Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Schr\"odinger Holography with and without Hyperscaling Violation

We study the properties of the Schr\"odinger-type non-relativistic holography for general dynamical exponent z with and without hyperscaling violation exponent \theta. The scalar correlation function has a more general form due to general z as well as the presence of \theta, whose effects also modify the scaling dimension of the scalar operator. We propose a prescription for minimal surfaces of this "codimension 2 holography," and demonstrate the (d-1) dimensional area law for the entanglement entropy from (d+3) dimensional Schr\"odinger backgrounds. Surprisingly, the area law is violated for d+1 < z < d+2, even without hyperscaling violation, which interpolates between the logarithmic violation and extensive volume dependence of entanglement entropy. Similar violations are also found in the presence of the hyperscaling violation. Their dual field theories are expected to have novel phases for the parameter range, including Fermi surface. We also analyze string theory embeddings using non-relativistic branes.Comment: 62 pages and 6 figures, v2: several typos in section 5 corrected, references added, v3: typos corrected, references added, published versio

Direct aperture optimization as a means of reducing the complexity of intensity modulated radiation therapy plans

Intensity Modulated Radiation Therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. This is done by dividing a large beam into many small beamlets. Dose constraints are assigned to both the target and sensitive structures and computerised inverse optimization is performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. The optimized intensity patterns are then decomposed into a series of deliverable multi leaf collimator (MLC) shapes in the sequencing step

Parity-Violating Hydrodynamics in 2+1 Dimensions

We study relativistic hydrodynamics of normal fluids in two spatial dimensions. When the microscopic theory breaks parity, extra transport coefficients appear in the hydrodynamic regime, including the Hall viscosity, and the anomalous Hall conductivity. In this work we classify all the transport coefficients in first order hydrodynamics. We then use properties of response functions and the positivity of entropy production to restrict the possible coefficients in the constitutive relations. All the parity-breaking transport coefficients are dissipationless, and some of them are related to the thermodynamic response to an external magnetic field and to vorticity. In addition, we give a holographic example of a strongly interacting relativistic fluid where the parity-violating transport coefficients are computable.Comment: 39+1 page

Evaluation of Microwave Steam Bags for the Decontamination of Filtering Facepiece Respirators

Reusing filtering facepiece respirators (FFRs) has been suggested as a strategy to conserve available supplies for home and healthcare environments during an influenza pandemic. For reuse to be possible, used FFRs must be decontaminated before redonning to reduce the risk of virus transmission; however, there are no approved methods for FFR decontamination. An effective method must reduce the microbial threat, maintain the function of the FFR, and present no residual chemical hazard. The method should be readily available, inexpensive and easily implemented by healthcare workers and the general public. Many of the general decontamination protocols used in healthcare and home settings are unable to address all of the desired qualities of an efficient FFR decontamination protocol. The goal of this study is to evaluate the use of two commercially available steam bags, marketed to the public for disinfecting infant feeding equipment, for FFR decontamination. The FFRs were decontaminated with microwave generated steam following the manufacturers' instructions then evaluated for water absorption and filtration efficiency for up to three steam exposures. Water absorption of the FFR was found to be model specific as FFRs constructed with hydrophilic materials absorbed more water. The steam had little effect on FFR performance as filtration efficiency of the treated FFRs remained above 95%. The decontamination efficacy of the steam bag was assessed using bacteriophage MS2 as a surrogate for a pathogenic virus. The tested steam bags were found to be 99.9% effective for inactivating MS2 on FFRs; however, more research is required to determine the effectiveness against respiratory pathogens

Predicting the Evolution of Sex on Complex Fitness Landscapes

Most population genetic theories on the evolution of sex or recombination are based on fairly restrictive assumptions about the nature of the underlying fitness landscapes. Here we use computer simulations to study the evolution of sex on fitness landscapes with different degrees of complexity and epistasis. We evaluate predictors of the evolution of sex, which are derived from the conditions established in the population genetic literature for the evolution of sex on simpler fitness landscapes. These predictors are based on quantities such as the variance of Hamming distance, mean fitness, additive genetic variance, and epistasis. We show that for complex fitness landscapes all the predictors generally perform poorly. Interestingly, while the simplest predictor, ΔVarHD, also suffers from a lack of accuracy, it turns out to be the most robust across different types of fitness landscapes. ΔVarHD is based on the change in Hamming distance variance induced by recombination and thus does not require individual fitness measurements. The presence of loci that are not under selection can, however, severely diminish predictor accuracy. Our study thus highlights the difficulty of establishing reliable criteria for the evolution of sex on complex fitness landscapes and illustrates the challenge for both theoretical and experimental research on the origin and maintenance of sexual reproduction

A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers

While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant (‘Faslodex’) is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect. This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 μg day−1. Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women

Holographic Vitrification

We establish the existence of stable and metastable stationary black hole bound states at finite temperature and chemical potentials in global and planar four-dimensional asymptotically anti-de Sitter space. We determine a number of features of their holographic duals and argue they represent structural glasses. We map out their thermodynamic landscape in the probe approximation, and show their relaxation dynamics exhibits logarithmic aging, with aging rates determined by the distribution of barriers.Comment: 100 pages, 25 figure

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

&lt;p&gt;&lt;b&gt;Background&lt;/b&gt; Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods&lt;/b&gt; We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, &#8805;2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results&lt;/b&gt; Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 &#8804; P &#8804; .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 &#8804; P &#8804; .04), hair color (.006 &#8804; P &#8804; .06), and number of nevi (6.9 × 10−6 &#8804; P &#8804; .02).&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusion&lt;/b&gt; Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.&lt;/p&gt