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Teacher-facilitation of play is proposed as an effective method for supporting early literacy learning, however, educators remain uncertain how to balance child-autonomy in play while also directing play toward explicit academic objectives. In response, this study sought to understand how kindergarten teachers can successfully facilitate play to support early literacy development. Classroom observations and semistructured interviews were gathered and qualitatively analyzed to identify key perspectives and classroom practices that lead to the educators' successful facilitation of play to support literacy. Results of this study showed how different core literacy skills can be supported through different types of play, with each offering unique and critical opportunities for learning. Results also demonstrated how a multitude of core literacy skills can be supported through guided approaches to play, and begin to illustrate how teachers are facilitating a continuum of guided play to support literacy learning.

Behavioral skills training (BST) is a performance- and competency-based training package composed of instructions, modeling, rehearsal, and feedback. Previous reviews have demonstrated that BST is an effective training package to teach interventionists to implement behavior analytic interventions (Kirkpatrick et al. in "Journal of Behavioral Education," 28, 344-361, Kirkpatrick et al., "Journal of Behavioral Education" 28344-361, 2019). The purpose of this review was to examine the characteristics of BST for training adult interventionists to implement behavior analytic procedures with children with autism spectrum disorder (ASD). Also, we investigated various factors that may lead to efficient BST delivery, compiled the external validity indicators included in BST research, and investigated the methodological quality of BST research studies. In this systematic review of 30 studies from 2004 to 2019, we found that trainers consistently taught the four BST components, yet implementation varied substantially across studies. Inconsistent reporting of factors affecting efficiency limited our ability to analyze which components and delivery methods was most efficient. External validity measures, such as generalization and outcome measures for children receiving the behavior analytic intervention, were often reported. The evidence quality and design quality were mixed. BST is generally accepted as an effective intervention for training a wide range of interventions; however, more high-quality research studies are needed including evaluation of explicit descriptions for all BST components.

The performance of superconducting qubits is degraded by a poorly characterized set of energy sources breaking the Cooper pairs responsible for superconductivity, creating a condition often called quasiparticle poisoning. Both superconducting qubits and low threshold dark matter calorimeters have observed excess bursts of quasiparticles or phonons that decrease in rate with time. Here, we show that a silicon crystal glued to its holder exhibits a rate of low-energy phonon events that is more than two orders of magnitude larger than in a functionally identical crystal suspended from its holder in a low-stress state. The excess phonon event rate in the glued crystal decreases with time since cooldown, consistent with a source of phonon bursts which contributes to quasiparticle poisoning in quantum circuits and the low-energy events observed in cryogenic calorimeters. We argue that relaxation of thermally induced stress between the glue and crystal is the source of these events.

One of the challenges in studying islet inflammation-insulitis-is that it is a transient phenomenon. Traditional reporting of the insulitis progression is based on cumulative, donor-averaged values of leucocyte density in the vicinity of pancreatic islets, that hinder intra- and inter-islet heterogeneity of disease progression. Here, we aimed to understand why insulitis is non-uniform, often with peri-insulitis lesions formed on one side of an islet. To achieve this, we demonstrated the applicability of network theory in detangling intra-islet multi-cellular interactions during insulitis. Specifically, we asked the question "What is unique about regions of the islet that interact with immune cells first". This study utilized the non-obese diabetic mouse model of type one diabetes and examined the interplay among α-, β-, T-cells, myeloid cells, and macrophages in pancreatic islets during the progression of insulitis. Disease evolution was tracked based on the T/β cell ratio in individual islets. In the early stage, we found that immune cells are preferentially interacting with α-cell-rich regions of an islet. At the islet periphery α-linked β-cells were found to be targeted significantly more compared to those without α-cell neighbors. Additionally, network analysis revealed increased T-myeloid, and T-macrophage interactions with all β-cells.

Skeletal muscle stem and progenitor cells including those derived from human pluripotent stem cells (hPSCs) offer an avenue towards personalized therapies and readily fuse to form human-mouse myofibres in vivo. However, skeletal muscle progenitor cells (SMPCs) inefficiently colonize chimeric stem cell niches and instead associate with human myofibres resembling foetal niches. We hypothesized competition with mouse satellite cells (SCs) prevented SMPC engraftment into the SC niche and thus generated an SC ablation mouse compatible with human engraftment. Single-nucleus RNA sequencing of SC-ablated mice identified the absence of a transient myofibre subtype during regeneration expressing Actc1. Similarly, ACTC1+ human myofibres supporting PAX7+ SMPCs increased in SC-ablated mice, and after re-injury we found SMPCs could now repopulate into chimeric niches. To demonstrate ACTC1+ myofibres are essential to supporting PAX7 SMPCs, we generated caspase-inducible ACTC1 depletion human pluripotent stem cells, and upon SMPC engraftment we found a 90% reduction in ACTC1+ myofibres and a 100-fold decrease in PAX7 cell numbers compared with non-induced controls. We used spatial RNA sequencing to identify key factors driving emerging human niche formation between ACTC1+ myofibres and PAX7+ SMPCs in vivo. This revealed that transient regenerating human myofibres are essential for emerging niche formation in vivo to support PAX7 SMPCs.

Introduction Diabetic kidney disease (DKD) is a common cause of chronic kidney disease with around 25-40% of patients with diabetes being affected. The course of DKD is variable and estimated glomerular filtration rate (eGFR) and albuminuria, the currently used clinical markers, are not able to accurately predict the individual disease trajectory, in particular in early stages of the disease. The aim of this study was to assess the association of urine levels of selected protein biomarkers with the progression of DKD at an early stage of disease. Methods We measured 22 protein biomarkers using the Mesoscale Discovery platform in 461 urine samples of the PROVALID cohort, an observational study of patients with type 2 diabetes mellitus followed at the primary health care level for a minimum of four years. Odds ratios (OR) were estimated for the effect of marker values above median on fast progression using unadjusted and adjusted logistic regression models. RNA expression at the single cell level in kidney biopsy samples obtained from a cohort of young persons with type 2 diabetes mellitus was in addition determined for markers showing significant associations with disease progression. Results Increased urinary levels of epidermal growth factor (EGF) were linked to lower odds of fast progression (defined as annual eGFR decline greater than 2.58 ml/min per 1.73 m2) with an odds ratio (OR) of 0.60 (95% CI 0.46, 0.78). The association with outcome was even stronger when adjusting for a set of 14 baseline clinical parameters including age, biological sex, eGFR, body mass index, albuminuria, and HbA1c. Elevated urinary levels of fatty acid binding protein 3 (FABP3) and vascular cell adhesion molecule 1 (VCAM1) were each significantly associated with fast progression with an OR of 1.44 (95% CI 1.11, 1.87) and an OR of 1.41 (95% CI 1.08, 1.83), respectively. Enriched expression of EGF and FABP3 was observed in distal convoluted tubular cells and VCAM1 in parietal epithelial cells at single cell level from biopsies of patients with early DKD. Conclusion In summary we show that lower urinary levels of EGF and higher urinary levels of FABP3 and VCAM1 are significantly associated with DKD progression in early-stage disease.

Electron tomography of frozen, hydrated samples allows structure determination of macromolecular complexes that are embedded in complex environments. Provided that the target complexes may be localised in noisy, three‐dimensional tomographic reconstructions, averaging images of multiple instances of these molecules can lead to structures with sufficient resolution for de novo atomic modelling. Although many research groups have contributed image processing tools for these tasks, a lack of standardisation and interoperability represents a barrier for newcomers to the field. Here, we present an image processing pipeline for electron tomography data in RELION‐5, with functionality ranging from the import of unprocessed movies to the automated building of atomic models in the final maps. Our explicit definition of metadata items that describe the steps of our pipeline has been designed for interoperability with other software tools and provides a framework for further standardisation.

Abstract Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.

Children identified with developmental disabilities or delays (DD) are increasingly being educated in inclusive mainstream classroom environments. At the kindergarten level, there have been pedagogical shifts towards the promotion of play-based learning, with few resources addressing how teachers can support inclusion in play. Forty-two Ontario kindergarten teachers completed an online survey with open-ended questions regarding the promotion of play and inclusion for children with DD. While participants shared differing conceptualizations of inclusion, the most common definition underscored the need to provide all children with appropriate academic support. In line with this definition, the majority of participants (74%) discussed the need for inclusive pedagogical strategies to promote greater academic inclusion in classroom learning activities. Several teachers (43%) also highlighted the need for strategies to promote a respectful classroom community. While teachers' views on the role of play complemented themes of academic and community inclusion, few teachers (24%) shared strategies to help support academic or community inclusion within children's play. These results provide insight into how kindergarten teachers conceptualise and promote inclusion primarily outside of the context of play and underscore a critical gap in research and practice.

Devastating school shootings have spawned a cottage industry of untested responses to school violence. Some involve target hardening, or making schools less vulnerable to violent attacks. School administrators and community members can be quick to gravitate towards target hardening measures for preventing school violence. However, crime prevention through environmental design (CPTED) is more consistent with best practices in school safety and may be linked to more positive student perceptions of school climate. The CPTED principle of natural surveillance implies that individuals will be less likely to commit crimes, infractions, and offenses if their behavior can be observed and reported. This involves having an open campus layout that provides clear sight lines to continually monitor shared spaces such as courtyards, playgrounds, cafeterias, and libraries. Based on the available research, CPTED school-based designs may offer some benefits without drawbacks. School psychologists can be involved in discussions about school design in multiple ways CPTED is an alternative approach to school safety that may evenly balance the need for physical safety with psychological comfort. Although school psychologists do not draft blueprints for school design, they can work with administrators, community stakeholders, and policy makers to advocate for ground-up strategies for healthy schools - not fortresses.

High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced immune responses. Here, we show that mice dual-dosed with AAV9 at 4-week intervals better recapitulate aspects of human immunity to AAV. In the model, anti-AAV9 immunoglobulin G (IgGs) increased in a linear fashion between the first and second AAV administrations. Complement activation was only observed in the presence of high levels of both AAV and anti-AAV IgG. Myeloid-derived pro-inflammatory cytokines were significantly induced in the same pattern as complement activation, suggesting that myeloid cell activation to AAV may rely on the presence of both AAV and anti-AAV IgG complexes. Single-cell RNA sequencing of peripheral blood mononuclear cells confirmed that activated monocytes were a primary source of pro-inflammatory cytokines and chemokines, which were significantly increased after a second AAV9 exposure. The same activated monocyte clusters expressed both Fcγ and complement receptors, suggesting that anti-AAV-mediated activation of myeloid cells through Fcγ receptors and/or complement receptors is one mechanism by which anti-AAV antigen complexes may prime antigen-presenting cells and amplify downstream immunity.

Abstract The performance of superconducting qubits is degraded by a poorly characterized set of energy sources breaking the Cooper pairs responsible for superconductivity, creating a condition often called “quasiparticle poisoning”. Both superconducting qubits and low threshold dark matter calorimeters have observed excess bursts of quasiparticles or phonons that decrease in rate with time. Here, we show that a silicon crystal glued to its holder exhibits a rate of low-energy phonon events that is more than two orders of magnitude larger than in a functionally identical crystal suspended from its holder in a low-stress state. The excess phonon event rate in the glued crystal decreases with time since cooldown, consistent with a source of phonon bursts which contributes to quasiparticle poisoning in quantum circuits and the low-energy events observed in cryogenic calorimeters. We argue that relaxation of thermally induced stress between the glue and crystal is the source of these events.

Abstract Background People with serious mental health problems (SMHP) are more likely to be admitted to psychiatric hospital following contact with crisis services. Admissions can have significant personal costs, be traumatic and are the most expensive form of mental health care. There is an urgent need for treatments to reduce suicidal thoughts and behaviours and reduce avoidable psychiatric admissions. Methods A multi-stage, multi-arm (MAMS) randomised controlled trial (RCT) with four arms conducted over two stages to determine the clinical and cost effectiveness of three psychosocial treatments, compared to treatment as usual (TAU), for people with SMHP who have had recent suicidal crisis. Primary outcome is any psychiatric hospital admissions over a 6-month period. We will assess the impact on suicidal thoughts and behaviour, hope, recovery, anxiety and depression. The remote treatments delivered over 3 months are structured peer support (PREVAIL); a safety planning approach (SAFETEL) delivered by assistant psychologists; and a CBT-based suicide prevention app accessed via a smartphone (BrighterSide). Recruitment is at five UK sites. Stage 1 includes an internal pilot with a priori progression criteria. In stage 1, the randomisation ratio was 1:1:1:2 in favour of TAU. This has been amended to 2:2:3 in favour of TAU following an unplanned change to remove the BrighterSide arm following the release of efficacy data from an independent RCT. Randomisation is via an independent remote web-based randomisation system using randomly permuted blocks, stratified by site. An interim analysis will be performed using data from the first 385 participants from PREVAIL, SAFETEL and TAU with outcome data at 6 months. If one arm is dropped for lack of benefit in stage 2, the allocation ratio of future participants will be 1:1. The expected total sample size is 1064 participants (1118 inclusive of BrighterSide participants). Discussion There is a need for evidence-based interventions to reduce psychiatric admissions, via reduction of suicidality. Our focus on remote delivery of established brief psychosocial interventions, utilisation of different modalities of delivery that can provide sustainable and scalable solutions, which are also suitable for a pandemic or national crisis context, will significantly advance treatment options. Trial registration ISRCTN33079589. Registered on June 20, 2022.

Abstract Mitochondrial function is critical to continued cellular vitality and is an important contributor to a growing number of human diseases. Mitochondrial dysfunction is typically heterogeneous, mediated through the clonal expansion of mitochondrial DNA (mtDNA) variants in a subset of cells in a given tissue. To date, our understanding of the dynamics of clonal expansion of mtDNA variants has been technically limited to the single cell-level. Here, we report the use of nanobiopsy for subcellular sampling from human tissues, combined with next-generation sequencing to assess subcellular mtDNA mutation load in human tissue from mitochondrial disease patients. The ability to map mitochondrial mutation loads within individual cells of diseased tissue samples will further our understanding of mitochondrial genetic diseases.

Policies related to the inclusion of children with disabilities in mainstream classrooms have led to questions regarding how teachers can help cultivate inclusive learning communities where all children are supported and valued. In play-based kindergarten programs, teachers are tasked with ensuring goals for children's learning and development are cultivated in play. However, debates persist regarding the optimal role of the teacher in play and how to meaningfully support the play of children with disabilities. The current multiple case study explored the perspectives and approaches of three kindergarten teachers who highly valued, and strived to enable, participation and inclusion in play-based learning, referred to here as enactors. A minimum of three hours of observation were conducted in each classroom in the fall, and semi-structured teacher interviews were conducted in the fall and spring of the school year. Enactors shared some common themes related to implementing play-based learning to promote inclusion, including a balance of child agency and teacher guidance, involvement that is child-centred and flexible, and the importance of supporting social interactions in play. These views informed both common and unique practices observed in play, including one-on-one conversations, supporting small groups, becoming an active play partner, and collaboratively addressing problems that arose in play. These results illustrate ways enactors gave meaning to the concept of inclusion through their play practices, providing salient examples of play alongside teachers' craft knowledge to help support inclusive play-based learning practices going forward.

As school authorities strive toward inclusive models of education for children with neurodevelopmental delay and disability (NDD), many kindergarten curricula have mandated pedagogy centered on learning through play. Children with NDD tend to experience greater social isolation and lower rates of social play engagement compared to typically developing peers. Consequently, issues related to social participation and inclusion may be particularly salient in play-based kindergarten classrooms. The current qualitative study explored how eight kindergarten teachers in Ontario, Canada conceptualized and promoted inclusion in play for children with NDD. Classroom observation and teacher interviews were conducted with a focus on the teacher's role in play. Teachers endorsed the use of several indirect (i.e., environmental) strategies to promote social participation, alongside proactive teacher support in play. Teachers who shared multiple aspects of an interventionist viewpoint toward disability, and identified the social benefits of inclusion in play for children with NDD, tended to provide more proactive support to all children in play. Teachers also provided reactive support in play to address emerging social conflict. Implications for fostering the meaningful inclusion of children with NDD in play-based learning are discussed.

Skeletal muscle disease severity can often progress asymmetrically across muscle groups and heterogeneously within tissues. An example is Duchenne Muscular Dystrophy (DMD) in which lack of dystrophin results in devastating skeletal muscle wasting in some muscles whereas others are spared or undergo hypertrophy. An efficient, non-invasive approach to identify sites of asymmetry and degenerative lesions could enable better patient monitoring and therapeutic targeting of disease. In this study, we utilized a versatile intravenously injectable mesoporous silica nanoparticle (MSNP) based nanocarrier system to explore mechanisms of biodistribution in skeletal muscle of mdx mouse models of DMD including wildtype, dystrophic, and severely dystrophic mice. Moreover, MSNPs could be imaged in live mice and whole muscle tissues enabling investigation of how biodistribution is altered by different types of muscle pathology such as inflammation or fibrosis. We found MSNPs were tenfold more likely to aggregate within select mdx muscles relative to wild type, such as gastrocnemius and quadriceps. This was accompanied by decreased biodistribution in off-target organs. We found the greatest factor affecting preferential delivery was the regenerative state of the dystrophic skeletal muscle with the highest MSNP abundance coinciding with the regions showing the highest level of embryonic myosin staining and intramuscular macrophage uptake. To demonstrate, muscle regeneration regulated MSNP distribution, we experimentally induced regeneration using barium chloride which resulted in a threefold increase of intravenously injected MSNPs to sites of regeneration 7 days after injury. These discoveries provide the first evidence that nanoparticles have selective biodistribution to skeletal muscle in DMD to areas of active regeneration and that nanoparticles could enable diagnostic and selective drug delivery in DMD skeletal muscle.

Elementary science education calls on teachers to facilitate student learning of the content of science while they engage in the work of scientists. Additionally, recent national and state standards incorporate the practices of engineering into science education throughout grades K-12. However, many practicing teachers receive little to no professional development related to this shift in educational practice for the science classroom. To exasperate the issue, elementary teachers are generalists by nature without content or practical expertise in science and engineering content or practices. This study investigated how two fifth-grade teachers experienced co-facilitating an independent engineering fair with their students. The findings from this study can inform the ways in which teacher educators can support the incorporation of authentic engineering practice in the elementary classroom.

The aim of this study is to examine the professional identities of the academic staff of the faculties of education in Turkey. The study employed the Q methodology, in which both quantitative and qualitative data can be used. The qualitative data were collected and analysed by interviewing seven academics working in the faculty of education in the first stage of the study, which was conducted in two sequential stages. The analysis of the qualitative data showed that the academic staff of the faculty of education defined their professional identities as a "Practitioner", "Researcher", "Instructor", "Coach", "Counsellor" and a "Preparer". In the second stage of the study, the Q measurement tool was developed by the researchers based on the specified definitions for professional identities. The quantitative data were collected from 21 academics working in the faculty of education and analysed with the Q measurement tool. According to the analysis of the quantitative data, the academic staff of the faculties of education were seen to adopt six professional identities defined in general. In addition, the professional identity as a "Researcher" was found to be the most preferred, while the professional identity as a "Preparer" was the least preferred of the given identities. According to the findings obtained in the study, it was concluded that the educational experience of the academic staff of education faculties significantly differentiate the preferences and attitudes towards professional identities. Based on the findings and results obtained in this study, it is highly recommended to examine the role of the educational experience of the academic staff of education faculties in the change and transformation of their professional identities.

While most detailed analyses of antibiotic resistance plasmids focus on those found in clinical isolates, less is known about the vast environmental reservoir of mobile genetic elements and the resistance and virulence factors they encode. We selectively isolated three strains of cefotaxime-resistant Escherichia coli from a wastewater-impacted coastal wetland. The cefotaxime-resistant phenotype was transmissible to a lab strain of E. coli after one hour, with frequencies as high as 10-3 transconjugants per recipient. Two of the plasmids also transferred cefotaxime resistance to Pseudomonas putida, but these were unable to back-transfer this resistance from P. putida to E. coli. In addition to the cephalosporins, E. coli transconjugants inherited resistance to at least seven distinct classes of antibiotics. Complete nucleotide sequences revealed large IncF-type plasmids with globally distributed replicon sequence types F31:A4:B1 and F18:B1:C4 carrying diverse antibiotic resistance and virulence genes. The plasmids encoded extended-spectrum β-lactamases blaCTX-M-15 or blaCTX-M-55, each associated with the insertion sequence ISEc9, although in different local arrangements. Despite similar resistance profiles, the plasmids shared only one resistance gene in common, the aminoglycoside acetyltransferase aac(3)-IIe. Plasmid accessory cargo also included virulence factors involved in iron acquisition and defense against host immunity. Despite their sequence similarities, several large-scale recombination events were detected, including rearrangements and inversions. In conclusion, selection with a single antibiotic, cefotaxime, yielded conjugative plasmids conferring multiple resistance and virulence factors. Clearly, efforts to limit the spread of antibiotic resistance and virulence among bacteria must include a greater understanding of mobile elements in the natural and human-impacted environments.