The Gut Microbiome and Cirrhosis: Basic Aspects

In this chapter the basic aspects helping to understand the microbiome in terms of quantity, diversity, complexity, function, and interaction with the host are discussed. First the nomenclature, definitions of taxa, and measures of diversity as well as methods to unravel this kingdom are outlined. A brief summary on its physiological relevance for general health and the functions exerted specifically by the microbiome is presented. Differences in the composition of the microbiome along the gastrointestinal tract and across the gut wall and its interindividual variations, enterotypes, and stability are highlighted. The reader will be familiarized with all different modulators impacting on the microbiome, namely, intrinsic and extrinsic factors. Intrinsic factors include gastrointestinal secretions (gastric acid, bile, pancreatic juice, mucus), antimicrobial peptides, motility, enteric nervous system, and host genotype. Extrinsic factors are mainly dietary choices, hygiene, stress, alcohol consumption, exercise, and medications. The second part of the chapter focuses on quantitative and qualitative changes in microbiome in liver cirrhosis. The mechanisms contributing to dysbiosis, small intestinal bacterial overgrowth, and bacterial translocation are delineated underscoring their role for the liver-gut axis.

A conserved pattern in plant-mediated interactions between herbivores

Plant‐mediated interactions between herbivores are important determinants of community structure and plant performance in natural and agricultural systems. Current research suggests that the outcome of the interactions is determined by herbivore and plant identity, which may result in stochastic patterns that impede adaptive evolution and agricultural exploitation. However, few studies have systemically investigated specificity versus general patterns in a given plant system by varying the identity of all involved players. We investigated the influence of herbivore identity and plant genotype on the interaction between leaf‐chewing and root‐feeding herbivores in maize using a partial factorial design. We assessed the influence of leaf induction by oral secretions of six different chewing herbivores on the response of nine different maize genotypes and three different root feeders. Contrary to our expectations, we found a highly conserved pattern across all three dimensions of specificity: The majority of leaf herbivores elicited a negative behavioral response from the different root feeders in the large majority of tested plant genotypes. No facilitation was observed in any of the treatment combinations. However, the oral secretions of one leaf feeder and the responses of two maize genotypes did not elicit a response from a root‐feeding herbivore. Together, these results suggest that plant‐mediated interactions in the investigated system follow a general pattern, but that a degree of specificity is nevertheless present. Our study shows that within a given plant species, plant‐mediated interactions between herbivores of the same feeding guild can be stable. This stability opens up the possibility of adaptations by associated organisms and suggests that plant‐mediated interactions may contribute more strongly to evolutionary dynamics in terrestrial (agro)ecosystems than previously assumed.

Mechanisms and evolution of plant resistance to aphids

Aphids are important herbivores of both wild and cultivated plants. Plants rely on unique mechanisms of recognition, signalling and defence to cope with the specialized mode of phloem feeding by aphids. Aspects of the molecular mechanisms underlying aphid-plant interactions are beginning to be understood. Recent advances include the identification of aphid salivary proteins involved in host plant manipulation, and plant receptors involved in aphid recognition. However, a complete picture of aphid-plant interactions requires consideration of the ecological outcome of these mechanisms in nature, and the evolutionary processes that shaped them. Here we identify general patterns of resistance, with a special focus on recognition, phytohormonal signalling, secondary metabolites and induction of plant resistance. We discuss how host specialization can enable aphids to co-opt both the phytohormonal responses and defensive compounds of plants for their own benefit at a local scale. In response, systemically induced resistance in plants is common and often involves targeted responses to specific aphid species or even genotypes. As co-evolutionary adaptation between plants and aphids is ongoing, the stealthy nature of aphid feeding makes both the mechanisms and outcomes of these interactions highly distinct from those of other herbivore-plant interactions. © 2016 Macmillan Publishers Limited.

Effects of team Knowledge and ecological constraints on decisional processes in customized football game scenarios

Several theories assume that successful team coordination is partly based on knowledge that helps anticipating individual contributions necessary in a situational task. It has been argued that a more ecological perspective needs to be considered in contexts evolving dynamically and unpredictably. In football, defensive plays are usually coordinated according to strategic concepts spanning all members and large areas of the playfield. On the other hand, fewer people are involved in offensive plays as these are less projectable and strongly constrained by ecological characteristics. The aim of this study is to test the effects of ecological constraints and player knowledge on decision making in offensive game scenarios. It is hypothesized that both knowledge about team members and situational constraints will influence decisional processes. Effects of situational constraints are expected to be of higher magnitude. Two teams playing in the fourth league of the Swiss Football Federation participate in the study. Forty customized game scenarios were developed based on the coaches’ information about player positions and game strategies. Each player was shown in ball possession four times. Participants were asked to take the perspective of the player on the ball and to choose a passing destination and a recipient. Participants then rated domain specific strengths (e.g., technical skills, game intelligence) of each of their teammates. Multilevel models for categorical dependent variables (team members) will be specified. Player knowledge (rated skills) and ecological constraints (operationalized as each players’ proximity and availability for ball reception) are included as predictor variables. Data are currently being collected. Results will yield effects of parameters that are stable across situations as well as of variable parameters that are bound to situational context. These will enable insight into the degree to which ecological constraints and more enduring team knowledge are involved in decisional processes aimed at coordinating interpersonal action.

Defying death: Cellular survival strategies following plasmalemmal injury by bacterial toxins

The perforation of the plasmalemma by pore-forming toxins causes an influx of Ca(2+) and an efflux of cytoplasmic constituents. In order to ensure survival, the cell needs to identify, plug and remove lesions from its membrane. Quarantined by membrane folds and isolated by membrane fusion, the pores are removed from the plasmalemma and expelled into the extracellular space. Outward vesiculation and microparticle shedding seem to be the strategies of choice to eliminate toxin-perforated membrane regions from the plasmalemma of host cells. Depending on the cell type and the nature of injury, the membrane lesion can also be taken up by endocytosis and degraded internally. Host cells make excellent use of an initial, moderate rise in intracellular [Ca(2+)], which triggers containment of the toxin-inflicted damage and resealing of the damaged plasmalemma. Additional Ca(2+)-dependent defensive cellular actions range from the release of effector molecules in order to warn neighbouring cells, to the activation of caspases for the initiation of apoptosis in order to eliminate heavily damaged, dysregulated cells. Injury to the plasmalemma by bacterial toxins can be prevented by the early sequestration of bacterial toxins. Artificial liposomes can act as a decoy system preferentially binding and neutralizing bacterial toxins.

Mechanisms of TGF-beta1-induced neuronal plasticity in Aplysia

Transforming growth factor beta-1 (TGF-β1) is a cytokine and neurotrophic factor whose neuromodulatory effects in Aplysia californica were recently described. Previous results demonstrated that TGF-β1 induces long-term increases in the efficacy of sensorimotor synapses, a neural correlate of sensitization of the defensive tail withdrawal reflex. These results provided the first evidence that a neurotrophic factor regulates neuronal plasticity associated with a simple form of learning in Aplysia, and raised many questions regarding the nature of the modulation. No homologs of TGF-β had previously been identified in Aplysia, and thus, it was not known whether components of TGF-β1 signaling pathways were present in Aplysia. Furthermore, the signaling mechanisms engaged by TGF-β1 had not been identified, and it was not known whether TGF-β1 regulated other aspects of neuronal function.^ The present investigation into the actions of TGF-β1 was initiated by examining the distribution of the type II TGF-β1 receptor, the ligand binding receptor. The receptor was widely distributed in the CNS and most neurons exhibited somatic and neuritic immunoreactivity. In addition, the ability of TGF-β1 to activate the cAMP/PKA and MAPK pathways, known to regulate several important aspects of neuronal function, was examined. TGF-β1 acutely decreased cAMP levels in sensory neurons, activated MAPK and triggered translocation of MAPK to the nucleus. MAPK activation was critical for both short- and long-term regulation of neuronal function by TGF-β1. TGF-β1 acutely decreased synaptic depression induced by low frequency stimuli in a MAPK-dependent manner. This regulation may result, at least in part, from the modulation of synapsin, a major peripheral synaptic vesicle protein. TGF-β1 stimulated MAPK-dependent phosphorylation of synapsin, a process believed to regulate synaptic vesicle mobilization from reserve to readily-releasable pools of neurotransmitter. In addition to its acute effect on synaptic efficacy, TGF-β1 also induced long-term increases in sensory neuron excitability. Whereas transient exposure to TGF-β1 was not sufficient to drive short-or long-term changes in excitability, prolonged exposure to TGF-β1 induced long-term changes in excitability that depended on MAPK. The results of these studies represent significant progress toward an understanding of the role of TGF-β1 in neuronal plasticity. ^

The role of sensory neuron outgrowth in long-term sensitization of the tail-elicited tail-siphon withdrawal reflex of Aplysia

Neuronal outgrowth has been proposed in many systems as a mechanism underlying memory storage. For example, sensory neuron outgrowth is widely accepted as an underlying mechanism of long-term sensitization of defensive withdrawal reflexes in Aplysia. The hypothesis is that learning leads to outgrowth and consequently to the formation of new synapses, which in turn strengthen the neural circuit underlying the behavior. However, key experiments to test this hypothesis have never been performed. ^ Four days of sensitization training leads to outgrowth of siphon sensory neurons mediating the siphon-gill withdrawal response in Aplysia . We found that a similar training protocol produced robust outgrowth in tail sensory neurons mediating the tail siphon withdrawal reflex. In contrast, 1 day of training, which effectively induces long-term behavioral sensitization and synaptic facilitation, was not associated with neuronal outgrowth. Further examination of the effect of behavioral training protocols on sensory neuron outgrowth indicated that this structural modification is associated only with the most persistent forms of sensitization, and that the induction of these changes is dependent on the spacing of the training trials over multiple days. Therefore, we suggest that neuronal outgrowth is not a universal mechanism underlying long-term sensitization, but is involved only in the most persistent forms of the memory. ^ Sensory neuron outgrowth presumably contributes to long-term sensitization through formation of new synapses with follower motor neurons, but this hypothesis has never been directly tested. The contribution of outgrowth to long-term sensitization was assessed using confocal microscopy to examine sites of contact between physiologically connected pairs of sensory and motor neurons. Following 4 days of training, the strength of both the behavior and sensorimotor synapse and the number of appositions with follower neurons was enhanced only on the trained side of the animal. In contrast, outgrowth was induced on both sides of the animal, indicating that although sensory neuron outgrowth does appear to contribute to sensitization through the formation of new synapses, outgrowth alone is not sufficient to account for the effects of sensitization. This indicates that key regulatory steps are downstream from outgrowth, possibly in the targeting of new processes and activation of new synapses. ^

Na 1 Nachlass Max Horkheimer, 642 - "Materialien. Druckseiten aus Zeitschriften", "Menschen im Großbetrieb" und "Vorwort zu: 'Zeugnisse. Theodor W. Adorno zum 60. Geburtstag'" (p. IX 20.11-76-IX 22)

11. Salomon, Albert: "The Spirit of the Soldier and Nazi Militarism". Social Research, Februar 1942, 13 Blatt; 12. Dicks, H.V.: "The Psychological Foundations of the Wehrmacht". Als Typoskript vervielfältigt, 42 Blatt; 13. Clark, Robert A.: "Aggressivness and Military Training". American Journal of Sociology, Volume 51, Number 5, March 1946, 5 Blatt; 14. Stagner, Ross: "Fascist Attitudes: Their Determening Conditions". The Journal of Social Psychology, Volume III, Number 4, 1936, 9 Blatt; 15. Apple, Kenneth E.: "Nationalism and Souvereignity: A Psychiatric View." The Journal of Normal and Abnorma Psychology, Volume 40, Number 4, October 1945, 4 Blatt; 16. Schreier, Fritz: "German Aggressivness- Its Reasons and Types". Journal of Normal and Abnormal Psychology, Volume 38, Number 2, April 1943, 7 Blatt; 17. Stagner, Ross: "Fascist Attitudes: An Exploratory Study". The Journal of Social Psychology, Volume III, Number 3, 1936, 6 Blatt; 18. Stagner, Ross und Katzoff, E. T.: "Fascist Attitudes: Factor Analysis of Item Correlations". The Journal of Social Psychology, 16, 1942, 4 Blatt; 19. Stagner, Ross und Osgood, Charles E.: "Impact of War on a Nationalistic Frame of Reference". The Journal of Social Psychology, 24, 1946, 15 Blatt; 20. Day, Daniel Droba und Quackenbusch, O.F.: Attitudes Towards Defensive, Cooperative and Aggressive War". The Journal of Social Psychology, 16, 1942, 5 Blatt; 21. Kecskemeti, Paul und Leites, Nathan: "Some Psychological Hypotheses on Nazi Germany: I". The Journal of Social Psychology, 26, 1947, 22 Blatt; 22. Dieselben: "Some Psychological Hypotheses on Nazi Germany: II". Ebenda, 27, 1948, 14 Blatt; 23. Parsons, Tollcott: "Certain Primary Sources and Pattersens of Aggression in the Social Structure of the Western World". Psychiatry, Volume 10, Number 2, May 1047, 8 Blatt; 24. Zerner, Elizabeth H.: "German Occupation and Anti-Semitism in France". Public Opinion Quarterly, Summer 1948, 5 Blatt; 25. Hauser, Ernest O.: "Doctor [Julian] Huxley`s Wonderful Zoo". The Saturday Evening Post, ohne Datum, 5 Blatt; 26. Zeitungsabschnitt, 1 Blatt; "Menschen im Großbetrieb" (GS 8, S. 95-105); Veröffentlicht in: Deutsche Zeitung, 19.02.1955. a) Typoskript mit dem Titel "Meinungsforschung im Betrieb" mit handschriftlichen Korrekturen, 10 Blatt b) Typoskript mit dem Titel "Der Mensch im Großbetrieb", mit eigenhändigen Korrekturen und einer handschriftlichen Notiz von Theodor W. Adorno, 17 Blatt c) Typoskript mit eigenhändigen Korrekturen, 17 Blatt d) Zeitungsdruck mit dem Titel "Menschen im Großbetrieb", mit eigenhändigen Korrekturen, 1 Blatt e)-f) Dasselbe , 1 Blatt; "Vorwort" zu: "Zeugnisse. Theodor W. Adorno zum 60. Geburtstag"; Veröffentlicht: Ebenda, Frankfurt am Main, 1963. a)-b) Typoskript mit eigenhändigen Korrekturen, 1 Blatt c) Typoskript, 2 Blatt;

Lactoferrin: An adjuvant to enhance the efficacy of the BCG vaccine

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB; an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed virtually unchanged since 1921. Intensive research is focused on developing a TB vaccine that can surpass and improve the existing BCG vaccine. Lactoferrin, an iron binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine. Specifically, Lactoferrin enhanced the ratio of IL-12:IL-10 production from macrophages stimulated with LFS or infected with BCG, indicating the potential to affect T-cell development in vivo. Five different vaccination protocols were investigated for generation of host protective responses against MTB infection using Lactoferrin admixed to the BCG vaccine. Mice immunized and boosted at 2 weeks with BCG/Lactofefrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology. The observed postchallenge results paralleled with increasing production of IFN-γ, IL-2, TNF-α, and IL-12 from BCG stimulated splenocytes. In vitro studies examined possible mechanisms of Lactoferrin action on BCG infected macrophages and dendritic cells. Addition of Lactoferrin to BCG infected macrophages and dendritic cells increased stimulation of presensitized CD3+ and CD4+ T-cells. Analysis by fluorescent activated cell sorting (FACS) revealed an increase in surface expression of MHC I and decreased ratio of CD80/86 from BCG infected macrophages cultured with Lactoferrin. In contrast, Lactoferrin decreased surface expression of MHC I, MHC II, CD80, CD86, and CD40, but increased CD 11c, from BCG infected dendritic cells, indicating involvement of adhesion molecules. Overall, these studies indicate that Lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine by enhancing generation of mycobacterial antigen specific T-cell responses through promotion of antigen presentation and T-cell stimulation.^

