Most Likely Transformations

We propose and study properties of maximum likelihood estimators in the class of conditional transformation models. Based on a suitable explicit parameterisation of the unconditional or conditional transformation function, we establish a cascade of increasingly complex transformation models that can be estimated, compared and analysed in the maximum likelihood framework. Models for the unconditional or conditional distribution function of any univariate response variable can be set-up and estimated in the same theoretical and computational framework simply by choosing an appropriate transformation function and parameterisation thereof. The ability to evaluate the distribution function directly allows us to estimate models based on the exact likelihood, especially in the presence of random censoring or truncation. For discrete and continuous responses, we establish the asymptotic normality of the proposed estimators. A reference software implementation of maximum likelihood-based estimation for conditional transformation models allowing the same flexibility as the theory developed here was employed to illustrate the wide range of possible applications.Comment: Accepted for publication by the Scandinavian Journal of Statistics 2017-06-1

Biochar-based fertilizer: Supercharging root membrane potential and biomass yield of rice

Biochar-based compound fertilizers (BCF) and amendments have proven to enhance crop yields and modify soil properties (pH, nutrients, organic matter, structure etc.) and are now in commercial production in China. While there is a good understanding of the changes in soil properties following biochar addition, the interactions within the rhizosphere remain largely unstudied, with benefits to yield observed beyond the changes in soil properties alone. We investigated the rhizosphere interactions following the addition of an activated wheat straw BCF at an application rates of 0.25% (g·g−1 soil), which could potentially explain the increase of plant biomass (by 67%), herbage N (by 40%) and P (by 46%) uptake in the rice plants grown in the BCF-treated soil, compared to the rice plants grown in the soil with conventional fertilizer alone. Examination of the roots revealed that micron and submicron-sized biochar were embedded in the plaque layer. BCF increased soil Eh by 85 mV and increased the potential difference between the rhizosphere soil and the root membrane by 65 mV. This increased potential difference lowered the free energy required for root nutrient accumulation, potentially explaining greater plant nutrient content and biomass. We also demonstrate an increased abundance of plant-growth promoting bacteria and fungi in the rhizosphere. We suggest that the redox properties of the biochar cause major changes in electron status of rhizosphere soils that drive the observed agronomic benefits

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ- and sex-specific

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis

Dark Spin-Cat States as Biased Qubits

We present a biased atomic qubit, universally implementable across all atomic platforms, encoded as a “spin cat” within ground state Zeeman levels. The key characteristic of our configuration is the coupling of the ground state spin manifold of size Fg≫1 to an excited Zeeman spin manifold of size Fe=Fg−1 using light. This coupling results in eigenstates of the driven atom that include exactly two dark states in the ground state manifold, which are decoupled from light and immune to spontaneous emission from the excited states. These dark states constitute the spin cat, leading to the designation “dark spin cat.” We demonstrate that under strong Rabi drive and for large Fg, the dark spin cat is autonomously stabilized against common noise sources and encodes a qubit with significantly biased noise. Specifically, the bit-flip error rate decreases exponentially with Fg relative to the dephasing rate. We provide an analysis of dark spin cats and their robustness to noise, and we discuss bias-preserving single qubit and entangling gates, exemplified on a Rydberg tweezer platform.</p

Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic β-cells.

KCNQ1/Kv7, a low-voltage-gated K+ channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and β-cell survival in hereditary diabetes pathology

Digital transformation of health and care to sustain Planetary Health : The MASK proof-of-concept for airway diseases-POLLAR symposium under the auspices of Finland's Presidency of the EU, 2019 and MACVIA-France, Global Alliance against Chronic Respiratory Diseases (GARD, WH0) demonstration project, Reference Site Collaborative Network of the European Innovation Partnership on Active and Healthy Ageing

In December 2019, a conference entitled "Europe That Protects: Safeguarding Our Planet, Safeguarding Our Health" was held in Helsinki. It was co-organized by the Finnish Institute for Health and Welfare, the Finnish Environment Institute and the European Commission, under the auspices of Finland's Presidency of the EU. As a side event, a symposium organized as the final POLLAR (Impact of air POLLution on Asthma and Rhinitis) meeting explored the digital transformation of health and care to sustain planetary health in airway diseases. The Finnish Allergy Programme collaborates with MASK (Mobile Airways Sentinel NetworK) and can be considered as a proof-of-concept to impact Planetary Health. The Good Practice of DG Sante (The Directorate-General for Health and Food Safety) on digitally-enabled, patient-centred care pathways is in line with the objectives of the Finnish Allergy Programme. The ARIACARE-Digital network has been deployed in 25 countries. It represents an example of the digital cross-border exchange of real-world data and experience with the aim to improve patient care. The integration of information technology tools for climate, weather, air pollution and aerobiology in mobile Health applications will enable the development of an alert system. Citizens will thus be informed about personal environmental threats, which may also be linked to indicators of Planetary Health and sustainability. The digital transformation of the public health policy was also proposed, following the experience of the Agency for Health Quality and Assessment of Catalonia (AQuAS).Peer reviewe

Does contrast echocardiography induce increases in markers of myocardial necrosis, inflammation and oxidative stress suggesting myocardial injury?

BACKGROUND: Contrast echocardiography is a precise tool for the non-invasive assessment of myocardial function and perfusion. Side effects of contrast echocardiography resulting from contrast-agent induced myocardial micro-lesions have been found in animals. The goal of this study is to measure markers of myocardial necrosis, inflammation and oxidative stress in humans to evaluate potential side-effects of contrast echocardiography. METHODS: 20 patients who underwent contrast echocardiography with Optison as the contrast medium were investigated. To evaluate myocardial micro-necrosis, inflammation and oxidative stress, cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, -8 and thiobarbituric acid reactive substances (TBARS) were measured at baseline and at 2, 4, 8 and 24 hours after contrast echocardiography. RESULTS: At baseline, 50% of the patients had cTnI and TBARS values outside the reference range. TNF-α, IL-6, IL-8 levels were within the reference range. Patients with cTnI above the RR clustered to significantly higher levels of TNF-α and IL-6. After contrast echocardiography, no statistically significant increase of cTnI, cytokines and TBARS was found. However, for nearly 50% of the patients, the intra-individual cTnI kinetics crossed the critical difference (threefold of methodical variation) which indicates a marker increase. This was neither predicted by the baseline levels of the cytokines nor the markers of oxidative stress. CONCLUSION: There are no clinically relevant increases in serum markers for micro-necrosis, inflammation and oxidative stress in humans after contrast echocardiography. Future studies have to address whether cTnI increase in some patients represent a subset with increased risk for side effects after contrast echocardiography