On the mechanical interplay between intra- and inter-synchronization during collective cell migration : a numerical investigation

Collective cell migration is a fundamental process that takes place during several biological phenomena such as embryogenesis, immunity response, and tumorogenesis, but the mechanisms that regulate it are still unclear. Similarly to collective animal behavior, cells receive feedbacks in space and time, which control the direction of the migration and the synergy between the cells of the population, respectively. While in single cell migration intra-synchronization (i.e. the synchronization between the protrusion-contraction movement of the cell and the adhesion forces exerted by the cell to move forward) is a sufficient condition for an efficient migration, in collective cell migration the cells must communicate and coordinate their movement between each other in order to be as efficient as possible (i.e. inter-synchronization). Here, we propose a 2D mechanical model of a cell population, which is described as a continuum with embedded discrete cells with or without motility phenotype. The decomposition of the deformation gradient is employed to reproduce the cyclic active strains of each single cell (i.e. protrusion and contraction). We explore different modes of collective migration to investigate the mechanical interplay between intra- and inter-synchronization. The main objective of the paper is to evaluate the efficiency of the cell population in terms of covered distance and how the stress distribution inside the cohort and the single cells may in turn provide insights regarding such efficiency

Clinical leadership in service redesign using Clinical Commissioning Groups: a mixed-methods study

Background: A core component of the Health and Social Care Act 2012 (Great Britain. Health and Social Care Act 2012. London: HMSO; 2012) was the idea of devolving to general practitioners (GPs) a health service leadership role for service redesign. For this purpose, new Clinical Commissioning Groups (CCGs) were formed in the English NHS.Objectives: This research examined the extent to which, and the methods by which, clinicians stepped forward to take up a leadership role in service redesign using CCGs as a platform.Design: The project proceeded in five phases: (1) a scoping study across 15 CCGs, (2) the design and administration of a national survey of all members of CCG governing bodies in 2014, (3) six main in-depth case studies, (4) a second national survey of governing body members in 2016, which allowed longitudinal comparisons, and (5) international comparisons.Participants: In addition to GPs serving in clinical lead roles for CCGs, the research included insights from accountable officers and other managers and perspectives from secondary care and other provider organisations (local authority councillors and staff, patients and the public, and other relevant bodies).Results: Instances of the exercise of clinical leadership utilising the mechanism of the CCGs were strikingly varied. Some CCG teams had made little of the opportunity. However, we found other examples of clinicians stepping forward to bring about meaningful improvements in services. The most notable cases involved the design of integrated care for frail elderly patients and others with long-term conditions. The leadership of these service redesigns required cross-boundary working with primary care, secondary care, community care and social work. The processes enabling such breakthroughs required interlocking processes of leadership across three arenas: (1) strategy-level work at CCG board level, (2) mid-range operational planning and negotiation at programme board level and (3) the arena of practical implementation leadership at the point of delivery. The arena of the CCG board provided the legitimacy for strategic change; the programme boards worked through the competing logics of markets, hierarchy and networks; and the practice arena allowed the exercise of clinical leadership in practical problemsolving, detailed learning and routinisation of new ways of working at a common-sense everyday level.Limitations: Although the research was conducted over a 3-year period, it could be argued that a much longer period is required for CCGs to mature and realise their potential.Conclusions: Despite the variation in practice, we found significant examples of clinical leaders forging new modes of service design and delivery. A great deal of the service redesign effort was directed at compensating for the fragmented nature of the NHS – part of which had been created by the 2012 reforms. This is the first study to reveal details of such work in a systematic way

RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb–PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2–deficient mice showed that PD-L2 expression on non–T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

Peculiarities of selecting the gearboxes and wheel shift coefficients in the optimization of drive gear transmissions

