Heterotic Cosmic Strings

We show that all three conditions for the cosmological relevance of heterotic cosmic strings, the right tension, stability and a production mechanism at the end of inflation, can be met in the strongly coupled M-theory regime. Whereas cosmic strings generated from weakly coupled heterotic strings have the well known problems posed by Witten in 1985, we show that strings arising from M5-branes wrapped around 4-cycles (divisors) of a Calabi-Yau in heterotic M-theory compactifications, solve these problems in an elegant fashion.Comment: 25 pages, v2: section and references adde

Dissection of human papillomavirus type 33 L2 domains involved in nuclear domains (ND) 10 homing and reorganization

AbstractWe have recently shown that the minor capsid protein L2 of human papillomavirus type 33 (HPV33) recruits the transcriptional repressor Daxx into nuclear domains (ND) 10 and causes the loss of the transcriptional activator Sp100 from these subnuclear structures (Florin et al., 2002b). In order to dissect L2 domains involved in nuclear translocation, ND10 homing, loss of Sp100, and recruitment of Daxx, a detailed deletion mutagenesis of L2 was performed. Using immunofluorescence and green fluorescent protein fusions, we have identified two nuclear localization signals (NLS) in the central and C-terminal part of L2, respectively, homologous to previously identified NLS in HPV6B L2 (Sun et al., 1995). We mapped the ND10 localization domain to within a 30 amino acid peptide in the C-terminal half of L2. L2-induced attraction of Daxx into ND10, coimmunoprecipitation of L2 and Daxx, as well as induction of the loss of Sp100 from ND10 require an intact ND10 localization domain. This domain contains conserved PXXP motives characteristic of some protein/protein interacting domains. Our data also suggest that the Daxx/L2 interaction may be the driving force for L2 accumulation in ND10

Intestinal Acid Sphingomyelinase Protects From Severe Pathogen-Driven Colitis

Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of Citrobacter (C.) rodentium-driven colitis. C. rodentium is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to C. rodentium infection. These mice showed increased levels of C. rodentium in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory Th1 and Th17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen C. rodentium

Compactifications of Heterotic Theory on Non-Kahler Complex Manifolds: I

We study new compactifications of the SO(32) heterotic string theory on compact complex non-Kahler manifolds. These manifolds have many interesting features like fewer moduli, torsional constraints, vanishing Euler character and vanishing first Chern class, which make the four-dimensional theory phenomenologically attractive. We take a particular compact example studied earlier and determine various geometrical properties of it. In particular we calculate the warp factor and study the sigma model description of strings propagating on these backgrounds. The anomaly cancellation condition and enhanced gauge symmetry are shown to arise naturally in this framework, if one considers the effect of singularities carefully. We then give a detailed mathematical analysis of these manifolds and construct a large class of them. The existence of a holomorphic (3,0) form is important for the construction. We clarify some of the topological properties of these manifolds and evaluate the Betti numbers. We also determine the superpotential and argue that the radial modulus of these manifolds can actually be stabilized.Comment: 75 pages, Harvmac, no figures; v2: Some new results added, typos corrected and references updated. Final version to appear in JHE

Three-Dimensional Supergravity and the Cosmological Constant

Witten has argued that in $2+1$ dimensions local supersymmetry can ensure the vanishing of the cosmological constant without requiring the equality of bose and fermi masses. We find that this mechanism is implemented in a novel fashion in the (2+1)-dimensional supersymmetric abelian Higgs model coupled to supergravity. The vortex solitons are annihilated by half of the supersymmetry transformations. The covariantly constant spinors required to define these supersymmetries exist by virtue of a surprising cancellation between the Aharonov-Bohm phase and the phase associated with the holonomy of the spin connection. However the other half of the supersymmetry transformations, whose actions ordinarily generate the soliton supermultiplet, are not well-defined and bose-fermi degeneracy is consequently absent in the soliton spectrum.Comment: 12 pages, phyzz

Detection of Methicillin Resistance in Staphylococcus aureus From Agar Cultures and Directly From Positive Blood Cultures Using MALDI-TOF Mass Spectrometry-Based Direct-on-Target Microdroplet Growth Assay

Matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry (MALDI-TOF MS)-based direct-on-target microdroplet growth assay (DOT-MGA) was recently described as a novel method of phenotypic antimicrobial susceptibility testing (AST). Here, we developed the application of MALDI-TOF MS-based DOT-MGA for Gram-positive bacteria including AST from agar cultures and directly from positive blood cultures (BCs) using the detection of methicillin resistance as example. Consecutively collected, a total of 14 methicillin-resistant Staphylococcus aureus (MRSA) and 14 methicillin-susceptible S. aureus (MSSA) clinical isolates were included. Furthermore, a collection of MRSA challenge strains comprising different SCCmec types, mec genes, and spa types was tested. Blood samples were spiked with MRSA and MSSA and positive BC broth processed by three different methods: serial dilution of BC broth, lysis/centrifugation, and differential centrifugation. Processed BC broth was directly used for rapid AST using DOT-MGA. Droplets of 6 μl with and without cefoxitin at the EUCAST breakpoint concentration were spotted in triplicates onto the surface of a MALDI target. Targets were incubated in a humidity chamber, followed by medium removal and on-target protein extraction with formic acid before adding matrix with an internal standard as a quality control (QC). Spectra were acquired and evaluated using MALDI Biotyper software. First, tests were considered as valid, if the growth control achieved an identification score of ≥1.7. For valid tests, same score criterion was used for resistant isolates when incubated with cefoxitin. An identification score <1.7 after incubation with cefoxitin defined susceptible isolates. On-target protein extraction using formic acid considerably improved detection of methicillin resistance in S. aureus and DOT-MGA showed feasible results for AST from agar cultures after 4 h incubation time. Comparing the different processing methods of positive BC broth, lysis/centrifugation method with a final dilution step 10–1 of the 0.5 McFarland suspension resulted in best test performance after 4 h incubation time. Overall, 96.4% test validity, 100% sensitivity, and 100% specificity were achieved for detection of methicillin resistance in clinical isolates. All strains of the MRSA challenge collection were successfully tested as methicillin-resistant. This first study on Gram-positive organisms showed feasibility and accuracy of MALDI-TOF MS-based DOT-MGA for rapid AST of S. aureus from agar cultures and directly from positive BCs

Rapid Detection of Extended-Spectrum β-Lactamases (ESBL) and AmpC β-Lactamases in Enterobacterales: Development of a Screening Panel Using the MALDI-TOF MS-Based Direct-on-Target Microdroplet Growth Assay

Introduction: Antibiotic resistant bacteria are a growing concern worldwide. Extended-spectrum β-lactamases (ESBL) represent the most common resistance mechanism of Gram-negative bacteria against β-lactams, underlining the need for adequate diagnostic methods that provide reliable information in the shortest time possible. AmpC, a less prevalent but increasingly relevant class of β-lactamases, pose an additional challenge as their detection is complex. Here, we present an ESBL and AmpC screening panel employing the MALDI-TOF MS-based direct-on-target microdroplet growth assay (DOT-MGA).Materials and Methods: Four reference strains recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to develop the panel, which was further validated on 50 clinical Enterobacterales isolates resistant to third generation cephalosporins. The panel relies on the synergistic effect between ESBL and/or AmpC β-lactamase inhibitors and cephalosporins, which indicates β-lactamase production. Microdroplets containing the tested microorganism, cephalosporins in different concentrations and inhibitors were pipetted onto an MBT Biotarget and incubated for 3 or 4 h at 35 ± 1°C. Afterward, the liquid medium was removed and the material adhered to the spots was analyzed by MALDI-TOF MS. Synergy was detected by determining and comparing the minimum inhibitory concentrations of the tested cephalosporins with and without β-lactamase inhibitors. Data were interpreted following a diagnostic algorithm proposed by EUCAST in order to establish a final diagnosis. In comparison, PCR, broth microdilution (BMD) and combination disk tests (CDT) were performed.Results: Compared to the PCR results, the following positive and negative percent agreement values (PPA/NPA) were obtained for each resistance mechanism: ESBL, 94.44/100%; AmpC, 94.44/93.75% and ESBL+AmpC, 100/100%. These results, obtained after 4 h of incubation, were comparable with those of BMD and showed a higher accuracy than CDT.Discussion: We propose a novel phenotypic method for detection of ESBL and AmpC β-lactamases in Enterobacterales that provides reliable results in a short time, representing a promising alternative to the diagnostic techniques currently available. This easy-to-perform approach has potential for being implemented in routine laboratories, contributing to the further diversification of mass spectrometry technology into other fields such as antibiotic resistance testing

T Cell-Specific Overexpression of Acid Sphingomyelinase Results in Elevated T Cell Activation and Reduced Parasitemia During Plasmodium yoelii Infection

The enzyme acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and is thereby involved in several cellular processes such as differentiation, proliferation, and apoptosis in different cell types. However, the function of ASM in T cells is still not well characterized. Here, we used T cell-specific ASM overexpressing mice (t-ASM/CD4cre) to clarify the impact of cell-intrinsic ASM activity on T cell function in vitro and in vivo. We showed that t-ASM/CD4cre mice exhibit decreased frequencies of Foxp3+ T regulatory cells (Tregs) within the spleen. Enforced T cell-specific ASM expression resulted in less efficient induction of Tregs and promoted differentiation of CD4+CD25− naïve T cells into IFN-γ producing Th1 cells in vitro. Further analysis revealed that ASM-overexpressing T cells from t-ASM/CD4cre mice show elevated T cell receptor (TCR) signaling activity accompanied with increased proliferation upon stimulation in vitro. Plasmodium yoelii infection of t-ASM/CD4cre mice resulted in enhanced T cell activation and was associated with reduced parasitemia in comparison to infected control mice. Hence, our results provide evidence that ASM activity modulates T cell function in vitro and in vivo

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully-differentiated cultures of primary human airway epithelial cells and co-cultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting and quantitative polymerase chain reaction were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium due to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to Pseudomonas aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in the apical membrane of cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes