Feed rate modeling in circular–circular interpolation discontinuity for high-speed milling

In this paper, a modeling approach is presented in order to evaluate feed rate during a circular interpolation in high-speed milling. The developed model depends on the type of discontinuity and the kinematic performance of the machine tool. To begin with, a feed rate modeling for circular interpolation with continuity in tangency is developed. After, the discontinuity in tangency between two circular interpolations is replaced by discontinuity in curvature by adding a fillet which is in relation to the functional tolerance ε imposed in the part design. An experimental study has been carried out to validate the models

Hole-doping effects on a frustrated spin ladder

Hole-doping effects are investigated on the {\it t-J} ladder model with the linked-tetrahedra structure. We discuss how a metal-insulator transition occurs upon hole doping with particular emphasis on the effects of geometrical frustration. By computing the electron density and the spin correlation function by the density matrix renormalization group, we show that strong frustration triggers a first-order transition to a metallic phase, when holes are doped into the plaquette-singlet phase. By examining spin excitations in a metallic case in detail, we discuss whether the spin-gap phase persists upon hole doping according to the strength of frustration. It is further shown that the lowest excited state in a spin-gap metallic phase can be described in two independent quasiparticles.Comment: 7 pages, 9 figure

The Wisconsin Plasma Astrophysics Laboratory

The Wisconsin Plasma Astrophysics Laboratory (WiPAL) is a flexible user facility designed to study a range of astrophysically relevant plasma processes as well as novel geometries that mimic astrophysical systems. A multi-cusp magnetic bucket constructed from strong samarium cobalt permanent magnets now confines a 10 m$^3$, fully ionized, magnetic-field free plasma in a spherical geometry. Plasma parameters of $T_{e}\approx5$ to $20$ eV and $n_{e}\approx10^{11}$ to $5\times10^{12}$ cm$^{-3}$ provide an ideal testbed for a range of astrophysical experiments including self-exciting dynamos, collisionless magnetic reconnection, jet stability, stellar winds, and more. This article describes the capabilities of WiPAL along with several experiments, in both operating and planning stages, that illustrate the range of possibilities for future users.Comment: 21 pages, 12 figures, 2 table

Inscuteable Regulates the Pins-Mud Spindle Orientation Pathway

During asymmetric cell division, alignment of the mitotic spindle with the cell polarity axis ensures that the cleavage furrow separates fate determinants into distinct daughter cells. The protein Inscuteable (Insc) is thought to link cell polarity and spindle positioning in diverse systems by binding the polarity protein Bazooka (Baz; aka Par-3) and the spindle orienting protein Partner of Inscuteable (Pins; mPins or LGN in mammals). Here we investigate the mechanism of spindle orientation by the Insc-Pins complex. Previously, we defined two Pins spindle orientation pathways: a complex with Mushroom body defect (Mud; NuMA in mammals) is required for full activity, whereas binding to Discs large (Dlg) is sufficient for partial activity. In the current study, we have examined the role of Inscuteable in mediating downstream Pins-mediated spindle orientation pathways. We find that the Insc-Pins complex requires Gαi for partial activity and that the complex specifically recruits Dlg but not Mud. In vitro competition experiments revealed that Insc and Mud compete for binding to the Pins TPR motifs, while Dlg can form a ternary complex with Insc-Pins. Our results suggest that Insc does not passively couple polarity and spindle orientation but preferentially inhibits the Mud pathway, while allowing the Dlg pathway to remain active. Insc-regulated complex assembly may ensure that the spindle is attached to the cortex (via Dlg) before activation of spindle pulling forces by Dynein/Dynactin (via Mud)

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Heart failure subtypes and thromboembolic risk in patients with atrial fibrillation::The PREFER in AF - HF substudy

BACKGROUND AND OBJECTIVES: To assess thromboembolic and bleeding risks in patients with heart failure (HF) and atrial fibrillation (AF) according to HF type. METHODS: We analyzed 6170 AF patients from the Prevention of thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), and categorized patients into: HF with reduced left-ventricular ejection fraction (HFrEF; LVEF60%), and no HF. Outcomes were ischemic stroke, major adverse cardiovascular and cerebral events (MACCE) and major bleeding occurring within 1-year. RESULTS: The annual incidence of stroke was linearly and inversely related to LVEF, increasing by 0.054% per each 1% of LVEF decrease (95% CI: 0.013%-0.096%; p=0.031). Patients with HFHpEF had the highest CHA2DS2-VASc score, but significantly lower stroke incidence than other HF groups (0.65%, compared to HFLpEF 1.30%; HFmrEF 1.71%; HFrEF 1.75%; trend p=0.014). The incidence of MACCE was also lower in HFHpEF (2.0%) compared to other HF groups (range: 3.8-4.4%; p=0.001). Age, HF type, and NYHA class were independent predictors of thromboembolic events. Conversely, major bleeding did not significantly differ between groups (p=0.168). CONCLUSION: Our study in predominantly anticoagulated patients with AF shows that, reduction in LVEF is associated with higher thromboembolic, but not higher bleeding risk. HFHpEF is a distinct and puzzling group, featuring the highest CHA2DS2-VASc score but the lowest residual risk of thromboembolic events, which warrants further investigation

TAp73 is a central transcriptional regulator of airway multiciliogenesis.

Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation