Data-driven discovery of cardiolipin-selective small molecules by computational active learning

Subtle variations in the lipid composition of mitochondrial membranes can have a profound impact on mitochondrial function. The inner mitochondrial membrane contains the phospholipid cardiolipin, which has been demonstrated to act as a biomarker for a number of diverse pathologies. Small molecule dyes capable of selectively partitioning into cardiolipin membranes enable visualization and quantification of the cardiolipin content. Here we present a data-driven approach that combines a deep learning-enabled active learning workflow with coarse-grained molecular dynamics simulations and alchemical free energy calculations to discover small organic compounds able to selectively permeate cardiolipin-containing membranes. By employing transferable coarse-grained models we efficiently navigate the all-atom design space corresponding to small organic molecules with molecular weight less than ≈500 Da. After direct simulation of only 0.42% of our coarse-grained search space we identify molecules with considerably increased levels of cardiolipin selectivity compared to a widely used cardiolipin probe 10-N-nonyl acridine orange. Our accumulated simulation data enables us to derive interpretable design rules linking coarse-grained structure to cardiolipin selectivity. The findings are corroborated by fluorescence anisotropy measurements of two compounds conforming to our defined design rules. Our findings highlight the potential of coarse-grained representations and multiscale modelling for materials discovery and design

Temperature perturbation model of the opto-galvanic effect in CO2-laser discharges

A detailed discharge model of the opto-galvanic effect in molecular laser gas mixtures is developed based on the temperature perturbation or discharge cooling mechanism of Smith and Brooks (1979). Excellent agreement between the model and experimental results in CO2 laser gas mixtures is obtained. The model should be applicable to other molecular systems where the OGE is being used for laser stabilisation and as a spectroscopic tool

Vacuum-Induced Surface Freezing for the Freeze-Drying of the Human Growth Hormone: How Does Nucleation Control Affect Protein Stability?

Abstract In the present work, the effect of controlled nucleation on the stability of human growth hormone (hGH) during freeze-drying has been investigated. More specifically, the vacuum-induced surface freezing technique has been compared to conventional freezing, both with and without an annealing step. Size exclusion chromatography and cell-based potency assays have been used to characterize the formation of soluble aggregates and the biological activity of hGH, respectively. The results obtained indicate that controlled nucleation has a positive effect on both cycle performance and product homogeneity because of the formation of bigger ice crystals, and characterized by a narrower dimensional distribution. From the point of view of hGH stability, we observed that vacuum-induced surface freezing is not detrimental to the biological activity of the protein, or aggregate formation. In addition, the effect of 2 different formulations, including trehalose or cellobiose, on protein preservation was also considered for this study

Pay or delay: the role of technology when managing a low income

This paper reports on a qualitative study of 38 low-income individuals living in the North East of England. The participants' experiences of money, banking and the role digital technology plays in their financial practices were identified through semi-structured interviews in people's homes and group workshops. A grounded theory analysis of these data characterises how technology both helped and hindered participants to keep close control of their finances. These findings suggest design opportunities for future digital banking technologies that extend the already sophisticated practices of individuals managing a low income, focusing on: delaying, prioritising, planning, watching, and hiding monetary transactions

First Detection of the White-Dwarf Cooling Sequence of the Galactic Bulge

We present Hubble Space Telescope data of the low-reddening Sagittarius window in the Galactic bulge. The Sagittarius Window Eclipsing Extrasolar Planet Search field (3'x3'), together with three more Advanced Camera for Surveys and eight Wide Field Camera 3 fields, were observed in the F606W and F814W filters, approximately every two weeks for two years, with the principal aim of detecting a hidden population of isolated black holes and neutron stars through astrometric microlensing. Proper motions were measured with an accuracy of ~0.1 mas/yr (~4 km/s) at F606W~25.5 mag, and better than ~0.5 mas/yr (20 km/s) at F606W~28 mag, in both axes. Proper-motion measurements allowed us to separate disk and bulge stars and obtain a clean bulge color-magnitude diagram. We then identified for the first time a white dwarf (WD) cooling sequence in the Galactic bulge, together with a dozen candidate extreme horizontal branch stars. The comparison between theory and observations shows that a substantial fraction of the WDs (30%) are systematically redder than the cooling tracks for CO-core H-rich and He-rich envelope WDs. This evidence would suggest the presence of a significant number of low-mass WDs and WD - main sequence binaries in the bulge. This hypothesis is further supported by the finding of two dwarf novae in outburst, two short-period (P < 1 d) ellipsoidal variables, and a few candidate cataclysmic variables in the same field.Comment: 9 pages, 5 figures, accepted for publication on Ap

Predictive validity of the UK clinical aptitude test in the final years of medical school:a prospective cohort study

Peer reviewedPublisher PD

New Constraints on the Lyman Continuum Escape Fraction at z~1.3

We examine deep far-ultraviolet (1600 Angstrom) imaging of the Hubble Deep Field-North (HDFN) and the Hubble Ultra Deep Field (HUDF) to search for leaking Lyman continuum radiation from starburst galaxies at z~1.3. There are 21 (primarily sub-L*) galaxies with spectroscopic redshifts between 1.1<z<1.5 and none are detected in the far-UV. We fit stellar population templates to the galaxies' optical/near-infrared SEDs to determine the starburst age and level of dust attenuation, giving an accurate estimate of the intrinsic Lyman continuum ratio, f_1500/f_700, and allowing a conversion from f_700 limits to relative escape fractions. We show that previous high-redshift studies may have underestimated the amplitude of the Lyman Break, and thus the relative escape fraction, by a factor of ~2. Once the starburst age and intergalactic HI absorption are accounted for, 18 galaxies in our sample have limits to the relative escape fraction, f_esc,rel < 1.0 with some limits as low as f_esc,rel < 0.10 and a stacked limit of f_esc,rel < 0.08. This demonstrates, for the first time, that most sub-L* galaxies at high redshift do not have large escape fractions. When combined with a similar study of more luminous galaxies at the same redshift we show that, if all star-forming galaxies at z~1 have similar relative escape fractions, the value must be less than 0.14 (3 sigma). We also show that less than 20% (3 sigma) of star-forming galaxies at z~1 have relative escape fractions near unity. These limits contrast with the large escape fractions found at z~3 and suggest that the average escape fraction has decreased between z~3 and z~1. (Abridged)Comment: Accepted for publication in ApJ. aastex format. 39 pages, 11 figure

New insights on the Galactic Bulge Initial Mass Function

We have derived the Galactic bulge initial mass function of the SWEEPS field in the mass range 0.15 $< M/M_{\odot}<$ 1.0, using deep photometry collected with the Advanced Camera for Surveys on the Hubble Space Telescope. Observations at several epochs, spread over 9 years, allowed us to separate the disk and bulge stars down to very faint magnitudes, F814W $\sim$ 26 mag, with a proper-motion accuracy better than 0.5 mas/yr. This allowed us to determine the initial mass function of the pure bulge component uncontaminated by disk stars for this low-reddening field in the Sagittarius window. In deriving the mass function, we took into account the presence of unresolved binaries, errors in photometry, distance modulus and reddening, as well as the metallicity dispersion and the uncertainties caused by adopting different theoretical color-temperature relations. We found that the Galactic bulge initial mass function can be fitted with two power laws with a break at M $\sim$ 0.56 $M_{\odot}$, the slope being steeper ($\alpha$ = -2.41$\pm$0.50) for the higher masses, and shallower ($\alpha$ = -1.25$\pm$0.20) for the lower masses. In the high-mass range, our derived mass function agrees well with the mass function derived for other regions of the bulge. In the low-mass range however, our mass function is slightly shallower, which suggests that separating the disk and bulge components is particularly important in the low-mass range. The slope of the bulge mass function is also similar to the slope of the mass function derived for the disk in the high-mass regime, but the bulge mass function is slightly steeper in the low-mass regime. We used our new mass function to derive stellar M/L values for the Galactic bulge and we obtained 2.1 $<M/L_{F814W}<$ 2.4 and 3.1 $< M/L_{F606W}<$ 3.6 according to different assumptions on the slope of the IMF for masses larger than 1 $M_{\odot}$.Comment: 13 pages, 8 figures, accepted for publication on Ap