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Hydrogenases catalyze hydrogen/proton interconversion that is normally electrochemically reversible (having minimal overpotential requirement), a special property otherwise almost exclusive to platinum metals. The mechanism of [NiFe]-hydrogenases includes a long-range proton-coupled electron-transfer process involving a specific Ni-coordinated cysteine and the carboxylate of a nearby glutamate. A variant in which this cysteine has been exchanged for selenocysteine displays two distinct changes in electrocatalytic properties, as determined by protein film voltammetry. First, proton reduction, even in the presence of H2(a strong product inhibitor), is greatly enhanced relative to H2oxidation: this result parallels a characteristic of natural [NiFeSe]-hydrogenases which are superior H2production catalysts. Second, an inflection (an S-shaped “twist” in the trace) appears around the formal potential, the small overpotentials introduced in each direction (oxidation and reduction) signaling a departure from electrocatalytic reversibility. Concerted proton–electron transfer offers a lower energy pathway compared to stepwise transfers. Given the much lower proton affinity of Se compared to that of S, the inflection provides compelling evidence that concerted proton–electron transfer is important in determining why [NiFe]-hydrogenases are reversible electrocatalysts.

This paper draws on a qualitative interview-based study that explored online mental health and wellbeing interventions and services for care-experienced young people. The study involved young people (n= 4), foster carers (n= 8), kinship carers (n= 2) and social care professionals (n= 9) in Wales, UK. The paper reflects on the complexities of online communication in the space of ‘the home’. It documents the ways in which care-experienced young people’s living arrangements can restrict access to services and complicate confidentiality within portals to the virtual world, creating an environment where young people and their carers ‘wouldn’t want to talk about anything too personal’. Drawing on data generated in a study focused on services and interventions to support the mental health and wellbeing of care-experienced children and young people, the paper considers privacy, confidentiality and surveillance in the home and reflects on how associated relational practices impact on care-experienced young people. While the data discussed in this paper was generated during the Covid-19 pandemic, its findings have implications for how care-experienced young people and their carers can be supported to engage with the digital world in the future.

IntroductionThe UK Medical Research Council and National Institute for Health Research have funded the ADAPT study (2018–2020), to develop methodological guidance for the adaptation of complex population health interventions for new contexts. While there have been advances in frameworks, there are key theoretical and methodological debates to progress. The ADAPT study convened a panel meeting to identify and enrich these debates. This paper presents the panel’s discussions and suggests directions for future research.MethodsSixteen researchers and one policymaker convened for a 1-day meeting in July 2019. The aim was to reflect on emerging study findings (systematic review of adaptation guidance; scoping review of case examples; and qualitative interviews with funders, journal editors, researchers and policymakers), progress theoretical and methodological debates, and consider where innovation may be required to address research gaps.DiscussionDespite the proliferation of adaptation frameworks, questions remain over the definition of basic concepts (eg, adaptation). The rationale for adaptation, which often focuses on differences between contexts, may lead to adaptation hyperactivity. Equal emphasis should be placed on similarities. Decision-making about intervention modification currently privileges the concept of ‘core components’, and work is needed to progress the use and operationalisation of ‘functional fidelity’. Language and methods must advance to ensure meaningful engagement with diverse stakeholders in adaptation processes. Further guidance is required to assess the extent of re-evaluation required in the new context. A better understanding of different theoretical perspectives, notably complex systems thinking, implementation science and realist evaluation may help in enhancing research on adaptation.

Bacterial infections present one of the leading causes of mortality worldwide, resulting in an urgent need for sensitive, selective, cost-efficient, and easy-to-handle technologies to rapidly detect contaminations and infections with pathogens. The presented research reports a fully functional chemical-detection principle, addressing all of the above-mentioned requirements for a successful biosensing device. With the examples of Escherichia coliand Neisseria gonorrheae, we present an electrochemical biosensor based on the bacterial expression of cytochrome c oxidase for the selective detection of clinically relevant concentrations within seconds after pathogen immobilization. The generality of the biochemical reaction, as well as the easy substitution of target-specific antibodies make this concept applicable to a large number of different pathogenic bacteria. The successful transfer of this semidirect detection principle onto inexpensive, screen-printed electrodes for portable devices represents a potential major advance in the field of biosensor development.

Positive relationships with family, friends and school staff are consistently linked with health and wellbeing during adolescence, though fewer studies explore how these micro-systems interact to influence adolescent health. This study tests the independent and interacting roles of family, peer and school relationships in predicting substance use, subjective wellbeing and mental health symptoms among 11–16 year olds in Wales. It presents cross-sectional analyses of the 2013 Health Behaviour in School-aged Children survey, completed by 9055 young people aged 11–16 years. Multilevel logistic regression analyses are used to test associations of family communication, family support, relationships with school staff, school peer connectedness, and support from friends, with tobacco use, cannabis use, alcohol use, subjective wellbeing and mental health symptoms. Positive relationships with family and school staff were consistently associated with better outcomes. Support from friends was associated with higher use of all substances, while higher school peer connectedness was associated with better subjective wellbeing and mental health. Better relationships with school staff were most strongly associated with positive subjective wellbeing, and fewer mental health symptoms where pupils reported less family support. Support from friends was associated with higher cannabis use and worse mental health among pupils with lower family support. Relationships with family and school staff may be important in protecting young people against substance use, and improving wellbeing and mental health. Interventions focused on student-staff relationships may be important for young people with less family support. Interventions based on peer support should be mindful of potential harmful effects for pupils with less support from family.

Catalytic long-range proton transfer in [NiFe]-hydrogenases has long been associated with a highly conserved glutamate (E) situated within 4 Å of the active site. Substituting for glutamine (Q) in the O2-tolerant [NiFe]-hydrogenase-1 from Escherichia coliproduces a variant (E28Q) with unique properties that have been investigated using protein film electrochemistry, protein film infrared electrochemistry, and X-ray crystallography. At pH 7 and moderate potential, E28Q displays approximately 1% of the activity of the native enzyme, high enough to allow detailed infrared measurements under steady-state conditions. Atomic-level crystal structures reveal partial displacement of the amide side chain by a hydroxide ion, the occupancy of which increases with pH or under oxidizing conditions supporting formation of the superoxidized state of the unusual proximal [4Fe–3S] cluster located nearby. Under these special conditions, the essential exit pathway for at least one of the H+ions produced by H2oxidation, and assumed to be blocked in the E28Q variant, is partially repaired. During steady-state H2oxidation at neutral pH (i.e., when the barrier to H+exit via Q28 is almost totally closed), the catalytic cycle is dominated by the reduced states “Nia-R” and “Nia-C”, even under highly oxidizing conditions. Hence, E28 is not involved in the initial activation/deprotonation of H2, but facilitates H+exit later in the catalytic cycle to regenerate the initial oxidized active state, assumed to be Nia-SI. Accordingly, the oxidized inactive resting state, “Ni-B”, is not produced by E28Q in the presence of H2at high potential because Nia-SI (the precursor for Ni-B) cannot accumulate. The results have important implications for understanding the catalytic mechanism of [NiFe]-hydrogenases and the control of long-range proton-coupled electron transfer in hydrogenases and other enzymes.

Recent years have seen a growing emphasis on the value of building and testing middle range theory throughout the development and evaluation of complex population health interventions. We agree that a coherent theoretical basis for intervention development, and use of evaluation to test key causal assumptions and build theory, are crucial. However, in this editorial, we argue that such recommendations have often been operationalised in somewhat simplistic terms with potentially perverse consequences, and that an uncritical assumption that an intervention explicitly based on theory is inherently superior carries significant risks. We first argue that the drive for theory-based approaches may have exacerbated a propensity to select ‘off-the-shelf’ theories, leading to the selection of inappropriate theories which distract attention from the mechanisms through which a problem is actually sustained. Second, we discuss a tendency toward over-reliance on individual-level theorising. Finally, we discuss the relatively slow progress of population health intervention research in attending to issues of context, and the ecological fit of interventions with the systems whose functioning they attempt to change. We argue that while researchers should consider a broad range of potential theoretical perspectives on a given population health problem, citing a popular off-the-shelf theory as having informed an intervention and its evaluation does not inherently make for better science. Before identifying or developing a theory of change, researchers should develop a clear understanding of how the problem under consideration is created and sustained in context. A broader conceptualisation of theory that reaches across disciplines is vital if theory is to enhance, rather than constrain, the contribution of intervention research. Finally, intervention researchers need to move away from viewing interventions as discrete packages of components which can be described in isolation from their contexts, and better understand the systems into which change is being introduced.