The mechanism of action of a novel benzo[c]phenanthridine alkaloid, NK314 and the cellular responses

NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that is currently in clinical trials as an antitumor compound, based on impressive activities in preclinical models. However, its mechanism of action is unknown. The present investigations were directed at determining the mechanism of action of this agent and cellular responses to NK314. My studies demonstrated that NK314 intercalated into DNA, trapped topoisomerase IIα in its cleavage complex intermediate, and inhibited the ability of topoisomerase IIα to relax super-coiled DNA. CEM/VM1 cells, which are resistant to etoposide due to mutations in topoisomerase IIα, were cross-resistant to NK314. However, CEM/C2 cells, which are resistant to camptothecin due to mutations in topoisomerase I, retained sensitivity. This indicates topoisomerase IIα is the target of NK314 in the cells. NK314 caused phosphorylation of the histone variant, H2AX, which is considered a marker of DNA double-strand breaks. DNA double-strand breaks were also evidenced by pulsed-field gel electrophoresis and visualized as chromosomal aberrations after cells were treated with NK314 and arrested in mitosis. Cell cycle checkpoints are activated following DNA damage. NK314 induced significant G2 cell cycle arrest in several cell lines, independent of p53 status, suggesting the existence of a common mechanism of checkpoint activation. The Chk1-Cdc25C-Cdk1 G2 checkpoint pathway was activated in response to NK314, which can be abrogated by the Chk1 inhibitor UCN-01. Cell cycle checkpoint activation may be a defensive mechanism that provides time for DNA repair. DNA double-strand breaks are repaired either through ATM-mediated homologous recombination or DNA-PK-mediated non-homologous end-joining repair pathways. Clonogenic assays demonstrated a significant decrease of colony formation in both ATM deficient and DNA-PK deficient cells compared to ATM repleted and DNA-PK wild type cells respectively, indicating that both ATM and DNA-PK play important roles in the survival of the cells in response to NK314. The DNA-PK specific inhibitor NU7441 also significantly sensitized cells to NK314. In conclusion, the major mechanism of NK314 is to intercalate into DNA, trap and inhibit topoisomerase IIα, an action that leads to the generation of double-strand DNA breaks, which activate ATM and DNA-PK mediated DNA repair pathways and Chk1 mediated G2 checkpoint pathway. ^

Seasonality of respiratory syncytial virus infection in Texas

Respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and children that can result in bronchiolitis or pneumonia. Each year in the United States, it causes up to 400 deaths and 125,000 hospitalizations among children less than one year of age. RSV is transmitted by direct or close contact with contaminated secretions, which may involve droplets and fomites. Monthly administration of a monoclonal RSV antibody, palivizumab (Synagis™, MedImmune, Gaithersburg, MD), in premature infants, infants with chronic lung disease, or congenital heart disease has been shown to significantly reduce the risk of severe RSV infection. The Centers for Disease Control and Prevention's (CDC) National Respiratory and Enteric Virus Surveillance System (NREVSS) is a laboratory based passive reporting system that collects state, regional, and national RSV data. The CDC defines the RSV season onset as “the first of 2 consecutive weeks during which the mean percentage of specimens testing positive for RSV antigen is 10%.” RSV season offset is defined as the last of 2 consecutive weeks during which the percentage of positive specimens is less than or equal to 10%. Annual RSV epidemics generally occur during the winter and early spring months, but the RSV season is known to vary by national regions. Precise delineation of the RSV epidemiology by region could maximize protection from RSV and minimize the cost of RSV immune prophylaxis. ^ The purpose of this thesis is to define the RSV season in Texas over time; compare the RSV season of the state of Texas and its regions with the national norms; and to compare RSV seasonality between the various regions in Texas. ^ This study was a retrospective analysis of data reported to NREVSS to evaluate potential disparities in the onset weeks, offset weeks, and duration of the annual RSV season in Texas. Data were collected from 70 reporting sites, and includes information from the 2004–2005 to 2009–2010 RSV seasons. ^ The observed median onset (week 44) and offset week (week 8) for the Texas were consistent with national estimates for the South. Regional estimates and statistical analysis suggested that the RSV season in Texas would be better represented by regions. Regional seasonal comparisons revealed considerable variation in season offset and duration between many of the geographic regions within Texas. This trend should be studied further.^

Ensayo, viaje y memoria : lectura de El destino de un continente (1923) de Manuel Ugarte

Dentro del corpus ensayístico de Manuel Ugarte figura una obra titulada El destino de un continente (1923) que da cuenta de su gira por el continente americano. El propósito de este largo viaje que emprende Ugarte es de carácter propagandístico, pues sostiene públicamente —a través de conferencias, mítines— la tesis de la unidad continental como estrategia defensiva contra la política intervencionista norteamericana. Pareciera, inicialmente, que el texto en cuestión merecería un abordaje desde los estudios de la literatura de viaje, lo que es en sí mismo correcto aunque, a nuestro entender, insuficiente. De manera que tenemos un problema de orden genérico que bien vale la pena plantear a fin de ajustar nuestra lectura. Es cierto que se trata de un viaje, pero no de un viaje cualquiera, en términos de un sujeto que se traslada de un sitio a otro con propósitos meramente turísticos, sino que la motivación central del desplazamiento ugarteano se sitúa en una acción catequística, si se quiere, de prédica que pretende mover a la acción.

Prácticas defensivas, conflictos y autoridades en la frontera bonaerense.Los pagos de Magdalena y Pergamino (1752-1780)

Este trabajo ahonda en el funcionamiento de la frontera bonaerense a partir del análisis de distintas Comandancias de Fronteras, principalmente las ubicadas en los pagos de Pergamino al norte y Magdalena al sur de la jurisdicción, haciendo hincapié en la articulación generada entre las fuerzas militares regulares y los cuerpos milicianos para llevar a cabo la práctica defensiva. El recorte temporal (1752-1780) contempla desde la puesta en funcionamiento de las Comandancias hasta las reformas defensivas efectuadas por el Virrey Vértiz, que trastocaron algunos rasgos básicos de nuestro objeto de estudio. Nos interesa conocer la formación de tal frontera, las prácticas concretas que le daban vida, los sujetos sociales que emergieron en este proceso y los conflictos que protagonizaron. Seguimos las trayectorias de los Sargentos Mayores de Milicias -en especial, Diego Trillo en Pergamino y Clemente López Osornio en Magdalena- como ejemplos de una forma de autoridad local resultante de la legitimidad que proveía el ejercicio de la "defensa".

La "frontera" bonaerense en el siglo XVIII, un espacio políticamente concertado. Resistencia y complementariedad política entre vecinos e indígenas en los pagos de Luján

El trabajo se propone argumentar porqué se define la frontera bonaerense como un espacio políticamente concertado. Para esto se analizan las acciones defensivas practicadas, para determinar que los recursos materiales constructivos y los efectivos militares de carrera fueron insuficientes para proteger la región. Por el contrario, se demuestra que el servicio en las milicias resultó esencial para proteger el espacio y resultó constituyente de condiciones de vecindad que posibilitaron que algunos vecinos-milicianos pudieran acceder a instancias de autoridad. Poderes locales que se desplazaban desde el ámbito urbano, la villa de Luján, a la campaña, espacios de frontera. Para argumentar esto se exponen los conocimientos arribados sobre el servicio miliciano y la estructura -red- defensiva que se organizó en la jurisdicción de Buenos Aires durante la primera mitad del siglo XVIII.