B cell immunosenescence: different features of naive and memory B cells in elderly

Elderly people show a reduced protection against new infections and a decreased response to vaccines as a consequence of impairment of both cellular and humoral immunity. In this paper we have studied memory/na\uefve B cells in the elderly, evaluating surface immunoglobulin expression, production of the pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-\u3b1 and interleukin (IL)-10, and presence of somatic hypermutation, focusing on the IgG(+)IgD(-)CD27(-) double negative (DN) B cells that are expanded in the elderly. Our results show that na\uefve B cells from young donors need a sufficiently strong stimulus to be activated "in vitro", while na\uefve B cells from old subjects are able to produce IL-10 and TNF-\u3b1 when stimulated "physiologically" (\u3b1-CD40/IL-4), suggesting that these cells might play a role in the control of the immuno-inflammatory environment in the elderly. In addition, in the elderly there is an accumulation of DN B cells with a reduced rate of somatic hypermutation. Thus, DN B lymphocytes may be exhausted cells that are expanded and accumulate as a by-product of persistent stimulation or impaired germinal center formatio

Optimisation of grolishing freeform surfaces with rigid and semi-rigid tools

After the formal acceptance of our fabrication of E-ELT segments, we aim to further accelerate the mass production by introducing an intermediate grolishing procedure using industrial robots, reducing the total process time by this much faster and parallel link. In this paper, we have presented research outputs on tool design, tool path generation, study of mismatch between rigid, semi-rigid tool and aspheric surface. It is indicated that the generation of mid-spatial frequency is proportional to the grit size and misfit between work piece and tool surfaces. Using a Non-Newtonian material tool with a spindle speed of 30 rpm has successfully reduce the mid-spatial error. The optimization of process parameters involve the study the combination effects of the above factors. These optimized parameters will result in a lookup table for reference of given input surface quality. Future work may include the higher spindle speed for grolishing with non- Newtonian tool looking for potential applications regarding to form correction, higher removal rate and edge contro

Robotic automation in computer controlled polishing

We first present a Case Study – the manufacture of 1.4 m prototype mirror-segments for the European Extremely Large Telescope, undertaken by the National Facility for Ultra Precision Surfaces, at the OpTIC facility operated by Glyndwr University. Scale-up to serial-manufacture demands delivery of a 1.4 m off-axis aspheric hexagonal segment with surface precision < 10 nm RMS every four days, compared with a typical year or more for an one-off part. This requires a radically-new approach to large optics fabrication, which will inevitably propagate into wider industrial optics. We report on how these ambitious requirements have stimulated an investigation into the synergy between robots and computer numerically controlled (‘CNC’) polishing machines for optical fabrication. The objective was not to assess which is superior. Rather, it was to understand for the first time their complementary properties, leading us to operate them together as a unit, integrated in hardware and software. Three key areas are reported. First is the novel use of robots to automate currently-manual operations on CNC polishing machines, to improve work-throughput, mitigate risk of damage to parts, and reduce dependence on highly-skilled staff. Second is the use of robots to pre-process surfaces prior to CNC polishing, to reduce total process time. The third draws the threads together, describing our vision of the automated manufacturing cell, where the operator interacts at cell rather than machine level. This promises to deliver a step-change in end-to-end manufacturing times and costs, compared with either platform used on its own or, indeed, the state-of-the-art used elsewhere

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

Meditation Awareness Training (MAT) for Work-related Wellbeing and Job Performance: A Randomised Controlled Trial

Due to its potential to concurrently improve work-related wellbeing (WRW) and job performance, occupational stakeholders are becoming increasingly interested in the applications of meditation. The present study conducted the first randomized controlled trial to assess the effects of meditation on outcomes relating to both WRW and job performance. Office-based middle-hierarchy managers (n = 152) received an eight-week meditation intervention (Meditation Awareness Training; MAT) or an active control intervention. MAT participants demonstrated significant and sustainable improvements (with strong effect sizes) over control-group participants in levels of work-related stress, job satisfaction, psychological distress, and employer-rated job performance. There are a number of novel implications: (i) meditation can effectuate a perceptual shift in how employees experience their work and psychological environment and may thus constitute a cost-effective WRW intervention, (ii) meditation-based (i.e., present-moment-focussed) working styles may be more effective than goal-based (i.e., future-orientated) working styles, and (iii) meditation may reduce the separation made by employees between their own interests and those of the organizations they work for

Mechanism of sphingolipid homeostasis revealed by structural analysis of \u3ci\u3eArabidopsis\u3c/i\u3e SPT-ORM1 complex

The serine palmitoyltransferase (SPT) complex catalyzes the first and rate-limiting step in sphingolipid biosynthesis in all eukaryotes. ORM/ORMDL proteins are negative regulators of SPT that respond to cellular sphingolipid levels. However, the molecular basis underlying ORM/ORMDL-dependent homeostatic regulation of SPT is not well understood.We determined the cryo–electron microscopy structure of Arabidopsis SPT-ORM1 complex, composed of LCB1, LCB2a, SPTssa, and ORM1, in an inhibited state. A ceramide molecule is sandwiched between ORM1 and LCB2a in the cytosolic membrane leaflet. Ceramide binding is critical for the ORM1-dependent SPT repression, and dihydroceramides and phytoceramides differentially affect this repression. A hybrid β sheet, formed by the amino termini of ORM1 and LCB2a and induced by ceramide binding, stabilizes the amino terminus of ORM1 in an inhibitory conformation. Our findings provide mechanistic insights into sphingolipid homeostatic regulation via the binding of ceramide to the SPT-ORM/ORMDL complex that may have implications for plant-specific processes such as the hypersensitive response for microbial pathogen resistance

Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium

Fundamental properties of Fanaroff-Riley II radio galaxies investigated via Monte Carlo simulations

[Abridged] Radio galaxies and quasars are among the largest and most powerful single objects known and are believed to have had a significant impact on the evolving Universe and its large scale structure. We explore the intrinsic and extrinsic properties of the population of FRII objects (kinetic luminosities, lifetimes, and the central densities of their environments). In particular, the radio and kinetic luminosity functions of FRIIs are investigated using the complete, flux limited radio catalogues of 3CRR and Best et al. We construct multidimensional Monte Carlo simulations using semi-analytical models of FRII radio source growth to create artificial samples of radio galaxies. Unlike previous studies, we compare radio luminosity functions found with both the observed and simulated data to explore the fundamental source parameters. We allow the source physical properties to co-evolve with redshift, and we find that all the investigated parameters most likely undergo cosmological evolution. Strikingly, we find that the break in the kinetic luminosity function must undergo redshift evolution of at least (1+z)^3. The fundamental parameters are strongly degenerate, and independent constraints are necessary to draw more precise conclusions. We use the estimated kinetic luminosity functions to set constraints on the duty cycles of these powerful radio sources. A comparison of the duty cycles of powerful FRIIs with those determined from radiative luminosities of AGN of comparable black hole mass suggests a transition in behaviour from high to low redshifts, corresponding to either a drop in the typical black hole mass of powerful FRIIs at low redshifts, or a transition to a kinetically-dominated, radiatively-inefficient FRII population.Comment: Accepted to MNRAS. 30 pages, 18 figures, 4 tables + online material (in appendix): 9 pages, 14 figure

Parental Smoking Modifies the Relation between Genetic Variation in Tumor Necrosis Factor-α (TNF) and Childhood Asthma

BACKGROUND: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-α (TNF) and lymphotoxin-α (LTA, also called TNF-β) have been associated with asthma and atopy in some studies. Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. OBJECTIVES: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. METHODS: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4–17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. RESULTS: The A allele of the TNF-308 SNP was associated with increased risk of asthma [relative risk (RR) = 1.54; 95% confidence interval (CI), 1.04–2.28], especially among children of non-smoking parents (RR = 2.06; 95% CI, 1.19–3.55; p for interaction = 0.09). Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21; 95% CI, 1.14–4.30; p for interaction = 0.01). LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. CONCLUSIONS: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking