Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Classical and semi-classical energy conditions

The standard energy conditions of classical general relativity are (mostly) linear in the stress-energy tensor, and have clear physical interpretations in terms of geodesic focussing, but suffer the significant drawback that they are often violated by semi-classical quantum effects. In contrast, it is possible to develop non-standard energy conditions that are intrinsically non-linear in the stress-energy tensor, and which exhibit much better well-controlled behaviour when semi-classical quantum effects are introduced, at the cost of a less direct applicability to geodesic focussing. In this article we will first review the standard energy conditions and their various limitations. (Including the connection to the Hawking--Ellis type I, II, III, and IV classification of stress-energy tensors). We shall then turn to the averaged, nonlinear, and semi-classical energy conditions, and see how much can be done once semi-classical quantum effects are included.Comment: V1: 25 pages. Draft chapter, on which the related chapter of the book "Wormholes, Warp Drives and Energy Conditions" (to be published by Springer), will be based. V2: typos fixed. V3: small typo fixe

Mapping transcription mechanisms from multimodal genomic data

Background Identification of expression quantitative trait loci (eQTLs) is an emerging area in genomic study. The task requires an integrated analysis of genome-wide single nucleotide polymorphism (SNP) data and gene expression data, raising a new computational challenge due to the tremendous size of data. Results We develop a method to identify eQTLs. The method represents eQTLs as information flux between genetic variants and transcripts. We use information theory to simultaneously interrogate SNP and gene expression data, resulting in a Transcriptional Information Map (TIM) which captures the network of transcriptional information that links genetic variations, gene expression and regulatory mechanisms. These maps are able to identify both cis- and trans- regulating eQTLs. The application on a dataset of leukemia patients identifies eQTLs in the regions of the GART, PCP4, DSCAM, and RIPK4 genes that regulate ADAMTS1, a known leukemia correlate. Conclusions The information theory approach presented in this paper is able to infer the dependence networks between SNPs and transcripts, which in turn can identify cis- and trans-eQTLs. The application of our method to the leukemia study explains how genetic variants and gene expression are linked to leukemia.National Human Genome Research Institute (U.S.) (R01HG003354)National Institute of Allergy and Infectious Diseases (U.S.) (U19 AI067854-05)National Heart, Lung, and Blood Institute (grant T32 HL007427-28)National Institutes of Health (U.S.) (grant K99 LM009826

A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus

<p>Abstract</p> <p>Background</p> <p>Neramexane is a new substance that exhibits antagonistic properties at α₉α₁₀cholinergic nicotinic receptors and <it>N</it>-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus.</p> <p>Methods</p> <p>A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat) efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12).</p> <p>Results</p> <p>Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (<it>p </it>= 0.098 for 50 mg/d; <it>p </it>= 0.289 for 75 mg/d neramexane), but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with <it>p </it>values of < 0.05 for the 50 mg/d neramexane group associated with the functional-communicational subscores of the THI-12 and the assessments of tinnitus annoyance and tinnitus impact on life as measured on an 11-point Likert-like scale. No relevant changes were observed for puretone threshold, for tinnitus pitch and loudness match, or for minimum masking levels. The 25 mg/d neramexane group did not differ from placebo. Neramexane was generally well tolerated and had no relevant influence on laboratory values, electrocardiography and vital signs. Dizziness was the most common adverse event and showed a clear dose-dependence.</p> <p>Conclusions</p> <p>This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00405886</p

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older

BACKGROUND: The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence. The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence, potentially by bolstering T-cell mediated responses. METHODS: This observer-blind study, conducted in the United States (US) and Spain during the 2008-2009 influenza season, evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine (TIV) in >/=65 year-old adults.Medically-stable adults aged >/=65 years were randomly allocated to receive a single dose of AS03-adjuvanted TIV (TIV/AS03) or TIV. Healthy adults aged 18-40 years received only TIV. Blood samples were collected on Day 0, Day 21, Day 42 and Day 180. Influenza-specific CD4+ T cells, defined by the induction of the immune markers CD40L, IL-2, IFN-gamma, or TNF-alpha, were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells. RESULTS: A total of 192 adults were vaccinated: sixty nine and seventy three >/=65 year olds received TIV/AS03 and TIV, respectively; and fifty 18 - 40 year olds received TIV. In the >/=65 year-old group on Day 21, the frequency of CD4+ T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV (p /=65 year-old recipients of TIV/AS03 than in the 18 - 40 year old recipients of TIV on Days 21 (p = 0.006) and 42 (p = 0.011). CONCLUSION: This positive effect of AS03 Adjuvant System on the CD4+ T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population. TRIAL REGISTRATION: (Clinicaltrials.gov.). NCT00765076

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Influence of Oscillating Flow on LDL Transport and Wall Shear Stress in the Normal Aortic Arch

Lipid accumulation in the aortic wall is an important factor in the development of atherosclerosis. The Low Density Lipoprotein (LDL) at the surface of the endothelium in relation to Wall Shear Stress (WSS) in the normal human aortic arch under unsteady, normal flow and mass conditions was computationally analysed. Concave sides of the aortic arch exhibit, relatively to the convex ones, elevated LDL levels at the surface of the endothelium for all time steps. At the peak systolic velocity, the LDL level reaches a value 23.0% higher than that at entrance in the ascending-descending aorta region. The corresponding LDL levels at the surface of the endothelium for the near minimum entrance velocity instant reaches 26.0%. During the cardiac cycle, the highest area averaged normalized LDL taken up as compared to the lowest one is 0.69%. WSS plays an important role in the lipid accumulation. Low WSS regions are exposed to high LDL levels at the surface of the endothelium. Regions of elevated LDL levels do not necessarily co-locate to the sites of lowest WSS. The near wall paths of the velocities might be the most important factor for the elevated LDL levels at the surface of the endothelium

Association study of promoter polymorphisms at the dopamine transporter gene in Attention Deficit Hyperactivity Disorder

<p>Abstract</p> <p>Background</p> <p>Attention deficit hyperactivity disorder (ADHD) is a complex neurobehavioral disorder. The dopamine transporter gene (DAT1/<it>SLC6A3</it>) has been considered a good candidate for ADHD. Most association studies with ADHD have investigated the 40-base-pair variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1. Only few studies have reported association between promoter polymorphisms of the gene and ADHD.</p> <p>Methods</p> <p>To investigate the association between the polymorphisms -67A/T (rs2975226) and -839C/T (rs2652511) in promoter region of DAT1 in ADHD, two samples of ADHD patients from the UK (n = 197) and Taiwan (n = 212) were genotyped, and analysed using within-family transmission disequilibrium test (TDT).</p> <p>Results</p> <p>A significant association was found between the T allele of promoter polymorphism -67A/T and ADHD in the Taiwanese population (<it>P </it>= 0.001). There was also evidence of preferential transmission of the T allele of -67A/T polymorphism in combined samples from the UK and Taiwan (<it>P </it>= 0.003). No association was detected between the -839C/T polymorphism and ADHD in either of the two populations.</p> <p>Conclusion</p> <p>The finding suggests that genetic variation in the promoter region of DAT1 may be a risk factor in the development of ADHD.</p