Development of CmeABC Efflux Pump- Based Intervention Strategies Against Campylobacter

CmeABC, a multidrug efflux pump, contributes to Campylobacter resistance to a broad spectrum of antimicrobial agents and is also essential for Campylobacter colonization by mediation of bile resistance. We hypothesize that inhibition of CmeABC will not only control antibiotic resistance but also increase the susceptibility of Campylobacter to in vivo bile salts, consequently decreasing the colonization level of Campylobacter. Using both in vitro and in vivo systems, we examined the effect of an efflux pump inhibitor (EPI) MC-207,110 on the susceptibility of Campylobacter to various antimicrobials. Presence of the EPI resulted in 2- to 2048-fold reduction in the MICs of antimicrobials known to be substrates of CmeABC pump in all Campylobacter strains. Particularly, the MICs of selected bile salts were dramatically decreased 64- to 512-fold when the EPI was used. The intrinsic and acquired resistance of C. jejuni to macrolide was decreased significantly (32- to 64-fold reduction in the MIC of erythromycin) in the presence of the EPI while the MICs of fluoroquinolones were only slightly decreased (2-4 folds). Investigation of 57 clinical Campylobacter isolates of various origins further showed that the EPI decreased the MICs of erythromycin (2- to 512-fold) in all isolates. Compared to wild-type strains, the isogenic CmeB mutants displayed much lower magnitude of reduction in the MICs of antimicrobials in the presence of the EPI. The inhibitory effect of the EPI was does-dependents and as low as 0.5 μg/ml of the EPI resulted in decreased MIC of antimicrobials in C. jejuni. Presence of the EPI decreased the frequency of emergence of erythromycin-resistant mutants in C. jejuni (\u3c10-11), which is well below normal frequency of approximate 10-8. Notably, MIC of erythromycin was also greatly decreased (\u3e 4-fold) in CmeB mutants in the presence of EPI, suggesting the existence of other pump(s) involved in macrolide resistance in C. jejuni. Chicken colonization study demonstrated that oral administration of EPI dramatically reduced the colonization of Campylobacter in the intestine. In addition, anti-CmeC antibodies also enhanced the susceptibility of C. jejuni to bile salt, suggesting immune intervention by targeting CmeC may be another effective strategy to inhibit CmeABC efflux pump. Together, these findings indicate that inhibition of CmeABC by specific EPI or antibodies is a promising approach to control antibiotic resistance and colonization of Campylobacter in human and animals

Cascades with Adjoint Matter: Adjoint Transitions

A large class of duality cascades based on quivers arising from non-isolated singularities enjoy adjoint transitions - a phenomenon which occurs when the gauge coupling of a node possessing adjoint matter is driven to strong coupling in a manner resulting in a reduction of rank in the non-Abelian part of the gauge group and a subsequent flow to weaker coupling. We describe adjoint transitions in a simple family of cascades based on a Z2-orbifold of the conifold using field theory. We show that they are dual to Higgsing and produce varying numbers of U(1) factors, moduli, and monopoles in a manner which we calculate. This realizes a large family of cascades which proceed through Seiberg duality and Higgsing. We briefly describe the supergravity limit of our analysis, as well as a prescription for treating more general theories. A special role is played by N=2 SQCD. Our results suggest that additional light fields are typically generated when UV completing certain constructions of spontaneous supersymmetry breaking into cascades, potentially leading to instabilities.Comment: 29 pages, a few typos fixed, improved discussion, added figure; now there is 1 figur

Extinction times in the subcritical stochastic SIS logistic epidemic

Many real epidemics of an infectious disease are not straightforwardly super- or sub-critical, and the understanding of epidemic models that exhibit such complexity has been identified as a priority for theoretical work. We provide insights into the near-critical regime by considering the stochastic SIS logistic epidemic, a well-known birth-and-death chain used to model the spread of an epidemic within a population of a given size $N$. We study the behaviour of the process as the population size $N$ tends to infinity. Our results cover the entire subcritical regime, including the "barely subcritical" regime, where the recovery rate exceeds the infection rate by an amount that tends to 0 as $N \to \infty$ but more slowly than $N^{-1/2}$. We derive precise asymptotics for the distribution of the extinction time and the total number of cases throughout the subcritical regime, give a detailed description of the course of the epidemic, and compare to numerical results for a range of parameter values. We hypothesise that features of the course of the epidemic will be seen in a wide class of other epidemic models, and we use real data to provide some tentative and preliminary support for this theory.Comment: Revised; 34 pages; 6 figure

Trees and shrubs as sources of fodder in Australia

Experience with browse plants in Australia is briefly reviewed in terms of their forage value to animals, their economic value to the landholder and their ecological contribution to landscape stability. Of the cultivated species only two have achieved any degree of commercial acceptance (Leucaena leucocephala and Chamaecytisus palmensis). Both of these are of sufficiently high forage value to be used as the sole source of feed during seasonal periods of nutritional shortage. Both are also leguminous shrubs that establish readily from seed. It is suggested that a limitation in their present use is the reliance on stands of single species which leaves these grazing systems vulnerable to disease and insects. Grazing systems so far developed for high production and persistence of cultivated species involve short periods of intense grazing followed by long periods of recovery. Similar management may be necessary in the arid and semi-arid rangelands where palatable browse species are in decline

Bounds on 4D Conformal and Superconformal Field Theories

We derive general bounds on operator dimensions, central charges, and OPE coefficients in 4D conformal and N=1 superconformal field theories. In any CFT containing a scalar primary phi of dimension d we show that crossing symmetry of implies a completely general lower bound on the central charge c >= f_c(d). Similarly, in CFTs containing a complex scalar charged under global symmetries, we bound a combination of symmetry current two-point function coefficients tau^{IJ} and flavor charges. We extend these bounds to N=1 superconformal theories by deriving the superconformal block expansions for four-point functions of a chiral superfield Phi and its conjugate. In this case we derive bounds on the OPE coefficients of scalar operators appearing in the Phi x Phi* OPE, and show that there is an upper bound on the dimension of Phi* Phi when dim(Phi) is close to 1. We also present even more stringent bounds on c and tau^{IJ}. In supersymmetric gauge theories believed to flow to superconformal fixed points one can use anomaly matching to explicitly check whether these bounds are satisfied.Comment: 47 pages, 9 figures; V2: small corrections and clarification

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN