University of East Anglia

Ferritins are ubiquitous proteins that function in iron storage/detoxification by catalyzing the oxidation of Fe²⁺ ions and solubilizing the resulting Fe³⁺-oxo mineral. Mammalian tissues that are metabolically highly active contain, in addition to the widespread cytosolic ferritin, a ferritin that is localized to mitochondria. Mitochondrial ferritin (FtMt) protects against oxidative stress and is found at higher levels in diseases associated with abnormal iron accumulation, including Alzheimer’s and Parkinson’s. Here we demonstrate that, despite 80% sequence identity with cytosolic human H-chain ferritin, Fe²⁺ oxidation at the catalytic diiron ferroxidase center of FtMt proceeds via a distinct mechanism. This involves a mixed-valent ferroxidase center (MVFC) that is readily detected under the O2-limiting conditions typical of mitochondria, and formation of a radical on a strictly conserved Tyr residue (Tyr34) that is key for the activation of O2 and stability of the MVFC. The possible origin of the mechanistic differences exhibited by the highly-related human mitochondrial and cytosolic H-chain ferritins is explored.

Background To improve the efficacy of digital smoking cessation interventions for young adults, intervention messages need to be acceptable and appropriate for this population. The current study compared ratings of smoking cessation and urge reduction messages based on Cognitive Behavioral Therapy (distraction themed) and Acceptance and Commitment Therapy (acceptance themed) in young adults who smoke. Methods A total of 124 intervention messages were rated by an online Qualtrics panel of N = 301 diverse young adults who currently smoked tobacco cigarettes (Age M = 26.6 years; 54.8% male; 51.5% racial/ethnic minority; 16.9% sexual or gender minority (SGM); 62.5% daily smoking). Each participant rated 10 randomly selected messages (3,010 total message ratings; 24.3 ratings per message) on 5-point scales (higher scores representing more favorable ratings) evaluating quality of content, quality of design, perceived support for coping with smoking urges, and perceived support for quitting smoking. Mixed models examined associations between message category (distraction vs. acceptance), participant level predictors (sociodemographic variables, readiness and motivation to quit, daily smoking, psychological flexibility), and message ratings. Results Overall ratings ranged from M = 3.61 (SD = 1.25) on support for coping with urges to M = 3.90 (SD = 1.03) on content, with no differences between distraction and acceptance messages. Male participants gave more favorable ratings on the dimensions of support for coping (p < 0.01) and support for quitting (p < 0.01). Participants identifying as SGM gave lower ratings for message design (p < 0.05). Participants with a graduate degree gave higher ratings on support for coping with urges and support for quitting (both p < 0.05). Higher motivation to quit was associated with more favorable scores across all dimensions (all p < 0.01). Those smoking daily rated messages as less helpful for coping with urges (p < 0.01) and quitting smoking (p < 0.05) compared to those smoking non-daily. Few interactions were found between message category distraction vs. acceptance and participant characteristics. Conclusions Distraction and acceptance messages received similar ratings among young adults who smoke cigarettes. Message revisions may be needed to increase appeal to women, SGM, those with lower education, and those less motivated to quit. Messages will be refined and used in an ongoing micro-randomized trial to investigate their real-time impact on smoking urges and behaviors.

This short piece is a response to the comment by Anthony and colleagues on our paper on methane emissions from manure management published in this journal in 2024. It explains the motive behind publishing our paper – that we judged there was insufficient attention being paid to manure management as a source of methane emissions compared to enteric emissions, and that our field measurements were suggesting levels of emissions significantly higher than what we would expect from the calculations in the National Inventory. Our response clarifies aspects of the methodology and presents further analysis of the claim that covering a slurry storage facility will increase emissions. We reiterate our conclusion that it would be valuable to develop a stronger understanding of the potential variability of methane emissions from manure management under different geographical and environmental conditions.

