Complex zoning behavior in pyroxene in FeO-rich chondrules in the Semarkona ordinary chondrite

A detailed understanding of the properties of silicate minerals in chondrules is essential to the interpretation of chondrule formation conditions. This study is further work in a series of petrologic studies of chondrules in the least equilibrated LL chondrite, Semarkona (LL3.0). The objectives of this work are as follows: (1) to understand chondrule formation conditions and nebular processes; and (2) to use the data as a basis for understanding the effects of metamorphism in more equilibrated chondrites. FeO-rich pyroxene in the chondrules described shows complex zoning behavior. Low-Ca clinopyroxene, orthopyroxene, pigeonite, and augite are all observed, in various associations with one another. Coexisting olivine phenocrysts are also FeO-rich and strongly zoned. Compositional and zoning properties are similar to those observed in boninites and are interpreted as resulting from rapid cooling of individual chondrules

Phosphate minerals in LL chondrites: A record of the action of fluids during metamorphism on ordinary chondrite parent bodies

Ordinary chondrites contain two phosphate minerals, merrillite and chlorapatite, both of which are secondary minerals that developed in response to metamorphism on the chondrite parent bodies. We have studied the phosphate mineralogy of four LL chondrites, of petrologic types 3.9–6, in order to determine the petrogenesis of the two minerals and interpret the conditions under which they formed. Characterization of merrillite and apatite includes textural observations, mineral compositions determined by electron probe microanalysis, and ion microprobe analyses of trace element and volatile anion elemental abundances. Initial formation of phosphate minerals during mild metamorphism, to petrologic type 4 conditions, resulted in oxidation of P that was originally incorporated in metal, and growth of merrillite as inclusions within metal grains. Subsequent development of both phosphate minerals occurred in response to diffusional equilibration, possible precipitation from fluids as well as replacement reactions resulting from interactions with fluids. Porosity and vein-filling textures in both merrillite and chlorapatite, as well as textures indicating replacement of merrillite by chlorapatite, support a model in which fluid played a significant role and suggest an interface-coupled dissolution–reprecipitation mechanism during metasomatism. Some associations of phosphate minerals with chromite-plagioclase assemblages suggest that phosphate minerals could also be related to impact processes, either as precipitation from an impact melt or as a result of interactions with a fluid or vapor derived from an impact melt. Fluid compositions may have been water-bearing initially, at low temperatures of metamorphism, but later evolved to become halogen-rich and very dry. Late-stage halogen-rich fluids that dominated during cooling of LL chondrite material may have been derived from vaporization of partial melts in the interior of the parent body. Overall, the LL chondrite parent body underwent a complex chemical evolution, in which metasomatism played a significant role

Investigating the Variation of Benzene and 1,3-Butadiene in the UK during 2000–2020

The concentrations of benzene and 1,3-butadiene in urban, suburban, and rural sites of the U.K. were investigated across 20 years (2000–2020) to assess the impacts of pollution control strategies. Given the known toxicity of these pollutants, it is necessary to investigate national long-term trends across a range of site types. We conclude that whilst legislative intervention has been successful in reducing benzene and 1,3-butadiene pollution from vehicular sources, previously overlooked sources must now be considered as they begin to dominate in contribution to ambient pollution. Benzene concentrations in urban areas were found to be ~5-fold greater than those in rural areas, whilst 1,3-butadiene concentrations were up to ~10-fold greater. The seasonal variation of pollutant concentration exhibited a maximum in the winter and a minimum in the summer with summer: winter ratios of 1:2.5 and 1:1.6 for benzene and 1,3-butadiene, respectively. Across the period investigated (2000–2020), the concentrations of benzene decreased by 85% and 1,3-butadiene concentrations by 91%. A notable difference could be seen between the two decades studied (2000–2010, 2010–2020) with a significantly greater drop evident in the first decade than in the second, proving, whilst previously successful, legislative interventions are no longer sufficiently limiting ambient concentrations of these pollutants. The health impacts of these pollutants are discussed, and cancer impact indices were utilized allowing estimation of cancer impacts across the past 20 years for different site types. Those particularly vulnerable to the adverse health effects of benzene and 1,3-butadiene pollution are discussed

Therapeutic targeting of integrin αvβ6 in breast cancer

BACKGROUND: Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n &gt; 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P &lt; .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.<br/

Observational study on variability between biobanks in the estimation of DNA concentration.

BACKGROUND: There is little confidence in the consistency of estimation of DNA concentrations when samples move between laboratories. Evidence on this consistency is largely anecdotal. Therefore there is a need first to measure this consistency among different laboratories and then identify and implement remedies. A pilot experiment to test logistics and provide initial data on consistency was therefore conceived. METHODS: DNA aliquots at nominal concentrations between 10 and 300 ng/mul were dispensed into the wells of 96-well plates by one participant - the coordinating centre. Participants estimated the concentration in each well and returned estimates to the coordinating centre. RESULTS: Considerable overall variability was observed among estimates. There were statistically significant differences between participants' measurements and between fluorescence emission and absorption spectroscopy. CONCLUSION: Anecdotal evidence of variability in DNA concentration estimation has been substantiated. Reduction in variability between participants will require the identification of major sources of variation, specification of effective remedies and their implementation

The Winchcombe meteorite – a regolith breccia from a rubble-pile CM chondrite asteroid

The Winchcombe meteorite is a CM chondrite breccia composed of eight distinct lithological units plus a cataclastic matrix. The degree of aqueous alteration varies between intensely altered CM2.0 and moderately altered CM2.6. Although no lithology dominates, three heavily altered rock types (CM2.1-2.3) represent >70 area%. Tochilinite-cronstedtite intergrowths (TCIs) are common in several lithologies. Their compositions can vary significantly, even within a single lithology, which can prevent a clear assessment of alteration extent if only TCI composition is considered. We suggest this is due to early alteration under localised geochemical microenvironments creating a diversity of compositions and because later reprocessing was incomplete, leaving a record of the parent body’s fluid history. In Winchcombe fragments of primary accretionary rock are held within a cataclastic matrix (~15 area%). This material is impact-derived fallback debris. Its grain size and texture suggest that the disruption of the original parent asteroid responded by intergranular fracture at grain sizes <100 µm, while larger phases, such as whole chondrules, splintered apart. Re-accretion formed a poorly lithified body. During atmospheric entry, the Winchcombe meteoroid broke apart with new fractures preferentially cutting through the weaker cataclastic matrix and separating the breccia into its component clasts. The strength of the cataclastic matrix imparts a control on the survival of CM chondrite meteoroids. Winchcombe’s unweathered state and diversity of lithologies makes it an ideal sample for exploring the geological history of the CM chondrite group.Additional authors: H. Mansour, S. Piazolo, T. Salge, R. Heard, R. Findlay, A. J. King, H. C. Bates, M. R. Lee, N. R. Stephen, F. M. Willcocks, R. C. Greenwood, I. A. Franchi, S. S. Russell, C. S. Harrison, P. F. Schofield, N. V. Almeida, C. Floyd, P.-E. Martin, K. H. Joy, P. J. Wozniakiewicz, D. Hallatt, M. J. Burchell, L. S. Alesbrook, V. Spathis, L. T. Cornwell, A. Digna

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST)

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)