Multi-signal regulation of the GSK-3ß homolog Rim11 controls meiosis entry in budding yeast.

Starvation in diploid budding yeast cells triggers a cell-fate program culminating in meiosis and spore formation. Transcriptional activation of early meiotic genes (EMGs) hinges on the master regulator Ime1, its DNA-binding partner Ume6, and GSK-3ß kinase Rim11. Phosphorylation of Ume6 by Rim11 is required for EMG activation. We report here that Rim11 functions as the central signal integrator for controlling Ume6 phosphorylation and EMG transcription. In nutrient-rich conditions, PKA suppresses Rim11 levels, while TORC1 retains Rim11 in the cytoplasm. Inhibition of PKA and TORC1 induces Rim11 expression and nuclear localization. Remarkably, nuclear Rim11 is required, but not sufficient, for Rim11-dependent Ume6 phosphorylation. In addition, Ime1 is an anchor protein enabling Ume6 phosphorylation by Rim11. Subsequently, Ume6-Ime1 coactivator complexes form and induce EMG transcription. Our results demonstrate how various signaling inputs (PKA/TORC1/Ime1) converge through Rim11 to regulate EMG expression and meiosis initiation. We posit that the signaling-regulatory network elucidated here generates robustness in cell-fate control.

Heart rate responses, agreement and accuracy among persons with severe disabilities participating in the indirect movement program: Team Twin-an observational study.

Introduction: Heart rate (HR) monitors are rarely used by people living with disabilities (PLWD), and their accuracy is undocumented. Thus, this study aims to describe the HR response during the Team Twin co-running program and, secondly, to assess the agreement and accuracy of using HR monitors among PLWD. Methods: This 16-week single-arm observational study included 18 people with various disabilities. During the study, the subjects wore a Garmin Vivosmart 4 watch (wrist). To evaluate the agreement and accuracy we applied Garmin's HRM-DUAL™ chest-worn HR monitors for comparison with the Vivosmart 4. The HR response analysis was performed descriptively and with a mixed regression model. The HR agreement and accuracy procedure was conducted on a subsample of five subjects and analyzed using Lin's concordance analysis, Bland and Altman's limits of agreement, and Cohen's kappa analysis of intensity zone agreement. This study was prospectively registered at Clinical Trials.gov (NCT04536779). Results: The subjects had a mean age of 35 (±12.6), 61% were male, 72% had cerebral palsy were 85% had GMFCS V-IV. HR was monitored for 202:10:33 (HH:MM:SS), with a mean HR of 90 ± 17 bpm during training and race. A total of 19% of the time was spent in intensity zones between light and moderate (30%-59% HR reserve) and 1% in vigorous (60%-84% HR reserve). The remaining 80% were in the very light intensity zone (<29% HR reserve). HR was highest at the start of race and training and steadily decreased. Inter-rater agreement was high (k = 0.75), limits of agreement were between -16 and 13 bpm, and accuracy was acceptable (Rc = 0.86). Conclusion: Disability type, individual, and contextual factors will likely affect HR responses and the agreement and accuracy for PLWD. The Vivosmart 4, while overall accurate, had low precision due to high variability in the estimation. These findings implicate the methodical and practical difficulties of utilizing HR monitors to measure HR and thus physical activity in adapted sports activities for severely disabled individuals.

Modelling capture efficiency of single-cell RNA-sequencing data improves inference of transcriptome-wide burst kinetics.

MOTIVATION: Gene expression is characterized by stochastic bursts of transcription that occur at brief and random periods of promoter activity. The kinetics of gene expression burstiness differs across the genome and is dependent on the promoter sequence, among other factors. Single-cell RNA sequencing (scRNA-seq) has made it possible to quantify the cell-to-cell variability in transcription at a global genome-wide level. However, scRNA-seq data are prone to technical variability, including low and variable capture efficiency of transcripts from individual cells. RESULTS: Here, we propose a novel mathematical theory for the observed variability in scRNA-seq data. Our method captures burst kinetics and variability in both the cell size and capture efficiency, which allows us to propose several likelihood-based and simulation-based methods for the inference of burst kinetics from scRNA-seq data. Using both synthetic and real data, we show that the simulation-based methods provide an accurate, robust and flexible tool for inferring burst kinetics from scRNA-seq data. In particular, in a supervised manner, a simulation-based inference method based on neural networks proves to be accurate and useful when applied to both allele and nonallele-specific scRNA-seq data. AVAILABILITY AND IMPLEMENTATION: The code for Neural Network and Approximate Bayesian Computation inference is available at https://github.com/WT215/nnRNA and https://github.com/WT215/Julia_ABC, respectively.

