A moving mesh method for modelling defects in nematic liquid crystals

The properties of liquid crystals can be modelled using an order parameter which describes the variability of the local orientation of rod-like molecules. Defects in the director field can arise due to external factors such as applied electric or magnetic fields, or the constraining geometry of the cell containing the liquid crystal material. Understanding the formation and dynamics of defects is important in the design and control of liquid crystal devices, and poses significant challenges for numerical modelling. In this paper we consider the numerical solution of a Q-tensor model of a nematic liquid crystal, where defects arise through rapid changes in the Q-tensor over a very small physical region in relation to the dimensions of the liquid crystal device. The efficient solution of the resulting six coupled partial differential equations is achieved using a finite element based adaptive moving mesh approach, where an unstructured triangular mesh is adapted towards high activity regions, including those around defects. Spatial convergence studies are presented using a stationary defect as a model test case, and the adaptive method is shown to be optimally convergent using quadratic triangular finite elements. The full effectiveness of the method is then demonstrated using a challenging two-dimensional dynamic Pi-cell problem involving the creation, movement, and annihilation of defects

Enigmatic Red Beds Exposed at Point of Rocks, Cimarron National Grassland, Morton County, Kansas: Chronostratigraphic Constraints from Uranium-Lead Dating of Detrital Zircons

Point of Rocks, a high-relief bluff overlooking the Cimarron River valley in Morton County, Kansas, is capped by distinct white beds of Neogene Ogallala Formation calcrete that overlie red beds of shale, siltstone, and sandstone. These unfossiliferous red beds are currently assigned to the Jurassic System; however, their age has long been debated due to a lack of marker beds, index fossils, and nearby correlative outcrops. As a result, geologists over the years have assigned the rocks to systems ranging from the Permian to the Cretaceous. In this study, four stratigraphic sections were measured in the red beds and three bulk samples were collected to determine the uranium-lead age distributions of detrital zircon (DZ) populations. Red-bed strata composed of fissile shale and sandstone are interpreted as alluvial overbank deposits, while dominantly trough cross-bedded and planar-laminated sandstones are interpreted as tidally influenced fluvial deposits. Detrital zircon age peaks can be grouped into at least seven subpopulations with a youngest single zircon age of 263.8 ± 12.1 Ma, a more conservative age of 293.0 ± 6.95 Ma based on the youngest grouping of three grain ages overlapping at 2σ, and a complete absence of Mesozoic age zircons. In addition, copper oxides along partings and fractures suggest that the red beds once hosted copper sulfides, a common constituent of regional Permian-Triassic red beds. The DZ data--in conjunction with the identification of the Permian Day Creek Dolomite marker bed in logs of nearby drilling tests--strongly suggest that the enigmatic red beds cropping out at the base of Point of Rocks should be assigned to the Guadalupian Big Basin Formation, the uppermost Permian unit in Kansas

Developmental risk among Aboriginal children living in urban areas in Australia : the Study of Environment on Aboriginal Resilience and Child Health (SEARCH)

Background: Most Australian Aboriginal children are on track with their development, however, the prevalence of children at risk of or with a developmental or behavioural problem is higher than in other children. Aboriginal child development data mostly comes from remote communities, whereas most Aboriginal children live in urban settings. We quantified the proportion of participating children at moderate and high developmental risk as identified by caregivers' concerns, and determined the factors associated with developmental risk among urban Aboriginal communities. Methods: Study methods were co-designed and implemented with four participating urban Aboriginal Community Controlled Health Services in New South Wales, Australia, between 2008 and 2012. Caregiver-reported data on children < 8 years old enrolled in a longitudinal cohort study (Study of Environment on Aboriginal Resilience and Child Health: SEARCH) were collected by interview. The Parents' Evaluation of Developmental Status (PEDS) was used to assess developmental risk through report of caregiver concerns. Odds ratios (OR) were calculated using multinomial logistic regression to investigate risk factors and develop a risk prediction model. Results: Of 725 children in SEARCH with PEDS data (69% of eligible), 405 (56%) were male, and 336 (46%) were aged between 4.5 and 8 years. Using PEDS, 32% were at high, 28% moderate, and 40% low/no developmental risk. Compared with low/no risk, factors associated with high developmental risk in a mutually-adjusted model, with additional adjustment for study site, were male sex (OR 2.42, 95% confidence intervals 1.62-3.61), being older (4.5 to < 8 years versus < 3 years old, 3.80, 2.21-6.54), prior history of ear infection (1.95, 1.21-3.15), having lived in 4 or more houses versus one house (4.13, 2.04-8.35), foster care versus living with a parent (5.45, 2.32-12.78), and having a caregiver with psychological distress (2.40, 1.37-4.20). Conclusion: In SEARCH, 40% of urban Aboriginal children younger than 8 years were at no or low developmental risk. Several factors associated with higher developmental risk were modifiable. Aboriginal community-driven programs to improve detection of developmental problems and facilitate early intervention are needed

Breast cancer risk reduction:is it feasible to initiate a randomised controlled trial of a lifestyle intervention programme (ActWell) within a national breast screening programme?

BackgroundBreast cancer is the most commonly diagnosed cancer and the second cause of cancer deaths amongst women in the UK. The incidence of the disease is increasing and is highest in women from least deprived areas. It is estimated that around 42% of the disease in post-menopausal women could be prevented by increased physical activity and reductions in alcohol intake and body fatness. Breast cancer control endeavours focus on national screening programmes but these do not include communications or interventions for risk reductionThis study aimed to assess the feasibility of delivery, indicative effects and acceptability of a lifestyle intervention programme initiated within the NHS Scottish Breast Screening Programme (NHSSBSP).MethodsA 1:1 randomised controlled trial (RCT) of the 3 month ActWell programme (focussing on body weight, physical activity and alcohol) versus usual care conducted in two NHSSBSP sites between June 2013 and January 2014. Feasibility assessments included recruitment, retention, and fidelity to protocol. Indicative outcomes were measured at baseline and 3 month follow-up (body weight, waist circumference, eating and alcohol habits and physical activity. At study end, a questionnaire assessed participant satisfaction and qualitative interviews elicited women¿s, coaches and radiographers¿ experiences. Statistical analysis used Chi squared tests for comparisons in proportions and paired t tests for comparisons of means. Linear regression analyses were performed, adjusted for baseline values, with group allocation as a fixed effectResultsA pre-set recruitment target of 80 women was achieved within 12 weeks and 65 (81%) participants (29 intervention, 36 control) completed 3 month assessments. Mean age was 58¿±¿5.6 years, mean BMI was 29.2¿±¿7.0 kg/m2 and many (44%) reported a family history of breast cancer.The primary analysis (baseline body weight adjusted) showed a significant between group difference favouring the intervention group of 2.04 kg (95%CI ¿3.24 kg to ¿0.85 kg). Significant, favourable between group differences were also detected for BMI, waist circumference, physical activity and sitting time. Women rated the programme highly and 70% said they would recommend it to others.ConclusionsRecruitment, retention, indicative results and participant acceptability support the development of a definitive RCT to measure long term effects.Trial registrationThe trial was registered with Current Controlled Trials (ISRCTN56223933)

Characterization of a novel novobiocin analogue as a putative Cterminal inhibitor of heat shock protein 90 in prostate cancer cells

PURPOSE: Hsp90 is important in the folding, maturation and stabilization of pro-tumorigenic client proteins and represents a viable drug target for the design of chemotherapies. Previously, we reported the development of novobiocin analogues designed to inhibit the C-terminal portion of Hsp90, which demonstrated the ability to decrease client protein expression. We now report the characterization of the novel novobiocin analogue, F-4, which demonstrates improved cytotoxicity in prostate cancer cell lines compared to the N-terminal inhibitor, 17-AAG. MATERIALS AND METHODS: LNCaP and PC-3 cells were treated with 17-AAG or F-4 in anti-proliferative, apoptosis, cell cycle and cytotoxicity assays. Western blot and prostate specific antigen (PSA) ELISAs were used to determine client protein degradation, induction of Hsp90 and to assess the functional status of the androgen receptor (AR) in response to F-4 treatment. Surface Plasmon Resonance (SPR) was also used to determine the binding properties of F-4 to Hsp90. RESULTS: F-4 demonstrated improved potency and efficacy compared to novobiocin in anti-proliferative assays and decreased expression of client proteins. PSA secretion was inhibited in a dose-dependent manner that paralleled a decrease in AR expression. The binding of F-4 to Hsp90 was determined to be saturable with a binding affinity (Kd) of 100 µM. In addition, superior efficacy was demonstrated by F-4 compared to 17-AAG in experiments measuring cytotoxicity and apoptosis. CONCLUSIONS: These data reveal distinct modes of action for N-terminal and C-terminal Hsp90 inhibitors, which may offer unique therapeutic benefits for the treatment of prostate cancer

Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion

The antimicrobial activity of a carbon monoxide releasing molecule (EBOR-CORM-1) is shaped by intraspecific variation within3 Pseudomonas aeruginosa populations

Carbon monoxide releasing molecules (CORMs) have been suggested as a new synthetic class of antimicrobials to treat bacterial infections. Here we utilized a novel EBOR-CORM-1 ([NEt4][MnBr2(CO)4]) capable of water-triggered CO-release, and tested its efficacy against a collection of clinical Pseudomonas aeruginosa strains that differ in infection-related virulence traits. We found that while EBOR-CORM-1 was effective in clearing planktonic and biofilm cells of P. aeruginosa strain PAO1 in a concentration dependent manner, this effect was less clear and varied considerably between different P. aeruginosa cystic fibrosis (CF) lung isolates. While a reduction in cell growth was observed after 8 h of CORM application, either no effect or even a slight increase in cell densities and the amount of biofilm was observed after 24 h. This variation could be partly explained by differences in bacterial virulence traits: while CF isolates showed attenuated in vivo virulence and growth compared to strain PAO1, they formed much more biofilm, which could have potentially protected them from the CORM. Even though no clear therapeutic benefits against a subset of isolates was observed in an in vivo wax moth acute infection model, EBOR-CORM-1 was more efficient at reducing the growth of CF isolate co-culture populations harboring intraspecific variation, in comparison with efficacy against more uniform single isolate culture populations. Together these results suggest that CORMs could be effective at controlling genetically diverse P. aeruginosa populations typical for natural chronic CF infections and that the potential benefits of some antibiotics might not be observed if tested only against clonal bacterial populations

Association between malaria control and paediatric blood transfusions in rural Zambia: an interrupted time-series analysis

BACKGROUND: Blood transfusions can reduce mortality among children with severe malarial anaemia, but there is limited evidence quantifying the relationship between paediatric malaria and blood transfusions. This study explores the extent to which the use of paediatric blood transfusions is affected by the number of paediatric malaria visits and admissions. It assesses whether the scale-up of malaria control interventions in a facility catchment area explains the use of paediatric blood transfusions. METHODS: The study was conducted at a referral hospital for 13 rural health centres in rural Zambia. Data were used from facility and patient records covering all paediatric malaria admissions from 2000 to 2008. An interrupted time series analysis using an autoregression-moving-average model was conducted to assess the relationship between paediatric malaria outpatient visits and admissions and the use of paediatric blood transfusions. Further investigation explored whether the use of paediatric blood transfusions over time was consistent with the roll out of malaria control interventions in the hospital catchment area. RESULTS: For each additional paediatric malaria outpatient visit, there were 0.07 additional paediatric blood transfusions (95% CI 0.01-0.13; p < 0.05). For each additional paediatric admission for severe malarial anaemia, there were 1.09 additional paediatric blood transfusions (95% CI 0.95-1.23; p < 0.01). There were 19.1 fewer paediatric blood transfusions per month during the 2004–2006 malaria control period (95% CI 12.1-26.0; p < 0.01), a 50% reduction compared to the preceding period when malaria control was relatively limited. During the 2007–2008 malaria control period, there were 27.5 fewer paediatric blood transfusions per month (95% CI 14.6-40.3; p < 0.01), representing a 72% decline compared to the period with limited malaria control. CONCLUSIONS: Paediatric admissions for severe malarial anaemia largely explain total use of paediatric blood transfusions. The reduction in paediatric blood transfusions is consistent with the timing of the malaria control interventions. Malaria control seems to influence the use of paediatric blood transfusions by reducing the number of paediatric admissions for severe malarial anaemia. Reduced use of blood transfusions could benefit other areas of the health system through greater blood availability, particularly where supply is limited