Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

Background: The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF. Methods: Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases). Results: Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10−6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12, P = 3 × 10−7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease. Conclusions: This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention

Resistance of MLL–AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation

Mixed-lineage leukemia (MLL)–AFF1 (MLL–AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL–AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL–AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL–AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53–caspase 8–caspase 3 pathway were observed only in MLL–AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53–caspase 8–caspase 3 pathway of MLL–AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL–AFF1 transgenic mice. These results suggest that MLL–AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53–caspase 8–caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL–AFF1-positive ALL in combination with allo-HSCT

The coarse geometry of Tsirelson’s space and application

International audienceThe main result of this article is a rigidity result pertaining to the spreading model structure for Banach spaces coarsely embeddable into Tsirelson's original space T *. Every Banach space that is coarsely embeddable into T * must be reflexive and all its spreading models must be isomorphic to c0. Several important consequences follow from our rigidity result. We obtain a coarse version of an influential theorem of Tsirelson: T * does not coarsely contain c0 nor p for p ∈ [1, ∞). We show that there is no infinite dimensional Banach space that coarsely embeds into every infinite dimensional Banach space. In particular, we disprove the conjecture that the separable infinite dimensional Hilbert space coarsely embeds into every infinite dimensional Banach space. The rigidity result follows from a new concentration inequality for Lipschitz maps on the infinite Hamming graphs and taking values in T * , and from the embeddability of the infinite Hamming graphs into Banach spaces that admit spreading models not isomorphic to c0. Also, a purely metric characterization of finite dimensionality is obtained

COARSE AND LIPSCHITZ UNIVERSALITY

International audienceIn this paper we provide several metric universality results. We exhibit for certain classes C of metric spaces, families of metric spaces (M i , d i) i∈I which have the property that a metric space (X, d X) in C is coarsely, resp. Lipschitzly, universal for all spaces in C if the collection of spaces (M i , d i) i∈I equi-coarsely, respectively equi-Lipschitzly, embeds into (X, d X). Such families are built as certain Schreier-type metric subsets of c 0. We deduce a metric analog to Bourgain's theorem, which generalized Szlenk's theorem, and prove that a space which is coarsely universal for all separable reflexive asymptotic-c 0 Banach spaces is coarsely universal for all separable metric spaces. One of our coarse universality results is valid under Martin's Axiom and the negation of the Continuum Hypothesis. We discuss the strength of the universality statements that can be obtained without these additional set theoretic assumptions. In the second part of the paper, we study universality properties of Kalton's interlacing graphs. In particular, we prove that every finite metric space embeds almost isometrically in some interlacing graph of large enough diameter

The geometry of Hamming-type metrics and their embeddings into Banach spaces

International audienceWithin the class of reflexive Banach spaces, we prove a metric characterization of the class of asymptotic-c 0 spaces in terms of a bi-Lipschitz invariant which involves metrics that generalize the Hamming metric on k-subsets of N. We apply this characterization to show that the class of separable, reflexive, and asymptotic-c 0 Banach spaces is non-Borel co-analytic. Finally, we introduce a relaxation of the asymptotic-c 0 property, called the asymptotic-subsequential-c 0 property, which is a partial obstruction to the equi-coarse embeddability of the sequence of Hamming graphs. We present examples of spaces that are asymptotic-subsequential-c 0. In particular T * (T *) is asymptotic-subsequential-c 0 where T * is Tsirelson's original space