The natural products actinonin and matlystatin feature an N -hydroxy-2-pentyl-succinamyl (HPS) chemophore that facilitates metal chelation and confers their metalloproteinase inhibitory activity. Actinonin is the most potent natural inhibitor of peptide deformylase (PDF) and exerts antimicrobial and herbicidal bioactivity by disrupting protein synthesis. Here, we used a genomics-led approach to identify candidate biosynthetic gene clusters (BGCs) hypothesized to produce HPS-containing natural products. We show that one of these BGCs is on the pathogenicity megaplasmid of the plant pathogen Rhodococcus fascians and produces lydiamycin A, a macrocyclic pentapeptide. The presence of genes predicted to make an HPS-like chemophore informed the structural recharacterization of lydiamycin via NMR and crystallography to show that it features a rare 2-pentyl-succinyl chemophore. We demonstrate that lydiamycin A inhibits bacterial PDF in vitro and show that a cluster-situated PDF gene confers resistance to lydiamycin A, representing an uncommon self-immunity mechanism associated with the production of a PDF inhibitor . In planta competition assays showed that lydiamycin enhances the fitness of R. fascians during plant colonization. This study highlights how a BGC can inform the structure, biochemical target, and ecological function of a natural product.

Background The diagnosis of an intellectual disability is suggested to have particularly stigmatising connotations, particularly within the criminal justice system (CJS). This paper aims to synthesise qualitative studies investigating the attitudes of CJS professionals to people with intellectual disabilities (PWID), specifically offenders with intellectual disabilities, and to appraise their methodological quality. Methods A systematic search was conducted using PsychINFO, Web of Science, MEDLINE, EMBASE, CINAHL Complete and EThOS databases. Articles were screened for inclusion by title, abstract and full text to ensure predefined inclusion criteria were met. Individual study quality was rated using the 10‐item Critical Appraisal Skills Programme (CASP) checklist, with the addition of an eleventh item to capture included studies' theoretical underpinnings and optimise the value of the quality appraisal. Thematic synthesis was then used to explore and synthesise the findings of the included studies. Results Ten papers were included in the review, spanning 766 participants. Studies included utilised mixed methods surveys ( n = 3), qualitative surveys ( n = 1), semistructured interviews ( n = 3), semistructured focus groups ( n = 1), unstructured interviews ( n = 1) and secondary analysis of previously collected research data ( n = 1). Methodological quality was broadly of a high standard; however, all included papers failed to reflect on the relationship between the researchers and participants. Five themes were identified: conflating diagnoses, perceptions of PWID as offenders, procedural issues affecting PWID, development and maintenance of perceptions, and impact of training. Conclusions This review highlights pervasive negative perceptions of offenders with intellectual disabilities within CJS staff groups. Clinician‐ and system‐level factors are considered in the development and maintenance of such attitudes and suggestions made for improving CJS staff perceptions and knowledge of offenders with intellectual disabilities.

Background Anorectal cancer excisions can result in extensive perineal defects requiring soft tissue reconstruction. Increasing use of laparoscopic and robotic techniques to avoid laparotomy has necessitated a change in the approach to flap reconstruction. As a result, reconstructions using pedicled gracilis flaps have become a primary choice in perineal reconstruction in our unit. We have evaluated outcomes following gracilis-based reconstructions (GBR) and compared them with the more established vertical rectus abdominis myocutaneous (VRAM) to determine equivalence. Methods We compiled retrospective data (patient demographics, perioperative management & post-operative complications) on patients undergoing perineal reconstructions following colorectal surgery from 2008 to 2022. Results There were a total of 102 colorectal perineal reconstructions with 36 VRAM flaps and 63 GBR. There were two flap failures reported within the VRAM group, and one reported with gracilis and PAP-based reconstructions. Long term complications included two perineal hernias in the VRAM cohort, one necessitating a re-do reconstruction with bilateral pedicled gracilis flaps 112 months later. No perineal hernias were identified in the GBR cohort. Conclusions Our unit has found the gracilis muscle flap to be a viable reconstruction option, favourable in its outcomes of perineal hernias. We report a few gracilis flap failures and favourable comparative outcomes to VRAM flap reconstruction. Level of evidence: Level III, therapeutic study.

