In-cell NMR characterization of the secondary structure populations of a disordered conformation of α-Synuclein within E. coli cells

α-Synuclein is a small protein strongly implicated in the pathogenesis of Parkinson’s disease and related neurodegenerative disorders. We report here the use of in-cell NMR spectroscopy to observe directly the structure and dynamics of this protein within E. coli cells. To improve the accuracy in the measurement of backbone chemical shifts within crowded in-cell NMR spectra, we have developed a deconvolution method to reduce inhomogeneous line broadening within cellular samples. The resulting chemical shift values were then used to evaluate the distribution of secondary structure populations which, in the absence of stable tertiary contacts, are a most effective way to describe the conformational fluctuations of disordered proteins. The results indicate that, at least within the bacterial cytosol, α-synuclein populates a highly dynamic state that, despite the highly crowded environment, has the same characteristics as the disordered monomeric form observed in aqueous solution

Underwriting Apophenia and Cryptids: Are Cycles Statistical Figments of our Imagination?

This paper re-examines the evidence in favour of the existence of underwriting cycles in property and casualty insurance and their economical significance. Using a meta-analysis of published papers in the area of insurance economics, we show that the evidence supporting the existence of underwriting cycles is misleading. There is, in fact, little evidence in favour of insurance cycles with a linear autoregressive character. This means that any cyclicality in firm profitability in the property and casualty insurance industry is not predictable in a classical econometric framework. It follows that pricing in the property and casualty insurance industry is not incompatible with that of a competitive market

Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations

BB flavour tagging using charm decays at the LHCb experiment

An algorithm is described for tagging the flavour content at production of neutral $B$ mesons in the LHCb experiment. The algorithm exploits the correlation of the flavour of a $B$ meson with the charge of a reconstructed secondary charm hadron from the decay of the other $b$ hadron produced in the proton-proton collision. Charm hadron candidates are identified in a number of fully or partially reconstructed Cabibbo-favoured decay modes. The algorithm is calibrated on the self-tagged decay modes $B^+ \to J/\psi \, K^+$ and $B^0 \to J/\psi \, K^{*0}$ using $3.0\mathrm{\,fb}^{-1}$ of data collected by the LHCb experiment at $pp$ centre-of-mass energies of $7\mathrm{\,TeV}$ and $8\mathrm{\,TeV}$. Its tagging power on these samples of $B \to J/\psi \, X$ decays is $(0.30 \pm 0.01 \pm 0.01) \%$.Comment: All figures and tables, along with any supplementary material and additional information, are available at http://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-027.htm

Ultrafast Light and Electrons: Imaging the Invisible

In this chapter, the evolutionary and revolutionary developments of microscopic imaging are overviewed with focus on ultrashort light and electrons pulses; for simplicity, we shall use the term “ultrafast” for both. From Alhazen’s camera obscura, to Hooke and van Leeuwenhoek’s optical micrography, and on to three- and four-dimensional (4D) electron microscopy, the developments over a millennium have transformed humans’ scope of visualization. The changes in the length and time scales involved are unimaginable, beginning with the visible shadows of candles at the centimeter and second scales, and ending with invisible atoms with space and time dimensions of sub-nanometer and femtosecond, respectively. With these advances it has become possible to determine the structures of matter and to observe their elementary dynamics as they fold and unfold in real time, providing the means for visualizing materials behavior and biological function, with the aim of understanding emergent phenomena in complex systems. Both light and light-generated electrons are now at the forefront of femtosecond and attosecond science and technology, and the scope of applications has reached beyond the nuclear motion as electron dynamics become accessible

MFV Reductions of MSSM Parameter Space

The 100+ free parameters of the minimal supersymmetric standard model (MSSM) make it computationally difficult to compare systematically with data, motivating the study of specific parameter reductions such as the cMSSM and pMSSM. Here we instead study the reductions of parameter space implied by using minimal flavour violation (MFV) to organise the R-parity conserving MSSM, with a view towards systematically building in constraints on flavour-violating physics. Within this framework the space of parameters is reduced by expanding soft supersymmetry-breaking terms in powers of the Cabibbo angle, leading to a 24-, 30- or 42-parameter framework (which we call MSSM-24, MSSM-30, and MSSM-42 respectively), depending on the order kept in the expansion. We provide a Bayesian global fit to data of the MSSM-30 parameter set to show that this is manageable with current tools. We compare the MFV reductions to the 19-parameter pMSSM choice and show that the pMSSM is not contained as a subset. The MSSM-30 analysis favours a relatively lighter TeV-scale pseudoscalar Higgs boson and $\tan \beta \sim 10$ with multi-TeV sparticles.Comment: 2nd version, minor comments and references added, accepted for publication in JHE

FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship

Assessment of the anthelmintic activity of medicinal plant extracts and purified condensed tannins against free-living and parasitic stages of Oesophagostomum dentatum

Background: Plant-derived condensed tannins (CT) show promise as a complementary option to treat gastrointestinal helminth infections, thus reducing reliance on synthetic anthelmintic drugs. Most studies on the anthelmintic effects of CT have been conducted on parasites of ruminant livestock. Oesophagostomum dentatum is an economically important parasite of pigs, as well as serving as a useful laboratory model of helminth parasites due to the ability to culture it in vitro for long periods through several life-cycle stages. Here, we investigated the anthelmintic effects of CT on multiple life-cycles stages of O. dentatum. Methods: Extracts and purified fractions were prepared from five plants containing CT and analysed by HPLC-MS. Anthelmintic activity was assessed at five different stages of the O. dentatum life cycle; the development of eggs to infective third-stage larvae (L3), the parasitic L3 stage, the moult from L3 to fourth-stage larvae (L4), the L4 stage and the adult stage. Results: Free-living larvae of O. dentatum were highly susceptible to all five plant extracts. In contrast, only two of the five extracts had activity against L3, as evidenced by migration inhibition assays, whilst three of the five extracts inhibited the moulting of L3 to L4. All five extracts reduced the motility of L4, and the motility of adult worms exposed to a CT-rich extract derived from hazelnut skins was strongly inhibited, with electron microscopy demonstrating direct damage to the worm cuticle and hypodermis. Purified CT fractions retained anthelmintic activity, and depletion of CT from extracts by pre-incubation in polyvinylpolypyrrolidone removed anthelmintic effects, strongly suggesting CT as the active molecules. Conclusions: These results suggest that CT may have promise as an alternative parasite control option for O. dentatum in pigs, particularly against adult stages. Moreover, our results demonstrate a varied susceptibility of different life-cycle stages of the same parasite to CT, which may offer an insight into the anthelmintic mechanisms of these commonly found plant compounds

Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses

Background: In most high and middle income countries across the world, at least 1:4 women give birth by cesarean section. Rates of labour induction and augmentation are rising steeply; and in some countries up to 50 % of laboring women and newborns are given antibiotics. Governments and international agencies are increasingly concerned about the clinical, economic and psychosocial effects of these interventions. Discussion: There is emerging evidence that certain intrapartum and early neonatal interventions might affect the neonatal immune response in the longer term, and perhaps trans-generationally. Two theories lead the debate in this area. Those aligned with the hygiene (or ‘Old Friends’) hypothesis have examined the effect of gut microbiome colonization secondary to mode of birth and intrapartum/neonatal pharmacological interventions on immune response and epigenetic phenomena. Those working with the EPIIC (Epigenetic Impact of Childbirth) hypothesis are concerned with the effects of eustress and dys-stress on the epigenome, secondary to mode of birth and labour interventions. Summary: This paper examines the current and emerging findings relating to childbirth and atopic/autoimmune disease from the perspective of both theories, and proposes an alliance of research effort. This is likely to accelerate the discovery of important findings arising from both approaches, and to maximize the timely understanding of the longer-term consequences of childbirth practices