The active site of Hyd-1, an oxygen-tolerant membrane-bound [NiFe]-hydrogenase from Escherichia coli, contains four highly conserved residues that form a “canopy” above the bimetallic center, closest to the site at which exogenous agents CO and O2interact, substrate H2binds, and a hydrido intermediate is stabilized. Genetic modification of the Hyd-1 canopy has allowed the first systematic and detailed kinetic and structural investigation of the influence of the immediate outer coordination shell on H2activation. The central canopy residue, arginine 509, suspends a guanidine/guanidinium side chain at close range above the open coordination site lying between the Ni and Fe atoms (N–metal distance of 4.4 Å): its replacement with lysine lowers the H2oxidation rate by nearly 2 orders of magnitude and markedly decreases the H2/D2kinetic isotope effect. Importantly, this collapse in rate constant can now be ascribed to a very unfavorable activation entropy (easily overriding the more favorable activation enthalpy of the R509K variant). The second most important canopy residue for H2oxidation is aspartate 118, which forms a salt bridge to the arginine 509 headgroup: its mutation to alanine greatly decreases the H2oxidation efficiency, observed as a 10-fold increase in the potential-dependent Michaelis constant. Mutations of aspartate 574 (also salt-bridged to R509) to asparagine and proline 508 to alanine have much smaller effects on kinetic properties. None of the mutations significantly increase sensitivity to CO, but neutralizing the expected negative charges from D118 and D574 decreases O2tolerance by stabilizing the oxidized resting NiIII–OH state (“Ni-B”). An extensive model of the catalytic importance of residues close to the active site now emerges, whereby a conserved gas channel culminates in the arginine headgroup suspended above the Ni and Fe.

Abstract.Background:Concern has been expressed about the potentially contagious effect of television soap opera suicides and suicidal language in social media. Aims:Twitter content was analyzed during the week in which a fictional assisted suicide was broadcast on a British television soap opera, "Coronation Street." Method:Tweets were collected if they contained language indicating possible suicidal intent or used the word suicide. The modified Thompson tau method was used to test for any differences in the volume of tweets in both categories on the day of screening. Content analysis broke down the use of the word suicide into six thematic categories. Results:There was no evidence on the day of screening of an increase in tweets expressing possible suicidal intent but there was an increase in tweets containing the word suicide. Content analysis found the most common thematic category to be information or support, followed by the raising of moral issues in relation to suicide. Conclusion:It is possible that for certain high-profile media events Twitter may be used more as a civic reactive forum than as a medium for introspection or disclosure of distress.

Background:While concerns abound regarding the impact of the Internet on suicidal behaviors, its role as a medium for suicide prevention remains underexplored. Aims:The study examines what is currently known about the operation and effectiveness of Internet programs for suicide and self-harm prevention that are run by professionals. Method:Systematic searches of scholarly databases and suicide-related academic journals yielded 15 studies that presented online prevention strategies. Results:No professional programs with a sole focus on nonsuicidal self-harm were identified, thus all studies reviewed focused on suicide prevention. Studies were predominantly descriptive and summarized the nature of the strategy and the target audience. There was no formal evaluation of program effectiveness in preventing suicide. Studies either presented strategies that supported individuals at risk of suicide (n= 8), supported professionals working with those at risk (n= 6), or attempted to improve website quality (n= 1). Conclusion:Although the Internet increasingly serves as an important medium for suicidal individuals, and there is concern about websites that both promote and encourage suicidal activity, there is lack of published evidence about online prevention strategies. More attention is needed in the development and evaluation of such preventative approaches.

Adjuvant therapy is used following radical treatment to reduce the risk of cancer recurrence and improve survival. The rationale for its use is its potential to treat local and/or distal occult microscopic disease. However, it can be associated with significant adverse effects. The potential benefit of treatment must therefore be assessed on an individual basis, considering both tumour and patient characteristics. This article discusses the basic principles of adjuvant and neoadjuvant therapy, focussing on breast and colorectal cancer. We also discuss some of the adverse effects of therapy and look at potential future developments.