The gut microbiome plays a vital role in physiological functions including metabolism, immune regulation, and gut-brain communication. Alterations in gut microbe makeup and function, termed microbial dysbiosis, are associated with various metabolic, inflammatory, and neurological disorders. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients often display gut microbial dysbiosis and increased intestinal barrier permeability (“leaky gut”). This “leaky gut" allows for microbial products and toxins, such as lipopolysaccharides (LPS), to enter the bloodstream, triggering systemic inflammation and immune dysregulation. ME/CFS patients exhibit altered immune responses, including production of antibodies reactive with gut microbial antigens, although the significance of these antibodies in promoting pathogenic or protective immune responses remains unclear. This chapter outlines methodologies for quantifying antibody reactivity to intestinal microbes and identifying stool-bound IgG in ME/CFS patients and healthy same household controls, to further investigate the role of anti-microbial IgG in ME/CFS pathogenesis.

This paper offers new insights into gender norms, roles, participation, relations, and benefits derived by women and men engaged in the aquaculture sector in Ogun and Delta States in Nigeria. Data were collected using mixed methods, including structured surveys of 410 farmers, 175 market actors, and 53 input suppliers, 116 semi-structured key informant interviews, and 11 focus group discussions (FGDs). Overall results of the study revealed the linkages within the aquaculture value chain, which was highly gendered, with men dominating all the three main stages of the value chain as indicated by Duncan’s index of dissimilarity of 17.35%. Results also revealed a gender difference in the value of assets, ownership, and wage rate among men and women participants in paid labor in the input supply and fish trading segments. Men tended to realize more profits than women, indicating an imbalance in the distribution of benefits by gender along the aquaculture value chain. Results revealed that the participation of women in decision-making was relatively high, attributable to their involvement in aquaculture value chain activities. The findings highlight the need for governments, development agencies, and non-governmental organizations to address gender disparities in policies designed to improve the imbalance in the distribution of benefits between women and men.

Background The integration of artificial intelligence (AI) in radiology has the potential to improve diagnostic accuracy and efficiency. Medical students and junior doctors will likely use AI more frequently in the future, making their perceptions essential for identifying educational gaps. Purpose To explore the perceptions of UK medical students and junior doctors regarding AI in radiology. Material and Methods A cross-sectional survey was distributed across UK medical schools and foundation programs. A total of 250 responses were analyzed using descriptive statistics and non-parametric tests, focusing on career impact, clinical effectiveness, educational development, and ethical concerns. Results Most respondents (55.2%) were undeterred by career uncertainties related to AI, with 64% confident that AI would not replace radiologists. Up to 80.6% supported AI's clinical benefits, and 63.2% endorsed its educational integration. However, there were concerns about job displacement and insufficient AI training. Medical students were more worried about job security than junior doctors, while those committed to radiology were less apprehensive and viewed AI as complementary. Conclusion Educational programs and regulatory frameworks are essential to facilitate AI integration in radiology. Addressing concerns about job displacement and improving AI education will be key to preparing future radiologists for technological advancements.

The Southern Ocean is an important CO 2 sink, mitigating climate change, but its future evolution is uncertain due to the confounding effects of stratospheric ozone recovery and climate change on ocean circulation. Using an Earth System Model, we quantify the relative influence of ozone-depleting substances and greenhouse gas emissions on this sink from 1950 to 2100. Ozone effects dominated changes in ocean circulation during 1950–2000, but not this century, implying that past trends cannot serve as proxies for future changes. Despite substantial future circulation changes induced by climate change, their effect on the CO 2 sink decreases over the 21st century because of compensating factors. Thus, the Southern Ocean is unlikely to be a major future source of amplifying carbon-climate feedbacks this century.

Background Public involvement is crucial to ensure research is relevant and addresses the needs of its target population. However, care home residents, a potentially vulnerable group, are often excluded from research that could directly benefit them. This systematic review examined the existing literature on public involvement approaches in research involving older adults residing in long-term care homes. Methods A systematic search of CINAHL, MEDLINE and PsychINFO was conducted, using search terms related to public involvement and long-term care. The search was limited to English language papers published from 2014, building on a 2016 review conducted by Backhouse et al. Articles were screened by title and abstract, and full texts of potentially eligible papers were reviewed for inclusion. Data from included studies was extracted and synthesised using a narrative approach. Results This review identified 15,809 citations, abstract-screened 4000, and ultimately included six articles after applying eligibility criteria and a rigorous screening process. Reported public involvement in this setting was limited, with even fewer studies demonstrating genuine collaboration and the full involvement of residents throughout the research process. There was a lack of representation of residents with advanced cognitive decline or dementia. Terminology used to describe public involvement varied considerably across studies, highlighting a lack of clarity in defining and reporting activities. Conclusions This review highlights the need for greater emphasis on public involvement in care home research, particularly for residents with cognitive impairments. Future research should prioritise transparent reporting of public involvement processes, involving residents as active partners from the outset, and ensuring research findings are effectively communicated for all stakeholders, including residents. Barriers and facilitators to public involvement activities in care homes are summarised.

We present the first observations of ocean turbulent mixing rate in front of the Dotson Ice Shelf, where meltwater‐enriched water leaves the cavity. The observations showed elevated turbulent kinetic energy dissipation rates (ε $\varepsilon$; ∼10⁻⁷ W kg⁻¹) and turbulent diapycnal diffusivities (κ $\kappa$; ∼10⁻² m² s⁻¹) near the seabed and in middepth layers, which are three orders of magnitude above background values away from the outflow. Elevated diapycnal fluxes of heat and salt were observed in regions of high mixing, moving vertically on average O ∼ 10 W m⁻² and O ∼ 10⁻⁶ kg m⁻² s⁻¹, respectively, toward shallow depths. At middepth layers, the overturning instabilities are characterized by shear‐driven symmetric and centrifugal instabilities. Our observations provide an understanding of mixing in front of fast‐melting ice shelves and are key to developing better parameterizations and representations of mixing in climate models.

The Mediterranean diet is associated with reduced mortality and cognitive decline, largely due to its polyphenol content. However, Western populations often do not meet recommended fruit and vegetable intakes. Polyphenols...

Betaine-30 is well-established as a standard dye for solvatochromism and has long been studied by ultrafast spectroscopy. Electronic excitation leads to rapid intramolecular electron transfer, while the decay of the resulting state corresponds to back electron transfer to the electronic ground state. Thus, Betaine-30’s photophysics offers a route to probing the role that vibrational excitation and solvent dynamics play in electron transfer reaction rates. Here, we probe the excited state dynamics of Betaine-30 in two solvents (ethanol and acetonitrile) by means of two-dimensional electronic spectroscopy. Population dynamics in ethanol are measured at two pump wavelengths, and global analysis reveals a wavelength dependence of the electron transfer rate. This is assigned to excitation of distinct ground state conformers, which is confirmed by quantum chemical calculations. “Beatmaps” of coherently excited vibrations are recovered and analyzed in terms of the contribution of Raman active modes in ground and excited states. The contribution of modes in the excited state is a strong function of the rate of the electron transfer reaction.

Indene (C9H8) is the only polycyclic pure hydrocarbon identified in the interstellar medium to date, with an observed abundance orders of magnitude higher than predicted by astrochemical models. The dissociation and radiative stabilization of vibrationally hot indene cations are investigated by measuring the time-dependent neutral particle emission rate from ions in a cryogenic ion-beam storage ring for up to 100 ms. Time-resolved measurements of the kinetic energy released upon hydrogen atom loss from C9H8+, analyzed in view of a model of tunneling through a potential energy barrier, provide the dissociation rate coefficient. Master equation simulations of the dissociation in competition with vibrational and electronic radiative cooling reproduce the measured dissociation rate. We find that radiative stabilization arrests one of the main C9H8 destruction channels included in astrochemical models, helping to rationalize its high observed abundance.