Data-driven spatio-temporal modelling of glioblastoma.

Mathematical oncology provides unique and invaluable insights into tumour growth on both the microscopic and macroscopic levels. This review presents state-of-the-art modelling techniques and focuses on their role in understanding glioblastoma, a malignant form of brain cancer. For each approach, we summarize the scope, drawbacks and assets. We highlight the potential clinical applications of each modelling technique and discuss the connections between the mathematical models and the molecular and imaging data used to inform them. By doing so, we aim to prime cancer researchers with current and emerging computational tools for understanding tumour progression. By providing an in-depth picture of the different modelling techniques, we also aim to assist researchers who seek to build and develop their own models and the associated inference frameworks. Our article thus strikes a unique balance. On the one hand, we provide a comprehensive overview of the available modelling techniques and their applications, including key mathematical expressions. On the other hand, the content is accessible to mathematicians and biomedical scientists alike to accommodate the interdisciplinary nature of cancer research.

Efficient Bayesian inference for stochastic agent-based models.

The modelling of many real-world problems relies on computationally heavy simulations of randomly interacting individuals or agents. However, the values of the parameters that underlie the interactions between agents are typically poorly known, and hence they need to be inferred from macroscopic observations of the system. Since statistical inference rests on repeated simulations to sample the parameter space, the high computational expense of these simulations can become a stumbling block. In this paper, we compare two ways to mitigate this issue in a Bayesian setting through the use of machine learning methods: One approach is to construct lightweight surrogate models to substitute the simulations used in inference. Alternatively, one might altogether circumvent the need for Bayesian sampling schemes and directly estimate the posterior distribution. We focus on stochastic simulations that track autonomous agents and present two case studies: tumour growths and the spread of infectious diseases. We demonstrate that good accuracy in inference can be achieved with a relatively small number of simulations, making our machine learning approaches orders of magnitude faster than classical simulation-based methods that rely on sampling the parameter space. However, we find that while some methods generally produce more robust results than others, no algorithm offers a one-size-fits-all solution when attempting to infer model parameters from observations. Instead, one must choose the inference technique with the specific real-world application in mind. The stochastic nature of the considered real-world phenomena poses an additional challenge that can become insurmountable for some approaches. Overall, we find machine learning approaches that create direct inference machines to be promising for real-world applications. We present our findings as general guidelines for modelling practitioners.

The development of a health-promoting employment intervention with physical activity for young people Not in Education, Employment or Training (NEET): NEXT STEP-on the path to education and job.

BACKGROUND: In the EU, approx. 16.5% of the 20-34-year-olds are Not in Education, Employment or Training (NEET). Research shows that good health is an important progression factor towards employment, and daily physical activity as well as participation in sports has a positive effect on physical and mental health as well as in the development of life skill. However, there is an absence of studies investigating what role physical activity can play in the employment efforts. The aim of this study is to investigate experiences with physical activity in employment interventions and to describe the development of a health-promoting employment intervention with physical activity for young people aged 18-30 years who are NEET. METHODS: The study combined an evidence-based approach with practice-based experiences. It included a Mapping of Danish employment interventions with physical activity for young people NEET, an overview of national reports and international literature, a workshop with leaders and employees from Danish municipalities, and fieldwork in four municipalities. Key findings were grouped thematically and were transformed into intervention content in a close dialog with relevant researchers and practitioners. RESULTS: In general, physical activity was assessed as a meaningful method when working with young people NEET. A range of positive experiences was highlighted, including successful experiences, surplus of mental resources, new ways of meeting, and new social relations. Based on these findings, a 16-week health-promoting employment intervention, NEXT STEP, was developed with the following intervention components: (1) fixed boundaries, (2) body and physical activity, (3) social relations and network, and (4) life skills and future. NEXT STEP is designed to be implemented in Danish job centers. CONCLUSION: The study found the great potential of including physical activity in employment interventions for young people NEET. The planning and development of the intervention have reinforced a comprehensive evaluation; however, the first intervention in its entirety is ready for testing in a randomized feasibility trial.

The Danish National Youth Study 2019: study design and participant characteristics.

AIM: To present the study design, study population and questionnaire content of the Danish National Youth Study 2019, and to describe the differences between participants and non-participants regarding demographic and socioeconomic characteristics. METHOD: The Danish National Youth Study 2019 is a nationwide web-survey among high school students in Denmark. Data was collected from January to April 2019 through a self-administered questionnaire in the classroom. The questionnaire included 120 questions on, for example, physical and mental health, health behaviour and well-being. Data collection took place at 50 general high schools, 32 preparatory high schools, 15 commercial high school and 19 technical high schools. RESULTS: A total of 29,086 students participated (20,287 general high school students, 2,113 preparatory higher school students, 4027 commercial high school students and 2659 technical high school students) corresponding to 66% of the students in the 88 participating schools (31% of invited schools). Among students, 55% were female and the mean age was 17.8 years. Participants were more likely to be female, to be younger, to be of Danish origin, and have family disposable income in the highest quartile compared to non-participants. CONCLUSIONS: The Danish National Youth Study 2019 contributes to knowledge on high school students' health, health behaviour and well-being that can support health planning and prioritizing, through identification of specific risk groups at both local and national level. The study also offers great opportunities for future research as it provides possibility of linkage to various Danish national registers.

When Movement Moves: Study Protocol for a Multi-Method Pre/Post Evaluation Study of Two Programmes; the Danish Team Twin and Cycling Without Age.

Physical activity (PA) can improve physical, mental, and social health, leading to quality of life (QoL). However, some are unable to participate independently due to age-related impairments or disabilities. This study protocol presents the design, methods, outcomes, strengths and limitations of the study "When Movement Moves" (WMM). WMM investigates whether indirect PA in a social context, where persons are unable to participate independently, can result in outcomes similar to those of independent PA, by evaluating the effects of disabled's, elderly, volunteers', relatives' and nursing staff's participation in either the running programme (Team Twin) or cycling programme (Cycling Without Age). Both programmes seek to enhance QoL through indirect PA in a social context, making PA possible for elderly and disabled persons through PA conducted by abled-bodied volunteers. WMM is a multi-method 12-16-week pre/post evaluation with quality of life, physical, mental and social health as main outcomes. Pre/post measurements consist of questionnaires, clinical examinations, and physical and cognitive appraisal. Throughout, interviews and participant observations will be conducted. Combined results will provide essential knowledge on the effects and experiences of indirect PA. Explorative data will pave the way for further research. Findings may inform policies, guidelines and health promotion among the elderly and disabled.

Adaptation, Student Participation and Gradual Withdrawal by Researchers as Sustainability Strategies in the High School-Based Young and Active Intervention: School Coordinators' Perspectives.

Ensuring the sustainability of school-based public health intervention activities remains a challenge. The Young and Active (Y&A) intervention used peer-led workshops to promote movement and strengthen students' sense of community in 16 Danish high schools. Peer mentors inspired first-year students to implement movement activities. To support sustainability, we applied a three-year stepwise implementation strategy using university students as peer mentors in year 1 and senior high school students in the following two years. This study explores the sustainability potential of Y&A, focusing on school coordinators' reflections on the intervention's fit to their schools and the student-driven approach, and we assess the three-step implementation strategy. The study is based on telephone interviews with coordinators (n = 7) from schools that participated in all three years and participant observations of four workshops (a total of approximately 250 participating students). Results were generated through an abductive analysis. Seven schools continued the intervention throughout the three years and adapted it to fit their priorities. The student-driven approach was perceived to be valuable, but few student-driven activities were initiated. Teacher support seemed crucial to support students in starting up activities and acting as peer mentors in workshops. The three-step implementation strategy proved valuable due to the peer-approach and the possibility of gradual adaptation. In future similar initiatives, it is important to address how the adequate staff support of students can be facilitated.

Carbon assimilation through a vertical light gradient in the canopy of invasive herbs grown under different temperature regimes is determined by leaf and whole-plant architecture.

This study examined the acclimation to temperature of two globally invasive species Iris pseudacorus and Lythrum salicaria, which share the same habitat type but differ in morphology. Iris pseudacorus has long vertical leaves, allowing light penetration through the canopy, while L. salicaria has stems with small horizontal leaves, creating significant self-shading. We aimed to build a physiological understanding of how these two species respond to different growth temperatures with regard to growth and gas exchange-related traits over the canopy. Growth and gas exchange-related traits in response to low (15 °C) and high (25 °C) growth temperature regimes were compared. Plants were grown in growth chambers, and light response curves were measured with infrared gas analysers after 23-33 days at three leaf positions on each plant, following the vertical light gradient through the canopy. After 37 days of growth, above-ground biomass, photosynthetic pigments and leaf N concentration were determined. The maximum photosynthesis rate was lower in lower leaf positions but did not differ significantly between temperatures. Iris pseudacorus photosynthesis decreased with decreasing leaf position, more so than L. salicaria. This was explained by decreasing N and chlorophyll concentrations towards the leaf base in I. pseudacorus, while pigment concentrations increased towards the lower canopy in L. salicaria. Biomass, shoot height and specific leaf area increased with temperature, more so in I. pseudacorus than in L. salicaria. Light response curves revealed that L. salicaria had a higher degree of shade acclimation than I. pseudacorus, probably due to self-shading in L. salicaria. High temperature decreased C assimilation at the bottom of the canopy in L. salicaria, while C assimilation in I. pseudacorus was less affected by temperature. As vegetative growth and flowering was stimulated by temperature, the invasive potential of these species is predicted to increase under global warming.

No Impact of Pre-existing Cardiovascular Disease on Prescribing Patterns of Sulphonylureas in Denmark - A Registry-based Nationwide Study.

Uncertainty exists regarding cardiovascular (CV) safety of sulphonylureas (SUs) as reflected in package labels and treatment guidelines. This study evaluated clinical treatment practice for SUs by analysing prescription patterns for SUs relative to patient history of CV disease (CVD). Patients in Denmark initiating treatment with SU or other anti-hyperglycaemic drugs during 2006-12 were retrospectively identified using national health registries. Pre-existing (previous 12 years) overall CVD, coronary heart disease (CHD) and myocardial infarction (MI) were subsequently identified. Proportion of patients with pre-existing CVD was compared between new users of SU and new users of other anti-hyperglycaemic drugs. In total, 50,425 (42.2% females, mean ± SD age 63.3 ± 13.5 years) and 190,438 (46.5% females, age 60.3 ± 15.0 years) patients initiated treatment with SU or other anti-hyperglycaemic drugs, respectively, during 2006-12. The number of patients initiating SU treatment decreased by 63% during 2006-12. The proportion of patients with pre-existing CVD varied between 46.9% and 49.8% among new SU users versus 39.9% and 44.8% among new users of other anti-hyperglycaemic drugs. Corresponding proportions for CHD (17.9-19.9% versus 15.4-16.9%) and MI (6.3-7.5% versus 5.8-6.2%) showed the same pattern. Excluding new gliclazide users (9.6% of all new SU users) from the SU definition did not alter the results. Despite a potentially increased CV risk associated with use of SUs, pre-existing CVD did not decrease clinicians' relative prescriptions of SUs.

Effects of sodium nitrite on renal function and blood pressure in hypertensive vs. healthy study participants: a randomized, placebo-controlled, crossover study.

OBJECTIVE: Nitric oxide is a key player in regulating vascular tone. Impaired endothelial nitric oxide synthesis plays an important role in hypertension. Replenishing of nitric oxide by sodium nitrite (NaNO2) has not been investigated in patients with essential hypertension (EHT). We aimed to determine the effects of NaNO2 on blood pressure (BP) and renal sodium and water regulation in patients with EHT compared with healthy control study participants (CON). METHODS: In a placebo-controlled, crossover study, we infused 240 µg NaNO2/kg/h or isotonic saline for 2 h in 14 EHT and 14 CON. During infusion, we measured changes in brachial and central BP, free water clearance, fractional sodium excretion, and urinary excretion rate of γ-subunit of the epithelial sodium channel (U-ENaCγ), and aquaporin-2 (U-AQP2). RESULTS: Placebo-adjusted brachial SBP decreased 18 mmHg (P < 0.001) during NaNO2 infusion in EHT and 12 mmHg (P < 0.001) in CON (Pbetween = 0.024). Brachial DBP and central SBP decreased equally in both groups during NaNO2. In EHT, we found a decrease in U-ENaCγ during NaNO2 infusion. In both groups, we observed a decrease in fractional sodium excretion, free water clearance, and U-AQP2 during NaNO2 infusion. CONCLUSION: This study demonstrated an augmented BP-lowering effect of NaNO2 in patients with EHT. We observed an antinatriuretic and antidiuretic effect of NaNO2 in both groups, and a decrease in U-ENaCγ, solely in EHT. In both groups, we detected a nonvasopressin mediated decrease in U-AQP2, which is most likely compensatory to the decline in diuresis.

Traumatic separation of osseous segments in a double-layered patella.

INTRODUCTION: Double-layered patella is a rare intra-articular disorder associated with multiple epiphyseal dysplasia. PRESENTATION OF CASE: We present a case of a 40-year old man with acute pain in his left knee after a tackle during soccer play. DISCUSSION: Clinical examination and radiographs confirmed the diagnosis of a bilateral double-layered patella with traumatic separation of the osseous segments on the afflicted left side. Surgical management comprised of open arthrotomy and debridement of the bony interface. Stabilization was performed with tension cerclage, supported by a lag screw with excellent outcome at 12 months follow-up. CONCLUSION: It is possible that micromovement in a double-layered patella can dispose to a traumatic coronal segment displacement. Osseous fusion of traumatic patellar segments can be achieved.

Validation of the Danish version of the Oxford Elbow Score.

INTRODUCTION: The Oxford Elbow Score (OES) is a patient-related outcome measure quantifying quality of life in relation to elbow disorders. This 12-item patient-administered English questionnaire comprises three domains: function, social-psychological status and pain. The purpose of this study was to examine the structure and reliability of the Danish version of the OES (D-OES). MATERIAL AND METHODS: A total of 130 patients who had total elbow arthroplasty (TEA) surgery performed in the period from 1981 to 2008 completed the D-OES. The Disability of the Arm, Shoulder and Hand score (DASH) and the Mayo Elbow Performance Score (MEPS) were also completed with a view to examining the convergent validity of the D-OES. In 45 cases, the questionnaire was completed twice to allow for calculation of test-retest reliability. The structure of the questionnaire was tested using Rasch analysis. RESULTS: Overall internal consistency tested by Cronbach's alpha was 0.99. The test-retest reliability correlation coefficient was 0.99. Expressed in terms of Pearson's correlation coefficient, the convergent validity of the D-OES's functional, social-psychological and pain domain was 0.78, 0.80 and 0.81, respectively, for the MEPS and -0.66, -0.58 and -0.49, respectively, for the DASH. The 12 items of the D-OES fitted the Rasch model, and the multidimensionality of the OES was confirmed. CONCLUSION: The Danish 12-item OES is a valid and reliable-patient administered questionnaire that can be used to quantify quality of life in patients with TEA.

Wet deposition of pesticides and nitrophenols at two sites in Denmark: measurements and contributions from regional sources.

The concentrations of selected pesticides, of some of their degradation products and nitrophenols in rain were measured at two stations in Denmark in the period January 2000-July 2001. Forty compounds were quantified at least at one station during at least one sampling period. Additionally 17 compounds could be detected but not quantified, and 22 compounds could not be detected at all. The highest depositions of pesticides were observed for pendimethalin and desethylterbuthylazine, which is a degradation product of terbuthylazine. The deposition of the nitrophenols 2,4-dinitrophenol, DNOC, 3-methyl-4-nitrophenol was much higher than that of pesticides. The deposition of 2,4-dinitrophenol was e.g. up to a factor of 40 higher than that of pendimethalin. Atrazine, chloridazon, 2,4-D, dieldrin, disulfoton, fenitrothion, isoproturon, lenacil, metazachlor and propachlor were found in precipitation, although these pesticides are not allowed in Denmark. It can therefore be concluded that they came from abroad and have been transported over at least 60-80 km. For some of these compounds the transport distance is much longer.