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Living organisms are constructed from proteins that assemble into biomolecular complexes, each with a unique shape and function. Our knowledge about the structure–activity relationship of these complexes is still limited, mainly because of their small size, complex structure, fast processes, and changing environment. Furthermore, the constraints of current microscopic tools and the difficulty in applying molecular dynamic simulations to capture the dynamic response of biomolecular complexes and long-term phenomena call for new supplementary tools and approaches that can help bridge this gap. In this paper, we present an approach to comparing biomolecular and origami hierarchical structures and apply it to comparing bacterial microcompartments (BMCs) with spiral-based origami models. Our first analysis compares proteins that assemble the BMC with an origami model called “flasher”, which is the unit cell of an assembled origami model. Then, the BMC structure is compared with the assembled origami model and based on the similarity, a physical scaled-up origami model, which is analogous to the BMC, is constructed. The origami model is translated into a computer-aided design model and manufactured via 3D-printing technology. Finite element analysis and physical experiments of the origami model and 3D-printed parts reveal trends in the mechanical response of the icosahedron, which is constructed from tiled-chiral elements. The chiral elements rotate as the icosahedron expands and we deduce that it allows the BMC to open gates for transmembrane passage of materials.

Background Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting UK general practices. Participants Children aged 1–12 years with acute uncomplicated lower respiratory tract infections. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child’s cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when ‘necessary’, and clinicians noted a reduction in parents’ expectations for antibiotics. Limitations The study was underpowered to detect small benefits in key subgroups. Conclusion Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child’s illness and safety-netting. Future work The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information. Plain language summary Background Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. Methods A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection’s duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an ‘observational study’). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. Results After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child’s symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when ‘necessary’. Clinicians noted a reduction in parents’ expectations for antibiotics. Conclusion Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned. Scientific summary Background Antimicrobial resistance (AMR) is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infection, but there is little randomised evidence of the effectiveness of antibiotics for treating these, either overall or among key clinical subgroups. Objective The objective was to undertake a trial of antibiotics for children presenting with lower respiratory tract infection in primary care, with a parallel observational study. Aims The aims were to: 1.estimate the effectiveness of amoxicillin overall and in key clinical subgroups of children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 2.estimate the cost-effectiveness of antibiotics overall in children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 3.explore the estimates of effectiveness according to key pathophysiological subgroups (the presence of bacterial pathogens) 4.explore which variables predict poor prognosis and develop a prediction model for poor prognosis 5.explore the views of parents and clinicians regarding management of children and participation in the trial. Design This was a placebo-controlled trial with qualitative research and health economic analysis, and a parallel observational cohort. Setting UK general practices. Participants Participants were children aged between 6 months and 12 years presenting to primary care with an acute lower respiratory tract infection, defined as one in which an acute cough is the predominant symptom and judged by the general practitioner (GP) to be infective in origin, lasting < 21 days, and with other symptoms or signs localising to the lower respiratory tract (shortness of breath, sputum, pain), and in whom pneumonia was not suspected clinically. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). The secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; progression of illness sufficient to require hospital assessment; side effects; and resource use. Ethics The protocol was approved by the South West – Central Bristol Research Ethics Committee (reference 15/SW/0300). Methods Children were randomised to receive 50 mg/kg/day oral amoxicillin in divided doses for 7 days, or placebo, using pre-prepared packs randomised by an independent statistician using computer-generated random numbers. Children whom clinicians were unwilling to randomise or parents who were unwilling for their child to be randomised were invited to participate in an observational study in which the same data as in the trial were collected. The revised target sample size (agreed with the Trial Steering Committee, the Data Monitoring and Ethics Committee and the funder) to detect an important clinical difference of 3 days in symptoms duration was 298 participants for 80% power and 398 participants for 90% power. Semistructured interviews were used to explore the views of management and the decisions to participate in the trial. Parents were purposefully sampled by whether they took part in the trial or the observational study, and by practice. Clinicians who recruited participants into the study were also invited to take part in a telephone interview. The interviews were analysed using thematic analysis. Throat swabs were analysed for the presence of bacteria and viruses by multiplex polymerase chain reaction. Statistical analysis Cox regression was used for the primary outcome and for total symptom duration, adjusting for age, baseline symptom severity, prior duration of illness and comorbidity. Linear regression was used for symptom severity, and logistic regression was used for reconsultation, progression of illness and side effects, adjusting for the same baseline covariates as in the primary analysis. Analysis was by intention to treat, as randomised regardless of non-adherence or protocol deviations. Multiple imputation was used as the primary analysis, comprising all variables from the analysis model and any predictors of missingness, and using 100 imputations. Prespecified subgroup analyses were carried out on chest signs, sputum/rattly chest, history of fever, physician rating of unwell, shortness of breath, oxygen saturation below 95%, and STARWAVe clinical prediction rule for hospitalisation. For the observational data set, stratification by propensity scores was used to control for confounding by indication, and the data were merged with the trial data set to facilitate more powerful analyses. A logistic regression model was built to predict the progression of illness, and discrimination was assessed using estimates of area under the receiver operator curve that were bootstrapped for internal validation. Health economic analysis Both cost-effectiveness (in GBP per unit of primary outcome) and cost per quality-adjusted life-year (QALY) were estimated. The base case took an NHS perspective, but some non-NHS costs were also included (remedies and time off work). Resource use data were collected by a notes review in primary care supplemented by the diary. Unit costs of primary care consultation, community services, outpatient visits and accident and emergency attendances were costed based on the Personal Social Services Research Unit. National reference costs were used to cost hospital stay based on corresponding diagnostic categories. Medications were priced based on the British National Formulary. All costs were based on 2019 prices. QALYs were based on the EQ-5D-Y (EuroQol-5 Dimensions Youth), collected weekly, and on the recommended national tariff. Trial results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The duration of moderately bad symptoms was similar in the two groups [median 5 vs. 6 days, respectively; hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.90 to 1.42]. Return with new or worsening symptoms (29.7% vs. 38.2%; risk ratio 0.80, 95% CI 0.58 to 1.05), progression of illness requiring hospital assessment (2.4% vs 2.0%) and side effects (38% vs. 34%) were also similar in the two groups. A small difference in mean symptom severity on days 2–4 (1.8 vs. 2.1 points; difference 0.28 points, 95% CI 0.04 to 0.51) is unlikely to be clinically meaningful. No differences were seen for the primary outcome in the five prespecified clinical subgroups in which antibiotic prescribing is common: chest signs subgroup (antibiotics 6 days vs. placebo 6 days; HR 0.97, 95% CI 0.65 to 1.43), sputum/rattly chest (5 vs. 7 days; 1.16, 95% CI 0.83 to 1.64), fever (5 vs. 6 days; 1.23, 95% CI 0.88 to 1.73), physician rating of unwell (5 vs. 6 days; 1.25, 95% CI 0.85 to 1.83) and shortness of breath (5 vs. 6 days; 1.13, 95% CI 0.72 to 1.77). There was also no evidence that the presence of bacteria in the throat swab mediated antibiotic effectiveness. Estimates from complete cases (n = 317) were very similar, as were estimates from a per-protocol analysis for children taking 11 or more of the of 15 doses in the first 5 days. NHS costs per child were slightly higher with antibiotics (antibiotic, £29; placebo, £26) and non-NHS costs were the same (antibiotics, £33; placebo, £33), but QALY data were too incomplete for robust imputation. The incremental cost per QALY (incremental cost-effectiveness ratio) was £30,851 (95% CI –£73,639 to £109,429) based on estimates from the means of complete cases and £6417 (95% CI –£12,240 to £20,535) based on the estimates using imputed data. Observational study A total of 326 children were recruited to the observational study. The estimate of benefit of antibiotics for the primary outcome was similar to that in the trial (HR 1.16, 95% CI 0.95 to 1.41). A prognostic model to predict the progression of illness consisting of seven variables (baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.85) and calibration, and a three-item model (respiratory rate, oxygen saturation, sputum/rattly chest) also performed well (area under the receiver operator curve 0.81). Qualitative results Thirty semistructured telephone interviews were conducted with 16 parents and 14 clinicians. Parents found it difficult to interpret the symptoms and signs, and commonly used the sounds of the cough to judge severity, which highlights the need to provide better information to support parents. Many parents said that the main reason for consulting was to receive a clinical examination and reassurance regarding illness severity. Parents acknowledged that antibiotics should be used only when ‘necessary’, and many of the clinicians also noted a shift in parents’ expectations about antibiotics and that they were satisfied with a clinical assessment, reassurance and advice. Decisions to take part in the trial were influenced by the perceived risks associated with taking a placebo compared with immediate antibiotics, and with taking antibiotics unnecessarily. Clear communication about the self-management of their child’s illness and ‘safety-netting’ (information on the natural course of the illness and advice about when it might be necessary to reconsult) were identified as important when implementing ‘no antibiotic’ prescribing strategies to reassure parents and to support prescribing decisions. Limitations The study was underpowered to detect small benefits in the key clinical subgroups. The trial included children who were more unwell than those in recent large generalisable cohorts, which suggests that, if anything, the benefit of antibiotics has been overestimated. Given the very large numbers of missing data, the imputed estimates in the economic analysis must be viewed with caution. If the costs of AMR were included, then these estimates of cost-effectiveness would worsen. Conclusions Implications for clinical care Amoxicillin for uncomplicated chest infections in children makes little difference to symptom burden or to health or societal costs. Better access to information is needed to support parents’ decision-making, as is clear clinician communication about the self-management of their child’s illness and safety-netting. A prognostic score using variables that can be collected very easily during consultations can be used to identify children who are at low risk of illness progression. Implications for future research •The data can be incorporated in a Cochrane review and an individual patient data meta-analysis. •Further work on the incremental QALY gain from antibiotics is needed, assessing a range of models and their implications when imputing missing QALY data, and better evidence is needed about how to incorporate AMR resource implications in modelling. •The prognostic score should be externally validated and could be developed as an app with automated outputs, and thereafter used as a tool to reduce antibiotic prescribing for antimicrobial stewardship interventions. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Perceptions of program safety for youth might include such features as physical safety, psychological safety, and social-relational safety. A holistic sense of safety, or one that inclusively encompasses and integrates features of, and relations with, the ecology in which youth develop, could be engendered through programmatic designs that attend to the dynamic relations among physical, psychological, and social-relational safety. Having a better understanding of the phenomenology of safety among program participants, and how such perceptions function in youth programs would enable positive youth development (PYD) program practitioners to better align their conceptions -- that is, their "objective" definitions -- of program safety with the phenomenological experiences of youth and, in so doing, better promote PYD and thriving outcomes. The present study was informed by preliminary quantitative findings emerging from the broader Compassion International (CI) Study of PYD (Lerner et al., 2019; Tirrell et al., 2021; Tirrell, Gansert, et al., 2019; Tirrell, Geldhof, et al., 2019). As described in this article, youth who engaged in CI-supported programs in El Salvador reported feeling safe at the CI programs, but also reported feeling generally unsafe, and worrying about their safety, in the broader contexts of their lives.

Work-integrated learning (WIL), as an educational approach, is facilitated through relationships between Higher Education Institutions (HEIs) and external 'host' organizations. Responsible host organizations should recognize that students undertaking WIL come from a range of different cultures, socio-economic backgrounds, and have varying academic, physical, and other capabilities. An inclusive workplace will seek to facilitate a positive and rewarding experience for all WIL students. Recent WIL literature has seen a strong focus on inclusive access to WIL. This article examines key elements that can contribute to host organizations providing an inclusive environment for students. Socio-cultural theories related to learning in the workplace are used as a theoretical lens. An Inclusive WIL Workplace Framework is proposed, highlighting principles, practices, and supervisor and co-worker characteristics, that can be utilized by workplaces to assess their inclusivity and address any gaps, and by students to understand the expectations of HEIs on host organizations.

Providing behavioural support to all students is increasingly recognised as an integral part of teaching and learning in schools throughout the world. This small-scale, qualitative study reports on the perceived challenges faced by staff in implementing school-wide behavioural support at two remote Indigenous primary schools in Queensland, Australia. Individual semi-structured interviews held with two administrators and six teachers revealed implementation barriers to be clustered around four themes: staff turnover and leadership change; staff training; consistency in teaching and responding to student behaviour; and involvement of parents and remote community. These initial findings highlight the need to extend investigations into barriers associated with implementing and sustaining this behavioural approach in other remote schools throughout Australia, as student behaviour influences student learning, and lifting educational outcomes for Indigenous students is a national priority.

