Predicting the conformations of peptides and proteins in early evolution. A review article submitted to Biology Direct

Considering that short, mainly heterochiral, polypeptides with a high glycine content are expected to have played a prominent role in evolution at the earliest stage of life before nucleic acids were available, we review recent knowledge about polypeptide three-dimensional structure to predict the types of conformations they would have adopted. The possible existence of such structures at this time leads to a consideration of their functional significance, and the consequences for the course of evolution

Structure motivator: a tool for exploring small three-dimensional elements in proteins

<br>Background: Protein structures incorporate characteristic three-dimensional elements defined by some or all of hydrogen bonding, dihedral angles and amino acid sequence. The software application, Structure Motivator, allows interactive exploration and analysis of such elements, and their resolution into sub-classes.</br> <br>Results: Structure Motivator is a standalone application with an embedded relational database of proteins that, as a starting point, can furnish the user with a palette of unclassified small peptides or a choice of pre-classified structural motifs. Alternatively the application accepts files of data generated externally. After loading, the structural elements are displayed as two-dimensional plots of dihedral angles (φ/ψ, φ/χ1 or in combination) for each residue, with visualization options to allow the conformation or amino acid composition at one residue to be viewed in the context of that at other residues. Interactive selections may then be made and structural subsets saved to file for further sub-classification or external analysis. The application has been applied both to classical motifs, such as the β-turn, and ‘non-motif’ structural elements, such as specific segments of helices.</br> <br>Conclusions: Structure Motivator allows structural biologists, whether or not they possess computational skills, to subject small structural elements in proteins to rapid interactive analysis that would otherwise require complex programming or database queries. Within a broad group of structural motifs, it facilitates the identification and separation of sub-classes with distinct stereochemical properties.</br&gt

HLAs: Key regulators of T-cell-mediated drug hypersensitivity

Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding

Role of the dental hospital-based paediatric liaison nurse in safeguarding children

Aim: Service evaluation of our dental hospital paediatric liaison nursing (DH-PLN) service which provides an additional route for information sharing about safeguarding concerns via an agreed pathway for two-way communication with public health nurses. Method: Retrospective analysis of clinical records of all children referred by DH teams to PLN in the three months October-December 2016. Results: One hundred and four children were referred; mean age was 6.2 years, 89.4% from Index of Multiple Deprivation (IMD) quintiles 4 and 5, and 70.2% were attending for dental general anaesthesia. The most common referral reason was dental neglect in 66.3%, followed by missed appointments in 50.0%. The PLN checked child health databases and shared information with health visitors and school nurses (46.2% and 53.8% respectively). Feedback retrieved included known child maltreatment risk factors in 7.7%. This prompted additional child protection referrals to children's social services for seven children (6.7%). Dental outcomes six months later were: treatment complete in 50.0%, treatment ongoing 28.8%, discharged to original referrer with treatment incomplete in 21.1%. Conclusion: This DH-PLN service promotes integrated multidisciplinary working, helping overcome barriers to dentistry's involvement in safeguarding. It facilitates more accurate assessments of risk of harm to children receiving dental care and prompts additional child protection referrals to social services

Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity

Purpose of review: Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. Recent findings: Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. Summary: In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct ‘allergy label’ is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines

The β-link motif in protein architecture

The β-link is a composite protein motif consisting of a G1β β-bulge and a type II β-turn, and is generally found at the end of two adjacent strands of antiparallel β-sheet. The 1,2-positions of the β-bulge are also the 3,4-positions of the β-turn, with the result that the N-terminal portion of the polypeptide chain is orientated at right angles to the β-sheet. Here, it is reported that the β-link is frequently found in certain protein folds of the SCOPe structural classification at specific locations where it connects a β-sheet to another area of a protein. It is found at locations where it connects one β-sheet to another in the β-sandwich and related structures, and in small (four-, five- or six-stranded) β-barrels, where it connects two β-strands through the polypeptide chain that crosses an open end of the barrel. It is not found in larger (eight-stranded or more) β-barrels that are straightforward β-meanders. In some cases it initiates a connection between a single β-sheet and an α-helix. The β-link also provides a framework for catalysis in serine proteases, where the catalytic serine is part of a conserved β-link, and in cysteine proteases, including Mpro of human SARS-CoV-2, in which two residues of the active site are located in a conserved β-link

First direct measurements of hydraulic jumps in an active submarine density current

For almost half a century, it has been suspected that hydraulic jumps, which consist of a sudden decrease in downstream velocity and increase in flow thickness, are an important feature of submarine density currents such as turbidity currents and debris flows. Hydraulic jumps are implicated in major seafloor processes, including changes from channel erosion to fan deposition, flow transformations from debris flow to turbidity current, and large-scale seafloor scouring. We provide the first direct evidence of hydraulic jumps in a submarine density current and show that the observed hydraulic jumps are in phase with seafloor scours. Our measurements reveal strong vertical velocities across the jumps and smaller than predicted decreases in downstream velocity. Thus, we demonstrate that hydraulic jumps need not cause instantaneous and catastrophic deposition from the flow as previously suspected. Furthermore, our unique data set highlights problems in using depth-averaged velocities to calculate densimetric Froude numbers for gravity currents

A survey of solution techniques for the partially observed Markov decision process

We survey several computational procedures for the partially observed Markov decision process (POMDP) that have been developed since the Monahan survey was published in 1982. The POMDP generalizes the standard, completely observed Markov decision process by permitting the possibility that state observations may be noise-corrupted and/or costly. Several computational procedures presented are convergence accelerating variants of, or approximations to, the Smallwood-Sondik algorithm. Finite-memory suboptimal design results are reported, and new research directions involving heuristic search are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44198/1/10479_2005_Article_BF02204836.pd