From Koszul duality to Poincar\'e duality

We discuss the notion of Poincar\'e duality for graded algebras and its connections with the Koszul duality for quadratic Koszul algebras. The relevance of the Poincar\'e duality is pointed out for the existence of twisted potentials associated to Koszul algebras as well as for the extraction of a good generalization of Lie algebras among the quadratic-linear algebras.Comment: Dedicated to Raymond Stora. 27 page

Compactification on negatively curved manifolds

We show that string/M theory compactifications to maximally symmetric space-times using manifolds whose scalar curvature is everywhere negative, must have significant warping, large stringy corrections, or both.Comment: 18 pages, JHEP3.cl

Time-dependent response of a zonally averaged ocean–atmosphere–sea ice model to Milankovitch forcing

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Springer-Verlag for personal use, not for redistribution. The definitive version was published in Climate Dynamics 6 (2010): 763-779, doi:10.1007/s00382-010-0790-6.An ocean-atmosphere-sea ice model is developed to explore the time-dependent response of climate to Milankovitch forcing for the time interval 5-3 Myr BP. The ocean component is a zonally averaged model of the circulation in five basins (Arctic, Atlantic, Indian, Pacific, and Southern Oceans). The atmospheric component is a one-dimensional (latitudinal) energy balance model, and the sea-ice component is a thermodynamic model. Two numerical experiments are conducted. The first experiment does not include sea ice and the Arctic Ocean; the second experiment does. Results from the two experiments are used to investigate (i) the response of annual mean surface air and ocean temperatures to Milankovitch forcing, and (ii) the role of sea ice in this response. In both experiments, the response of air temperature is dominated by obliquity cycles at most latitudes. On the other hand, the response of ocean temperature varies with latitude and depth. Deep water formed between 45°N-65°N in the Atlantic Ocean mainly responds to precession. In contrast, deep water formed south of 60°S responds to obliquity when sea ice is not included. Sea ice acts as a time-integrator of summer insolation changes such that annual mean sea-ice conditions mainly respond to obliquity. Thus, in the presence of sea ice, air temperature changes over the sea ice are amplified, and temperature changes in deep water of southern origin are suppressed since water below sea ice is kept near the freezing point.This work was supported by an NSERC Discovery Grant awarded to L.A.M. We also thank GEC3 for a Network Grant

Orientation and symmetries of Alexandrov spaces with applications in positive curvature

We develop two new tools for use in Alexandrov geometry: a theory of ramified orientable double covers and a particularly useful version of the Slice Theorem for actions of compact Lie groups. These tools are applied to the classification of compact, positively curved Alexandrov spaces with maximal symmetry rank.Comment: 34 pages. Simplified proofs throughout and a new proof of the Slice Theorem, correcting omissions in the previous versio

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Vanishing Minors in the Neutrino Mass Matrix from Abelian Gauge Symmetries

Augmenting the Standard Model by three right-handed neutrinos allows for an anomaly-free gauge group extension G_max = U(1)_(B-L) x U(1)_(L_e-L_mu) x U(1)_(L_mu-L_tau). While simple U(1) subgroups of G_max have already been discussed in the context of approximate flavor symmetries, we show how two-zero textures in the right-handed neutrino Majorana mass matrix can be enforced by the flavor symmetry, which is spontaneously broken very economically by singlet scalars. These zeros lead to two vanishing minors in the low-energy neutrino mass matrix after the seesaw mechanism. This study may provide a new testing ground for a zero-texture approach: the different classes of two-zero textures with almost identical neutrino oscillation phenomenology can in principle be distinguished by their different Z' interactions at colliders.Comment: 12 pages; Extended and clarified discussion; comments on finetuning in the textures; matches published versio

Enhancement of CD8 T-cell function through modifying surface glycoproteins in young and old mice

Previous work from our laboratory has shown that modifying cell surface glycosylation with either a Clostridium perfringens -derived sialidase (CP-Siase), or an O-linked glycoprotein endopeptidase (OSGE) can enhance the function of CD4 T cells from both young and old mice at multiple levels. Here we have re-assessed the effect of age on CD8 T-cell function, and examined the outcome of enzymatic treatment with CP-Siase and OSGE on its different aspects. Pre-treatment of CD8 T cells with either CP-Siase or OSGE led to a significant increase in anti-CD3-mediated Ca 2+ response in both young and old mice. Pre-treated CD8 T cells from both age groups also displayed a significant increase in activation-induced CD69 and CD25 expression, and produced significantly higher amounts of interleukin-2 and interferon-γ in comparison to their untreated counterparts. Furthermore, pretreatment with either enzyme enhanced granzyme B expression in CD8 T cells, and increased their cytolytic activity in vitro . These data support the notion that glycosylated surface proteins hinder CD8 T-cell activation and function in both young and old mice, and raise the possibility of significantly improving CD8 T cell function in older individuals through enzymatic alteration of surface glycoproteins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75199/1/j.1365-2567.2006.02420.x.pd

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses