In search of the authentic nation: landscape and national identity in Canada and Switzerland

While the study of nationalism and national identity has flourished in the last decade, little attention has been devoted to the conditions under which natural environments acquire significance in definitions of nationhood. This article examines the identity-forming role of landscape depictions in two polyethnic nation-states: Canada and Switzerland. Two types of geographical national identity are identified. The first – what we call the ‘nationalisation of nature’– portrays zarticular landscapes as expressions of national authenticity. The second pattern – what we refer to as the ‘naturalisation of the nation’– rests upon a notion of geographical determinism that depicts specific landscapes as forces capable of determining national identity. The authors offer two reasons why the second pattern came to prevail in the cases under consideration: (1) the affinity between wild landscape and the Romantic ideal of pure, rugged nature, and (2) a divergence between the nationalist ideal of ethnic homogeneity and the polyethnic composition of the two societies under consideration

Developing an inverted Barrovian sequence; insights from monazite petrochronology

In the Himalayan region of Sikkim, the well-developed inverted metamorphic sequence of the Main Central Thrust (MCT) zone is folded, thus exposing several transects through the structure that reached similar metamorphic grades at different times. In-situ LA-ICP-MS U–Th–Pb monazite ages, linked to pressure–temperature conditions via trace-element reaction fingerprints, allow key aspects of the evolution of the thrust zone to be understood for the first time. The ages show that peak metamorphic conditions were reached earliest in the structurally highest part of the inverted metamorphic sequence, in the Greater Himalayan Sequence (GHS) in the hanging wall of the MCT. Monazite in this unit grew over a prolonged period between ~37 and 16 Ma in the southerly leading-edge of the thrust zone and between ~37 and 14.5 Ma in the northern rear-edge of the thrust zone, at peak metamorphic conditions of ~790 ◦C and 10 kbar. Monazite ages in Lesser Himalayan Sequence (LHS) footwall rocks show that identical metamorphic conditions were reached ~4–6 Ma apart along the ~60 km separating samples along the MCT transport direction. Upper LHS footwall rocks reached peak metamorphic conditions of ~655 ◦C and 9 kbar between ~21 and 16 Ma in the more southerly-exposed transect and ~14.5–12 Ma in the northern transect. Similarly, lower LHS footwall rocks reached peak metamorphic conditions of ~580 ◦C and 8.5 kbar at ~16 Ma in the south, and 9–10 Ma in the north. In the southern transect, the timing of partial melting in the GHS hanging wall (~23–19.5 Ma) overlaps with the timing of prograde metamorphism (~21 Ma) in the LHS footwall, confirming that the hanging wall may have provided the heat necessary for the metamorphism of the footwall. Overall, the data provide robust evidence for progressively downwards-penetrating deformation and accretion of original LHS footwall material to the GHS hanging wall over a period of ~5 Ma. These processes appear to have occurred several times during the prolonged ductile evolution of the thrust. The preserved inverted metamorphic sequence therefore documents the formation of sequential ‘paleothrusts’ through time, cutting down from the original locus of MCT movement at the LHS–GHS protolith boundary and forming at successively lower pressure and temperature conditions. The petrochronologic methods applied here constrain a complex temporal and thermal deformation history, and demonstrate that inverted metamorphic sequences can preserve a rich record of the duration of progressive ductile thrusting

Intermediated Social Preferences: Altruism in an Algorithmic Era

What are the consequences of intermediating moral responsibility through complex organizations or transactions? This paper examines individual decision-making when choices are known to be obfuscated under randomization. It reports the results of a data entry experiment in an online labor market. Individuals enter data, grade another individual’s work, and decide to split a bonus. However, before they report their decision, they are randomized into settings with different degrees of intermediation. The key finding is that less generosity results when graders are told the split might be implemented by a new procurement algorithm. Those whose decisions are averaged or randomly selected among a set of graders are more generous relative to the asocial treatment. These findings relate to “the great transformation” whereby moral mentalities are shaped by modes of (a)social interaction

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

A novel approach for the generation of genetically modified mammary epithelial cell cultures yields new insights into TGF-beta signaling in the mammary gland

Abstract Introduction Molecular dissection of the signaling pathways that underlie complex biological responses in the mammary epithelium is limited by the difficulty of propagating large numbers of mouse mammary epithelial cells, and by the inability of ribonucleic acid interference-based knockdown approaches to fully ablate gene function. Here we describe a method for the generation of conditionally immortalized mammary epithelial cells with defined genetic defects, and we show how such cells can be used to investigate complex signal transduction processes using the transforming growth factor beta (TGFβ)/Smad pathway as an example. Methods We intercrossed the previously described H-2Kb-tsA58 transgenic mouse (Immortomouse), which expresses a temperature-sensitive mutant of the simian virus-40 large T-antigen (tsTAg), with mice of differing Smad genotypes. Conditionally immortalized mammary epithelial cell cultures were derived from the virgin mammary glands of offspring of these crosses and were used to assess the Smad dependency of different biological responses to TGFβ. Results IMECs could be propagated indefinitely at permissive temperatures and had a stable epithelial phenotype, resembling primary mammary epithelial cells with respect to several criteria, including responsiveness to TGFβ. Using this panel of cells, we demonstrated that Smad3, but not Smad2, is necessary for TGFβ-induced apoptotic, growth inhibitory and epithelial-to-mesenchymal transition responses, whereas either Smad2 or Smad3 can support TGFβ-induced invasion as long as a threshold level of total Smad is exceeded. Conclusions The present work demonstrates the practicality and utility of generating conditionally immortalized mammary epithelial cell lines from genetically modified Immortomice for detailed investigation of complex signaling pathways in the mammary epithelium.http://deepblue.lib.umich.edu/bitstream/2027.42/78285/1/bcr2728.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78285/2/bcr2728.pdfPeer Reviewe

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment