Role of Monoubiquitylation on the Control of IκBα Degradation and NF-κB Activity

9 p.

An Estimated New-Keynesian Model with Unemployment as Excess Supply of Labor

Wage stickiness is incorporated to a New-Keynesian model with variable capital to drive endogenous unemployment uctuations de ned as the log di¤erence between aggregate labor supply and aggregate labor demand. We estimated such model using Bayesian econometric techniques and quarterly U.S. data. The second-moment statistics of the unemployment rate in the model give a good t to those observed in U.S. data. Our results also show that wage-push shocks, demand shifts and monetary policy shocks are the three major determinants of unemployment fl uctuations. Compared to an estimated New-Keynesian model without unemployment (Smets and Wouters, 2007): wage stickiness is higher, labor supply elasticity is lower, the slope of the New-Keynesian Phillips curve is flatter, and the importance of technology innovations on output variability increases.

Impacto de las políticas crediticias de la banca en los resultados ex post : una aproximación desde las teorías económicas del ciclo crediticio

[ES]Este trabajo se centra en el análisis de la relación entre las políticas crediticias de las entidades de crédito y el comportamiento de las mismas ex post. Se hace una revisión de la teoría que justifica que los mercados crediticios pueden estar sujetos, en determinadas circunstancias, a un componente endógeno más elevado de lo que, en general, se atribuye. Se plantea como hipótesis de trabajo la existencia de una relación entre la intensidad en el crecimiento de la cartera crediticia de los bancos en las fases de expansión crediticia y su comportamiento ex post. Los resultados preliminares presentados confirman la hipótesis de que las entidades que más desvían su crecimiento crediticio respecto del crecimiento del PIB nominal, están sujetas a un peor comportamiento en cuanto a la evolución posterior de sus beneficios, rentabilidades e insolvencias.

Explorando la relación entre políticas crediticias y resultados de la banca española ex-post

© Este trabajo está licenciado bajo la licencia Creative Commons Attribution 3.0.

Institutional designs to face the dark side of total allowable catches

Setting total allowable catches (TACs) is an endogenous process in which different agents and institutions, often with conflicting interests and opportunistic behaviour, try to influence policy-makers. Such policy-makers, far from being the benevolent social planners many would wish them to be, may also pursue self-interest when making final decisions. Although restricted knowledge of stock abundance and population dynamics, and weakness in enforcement, have effects, these other factors may explain the reason why TAC management has failed to guarantee sustainable exploitation of fish resources. Rejecting the exogeneity of the TAC and taking advantage of fruitful debate on economic policy (i.e. the rules vs. discretion debate, and that surrounding the independence of central banks), two institutional developments are analysed as potential mechanisms to face up to misconceptions about TACs: long-term harvest control rules, and a central bank of fish.

Endocrine disruption in fish: An assessment of recent research and results

This report provides an assessment of recent investigations into endocrine disruption in fresh and saltwater species of fish. Most work to date has concen-trated on reproductive endocrine disruption. Laboratory studies have shown a variety of synthetic and natural chemicals including certain industrial intermediates, PAHs, PCBs, pesticides, dioxins, trace elements and plant sterols can interfere with the endocrine system in fish. The potency of most of these chemicals, however, is typically hundreds to thousands of times less than that of endog-enous hormones. Evidence of environmental endocrine disruption ranges from the presence of female egg proteins in males and reduced levels of endogenous hormones in both males and females, to gonadal histopathologies and intersex (presence of ovotestes) fish. Overt endocrine disruption in fish does not appear to be a ubiquitous environmental phenomenon, but rather more likely to occur near sewage treatment plants, pulp and paper mills, and in areas of high organic chemical contamination. However, more wide-spread endocrine disruption can occur in rivers with smaller flows and correspondingly large or numerous wastewater inputs. Some of the most severe examples of endocrine disruption in fish have been found adjacent to sewage treatment plants. Effects are thought to be caused prima-rily by natural and synthetic estrogens and to a lesser extent by the degradation products of alkylphenol poly-ethoxylate surfactants. Effects found in fish near pulp and paper mills include reduced levels of estrogens and androgens as well as masculinization of females, and has been linked to the presence of β-sitosterol, a plant sterol. Effects seen in areas of heavy industrial activity typically include depressed levels of estrogens and androgens as well as reduced gonadal growth, and may be linked to the presence of PAHs, PCBs, and possibly dioxins. At this time, however, there is no clear indication that large populations of fish are being seriously impacted as a result of endocrine disruption, although additional work is needed to address this possibility. (PDF contains 63 pages)

Increased opioid dependence in a mouse model of panic disorder

[EN] Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

Income Taxation and Growth in an OLG Economy: Does Aggregate Uncertainty Play any Role?

We analyze the effects of capital income taxation on long-run growth in a stochastic, two-period overlapping generations economy. Endogenous growth is driven by a positive externality of physical capital in the production sector that makes firms exhibit an aggregate technology in equilibrium. We distinguish between capital income and labor income, and between attitudes towards risk and intertemporal substitution of consumption. We show necessary and sufficient conditions such that i) increments in the capital income taxation lead to higher equilibrium growth rates, and ii) the effect of changes in the capital income tax rate on the equilibrium growth may be of opposite signs in stochastic and in deterministic economies. Such a sign reversal is shown to be more likely depending on i) how the intertemporal elasticity of substitution compares to one, and ii) the size of second- period labor supply. Numerical simulations show that for reasonable values of the intertemporal elasticity of substitution, a sign reversal shows up only for implausibly high values of the second- period’s labor supply. The conclusion is that deterministic OLG economies are a good approximation of the effect of taxes on the equilibrium growth rate as in Smith (1996).

Herstellung und Zusammensetzung von asiatischen Fischsaucen

Abstract Fish sauce belongs to the most important condiments in Southeast Asian cuisine. It is a clear, amber to reddish liquid with an intensive smell. Fish sauce is used instead of salt for nearly each meal. Asian fish sauce is made from anchovies and other small fish. For the traditional process whole fresh fish are mixed with salt in the ratio 1:1 to 6:1 in wooden, clay or concrete tanks at tropical temperatures for 6 to 18 months. The liquefaction of the fish tissue is due to the action of endogenous enzymes in fish and exogenous enzymes from bacteria. During the fermentation amino acids, peptides and a lot of other substances are built, which are responsible for the characteristic aroma and flavour of these sauces. You can buy pure fish sauce, diluted fish sauce and fish sauce made from other types of animals like mussels, prawns and squids. In single Asian countries there are different national standards for the quality of fish sauces. In order to get a general idea of these products we have bought 16 fish and two oyster sauces from the retail trade in Hamburg and analyzed them with physical, chemical, sensory and microbiological methods. Kurzfassung Fischsauce gehört zu den wichtigsten Würzsaucen in der südostasiatischen Küche. Es ist eine klare, bernsteinfarbene bis rötlichbraune, sehr intensiv riechende Flüssigkeit. Sie wird anstelle von Salz verwendet und daher fast zu jedem Essen gereicht. Zur Herstellung von Fischsaucen werden hauptsächlich Anchovis und ähnliche kleine Fische verwendet. Bei der traditionellen Herstellung werden die ganzen Fische mit Meersalz in einem Holzfass, Tongefäß oder Betontank im Verhältnis 1:1 bis 6:1 gemischt. Während der anschließenden 6 – 18 Monate dauernden Lagerung bei tropischen Temperaturen bauen sich die Gewebeproteine durch fischeigene Enzyme und Mikroorganismen ab. Bei diesem mehrmonatigen Fermentationsprozess entstehen die für den Geschmack wichtigen Aminosäuren, Peptide und Aromastoffe. Es gibt neben reiner Fischsauce, auch verdünnte Fischsauce und Fischsaucen aus anderen Tieren wie Muscheln, Garnelen und Tintenfische. In den einzelnen asiatischen Ländern gibt es unterschiedliche nationale Qualitätsstandards. Um diese Produktgruppe näher kennen zu lernen, haben wir 16 Fisch- und 2 Austernsaucen aus dem Einzelhandel (Hamburg) mit physikalischen, chemischen, sensorischen und mikrobiologischen Verfahren untersucht.

Analysis of SUMOylated proteins using SUMO-traps

6 p. [+ 7 p. Supplementary Information]

Foreign Aid Linked to Infrastructure and/or Pollution Abatement

This paper studies the macroeconomic effects of a permanent increase in foreign aid in a model that takes into account environmental quality. We develop a dynamic equilibrium model in which both public investment in infrastructure and environmental protection can be financed using domestic resources and international aid programs. The framework considers four scenarios for international aid: untied aid,aid fully tied to infrastructure, aid fully tied to abatement, and aid equally tied to both types of expenditures. We find that the effects of the transfers may depend on (i) the structural characteristics of the recipient country (the elasticity of substitution in production and its dependence on environment and natural resources) and on (ii) how recipient countries distribute their public expenditure. These results underscore the importance of these factors when deciding how and to what extent to tie aid to infrastructure and/or pollution abatement.

Design and synthesis of biofunctional magnetic/fluorescent glyco-nanoparticles and quantum dots and their application as specific molecular imaging probes

206 p.

Single cell proteomics microchip to profile immune function, with applications in stem cell biology, translational disease mechanism study and clinical therapeutics monitoring

In response to infection or tissue dysfunction, immune cells develop into highly heterogeneous repertoires with diverse functions. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. However, currently only 3-5 functional proteins can be measured from single cells. We developed a single cell functional proteomics approach that integrates a microchip platform with multiplex cell purification. This approach can quantitate 20 proteins from >5,000 phenotypically pure single cells simultaneously. With a 1-million fold miniaturization, the system can detect down to ~100 molecules and requires only ~104 cells. Single cell functional proteomic analysis finds broad applications in basic, translational and clinical studies. In the three studies conducted, it yielded critical insights for understanding clinical cancer immunotherapy, inflammatory bowel disease (IBD) mechanism and hematopoietic stem cell (HSC) biology.

To study phenotypically defined cell populations, single cell barcode microchips were coupled with upstream multiplex cell purification based on up to 11 parameters. Statistical algorithms were developed to process and model the high dimensional readouts. This analysis evaluates rare cells and is versatile for various cells and proteins. (1) We conducted an immune monitoring study of a phase 2 cancer cellular immunotherapy clinical trial that used T-cell receptor (TCR) transgenic T cells as major therapeutics to treat metastatic melanoma. We evaluated the functional proteome of 4 antigen-specific, phenotypically defined T cell populations from peripheral blood of 3 patients across 8 time points. (2) Natural killer (NK) cells can play a protective role in chronic inflammation and their surface receptor – killer immunoglobulin-like receptor (KIR) – has been identified as a risk factor of IBD. We compared the functional behavior of NK cells that had differential KIR expressions. These NK cells were retrieved from the blood of 12 patients with different genetic backgrounds. (3) HSCs are the progenitors of immune cells and are thought to have no immediate functional capacity against pathogen. However, recent studies identified expression of Toll-like receptors (TLRs) on HSCs. We studied the functional capacity of HSCs upon TLR activation. The comparison of HSCs from wild-type mice against those from genetics knock-out mouse models elucidates the responding signaling pathway.

In all three cases, we observed profound functional heterogeneity within phenotypically defined cells. Polyfunctional cells that conduct multiple functions also produce those proteins in large amounts. They dominate the immune response. In the cancer immunotherapy, the strong cytotoxic and antitumor functions from transgenic TCR T cells contributed to a ~30% tumor reduction immediately after the therapy. However, this infused immune response disappeared within 2-3 weeks. Later on, some patients gained a second antitumor response, consisted of the emergence of endogenous antitumor cytotoxic T cells and their production of multiple antitumor functions. These patients showed more effective long-term tumor control. In the IBD mechanism study, we noticed that, compared with others, NK cells expressing KIR2DL3 receptor secreted a large array of effector proteins, such as TNF-α, CCLs and CXCLs. The functions from these cells regulated disease-contributing cells and protected host tissues. Their existence correlated with IBD disease susceptibility. In the HSC study, the HSCs exhibited functional capacity by producing TNF-α, IL-6 and GM-CSF. TLR stimulation activated the NF-κB signaling in HSCs. Single cell functional proteome contains rich information that is independent from the genome and transcriptome. In all three cases, functional proteomic evaluation uncovered critical biological insights that would not be resolved otherwise. The integrated single cell functional proteomic analysis constructed a detail kinetic picture of the immune response that took place during the clinical cancer immunotherapy. It revealed concrete functional evidence that connected genetics to IBD disease susceptibility. Further, it provided predictors that correlated with clinical responses and pathogenic outcomes.