Previous studies report that exposure to the Maori language on a regular basis allows New Zealand adults who cannot speak Maori to build a proto-lexicon of Maori -- an implicit memory of word forms without detailed knowledge of meaning. How might this knowledge feed into explicit language learning? Is it possible to "awaken" the proto-lexicon in the context of overt language learning? We investigate whether implicit linguistic knowledge represented in a proto-lexicon gives any advantages for intentional language learning in a tertiary educational environment. We conducted a three-task experiment which: (a) assessed participants' Maori proto-lexicon; (b) assessed their phonotactic knowledge; and (c) tested them on Maori vocabulary that they had been exposed to during the course at two time points. The results show that students with larger Maori proto-lexicons learn more words in a classroom setting. This study shows that proto-lexicon acquired from ambient exposure can lead to significant benefits in language learning.

This longitudinal study used regression path models to predict the influence on students' reading comprehension ability of three self-perception variables (reading self-concept; reading/English effort; academic self-handicapping); three teacher rating behaviour variables (attentive behaviour; sociable behaviour; and settled behaviour) and past reading comprehension. As part of the study, a 12-item reading/English effort scale was developed, and its psychometrics characteristics reported (N = 254) The participants were Australian primary school students, followed from Years 3 and 4 to Years 5 and 6 (n = 127). The first path model identified that attending behaviours, low levels of self-handicapping, and reading self-concept were the main predictors of reading achievement. Reading achievement was reassessed two years on, with this path model including past reading attainment. In this model past reading achievement and self-handicapping predicted reading achievement. This research reiterates: the relevance of social-emotional and cognitive variables in education; the need to teach reading across the school years; and the need to enhance students' sense of control and certainty over their learning.

This paper responds directly to the question, how do we communicate our philosophy of art education? It does this by drawing upon previous research with "House of Imagination, School Without Walls" and doctoral research exploring children's learning identity as artists, to illuminate a philosophical approach to art education and its pedagogy that highlights both human and more-than-human dimensions of learning in communities of practice involving artists, researchers and educators working alongside children and young people where spaces of possibility for practice and innovation emerge. The paper focuses particularly on current and creative research in the "Forest of Imagination," a long-term participatory contemporary arts and architecture event in Bath, UK. "Forest of Imagination" offers an alternative, creative approach to learning, focusing on ecological imagination and nature connection. As a new aesthetic imaginary, the Forest of Imagination is a living, breathing art classroom, inspiring curiosity, imagination and a deeper connection with the natural world.

Abstract: Recent findings show adult New Zealanders who do not speak te reo Māori (the Māori language, the indigenous language of New Zealand) nonetheless have impressive implicit lexical and phonotactic knowledge of the language. These findings have been interpreted as showing that regular ambient exposure to a non-native language develops an implicit “proto-lexicon”, a memory store of lexical forms in that language, without any meaning. However, what is not known is the timeframe over which this knowledge is acquired. Does the knowledge stem exclusively from implicit learning during childhood, or does it continue to grow based on exposure during adulthood? To investigate this question, we directly compare non-Māori-speaking school-aged adolescents and adults in New Zealand and explore how age affects the degree of observed knowledge. Our results show that ambient exposure leads to implicit knowledge both in childhood and adulthood, and that continuing exposure throughout the lifespan leads to increased knowledge.

Background and purpose — Congenital pseudarthrosis of the tibia (CPT) is caused by local periosteal disease that can lead to bowing, fracturing, and pseudarthrosis. Current most successful treatment methods are segmental bone transport and vascularized and non-vascularized bone grafting. These methods are commonly hampered by discomfort, reoperations, and long-term complications. We report a combination of a vascularized fibula graft and large bone segment allograft, to improve patient comfort with similar outcomes. Patients and methods — 7 limbs that were operated on in 6 patients between November 2007 and July 2018 with resection of the CPT and reconstruction with a vascularized fibula graft in combination with a bone allograft were retrospectively studied. The mean follow-up time was 5.4 years (0.9–9.6). Postoperative endpoints: time to discharge, time to unrestricted weight bearing, complications within 30 days, consolidation, number of fractures, and secondary deformities. Results — The average time to unrestricted weight bearing with removable orthosis was 3.5 months (1.2–7.8). All proximal anastomoses consolidated within 10 months (2–10). 4 of the 7 grafts fractured at the distal anastomosis between 6 and 14 months postoperatively. After reoperation, consolidation of the distal anastomosis was seen after 2.8 months (2–4). 1 patient required a below-knee amputation. Interpretation — This case series showed favorable results of the treatment of CPT through a combination of a vascularized fibula graft and large bone segment allograft, avoiding the higher reintervention rate and discomfort with ring frame bone transport, and the prolonged non-weight bearing with vascularized fibula transfer without reinforcement with a massive large bone segment allograft.

We report the findings of a multi-language and multi-lab investigation of young infants' ability to discriminate lexical tones as a function of their native language, age and language experience, as well as of tone properties. Given the high prevalence of lexical tones across human languages, understanding lexical tone acquisition is fundamental for comprehensive theories of language learning. While there are some similarities between the developmental course of lexical tone perception and that of vowels and consonants, findings for lexical tones tend to vary greatly across different laboratories. To reconcile these differences and to assess the developmental trajectory of native and non-native perception of tone contrasts, this study employed a single experimental paradigm with the same two pairs of Cantonese tone contrasts (perceptually similar vs. distinct) across 13 laboratories in Asia-Pacific, Europe and North-America testing 5-, 10- and 17-month-old monolingual (tone, pitch-accent, non-tone) and bilingual (tone/non-tone, non-tone/non-tone) infants. Across the age range and language backgrounds, infants who were not exposed to Cantonese showed robust discrimination of the two non-native lexical tone contrasts. Contrary to this overall finding, the statistical model assessing native discrimination by Cantonese-learning infants failed to yield significant effects. These findings indicate that lexical tone sensitivity is maintained from 5 to 17 months in infants acquiring tone and non-tone languages, challenging the generalisability of the existing theoretical accounts of perceptual narrowing in the first months of life.

Protein folding and structural biology are highly active disciplines that combine basic research in various fields, including biology, chemistry, physics, and computer science, with practical applications in biomedicine and nanotechnology. However, there are still gaps in the understanding of the detailed mechanisms of protein folding, and protein structure-function relations. In an effort to bridge these gaps, this paper studies the equivalence of proteins and origami. Research on proteins and origami provides strong evidence to support the use of origami folding principles and mechanical models to explain aspects of proteins formation and function. Although not identical, the equivalence of origami and proteins emerges in: (i) the folding processes, (ii) the shape and structure of proteins and origami models, and (iii) the intrinsic mechanical properties of the folded structures/models, which allows them to synchronically fold/unfold and effectively distribute forces to the whole structure. As a result, origami can contribute to the understanding of various key protein-related mechanisms and support the design of de novo proteins and nanomaterials.

Both the California Digital Library (CDL) and Michigan Publishing are migrating their journal publishing programs away from aging open source systems to the relatively new Janeway platform, also open source and developed by a team at the Open Library of Humanities. What does Janeway offer that has prompted this move? How might these migrations align with broader efforts to develop sustainable models for academy-owned OA publishing programs? How can library publishers, operating in a space dominated by the large commercial publishers and the platforms they own, help ensure that academy-owned, open infrastructure like Janeway is sustainable in the long term?In this session, CDL and Michigan will discuss their distinct approaches to platform migration, Janeway’s capabilities as a platform for both journals and preprints, and how all three of these organizations are committed to long-term sustainability and collaboration with each other. The Janeway team will also offer thoughts on how development of the platform is driven by its community of users and how they are approaching both financial and technical sustainability as staff of an academic institution.

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo. METHODS: CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau. RESULTS: Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42. CONCLUSIONS: Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aβ accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.

