Discovering latent influence in online social activities via shared cascade poisson processes

Many people share their activities with others through on-line communities. These shared activities have an impact on other users ’ activities. For example, users are likely to become interested in items that are adopted (e.g. liked, bought and shared) by their friends. In this paper, we pro-pose a probabilistic model for discovering latent influence from sequences of item adoption events. An inhomogeneous Poisson process is used for modeling a sequence, in which adoption by a user triggers the subsequent adoption of the same item by other users. For modeling adoption of multiple items, we employ multiple inhomogeneous Poisson processes, which share parameters, such as influence for each user and relations between users. The proposed model can be used for finding influential users, discovering relations between users and predicting item popularity in the future. We present an efficient Bayesian inference procedure of the proposed model based on the stochastic EM algorithm. The effectiveness of the proposed model is demonstrated by using real data sets in a social bookmark sharing service

Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary

Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition.

Small-cell lung cancer (SCLC) is a particularly aggressive cancer, which metastasises early. Despite initial sensitivity to radio- and chemo-therapy, it invariably relapses, so that the 2-year survival remains less than 5%. Neuropeptides particularly arginine vasopressin (AVP) and gastrin-releasing peptide (GRP) act as autocrine and paracrine growth factors and the expression of these and their receptors are a hallmark of the disease. Substance-P analogues including [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7,9,NmePhe8]-substance-P (6-11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V1A receptors expression leads to the development of a transformed phenotype. Addition of neuropeptide provides some protection from etoposide-induced cytotoxicity. Receptor expression also leads to an increased sensitivity to substance-P analogue-induced growth inhibition. We show that SP-D and SP-G act as biased agonists at GRP and V1A receptors causing blockade of Gq-mediated Ca2+ release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V1A receptors. This unique pharmacology governs the antiproliferative properties of these agents and highlights their potential therapeutic potential for the treatment of SCLC and particularly in tumours, which have developed resistance to chemotherapy

PKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades

G-protein-coupled receptors sense extracellular chemical or physical stimuli and transmit these signals to distinct trimeric G-proteins. Activated Gα-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. Gαs- or Gαi-coupled receptor cascades are mechanistically conserved and mediate many sensory processes, including synaptic transmission, cell proliferation and chemotaxis. Here we show that a central, conserved component of Gαs-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3′-5′-cyclic monophosphate (cAMP)-dependent binding to Gαi. Stimulation of a mammalian Gαi-coupled receptor and concomitant cAMP-RII binding to Gαi, augments the sensitivity, amplitude and duration of Gαi:βγ activity and downstream mitogen-activated protein kinase signalling, independent of protein kinase A kinase activity. The mechanism is conserved in budding yeast, causing nutrient-dependent modulation of a pheromone response. These findings suggest a direct mechanism by which coincident activation of Gαs-coupled receptors controls the precision of adaptive responses of activated Gαi-coupled receptor cascades

The cellular basis of organ failure in sepsis—signaling during damage and repair processes

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This definition, updated in 2016, shifted the conceptual focus from exclusive attention to the systemic inflammatory response toward the multifactorial tissue damage that occurs during the progression of infection to sepsis and shock. Whereas targeting the inflammatory host response to infection did not translate into improved clinical management of sepsis, recent findings might shed new light on the maladaptive host-pathogen interaction in sepsis and pave the way for 'theranostic' interventions. In addition to the well-known resistance responses of the immune system that result in pathogen clearance, 'disease tolerance' has recently been acknowledged as a coping mechanism of presumably equal importance. We propose that both defense mechanisms, 'resistance' and 'disease tolerance', can get out of control in sepsis. Whereas excessive activation of resistance pathways propagates tissue damage via immunopathology, an inappropriate 'tolerance' might entail immunoparalysis accompanied by fulminant, recurrent or persisting infection. The review introduces key signaling processes involved in infection-induced 'resistance' and 'tolerance'. We propose that elaboration of these signaling pathways allows novel insights into sepsis-associated tissue damage and repair processes. Moreover theranostic opportunities for the specific treatment of sepsis-related hyperinflammation or immunoparalysis will be introduced. Agents specifically affecting either hyperinflammation or immunoparalysis in the course of sepsis might add to the therapeutic toolbox of personalized care in the field of organ dysfunction caused by infection. (This article is freely available.)

Aufbau von automatisierten molekularen Screeningsystemen zur Auffindung neuer biomedizinisch wirksamer Naturstoffe. Teilprojekt: Rekombinante Integrin-EGF-Rezeptorchimaeren Abschlussbericht

Available from TIB Hannover: DtF QN1(76,39) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman