Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation

Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis

Updating the Shared Socioeconomic Pathways (SSPs) Global Population and Human Capital Projections

The first set of population projections following the Shared Socioeconomic Pathways (SSPs) was developed in 2013. These projections have found widespread use within the environmental and climate change community, among others. In 2018, an SSPs update was generated but not integrated into the SSP database. In 2021, the SSP community requested an update of the human core of the SSPs, which is detailed in this report. This updated version is based on 2020 as the reference year, with adjustments to certain short-term assumptions extending to 2030. Consequently, the assumptions' trend component is grounded in recent observed changes. The modeling approaches for fertility, mortality, and educational attainment have been revised. Notably, there are updates to education-specific fertility rates with new estimates. Education-specific mortality has been made specific to countries and regions. Additionally, this version introduces explicit education-specific migration differentials. The paper presents a comparison between the methodology used for developing the global population and education projections under the five SSPs and the previous method. Furthermore, a brief analysis is conducted on the primary results regarding population size and composition, with comparisons made to earlier projections and other organizations, including the United Nations Population Division

Linking formal child care characteristics to children's socioemotional well-being: A comparative perspective

Most research on formal child care and children’s outcomes has focused on single countries. We, however, contend that policy context may moderate the association between formal child care characteristics and children’s socioemotional well-being. We examined this by comparing the Netherlands, Finland and the UK; three countries that differ regarding family policies. Of these three countries, Finland was recently ranked highest (ranked 1st) with regards to quality of child care in a recent analysis by the Economist ,followed by the UK (ranked 3rd) and then the Netherlands (ranked 7th) .We hypothesized that children who attend child - care settings in countries with higher- uality formal child- are provision would generally show better socioemotional outcomes. Data from the comparative ‘F amilies 24/7’ survey were used, including 990 parents with children aged 0–12. We distinguished between two age groups in our analysis. Results indicated that, compared to the UK, longer hours in formal care were less beneficial in the Netherlands. Furthermore, spen ding time in formal care during nonstandard hours was more harmful for children in Finland compared to the UK. Lastly, receiving care from multiple caregivers was more disruptive for British children than for Dutch children. No differences were found between Finland and the Netherlands

The reliability of side to side measurements of upper extremity activity levels in healthy subjects

<p>Abstract</p> <p>Background</p> <p>In both clinical and occupational settings, ambulatory sensors are becoming common for assessing all day measurements of arm motion. In order for the motion of a healthy, contralateral side to be used as a control for the involved side, the inherent side to side differences in arm usage must be minimal. The goal of the present study was to determine the reliability of side to side measurements of upper extremity activity levels in healthy subjects.</p> <p>Methods</p> <p>Thirty two subjects with no upper extremity pathologies were studied. Each subject wore a triaxial accelerometer on both arms for three and a half hours. Motion was assessed using parameters previously reported in the literature. Side to side differences were compared with the intraclass correlation coefficient, standard error of the mean, minimal detectable change scores and a projected sample size analysis.</p> <p>Results</p> <p>The variables were ranked based on their percentage of minimal detectable change scores and sample sizes needed for paired t-tests. The order of these rankings was found to be identical and the top ranked parameters were activity counts per hour (MDC% = 9.5, n = 5), jerk time (MDC% = 15.8, n = 8) and percent time above 30 degrees (MDC% = 34.7, n = 9).</p> <p>Conclusions</p> <p>In general, the mean activity levels during daily activities were very similar between dominant and non-dominant arms. Specifically, activity counts per hour, jerk time, and percent time above 30 degrees were found to be the variables most likely to reveal significant difference or changes in both individuals and groups of subjects. The use of ambulatory measurements of upper extremity activity has very broad uses for occupational assessments, musculoskeletal injuries of the shoulder, elbow, wrist and hand as well as neurological pathologies.</p

Stroke Rehabilitation Reaches a Threshold

Motor training with the upper limb affected by stroke partially reverses the loss of cortical representation after lesion and has been proposed to increase spontaneous arm use. Moreover, repeated attempts to use the affected hand in daily activities create a form of practice that can potentially lead to further improvement in motor performance. We thus hypothesized that if motor retraining after stroke increases spontaneous arm use sufficiently, then the patient will enter a virtuous circle in which spontaneous arm use and motor performance reinforce each other. In contrast, if the dose of therapy is not sufficient to bring spontaneous use above threshold, then performance will not increase and the patient will further develop compensatory strategies with the less affected hand. To refine this hypothesis, we developed a computational model of bilateral hand use in arm reaching to study the interactions between adaptive decision making and motor relearning after motor cortex lesion. The model contains a left and a right motor cortex, each controlling the opposite arm, and a single action choice module. The action choice module learns, via reinforcement learning, the value of using each arm for reaching in specific directions. Each motor cortex uses a neural population code to specify the initial direction along which the contralateral hand moves towards a target. The motor cortex learns to minimize directional errors and to maximize neuronal activity for each movement. The derived learning rule accounts for the reversal of the loss of cortical representation after rehabilitation and the increase of this loss after stroke with insufficient rehabilitation. Further, our model exhibits nonlinear and bistable behavior: if natural recovery, motor training, or both, brings performance above a certain threshold, then training can be stopped, as the repeated spontaneous arm use provides a form of motor learning that further bootstraps performance and spontaneous use. Below this threshold, motor training is “in vain”: there is little spontaneous arm use after training, the model exhibits learned nonuse, and compensatory movements with the less affected hand are reinforced. By exploring the nonlinear dynamics of stroke recovery using a biologically plausible neural model that accounts for reversal of the loss of motor cortex representation following rehabilitation or the lack thereof, respectively, we can explain previously hard to reconcile data on spontaneous arm use in stroke recovery. Further, our threshold prediction could be tested with an adaptive train–wait–train paradigm: if spontaneous arm use has increased in the “wait” period, then the threshold has been reached, and rehabilitation can be stopped. If spontaneous arm use is still low or has decreased, then another bout of rehabilitation is to be provided

Competences of Mathematics Teachers in Diagnosing Teaching Situations and Offering Feedback to Students:Specificity, Consistency and Reification of Pedagogical and Mathematical Discourses

In the study we report in this chapter, we investigate the competences of mathematics pre- and in-service teachers in diagnosing situations pertaining to mathematics teaching and in offering feedback to the students at the heart of said situations. To this aim we deploy a research design that involves engaging teachers with situation-specific tasks in which we invite participants to: solve a mathematical problem; examine a (fictional yet research-informed) solution proposed by a student in class and a (fictional yet research-informed) teacher response to the student; and, describe the approach they themselves would adopt in this classroom situation. Participants were 23 mathematics graduates enrolled in a post-graduate mathematics education programme, many already in-service teachers. They responded to a task that involved debating the identification of a tangent line at an inflection point of a cubic function through resorting to the formal definition of tangency or the function graph. Analysis of their written responses to the task revealed a great variation in the participants’ diagnosing and addressing of teaching issues – in this case involving the role of visualisation in mathematical reasoning. We describe this variation in terms of a typology of four interrelated characteristics that emerged from the data analysis: consistency between stated beliefs/knowledge and intended practice, specificity of the response to the given classroom situation, reification of pedagogical discourses, and reification of mathematical discourses. We propose that deploying the theoretical construct of these characteristics in tandem with our situation-specific task design can contribute towards the identification – as well as reflection upon and development – of mathematics teachers’ diagnostic competences in teacher education and professional development programmes

Conceptualizing national family policies: A capabilities approach

Comparative family policy research has advanced significantly in recent years. The growing availability of more and better data have improved our understanding of cross-national similarities and differences in family policies, as well as how they shape the lives of different families. Despite these advancements, comparative family policy research continues to face difficulties. The multifaceted nature of family policies makes cross-country comparisons complex. Conceptualizing our theoretical understanding of which policy aspects matter and why as well as operationalizing them into measurable indicators, often remains problematic for comparative analyses. Using examples of British and Swedish policies on childcare, a policy area particularly prone to conceptual challenges, we discuss the difficulties involved in conceptualizing family policies in comparative research. We argue that taking a capabilities approach provides a useful way forward in the field and show how such a conceptual framework allows us to more meaningfully analyze both work-family policies and their outcomes

Alternative Formula for the Series of Consecutive m-Squares under Alternating Signs

Abstract This paper developed a simple but elegant formula for the series of consecutive square of natural numbers under alternating signs. Furthermore, this study investigated the said formula under odd and even number of terms and discuss some important results. Keywords: consecutive -squares; alternating signs; odd and even terms.   Abstrak Dalam paper ini kita membangun formula yang sederhana namun elegan untuk menghitung jumlah deret berganti-tanda dari kuadrat bilangan-bilangan asli berurutan.  Kita akan menyelidiki formula untuk kasus banyaknya suku ganjil maupun genap dan mendiskusikan beberapa hasil yang penting. Kata kunci: -kuadrat berurutan; berganti-tanda; bersuku ganjil dan bersuku genap