Odontocetes obtain nutrients including essential elements through their diet and are exposed to heavy metal contaminants via ingestion of contaminated prey. We evaluated the prevalence, concentration, and tissue distribution of essential and non-essential trace elements, including heavy metal toxicants, in tissue (blubber, kidney, liver, skeletal muscle, skin) and fecal samples collected from 90 odontocetes, representing nine species, that stranded in Georgia and Florida, USA during 2007-2021. Samples were analyzed for concentrations of seven essential (cobalt, copper, iron, manganese, molybdenum, selenium, zinc) and five non-essential (arsenic, cadmium, lead, mercury, thallium) elemental analytes using inductively-coupled plasma mass spectrometry. Rissos dolphins (Grampus griseus) and short-finned pilot whales (Globicephala macrorhynchus) had the highest median concentrations of mercury, cadmium, and lead, while dwarf sperm whales (Kogia sima) had the lowest. Adult pygmy and dwarf sperm whales that stranded in 2019-2021 had higher concentrations of arsenic, copper, iron, lead, manganese, selenium, thallium, and zinc compared to those that stranded in 2010-2018, suggesting an increasing risk of exposure over time. The highest concentrations of many elements (e.g., cadmium, cobalt, copper, manganese, molybdenum, thallium, zinc) were in fecal samples, illustrating the usefulness of this noninvasively collected sample. Aside from fecal samples, hepatic tissues had the highest concentrations of iron, manganese, mercury, molybdenum, and selenium in most species; renal tissues had the highest concentrations of cadmium; skin had the highest concentrations of zinc; and copper, arsenic, and lead concentrations were primarily distributed among the liver and kidneys. Phylogenetic differences in patterns of trace element concentrations likely reflect species-specific differences in diet, trophic level, and feeding strategies, while heterogeneous distributions of elemental analytes among different organ types reflect differences in elemental biotransformation, elimination, and storage. This study illustrates the importance of monitoring toxic contaminants in stranded odontocetes, which serve as important sentinels of environmental contamination, and whose health may be linked to human health.

Giant viruses (Nucleocytoviricota) are significant lethality agents of various eukaryotic hosts. Although metagenomics indicates their ubiquitous distribution, available giant virus isolates are restricted to a very small number of protist and algal hosts. Here we report on the first viral isolate that replicates in the amoeboflagellate Naegleria. This genus comprises the notorious human pathogen Naegleria fowleri, the causative agent of the rare but fatal primary amoebic meningoencephalitis. We have elucidated the structure and infection cycle of this giant virus, Catovirus naegleriensis (a.k.a. Naegleriavirus, NiV), and show its unique adaptations to its Naegleria host using fluorescence in situ hybridization, electron microscopy, genomics, and proteomics. Naegleriavirus is only the fourth isolate of the highly diverse subfamily Klosneuvirinae, and like its relatives the NiV genome contains a large number of translation genes, but lacks transfer RNAs (tRNAs). NiV has acquired genes from its Naegleria host, which code for heat shock proteins and apoptosis inhibiting factors, presumably for host interactions. Notably, NiV infection was lethal to all Naegleria species tested, including the human pathogen N. fowleri. This study expands our experimental framework for investigating giant viruses and may help to better understand the basic biology of the human pathogen N. fowleri.

Abstract: Previous studies report that exposure to the Māori language on a regular basis allows New Zealand adults who cannot speak Māori to build a proto‐lexicon of Māori—an implicit memory of word forms without detailed knowledge of meaning. How might this knowledge feed into explicit language learning? Is it possible to “awaken” the proto‐lexicon in the context of overt language learning? We investigate whether implicit linguistic knowledge represented in a proto‐lexicon gives any advantages for intentional language learning in a tertiary educational environment. We conducted a three‐task experiment which: (a) assessed participants’ Māori proto‐lexicon, (b) assessed their phonotactic knowledge, and (c) tested them on Māori vocabulary that they had been exposed to during the course at two time points. The results show that students with larger Māori proto‐lexicons learn more words in a classroom setting. This study shows that proto‐lexicon acquired from ambient exposure can lead to significant benefits in language learning.

Abstract: Previous research has shown that non-Māori Speaking New Zealanders have extensive latent knowledge of Māori, despite not being able to speak it. This knowledge plausibly derives from a memory store of Māori forms (Oh et al., 2020; Panther et al., 2023). Modelling suggests that this ‘proto-lexicon’ includes not only Māori words, but also word-parts; however, this suggestion has not yet been tested experimentally. We present the results of a new experiment in which non-Māori speaking New Zealanders and non-New Zealanders were asked to segment a range of Māori words into parts. We show that the degree to which segmentations of non-Māori speakers correlate to the segmentations of two fluent speakers of Māori is stronger among New Zealanders than non-New Zealanders. This research adds to the growing evidence that even in a largely ‘monolingual’ population, there is evidence of latent bilingualism through long-term exposure to a second language.