Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-&amp;#x03BA;B (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK&lt;sup&gt;-/-&lt;/sup&gt; BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.</jats:p

The changing sensitivity of power systems to meteorological drivers: a case study of Great Britain

The increasing use of intermittent renewable generation (such as wind) is increasing the exposure of national power systems to meteorological variability. This study identifies how the integration of wind power in one particular country (Great Britain, GB) is affecting the overall sensitivity of the power system to weather using three key metrics: total annual energy requirement and peak residual load (from sources other than wind) and wind power curtailment. The present-day level of wind power capacity (approximately 15GW) is shown to have already changed the power system's overall sensitivity to weather in terms of the total annual energy requirement, from a temperature- to a wind-dominated regime (which occurred with 6GW of installed wind power capacity). Peak residual load from sources other than wind also shows a similar shift. The associated changes in the synoptic- and large-scale meteorological drivers associated with each metric are identified and discussed. In a period where power systems are changing rapidly, it is therefore argued that past experience of the weather impacts on the GB power system may not be a good guide for the impact on the present or near-future power system

Force distributions in 3D granular assemblies: Effects of packing order and inter-particle friction

We present a systematic investigation of the distribution of normal forces at the boundaries of static packings of spheres. A new method for the efficient construction of large hexagonal-close-packed crystals is introduced and used to study the effect of spatial ordering on the distribution of forces. Under uniaxial compression we find that the form for the probability distribution of normal forces between particles does not depend strongly on crystallinity or inter-particle friction. In all cases the distribution decays exponentially at large forces and shows a plateau or possibly a small peak near the average force but does not tend to zero at small forces.Comment: 9 pages including 8 figure

Power law velocity fluctuations due to inelastic collisions in numerically simulated vibrated bed of powder}

Distribution functions of relative velocities among particles in a vibrated bed of powder are studied both numerically and theoretically. In the solid phase where granular particles remain near their local stable states, the probability distribution is Gaussian. On the other hand, in the fluidized phase, where the particles can exchange their positions, the distribution clearly deviates from Gaussian. This is interpreted with two analogies; aggregation processes and soft-to-hard turbulence transition in thermal convection. The non-Gaussian distribution is well-approximated by the t-distribution which is derived theoretically by considering the effect of clustering by inelastic collisions in the former analogy.Comment: 7 pages, using REVTEX (Figures are inculded in text body) %%%Replacement due to rivision (Europhys. Lett., in press)%%

Factors influencing the utilisation of free-standing and alongside midwifery units in England: a qualitative research study

OBJECTIVE: To identify factors influencing the provision, utilisation and sustainability of midwifery units (MUs) in England. DESIGN: Case studies, using individual interviews and focus groups, in six National Health Service (NHS) Trust maternity services in England. SETTING AND PARTICIPANTS: NHS maternity services in different geographical areas of England Maternity care staff and service users from six NHS Trusts: two Trusts where more than 20% of all women gave birth in MUs, two Trusts where less than 10% of all women gave birth in MUs and two Trusts without MUs. Obstetric, midwifery and neonatal clinical leaders, managers, service user representatives and commissioners were individually interviewed (n=57). Twenty-six focus groups were undertaken with midwives (n=60) and service users (n=52). MAIN OUTCOME MEASURES: Factors influencing MU use. FINDINGS: The study findings identify several barriers to the uptake of MUs. Within a context of a history of obstetric-led provision and lack of decision-maker awareness of the clinical and economic evidence, most Trust managers and clinicians do not regard their MU provision as being as important as their obstetric unit (OU) provision. Therefore, it does not get embedded as an equal and parallel component in the Trust's overall maternity package of care. The analysis illuminates how implementation of complex interventions in health services is influenced by a range of factors including the medicalisation of childbirth, perceived financial constraints, adequate leadership and institutional norms protecting the status quo. CONCLUSIONS: There are significant obstacles to MUs reaching their full potential, especially free-standing midwifery units. These include the lack of commitment by providers to embed MUs as an essential service provision alongside their OUs, an absence of leadership to drive through these changes and the capacity and willingness of providers to address women's information needs. If these remain unaddressed, childbearing women's access to MUs will continue to be restricted

Stresses in isostatic granular systems and emergence of force chains

Progress is reported on several questions that bedevil understanding of granular systems: (i) are the stress equations elliptic, parabolic or hyperbolic? (ii) how can the often-observed force chains be predicted from a first-principles continuous theory? (iii) How to relate insight from isostatic systems to general packings? Explicit equations are derived for the stress components in two dimensions including the dependence on the local structure. The equations are shown to be hyperbolic and their general solutions, as well as the Green function, are found. It is shown that the solutions give rise to force chains and the explicit dependence of the force chains trajectories and magnitudes on the local geometry is predicted. Direct experimental tests of the predictions are proposed. Finally, a framework is proposed to relate the analysis to non-isostatic and more realistic granular assemblies.Comment: 4 pages, 2 figures, Corrected typos and clkearer text, submitted to Phys. Rev. Let