Effects of ignoring inbreeding in model-based accuracy for BLUP and SSGBLUP

[EN] Model-based accuracy, defined as the theoretical correlation between true and estimated breeding value, can be obtained for each individual as a function of its prediction error variance (PEV) and inbreeding coefficient F, in BLUP, GBLUP and SSGBLUP genetic evaluations. However, for computational convenience, inbreeding is often ignored in two places. First, in the computation of reliability = 1-PEV/(1 + F). Second, in the set-up, using Henderson's rules, of the inverse of the pedigree-based relationship matrix A. Both approximations have an effect in the computation of model-based accuracy and result in wrong values. In this work, first we present a reminder of the theory and extend it to SSGBLUP. Second, we quantify the error of ignoring inbreeding with real data in three scenarios: BLUP evaluation and SSGBLUP in Uruguayan dairy cattle, and BLUP evaluations in a line of rabbit closed for >40 generations with steady increase of inbreeding up to an average of 0.30. We show that ignoring inbreeding in the set-up of the A-inverse is equivalent to assume that non-inbred animals are actually inbred. This results in an increase of apparent PEV that is negligible for dairy cattle but considerable for rabbit. Ignoring inbreeding in reliability = 1-PEV/(1 + F) leads to underestimation of reliability for BLUP evaluations, and this underestimation is very large for rabbit. For SSGBLUP in dairy cattle, it leads to both underestimation and overestimation of reliability, both for genotyped and non-genotyped animals. We strongly recommend to include inbreeding both in the set-up of A-inverse and in the computation of reliability from PEVs.FEDER; INRA; Universidad Nacional de Lomas de Zamora; European Unions' Horizon 2020 Research & Innovation Programme, Grant/Award Number: No772787Aguilar, I.; Fernandez, EN.; Blasco Mateu, A.; Ravagnolo, O.; Legarra, A. (2020). Effects of ignoring inbreeding in model-based accuracy for BLUP and SSGBLUP. 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Short communication: Calculating analytical reliabilities for single-step predictions. Journal of Dairy Science, 102(4), 3259-3265. doi:10.3168/jds.2018-15707Fernández, E. N., Sánchez, J. P., Martínez, R., Legarra, A., & Baselga, M. (2017). Role of inbreeding depression, non-inbred dominance deviations and random year-season effect in genetic trends for prolificacy in closed rabbit lines. Journal of Animal Breeding and Genetics, 134(6), 441-452. doi:10.1111/jbg.12284Golden, B. L., Brinks, J. S., & Bourdon, R. M. (1991). A performance programmed method for computing inbreeding coefficients from large data sets for use in mixed-model analyses. Journal of Animal Science, 69(9), 3564-3573. doi:10.2527/1991.6993564xGroeneveld E. Kovac M. &Wang T.(1990).PEST a general purpose BLUP package for multivariate prediction and estimation. Proceedings of the 4th World Congress on Genetics Applied to Livestock Production Edinburgh 13 488–491.Henderson, C. R. (1975). 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Technical note: Genomic evaluation for crossbred performance in a single-step approach with metafounders1. Journal of Animal Science, 95(4), 1472-1480. doi:10.2527/jas.2016.115

Why do some asthma patients respond poorly to glucocorticoid therapy?

Glucocorticosteroids are the first-line therapy for controlling airway inflammation in asthma. They bind intracellular glucocorticoid receptors to trigger increased expression of anti-inflammatory genes and suppression of pro-inflammatory gene activation in asthmatic airways. In the majority of asthma patients, inhaled glucocorticoids are clinically efficacious, improving lung function and preventing exacerbations. However, 5–10 % of the asthmatic population respond poorly to high dose inhaled and then systemic glucocorticoids. These patients form a category of severe asthma associated with poor quality of life, increased morbidity and mortality, and constitutes a major societal and health care burden. Inadequate therapeutic responses to glucocorticoid treatment is also reported in other inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease; however, asthma represents the most studied steroid-refractory disease. Several cellular and molecular events underlying glucocorticoid resistance in asthma have been identified involving abnormalities of glucocorticoid receptor signaling pathways. These events have been strongly related to immunological dysregulation, genetic, and environmental factors such as cigarette smoking or respiratory infections. A better understanding of the multiple mechanisms associated with glucocorticoid insensitivity in asthma phenotypes could improve quality of life for people with asthma but would also provide transferrable knowledge for other inflammatory diseases. In this review, we provide an update on the molecular mechanisms behind steroid-refractory asthma. Additionally, we discuss some therapeutic options for treating those asthmatic patients who respond poorly to glucocorticoid therapy

Fusion-Fission of 16O+197Au at Sub-Barrier Energies

The recent discovery of heavy-ion fusion hindrance at far sub-barrier energies has focused much attention on both experimental and theoretical studies of this phenomenon. Most of the experimental evidence comes from medium-heavy systems such as Ni+Ni to Zr+Zr, for which the compound system decays primarily by charged-particle evaporation. In order to study heavier systems, it is, however, necessary to measure also the fraction of the decay that goes into fission fragments. In the present work we have, therefore, measured the fission cross section of 16O+197Au down to unprecedented far sub-barrier energies using a large position sensitive PPAC placed at backward angles. The preliminary cross sections will be discussed and compared to earlier studies at near-barrier energies. No conclusive evidence for sub-barrier hindrance was found, probably because the measurements were not extended to sufficiently low energies.Comment: Fusion06 - Intl. Conf. on Reaction Mechanisms and Nuclear Structure at the Coulomb Barrier, San Servolo, Venezia, Italy, March 19-223, 2006 5 pages, 4 figure

