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Virtual environment software is increasingly being employed as a non-invasive method in primate cognition research. Familiar and novel stimuli can be presented in new ways, opening the door to studying aspects of cognition in captivity which previously may not have been feasible. Despite the increased complexity of visual input compared to more traditional computerised studies, several groups of captive primates have now been trained to navigate virtual three-dimensional environments. Here, we outline a method for training primates to use a computerised virtual foraging task presented on a touchscreen. We document how to tailor this method to groups facing different training challenges. We present data from three groups: touchscreen-experienced chimpanzees (Pan troglodytes), touchscreen-naïve orang-utans (Pongo abelii), and chimpanzees tested in a group setting. Subjects from all groups mastered basic navigation challenges with relative ease (some in as little as 16 days), setting them up for systematic studies of primate cognition within virtual environments. The training method we present is flexible, yet structured, and we encourage other researchers to adapt it to implement virtual environment research with more individuals and across more species., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Evidence has accumulated that Cannabis -derived compounds have the potential to treat neuroinflammatory changes present in neurodevelopmental conditions such as autism spectrum disorder. However, research is needed on the specific brain health benefits of strains of whole Cannabis extract that are ready for commercial production. Here, we explore the anti-inflammatory and neuroprotective effects of NTI-164, a genetically unique high-cannabidiol (CBD), low-Δ9-tetrahydrocannabinol extract, and also CBD alone on BV-2 microglia and SHSY-5Y neurons. Inflammation-induced up-regulation of microglial inflammatory markers was significantly attenuated by NTI-164, but not by CBD. NTI-164 promoted undifferentiated neuron proliferation and differentiated neuron survival under excitotoxic conditions. These effects suggest the potential for NTI-164 as a treatment for neuropathologies.

Background: Experiencing a traumatic event can significantly impact mental and emotional well-being. Social media platforms offer spaces for sharing stories, seeking support, and accessing psychoeducation. TikTok (ByteDance), a rapidly growing social media platform, is increasingly used for advice, validation, and information, although the content of this requires further study. Research is particularly needed to better understand TikTok content relating to trauma and the potential implications for young viewers, considering the distressing nature of the subject and the possibility of users experiencing vicarious trauma through exposure to these videos., Objective: This study aims to explore the content of trauma-related videos on TikTok, focusing on hashtags related to trauma. Specifically, this study analyzes how TikTok videos present information, advice, stories, and support relating to trauma., Methods: A quantitative cross-sectional descriptive content analysis was performed on TikTok in December 2022. A total of 5 hashtags related to trauma were selected: #trauma, #traumatized, #traumatok, #traumatic, and #traumabond, with the top 50 videos from each hashtag analyzed (total N=250 videos). A standardized codebook was developed inductively to analyze the content of the videos, while an existing generic codebook was used to collect the video features (eg, age of people in the video) and metadata (likes, comments, and shares) for each video., Results: A total of 2 major content themes were identified, which were instructional videos (54/250, 21.6%) and videos disclosing personal stories (168/250, 67.3%). The videos garnered significant engagement, with a total of 296.6 million likes, 2.3 million comments, and 4.6 million shares, indicating that users find this content engaging and useful. Alarmingly, only 3.7% (9/250) of videos included a trigger warning, despite many featuring highly distressing stories that young people and those with trauma may be exposed to., Conclusions: The study highlights the potential risks of vicarious trauma due to trauma dumping without trigger warnings on TikTok, and the need for further research to assess the accuracy of advice and information in these videos. However, it also underscores the platform's potential to foster social connections, provide validation, and reduce stigma around mental health issues. Public health professionals should leverage social media to disseminate accurate mental health information, while promoting user education and content moderation to mitigate potential harms. People often use social media, such as TikTok to share advice, stories, and support around mental health, including their experiences with trauma. Out of 250 videos, most were either giving advice (54/250, 21.6%) or sharing personal experiences (168/250, 67.3%). The study found many videos lacked warnings about upsetting content, which could potentially harm young viewers or people suffering from trauma. While TikTok can help people feel connected and reduce the stigma around mental health, it is important to seek support from professionals when needed., (©Alix Woolard, Rigel Paciente, Emily Munro, Nicole Wickens, Gabriella Wells, Daniel Ta, Joelie Mandzufas, Karen Lombardi. Originally published in JMIR Formative Research (https://formative.jmir.org), 07.11.2024.)

We compare the effects of burrowing behavior on appendicular bone structure in two Peromyscus (deer mouse) species. P. polionotus creates complex burrows in their territories, while P. eremicus is a non-burrowing nesting mouse. We examined museum specimens' bones of wild-caught mice of the two species and lab-reared P. polionotus not given the opportunity to burrow. Bones were scanned using micro-computed tomography, and cortical and trabecular bone structural properties were quantified. Wild P. polionotus mice had a larger moment of area in the ulnar and tibial cortical bone compared with their lab-reared counterparts, suggesting developmental adaptation to bending resistance. Wild P. polionotus had a larger normalized second moment of area and cross-sectional area in the tibia compared with P. eremicus. Tibial trabecular analysis showed lower trabecular thickness and spacing in wild P. polionotus than in P. eremicus and femoral analysis showed wild P. polionotus had lower thickness than P. eremicus and lower spacing than lab-reared P. polionotus, suggesting adaptation to high loads from digging. Results lay the groundwork for future exploration of the ontogenetic and evolutionary basis of mechanoadaptation in Peromyscus., (© 2024 American Association for Anatomy.)

Objective: To investigate how dieting is portrayed on TikTok and the potential implications for public health considering the effect of diet culture on eating disorders amongst young people., Design: A cross-sectional descriptive content analysis of 250 videos from the five most popular diet-related hashtags. A codebook was developed to analyse the content of the videos and collect the engagement for each video (likes, comments and shares)., Setting: TikTok website., Participants: There were no participants in this study., Results: More than half of the videos portrayed 'body checking', a potentially harmful practice for body image. Of the videos that represented body image, almost half represented body image negatively. However, most videos promoted the idea of 'healthy eating', and only 6·4 % displayed disordered eating behaviours. Over half of the videos provided dietary advice, and of those videos, most content creators claimed to be experts (64 %). Claiming expertise was not significantly associated with engagement; however, the use of humour was significantly associated with engagement. Additionally, males were more likely than females to disclose their goals of the diet., Conclusions: Overall, it appears that TikTok is commonly used to share nutrition tips and personal experiences around dieting and eating in general, often employing humour as an effective technique. The popularity of the platform and rapid dissemination of information would be a useful tool for health professionals, especially those working with eating disorders, to utilise.

Studies of PAR polarity have emphasized a paradigm in which mutually antagonistic PAR proteins form complementary polar domains in response to transient cues. A growing body of work suggests that the oligomeric scaffold PAR-3 can form unipolar asymmetries without mutual antagonism, but how it does so is largely unknown. Here we combine single molecule analysis and modeling to show how the interplay of two positive feedback loops promote dynamically stable unipolar PAR-3 asymmetries in early C. elegans embryos. First, the intrinsic dynamics of PAR-3 membrane binding and oligomerization encode negative feedback on PAR-3 dissociation. Second, membrane-bound PAR-3 promotes its own recruitment through a mechanism that requires the anterior polarity proteins CDC-42, PAR-6 and PKC-3. Using a kinetic model tightly constrained by our experimental measurements, we show that these two feedback loops are individually required and jointly sufficient to encode dynamically stable and locally inducible unipolar PAR-3 asymmetries in the absence of posterior inhibition. Given the central role of PAR-3, and the conservation of PAR-3 membrane-binding, oligomerization, and core interactions with PAR-6/aPKC, these results have widespread implications for PAR-mediated polarity in metazoa., Competing Interests: Declaration of interests The authors declare no competing interests

The formation of online communities instils a sense of connectedness which can ameliorate the mental health concerns that result from minority stressors for lesbian, gay, queer, intersex, asexual, and other diverse genders/sexualities (LGBTQIA+). The aim of this study was to explore how LGBTQIA + people communicate social and mental health concerns on TikTok. It was anticipated that factors affecting mental health, such as minority stressors and community connectedness, would be addressed by the videos collected. Engagement statistics, demographics and content analysis were used to describe the 50 most-viewed videos across the top five related hashtags: #genderidentity, #lgbtqawareness, #sexualidentity, #lgbtmentalhealth, and #transmentalhealth. The content analysis indicates that TikTok is used as a way for members of the LGBTQIA + community to connect with each other and enhance feelings of community connectedness, which research shows may buffer the effects of minority stressors. Engagement with social media can be especially beneficial for those who may not be able to connect in the real-world. Further interactions, such as analysis of the comment section, should be investigated to develop a fuller understanding of how LGBTQIA + TikTok users respond to these contents.

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers., Methods: Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded., Results: Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications., Conclusions: APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians., (© 2024. The Author(s).)

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The number of people living with dementia (PLWD) in Aotearoa New Zealand (NZ) was estimated at 96,713 in 2020 and it is anticipated that this number will increase to 167,483 by 2050, including an estimated 12,039 Māori (indigenous people of NZ) with dementia. Experiencing urinary incontinence (UI) or faecal incontinence (FI) is common for PLWD, particularly at the later stages of the disease. However, there is no robust estimate for either prevalence or incidence of UI or FI for PLWD in NZ. Although caregivers rate independent toilet use as the most important activity of daily living to be preserved, continence care for PLWD in the community is currently not systematised and there is no structured care pathway. The evidence to guide continence practice is limited, and more needs to be known about caregiving and promoting continence and managing incontinence for PLWD in the community. This project will seek to understand the extent of the challenge and current practices of health professionals, PLWD, caregivers and family; identify promising strategies; co-develop culturally appropriate guidelines and support materials to improve outcomes; and identify appropriate quality indicators so that good continence care can be measured in future interventions., Methods and Analysis: A four-phase mixed methods study will be delivered over three years: three phases will run concurrently, followed by a fourth transformative sequential phase. Phase 1 will identify the prevalence and incidence of incontinence for PLWD in the community using a cohort study from standardised home care interRAI assessments. Phase 2 will explore continence management for PLWD in the community through a review of clinical policies and guidance from publicly funded continence services, and qualitative focus group interviews with health professionals. Phase 3 will explore experiences, strategies, impact and consequences of promoting continence and managing incontinence for PLWD in the community through secondary data analysis of an existing carers' study, and collecting new cross-sectional and longitudinal qualitative data from Māori and non-Māori PLWD and their caregivers. In Phase 4, two adapted 3-stage Delphi processes will be used to co-produce clinical guidelines and a core outcome set, while a series of workshops will be used to co-produce caregiver resources., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Burholt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Stress affects cognition, behavior, and physiology, leading to lasting physical and mental illness. The ability to detect and measure stress, however, is poor. Increased circulating cortisol during stress is mirrored by cortisol release from sweat glands, providing an opportunity to use it as an external biomarker for monitoring internal emotional state. Despite the attempts at using wearable sensors for monitoring sweat cortisol, there is a lack of reliable wearable sweat collection devices that preserve the concentration and integrity of sweat biomolecules corresponding to stress levels. Here, a flexible, self-powered, evaporation-free, bubble-free, surfactant-free, and scalable capillary microfluidic device, MicroSweat, is fabricated to reliably collect human sweat from different body locations. Cortisol levels are detected corresponding to severe stress ranging from 25 to 125 ng mL -1 averaged across multiple body regions and 100-1000 ng mL -1 from the axilla. A positive nonlinear correlation exists between cortisol concentration and stress levels quantified using the perceived stress scale (PSS). Moreover, owing to the sweat variation in response to environmental effects and physiological differences, the longitudinal and personalized profile of sweat cortisol is acquired, for the first time, for various body locations. The obtained sweat cortisol data is crucial for analyzing human stress in personalized and clinical healthcare sectors., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Primate cognition research is reliant on access to members of the study sp ecies and logistical infrastructures to conduct observations and experiments. Historically founded in research centers and private collections, and spreading to modern zoos, sanctuaries, and the field, primate cognition has been investigated in diverse settings, each with benefits and challenges. In our systematic review of 12 primatology, animal behavior, and animal cognition journals over the last 15 years, we turn a spotlight on zoos to quantify their current impact on the field and to highlight their potential as robust contributors to future work. To put zoo-based research in context, we compare zoos to three other site types: university-owned or independent research centers, sanctuaries, and field sites. We assess the contributions of zoos across several critical considerations in primate cognition research, including number of investigations, species diversity, sample size, research topic diversity, and methodology. We identified 1119 publications reporting studies of primate cognition, almost 25% of which report research conducted in zoos. Across publications, zoo-based research has greater species diversity than research centers and covers a diverse range of research topics. Although our review is merely a snapshot of primate cognition research, our findings suggest that zoos may present advantages to researchers regarding species diversity, and lack some of the methodological constraints of field sites, allowing greater ease of access to a diverse range of subjects for cognition investigations. We suggest that zoos have great potential as key contributors for future investigations in primate cognition. Finally, we shed light on the symbiotic relationship that can emerge between researchers and zoos, forming partnerships that bring unique advantages to both parties., (© 2022 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

For a group of cells to migrate together, each cell must couple the polarity of its migratory machinery with that of the other cells in the cohort. Although collective cell migrations are common in animal development, little is known about how protrusions are coherently polarized among groups of migrating epithelial cells. We address this problem in the collective migration of the follicular epithelial cells in Drosophila melanogaster . In this epithelium, the cadherin Fat2 localizes to the trailing edge of each cell and promotes the formation of F-actin-rich protrusions at the leading edge of the cell behind. We show that Fat2 performs this function by acting in trans to concentrate the activity of the WASP family verprolin homolog regulatory complex (WAVE complex) at one long-lived region along each cell's leading edge. Without Fat2, the WAVE complex distribution expands around the cell perimeter and fluctuates over time, and protrusive activity is reduced and unpolarized. We further show that Fat2's influence is very local, with sub-micron-scale puncta of Fat2 enriching the WAVE complex in corresponding puncta just across the leading-trailing cell-cell interface. These findings demonstrate that a trans interaction between Fat2 and the WAVE complex creates stable regions of protrusive activity in each cell and aligns the cells' protrusions across the epithelium for directionally persistent collective migration., Competing Interests: AW, SD, EM, SH No competing interests declared, (© 2022, Williams et al.)

Background: Originating as a cluster of unexplained cases of pneumonia in Wuhan, China, a novel coronavirus disease, officially named as COVID-19 by WHO, has now reached a pandemic level. In the wake of this global health crisis, stringent public health measures were implemented to curtail the spread of COVID-19. At a local level, the University Hospitals of North Midlands National Health Service Trust suspended all elective and outpatient activity, primarily to address the current potential implications of the COVID-19 outbreak. Within respiratory physiology, all but urgent and emergency work was suspended., Methods: In June 2020, the service commenced its restoration/recovery plan, which was based on national and international guidelines to ensure safe practice for patients and staff alike. The plan was a roadmap developed to upscale the respiratory physiology service to deliver urgent and routine care and to assist the service to undertake the essential task of managing the patient backlog as a consequence of the interruption of service. Patient concerns and anxieties due to the pandemic was a key aspect of the restoration/recovery plan. The service developed numerous initiatives along with a questionnaire to assess patient experience following attendance for investigations or assessment., Results: The questionnaire confirmed that the initiatives put in place as part of the restoration/recovery plan achieve high levels of satisfaction in terms of communication, interaction within the service, professionalism and importantly patient safety., Conclusion: COVID-19 had a significant impact on routine clinical care and out-patient activity. This brought about significant change in service delivery that required a strict regimen to ensure COVID-19 free status and minimise cross-contamination of service users. The systems and processes introduced demonstrated positive responses and confirmed the objective of patient safety, which translated to the service users., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intraventricular hemorrhage causes significant lifelong mortality and morbidity, especially in preterm born infants. Progress in finding an effective therapy is stymied by a lack of preterm animal models with long-term follow-up. This study addresses this unmet need, using an established model of preterm rabbit IVH and analyzing outcomes out to 1 month of age., Methods: Rabbit pups were delivered preterm and administered intraperitoneal injection of glycerol at 3 h of life and approximately 58% developed IVH. Neurobehavioral assessment was performed at 1 month of age followed by immunohistochemical labeling of epitopes for neurons, synapses, myelination, and interneurons, analyzed by means of digital quantitation and assessed via two-way ANOVA or Student's t test., Results: IVH pups had globally reduced myelin content, an aberrant cortical myelination microstructure, and thinner upper cortical layers (I-III). We also observed a lower number of parvalbumin (PV)-positive interneurons in deeper cortical layers (IV-VI) in IVH animals and reduced numbers of neurons, synapses, and microglia. However, there were no discernable changes in behaviors., Conclusions: We have established in this preterm pup model that long-term changes after IVH include significant wide-ranging alterations to cortical organization and microstructure. Further work to improve the sensitivity of neurocognitive testing in this species at this age may be required., Impact: This study uses an established animal model of preterm birth, in which the rabbit pups are truly born preterm, with reduced organ maturation and deprivation of maternally supplied trophic factors. This is the first study in preterm rabbits that explores the impacts of severe intraventricular hemorrhage beyond 14 days, out to 1 month of age. Our finding of persisting but subtle global changes including brain white and gray matter will have impact on our understanding of the best path for therapy design and interventions., (© 2022. The Author(s).)

Pulsatile RhoA dynamics underlie a wide range of cell and tissue behaviors. The circuits that produce these dynamics in different cells share common architectures based on fast positive and delayed negative feedback through F-actin, but they can produce very different spatiotemporal patterns of RhoA activity. However, the underlying causes of this variation remain poorly understood. Here we asked how this variation could arise through modulation of actin network dynamics downstream of active RhoA in early Caenorhabditis elegans embryos. We find that perturbing two RhoA effectors-formin and anillin-induce transitions from nonrecurrent focal pulses to either large noisy oscillatory pulses (formin depletion) or noisy oscillatory waves (anillin depletion). In both cases these transitions could be explained by changes in local F-actin levels and depletion dynamics, leading to changes in spatial and temporal patterns of RhoA inhibition. However, the underlying mechanisms for F-actin depletion are distinct, with different dependencies on myosin II activity. Thus, modulating actomyosin network dynamics could shape the spatiotemporal dynamics of RhoA activity for different physiological or morphogenetic functions.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Background: Of the 200 million patients worldwide affected by peripheral arterial disease (PAD), 4% will inevitably require major limb amputation. Previous systematic reviews presented a conflicting body of evidence in terms of vascular endothelial growth factor (VEGF) family member effects upon PAD natural progression. Despite that, modulation of intrinsic angiogenesis mechanisms targeting the VEGF family members still confers an attractive therapeutic target. The aim of the present study was to evaluate current evidence of VEGF modulation in the context of PAD., Methods: This is a systematic literature review conducted according to the PRISMA guidelines and registered under PROSPERO database [CRD42021285988]. Independent literature search was performed up to April 1, 2022, on six databases. A total of 22 eligible studies were identified [N: 3, interventional patient studies; N: 19, animal studies]. Animal studies were appraised by the SYRCLE risk of bias tool, while human participant studies were assessed by the Newcastle Ottawa scale. Overall, quality of evidence was deemed fair for both animal and human studies. Main study outcomes were percentage change of injured vessel lumen stenosis and neointimal area formation upon VEGF modulation (inhibition or activation) in comparison with control group., Findings: Nineteen animal models and three human participant studies were included in the systematic review and assessed separately. Positive modulation of VEGF-A in animal models resulted in a median decrease of 65.58% [95% CI 45.2; 71.87] in lumen stenosis [14 studies]. Furthermore, positive modulation of VEGF-A was found to reduce neointimal area proliferation by a median decrease of 63.41% [95% CI 41.6; 79.59] [14 studies]. Median end of study duration was 28 days [range: 14-84 days]. Data were insufficient to assess these outcomes with respect to VEGF-B or VEGF-C modulation. The limited number of available human studies presented inadequate outcome assessment despite their overall fair NOS grading., Interpretation: VEGF-A-positive modulation decreases lumen stenosis and neointimal hyperplasia in PAD simulation animal models. Previously identified variability among outcomes was found to strongly stem from the variability of experimental designs. Clinical applicability and safety profile of VEGF-A in the context of PAD remain to be defined by a robust and uniformly designed body of further animal model-based experiments., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

During cytokinesis, animal cells rapidly remodel the equatorial cortex to build an aligned array of actin filaments called the contractile ring. Local reorientation of filaments by active equatorial compression is thought to underlie the emergence of filament alignment during ring assembly. Here, combining single molecule analysis and modeling in one-cell C. elegans embryos, we show that filaments turnover is far too fast for reorientation of individual filaments by equatorial compression to explain the observed alignment, even if favorably oriented filaments are selectively stabilized. By tracking single formin/CYK-1::GFP particles to monitor local filament assembly, we identify a mechanism that we call filament-guided filament assembly (FGFA), in which existing filaments serve as templates to orient the growth of new filaments. FGFA sharply increases the effective lifetime of filament orientation, providing structural memory that allows cells to build highly aligned filament arrays in response to equatorial compression, despite rapid turnover of individual filaments., Competing Interests: Declaration of interests E.M. is a member of the editorial advisory board for Developmental Cell., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The study aimed to: (1) test MRI repeatability of measurements of optic nerve sheath diameter (ONSD), optic nerve diameter (OND) and eye globe transverse diameter (ETD); (2) investigate the associations between the OND, ONSD and ETD; (3) assess whether these measurements are affected by age or body weight; and (4) test the association between ONSD, OND, ETD and ONSD:ETD ratio with presumed intracranial pressure (ICP) status., Methods: This was a retrospective and blinded study where patients were allocated to presumed normal or intracranial hypertension groups based on MRI findings. The ONSD and ETD were measured and recorded. Interclass correlation coefficient (ICC) was calculated to investigate interobserver agreement. Data were analysed using the Pearson correlation coefficient, two-sample t -test and general linear model ANOVA., Results: Seventy-seven cats were included, 62 with presumed normal ICP and 15 with presumed intracranial hypertension. The ICC showed moderate-to-good reliability for all measurements. Positive correlations were identified for: (1) ETD and weight; (2) ONSD and age; (3) OND and age; (4) ONSD and ETD; (5) ONSD:ETD ratio and presumed ICP status; and (6) ONSD and presumed ICP status. No difference was detected between the presumed normal and intracranial hypertension groups and ONSD, as well as ONSD:ETD ratio and presumed ICP status when patient age was considered., Conclusions and Relevance: The measurement of the ONSD and the ONSD:ETD ratio on T2-weighted MRI might not be reliable as non-invasive tests for diagnosing intracranial hypertension in cats.

The actin cytoskeleton is a soft, structural material that underlies biological processes such as cell division, motility, and cargo transport. The cross-linked actin filaments self-organize into a myriad of architectures, from disordered meshworks to ordered bundles, which are hypothesized to control the actomyosin force generation that regulates cell migration, shape, and adhesion. Here, we use fluorescence microscopy and simulations to investigate how actin bundle architectures with varying polarity, spacing, and rigidity impact myosin II dynamics and force generation. Microscopy reveals that mixed-polarity bundles formed by rigid cross-linkers support slow, bidirectional myosin II filament motion, punctuated by periods of stalled motion. Simulations reveal that these locations of stalled myosin motion correspond to sustained, high forces in regions of balanced actin filament polarity. By contrast, mixed-polarity bundles formed by compliant, large cross-linkers support fast, bidirectional motion with no traps. Simulations indicate that trap duration is directly related to force magnitude and that the observed increased velocity corresponds to lower forces resulting from both the increased bundle compliance and filament spacing. Our results indicate that the microstructures of actin assemblies regulate the dynamics and magnitude of myosin II forces, highlighting the importance of architecture and mechanics in regulating forces in biological materials., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC., Methods: Immunohistochemical analysis of TMA with 181 EOC samples was used to determine expression levels for DNA repair proteins (PARP, PTEN, p53, H2Ax, FANCD2, and ATM) and immune-markers (CD4, CD8, CD68, PD-L2, PD-L1, and FOXP3). Biomarker expression was correlated to clinical data. Prognostic discriminatory ability was assessed per the combination of biomarkers., Results: Tumor immunity biomarkers correlated with HRD biomarkers. High PD-L2 was significantly associated with high expression of CD8 ( r = 0.18), CD68 ( r = 0.17), and FOXp3 ( r = 0.16) (all, p < 0.05). In a multivariate analysis, PD-L2 (hazard ratio (HR) 1.89), PARP (HR 1.75), and PTEN (HR 1.96) expressions were independently associated with decreased progression-free survival (PFS), whereas PD-L1 (HR 0.49) and CD4 (HR 0.67) were associated with improved PFS (all, p < 0.05). In 15 biomarker combinations, six combinations exhibited a discriminatory ability of >20% for the 4.5-year PFS rate, with four based on PD-L2 (PARP, PTEN, CD4, and PD-L1, 20.5-30.0%)., Conclusions: Increased PD-L2 expression is a prognostic marker of decreased survival in EOC. Interaction between tumor DNA repair and microenvironment determines tumor progression and survival.

The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development., (Creative Commons Attribution license.)

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.

Global tissue tension anisotropy has been shown to trigger stereotypical cell division orientation by elongating mitotic cells along the main tension axis. Yet, how tissue tension elongates mitotic cells despite those cells undergoing mitotic rounding (MR) by globally upregulating cortical actomyosin tension remains unclear. We addressed this question by taking advantage of ascidian embryos, consisting of a small number of interphasic and mitotic blastomeres and displaying an invariant division pattern. We found that blastomeres undergo MR by locally relaxing cortical tension at their apex, thereby allowing extrinsic pulling forces from neighboring interphasic blastomeres to polarize their shape and thus division orientation. Consistently, interfering with extrinsic forces by reducing the contractility of interphasic blastomeres or disrupting the establishment of asynchronous mitotic domains leads to aberrant mitotic cell division orientations. Thus, apical relaxation during MR constitutes a key mechanism by which tissue tension anisotropy controls stereotypical cell division orientation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation., (Copyright © 2020 Ross-Munro, Kwa, Kreiner, Khore, Miller, Tolcos, Fleiss and Walker.)

Consuming coffee immediately prior to a nap, known as a caffeine-nap, has been shown to improve alertness during the day, but it is unknown whether a caffeine-nap is effective at reducing sleep inertia during the night. A simulated shiftwork cross-over laboratory study was conducted whereby participants (N = 6, 4 F, 21-36y) consumed 200 mg of caffeine, or decaffeinated coffee (placebo), immediately prior to a 30 min nap opportunity at 03:30 h. Compared to placebo, the caffeine-nap resulted in improved vigilant attention and subjective fatigue in the 45 min post-nap opportunity. The caffeine-nap may be useful in reducing sleep inertia in shift workers who nap on nightshift.

Objectives: Compare the incidence and mortality of gynecologic cancers among American Indian/Alaska Native (AI/AN) women to the Non-Hispanic White (NHW) population in the Pacific Northwest., Methods: Age-adjusted cancer incidence (1996-2016) and mortality (2006-2016) rates were calculated from population-based state cancer registry and death certificate data obtained from Washington, Oregon, and Idaho, and corrected for AI/AN misclassification. Incidence and mortality rate ratios (RR) were calculated to compare AI/AN and NHW women with gynecologic cancers., Results: Across all gynecologic cancer sites, AI/AN women were diagnosed at a younger age compared to NHW women. AI/AN women had a higher incidence of cervical cancer compared to NHW women with a RR of 1.53 (95% CI: 1.34, 1.75). For all age groups, AI/AN women had a higher incidence of cervical cancer and the disparity was greatest in the 50-64 age group with a RR of 1.76 (95% CI: 1.36, 2.30). Cervical cancer mortality was greater among AI/AN women, with an all-ages RR of 1.79 (95% CI: 1.30, 2.46); the disparity was greatest in the 50-64 age group (RR: 2.88, 95% CI: 1.89, 4.38). For uterine cancer, AI/AN women had similar incidence rates as NHW women but higher mortality rates (RR: 1.35, 95% CI: 1.03-1.75). Incidence and mortality for ovarian cancer were similar between groups., Conclusion: Our analysis of gynecologic cancers among AI/AN in the PNW found significant disparities relative to NHW women in cervical cancer incidence and mortality. These disparities persist despite advances in prevention strategies., Competing Interests: Declaration of competing interest The following authors have national grant funding supporting this work: Joshi: Centers for Disease Control and Prevention #NU58DP006385 Bruegl: Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR002370. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Published by Elsevier Inc.)

Objective: Low-risk non-metastatic gestational trophoblastic neoplasia (GTN) has been treated with single agent chemotherapy, but second curettage is emerging as an alternative strategy with reported cure rates of 40%. We sought to estimate the cost-effectiveness of second curettage as the first line treatment of low-risk GTN., Methods: A decision-analytic model was created using TreeAge software to compare costs and outcomes for women with WHO staged low-risk GTN undergoing treatment with 5-day methotrexate (MTX), biweekly pulsed actinomycin-D, or second curettage. Probabilities were derived from the literature. Outcomes of interest included side effects from chemotherapy, need for additional agents, hemorrhage, uterine perforation, and cure rates. Utilities were applied to discounted life expectancy at a rate of 3% to generate quality adjusted life years (QALYs). Sensitivity analyses were then performed in order to assess the robustness of our assumptions., Results: Of the three treatment arms, MTX was associated with the lowest cost and had similar QALYs to the other studied modalities. Second curettage was associated with 49 additional cures when applied to a theoretic cohort of 1000 women, as well as an additional 83 hemorrhages and 17 uterine perforations. Sensitivity analysis on the cure rate of second curettage revealed that second curettage was not cost-effective over MTX unless its probability of cure was 98%., Conclusion: Our study found 5-day MTX was the cost-effective strategy for treatment of women with low-risk, non-metastatic GTN when compared to second curettage and actinomycin-D. In a carefully selected patient population, second curettage may be an additional treatment strategy., Competing Interests: Declaration of competing interest The authors have no sources of funding to disclose and no conflicts of interest to disclose., (Published by Elsevier Inc.)

P granules are phase-separated liquid droplets that play important roles in the maintenance of germ cell fate in Caenorhabditis elegans Both the localization and formation of P granules are highly dynamic, but mechanisms that regulate such processes remain poorly understood. Here, we show evidence that the VASA-like germline RNA helicase GLH-1 couples distinct steps of its ATPase hydrolysis cycle to control the formation and disassembly of P granules. In addition, we found that the phenylalanine-glycine-glycine repeats in GLH-1 promote its localization at the perinucleus. Proteomic analyses of the GLH-1 complex with a GLH-1 mutation that interferes with P granule disassembly revealed transient interactions of GLH-1 with several Argonautes and RNA-binding proteins. Finally, we found that defects in recruiting the P granule component PRG-1 to perinuclear foci in the adult germline correlate with the fertility defects observed in various GLH-1 mutants. Together, our results highlight the versatile roles of an RNA helicase in controlling the formation of liquid droplets in space and time., (Copyright © 2020 by the Genetics Society of America.)

Epithelial remodeling involves ratcheting behavior whereby periodic contractility produces transient changes in cell-cell contact lengths, which stabilize to produce lasting morphogenetic changes. Pulsatile RhoA activity is thought to underlie morphogenetic ratchets, but how RhoA governs transient changes in junction length, and how these changes are rectified to produce irreversible deformation, remains poorly understood. Here, we use optogenetics to characterize responses to pulsatile RhoA in model epithelium. Short RhoA pulses drive reversible junction contractions, while longer pulses produce irreversible junction length changes that saturate with prolonged pulse durations. Using an enhanced vertex model, we show this is explained by two effects: thresholded tension remodeling and continuous strain relaxation. Our model predicts that structuring RhoA into multiple pulses overcomes the saturation of contractility and confirms this experimentally. Junction remodeling also requires formin-mediated E-cadherin clustering and dynamin-dependent endocytosis. Thus, irreversible junction deformations are regulated by RhoA-mediated contractility, membrane trafficking, and adhesion receptor remodeling., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Embryos control force generation at tissue boundaries, but how they do so remains poorly understood. Here we show how tissue-specific expression of the type II cadherin, Cadherin2, patterns actomyosin contractility along tissue boundaries to control zippering and neural tube closure in the basal chordate, Ciona robusta. Cadherin2 is differentially expressed and homotypically enriched in neural cells along the neural/epidermal (Ne/Epi) boundary, where RhoA and myosin are activated during zipper progression. Homotypically enriched Cadherin2 sequesters the Rho GTPase-activating protein, Gap21/23, to homotypic junctions. Gap21/23 in turn redirects RhoA/myosin activity to heterotypic Ne/Epi junctions. By activating myosin II along Ne/Epi junctions ahead of the zipper and inhibiting myosin II along newly formed Ne/Ne junctions behind the zipper, Cadherin2 promotes tissue-level contractile asymmetry to drive zipper progression. We propose that dynamic coupling of junction exchange to local changes in contractility may control fusion and separation of epithelia in many other contexts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tissue morphogenesis arises from coordinated changes in cell shape driven by actomyosin contractions. Patterns of gene expression regionalize cell behaviours by controlling actomyosin contractility. Here we report two modes of control over Rho1 and myosin II (MyoII) activation in the Drosophila endoderm. First, Rho1-MyoII are induced in a spatially restricted primordium via localized transcription of the G-protein-coupled receptor ligand Fog. Second, a tissue-scale wave of Rho1-MyoII activation and cell invagination progresses anteriorly away from the primordium. The wave does not require sustained gene transcription, and is not governed by regulated Fog delivery. Instead, MyoII inhibition blocks Rho1 activation and propagation, revealing a mechanical feedback driven by MyoII. We find that MyoII activation and invagination in each row of cells drives adhesion to the vitelline membrane mediated by integrins, apical spreading, MyoII activation and invagination in the next row. Endoderm morphogenesis thus emerges from local transcriptional initiation and a mechanically driven cycle of cell deformation.

Although it has long been stated that the level of spinal cord termination varies depending on the size of the dog, the evidence for this remains limited. The aim of this study is to investigate the position of the conus medullaris (CM) and dural sac (DS) in a population of dogs of varying size. MRIs of the thoracolumbosacral spine of 101 dogs were included. The location of CM and DS was determined on sagittal T2-weighted images and T1-weighted images, respectively, by three independent observers. The bodyweight and the back length were used as markers of size. Regression analysis showed that the termination point of the CM had a statistically significant relationship with bodyweight (R 2 =0.23, P<0.05). Although not statistically significant (P=0.058), a similar relationship was found between CM and back length (R 2 =0.21). No statistically significant relationship was found between the termination point of the DS and bodyweight (P=0.24) or back length (P=0.19). The study confirms the terminal position of the CM is dependent on size, with a more cranial position with increasing size; however, the termination point of DS remains constant irrespective of dog size., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In this issue of Developmental Cell, Budnar and colleagues report how the scaffolding protein anillin uses cycles of transient binding interactions to enhance the residence time and signaling output of active RhoA to control actomyosin contractility at epithelial junctions and during cell division., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Case Summary: A 9-year-old male neutered domestic longhair cat was presented with a 3 week history of lethargy and pain of unknown origin. A large extra-axial mass was demonstrated on MRI of the head, with cribriform plate destruction, extensive nasal invasion and intracranial expansion, producing a severe mass effect. The mass was isointense on T1-weighted imaging, predominantly hypointense with some hyperintense areas on T2-weighted imaging and fluid attenuation inversion recovery, markedly contrast enhancing, and caused transtentorial and cerebellar herniation. Histopathological evaluation confirmed a transitional (mixed) meningioma., Relevance and Novel Information: To our knowledge this is the first report of a meningioma with extensive nasal involvement in a cat. Based on this case, meningioma should be considered as a differential diagnosis for tumours involving the nasal cavity and frontal lobe with cribriform plate destruction., Competing Interests: Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Protein concentration gradients organize cells and tissues and commonly form through diffusion away from a local source of protein. Interestingly, during the asymmetric division of the Caenorhabditis elegans zygote, the RNA-binding proteins MEX-5 and PIE-1 form opposing concentration gradients in the absence of a local source. In this study, we use near-total internal reflection fluorescence (TIRF) imaging and single-particle tracking to characterize the reaction/diffusion dynamics that maintain the MEX-5 and PIE-1 gradients. Our findings suggest that both proteins interconvert between fast-diffusing and slow-diffusing states on timescales that are much shorter (seconds) than the timescale of gradient formation (minutes). The kinetics of diffusion-state switching are strongly polarized along the anterior/posterior (A/P) axis by the PAR polarity system such that fast-diffusing MEX-5 and PIE-1 particles are approximately symmetrically distributed, whereas slow-diffusing particles are highly enriched in the anterior and posterior cytoplasm, respectively. Using mathematical modeling, we show that local differences in the kinetics of diffusion-state switching can rapidly generate stable concentration gradients over a broad range of spatial and temporal scales., Competing Interests: The authors declare no conflict of interest.

A fundamental challenge in developmental biology is to understand how forces produced by individual cells are patterned in space and time and then integrated to produce stereotyped changes in tissue-level or embryo-level morphology. Ascidians offer a unique opportunity to address this challenge by studying how small groups of cells collectively execute complex, but highly stereotyped morphogenetic movements. Here we highlight recent progress and open questions in the study of ascidian morphogenesis, emphasizing the dynamic interplay of cell fate determination, cellular force generation and tissue-level mechanics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

PAR proteins constitute a highly conserved network of scaffolding proteins, adaptors and enzymes that form and stabilize cortical asymmetries in response to diverse inputs. They function throughout development and across the metazoa to regulate cell polarity. In recent years, traditional approaches to identifying and characterizing molecular players and interactions in the PAR network have begun to merge with biophysical, theoretical and computational efforts to understand the network as a pattern-forming biochemical circuit. Here, we summarize recent progress in the field, focusing on recent studies that have characterized the core molecular circuitry, circuit design and spatiotemporal dynamics. We also consider some of the ways in which the PAR network has evolved to polarize cells in different contexts and in response to different cues and functional constraints., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

In this issue of Developmental Cell, Dickinson et al. (2017) and Rodriguez et al. (2017), along with Wang et al. (2017) in Nature Cell Biology, show how PAR protein oligomerization can dynamically couple protein diffusion and transport by cortical flow to control kinase activity gradients and polarity in the C. elegans zygote., (Copyright © 2017. Published by Elsevier Inc.)

The aim of this study was to demonstrate for the first time that sexual maturation induces a constitutive increase in Mx gene expression and protein production in Atlantic salmon. This could explain the reduction in IPNV prevalence previously observed in broodfish at the time of ova/milt stripping. For this purpose, Mx transcript and protein levels were analysed in different tissues/samples and compared between mature broodfish (female and male) and immature parr., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objective: Objective structured clinical examinations (OSCE) are widely used for summative assessment in surgery. Despite standardizing these as much as possible, variation, including examiner scoring, can occur which may affect reliability. In study of a high-stakes UK postgraduate surgical OSCE, we investigated whether examiners changing stations once during a long examining day affected marking, reliability, and overall candidates' scores compared with examiners who examined the same scenario all day., Design, Setting, and Participants: An observational study of 18,262 examiner-candidate interactions from the UK Membership of the Royal College of Surgeons examination was carried at 3 Surgical Colleges across the United Kingdom. Scores between examiners were compared using analysis of variance. Examination reliability was assessed with Cronbach's alpha, and the comparative distribution of total candidates' scores for each day was evaluated using t-tests of unit-weighted z scores., Results: A significant difference was found in absolute scores differences awarded in the morning and afternoon sessions between examiners who changed stations at lunchtime and those who did not (p < 0.001). No significant differences were found for the main effects of either broad content area (p = 0.290) or station content area (p = 0.450). The reliability of each day was not affected by examiner switching (p = 0.280). Overall, no difference was found in z-score distribution of total candidate scores and categories of examiner switching., Conclusions: This large study has found that although the range of marks awarded varied when examiners change OSCE stations, examination reliability and the likely candidate outcome were not affected. These results may have implications for examination design and examiner experience in surgical OSCEs and beyond., (Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Increased clinical research in the NHS has led to a need to improve and standardise education on research provided to nurses. A group of senior research nurses developed and piloted a course on research skills that, after positive evaluations, has been rolled out nationally.

It has been shown that N-fold symmetric line current (henceforth denoted as N-SYLC) produces 2N-pole magnetic fields. In this paper, a threefold symmetric line current (N3-SYLC in short) is proposed for correcting 3rd order spherical aberration of round lenses. N3-SYLC can be realized without using magnetic materials, which makes it free of the problems of hysteresis, inhomogeneity and saturation. We investigate theoretically the basic properties of an N3-SYLC configuration which can in principle be realized by simple wires. By optimizing the parameters of a system with beam energy of 5.5keV, the required excitation current for correcting 3rd order spherical aberration coefficient of 400 mm is less than 1AT, and the residual higher order aberrations can be kept sufficiently small to obtain beam size of less than 1 nm for initial slopes up to 5 mrad., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dynamic maintenance of cell polarity is essential for development and physiology. Here we combine experiments and modeling to elucidate mechanisms that maintain cortical polarity in the C. elegans zygote. We show that polarity is dynamically stabilized by two coupled cross-inhibitory feedback loops: one involves the oligomeric scaffold PAR-3 and the kinase PAR-1, and the other involves CDC-42 and its putative GAP CHIN-1. PAR-3 and CDC-42 are both required locally to recruit PAR-6/PKC-3, which inhibits PAR-1 (shown previously) and inhibits local growth/accumulation of CHIN-1 clusters. Conversely, PAR-1 inhibits local accumulation of PAR-3 oligomers, while CHIN-1 inhibits CDC-42 (shown previously), such that either PAR-1 or CHIN-1 can prevent recruitment of PAR-6/PKC-3, but loss of both causes complete loss of polarity. Ultrasensitive dependence of CHIN-1 cluster growth on PAR-6/PKC-3 endows this core circuit with bistable dynamics, while transport of CHIN-1 clusters by cortical flow can stabilize the AP boundary against diffusive spread of PAR-6/PKC-3., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Tissue morphogenesis is orchestrated by cell shape changes. Forces required to power these changes are generated by non-muscle myosin II (MyoII) motor proteins pulling filamentous actin (F-actin). Actomyosin networks undergo cycles of assembly and disassembly (pulses) to cause cell deformations alternating with steps of stabilization to result in irreversible shape changes. Although this ratchet-like behaviour operates in a variety of contexts, the underlying mechanisms remain unclear. Here we investigate the role of MyoII regulation through the conserved Rho1-Rok pathway during Drosophila melanogaster germband extension. This morphogenetic process is powered by cell intercalation, which involves the shrinkage of junctions in the dorsal-ventral axis (vertical junctions) followed by junction extension in the anterior-posterior axis. While polarized flows of medial-apical MyoII pulses deform vertical junctions, MyoII enrichment on these junctions (planar polarity) stabilizes them. We identify two critical properties of MyoII dynamics that underlie stability and pulsatility: exchange kinetics governed by phosphorylation-dephosphorylation cycles of the MyoII regulatory light chain; and advection due to contraction of the motors on F-actin networks. Spatial control over MyoII exchange kinetics establishes two stable regimes of high and low dissociation rates, resulting in MyoII planar polarity. Pulsatility emerges at intermediate dissociation rates, enabling convergent advection of MyoII and its upstream regulators Rho1 GTP, Rok and MyoII phosphatase. Notably, pulsatility is not an outcome of an upstream Rho1 pacemaker. Rather, it is a self-organized system that involves positive and negative biomechanical feedback between MyoII advection and dissociation rates.