Reforms to the means tests in England for state-financed long-term care were planned for implementation in 2025. They included a lifetime limit (cap) on how much an individual must contribute to their care, with the state meeting subsequent care costs. We present projections of the costs and distributional impacts of these reforms for older people, using two linked simulation models which draw on a wide range of data. We project that by 2038 public spending on long-term care for older people in England would be about 14% higher than without the reforms. While the main direct beneficiaries of the lifetime cap would have been the better off who currently receive no state help with their care costs, the reforms also treated capital assets more generously than the current system, helping people with more modest incomes and wealth. When analysing the impacts of the reforms it is therefore important to consider the whole reform package. Our results depend on a range of assumptions, and the impacts of the reforms would be sensitive to the levels of the cap and other reformed parameters of the means test on implementation.

Background Age-associated changes to the intestinal microbiome may be linked to inflammageing and the development of age-related chronic diseases. Cynomolgus macaques, a common animal model in biomedical research, have strong genetic physiological similarities to humans and may serve as beneficial models for the effect of age on the human microbiome. However, age-associated changes to their intestinal microbiome have previously only been investigated in faecal samples. Here, we have characterised and investigated the effects of age in the cynomolgus macaque intestinal tract in luminal samples from both the small and large intestine. Results Whole metagenomic shotgun sequencing was used to analyse the microbial communities in intestinal content obtained from six different intestinal regions, covering the duodenum to distal colon, of 24 healthy, captive-bred cynomolgus macaques, ranging in age from 4 to 20 years. Both reference-based and assembly-based computational profiling approaches were used to analyse changes to intestinal microbiota composition and metabolic potential associated with intestinal biogeography and age. Reference-based computational profiling revealed a significant and progressive increase in both species richness and evenness along the intestinal tract. The microbial community composition also significantly differed between the small intestine, caecum, and colon. Notably, no significant changes in the taxonomic abundance of individual taxa with age were found except when sex was included as a covariate. Additionally, using an assembly-based computational profiling approach, 156 putative novel bacterial and archaeal species were identified. Conclusions We observed limited effects of age on the composition of the luminal microbiota in the profiled regions of the intestinal tract except when sex was included as a covariate. The enteric microbial communities of the small and the large intestine were, however, distinct, highlighting the limitations of frequently used faecal microbial profiling as a proxy for the intestinal microbiota. The identification of a number of putative novel microbial taxa contributes to knowledge of the full diversity of the cynomolgus macaque intestinal microbiome.

Recurrent events for many clinical conditions, such as asthma, can indicate poor health outcomes. Recurrent events data are often analysed using statistical methods such as Cox regression or negative binomial regression, suffering event or time information loss. This article re-analyses the preventing and lessening exacerbations of asthma in school-age children associated with a new term (PLEASANT) trial data as a case study, investigating the utility, extending recurrent events survival analysis methods to cluster randomised trials. A conditional frailty model is used, with the frailty term at the general practitioner practice level, accounting for clustering. A rare events bias adjustment is applied if few participants had recurrent events and truncation of small event risk sets is explored, to improve model accuracy. Global and event-specific estimates are presented, alongside a mean cumulative function plot to aid interpretation. The conditional frailty model global results are similar to PLEASANT results, but with greater precision (include time, recurrent events, within-participant dependence, and rare events adjustment). Event-specific results suggest an increasing risk reduction in medical appointments for the intervention group, in September–December 2013, as medical contacts increase over time. The conditional frailty model is recommended when recurrent events are a study outcome for clinical trials, including cluster randomised trials, to help explain changes in event risk over time, assisting clinical interpretation.