Variability of Pennsylvanian-Permian Carbonate Associations and Implications for NW Pangea Palaeogeography, East-Central British Columbia, Canada

Different stages of Pennsylvanian-Permian carbonate sedimentation in east-central British Columbia record a complex history of changing environments influenced by evolving palaeogeography and climate. Newly recognized tectonically controlled features affected the distribution and variability of carbonate associations, providing new interpretations for this portion of the west coast of Pangea. Both a heterozoan (cool water) and photozoan (warm-water) association were identified on either side of a palaeogeographic high here informally termed “Tipinahokan Peninsula”. Cool water carbonates were located outboard, or to the west of this high, an area influenced by upwelling waters. Inboard of this high, a warm, protected sea developed, here termed “Kisosowin Sea”. This configuration and palaeolatitude is similar to that of Baja California, Mexico and the Sea of Cortéz, providing a good modern analog for these deposits where warm water carbonates grow at latitudes otherwise dominated by cool water deposits. The warm sea provided a place for a photozoan association to develop during the Permian when the low latitude NW coast of Pangea was dominated by cool water carbonates

Quantum turbulence at finite temperature: the two-fluids cascade

To model isotropic homogeneous quantum turbulence in superfluid helium, we have performed Direct Numerical Simulations (DNS) of two fluids (the normal fluid and the superfluid) coupled by mutual friction. We have found evidence of strong locking of superfluid and normal fluid along the turbulent cascade, from the large scale structures where only one fluid is forced down to the vorticity structures at small scales. We have determined the residual slip velocity between the two fluids, and, for each fluid, the relative balance of inertial, viscous and friction forces along the scales. Our calculations show that the classical relation between energy injection and dissipation scale is not valid in quantum turbulence, but we have been able to derive a temperature--dependent superfluid analogous relation. Finally, we discuss our DNS results in terms of the current understanding of quantum turbulence, including the value of the effective kinematic viscosity

Flow Induced Organization and Memory of a Vortex Lattice

We report on experiments probing the evolution of a vortex state in response to a driving current in 2H-NbSe$_2$ crystals. By following the vortex motion with fast transport measurements we find that the current enables the system to reorganize and access new configurations. During this process the system exhibits a long-term memory: if the current is turned off the vortices freeze in place remembering their prior motion. When the current is restored the motion resumes where it stopped. The experiments provide evidence for a dynamically driven structural change of the vortex lattice and a corresponding dynamic phase diagram that contains a previously unknown regime where the critical current can be either $increased$ or $decreased$ by applying an appropriate driving current.Comment: 5 pages, 4figure

Water incident related hospital activity across England between 1997/8 and 2003/4: a retrospective descriptive study

Every year in the United Kingdom, 10,000 people will die from accidental injury and the treatment of these injuries will cost the NHS £2 billion and the consequences of injuries received at home cost society a further £25 billion [1]. Non-fatal injuries result in 720,000 people being admitted to hospital a year and more than six million visits to accident and emergency departments each year [2]. Drowning is the second leading cause of unintentional injury mortality globally behind road traffic injuries. It is estimated that a total of 409, 272 people drown each year [3]. This equates to a global incident rate of 7.4 deaths per 100, 000 people worldwide and relates to a further 1.3 million Disability Adjusted Life Years (DALYs) which are lost as a result of premature death or disability [4]. 'Death' represents only the tip of the injury "iceberg" [5]. For every life lost from an injury, many more people are admitted to hospital, attend accident and emergency departments or general practitioners, are rescued by search and rescue organisations or resolve the situation themselves. It is estimated that 1.3 million people are injured as a result of near drowning episodes globally and that many more hundreds of thousands of people are affected through incidents and near misses but there are no accurate data [4]. The United Kingdom has reported a variable drowning fatality rate, the injury chart book reports a rate of 1.0 – 1.5 per 100,000 [6] and other studies suggest a rate as low as 0.5 per 100, 000 population [7] for accidental drowning and submersion, based on the International Classification of Disease 10 code W65 – 74, however, the problem is even greater and these Global Burden of Disease (GDB) figures are an underestimate of all drowning deaths, since they exclude drownings due to cataclysms (floods), water related transport accidents, assaults and suicide [3]. A recent study in Scotland highlighted this underestimation in drowning fatality data and found that the overall death rate due to drownings in Scotland 3.26 per 100,000 [8]. Even though drowning fatality rates in the United Kingdom vary, little is known about the people who are admitted to hospital after an incident either in or on water. This paper seeks to address this gap in our knowledge through the investigation of the data available on those admitted to NHS hospitals in England

Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642)

Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = \u3c0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping