Local stability and a renormalized Newton Method for equilibrium liquid crystal director modeling

We consider the nonlinear systems of equations that result from discretizations of a prototype variational model for the equilibrium director field characterizing the orientational properties of a liquid crystal material. In the presence of pointwise unit-vector constraints and coupled electric fields, the numerical solution of such equations by Lagrange-Newton methods leads to problems with a double saddle-point form, for which we have previously proposed a preconditioned nullspace method as an effective solver [A. Ramage and E. C. Gartland, Jr., submitted]. The characterization of local stability of solutions is complicated by the double saddle-point structure, and here we develop efficiently computable criteria in terms of minimum eigenvalues of certain projected Schur complements. We also propose a modified outer iteration (“Renormalized Newton Method”) in which the orientation variables are normalized onto the constraint manifold at each iterative step. This scheme takes advantage of the special structure of these problems, and we prove that it is locally quadratically convergent. The Renormalized Newton Method bears some resemblance to the Truncated Newton Method of computational micromagnetics, and we compare and contrast the two

A preconditioned nullspace method for liquid crystal director modelling

We present a preconditioned nullspace method for the numerical solution of large sparse linear systems that arise from discretizations of continuum models for the orientational properties of liquid crystals. The approach effectively deals with pointwise unit-vector constraints, which are prevalent in such models. The indefinite, saddle-point nature of such problems, which can arise from either or both of two sources (pointwise unit-vector constraints, coupled electric fields), is illustrated. Both analytical and numerical results are given for a model problem

Feedback for future learning: delivering enhancements and evidencing impacts on the student learning experience

Enhancing the student learning experience through the provision of improved student feedback is both challenging and complex. ‘Feedback for Future Learning’ was a Glasgow Caledonian University(GCU)-wide project intended to enhance feedback practices from both the student and staff perspectives; to ensure greater awareness of, and reflection upon, feedback by students; and to encourage greater use of feedback to inform future student learning. The design, implementation and evaluation of approaches to ‘Feedback for Future Learning’ are described with an emphasis on STEM disciplines. The conceptualisation, design and implementation of a range of student feedback tools and approaches aimed to develop understanding of learning processes, reinforce learning and improve performance. This was achieved through collaboration with the GCU Students’ Association and the establishment of the University Feedback Enhancement Group. A series of generic and bespoke seminars, workshops, individual programme interventions and competitions were used to enhance comprehension of the perception, experience and use of formative and summative assessment feedback by students.   Providing opportunities for reflection and evaluation together with qualitative and quantitative metrics have demonstrated 93% satisfaction with student feedback enhancement workshops, a trebling of engagement with memorable feedback survey initiatives and a 9% increase in National Student Survey assessment and feedback satisfaction. A 16% rise in student satisfaction with the promptness of feedback, a 14% improvement in satisfaction with the detailed comments received and an 8% increase in satisfaction with the helpfulness of comments received were achieved. The lessons learned inform the continuing and sustainable enhancement of the student learning experience for STEM students and the wider University community. Keywords: Feedback, future learning, dialogue, engagement, reflection, enhancemen

Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury

Context: Military recruits and elite athletes are susceptible to stress fracture injuries. Genetic predisposition has been postulated to have a role in their development. The P2X7 receptor (P2X7R) gene, a key regulator of bone remodelling, is a genetic candidate that may contribute to stress fracture predisposition. Objective: To evaluate the putative contribution of P2X7R to stress fracture injury in two separate cohorts, military personnel and elite athletes. Methods: In 210 Israeli Defence Forces (IDF) military conscripts, stress fracture injury was diagnosed (n=43) based on symptoms and a positive bone scan. In a separate cohort of 518 elite athletes, self-reported medical imaging scan-certified stress fracture injuries were recorded (n=125). Non-stress fracture controls were identified from these cohorts who had a normal bone scan or no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allele-specific PCR assay. Pearson Chi-square (χ2) tests, corrected for multiple comparisons, were used to assess associations in genotype frequencies. Results: The variant allele of P2X7R SNP rs3751143 (Glu496Ala- loss of function) was associated with stress fracture injury, while the variant allele of rs1718119 (Ala348Thr- gain of function) was associated with a reduced occurrence of stress fracture injury in military conscripts (P<0.05). The association of the variant allele of rs3751143 with stress fractures was replicated in elite athletes (P<0.05), whereas the variant allele of rs1718119 was also associated with reduced multiple stress fracture cases in elite athletes (P<0.05). Conclusions: The association between independent P2X7R polymorphisms with stress fracture prevalence supports the role of a genetic predisposition in the development of stress fracture injury

Immune modulatory properties of nanoparticles on human dendritic cells

Dendritic cells (DCs) are professional antigen presenting cells that play a potent role as a key link between innate and adaptive immunity. Given the quintessential role of DCs in orchestrating immune responses, better understanding of conditions that control DC function could provide opportunities for developing new treatment strategies for infectious and autoimmune diseases. Recently, there is a growing interest to utilize nanoparticles (NPs) with diverse chemistry, size and other physicochemical attributes in vaccination, drug delivery systems, and diagnostics. There is emerging evidence for the effect of NPs size, shape, and other physiochemical properties on cellular responses; however, the impact of NPs on the immune system, and particularly the function and phenotype of DCs, is yet to be fully understood. The overall aim of this study was investigating the influence of different properties of NPs on DC phenotype, cytokine profile, function (e.g. endocytic ability) and metabolic profile. This was done by exposing DCs to a defined concentration of NPs, particularly, PLGA NPs, Silica (SNPs) and polystyrene (PS NPs), which were successfully fabricated or commercially sourced, respectively. The findings clearly demonstrated that particle size and the choice of material can affect different aspects of DC phenotype. While spherical Silica and PLGA NPs of 100 nm and 160 nm size range respectively do not change DC phenotype and function (endocytic ability), PS NPs of similar size and PLGA NPs of 500 nm size induce significant changes in DC phenotype and function. PS NPs of 150 nm and 200 nm size significantly suppress the expression of mannose receptor (MR or CD206) on DCs by around 90%-80% without affecting their viability, maturation status or cytokine profile. In addition, PLGA NPs of 500 nm size induced DC maturation as evidenced by high levels of CD83 expression. Accordingly, the impact of NP properties on one DC key function, namely endocytic ability, was investigated. Interestingly, the data showed that PS NPs (150 nm/200 nm) and PLGA NPs (500 nm) significantly influenced this function. While PLGA NPs (160 nm) and SNPs (100 nm/500 nm) did not induce changes in DC endocytic ability. Furthermore, with regard to NP cellular uptake by antigen presenting cells, our data demonstrated that specific NP size and material (PLGA NPs 120 nm) reflect a preferential uptake by DCs compared to 500 nm PLGA NPs. By contrast, macrophages (Mϕs) showed similar trend of uptake for both PLGA NP sizes. Our data also showed the role of NP surface modification on cellular uptake. Modified SNPs to positive charge showed high percentage of uptake by DCs. Examining the impact of NP material type (PLGA NPs and PS NPs) on DC metabolic profile could provide valuable information about the impact of NPs on overall DC function in an unbiased manner. The metabolomics profile data showed a significant increase in glycolysis pathway upon stimulation by PLGA NPs and PS NPs, as indicated by lactate production. Also, significant changes were observed in DC purine and amino acid metabolism upon PLGA NPs and PS NPs treatment, respectively. In conclusion, this study gives new insights into understanding how DCs react to different properties of NPs, which can pave the way for the rational design of NPs with tuneable immune-modulatory properties for immunotherapy applications

Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women

The P2X7 receptor gene (P2RX7) is highly polymorphic with five previously described loss-of-function (LOF) single-nucleotide polymorphisms (SNP; c.151+1G>T, c.946G>A, c.1096C>G, c.1513A>C and c.1729T>A) and one gain-of-function SNP (c.489C>T). The purpose of this study was to determine whether the functional P2RX7 SNPs are associated with lumbar spine (LS) bone mineral density (BMD), a key determinant of vertebral fracture risk, in post-menopausal women. We genotyped 506 post-menopausal women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) for the above SNPs. Lumbar spine BMD was measured at baseline and at 6–7 year follow-up. P2RX7 genotyping was performed by homogeneous mass extension. We found association of c.946A (p.Arg307Gln) with lower LS-BMD at baseline (P=0.004, β=−0.12) and follow-up (P=0.002, β=−0.13). Further analysis showed that a combined group of subjects who had LOF SNPs (n=48) had nearly ninefold greater annualised percent change in LS-BMD than subjects who were wild type at the six SNP positions (n=84; rate of loss=−0.94%/year and −0.11%/year, respectively, P=0.0005, unpaired t-test). This is the first report that describes association of the c.946A (p.Arg307Gln) LOF SNP with low LS-BMD, and that other LOF SNPs, which result in reduced or no function of the P2X7 receptor, may contribute to accelerated bone loss. Certain polymorphic variants of P2RX7 may identify women at greater risk of developing osteoporosis

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis,independent of RANK ligand, which disrupts normal bone homeostasisleading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications

A renormalized Newton method for liquid crystal director modeling

We consider the nonlinear systems of equations that result from discretizations of a prototype variational model for the equilibrium director field characterizing the orientational properties of a liquid crystal material. In the presence of pointwise unit-vector constraints and coupled electric fields, the numerical solution of such equations by Lagrange-Newton methods leads to linear systems with a double saddle-point form, for which we have previously proposed a preconditioned nullspace method as an effective solver [A. Ramage and E. C. Gartland, Jr., SIAM J. Sci. Comput., 35 (2013), pp. B226–B247]. Here we propose and analyze a modified outer iteration (“Renormalized Newton Method”) in which the orientation variables are normalized onto the constraint manifold at each iterative step. This scheme takes advantage of the special structure of these problems, and we prove that it is locally quadratically convergent. The Renormalized Newton Method bears some resemblance to the Truncated Newton Method of computational micromagnetics, and we compare and contrast the two. This brings to light some anomalies of the Truncated Newton Method