Cycle-centrality in complex networks

Networks are versatile representations of the interactions between entities in complex systems. Cycles on such networks represent feedback processes which play a central role in system dynamics. In this work, we introduce a measure of the importance of any individual cycle, as the fraction of the total information flow of the network passing through the cycle. This measure is computationally cheap, numerically well-conditioned, induces a centrality measure on arbitrary subgraphs and reduces to the eigenvector centrality on vertices. We demonstrate that this measure accurately reflects the impact of events on strategic ensembles of economic sectors, notably in the US economy. As a second example, we show that in the protein-interaction network of the plant Arabidopsis thaliana, a model based on cycle-centrality better accounts for pathogen activity than the state-of-art one. This translates into pathogen-targeted-proteins being concentrated in a small number of triads with high cycle-centrality. Algorithms for computing the centrality of cycles and subgraphs are available for download

Mixed Mediation of Supersymmetry Breaking with Anomalous U(1) Gauge Symmetry

Models with anomalous U(1) gauge symmetry contain various superfields which can have nonzero supersymmetry breaking auxiliary components providing the origin of soft terms in the visible sector, e.g. the U(1) vector superfield, the modulus or dilaton superfield implementing the Green-Schwarz anomaly cancellation mechanism, U(1)-charged but standard model singlet matter superfield required to cancel the Fayet-Iliopoulos term, and finally the supergravity multiplet. We examine the relative strength between these supersymmetry breaking components in a simple class of models, and find that various different mixed mediations of supersymmetry breaking, involving the modulus, gauge, anomaly and D-term mediations, can be realized depending upon the characteristics of D-flat directions and how those D-flat directions are stabilized with a vanishing cosmological constant. We identify two parameters which represent such properties and thus characterize how the various mediations are mixed. We also discuss the moduli stabilization and soft terms in a variant of KKLT scenario, in which the visible sector K\"ahler modulus is stabilized by the D-term potential of anomalous U(1) gauge symmetry.Comment: 30 pages, 5 figure

Soy protein–gum karaya conjugate: emulsifying activity and rheological behavior in aqueous system and oil in water emulsion

The main objective of this study is to investigate the effects of mixing and conjugation of soy protein isolate (SPI) with gum karaya on the characteristics of the hybrid polymer (protein–gum) in both aqueous systems and oil-in-water (O/W) emulsions. It was hypothesized that the covalent linkage of gum karaya with SPI would improve the emulsifying activity and rheological properties of both polymers. Conjugation occurred under controlled conditions (i.e., 60 °C and 75 % relative humidity, 3 days). The conjugated hybrid polymer produced smaller droplet with better uniformity, higher viscosity and stronger emulsifying activity than native gum karaya, suggesting the conjugated polymer provided a bulkier secondary layer with more efficient coverage around oil droplets, thereby inducing stronger resistance against droplet aggregation and flocculation. Emulsions containing the native gum karaya produced the largest droplet size among all prepared emulsions (D 3,2 = 8.6 μm; D 4,3 = 22.4 μm); while the emulsion containing protein–gum conjugate (1:1 g/g) had the smallest droplet size (D 3,2 = 0.2 μm; D 4,3 = 0.7 μm) with lower polydispersity. The protein–gum conjugate (1:1 g/g) also showed the highest elastic and viscous modulus, the lowest polydispersity (span) and the highest emulsifying activity among all native, mixed and conjugated polymers. Therefore, the percentage of gum karaya used for production of O/W emulsion can be decreased by partially replacing it with the conjugated gum

Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction

Plate-based diversity subset screening generation 2: An improved paradigm for high throughput screening of large compound files

High throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time-consuming and costly and the use of subsets as an efficient alternative to screening these large collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity, or biological target focus. Previously we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer

Comparison of Hospital Costs and Length of Stay for Community Internists, Hospitalists, and Academicians

