Hydrogen bonding and the stability of the polypeptide backbone

The tertiary structures of globular proteins are crucial in determining reactivity and specificity as biological catalysts and signalling systems. The rules determining the final fold of a protein are still unknown, but some progress has been made in defining tertiary structure in terms of the secondary structure, the conformation of the polypeptide chain. Perhaps surprisingly, not all of the conformational properties of this backbone are known, and several new approaches to studying these are described. Most studies of peptide structure have focused on hydrogen bonding, and this is used as a starting point for this study. Different descriptions of the hydrogen bond, from geometric rules to ab initio calculations, are considered, and an approach based on analysing contributions of individual polar groups to the potential energy using semi empirical Lennard-Jones calculations is chosen on grounds of accuracy, flexibility, and ease of calculation. Using this approach, it is shown that electrostatic interactions between main chain atoms stabilise the right handed twist found in Beta-strands and similar interactions between main-chain atoms not hydrogen bonded to each other influence the geometries of hydrogen bonds in Alpha-helices and Beta-sheets. A role for water and tertiary hydrogen bonds in determining backbone conformation is suggested. The same technique makes it possible to investigate interatomic repulsions as well as attractions. A detailed analysis of the attractions and repulsions in an idealised polypeptide explains many of the features of helical structures in proteins, and suggests a hitherto unexpected directional helix forming pathway, which is supported by a range of kinetic and structural data. Software for automated searching of a hydrogen bond database is developed, and used to identify hydrogen bonded rings formed by amide side chains and main chain peptides. Integrating the database with novel visualisation techniques allows a previously unidentified property of beta sheets, the hydrophobic ridge, to be detected. A range of different computational approaches was used surging this research, from molecular modelling to database searching. Several pieces of software were developed, and these are described together with some observations about the types of software and working environments which were found to be useful in structural biochemistry, and what types of software technology could be developed to make this task easier

The Channel Tunnel, implications for regional development in Great Britain.

Massachusetts Institute of Technology. Dept. of Urban Studies and Planning. Thesis. 1969. M.C.P.Bibliography: leaves 88-91.M.C.P

Shifting senses in lexical semantic development

Most words are associated with multiple senses. A DVD can be round (when describing a disc), and a DVD can be an hour long (when describing a movie), and in each case DVD means something different. The possible senses of a word are often predictable, and also constrained, as words cannot take just any meaning: for example, although a movie can be an hour long, it cannot sensibly be described as round (unlike a DVD). Learning the scope and limits of word meaning is vital for the comprehension of natural language, but poses a potentially difficult learnability problem for children. By testing what senses children are willing to assign to a variety of words, we demonstrate that, in comprehension, the problem is solved using a productive learning strategy. Children are perfectly capable of assigning different senses to a word; indeed they are essentially adult-like at assigning licensed meanings. But difficulties arise in determining which senses are assignable: children systematically overestimate the possible senses of a word, allowing meanings that adults rule unlicensed (e.g., taking round movie to refer to a disc). By contrast, this strategy does not extend to production, in which children use licensed, but not unlicensed, senses. Children’s productive comprehension strategy suggests an early emerging facility for using context in sense resolution (a difficult task for natural language processing algorithms), but leaves an intriguing question as to the mechanisms children use to learn a restricted, adult-like set of senses

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics