Structural stability of the synthetic thermoelectric ternary and nickel-substituted tetrahedrite phases

The purity and structural stability of the high thermoelectric performance Cu12Sb4S13 and Cu10.4Ni1.6Sb4S13 tetrahedrite phases, synthesized by solid–liquid–vapor reaction and Spark Plasma Sintering, were studied at high temperature by Rietveld refinement using high resolution X-ray powder diffraction data, DSC/TG measurements and high resolution transmission electron microscopy. In a complementary study, the crystal structure of Cu10.5Ni1.5Sb4S13 as a function of temperature was investigated by powder neutron diffraction. The temperature dependence of the structural stability of ternary Cu12Sb4S13 is markedly different to that of the nickel-substituted phases, providing clear evidence for the significant and beneficial role of nickel substitution on both sample purity and stability of the tetrahedrite phase. Moreover, kinetic effects on the phase stability/decomposition have been identified and discussed in order to determine the maximum operating temperature for thermoelectric applications. The thermoelectric properties of these compounds have been determined for high density samples (>98%) prepared by Spark Plasma Sintering and therefore can be used as reference values for tetrahedrite samples. The maximum ZT of 0.8 was found for Cu10.4Ni1.6Sb4S13 at 700 K.

The resolution sensitivity of the South Asian monsoon and Indo-Pacific in a global 0.35◦ AGCM

The South Asian monsoon is one of the most significant manifestations of the seasonal cycle. It directly impacts nearly one third of the world’s population and also has substantial global influence. Using 27-year integrations of a high-resolution atmospheric general circulation model (Met Office Unified Model), we study changes in South Asian monsoon precipitation and circulation when horizontal resolution is increased from approximately 200 to 40 km at the equator (N96 to N512, 1.9 to 0.35◦). The high resolution, integration length and ensemble size of the dataset make this the most extensive dataset used to evaluate the resolution sensitivity of the South Asian monsoon to date. We find a consistent pattern of JJAS precipitation and circulation changes as resolution increases, which include a slight increase in precipitation over peninsular India, changes in Indian and Indochinese orographic rain bands, increasing wind speeds in the Somali Jet, increasing precipitation over the Maritime Continent islands and decreasing precipitation over the northern Maritime Continent seas. To diagnose which resolution related processes cause these changes we compare them to published sensitivity experiments that change regional orography and coastlines. Our analysis indicates that improved resolution of the East African Highlands results in the improved representation of the Somali Jet and further suggests that improved resolution of orography over Indochina and the Maritime Continent results in more precipitation over the Maritime Continent islands at the expense of reduced precipitation further north. We also evaluate the resolution sensitivity of monsoon depressions and lows, which contribute more precipitation over northeast India at higher resolution. We conclude that while increasing resolution at these scales does not solve the many monsoon biases that exist in GCMs, it has a number of small, beneficial impacts.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

The union of securitisation and demography: immigration detention in Israel

The chapter sets its analysis of the historical and contemporary detention of asylum seekers in Israel against a wider context of that country's national immigration policy. The chapter demonstrates that Israel perceives asylum seekers as a threat to its self-defined Jewish character. Its twofold conclusion argues that the government therefore subjects asylum seekers to harsh detention practices that afford detainees limited procedural guarantees, and that these procedures cut against the justification for detention as a measure to facilitate deportation.

Social and ecological drivers of success in agri-environment schemes: the roles of farmers and environmental context

1. Agri-environment schemes remain a controversial approach to reversing biodiversity losses, partly because the drivers of variation in outcomes are poorly understood. In particular, there is a lack of studies that consider both social and ecological factors. 2. We analysed variation across 48 farms in the quality and biodiversity outcomes of agri-environmental habitats designed to provide pollen and nectar for bumblebees and butterflies or winter seed for birds. We used interviews and ecological surveys to gather data on farmer experience and understanding of agri-environment schemes, and local and landscape environmental factors. 3. Multimodel inference indicated social factors had a strong impact on outcomes and that farmer experiential learning was a key process. The quality of the created habitat was affected positively by the farmer’s previous experience in environmental management. The farmer’s confidence in their ability to carry out the required management was negatively related to the provision of floral resources. Farmers with more wildlife-friendly motivations tended to produce more floral resources, but fewer seed resources. 4. Bird, bumblebee and butterfly biodiversity responses were strongly affected by the quantity of seed or floral resources. Shelter enhanced biodiversity directly, increased floral resources and decreased seed yield. Seasonal weather patterns had large effects on both measures. Surprisingly, larger species pools and amounts of semi-natural habitat in the surrounding landscape had negative effects on biodiversity, which may indicate use by fauna of alternative foraging resources. 5. Synthesis and application. This is the first study to show a direct role of farmer social variables on the success of agri-environment schemes in supporting farmland biodiversity. It suggests that farmers are not simply implementing agri-environment options, but are learning and improving outcomes by doing so. Better engagement with farmers and working with farmers who have a history of environmental management may therefore enhance success. The importance of a number of environmental factors may explain why agri-environment outcomes are variable, and suggests some – such as the weather – cannot be controlled. Others, such as shelter, could be incorporated into agri-environment prescriptions. The role of landscape factors remains complex and currently eludes simple conclusions about large-scale targeting of schemes.

Fibrin activates GPVI in human and mouse platelets

The glycoprotein VI (GPVI)-Fc receptor γ (FcRγ) chain is the major platelet signaling receptor for collagen. Paradoxically, in a FeCl3 injury model, occlusion, but not initiation of thrombus formation, is delayed in GPVI-deficient and GPVI-depleted mice. In this study, we demonstrate that GPVI is a receptor for fibrin and speculate that this contributes to development of an occlusive thrombus. We observed a marked increase in tyrosine phosphorylation, including the FcRγ chain and Syk, in human and mouse platelets induced by thrombin in the presence of fibrinogen and the αIIbβ3 blocker eptifibatide. This was not seen in platelets stimulated by a protease activated receptor (PAR)-4 peptide, which is unable to generate fibrin from fibrinogen. The pattern of tyrosine phosphorylation was similar to that induced by activation of GPVI. Consistent with this, thrombin did not induce tyrosine phosphorylation of Syk and the FcRγ chain in GPVI-deficient mouse platelets. Mouse platelets underwent full spreading on fibrin but not fibrinogen, which was blocked in the presence of a Src kinase inhibitor or in the absence of GPVI. Spreading on fibrin was associated with phosphatidylserine exposure (procoagulant activity), and this too was blocked in GPVI-deficient platelets. The ectodomain of GPVI was shown to bind to immobilized monomeric and polymerized fibrin. A marked increase in embolization was seen following FeCl3 injury in GPVI-deficient mice, likely contributing to the delay in occlusion in this model. These results demonstrate that GPVI is a receptor for fibrin and provide evidence that this interaction contributes to thrombus growth and stability.

Activation of glycoprotein VI (GPVI) and C-type lectin-like receptor-2 (CLEC-2) underlies platelet activation by diesel exhaust particles and other charged/hydrophobic ligands

Platelets are activated by a range of stimuli that share little or no resemblance in structure to each other or to recognized ligands, including diesel exhaust particles (DEP), small peptides [4N1-1, Champs (computed helical anti-membrane proteins), LSARLAF (Leu-Ser-Ala-Arg-Leu-Ala-Phe)], proteins (histones) and large polysaccharides (fucoidan, dextran sulfate). This miscellaneous group stimulate aggregation of human and mouse platelets through the glycoprotein VI (GPVI)-FcR γ-chain complex and/or C-type lectin-like receptor-2 (CLEC-2) as shown using platelets from mice deficient in either or both of these receptors. In addition, all of these ligands stimulate tyrosine phosphorylation in GPVI/CLEC-2-double-deficient platelets, indicating that they bind to additional surface receptors, although only in the case of dextran sulfate does this lead to activation. DEP, fucoidan and dextran sulfate, but not the other agonists, activate GPVI and CLEC-2 in transfected cell lines as shown using a sensitive reporter assay confirming a direct interaction with the two receptors. We conclude that this miscellaneous group of ligands bind to multiple proteins on the cell surface including GPVI and/or CLEC-2, inducing activation. These results have pathophysiological significance in a variety of conditions that involve exposure to activating charged/hydrophobic agents.

Growth factor receptor-bound protein 2 contributes to (hem)immunoreceptor tyrosine-based activation motif-mediated signaling in platelets

Rationale: Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor–bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown. Objective: We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets. Methods and Results: Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI–mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2–mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein–coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A2–induced G protein–coupled receptor signaling pathways. Conclusions: These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.

Don’t aim too high for your kids: parental over-aspiration undermines students’ learning in mathematics

Previous research has suggested that parents’ aspirations for their children’s academic attainment can have a positive influence on children’s actual academic performance. Possible negative effects of parental over-aspiration, however, have found little attention in the psychological literature. Employing a dual-change score model with longitudinal data from a representative sample of German schoolchildren and their parents (N = 3,530; grades 5 to 10), we showed that parental aspiration and children’s mathematical achievement were linked by positive reciprocal relations over time. Importantly, we also found that parental aspiration that exceeded their expectation (i.e., over-aspiration) had negative reciprocal relations with children’s mathematical achievement. These results were fairly robust after controlling for a variety of demographic and cognitive variables such as children’s gender, age, intelligence, school type, and family SES. The results were also replicated with an independent sample of US parents and their children. These findings suggest that unrealistically high parental aspiration can be detrimental for children’s achievement.

