Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria

Spherical structures on torus knots and links

The present paper considers two infinite families of cone-manifolds endowed with spherical metric. The singular strata is either the torus knot ${\rm t}(2n+1, 2)$ or the torus link ${\rm t}(2n, 2)$. Domains of existence for a spherical metric are found in terms of cone angles and volume formul{\ae} are presented.Comment: 17 pages, 5 figures; typo

Reconstructing the global topology of the universe from the cosmic microwave background

If the universe is multiply-connected and sufficiently small, then the last scattering surface wraps around the universe and intersects itself. Each circle of intersection appears as two distinct circles on the microwave sky. The present article shows how to use the matched circles to explicitly reconstruct the global topology of space.Comment: 6 pages, 2 figures, IOP format. To be published in the proceedings of the Cleveland Cosmology and Topology Workshop 17-19 Oct 1997. Submitted to Class. Quant. Gra

Quantum creation of an Inhomogeneous universe

In this paper we study a class of inhomogeneous cosmological models which is a modified version of what is usually called the Lema\^itre-Tolman model. We assume that we have a space with 2-dimensional locally homogeneous spacelike surfaces. In addition we assume they are compact. Classically we investigate both homogeneous and inhomogeneous spacetimes which this model describe. For instance one is a quotient of the AdS$_4$ space which resembles the BTZ black hole in AdS$_3$. Due to the complexity of the model we indicate a simpler model which can be quantized easily. This model still has the feature that it is in general inhomogeneous. How this model could describe a spontaneous creation of a universe through a tunneling event is emphasized.Comment: 21 pages, 5 ps figures, REVTeX, new subsection include

Right-veering diffeomorphisms of compact surfaces with boundary II

We continue our study of the monoid of right-veering diffeomorphisms on a compact oriented surface with nonempty boundary, introduced in [HKM2]. We conduct a detailed study of the case when the surface is a punctured torus; in particular, we exhibit the difference between the monoid of right-veering diffeomorphisms and the monoid of products of positive Dehn twists, with the help of the Rademacher function. We then generalize to the braid group B_n on n strands by relating the signature and the Maslov index. Finally, we discuss the symplectic fillability in the pseudo-Anosov case by comparing with the work of Roberts [Ro1,Ro2].Comment: 25 pages, 5 figure

Forgetful maps between Deligne-Mostow ball quotients

We study forgetful maps between Deligne-Mostow moduli spaces of weighted points on P^1, and classify the forgetful maps that extend to a map of orbifolds between the stable completions. The cases where this happens include the Livn\'e fibrations and the Mostow/Toledo maps between complex hyperbolic surfaces. They also include a retraction of a 3-dimensional ball quotient onto one of its 1-dimensional totally geodesic complex submanifolds

Software and information life cycle (SILC) for the Integrated Information Services Organization

This document describes the processes to be used for creating corporate information systems within the scope of the Integrated Information Services (IIS) Center. Issue B describes all phases of the life cycle, with strong emphasis on the interweaving of the Analysis and Design phases. This Issue B supersedes Issue A, which concentrated on the Analysis and Implementation phases within the context of the entire life cycle. Appendix A includes a full set of examples of the deliverables, excerpted from the Network Database. Subsequent issues will further develop these life cycle processes as we move toward enterprise-level management of information assets, including information meta-models and an integrated corporate information model. The phases described here, when combined with a specifications repository, will provide the basis for future reusable components and improve traceability of information system specifications to enterprise business rules

Entropy vs. Action in the (2+1)-Dimensional Hartle-Hawking Wave Function

In most attempts to compute the Hartle-Hawking ``wave function of the universe'' in Euclidean quantum gravity, two important approximations are made: the path integral is evaluated in a saddle point approximation, and only the leading (least action) extremum is taken into account. In (2+1)-dimensional gravity with a negative cosmological constant, the second assumption is shown to lead to incorrect results: although the leading extremum gives the most important single contribution to the path integral, topologically inequivalent instantons with larger actions occur in great enough numbers to predominate. One can thus say that in 2+1 dimensions --- and possibly in 3+1 dimensions as well --- entropy dominates action in the gravitational path integral.Comment: 17 page

AF-algebras and topology of mapping tori

A covariant functor from the category of mapping tori to a category of AF-algebras is constructed; the functor takes continuous maps between such manifolds to stable homomorphisms between the corresponding AF-algebras. We use this functor to develop an obstruction theory for the torus bundles of dimension 2, 3 and 4.Comment: to appear Czechoslovak Math.

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease