Maximal L p -regularity for the Laplacian on Lipschitz domains

We consider the Laplacian with Dirichlet or Neumann boundary conditions on bounded Lipschitz domains ?, both with the following two domains of definition:D1(?) = {u ? W1,p(?) : ?u ? Lp(?), Bu = 0}, orD2(?) = {u ? W2,p(?) : Bu = 0}, where B is the boundary operator.We prove that, under certain restrictions on the range of p, these operators generate positive analytic contraction semigroups on Lp(?) which implies maximal regularity for the corresponding Cauchy problems. In particular, if ? is bounded and convex and 1 < p ? 2, the Laplacian with domain D2(?) has the maximal regularity property, as in the case of smooth domains. In the last part,we construct an example that proves that, in general, the Dirichlet–Laplacian with domain D1(?) is not even a closed operator

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

The stability for the Cauchy problem for elliptic equations

We discuss the ill-posed Cauchy problem for elliptic equations, which is pervasive in inverse boundary value problems modeled by elliptic equations. We provide essentially optimal stability results, in wide generality and under substantially minimal assumptions. As a general scheme in our arguments, we show that all such stability results can be derived by the use of a single building brick, the three-spheres inequality.Comment: 57 pages, review articl

An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ.

Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers

A Survey on the Krein-von Neumann Extension, the corresponding Abstract Buckling Problem, and Weyl-Type Spectral Asymptotics for Perturbed Krein Laplacians in Nonsmooth Domains

In the first (and abstract) part of this survey we prove the unitary equivalence of the inverse of the Krein--von Neumann extension (on the orthogonal complement of its kernel) of a densely defined, closed, strictly positive operator, $S\geq \varepsilon I_{\mathcal{H}}$ for some $\varepsilon >0$ in a Hilbert space $\mathcal{H}$ to an abstract buckling problem operator. This establishes the Krein extension as a natural object in elasticity theory (in analogy to the Friedrichs extension, which found natural applications in quantum mechanics, elasticity, etc.). In the second, and principal part of this survey, we study spectral properties for $H_{K,\Omega}$, the Krein--von Neumann extension of the perturbed Laplacian $-\Delta+V$ (in short, the perturbed Krein Laplacian) defined on $C^\infty_0(\Omega)$, where $V$ is measurable, bounded and nonnegative, in a bounded open set $\Omega\subset\mathbb{R}^n$ belonging to a class of nonsmooth domains which contains all convex domains, along with all domains of class $C^{1,r}$, $r>1/2$.Comment: 68 pages. arXiv admin note: extreme text overlap with arXiv:0907.144

Inclusive J/ψ production at mid-rapidity in pp collisions at √s = 5.02 TeV

Inclusive J/ψ production is studied in minimum-bias proton-proton collisions at a centre-of-mass energy of s = 5.02 TeV by ALICE at the CERN LHC. The measurement is performed at mid-rapidity (|y| &lt; 0.9) in the dielectron decay channel down to zero transverse momentum pT, using a data sample corresponding to an integrated luminosity of Lint = 19.4 ± 0.4 nb−1. The measured pT-integrated inclusive J/ψ production cross sec- tion is dσ/dy = 5.64 ± 0.22(stat.) ± 0.33(syst.) ± 0.12(lumi.) μb. The pT-differential cross section d2σ/dpTdy is measured in the pT range 0–10 GeV/c and compared with state-of- the-art QCD calculations. The J/ψ 〈pT〉 and 〈pT2〉 are extracted and compared with results obtained at other collision energies. [Figure not available: see fulltext.]

Measurement of Λ (1520) production in pp collisions at √s=7TeV and p–Pb collisions at √sNN=5.02TeV

The production of the Λ (1520) baryonic resonance has been measured at midrapidity in inelastic pp collisions at s=7TeV and in p–Pb collisions at sNN=5.02TeV for non-single diffractive events and in multiplicity classes. The resonance is reconstructed through its hadronic decay channel Λ (1520) → pK - and the charge conjugate with the ALICE detector. The integrated yields and mean transverse momenta are calculated from the measured transverse momentum distributions in pp and p–Pb collisions. The mean transverse momenta follow mass ordering as previously observed for other hyperons in the same collision systems. A Blast-Wave function constrained by other light hadrons (π, K, KS0, p, Λ) describes the shape of the Λ (1520) transverse momentum distribution up to 3.5GeV/c in p–Pb collisions. In the framework of this model, this observation suggests that the Λ (1520) resonance participates in the same collective radial flow as other light hadrons. The ratio of the yield of Λ (1520) to the yield of the ground state particle Λ remains constant as a function of charged-particle multiplicity, suggesting that there is no net effect of the hadronic phase in p–Pb collisions on the Λ (1520) yield

Measurement of charged jet cross section in pp collisions at s =5.02 TeV

The cross section of jets reconstructed from charged particles is measured in the transverse momentum range of

Measurement of electrons from heavy-flavour hadron decays as a function of multiplicity in p-Pb collisions at √sNN = 5.02 TeV

The multiplicity dependence of electron production from heavy-flavour hadron decays as a function of transverse momentum was measured in p-Pb collisions at sNN = 5.02 TeV using the ALICE detector at the LHC. The measurement was performed in the centre-of-mass rapidity interval −1.07 &lt; ycms&lt; 0.14 and transverse momentum interval 2 &lt; pT&lt; 16 GeV/c. The multiplicity dependence of the production of electrons from heavy-flavour hadron decays was studied by comparing the pT spectra measured for different multiplicity classes with those measured in pp collisions (QpPb) and in peripheral p-Pb collisions (Qcp). The QpPb results obtained are consistent with unity within uncertainties in the measured pT interval and event classes. This indicates that heavy-flavour decay electron production is consistent with binary scaling and independent of the geometry of the collision system. Additionally, the results suggest that cold nuclear matter effects are negligible within uncertainties, in the production of heavy-flavour decay electrons at midrapidity in p-Pb collisions. [Figure not available: see fulltext.