Lithium and potassium isotope fractionation during silicate rock dissolution: An experimental approach

This study experimentally investigates the isotopic behaviors of Li and K during the dissolution of silicate rocks (i.e., basalt and granite). Proton-driven dissolution (in 0.8 M HNO3) and ligand-driven dissolution (in 5 mM critic acid or oxalic acid) experiments were performed in batch-closed systems over 15 days. We provide a time-series interpretation of Li and K isotope fractionation during silicate dissolution in ultra-acidic (unidirectional) and near-natural (biologically affected) environments. As the reaction progressed, we measured large isotope fractionation between the liquid (l) phase and the pristine silicate (s) phase, ranging from −10.3 to 0.1‰ (Δ7Lil-s) and from −1.01 to −0.11‰ (Δ41Kl-s) through the early stage of dissolution (<24 h). The enrichment of lighter Li and K isotopes in the solutions rapidly diminished as rock dissolution continued and gradually approached equilibrium to the end of experiments. In contrast, resorption of pre-leached isotopically lighter Li on silicate residuals during ligand-driven dissolution produced lighter isotope enrichment in the solutions compared to the initial rock by up to 2.8‰. Despite the preferential dissolution of specific minerals, the isotope fractionation patterns of Li and K do not vary with lithology, indicating limited inter-mineral isotopic differences. During the experiments, the Li and K isotopic pattern could be divided into two-to-three stages. The initial enrichment of light isotopes in the liquids can be ascribed to the kinetic isotope effect, confounded by diffusion and ion solvation. A later transition towards no isotope fractionation of Li and K may be explained by (i) the masking effect from dissolution, and (ii) an imprint from the destruction of 7Li/41K-enriched surface layers. Lateral resorption of solute Li after ~100 h reaction could be facilitated by the electrostatic attraction from increasing surface negative charges and active hydroxyls with increasing pH during ligand-driven dissolution (pH ~ 4) relative to proton-driven dissolution (pH ~ 0.2). Therefore, the presence of organic ligands impacts dissolution stoichiometry, and potentially modifies Li isotope fractionation in natural weathering environments. In comparison, K isotope fractionation driven by rock dissolution stops immediately (within days) after starting the experiments. This research helps to understand the mechanisms of Li and K isotope fractionation during chemical weathering and trace long-term climate change using geological records

Mobile encounters:bus 5A as a cross-cultural meeting place

The paper explores modes of encounters in the everyday practice of bus travel. Particularly, it addresses cross-cultural encounters located in the tension between familiarity and difference, between inclusion and exclusion. The paper is located in contemporary thoughts, approaching public transport not only as a moving device but also as a social arena. Furthermore, the bus is simultaneously perceived as a public space, at once composite, contradictory and heterogeneous, and as a meeting place involving ‘Throwntogetherness’. The encounters analysed are bodily, emotional charged and outspoken meetings between passengers, with the socio-materiality of the bus and drivers as co-riders and gatekeepers

From Big Society to Shared Society? Geographies of social cohesion and encounter in the UK’s National Citizen Service

This article explores and expands debates on the geographies of social cohesion and encounter, specifically in relation to young people and informal citizenship training. Three questions drive our agenda in this paper. First, how do certain youth spaces get enrolled into wider political discourses, functioning as geographical expressions of government visions to create a political legacy? Second, how are these spaces engineered and operate on-the-ground? Finally, how do young people understand their experiences of such spaces? To address these questions, we use the example of ‘National Citizen Service’ – a youth programme operating in England and Northern Ireland – to raise critical questions about the wider politics of spaces of informal education and attempts by the state to ‘make’ citizens and future neighbours. The article examines the rationale for this growing scheme, targeted at 15–17 year olds and designed to foster a ‘more cohesive, responsible and engaged society’. Drawing on original fieldwork with key architects, stakeholders and young people, we analyse the narratives that underlie NCS and its expansion – specifically around social cohesion and citizenship education. We explore the idea of ‘social mix’ as one of NCS’ guiding principles and its place as part of state narratives about the ‘Big Society’ and ‘Shared Society’

Sucrose Counteracts the Anti-Inflammatory Effect of Fish Oil in Adipose Tissue and Increases Obesity Development in Mice

BACKGROUND: Polyunsaturated n-3 fatty acids (n-3 PUFAs) are reported to protect against high fat diet-induced obesity and inflammation in adipose tissue. Here we aimed to investigate if the amount of sucrose in the background diet influences the ability of n-3 PUFAs to protect against diet-induced obesity, adipose tissue inflammation and glucose intolerance. METHODOLOGY/PRINCIPAL FINDINGS: We fed C57BL/6J mice a protein- (casein) or sucrose-based high fat diet supplemented with fish oil or corn oil for 9 weeks. Irrespective of the fatty acid source, mice fed diets rich in sucrose became obese whereas mice fed high protein diets remained lean. Inclusion of sucrose in the diet also counteracted the well-known anti-inflammatory effect of fish oil in adipose tissue, but did not impair the ability of fish oil to prevent accumulation of fat in the liver. Calculation of HOMA-IR indicated that mice fed high levels of proteins remained insulin sensitive, whereas insulin sensitivity was reduced in the obese mice fed sucrose irrespectively of the fat source. We show that a high fat diet decreased glucose tolerance in the mice independently of both obesity and dietary levels of n-3 PUFAs and sucrose. Of note, increasing the protein∶sucrose ratio in high fat diets decreased energy efficiency irrespective of fat source. This was accompanied by increased expression of Ppargc1a (peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha) and increased gluconeogenesis in the fed state. CONCLUSIONS/SIGNIFICANCE: The background diet influence the ability of n-3 PUFAs to protect against development of obesity, glucose intolerance and adipose tissue inflammation. High levels of dietary sucrose counteract the anti-inflammatory effect of fish oil in adipose tissue and increases obesity development in mice

Activation of Protein Kinase A and Exchange Protein Directly Activated by cAMP Promotes Adipocyte Differentiation of Human Mesenchymal Stem Cells

Human mesenchymal stem cells are primary multipotent cells capable of differentiating into several cell types including adipocytes when cultured under defined in vitro conditions. In the present study we investigated the role of cAMP signaling and its downstream effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in adipocyte conversion of human mesenchymal stem cells derived from adipose tissue (hMADS). We show that cAMP signaling involving the simultaneous activation of both PKA- and Epac-dependent signaling is critical for this process even in the presence of the strong adipogenic inducers insulin, dexamethasone, and rosiglitazone, thereby clearly distinguishing the hMADS cells from murine preadipocytes cell lines, where rosiglitazone together with dexamethasone and insulin strongly promotes adipocyte differentiation. We further show that prostaglandin I2 (PGI2) may fully substitute for the cAMP-elevating agent isobutylmethylxanthine (IBMX). Moreover, selective activation of Epac-dependent signaling promoted adipocyte differentiation when the Rho-associated kinase (ROCK) was inhibited. Unlike the case for murine preadipocytes cell lines, long-chain fatty acids, like arachidonic acid, did not promote adipocyte differentiation of hMADS cells in the absence of a PPARγ agonist. However, prolonged treatment with the synthetic PPARδ agonist L165041 promoted adipocyte differentiation of hMADS cells in the presence of IBMX. Taken together our results emphasize the need for cAMP signaling in concert with treatment with a PPARγ or PPARδ agonist to secure efficient adipocyte differentiation of human hMADS mesenchymal stem cells

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n\u2009=\u2009160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29