Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.Work in the DJH laboratory is supported by the Medical Research Council under grant ML/L007266/1. All calculations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England, and were funded by the EPSRC under grants EP/F032773/1 and EP/J017639/1

Developmental changes in children's facial preferences

Facial averageness, symmetry, health, and femininity are positively associated with adults' judgements of attractiveness, but little is known about the age at which preferences for individual facial traits develop. We investigated preferences for these facial traits and global attractiveness in 4- to 17-year-olds (N = 346). All age groups showed preferences for globally attractive faces. Preferences for averageness, symmetry, and health did not emerge until middle childhood and experienced apparent disruption or stasis around age 10- to 14-years; femininity was not preferred until early adulthood, and this preference was seen only in girls. Children's pubertal development was not clearly related to any facial preferences, but the results are consistent with the suggestion that early adrenal hormone release may play an activating role in mate preferences, while other constraints may delay further increases in preferences during later puberty

Structural effects on the luminescence properties of CsPbI3 nanocrystals

Metal halide perovskite nanocrystals (NCs) are promising for photovoltaic and light-emitting applications. Due to the softness of their crystal lattice, structural modifications have a critical impact on their optoelectronic properties. Here we investigate the size-dependent optoelectronic properties of CsPbI3 NCs ranging from 7 to 17 nm, employing temperature and pressure as thermodynamic variables to modulate the energetics of the system and selectively tune the interatomic distances. By temperature-dependent photoluminescence spectroscopy, we have found that luminescence quenching channels exhibit increased non-radiative losses and weaker exciton-phonon coupling in bigger particles, in turn affecting the luminescence efficiency. Through pressure-dependent measurements up to 2.5 GPa, supported by XRD characterization, we revealed a NC-size dependent solid-solid phase transition from the γ-phase to the δ-phase. Importantly, the optical response to these structural changes strongly depends on the size of the NC. Our findings provide an interesting guideline to correlate the size and structural and optoelectronic properties of CsPbI3 NCs, important for engineering the functionalities of this class of soft semiconductors

Catalytic Friedel-Crafts Reactions of Highly Electronically Deactivated Benzylic Alcohols

Highly electronically deactivated benzylic alcohols, including those with a CF3 group adjacent to the OH-bearing carbon, undergo dehydrative Friedel–Crafts reactions upon exposure to catalytic Brønsted acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent. Titration and kinetic experiments support the involvement of higher order solvent/acid clusters in catalysis

Deep-ultraviolet cavity ringdown spectroscopy

The sensitive optical detection technique of cavity ringdown spectroscopy is extended to the wavelength range 197-204 nm. A novel design narrowband Fourier-transform-limited laser is used, and the technique is applied to gas-phase extinction measurements in CO2, SF6, and O-2. Further demonstration of the system capabilities is given in high-resolution recordings of the Schumann-Runge (0, 0), (1, 0), and (2, 0) bands in O-2. (C) 2004 Optical Society of America

Prevalence and correlates of depressive disorders in people with Type 2 diabetes: results from the International Prevalence and Treatment of Diabetes and Depression (INTERPRET‐DD) study, a collaborative study carried out in 14 countries

Aims To assess the prevalence and management of depressive disorders in people with Type 2 diabetes in different countries. Methods People with diabetes aged 18–65 years and treated in outpatient settings were recruited in 14 countries and underwent a psychiatric interview. Participants completed the Patient Health Questionnaire and the Problem Areas in Diabetes scale. Demographic and medical record data were collected. Results A total of 2783 people with Type 2 diabetes (45.3% men, mean duration of diabetes 8.8 years) participated. Overall, 10.6% were diagnosed with current major depressive disorder and 17.0% reported moderate to severe levels of depressive symptomatology (Patient Health Questionnaire scores >9). Multivariable analyses showed that, after controlling for country, current major depressive disorder was significantly associated with gender (women) (PPPPP<0.0001). The proportion of those with either current major depressive disorder or moderate to severe levels of depressive symptomatology who had a diagnosis or any treatment for their depression recorded in their medical records was extremely low and non-existent in many countries (0–29.6%). Conclusions Our international study, the largest of this type ever undertaken, shows that people with diabetes frequently have depressive disorders and also significant levels of depressive symptoms. Our findings indicate that the identification and appropriate care for psychological and psychiatric problems is not the norm and suggest a lack of the comprehensive approach to diabetes management that is needed to improve clinical outcomes

Equine Rhinosporidiosis in United Kingdom

We report 4 cases of equine rhinosporidiosis in the United Kingdom. These cases provide evidence of spread of infectious agents from rhinosporidiosis-endemic areas to nonendemic areas by increased international movement of livestock. Surveillance should continue for this infective agent of potential relevance for numerous species, including humans

Nature's Notebook Provides Phenology Observations for NASA Juniper Phenology and Pollen Transport Project

Phenology Network has been established to provide national wide observations of vegetation phenology. However, as the Network is still in the early phases of establishment and growth, the density of observers is not yet adequate to sufficiently document the phenology variability over large regions. Hence a combination of satellite data and ground observations can provide optimal information regarding juniperus spp. pollen phenology. MODIS data was to observe Juniperus supp. pollen phenology. The MODIS surface reflectance product provided information on the Juniper supp. cone formation and cone density. Ground based observational records of pollen release timing and quantities were used as verification. Approximately 10, 818 records of juniper phenology for male cone formation Juniperus ashei., J. monosperma, J. scopulorum, and J. pinchotti were reported by Nature's Notebook observers in 2013 These observations provided valuable information for the analysis of satellite images for developing the pollen concentration masks for input into the PREAM (Pollen REgional Atmospheric Model) pollen transport model. The combination of satellite data and ground observations allowed us to improve our confidence in predicting pollen release and spread, thereby improving asthma and allergy alerts