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Background Children’s ability to regulate their emotions is a critical protective factor for early mental health and development and is strongly influenced by parenting. Parenting programs can improve these outcomes for children, however, most families, particularly those from diverse or disadvantaged backgrounds, never receive evidence-based support. There is a pressing need for parenting programs that are widely accessible and meaningfully tailored to individual needs and real-time parenting challenges to enhance parent engagement. This protocol outlines the design of two staged trials testing Daily Growth, a universal parenting app for parents/carers of children 2–5 years. The first trial will evaluate the app’s effectiveness as implemented in a real-world community-based trial, while the second will develop and test a machine learning system for personalising support based on Trial 1 data. Methods In Trial 1, parents/carers ( n  = 1,650) will be recruited and randomised to one of five groups: 150 to active control (government parenting website); 100 each to one of three programs (Emotion Coaching, Active Play, or Wayapa Wuurrk); 1,200 to a non-personalised random combination of all three. Trial 2 (non-randomised) will recruit 400 parents/carers to receive personalised support, with program content from the three programs allocated via a machine learning algorithm based on baseline data. Both trials will run for six weeks where participants will receive twice-daily prompts to complete a 1-min pre-ecological momentary intervention (pre-EMI) survey and non-control participants offered three-minute videos tailored to specific parenting challenges. A post-EMI survey will be delivered 15 min later to assess immediate outcomes. Participants in both trials will complete baseline, six-week, and six-month follow-up surveys. Outcomes from the non-personalised trial will be compared to the fully personalised app and control/single program groups via EMI and post/follow-up on parenting and parent/child emotion regulation. Discussion This study introduces a novel digital program combining co-designed parenting content, real-time delivery, tailoring to ensure practical relevance, and algorithm-driven personalisation. By testing standardised and personalised app versions, it will evaluate whether real-time personalised parenting support improves parent/child emotion regulation, engagement, and program acceptability. Findings will inform future approaches to scalable, inclusive, and responsive parenting support in early childhood. Trial registration This trial is registered with ANZCTR, registration number ACTRN12624000937516; ACTRN12624001023549, and includes all items from the WHO Trial Registration Data Set.

Climate-smart and sustainable crops are needed for the future. Engineering crops for tolerance of both abiotic and biotic stress is one approach. The accumulation of trehalose, controlled through trehalose-6-phosphate synthase (TPS) or OtsA and trehalose-6-phosphate phosphatase (TPP) or OtsB genes in microbes, is known to provide protection for many microbial and fungal species against abiotic stress. The effect of trehalose accumulation in plant species is less understood. Here, we studied the heterologous expression of Escherichia coli OtsB in potato (Solanum tuberosum var. ‘Desiree’) with regards to stress tolerance. The performance of transgenic lines was assessed in both growth chambers and greenhouse mesocosms. Overexpressing potato OtsB lines significantly increased resilience to heat, photoperiod, herbivory, and competition when compared with wildtype plants. Most strikingly, when subjected to high temperatures, transgenic lines exhibited a significantly lower reduction in tuber yield ranging from 40% to 77%, while wildtype plants experienced a 95% decrease in tuber yield. When exposed to competitors in a selected StSP3D::OtsB line, tuber yield was 1.6 times higher than wildtype. Furthermore, transgenic lines performed significantly better under low-nutrient regimes: under competition, yield increased by 1.5-fold. Together, these results demonstrate that increased trehalose has the potential to create more resistant and stable crop plants.

IntroductionParents shape child emotional competence and mental health via their beliefs about children’s emotions, emotion-related parenting, the emotional climate of the family and by modelling emotion regulation skills. However, much of the research evidence to date has been based on small samples with mothers of primary school-aged children. Further research is needed to elucidate the direction and timing of associations for mothers and fathers/partners across different stages of child development. The Child and Parent Emotion Study (CAPES) aims to examine longitudinal associations between parent emotion socialisation, child emotion regulation and socioemotional adjustment at four time points from pregnancy to age 12 years. CAPES will investigate the moderating role of parent gender, child temperament and gender, and family background.Methods and analysisCAPES recruited 2063 current parents from six English-speaking countries of a child 0–9 years and 273 prospective parents (ie, women/their partners pregnant with their first child) in 2018–2019. Participants will complete a 20–30 min online survey at four time points 12 months apart, to be completed in December 2022. Measures include validated parent-report tools assessing parent emotion socialisation (ie, parent beliefs, the family emotional climate, supportive parenting and parent emotion regulation) and age-sensitive measures of child outcomes (ie, emotion regulation and socioemotional adjustment). Analyses will use mixed-effects regression to simultaneously assess associations over three time-point transitions (ie, T1 to T2; T2 to T3; T3 to T4), with exposure variables lagged to estimate how past factors predict outcomes 12 months later.Ethics and disseminationEthics approval was granted by the Deakin University Human Research Ethics Committee and the Deakin University Faculty of Health Human Research Ethics Committee. We will disseminate results through conferences and open access publications. We will invite parent end users to co-develop our dissemination strategy, and discuss the interpretation of key findings prior to publication.Trial registerationProtocol pre-registration: DOI 10.17605/OSF.IO/NGWUY.

Key message This study describes an optimized plastid genetic engineering platform to produce full marker-free transplastomic plants with transgene integrated at homoplasmy in one step in tissue culture. Plastid engineering is attractive for both biotechnology and crop improvement due to natural bio-confinement from maternal inheritance, the absence of transgene positional effects and silencing, the ability to express transgenes in operons, and unparalleled production of heterologous proteins. While plastid engineering has had numerous successes in the production of high-value compounds, no transplastomic plants have been approved for use in agriculture. In order for transplastomic plants to be used in agriculture, the removal of antibiotic selection genes is required. In this work, we developed an optimized strategy to generate homoplasmic marker-free lines of potato ( Solanum tuberosum ) in a single transformation event. To achieve marker-free transplastomic lines, vectors were redesigned to enable integration of the transgene cassette into the plastid genome, while maintaining the selection cassette on the vector backbone. After an initial round of tissue culture with selection, the selective pressure was removed, leading to the elimination of the vector backbone, while retaining the integrated transgene cassette at homoplasmy. Marker-free transplastomic lines produced using this strategy had a normal phenotype, and transgene integration was stable across generations. The new vectors developed in this work for the generation of marker-free transplastomics will represent a valuable alternative platform for routine plastid genetic engineering in higher plants. It is also anticipated that this approach will contribute to speed the path to commercialization of these novel transplastomic plant varieties.

Progressive Supranuclear Palsy (PSP) is the most common atypical parkinsonism. Symptoms of this fatal neurodegenerative disease include motor impairment, postural instability, acoustic startle reflex deficits, and speech problems. Cognitive symptoms such as dementia, apathy, depression, and anxiety also occur in PSP. The pedunculopontine tegmentum (PPTg), a superior brainstem structure, has become a focus in the study of Parkinsonisms such as PSP. Pathologically, PSP shows an early extensive loss of PPTg cholinergic neurons, as well as aggregates of the microtubule-stabilizing protein tau, which are greatest in areas innervated by the PPTg. This suggests the PPTg may be an early node in disease progression and a target structure for novel therapeutics. Currently, there are no pharmacotherapies available for PSP patients, and drug discovery is hindered by the lack of an adequate preclinical model. Previously, selective cholinergic PPTg lesions in rats induced PSP-like symptomology and pathology including motor deficits, a significantly reduced acoustic startle reflex, substantia nigra (SN) dopaminergic loss, and enlarged lateral ventricles. However, lesioned rats showed no evidence of pathological tau. Building upon previous efforts, we hypothesize that the loss of PPTg cholinergic neurons, coupled with deposition of tau in areas seen in PSP, will mimic PSP symptomology and pathology. To achieve this, male and female ChAT-Cre Long Evans rats were injected in the PPTg with a virally mediated (adeno associated virus) human 1N4R tau construct (tau isoform implicated in PSP). GFP constructs were used as a control. Following surgery, rats were tested in a battery of behavioral paradigms. As early as four weeks post-surgery rats exhibited significant PSP-like motor impairments, ASR deficit, and increased anxiety-like behavior, which did not diminish over the duration of 20 weeks. Six months post-surgery, brains were taken for histological analysis. ChAT immunohistochemistry confirmed that expression of human WT 1N4R tau in the cholinergic PPTg is sufficient to produce loss of cholinergic PPTg neurons. This pathology also precipitated loss of dopaminergic SN neurons, recapitulating the results of the lesion model. In addition to neurodegeneration of areas affected in PSP, tau pathology was also observed. Hyperphosphorylated tau and abnormal conformation tau were confirmed to be present in the brainstem. Abnormal confirmation tau was also observed in the SN, a structure directly innervated by the PPTg. Although further studies are required to confirm neuron-to-neuron propagation of tau, this finding supports our hypothesis and suggests tau is spreading along PPTg projections, producing neuron loss relevant to PSP. Thus far, both behavior and histology results indicate the induction of tau in the cholinergic PPTg may be an adequate animal model for PSP. The validation of this model will aid in future PSP research and facilitate drug discovery.

This is an investigation into Goldoni's working relationship as a librettist with the King's Theatre in London and it covers the period between 1749 and 1793. The King's Theatre was known as the Italian Opera House and Goldoni was invited to write libretti for its productions. This he did successfully - so successfully that he can be said to have become an integral part of the cultural life of an exalted section of London society. The cultural climate in London in the 18th century favoured entertainments such as pantomime, farce and burlesque, that had derived from or imitated Commedia dell'Arte. This liking for traditional theatrical forms was a European phenomenon and had its roots in the theatre of Shakespeare in England as well as in the popular and the classical theatre in Prance. In Italy the Commedia dell'Arte never really died, although in the 18th century Goldoni tried to free himself from it in an attempt to modernise the Italian theatre. But even so, Commedia dell'Arte survived in libretti of the type Goldoni was writing and which proved suitable for Comic Opera. This was the result of an evolution from simpler musical forms such as intermezzi and cantata a llengua and soon rivalled Opera Seria in popularity. In the second half of the century and under the influence of proto-Romanticism comic-opera libretti became increasingly sentimental, a trend which was reflected in Goldoni's own libretti for this type of theatrical entertainment. Comic Opera was evolving in the direction of the type of \"melodrama\" which was to dominate the theatre of the 19th century. In this context Goldoni's La Buona Figliuola - one of the great successes of the King's Theatre - demonstrates that while preserving links with a traditional past Goldoni seemed to be looking forward to a future development in Comic-Opera libretti, which, dying as he did in 1793, he was not to live to see.

On Dec 8, 2020, deployment of the first SARS-CoV-2 vaccination authorised for UK use (BNT162b2 mRNA vaccine) began, followed by an adenoviral vector vaccine ChAdOx1 nCoV-19 on Jan 4, 2021. Care home residents and staff, frontline health-care workers, and adults aged 80 years and older were vaccinated first. However, few data exist regarding the effectiveness of these vaccines in older people with many comorbidities. In this post-implementation evaluation of two COVID-19 vaccines, we aimed to determine the effectiveness of one dose in reducing COVID-19-related admissions to hospital in people of advanced age. This prospective test-negative case-control study included adults aged at least 80 years who were admitted to hospital in two NHS trusts in Bristol, UK with signs and symptoms of respiratory disease. Patients who developed symptoms before receiving their vaccine or those who received their vaccine after admission to hospital were excluded, as were those with symptoms that started more than 10 days before hospital admission. We did logistic regression analysis, controlling for time (week), sex, index of multiple deprivations, and care residency status, and sensitivity analyses matched for time and sex using a conditional logistic model adjusting for index of multiple deprivations and care residency status. This study is registered with ISRCTN, number 39557. Between Dec 18, 2020, and Feb 26, 2021, 466 adults were eligible (144 test-positive and 322 test-negative). 18 (13%) of 135 people with SARS-CoV-2 infection and 90 (34%) of 269 controls received one dose of BNT162b2. The adjusted vaccine effectiveness was 71·4% (95% CI 46·5–90·6). Nine (25%) of 36 people with COVID-19 infection and 53 (59%) of 90 controls received one dose of ChAdOx1 nCoV-19. The adjusted vaccine effectiveness was 80·4% (95% CI 36·4–94·5). When BNT162b2 effectiveness analysis was restricted to the period covered by ChAdOx1 nCoV-19, the estimate was 79·3% (95% CI 47·0–92·5). One dose of either BNT162b2 or ChAdOx1 nCoV-19 resulted in substantial risk reductions of COVID-19-related hospitalisation in people aged at least 80 years. Pfizer.

Progression to exudative ‘wet’ age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression. In individuals diagnosed with age-related macular degeneration in one eye, a deep learning model can predict progression to the ‘wet’, sight-threatening form of the disease in the second eye within a 6-month time frame.

Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta (POLQ) transcription by binding its promoter loci, driving POLΘ-mediated MMEJ that is essential to withstand cyclin D1-induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced POLQ expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POLΘ in cyclin D1-overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POLΘ inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.