A New Era in the Quest for Dark Matter

There is a growing sense of `crisis' in the dark matter community, due to the absence of evidence for the most popular candidates such as weakly interacting massive particles, axions, and sterile neutrinos, despite the enormous effort that has gone into searching for these particles. Here, we discuss what we have learned about the nature of dark matter from past experiments, and the implications for planned dark matter searches in the next decade. We argue that diversifying the experimental effort, incorporating astronomical surveys and gravitational wave observations, is our best hope to make progress on the dark matter problem.Comment: Published in Nature, online on 04 Oct 2018. 13 pages, 1 figur

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization

Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection

Systematic identification of conserved motif modules in the human genome

<p>Abstract</p> <p>Background</p> <p>The identification of motif modules, groups of multiple motifs frequently occurring in DNA sequences, is one of the most important tasks necessary for annotating the human genome. Current approaches to identifying motif modules are often restricted to searches within promoter regions or rely on multiple genome alignments. However, the promoter regions only account for a limited number of locations where transcription factor binding sites can occur, and multiple genome alignments often cannot align binding sites with their true counterparts because of the short and degenerative nature of these transcription factor binding sites.</p> <p>Results</p> <p>To identify motif modules systematically, we developed a computational method for the entire non-coding regions around human genes that does not rely upon the use of multiple genome alignments. First, we selected orthologous DNA blocks approximately 1-kilobase in length based on discontiguous sequence similarity. Next, we scanned the conserved segments in these blocks using known motifs in the TRANSFAC database. Finally, a frequent pattern mining technique was applied to identify motif modules within these blocks. In total, with a false discovery rate cutoff of 0.05, we predicted 3,161,839 motif modules, 90.8% of which are supported by various forms of functional evidence. Compared with experimental data from 14 ChIP-seq experiments, on average, our methods predicted 69.6% of the ChIP-seq peaks with TFBSs of multiple TFs. Our findings also show that many motif modules have distance preference and order preference among the motifs, which further supports the functionality of these predictions.</p> <p>Conclusions</p> <p>Our work provides a large-scale prediction of motif modules in mammals, which will facilitate the understanding of gene regulation in a systematic way.</p

Mortality from cutaneous melanoma: evidence for contrasting trends between populations

In recent years several reports have been published concerning trends in melanoma mortality in different countries, some of which have indicated that rates are beginning to fall. Many of these reports, however, have been based on small populations and have used different forms of statistical analysis. Our objective was to analyse systematically to what degree the epidemic of melanoma mortality had evolved similarly in different populations and whether there were any divergent trends that might increase our understanding. Instead of using all available data, we focused on countries with a minimum time series of 30 years and a minimum of 100 deaths annually in at least one sex from melanoma. We first inspected sex-specific age-standardized mortality rates and then performed age-period-cohort modelling. We found that the increase in mortality observed after 1950 was more pronounced in the age group 60–79. Statistical modelling showed a general increase in mortality rates in generations born after the turn of the century. Downturns in mortality, essentially in women and starting with generations born just before World War II, were found in Australia (where the earliest decreases were noted), the Nordic countries and the USA. Small decreases in rates in more recent generations were found in the UK and Canada. However, in France, Italy and Czechoslovakia, mortality rates were seen to be still increasing in recent cohorts. Our analysis suggests that populations are at different places on the melanoma mortality epidemic curve. The three trend patterns we observed are in agreement with time differences between populations with respect to the promotion of sun protection and the surveillance of pigmented skin lesions. © 2000 Cancer Research Campaig

Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case-control study

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