Octopamine neurons mediate flight-induced modulation of visual processing in Drosophila melanogaster

Activity-dependent modulation of sensory systems has been documented in many organisms, and is likely to be essential for appropriate processing of information during different behavioral states. However, the mechanisms underlying these phenomena, and often their functional consequences, remain poorly characterized. I investigated the role of octopamine neurons in the flight-dependent modulation observed in visual interneurons in the fruit fly Drosophila melanogaster. The vertical system (VS) cells exhibit a boost in their response to visual motion during flight compared to quiescence. Pharmacological application of octopamine evokes responses in quiescent flies that mimic those observed during flight, and octopamine neurons that project to the optic lobes increase in activity during flight. Using genetic tools to manipulate the activity of octopamine neurons, I find that they are both necessary and sufficient for the flight-induced visual boost. This work provides the first evidence that endogenous release of octopamine is involved in state-dependent modulation of visual interneurons in flies. Further, I investigated the role of a single pair of octopamine neurons that project to the optic lobes, and found no evidence that chemical synaptic transmission via these neurons is necessary for the flight boost. However, I found some evidence that activation of these neurons may contribute to the flight boost. Wind stimuli alone are sufficient to generate transient increases in the VS cell response to motion vision, but result in no increase in baseline membrane potential. These results suggest that the flight boost originates not from a central command signal during flight, but from mechanosensory stimuli relayed via the octopamine system. Lastly, in an attempt to understand the functional consequences of the flight boost observed in visual interneurons, we measured the effect of inactivating octopamine neurons in freely flying flies. We found that flies whose octopamine neurons we silenced accelerate less than wild-type flies, consistent with the hypothesis that the flight boost we observe in VS cells is indicative of a gain control mechanism mediated by octopamine neurons. Together, this work serves as the basis for a mechanistic and functional understanding of octopaminergic modulation of vision in flying flies.

Pattern formation during Caenorhabditis Elegans vulval development

Pattern formation during animal development involves at least three processes: establishment of the competence of precursor cells to respond to intercellular signals, formation of a pattern of different cell fates adopted by precursor cells, and execution of the cell fate by generating a pattern of distinct descendants from precursor cells. I have analyzed the fundamental mechanisms of pattern formation by studying the development of Caenorhabditis elegans vulva.

In C. elegans, six multipotential vulval precursor cells (VPCs) are competent to respond to an inductive signal LIN-3 (EGF) mediated by LET- 23 (RTK) and a lateral signal via LIN-12 (Notch) to form a fixed pattern of 3°-3°-2°-1°-2°-3°. Results from expressing LIN-3 as a function of time in animals lacking endogenous LIN-3 indicate that both VPCs and VPC daughters are competent to respond to LIN-3. Although the daughters of VPCs specified to be 2° or 3° can be redirected to adopt the 1°fate, the decision to adopt the 1° fate is irreversible. Coupling of VPC competence to cell cycle progression reveals that VPC competence may be periodic during each cell cycle and involve LIN-39 (HOM-C). These mechanisms are essential to ensure a bias towards the 1° fate, while preventing an excessive response.

After adopting the 1° fate, the VPC executes its fate by dividing three rounds to form a fixed pattern of four inner vulF and four outer vulE descendants. These two types of descendants can be distinguished by a molecular marker zmp-1::GFP. A short-range signal from the anchor cell (AC), along with signaling between the inner and outer 1° VPC descendants and intrinsic polarity of 1° VPC daughters, patterns the 1° lineage. The Ras and the Wnt signaling pathways may be involved in these mechanisms.

The temporal expression pattern of egl-17::GFP, another marker ofthe 1° fate, correlates with three different steps of 1° fate execution: the commitment to the 1° fate, as well as later steps before and after establishment of the uterine-vulval connection. Six transcription factors, including LIN-1(ETS), LIN-39 (HOM-C), LIN-11(LIM), LIN-29 (zinc finger), COG-1 (homeobox) and EGL-38 (PAX2/5/8), are involved in different steps during 1° fate execution.