В якості вузлового моменту оптимізаційного проектування тягових зубчастих передач залізничного рухомого складу виділено процедуру обґрунтованого вибору коефіцієнтів зміщення шестерень і коліс за рахунок використання відповідних блокувальних контурів. Обґрунтовано актуальність досліджень з розроблення методичного забезпечення для раціонального отримання блокувальних контурів при проектуванні тягових зубастих передач. Представлені розроблені математичні залежності, що пов’язують фіксовані величині обмежувальних і контрольованих параметрів передач з числами зубців і коефіцієнтами зміщення шестерні та колеса. Їх використання дозволяє отримувати конкретні блокувальні контури для вибору коефіцієнтів зміщення шестерні та колеса при оптимізаційному проектуванні тягових зубчастих передач з різними початковими параметрами. Наведено приклад практичної реалізації розроблених математичних залежностей при отриманні блокувального контуру для вибору коефіцієнтів зміщення шестерні та колеса тягової зубчастої передачі сучасного магістрального вантажного тепловозу. Зроблено висновок про доцільність використання запропонованого методичного забезпечення при оптимізаційному проектуванні тягових зубчатих передач.As a key point in the optimization design of traction gears of the railway rolling stock, a procedure for a reasonable choice of the coefficients for the displacement of gears and wheels is provided by using the appropriate blocking circuits. The relevance of studies on the development of methodological support for the rational production of blocking contours in the design of traction-toothed gears is substantiated. The developed mathematical dependences connecting the fixed values of the limiting and controlled parameters of the gears with the numbers of the teeth and the gearing coefficients of the gears and wheels are presented. Their use makes it possible to obtain specific blocking contours for the selection of gear and wheel bias coefficients in the optimization design of traction gears with different initial parameters. An example of the practical implementation of the developed mathematical dependencies in obtaining a blocking contour for selecting the gear displacement coefficients and the traction gear wheel of a modern mainline freight locomotive is given. The conclusion is made about the expediency of using the proposed methodological support in the optimization design of traction gears

Altering gait by way of stimulation of the plantar surface of the foot: the immediate effect of wearing textured insoles in older fallers

Background: Evidence suggests that textured insoles can alter gait and standing balance by way of enhanced plantar tactile stimulation. However, to date, this has not been explored in older people at risk of falling. This study investigated the immediate effect of wearing textured insoles on gait and double-limb standing balance in older fallers.Methods: Thirty older adults >65 years (21 women, mean [SD] age 79.0 [7.1]), with self-reported history of ≥2 falls in the previous year, conducted tests of level-ground walking over 10 m (GAITRite system), and double-limb standing with eyes open and eyes closed over 30 seconds (Kistler force platform) under two conditions: wearing textured insoles (intervention) and smooth (control) insoles in their usual footwear.Results: Wearing textured insoles caused significantly lower gait velocity (P = 0.02), step length (P = 0.04) and stride length (P = 0.03) compared with wearing smooth insoles. No significant differences were found in any of the balance parameters (P > 0.05).Conclusions: A textured insole worn by older adults with a history of falls significantly lowers gait velocity, step length and stride length, suggesting that this population may not have an immediate benefit from this type of intervention. The effects of prolonged wear remain to be investigated

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Як уникнути підйому рівня води?

East Africa’s Lake Victoria provides resources and services to millions of people on the lake’s shores and abroad. In particular, the lake’s fisheries are an important source of protein, employment, and international economic connections for the whole region. Nonetheless, stock dynamics are poorly understood and currently unpredictable. Furthermore, fishery dynamics are intricately connected to other supporting services of the lake as well as to lakeshore societies and economies. Much research has been carried out piecemeal on different aspects of Lake Victoria’s system; e.g., societies, biodiversity, fisheries, and eutrophication. However, to disentangle drivers and dynamics of change in this complex system, we need to put these pieces together and analyze the system as a whole. We did so by first building a qualitative model of the lake’s social-ecological system. We then investigated the model system through a qualitative loop analysis, and finally examined effects of changes on the system state and structure. The model and its contextual analysis allowed us to investigate system-wide chain reactions resulting from disturbances. Importantly, we built a tool that can be used to analyze the cascading effects of management options and establish the requirements for their success. We found that high connectedness of the system at the exploitation level, through fisheries having multiple target stocks, can increase the stocks’ vulnerability to exploitation but reduce society’s vulnerability to variability in individual stocks. We describe how there are multiple pathways to any change in the system, which makes it difficult to identify the root cause of changes but also broadens the management toolkit. Also, we illustrate how nutrient enrichment is not a self-regulating process, and that explicit management is necessary to halt or reverse eutrophication. This model is simple and usable to assess system-wide effects of management policies, and can serve as a paving stone for future quantitative analyses of system dynamics at local scales