Protein motions may be perturbed by altering the properties of the reaction medium. Here we show that dielectric constant, but not viscosity, affects the rate of the hydride‐transfer reaction catalysed by dihydrofolate reductase from Thermotoga maritima(TmDHFR), in which quantum‐mechanical tunnelling has previously been shown to be driven by protein motions. Neither dielectric constant nor viscosity directly alters the kinetic isotope effect of the reaction or the mechanism of coupling of protein motions to tunnelling. Glycerol and sucrose cause a significant increase in the rate of hydride transfer, but lead to a reduction in the magnitude of the kinetic isotope effect as well as an extension of the temperature range over which “passive” protein dynamics (rather than “active” gating motions) dominate the reaction. Our results are in agreement with the proposal that non‐equilibrium dynamical processes (promoting motions) drive the hydride‐transfer reaction in TmDHFR.

Dihydrofolate reductase (DHFR) maintains the intracellular pool of tetrahydrofolate through catalysis of hydrogen transfer from reduced nicotinamide adenine dinucleotide to 7,8-dihydrofolate. We report results for pre-steady-state kinetic studies of the temperature dependence of the rates and the hydrogen/deuterium-kinetic isotope effects for the reactions catalysed by the enzymes from the mesophilic Escherichia coliand the hyperthermophilic Thermatoga maritima. We propose an evolutionary pattern in which catalysis progressed from a relatively rigid active site structure in the ancient thermophilic DHFR to a more flexible and kinetically more efficient structure in E. colithat actively promotes hydrogen transfer at physiological pH by modulating the tunnelling distance. The E. colienzyme appeared relatively robust, in that kinetically severely compromised mutants still actively propagated the reaction. The reduced hydrogen transfer rates of the extensively studied Gly121Val mutant of DHFR from E. coliwere most likely due to sterically unfavourable long-range effects from the introduction of the bulky isopropyl group.

For well over a decade Pliny's Historia Naturalishas been recognised as a work which deals with moral questions and imperial culture as much as (perhaps more than) science and nature. These reassessments of the Elder Pliny move away from the disdainful and anachronistic judgments of his writings as ill-judged, naïve and unscientific, and towards a more productive analysis of the Historia Naturalis' symbolic significance and coherence within its first century Roman context. Mary Beagon finds that Pliny is representative of a particular first century ‘emphasis on humanity and its needs and aspirations’, while commenting that it is at this period that mundusand kosmos(Latin and Greek respectively for ‘world’ or ‘universe’) take on the specific meaning of ‘the inhabited world’. The coherence that Beagon finds in Pliny's work is therefore concentrated around the relationship between nature and humankind. It is this relationship, and the symbolic value given to natural phenomena, which allows so much of the Historia Naturalisto act as a cultural commentary on contemporary society. For example, Beagon, Andrew Wallace-Hadrill and Trevor Murphy identify luxuria(‘luxury’) as a key term in Pliny, and insist not only upon his aversion to this concept, but also on his transcendence of the traditional Roman diatribe against decadence and extravagance. For Beagon, Pliny's objection to luxury is partly determined by contemporary political and economic factors, as she claims that Pliny's stance mirrors that of Vespasian, who was attempting to rebuild the state's finances after Nero had squandered them. More particularly, luxuriais the antithesis of uita(‘life’), to the extent that it corrupts and distorts life, leading to passivity and desidia(‘lethargy’)—the exact opposite of the programmatic statement found in the Historia NaturalisPreface 19: uita uigilia est(‘life is being awake’).

Blemyis capita absunt, uultus in pectore est. Satyris praeter effigiem nihil humani. Aegipanum quae celebratur ea forma est. haec de Africa.Pomponius Mela Chorographia1.48The Blemyes lack heads: their faces are in their chests. There is nothing typical of humans about the Satyrs, apart from their superficial appearance. The Aegipanes have the shape described in stories. So much for Africa.How useful are Roman geographical texts? Outrageous claims like the one cited above have invited scepticism concerning the scientific value of geographies and ethnographies produced by Roman authors. To a large extent, the importance attributed to a geographical text will depend on what is being sought from that text. For example, O.A.W. Dilke tells us that, ‘We are fortunate in possessing all seventeen books of the Geographyof Strabo,’ and that Strabo ‘shows good critical power in assessing earlier geographical writers and giving us a verbal picture of the known world of the time.’ However, ‘a contrast with Strabo's work is provided by the very simple and popular Chorographiaof Pomponius Mela,’ of which Dilke expresses die view that it would have been preferable had Juba II's work survived.

School teachers are at heightened risk of mental health difficulties. A small number of trials have introduced teacher training to improve support for students, but none have increased support available for teachers themselves. We aimed to evaluate the effect of a mental health support and training intervention on secondary school teachers’ and students’ wellbeing and mental health.