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Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To survive drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced by drying in vitro and in heterologous systems. CAHS proteins have been shown to form gels both in vitro and in vivo, which has been speculated to be linked to their protective capacity. However, the sequence features and mechanisms underlying gel formation and the necessity of gelation for protection have not been demonstrated. Here we report a mechanism of fibrillization and gelation for CAHS D similar to that of intermediate filament assembly. We show that in vitro, gelation restricts molecular motion, immobilizing and protecting labile material from the harmful effects of drying. In vivo, we observe that CAHS D forms fibrillar networks during osmotic stress. Fibrillar networking of CAHS D improves survival of osmotically shocked cells. We observe two emergent properties associated with fibrillization; (i) prevention of cell volume change and (ii) reduction of metabolic activity during osmotic shock. We find that there is no significant correlation between maintenance of cell volume and survival, while there is a significant correlation between reduced metabolism and survival. Importantly, CAHS Ds fibrillar network formation is reversible and metabolic rates return to control levels after CAHS fibers are resolved. This work provides insights into how tardigrades induce reversible biostasis through the self-assembly of labile CAHS gels.

Families are an important part of the educational success of children. They can provide children with the opportunities to participate in lifetime physical activities outside of the school setting. When families feel valued and welcomed, their engagement and satisfaction with teachers can become enhanced thereby developing positive outcomes for children. However, specific to adapted physical education, not all families perceive positive experiences with their involvement in APE such as difficulties in understanding APE services, approaching APE teachers, and how to support their children's physical activity needs. It is important for APE teachers to communicate with families and develop a collaborative relationship to demonstrate the benefits of physical activity and support families' efforts in recreational opportunities outside of school. Therefore, the purpose of this article is to provide APE teachers with strategies they can use to develop a partnership with families of children whom they support through the BRIDGES model. Explanations of each step within the framework are provided as well as examples APE teachers can use to start developing the home-school connection., Introduction Schools are comprised of numerous social exchanges among students, teachers, service providers, and administrators. In particular, interactions among school professionals and families can influence the development of collaborative relationships, [...]

Nikhil Sharma,1 Eilidh Martin,1 Edward Ian Pearce,1 Suzanne Hagan,1 Christine Purslow,2 Jennifer P Craig3 1Glasgow Caledonian University, Glasgow, Scotland, UK; 2Christine Purslow – School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, UK; 3Jennifer P Craig – Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, Auckland, New ZealandCorrespondence: Nikhil Sharma, Email Nikhil.Sharma@gcu.ac.ukAim: The primary aim of this study was to compare how eyecare professionals in disparate regions of the world diagnose and manage Demodex blepharitis. A secondary aim was to explore interprofessional differences in diagnostic and management practices.Methods: Ophthalmologists and optometrists from India and Australia/New Zealand, were invited to complete an online survey on Demodex blepharitis. Clinical practice patterns relating to patients with Demodex blepharitis, with details of how they investigate and manage Demodex blepharitis in clinical practice, were collected along with clinician demographics and general perceptions on eyelid health. Mann–Whitney U, and Fisher’s exact tests were used for statistical analysis.Results: A total of 261 eyecare professionals completed the survey, comprising 207 from India (84% optometrists) and 54 from Australia and New Zealand (91% optometrists). Almost 70% of practitioners across the 3 countries recognized Demodex blepharitis as a cause of ocular discomfort, yet only 45% reported attempting to identify Demodex in their patients. There were significant differences noted in clinical practice between those in Australasia and India. Perceived prevalence of Demodex blepharitis also differed (60% in Australasia vs 27% in India; p< 0.01), as well as, the choice of slit lamp magnification used to detect the mites (25x in Australasia vs 16x in India; p = 0.02), preferred treatment option to manage Demodex blepharitis (tea tree oil in Australasia vs Standard lid hygiene in India; p = 0.01), treatment duration (from 3– 4 weeks to over 12 weeks in Australasia vs 3– 4 weeks in India; p = 0.02) and treatment application frequency (once daily in Australasia vs twice daily in India; p = 0.01).Conclusions: This study highlights differences in clinical evaluation and treatment practices between eyecare professionals in India and Australasia. Overall, practitioners in Australia and New Zealand were more evidence-based in their investigation and management. However, in both regions, interprofessional differences in perceived optimal treatment duration and frequency were reported.Keywords: Demodex blepharitis, practitioners’ perspective, ocular surface, dry eye

Abstract We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Abstract High childhood disease prevalence and under-five mortality rates have been consistently reported in Nigeria. Vaccination is a cost-effective preventive strategy against childhood diseases. Therefore, this study aimed to identify the determinants of Incomplete Vaccination (IV) among children aged 12–23 months in Nigeria. This cross-sectional design study utilized the 2018 Nigeria Demographic and Health Survey (NDHS) dataset. A two-stage cluster sampling technique was used to select women of reproductive age who have children (n = 5475) aged 12–23 months. The outcome variable was IV of children against childhood diseases. Data were analyzed using Integrated Nested Laplace Approximation and Bayesian binary regression models (α0.05). Visualization of incomplete vaccination was produced using the ArcGIS software. Children’s mean age was 15.1 ± 3.2 months and the median number of vaccines received was four. Northern regions contributed largely to the IV. The likelihood of IV was lower among women aged 25–34 years (aOR = 0.67, 95% CI = 0.54–0.82, p

Abstract The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.

Abstract Background Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. Methods The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. Results Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. Conclusion Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Purpose: This research explores the key factors that contribute to the success of Black students in a predominantly White institution (PWI). Two measures of success are examined: cumulative grade point average (GPA) and graduation status. Design/methodology/approach: Using student-level data from a southeastern university, this research estimates education production functions using ordinary least squares regression. Findings: While the negative effect of being Black is significant for both cumulative GPA and graduation status, the effect becomes overshadowed when peer effects are added. The authors also found the critical effect of institutional support on student success. Research limitations/implications: The student-level data are restricted to a single institution over a relatively short period of time, which limits the authors' ability to analyze institution-level factors. Practical implications: This research provides a broad view of many significant factors for student success with particular highlights on the importance of encouraging Black students to utilize institutional support. Originality/value: This study is an extension of the education production function model in the field of student success. The study identified peer effects and institutional support as more powerful determinants of student success than race.

A semistructured preschool motor program was developed in response to the paucity of evidence-based motor programs for preschoolers with disabilities in inclusive classrooms. A randomized controlled trial (RCT) was undertaken to examine the impact of the "CHildren in Action: Motor Program for PreschoolerS (CHAMPPS)," a 21-week intervention that includes 42 Universal Design for Learning--embedded lessons with suggestions for supporting school readiness skills. Eight intervention and 8 control classrooms across 2 states participated in the RCT. Data on 51 children with disabilities provide initial evidence on how "CHAMPPS" positively impacted children's active engagement, motor, and social development. The promising results include gains in motor skills, sustained physical activity levels during motor play, increased on-task behavior, and high feasibility and usability ratings by teachers. Implications for practice and future research are discussed.

Abstract Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p

Abstract Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis‐decalin. In this paper, we demonstrate that the cis‐decalin section of signermycin B can be accessed by an anionic oxy‐Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels‐Alder reaction of a masked ortho‐benzoquinone, generated by oxidation of an α‐methoxyphenol in presence of cis‐2‐hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy‐Cope rearrangement to a cis‐decalinone. While we could show, that introduction of the 4‐ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4‐epi‐isomer was formed.

The purpose of this study was to understand how community youth sports organizations in United States and Serbia provide information to coaches and support to children with disabilities to facilitate the inclusion of children with disabilities in recreation-level programs. The information from this survey will be critical in understanding hoow children with disabilities are accommodated in youth sports recreation programs and guide efforts to design resources for youth sports coaches. Results found that very little training was provided to coaches and that sports club directors were willing to make some accommodations for children with disabilities. Keywords: Sports clubs, youth sports, disabilities, Physical activity and youth sports are of great importance for the proper growth and development of all children. Involvement in sport activity undoubtedly has a positive influence on the development [...]