BACKGROUND: The model of inpatient medical management has evolved toward Hospitalists because of greater cost efficiency compared to traditional practice. The optimal model of inpatient care is not known. OBJECTIVE: To compare three models of inpatient Internal Medicine (traditional private practice Internists, private Hospitalist Internists, and Academic Internists with resident teams) for cost efficiency and quality at a community teaching hospital. DESIGN: Single-institution retrospective cohort study. MEASUREMENTS AND MAIN RESULTS: Measurements were hospital cost, length of stay (LOS), mortality, and 30-day readmission rate adjusted for severity, demographics, and case mix. Academic Internist teams had 30% lower cost and 40% lower LOS compared to traditional private Internists and 24% lower cost and 30% lower LOS compared to private Hospitalists. Hospital mortality was equivalent for all groups. Academic teams had 2.3–2.6% more 30-day readmissions than the other groups. CONCLUSIONS: Academic teams compare favorably to private Hospitalists and traditional Internists for hospital cost efficiency and quality

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

OBJECTIVE: To assess the validity of CRB-65 (Confusion, Respiratory rate >30 breaths/min, BP<90/60 mmHg, age >65 years) as a pneumonia severity index in a Malawian hospital population, and determine whether an alternative score has greater accuracy in this setting. DESIGN: Forty three variables were prospectively recorded during the first 48 hours of admission in all patients admitted to Queen Elizabeth Central Hospital, Malawi, for management of lower respiratory tract infection over a two month period (N = 240). Calculation of sensitivity and specificity for CRB-65 in predicting mortality was followed by multivariate modeling to create a score with superior performance in this population. RESULTS: Median age 37, HIV prevalence 79.9%, overall mortality 18.3%. CRB-65 predicted mortality poorly, indicated by the area under the ROC curve of 0.649. Independent predictors of death were: Male sex, “S” (AOR 2.6); Wasting, “W” (AOR 6.6); non-ambulatory, “A” (AOR 2.5); Temp >38°C or <35°C, “T” (AOR 3.2); BP<100/60, “Bp” (AOR 3.7). Combining these factors to form a severity index (SWAT-Bp) predicted mortality with high sensitivity and specificity (AUC: 0.867). Mortality for scores 0–5 was 0%, 3.3%, 7.4%, 29.2%, 61.5% and 87.5% respectively. A score ≥3 was 84% sensitive and 77% specific for mortality prediction, with a negative predictive value of 95.8%. CONCLUSION: CRB-65 performs poorly in this population. The SWAT-Bp score can accurately stratify patients; ≤2 indicates non-severe infection (mortality 4.4%) and ≥3 severe illness (mortality 45%)

Herpesviruses carrying a Brainbow cassette reveal replication and expression of limited numbers of incoming genomes

Whether all the infectious herpesvirus particles entering a cell are able to replicate and/or express their genomes is not known. Here, we developed a general method to determine the number of viral genomes expressed in an infected cell. We constructed and analysed fluorophore expression from a recombinant pseudorabies virus (PRV263) carrying a Brainbow cassette (Cre-conditional expression of different fluorophores). Using three isogenic strains derived from PRV263, each expressing a single fluorophore, we analysed the colour composition of cells infected with these three viruses at different multiplicities. We estimate that fewer than seven incoming genomes are expressed per cell. In addition, those templates that are expressed are the genomes selected for replication and packaging into virions. This finite limit on the number of viral genomes that can be expressed is an intrinsic property of the infected cell and may be influenced by viral and cellular factors

The Herpesvirus Associated Ubiquitin Specific Protease, USP7, Is a Negative Regulator of PML Proteins and PML Nuclear Bodies

The PML tumor suppressor is the founding component of the multiprotein nuclear structures known as PML nuclear bodies (PML-NBs), which control several cellular functions including apoptosis and antiviral effects. The ubiquitin specific protease USP7 (also called HAUSP) is known to associate with PML-NBs and to be a tight binding partner of two herpesvirus proteins that disrupt PML NBs. Here we investigated whether USP7 itself regulates PML-NBs. Silencing of USP7 was found to increase the number of PML-NBs, to increase the levels of PML protein and to inhibit PML polyubiquitylation in nasopharyngeal carcinoma cells. This effect of USP7 was independent of p53 as PML loss was observed in p53-null cells. PML-NBs disruption was induced by USP7 overexpression independently of its catalytic activity and was induced by either of the protein interaction domains of USP7, each of which localized to PML-NBs. USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV. CK2α and RNF4, which are known regulators of PML, were dispensable for USP7-associated PML-NB disruption. The results are consistent with a novel model of PML regulation where a deubiquitylase disrupts PML-NBs through recruitment of another cellular protein(s) to PML NBs, independently of its catalytic activity