De novo mutations in regulatory elements in neurodevelopmental disorders

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordWe previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.Health Innovation Challenge FundWellcome TrustUK Department of HealthWellcome Trust Sanger Institut

The parabola theorem on continued fractions

Using geometric methods borrowed from the theory of Kleinian groups, we interpret the parabola theorem on continued fractions in terms of sequences of Möbius transformations. This geometric approach allows us to relate the Stern–Stolz series, which features in the parabola theorem, to the dynamics of certain sequences of Möbius transformations acting on three-dimensional hyperbolic space. We also obtain a version of the parabola theorem in several dimensions

Observation of squeezed light from one atom excited with two photons

Single quantum emitters like atoms are well-known as non-classical light sources which can produce photons one by one at given times, with reduced intensity noise. However, the light field emitted by a single atom can exhibit much richer dynamics. A prominent example is the predicted ability for a single atom to produce quadrature-squeezed light, with sub-shot-noise amplitude or phase fluctuations. It has long been foreseen, though, that such squeezing would be "at least an order of magnitude more difficult" to observe than the emission of single photons. Squeezed beams have been generated using macroscopic and mesoscopic media down to a few tens of atoms, but despite experimental efforts, single-atom squeezing has so far escaped observation. Here we generate squeezed light with a single atom in a high-finesse optical resonator. The strong coupling of the atom to the cavity field induces a genuine quantum mechanical nonlinearity, several orders of magnitude larger than for usual macroscopic media. This produces observable quadrature squeezing with an excitation beam containing on average only two photons per system lifetime. In sharp contrast to the emission of single photons, the squeezed light stems from the quantum coherence of photon pairs emitted from the system. The ability of a single atom to induce strong coherent interactions between propagating photons opens up new perspectives for photonic quantum logic with single emittersComment: Main paper (4 pages, 3 figures) + Supplementary information (5 pages, 2 figures). Revised versio

Midlands Cadences: Narrative Voices in the Work of Alan Sillitoe

This paper will examine excerpts from a range of Alan Sillitoe’s prose fiction, most notably Saturday Night and Sunday Morning (1958) and short stories from the collection The Loneliness of the Long-Distance Runner (1958), via a comparative exploration of the texts’ representations of Midlands English demotic. Both texts enact Bakhtin’s notion of novelistic dialogism and find much expressive capital in the tension between discourses: between the oral and the written. Indeed, it could be argued that much of Sillitoe’s work functions as a direct challenge to dominant notions of the literary. The narrative discourse attempts to trace a link between the quotidian experience of the Midlands English working classes represented and the demotic language which they speak. His technique also explores the link between language and sensibility; i.e. verbal articulacy need not be a limit to expression of a character’s distinctive identity. In contrast to the more radical techniques of novelists like James Kelman and Irvine Welsh, all instances of phonetically-rendered demotic remain imprisoned by what Joyce called ‘perverted commas’ – as direct speech. However, the diegetic narrative discourse itself is redolent of registers rooted in 1950s English working class life. The texts also contain different methods of representing their protagonists’ consciousness through their own idiolect. In Saturday Night and Sunday Morning, this is evidenced by the use of the second person ‘you’. It functions simultaneously as a representation of Seaton’s consciousness in the oral register which he might choose to articulate it, and as a dialogic ‘sideways glance’ at the reader and assumed shared experience. The second is more redolent of internal monologue, using the first-person form (as seen in the homodiegetic narration of the second novel); crucially, though, it remains in Standard English, if explicitly orientated towards oral register. Sillitoe’s is a novelistic discourse which refuses to normalise itself to accord with the conventions of classic realism, and as such prefigures the ambitions of many contemporary writers who incline their narrative voices towards the oral – asserting the right of a character’s dialect/idiolect to be the principal register of the narrative. The paper will demonstrate this thesis through the ideas of Bakhtin, and through an analytical taxonomy derived from literary stylistics. It aims to propose a model which can be used to analyse and explore any fiction which has been labelled as ‘working class’, and asserts that such an approach leads to a more principled characterisation of working class fiction (based on its use of language) than current literary-critical discussions based simply on cultural/social context and biography

Definitive hypofractionated radiotherapy for early glottic carcinoma: experience of 55Gy in 20 fractions

Introduction: A wide variety of fractionation schedules have been employed for the treatment of early glottic cancer. The aim is to report our 10-year experience of using hypofractionated radiotherapy with 55Gy in 20 fractions at 2.75Gy per fraction. Methods: Patients treated between 2004 and 2013 with definitive radiotherapy to a dose of 55Gy in 20 fractions over 4 weeks for T1/2 N0 squamous cell carcinoma of the glottis were retrospectively identified. Patients with prior therapeutic minor surgery (eg. laser stripping, cordotomy) were included. The probabilities of local control, ultimate local control (including salvage surgery), regional control, cause specific survival (CSS) and overall survival (OS) were calculated. Results: One hundred thirty-two patients were identified. Median age was 65 years (range 33–89). Median follow up was 72 months (range 7–124). 50 (38 %), 18 (14 %) and 64 (48 %) of patients had T1a, T1b and T2 disease respectively. Five year local control and ultimate local control rates were: overall - 85.6 % and 97.3 % respectively, T1a - 91.8 % and 100 %, T1b - 81.6 and 93.8 %, and T2 - 80.9 % and 95.8 %. Five year regional control, CSS and OS rates were 95.4 %, 95.7 % and 78.8 % respectively. There were no significant associations of covariates (e.g. T-stage, extent of laryngeal extension, histological grade) with local control on univariate analysis. Only increasing age and transglottic extension in T2 disease were significantly associated with overall survival (both p <0.01). Second primary cancers developed in 17 % of patients. 13 (9.8 %) of patients required enteral tube feeding support during radiotherapy; no patients required long term enteral nutrition. One patient required a tracheostomy due to a non-functioning larynx on long term follow up. Conclusions: Hypofractionated radiation therapy with a dose of 55Gy in 20 fractions for early stage glottic cancer provides high rates of local control with acceptable toxicity

Regional Genetic Structure in the Aquatic Macrophyte Ruppia cirrhosa Suggests Dispersal by Waterbirds

The evolutionary history of the genus Ruppia has been shaped by hybridization, polyploidisation and vicariance that have resulted in a problematic taxonomy. Recent studies provided insight into species circumscription, organelle takeover by hybridization, and revealed the importance of verifying species identification to avoid distorting effects of mixing different species, when estimating population connectivity. In the present study, we use microsatellite markers to determine population diversity and connectivity patterns in Ruppia cirrhosa including two spatial scales: (1) from the Atlantic Iberian coastline in Portugal to the Siculo-Tunisian Strait in Sicily and (2) within the Iberian Peninsula comprising the Atlantic-Mediterranean transition. The higher diversity in the Mediterranean Sea suggests that populations have had longer persistence there, suggesting a possible origin and/or refugial area for the species. The high genotypic diversities highlight the importance of sexual reproduction for survival and maintenance of populations. Results revealed a regional population structure matching a continent-island model, with strong genetic isolation and low gene flow between populations. This population structure could be maintained by waterbirds, acting as occasional dispersal vectors. This information elucidates ecological strategies of brackish plant species in coastal lagoons, suggesting mechanisms used by this species to colonize new isolated habitats and dominate brackish aquatic macrophyte systems, yet maintaining strong genetic structure suggestive of very low dispersal.Fundacao para a Cincia e Tecnologia (FCT, Portugal) [PTDC/MAR/119363/2010, BIODIVERSA/0004/2015, UID/Multi/04326/2013]Pew FoundationSENECA FoundationMurcia Government, Spain [11881/PI/09]FCT Investigator Programme-Career Development [IF/00998/2014]Spanish Ministry of Education [AP2008-01209]European Community [00399/2012]info:eu-repo/semantics/publishedVersio

Information Causality as a Physical Principle

Quantum physics exhibits remarkable distinguishing characteristics. For example, it gives only probabilistic predictions (non-determinism) and does not allow copying of unknown state (no-cloning). Quantum correlations may be stronger than any classical ones, nevertheless information cannot be transmitted faster than light (no-signaling). However, all these features do not single out quantum physics. A broad class of theories exist which share such traits with quantum mechanics, while they allow even stronger than quantum correlations. Here, we introduce the principle of Information Causality. It states that information that Bob can gain about a previously completely unknown to him data set of Alice, by using all his local resources (which may be correlated with her resources) and a classical communication from her, is bounded by the information volume of the communication. In other words, if Alice communicates m bits to Bob, the total information access that Bob gains to her data is not greater than m. For m=0, Information Causality reduces to the standard no-signaling principle. We show that this new principle is respected both in classical and quantum physics, whereas it is violated by all the no-signaling correlations which are stronger that the strongest quantum correlations. Maximally strong no-signalling correlations would allow Bob access to any m bit subset of the whole data set held by Alice. If only one bit is sent by Alice (m=1), this is tantamount to Bob being able to access the value of any single bit of Alice's data (but of course not all of them). We suggest that Information Causality, a generalization of no-signaling, might be one of the foundational properties of Nature.Comment: This version of the paper is as close to the published one as legally possibl

Resuming Work After Cancer: A Prospective Study of Occupational Register Data

Introduction Long-term employment rates have been studied in cancer survivors, but little is known about the return to work of cancer patients. This study investigated return to work (RTW) within 2 years after the diagnosis of different types of cancer. Methods This prospective study investigated the associations of demographics (age, gender, socioeconomic status, and residential region) and occupational factors (occupation, duration of employment, and company size) of employees absent from work due to cancer with the time to partial RTW, defined as working at least 50% of the earnings before sickness absence. Likewise, the associations of demographics and occupational factors with full RTW at equal earnings as before sickness absence were investigated. Results The cohort included 5,234 employees who had been absent from work due to cancer between January 2004 and December 2006. The time to partial RTW was shortest among employees with skin cancer (median 55 days) and longest among employees with lung cancer (median 377 days). There were no significant associations between RTW and demographics. With regard to the occupational factors, employees in high occupational classes started working earlier than those in low occupational classes, but the time to full RTW did not differ significantly across occupational classes. Employees working in large companies returned to work earlier than those working in small companies. Conclusion RTW after different types of cancer depended on occupational factors rather than demographics

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space

Measurements of neutrino oscillation in appearance and disappearance channels by the T2K experiment with 6.6 x 10(20) protons on target

111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee commentsWe thank the J-PARC staff for superb accelerator performance and the CERN NA61/SHINE Collaboration for providing valuable particle production data. We acknowledge the support of MEXT, Japan; NSERC, NRC, and CFI, Canada; CEA and CNRS/IN2P3, France; DFG, Germany; INFN, Italy; National Science Centre (NCN), Poland; RSF, RFBR and MES, Russia; MINECO and ERDF funds, Spain; SNSF and SER, Switzerland; STFC, UK; and the U. S. Deparment of Energy, USA. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, GridPP, UK, and the Emerald High Performance Computing facility in the Centre for Innovation, UK. In addition, participation of individual researchers and institutions has been further supported by funds from ERC (FP7), EU; JSPS, Japan; Royal Society, UK; and DOE Early Career program, USA