Nonadditive Genetic Effects in Animal Behavior

Heritabilities, commonly used to predict evolutionary potential, are notoriously low for behaviors. Apart from strong contributions of environmental variance in reducing heritabilities, the additive genetic components can be very low, especially when they are camouflaged by nonadditive genetic effects. We first report the heritabilities of courtship traits in founder‐flush and control populations of the housefly (Musca domestica L.). We estimated the heritability of each male and female display through the regression of the courtships involving daughters and sons (with randomly selected mates) onto the “midparental” courtship values of their parents. Overall, the average heritability was significantly higher for the parent‐daughter assays than for the parent‐son assays. We attributed the low (even negative) heritabilities to genotype‐by‐environment interactions whereby the male’s behavior is influenced by the “environment” of his mating partner’s preferences for the display, generating epistasis through indirect genetic effects. Moreover, bottlenecked lines had up to 800% of the heritability of the controls, suggesting “conversion” of additive genetic variance from nonadditive components. Second, we used line‐cross assays on separate populations that had been selected for divergence in mating behavior to identify dominance and epistasis through heterosis and outbreeding depression in courtship. Finally, our literature review confirms the prevalence of such low heritabilities (i.e., a conservative mean of 0.38) and nonadditive genetics in other behavioral repertoires (64% of the studies). We conclude that animal behavior is especially prone to the gamut of quantitative genetic complexities that can result in negative heritabilities, negative selection responses, inbreeding depression, conversion, heterosis, and outbreeding depression

Oxylipin concentration shift in exhaled breath condensate (EBC) of SARS-CoV-2 infected patients

Infection of airway epithelial cells with severe acute respiratory coronavirus 2 (SARS-CoV-2) can lead to severe respiratory tract damage and lung injury with hypoxia. It is challenging to sample the lower airways non-invasively and the capability to identify a highly representative specimen that can be collected in a non-invasive way would provide opportunities to investigate metabolomic consequences of COVID-19 disease. In the present study, we performed a targeted metabolomic approach using liquid chromatography coupled with high resolution chromatography (LC-MS) on exhaled breath condensate (EBC) collected from hospitalized COVID-19 patients (COVID+) and negative controls, both non-hospitalized and hospitalized for other reasons (COVID-). We were able to noninvasively identify and quantify inflammatory oxylipin shifts and dysregulation that may ultimately be used to monitor COVID-19 disease progression or severity and response to therapy. We also expected EBC-based biochemical oxylipin changes associated with COVID-19 host response to infection. The results indicated ten targeted oxylipins showing significative differences between SAR-CoV-2 infected EBC samples and negative control subjects. These compounds were prostaglandins A2 and D2, LXA4, 5-HETE, 12-HETE, 15-HETE, 5-HEPE, 9-HODE, 13-oxoODE and 19(20)-EpDPA, which are associated with specific pathways (i.e. P450, COX, 15-LOX) related to inflammatory and oxidative stress processes. Moreover, all these compounds were up-regulated by COVID+, meaning their concentrations were higher in subjects with SAR-CoV-2 infection. Given that many COVID-19 symptoms are inflammatory in nature, this is interesting insight into the pathophysiology of the disease. Breath monitoring of these and other EBC metabolites presents an interesting opportunity to monitor key indicators of disease progression and severity

Identifying existing Choosing Wisely recommendations of high relevance and importance to hematology

Choosing Wisely (CW) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. In an effort to learn from and leverage the work of others, the American Society of Hematology CW Task Force developed a method to identify and prioritize CW recommendations from other medical societies of high relevance and importance to patients with blood disorders and their physicians. All 380 CW recommendations were reviewed and assessed for relevance and importance. Relevance was assessed using the MORE TM relevance scale. Importance was assessed with regard to six guiding principles: harm avoidance, evidence, aggregate cost, relevance, frequency and impact. Harm avoidance was considered the most important principle. Ten highly relevant and important recommendations were identified from a variety of professional societies. Recommendations focused on decreasing unnecessary imaging, blood work, treatments and transfusions, as well as on increasing collaboration across disciplines and considering value when recommending treatments. Many CW recommendations have relevance beyond the society of origin. The methods developed by the ASH CW Task Force could be easily adapted by other Societies to identify additional CW recommendations of relevance and importance to their fields. Am. J. Hematol. 91:787–792, 2016. © 2016 Wiley Periodicals, Inc

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model.

Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans

Efficacy and safety of avapritinib in advanced systemic mastocytosis:interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10(-9)), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio