Chromatin Loops as Allosteric Modulators of Enhancer-Promoter Interactions

The classic model of eukaryotic gene expression requires direct spatial contact between a distal enhancer and a proximal promoter. Recent Chromosome Conformation Capture (3C) studies show that enhancers and promoters are embedded in a complex network of looping interactions. Here we use a polymer model of chromatin fiber to investigate whether, and to what extent, looping interactions between elements in the vicinity of an enhancer-promoter pair can influence their contact frequency. Our equilibrium polymer simulations show that a chromatin loop, formed by elements flanking either an enhancer or a promoter, suppresses enhancer-promoter interactions, working as an insulator. A loop formed by elements located in the region between an enhancer and a promoter, on the contrary, facilitates their interactions. We find that different mechanisms underlie insulation and facilitation; insulation occurs due to steric exclusion by the loop, and is a global effect, while facilitation occurs due to an effective shortening of the enhancer-promoter genomic distance, and is a local effect. Consistently, we find that these effects manifest quite differently for in silico 3C and microscopy. Our results show that looping interactions that do not directly involve an enhancer-promoter pair can nevertheless significantly modulate their interactions. This phenomenon is analogous to allosteric regulation in proteins, where a conformational change triggered by binding of a regulatory molecule to one site affects the state of another site

Polymer Models of Topological Insulators

Physic

Ca II H and K Chromospheric Emission Lines in Late K and M Dwarfs

We have measured the profiles of the Ca II H and K chromospheric emission lines in 147 main sequence stars of spectral type M5-K7 (0.30-0.55 solar masses) using multiple high resolution spectra obtained during six years with the HIRES spectrometer on the Keck 1 telescope. Remarkably, the average FWHM, equivalent widths, and line luminosities of Ca II H and K increase by a factor of 3 with increasing stellar mass over this small range of stellar masses. We fit the H and K lines with a double Gaussian model to represent both the chromospheric emission and the non-LTE central absorption. Most of the sample stars display a central absorption that is typically redshifted by ~0.1 km/s relative to the emission, but the nature of this velocity gradient remains unknown. The FWHM of the H and K lines increase with stellar luminosity, reminiscent of the Wilson-Bappu effect in FGK-type stars. Both the equivalent widths and FWHM exhibit modest temporal variability in individual stars. At a given value of M_v, stars exhibit a spread in both the equivalent width and FWHM of Ca II H and K, due both to a spread in fundamental stellar parameters including rotation rate, age, and possibly metallicity, and to the spread in stellar mass at a given M_v. The K line is consistently wider than the H line, as expected, and its central absorption is more redshifted, indicating that the H and K lines form at slightly different heights in the chromosphere where the velocities are slightly different. The equivalent width of H-alpha correlates with Ca II H and K only for stars having Ca II equivalent widths above ~2 angstroms, suggesting the existence of a magnetic threshold above which the lower and upper chromospheres become thermally coupled.Comment: 40 pages including 12 figures and 17 pages of tables, accepted for publication in PAS

Diabetes and corneal endothelial cell characteristics: a study based on Eye Bank data

The aim of the article is to determine whether corneal endothelial cell density and other characteristics, such as cell area, pleomorphism and polymegathism, are affected by diabetes. Corneal endothelial cell density and other characteristics of donor eyes collected during 2007 and 2008 in a local Eye Bank were measured by the HAI Eyebank Specular Microscope System. Adult donors aged 21 or older who consented to research were divided into healthy versus compromised eye-status groups based on eye disease or past eye surgeries. Differences in corneal measures between diabetic and non-diabetic subjects were analyzed separately in each group via Mixed Models ANCOVA, with Diabetes as the fixed effect, Donor as the random effect, and Age as the continuous covariate. A total of 253 subjects met study criteria, of which 81 (32%) had diabetes. In the 180 subjects with healthy eye status, the medians (ranges) of age were 62 (29-78) years among 52 diabetics (29%), versus 57 (21-79) years among non-diabetics (P=0.013). In the 73 subjects with compromised eye status, the medians (ranges) of age were 70 (32-78) years among 29 diabetics (40%), versus 70 (29-79) years among nondiabetics (P=0.77). Between diabetics and non-diabetics, eye disease and past eye surgeries were well-balanced in the compromised eye-status group, while race and sex were wellbalanced in both eye-status groups. Results from separate analyses on the two groups indicated that diabetes did not affect corneal cell density or other corneal-cell characteristics analyzed. Even though diabetics constituted a large percentage of the Eye Bank donor population, this disease did not have a statistically significant impact on corneal endothelial cell density, cell area, pleomorphism or polymegathism

Targeting Missing Persons Most Likely to Come to Harm Among 92,681 Cases Reported to Devon and Cornwall Police

Funder: University of CambridgeAbstractResearch questionGiven the information available to Devon and Cornwall Police at the time when they received a missing person report, which knowable variables indicated increased odds of the person coming to serious harm?DataThe study examines all 92,681 missing reports received by Devon and Cornwall Police over 11 years from 2008 through 2019, for which 3481 (3.8%) persons came to harm, or about one in 27. Variables known at the time the report was filed included (A) risk levels estimated by police applying the College of Policing risk assessment template (high, medium, low), and (B) the missing person’s age, gender, in-care status, disability, dyslexia, learning disability, hearing or visual impairment, reduced mobility, mental illness, child sexual exploitation risk, reported suicidal, vulnerable adult status and previous reports of being missing.MethodsOdds ratios are used to estimate differences in likelihood of missing persons coming to harm in a series of single-variable tests. Matrices are used to assess the accuracy of the current risk assessment process used by police services in England and Wales, as applied in Devon and Cornwall. Limited multivariate analysis was undertaken.FindingsApplication of the current College of Policing protocol for risk assessment by subjective professional judgements yields substantial error rates, with 89% of the predicted high risk cases having no actual harm and 59% of cases with actual harm after not being predicted as high risk. The odds of harm based on single variables examined are highly conditional on age and gender as third factors. Both men and women over 18 are 4 times more likely to be harmed (6.8%) than those under age 18 (1.7%).ConclusionsThis study casts substantial doubt on the accuracy of the current subjective risk assessment process for missing persons. As the authorizing body for Approved Professional Practice, the College of Policing could use this evidence to endorse further development and implementation of a multivariate evidence-based risk assessment tool for missing persons that takes into account the age and gender of the missing person as well as all other factors in a single forecasting model.</jats:sec

Judgement bias: A cognitive measure of affective state in sheep

Sheep welfare is predominately measured by identifying behavioural and physiological changes. While informative, they can often be difficult to interpret, identifying the arousal of a sheep in a particular situation but not the valence (positivity or negativity) of the affective state being experienced. Judgement bias has been proposed as a cognitive measure of affective state valence in animals. The aim of this thesis was to adapt a method of assessing judgement bias for use in sheep to identify cognitive changes influenced by affective states. In all studies, sheep were trained to a go/no-go operant task where they learnt to approach (go response) a bucket when placed in one corner of the testing facility to receive a positive reinforcer (feed reward), and not approach it when in the alternate corner (no-go response) to avoid a negative reinforcer (exposure to a dog or fan forced blower). Judgement bias testing involved exposing the sheep to ambiguous bucket locations between the two learnt ones. The sheep had to judge which way to respond to these ambiguous locations (go/no-go), which would give insight into their affective states. In the first study a restraint and isolation stressor (RIS) for 6 h/day on 3 consecutive days generated a significantly more positive judgement in sheep compared to controls. Two further studies, using a chronic, intermittent treatment and a pharmacological treatment using a serotonin antagonist respectively, generated more pessimistic-like judgement biases in the sheep compared to that of the controls. These studies suggest that judgement bias can identify affective state changes in sheep and that the response differs depending on the nature of the stress. Furthermore, the unexpected result generated from the RIS treatment suggests that judgement bias can be used to measure differently valenced affective states in sheep. Another study conducted into the method itself showed that the sheep learn not to approach the unreinforced ambiguous locations when repeatedly exposed to them and this affects their judgement of the bucket locations. This means that there are a limited number of times that the sheep can be exposed to the testing situations. Despite this and other methodological concerns discussed, these results strongly suggest that judgement bias can be used as a measure of affective state in sheep. The use of this method could help to improve the welfare assessment of sheep in the future, especially if used in conjunction with other measures of affective state

High-frequency pressure variations in the vicinity of a surface CO2 flux chamber

We report measurements of 2 Hz pressure fluctuations at and below the soil surface in the vicinity of a surface-based CO2 flux chamber. These measurements were part of a field experiment to examine the possible role of pressure pumping due to atmospheric pressure fluctuations on measurements of surface fluxes of CO2. Under the moderate wind speeds, warm temperatures, and dry soil conditions present at the time of our observations, the chamber had no effect on the pressure field in its near vicinity that could be detected above the level of natural pressure fluctuations in the vicinity. At frequencies at or \u3c2 Hz, pressure fluctuations easily penetrated the soil to depths of several cm with little attenuation. We conclude that the presence of the chamber does not introduce pressure perturbations that lead to biases in measurements of surface fluxes of CO2

Kepler-16: A Transiting Circumbinary Planet

We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size, and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20% and 69% as massive as the sun, and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5 degree of a single plane, suggesting that the planet formed within a circumbinary disk.Comment: Science, in press; for supplemental material see http://www.sciencemag.org/content/suppl/2011/09/14/333.6049.1602.DC1/1210923.Doyle.SOM.pd