMD footwall from 8.0 ± 1.3 Ma to 2.6 ± 0.7 Ma. Model simulations show a southward decrease in slip magnitude and rate along the GMD. In the north, initiation of the GMD range between 14 and 11 Ma with a mean fault slip rate of 5.0 ± 0.9 mm/yr. The central transect shows an initiation age from 14 to 11 Ma with a mean fault slip rate of 3.3 ± 0.6 mm/yr. In the south, initiation began between 15 and 8 Ma with a mean fault slip rate of 3.2 ± 1.6 mm/yr. The initiation ages and slip rates match the Karakoram fault across several timescales, supporting the idea that the two are kinematically linked. Specifically, the data are consistent with the GMD acting as an extensional stepover, with slip transferred southward into the Himalayas of western Nepal

Predicting Bevirimat resistance of HIV-1 from genotype

<p>Abstract</p> <p>Background</p> <p>Maturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1.</p> <p>Results</p> <p>We used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 ± 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the <it>α</it>-helix in p2, which hints at a possible resistance mechanism.</p> <p>Conclusions</p> <p>We found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.</p