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Peptides that self-assemble into nanostructures are of tremendous interest for biological, medical, photonic and nanotechnological applications. The enormous sequence space that is available from 20 amino acids probably harbours many interesting candidates, but it is currently not possible to predict supramolecular behaviour from sequence alone. Here, we demonstrate computational tools to screen for the aqueous self-assembly propensity in all of the 8,000 possible tripeptides and evaluate these by comparison with known examples. We applied filters to select for candidates that simultaneously optimize the apparently contradicting requirements of aggregation propensity and hydrophilicity, which resulted in a set of design rules for self-assembling sequences. A number of peptides were subsequently synthesized and characterized, including the first reported tripeptides that are able to form a hydrogel at neutral pH. These tools, which enable the peptide sequence space to be searched for supramolecular properties, enable minimalistic peptide nanotechnology to deliver on its promise. Peptides that self-assemble into nanostructures are of interest for many applications, including ones relevant to cosmetics, food, biomedicine and nanotechnology. Now, computational tools have been developed that enable peptide sequence space to be rapidly searched for supramolecular properties and this approach has been used to identify unprotected tripeptide hydrogelators.

Supramolecular gels, which demonstrate tunable functionalities, have attracted much interest in a range of areas, including healthcare, environmental protection and energy-related technologies. Preparing these materials in a reliable manner is challenging, with an increased level of kinetic defects observed at higher self-assembly rates. Here, by combining biocatalysis and molecular self-assembly, we have shown the ability to more quickly access higher-ordered structures. By simply increasing enzyme concentration, supramolecular order expressed at molecular, nano- and micro-levels is dramatically enhanced, and, importantly, the gelator concentrations remain identical. Amphiphile molecules were prepared by attaching an aromatic moiety to a dipeptide backbone capped with a methyl ester. Their self-assembly was induced by an enzyme that hydrolysed the ester. Different enzyme concentrations altered the catalytic activity and size of the enzyme clusters, affecting their mobility. This allowed structurally diverse materials that represent local minima in the free energy landscape to be accessed based on a single gelator structure. Supramolecular gels show promise in diverse areas, including healthcare and energy technologies, owing to tunable properties that arise directly from the organization of their building blocks. Researchers have now been able to control this behaviour by combining enzymatic catalysis with molecular self-assembly. Although it seems counter-intuitive, gels that assembled faster showed fewer defects.

Tuberculosis (TB) is a global health problem that affects over 10 million people. There is an urgent need to develop novel antimicrobial therapies to combat TB. To achieve this, a thorough understanding of key validated drug targets is required. The enoyl reductase InhA, responsible for synthesis of essential mycolic acids in the mycobacterial cell wall, is the target for the frontline anti-TB drug isoniazid. To better understand the activity of this protein a series of mutants, targeted to the NADH co-factor binding pocket were created. Residues P193 and W222 comprise a series of hydrophobic residues surrounding the cofactor binding site and mutation of both residues negatively affect InhA function. Construction of an M155A mutant of InhA results in increased affinity for NADH and DD-CoA turnover but with a reduction in V max for DD-CoA, impairing overall activity. This suggests that NADH-binding geometry of InhA likely permits long-range interactions between residues in the NADH-binding pocket to facilitate substrate turnover in the DD-CoA binding region of the protein. Understanding the precise details of substrate binding and turnover in InhA and how this may affect protein-protein interactions may facilitate the development of improved inhibitors enabling the development of novel anti-TB drugs.

[NiFe] hydrogenases are metalloenzymes that catalyze the reversible cleavage of dihydrogen (H2), a clean future fuel. Understanding the mechanism of these biocatalysts requires spectroscopic techniques that yield insights into the structure and dynamics of the [NiFe] active site. Due to the presence of CO and CN− ligands at this cofactor, infrared (IR) spectroscopy represents an ideal technique for studying these aspects, but molecular information from linear IR absorption experiments is limited. More detailed insights can be obtained from ultrafast nonlinear IR techniques like IRpump-IRprobe and two-dimensional (2D-)IR spectroscopy. However, fully exploiting these advanced techniques requires an in-depth understanding of experimental observables and the encoded molecular information. To address this challenge, we present a descriptive and predictive computational approach for the simulation and analysis of static 2D-IR spectra of [NiFe] hydrogenases and similar organometallic systems. Accurate reproduction of experimental spectra from a first-coordination-sphere model suggests a decisive role of the [NiFe] core in shaping the enzymatic potential energy surface. We also reveal spectrally encoded molecular information that is not accessible by experiments, thereby helping to understand the catalytic role of the diatomic ligands, structural differences between [NiFe] intermediates, and possible energy transfer mechanisms. Our studies demonstrate the feasibility and benefits of computational spectroscopy in the 2D-IR investigation of hydrogenases, thereby further strengthening the potential of this nonlinear IR technique as a powerful research tool for the investigation of complex bioinorganic molecules.

An engineered nanomaterial (ENM) may actually consist of a population of primary particles, aggregates and agglomerates of various sizes. Furthermore, their physico-chemical characteristics may change during the various life-cycle stages. It will probably not be feasible to test all varieties of all ENMs for possible health and environmental risks. There is therefore a need to further develop the approaches for risk assessment of ENMs. Within the EU FP7 project Managing Risks of Nanoparticles (MARINA) a two-phase risk assessment strategy has been developed. In Phase 1 (Problem framing) a base set of information is considered, relevant exposure scenarios (RESs) are identified and the scope for Phase 2 (Risk assessment) is established. The relevance of an RES is indicated by information on exposure, fate/kinetics and/or hazard; these three domains are included as separate pillars that contain specific tools. Phase 2 consists of an iterative process of risk characterization, identification of data needs and integrated collection and evaluation of data on the three domains, until sufficient information is obtained to conclude on possible risks in a RES. Only data are generated that are considered to be needed for the purpose of risk assessment. A fourth pillar, risk characterization, is defined and it contains risk assessment tools. This strategy describes a flexible and efficient approach for data collection and risk assessment which is essential to ensure safety of ENMs. Further developments are needed to provide guidance and make the MARINA Risk Assessment Strategy operational. Case studies will be needed to refine the strategy.

Purpose: Hamstring graft fixation on the patellar side during medial patellofemoral ligament (MPFL) reconstruction is usually with transosseous tunnels and can frequently lead to further problems. The aim of our study was to compare and analyse patellar complications in single patellar tunnel versus double tunnel hamstring graft fixation. Methods: Twenty-nine knees with MPFL reconstructions (group S) in which the hamstring tendon graft was transfixed using a suspensory fixation method in a single tunnel drilled across the patella were analysed in comparison with 29 knees (group D) with interference fixation of the graft through two tunnels drilled up to a predetermined depth in the patella. Primary outcome measured was any patellar complication like anterior knee pain and patella fracture. Secondary outcomes assessed were future functional instability and failure of reconstruction. Results: Anterior knee pain was noted in six patients in group S, of which three patients had removal of the irritating metalwork on the patella. In all, nine surgical interventions were needed in six patients in this group. Three patients in group D complained of knee pain, but no one in this group needed any further surgical interventions (p value 0.02). Symptomatic instability requiring revision surgery or realignment surgery was required in two patients in the group S and none in group D. No patellar fractures were seen in either group. Conclusion: Our study showed increasing problems with single tunnel patellar fixation, with more reoperation and failure rates compared to double tunnel fixation. The evidence supports the move towards anatomical double bundle MPFL reconstructions.

Background Within the UK, injecting in the femoral vein (FV), often called 'groin injecting', is a serious cause of risk and harm. This study aimed to use ultrasound scanning as a means to engage groin injectors (GIs), examine their femoral injecting sites and assess their venous health, with the intention of developing improved responses. Methods Between September 2006 and March 2009, GIs attending a network of community drug treatment centres in South East England were invited to attend an ultrasound 'health-check' clinic. This paper provides a narrative account of the scanning procedure and operation of the service, with descriptive statistical analysis of GIs who attended. The analysis uses a structured, specially-developed clinical data set that incorporates a categorisation for the severity of FV damage. Case studies using ultrasound images and a link to a video are provided to illustrate the range of presentations encountered and the categorisations used for severity. Results A total of 160 groin scans (76 bilateral and 8 unilateral) were performed in 84 GIs. The majority were men (69.0%) and the mean age of the sample was 36.8 years. The mean duration of drug use and injecting drug use was 19.7 years and 13.8 years, respectively. FV damage at the injecting site in the right groin was graded as minimal in 20 patients (25%), moderate in 27 (33.8%), severe in 16 (20.0%) and very-severe in 17 (21.3%). Corresponding figures for left FV were 24 (30.0%), 22 (27.5%), 18 (22.5%) and 16 (20.0%). Wide variation was observed in the time to the development of these grades of FV damage. Conclusions Modern, portable ultrasound scanners make it possible to examine the venous health of GIs in community treatment settings. Ultrasound scanning identified extensive FV damage, much hitherto-unrecognised in this population. These findings should further alert clinicians, policy-makers and patients to the urgent need for effective harm reduction responses to GI behaviour. Images of damaged FV in this paper might prove to be a useful resource for discussions about GI risks.

This paper reports on intake data from Quasi-Compulsory Treatment in Europe, a study of quasi-compulsory treatment (QCT) for drug dependent offenders. It explores the link between formal legal coercion, perceived pressure to be in treatment and motivation amongst a sample of 845 people who entered treatment for drug dependence in five European countries, half of them in quasi-compulsory treatment and half ‘voluntarily’. Using both quantitative and qualitative data, it suggests that those who enter treatment under QCT do perceive greater pressure to be in treatment, but that this does not necessarily lead to higher or lower motivation than ‘volunteers’. Many drug-dependent offenders value QCT as an opportunity to get treatment. Motivation is mutable and can be developed or diminished by the quality of support and services offered to drug-dependent offenders.

An Environmental Risk Assessment (ERA) for nanomaterials (NMs) is outlined in this paper. Contrary to other recent papers on the subject, the main data requirements, models and advancement within each of the four risk assessment domains are described, i.e., in the: (i) materials, (ii) release, fate and exposure, (iii) hazard and (iv) risk characterisation domains. The material, which is obviously the foundation for any risk assessment, should be described according to the legislatively required characterisation data. Characterisation data will also be used at various levels within the ERA, e.g., exposure modelling. The release, fate and exposure data and models cover the input for environmental distribution models in order to identify the potential (PES) and relevant exposure scenarios (RES) and, subsequently, the possible release routes, both with regard to which compartment(s) NMs are distributed in line with the factors determining the fate within environmental compartment. The initial outcome in the risk characterisation will be a generic Predicted Environmental Concentration (PEC), but a refined PEC can be obtained by applying specific exposure models for relevant media. The hazard information covers a variety of representative, relevant and reliable organisms and/or functions, relevant for the RES and enabling a hazard characterisation. The initial outcome will be hazard characterisation in test systems allowing estimating a Predicted No-Effect concentration (PNEC), either based on uncertainty factors or on a NM adapted version of the Species Sensitivity Distributions approach. The risk characterisation will either be based on a deterministic risk ratio approach (i.e., PEC/PNEC) or an overlay of probability distributions, i.e., exposure and hazard distributions, using the nano relevant models.