The oxygen isotope evolution of parent body aqueous solutions as recorded by multiple carbonate generations in the Lonewolf Nunataks 94101 CM2 carbonaceous chondrite

The CM2 carbonaceous chondrite LON 94101 contains aragonite and two generations of calcite that provide snapshots of the chemical and isotopic evolution of aqueous solutions during parent body alteration. Aragonite was the first carbonate to crystallize. It is rare, heterogeneously distributed within the meteorite matrix, and its mean oxygen isotope values are δ18O 39.9±0.6‰, Δ17O -0.3±1.0‰ (1σ). Calcite precipitated very soon afterwards, and following a fall in solution Mg/Ca ratios, to produce small equant grains with a mean oxygen isotope value of δ18O 37.5±0.7‰, Δ17O 1.4±1.1‰ (1σ). These grains were partially or completely replaced by serpentine and tochilinite prior to precipitation of the second generation of calcite, which occluded an open fracture to form a millimeter-sized vein, and replaced anhydrous silicates within chondrules and the matrix. The vein calcite has a mean composition of δ18O 18.4±0.3‰, Δ17O -0.5±0.5‰ (1σ). Petrographic and isotopic results therefore reveal two discrete episodes of mineralization that produced Ca-carbonates with contrasting δ18O, but whose Δ17O values are indistinguishable within error. The aragonite and equant calcite crystallized over a relatively brief period early in the aqueous alteration history of the parent body, and from static fluids that were evolving chemically in response to mineral dissolution and precipitation. The second calcite generation crystallized from solutions of a lower Δ17O, and a lower δ18O and/or higher temperature, which entered LON 9410 via a fracture network. As two generations of calcite whose petrographic characteristics and oxygen isotopic compositions are similar to those in LON 94101 occur in at least one other CM2, multiphase carbonate mineralization could be the typical outcome of the sequence of chemical reactions during parent body aqueous alteration. It is equally possible however that the second generation of calcite in formed in response to an event such as impact fracturing and concomitant fluid mobilisation that affected a large region of the common parent body of several CM2 meteorites. These findings show that integrated petrographic, chemical and isotopic studies can provide new insights into the mechanisms of parent body alteration including the spatial and temporal dynamics of the aqueous system

Pulmonary epithelial cell-derived cytokine TGF-β1 Is a critical cofactor for enhanced innate lymphoid cell function

SummaryEpithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions

Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function.

Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions

Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma

This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ⩾2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme

Recent evolution of the NF-κB and inflammasome regulating protein POP2 in primates

<p>Abstract</p> <p>Background</p> <p>Pyrin-only protein 2 (POP2) is a small human protein comprised solely of a pyrin domain that inhibits NF-κB p65/RelA and blocks the formation of functional IL-1β processing inflammasomes. Pyrin proteins are abundant in mammals and several, like POP2, have been linked to activation or regulation of inflammatory processes. Because <it>POP2 </it>knockout mice would help probe the biological role of inflammatory regulation, we thus considered whether <it>POP2 </it>is common in the mammalian lineage.</p> <p>Results</p> <p>BLAST searches revealed that <it>POP2 </it>is absent from the available genomes of not only mice and rats, but those of other domestic mammals and New World monkeys as well. <it>POP2 </it>is however present in the genome of the primate species most closely related to humans including <it>Pan troglodytes </it>(chimpanzees), <it>Macaca mulatta </it>(rhesus macaques) and others. Interestingly, chimpanzee POP2 is identical to human POP2 (huPOP2) at both the DNA and protein level. Macaque POP2 (mqPOP2), although highly conserved is not identical to the human sequence; however, both functions of the human protein are retained. Further, <it>POP2 </it>appears to have arisen in the mammalian genome relatively recently (~25 mya) and likely derived from retrogene insertion of <it>NLRP2</it>.</p> <p>Conclusion</p> <p>Our findings support the hypothesis that the NLR loci of mammals, encoding proteins involved in innate and adaptive immunity as well as mammalian development, have been subject to recent and strong selective pressures. Since POP2 is capable of regulating signaling events and processes linked to innate immunity and inflammation, its presence in the genomes of hominids and Old World primates further suggests that additional regulation of these signals is important in these species.</p

Elephant Moraine 96029, a very mildly aqueously altered and heated CM carbonaceous chondrite: Implications for the drivers of parent body processing

Elephant Moraine (EET) 96029 is a CMcarbonaceous chondrite regolith breccia with evidence for unusually mild aqueous alteration, a later phase of heating and terrestrial weathering. The presence of phyllosilicates and carbonates within chondrules and the fine-grained matrix indicates that this meteorite was aqueously altered in its parent body. Features showing that water-mediated processing was arrested at a very early stage include a matrix with a low magnesium/iron ratio, chondrules whose mesostasis contains glass and/or quench crystallites, and a gehlenite-bearing calcium- and aluminium-rich inclusion. EET 96029 is also rich in Fe,Ni metal relative to other CM chondrites, and more was present prior to its partial replacement by goethite during Antarctic weathering. In combination, these properties indicate that EET 96029 is one of the least aqueously altered CMs yet described (CM2.7) and so provides new insights into the original composition of its parent body. Following aqueous alteration, and whilst still in the parent body regolith, the meteorite was heated to ~400–600 °C by impacts or solar radiation. Heating led to the amorphisation and dehydroxylation of serpentine, replacement of tochilinite by magnetite, loss of sulphur from the matrix, and modification to the structure of organic matter that includes organic nanoglobules. Significant differences between samples in oxygen isotope compositions, and water/hydroxyl contents, suggests that the meteorite contains lithologies that have undergone different intensities of heating. EET 96029 may be more representative of the true nature of parent body regoliths than many other CM meteorites, and as such can help interpret results from the forthcoming missions to study and return samples from C-complex asteroids

Type 1 aqueous alteration in CM carbonaceous chondrites: Implications for the evolution of water-rich asteroids

The CM carbonaceous chondrite meteorites experienced aqueous alteration in the early solar system. They range from mildly altered type 2 to almost completely hydrated type 1 chondrites, and offer a record of geochemical conditions on water‐rich asteroids. We show that CM1 chondrites contain abundant (84–91 vol%) phyllosilicate, plus olivine (4–8 vol%), magnetite (2–3 vol%), Fe‐sulfide (120 °C), although higher water/rock ratios may also have played a role. The modal data provide constraints for interpreting the composition of asteroids and the mineralogy of samples returned from these bodies. We predict that “CM1‐like” asteroids, as has been proposed for Bennu—target for the OSIRIS‐REx mission—will have a high abundance of Mg‐rich phyllosilicates and Fe‐oxides, but be depleted in calcite

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology

Genetic variation in the ADIPOQ gene, adiponectin concentrations and risk of colorectal cancer: a Mendelian Randomization analysis using data from three large cohort studies

Higher levels of circulating adiponectin have been related to lower risk of colorectal cancer in several prospective cohort studies, but it remains unclear whether this association may be causal. We aimed to improve causal inference in a Mendelian Randomization meta-analysis using nested case–control studies of the European Prospective Investigation into Cancer and Nutrition (EPIC, 623 cases, 623 matched controls), the Health Professionals Follow-up Study (HPFS, 231 cases, 230 controls) and the Nurses’ Health Study (NHS, 399 cases, 774 controls) with available data on pre-diagnostic adiponectin concentrations and selected single nucleotide polymorphisms in the ADIPOQ gene. We created an ADIPOQ allele score that explained approximately 3% of the interindividual variation in adiponectin concentrations. The ADIPOQ allele score was not associated with risk of colorectal cancer in logistic regression analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable analysis (based on previously published data) with higher statistical power, no association between genetically determined twofold higher adiponectin and risk of colorectal cancer was observed (0.99, 95% CI 0.93, 1.06 in women and 0.94, 95% CI 0.88, 1.01 in men). Thus, our study does not support a causal effect of circulating adiponectin on colorectal cancer risk. Due to the limited genetic determination of adiponectin, larger Mendelian Randomization studies are necessary to clarify whether adiponectin is causally related to lower risk of colorectal cancer