An assessment of Indian monsoon seasonal forecasts and mechanisms underlying monsoon interannual variability in the Met Office GloSea5-GC2 system

We assess Indian summer monsoon seasonal forecasts in GloSea5-GC2, the Met Office fully coupled subseasonal to seasonal ensemble forecasting system. Using several metrics, GloSea5-GC2 shows similar skill to other state-of-the-art forecast systems. The prediction skill of the large-scale South Asian monsoon circulation is higher than that of Indian monsoon rainfall. Using multiple linear regression analysis we evaluate relationships between Indian monsoon rainfall and five possible drivers of monsoon interannual variability. Over the time period studied (1992-2011), the El Nino-Southern Oscillation (ENSO) and the Indian Ocean dipole (IOD) are the most important of these drivers in both observations and GloSea5-GC2. Our analysis indicates that ENSO and its teleconnection with the Indian rainfall are well represented in GloSea5-GC2. However, the relationship between the IOD and Indian rainfall anomalies is too weak in GloSea5-GC2, which may be limiting the prediction skill of the local monsoon circulation and Indian rainfall. We show that this weak relationship likely results from a coupled mean state bias that limits the impact of anomalous wind forcing on SST variability, resulting in erroneous IOD SST anomalies. Known difficulties in representing convective precipitation over India may also play a role. Since Indian rainfall responds weakly to the IOD, it responds more consistently to ENSO than in observations. Our assessment identifies specific coupled biases that are likely limiting GloSea5-GC2 prediction skill, providing targets for model improvement.

Steric sea level variability (1993-2010) in an ensemble of ocean reanalyses and objective analyses

Quantifying the effect of the seawater density changes on sea level variability is of crucial importance for climate change studies, as the sea level cumulative rise can be regarded as both an important climate change indicator and a possible danger for human activities in coastal areas. In this work, as part of the Ocean Reanalysis Intercomparison Project, the global and regional steric sea level changes are estimated and compared from an ensemble of 16 ocean reanalyses and 4 objective analyses. These estimates are initially compared with a satellite-derived (altimetry minus gravimetry) dataset for a short period (2003–2010). The ensemble mean exhibits a significant high correlation at both global and regional scale, and the ensemble of ocean reanalyses outperforms that of objective analyses, in particular in the Southern Ocean. The reanalysis ensemble mean thus represents a valuable tool for further analyses, although large uncertainties remain for the inter-annual trends. Within the extended intercomparison period that spans the altimetry era (1993–2010), we find that the ensemble of reanalyses and objective analyses are in good agreement, and both detect a trend of the global steric sea level of 1.0 and 1.1 ± 0.05 mm/year, respectively. However, the spread among the products of the halosteric component trend exceeds the mean trend itself, questioning the reliability of its estimate. This is related to the scarcity of salinity observations before the Argo era. Furthermore, the impact of deep ocean layers is non-negligible on the steric sea level variability (22 and 12 % for the layers below 700 and 1500 m of depth, respectively), although the small deep ocean trends are not significant with respect to the products spread.

Intercomparison and validation of the mixed layer depth fields of global ocean syntheses

Intercomparison and evaluation of the global ocean surface mixed layer depth (MLD) fields estimated from a suite of major ocean syntheses are conducted. Compared with the reference MLDs calculated from individual profiles, MLDs calculated from monthly mean and gridded profiles show negative biases of 10–20 m in early spring related to the re-stratification process of relatively deep mixed layers. Vertical resolution of profiles also influences the MLD estimation. MLDs are underestimated by approximately 5–7 (14–16) m with the vertical resolution of 25 (50) m when the criterion of potential density exceeding the 10-m value by 0.03 kg m−3 is used for the MLD estimation. Using the larger criterion (0.125 kg m−3) generally reduces the underestimations. In addition, positive biases greater than 100 m are found in wintertime subpolar regions when MLD criteria based on temperature are used. Biases of the reanalyses are due to both model errors and errors related to differences between the assimilation methods. The result shows that these errors are partially cancelled out through the ensemble averaging. Moreover, the bias in the ensemble mean field of the reanalyses is smaller than in the observation-only analyses. This is largely attributed to comparably higher resolutions of the reanalyses. The robust reproduction of both the seasonal cycle and interannual variability by the ensemble mean of the reanalyses indicates a great potential of the ensemble mean MLD field for investigating and monitoring upper ocean processes.

Interannual-decadal variability of wintertime mixed layer depths in the North Pacific detected by an ensemble of ocean syntheses

The interannual-decadal variability of the wintertime mixed layer depths (MLDs) over the North Pacific is investigated from an empirical orthogonal function (EOF) analysis of an ensemble of global ocean reanalyses. The first leading EOF mode represents the interannual MLD anomalies centered in the eastern part of the central mode water formation region in phase opposition with those in the eastern subtropics and the central Alaskan Gyre. This first EOF mode is highly correlated with the Pacific decadal oscillation index on both the interannual and decadal time scales. The second leading EOF mode represents the MLD variability in the subtropical mode water (STMW) formation region and has a good correlation with the wintertime West Pacific (WP) index with time lag of 3 years, suggesting the importance of the oceanic dynamical response to the change in the surface wind field associated with the meridional shifts of the Aleutian Low. The above MLD variabilities are in basic agreement with previous observational and modeling findings. Moreover the reanalysis ensemble provides uncertainty estimates. The interannual MLD anomalies in the first and second EOF modes are consistently represented by the individual reanalyses and the amplitudes of the variabilities generally exceed the ensemble spread of the reanalyses. Besides, the resulting MLD variability indices, spanning the 1948–2012 period, should be helpful for characterizing the North Pacific climate variability. In particular, a 6-year oscillation including the WP teleconnection pattern in the atmosphere and the oceanic MLD variability in the STMW formation region is first detected.