A Hilbertian projection method for constrained level set-based topology optimisation

We present an extension of the projection method proposed by Challis et al ($\textit{Int J Solids Struct}$. Volume $\textbf{45}$(14-15) (2008) 4130-4146) for constrained level set-based topology optimisation that harnesses the Hilbertian velocity extension-regularisation framework. Our $\textit{Hilbertian projection method}$ chooses a normal velocity for the level set function as a linear combination of: 1) an orthogonal projection operator applied to the extended optimisation objective shape sensitivity; and 2) a weighted sum of orthogonal basis functions for the extended constraint shape sensitivities. This combination aims for the best possible first-order improvement of the optimisation objective in addition to first-order improvement of the constraints. Our formulation utilising basis orthogonalisation naturally handles linearly dependent constraint shape sensitivities. Furthermore, use of the Hilbertian extension-regularisation framework ensures that the resulting normal velocity is extended away from the boundary and enriched with additional regularity. Our approach is generally applicable to any topology optimisation problem to be solved in the level set framework. We consider several benchmark constrained microstructure optimisation problems and demonstrate that our method is effective with little-to-no parameter tuning. We also find that our method performs well when compared to a Hilbertian sequential linear programming method.Comment: 23 pages, 8 figure

Characterization of Antiallodynic Actions of ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in the Rat1

There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 6 1.87 mM, 3.72 6 1.3 mM, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95% confidence intervals) for ALE- 0540 administered i.p. and i.th. were 38 (17.5– 83) mg/kg and 34.6 (17.3– 69.4) mg, respectively. ALE-0540 given i.th., at doses of 30 and 60 mg, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A50 value of 7.1 (5.6–8.8) mg/kg] than ALE- 0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered i.th. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain

The geometry of a vorticity model equation

We provide rigorous evidence of the fact that the modified Constantin-Lax-Majda equation modeling vortex and quasi-geostrophic dynamics describes the geodesic flow on the subgroup of orientation-preserving diffeomorphisms fixing one point, with respect to right-invariant metric induced by the homogeneous Sobolev norm $H^{1/2}$ and show the local existence of the geodesics in the extended group of diffeomorphisms of Sobolev class $H^{k}$ with $k\ge 2$.Comment: 24 page

Smooth 2D Coordinate Systems on Discrete Surfaces

International audienceWe introduce a new method to compute conformal param- eterizations using a recent definition of discrete conformity, and estab- lish a discrete version of the Riemann mapping theorem. Our algorithm can parameterize triangular, quadrangular and digital meshes. It can be adapted to preserve metric properties. To demonstrate the efficiency of our method, many examples are shown in the experiment section

Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.

Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors

Statins but Not Aspirin Reduce Thrombotic Risk Assessed by Thrombin Generation in Diabetic Patients without Cardiovascular Events: The RATIONAL Trial

The systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.Prospective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.While waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.ClinicalTrials.gov NCT00793754

The Astrocyte-Targeted Therapy by Bushi for the Neuropathic Pain in Mice

BACKGROUND: There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required. METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro. CONCLUSIONS: Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain

Explaining the competition between strength and toughness in perforated plates using computational finite fracture mechanics

We present a computational implementation of mode I finite fracture mechanics (FFM) that allows us to explore how hole shape and size affects the strength of linear elastic perforated plates. We compute the FFM predicted strength of a plate with centre crack, circle, diamond, and hexagon perforations of different sizes, as well as filleted (rounded) diamond perforations. Of the studied hole shapes, the diamond has the lowest predicted failure stress. By varying the toughness and strength material parameters, we elucidate how energy (toughness) and stress (strength) considerations compete for dominance in the coupled FFM failure criterion. We find that as the perforation radius goes to zero, failure is strength-dominated, while at small non-zero perforation sizes both strength and toughness play a role in determining failure. For perforation shapes with stress singularities (diamond, hexagon, centre crack), toughness dominates at larger perforation sizes, while strength strongly dominates at larger radii for circle perforations. The filleted diamond computations indicate that failure stress increases continuously as the hole shape deforms from a diamond into a circle, and so does the balance between toughness and strength in the coupled criterion. The presented results suggest new avenues for experimental work to further validate and explore the FFM coupled failure criterion. Our FFM implementation that uses Matlab and Ansys is provided as supplementary material