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We outline a procedure for consistent estimation of marginal and joint default risk in the euro area financial system. We interpret the latter risk as the intrinsic financial system fragility and derive several systemic fragility indicators for euro area banks and sovereigns, based on CDS prices. Our analysis documents that although the fragility of the euro area banking system had started to deteriorate before Lehman Brothers' file for bankruptcy, investors did not expect the crisis to affect euro area sovereigns' solvency until September 2008. Since then, and especially after November 2009, joint sovereign default risk has outpaced the rise of systemic risk within the banking system.
This paper studies the effect of graduating from college on lifetime earnings. We develop a quantitative model of college choice with uncertain graduation. Departing from much of the literature, we model in detail how students progress through college. This allows us to parameterize the model using transcript data. College transcripts reveal substantial and persistent heterogeneity in students’ credit accumulation rates that are strongly related to graduation outcomes. From this data, the model infers a large ability gap between college graduates and high school graduates that accounts for 54% of the college lifetime earnings premium.
his paper distils three lessons for bank regulation from the experience of the 2009-12 euro-area financial crisis. First, it highlights the key role that sovereign debt exposures of banks have played in the feedback loop between bank and fiscal distress, and inquires how the regulation of banks’ sovereign exposures in the euro area should be changed to mitigate this feedback loop in the future. Second, it explores the relationship between the forbearance of non-performing loans by European banks and the tendency of EU regulators to rescue rather than resolving distressed banks, and asks to what extent the new regulatory framework of the euro-area “banking union” can be expected to mitigate excessive forbearance and facilitate resolution of insolvent banks. Finally, the paper highlights that capital requirements based on the ratio of Tier-1 capital to banks’ risk-weighted assets were massively gamed by large banks, which engaged in various forms of regulatory arbitrage to minimize their capital charges while expanding leverage. This argues in favor of relying on a set of simpler and more robust indicators to determine banks’ capital shortfall, such as book and market leverage ratios.
We study a model where some investors ("hedgers") are bad at information processing, while others ("speculators") have superior information-processing ability and trade purely to exploit it. The disclosure of financial information induces a trade externality: if speculators refrain from trading, hedgers do the same, depressing the asset price. Market transparency reinforces this mechanism, by making speculators' trades more visible to hedgers. As a consequence, issuers will oppose both the disclosure of fundamentals and trading transparency. Issuers may either under- or over-provide information compared to the socially efficient level if speculators have more bargaining power than hedgers, while they never under-provide it otherwise. When hedgers have low financial literacy, forbidding their access to the market may be socially efficient.
Most simulated micro-founded macro models use solely consumer-demand aggregates in order to estimate deep economy-wide preference parameters, which are useful for policy evaluation. The underlying demand-aggregation properties that this approach requires, should be easy to empirically disprove: since household-consumption choices differ for households with more members, aggregation can be rejected if appropriate data violate an affine equation regarding how much individuals benefit from within-household sharing of goods. We develop a survey method that tests the validity of this equation, without utility-estimation restrictions via models. Surprisingly, in six countries, this equation is not rejected, lending support to using consumer-demand aggregates.
Riley (1979)'s reactive equilibrium concept addresses problems of equilibrium existence in competitive markets with adverse selection. The game-theoretic interpretation of the reactive equilibrium concept in Engers and Fernandez (1987) yields the Rothschild-Stiglitz (1976)/Riley (1979) allocation as an equilibrium allocation, however multiplicity of equilibrium emerges. In this note we imbed the reactive equilibrium's logic in a dynamic market context with active consumers. We show that the Riley/Rothschild-Stiglitz contracts constitute the unique equilibrium allocation in any pure strategy subgame perfect Nash equilibrium.
Background: According to current taxonomy only three out of 27 Sinohimalayan leaf warbler species (Phylloscopidae) are considered genetically uniform across their entire breeding range along the Southeastern margin of the Qinghai-Tibetan Plateau, the Buff-barred Warbler (Phylloscopus pulcher) being one of them. Because marked differentiation among Himalayan and Chinese populations has been recently demonstrated for a number of Phylloscopus species (or sister species) we investigated the intraspecific variation of a mitochondrial gene, songs and morphology of P. pulcher in a phylogeographic approach.
Methods: We sequenced a fragment of the mitochondrial cytochrome b, reconstructed haplotype networks and analyzed DNA polymorphism among Himalayan and Chinese populations. We measured time and frequency parameters of two distinct song types and analyzed among population-differentiation in a principal component analysis and a discriminant analysis. We also compared measurements of body size dimensions taken from museum specimens.
Results: The mitochondrial haplotype network (cytb) was divided into two distinct clusters corresponding to geographic origin of samples. Pairwise genetic distances among Himalayan and Chinese mtDNA lineages account for 1.3% which coincides with Pleistocene lineage separation at roughly 650,000 years ago. Genetic diversity is slightly higher in the Chinese part of the species’ range with respect to haplotype and nucleotide diversity while the less diversified Himalayan population lineage shows signs of recent range expansion. The vocal repertoire of P. pulcher comprises two distinct verse types that are combined with short interspersed click notes to long continuous song displays. Trill verse types showed significant differences among regions in almost all measured frequency and time parameters: Chinese males displayed more rapid and more broad-banded trills at a lower pitch. In contrast, warbling verse types showed a distinctively different structure among regions: Himalayan songs consisted of repeated syllables while Chinese songs comprised repetitions of single, long and strongly modulated elements. Subtle morphological differences among specimens from the two study regions could only be confirmed for plumage coloration but not for metric characters.
Conclusions: Based on the genetic and bioacoustic distinctiveness of Chinese Buff-barred Warbler populations, we recommend that the name Phylloscopus pulcher vegetus Bangs, 1913 should be re-validated for this taxon.
Herbaceous ground vegetation is an important pool of biomass and nutrients, which is also used as the major forage source for wild ungulates. Up to now no standard methods exist to estimate herbaceous biomass on a landscape level for temperate forests, which are characterised by deciduous trees with closed canopies. Quantity and quality of the herbaceous forage accessible to herbivores can be estimated from estimated cover in vegetation plot data and information on biomass and element concentrations in plant species. Vegetation was sampled stratified by community types and forest developmental phases in Bavarian Forst National Park, Germany. We adopted the PhytoCalc model to estimate biomass and bioelement stocks from vegetation plot data and adjusted species assignments and absolute levels of biomass to the conditions in the national park. We categorised attractiveness of plant species as forage for red deer (Cervus elaphus) and roe deer (Capreolus capreolus). Multiple controls of total biomass and of plant groups (graminoids, ferns, herbs, Vaccinium, Rubus) were studied by stepwise regression against stand and environmental predictors. Herbaceous mass had a highly skewed distribution in the park, with 75% of plots having less than 231 g*m-2 of biomass or 24 g*m-2 of raw protein. Contributions of plant groups were site-dependent and variable, but decreased in the order Vaccinium-graminoids-Rubus-herbs-ferns. Biomass appeared to be controlled by deciduous tree cover, by total cover of canopy and coarse woody debris and by site quality, with nutrient-poor, high elevation sites having higher herb biomass. As a consequence, montane beech forests offered less forage mass than coniferous communities of high elevations and mires. Stand disturbances by bark beetles and the corresponding forest developmental phases had no systematic effects on total biomass.
The endemic Floridian milliped genus, Floridobolus Causey, 1957, more closely related to tylobolinines in the western United States (US), Mexico, and Guatemala than syntopic spirobolines, is incorporated into Spirobolidae (Spirobolida: Spirobolidea). With taxonomic priority by one year, its monotypic family is reduced to Floridobolinae, n. stat., comprising Floridobolini and Tylobolini, n. stats., the counterpart to Spirobolinae, comprising Spirobolini and Aztecolini, n. tribe; relationships are Floridobolini + (Tylobolini + (Aztecolini + Spirobolini)). Like F. penneri Causey, 1957, 208 km (130 mi) to the south in the Lake Wales Ridge, Polk and Highlands counties (cos.), F. orini n. sp., inhabits “Big Scrub” environments in the Ocala National Forest, Marion Co. Biogeographic reconstructions, compatible with broader hypotheses on the class’ evolutionary history, indicate that, from a presumptive source area in northern Mexico where the subfamilies overlap, spirobolid stock penetrated the “proto-US” four times, once per tribe, before the Western Interior Seaway developed in the Cretaceous Period, Mesozoic Era. Three expansions headed northeastward into future “Appalachia,” from which taxa spread southward as the Seaway receded. Floridobolini, the fi rst invader, had to be in “proto-Georgia” and positioned to penetrate Florida when the sand dunes that comprise the “Central Highlands” emerged from the sea in the Oligocene (Cenozoic), ~25 mya. As sea levels rose and fell, the dunes fragmented into islands and the subcontinuous Floridobolus population was partitioned. The southernmost became F. penneri; F. orini inhabited a northern island; and a graduate student is investigating other insular remnants for additional species. Shortly after Floridobolini began spreading, Hiltonius/ Tylobolini arose and expanded both southward to Guatemala and northwestward to California; Tylobolus Cook, 1904, diverged in the latter area and dispersed northward to Washington and eastward to Utah/Arizona. The third invader, and the second to disperse northeastward, was Aztecolini, which probably eradicated Floridobolini from some of its established range and was partitioned into Mexican (Aztecolus Chamberlin, 1943) and US (Chicobolus Chamberlin, 1947) taxa by the Seaway. The fi nal invader, Spirobolini, dispersed northwestward and northeastward to both the Pacifi c and Atlantic coasts; instead of Trans-Beringia, we prefer penetration of the Asian part of “Asiamerica,” when it temporarily formed during the Cretaceous, to explain the Mongolian fossil genus, Gobiulus Dzik, 1975, herein assigned to Tylobolini, and the occurrence of Spirobolus Brandt, 1833, in China and Taiwan today. In the east, Narceus Rafi nesque, 1820, spread across Appalachia, eradicated most remaining populations of Floridobolus and Chicobolus, and expanded to Maine and Québec after retreat of the Wisconsin glaciation. Chicobolus and Narceus also penetrated earliest Florida; the former established itself in the Central Highlands, spread through the widening peninsula as sea levels fell, and remained on insular refugia when waters rose. Apparently fueled by the different Floridian environments, Narceus underwent time-consuming speciation; consequently, Floridobolus and Chicobolus still survive on the peninsula, and an allopatric population of the latter inhabits coastal South Carolina. However, N. gordanus (Chamberlin, 1943) occurs syntopically with both in peninsular Florida and may be actively eradicating them from their last stronghold. Trigoniulus niger, takahasii, and segmentatus, all by Takakuwa, 1940, are removed from Spirobolidae and returned toTrigoniulidae (Trigoniulidea). New records in the Appendix include the fi rst of Aztecolus from Durango and Jalisco, Mexico.
Background: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
Methods: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.
Results: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
Conclusions: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/− irinotecan in stage II/III colorectal cancer.
Background: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330].
Methods: Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72.
Results: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study.
Conclusions: Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.
Background: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV.
Methods: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population.
Results: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients.
Conclusion: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents.
Background: The federal state of Hesse, Germany, introduced a laboratory-based reporting scheme for carbapenem-resistant organisms (CROs).
Method: The results of the first year of mandated reporting of CROs from April 2012 through March 2013 to the Public Health Authority of Frankfurt/Main, responsible for a population of 700,000 inhabitants, are described.
Results: Within a period of 12 months 243 CROs were notified to the health authority. Of these 213 isolates had been reported from 16 of the 17 hospitals in Frankfurt/Main, 6 from ambulatory settings and 24 from clinics outside of Frankfurt/Main. Mean incidence rate per 1,000 patient days in hospitals was 0.138 (range 0.02-0.28).
Conclusion: In Frankfurt/Main almost all hospitals have reported CROs in the study period though the frequency of isolation varies strongly and many facilities only report CROs sporadically. Molecular data indicate a high diversity of different carbapenemases. Autochthonous transmission must be assumed despite the absence of major outbreaks. Rapid and coordinated efforts by clinicians and health departments are crucial to control the spread of CRO infections. The mandatory reporting scheme provides important data to guide the implementation of preventive measures.
Non-coding RNAs (ncRNAs) play various roles during central nervous system development. MicroRNAs (miRNAs) are a class of ncRNAs that exert their function together with argonaute proteins by post-transcriptional gene silencing of messenger RNAs (mRNAs). Several studies provide evidence for alterations in miRNA expression in patients with neurodegenerative diseases. Among these is huntington‘s disease (HD), a dominantly inherited fatal disorder characterized by deregulation of neuronal-specific mRNAs as well as miRNAs. Recently, next-generation sequencing (NGS) miRNA profiles from human HD and neurologically normal control brain tissues were reported. Five consistently upregulated miRNAs affect the expression of genes involved in neuronal differentiation, neurite outgrowth, cell death and survival. We re-analyzed the NGS data publicly available in array express and detected nineteen additional differentially expressed miRNAs. Subsequently, we connected these miRNAs to genes implicated in HD development and network analysis pointed to miRNA-mediated downregulation of twenty-two genes with roles in the pathogenesis as well as treatment of the disease. In silico prediction and reporter systems prove that levels of BDNF, a central node in the miRNA-mRNA regulatory network, can be post-transcriptionally controlled by upregulated miR-10b-5p and miR-30a-5p. Reduced BDNF expression is associated with neuronal dysfunction and death in HD. Moreover, the 3’UTR of CREB1 harbors a predicted binding site for these two miRNAs. CREB1 is similarly downregulated in HD and overexpression decreased susceptibility to 3-nitropropionic-induced toxicity in a cell model. In contradiction to these observations, it is presumed that miR-10b-5p upregulation in HD exerts a neuroprotective role in response to the mutation in the huntingtin gene. Therefore, the function of miR-10b-5p and especially its effect on BDNF expression in HD requires further academic research.
(Micro)plastics in the aquatic environment are an issue of emerging concern. However, to date, there is considerable lack of knowledge on the abundance and toxicity of plastic debris in aquatic ecosystems, especially with regard to the freshwater situation. In this editorial, we briefly discuss important aspects of the research on environmental (micro)plastics to stimulate research and call for papers.
Background: Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication.
Findings: Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages.
Conclusions: These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity.
Background: Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors.
Results: C57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone.
Conclusions: Regardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.
Background: High-intensity focused ultrasound (HIFU) allows to inflict intracorporal thermal lesions without penetrating the skin or damaging the surrounding tissue. This analysis intends to assess the magnitude of HIFU-induced ablations within benign thyroid nodules using scintigraphic imaging with 99mTc.
Methods: Ten cold, hot, or indifferent nodules were treated using multiple pulses of HIFU to induce temperatures of around 85°C within the ablation zone. Pre- and posttreatment, uptake values of 99mTc pertechnetate or 99mTc-MIBI were recorded. The pre-post reduction of nodular uptake was evaluated to assess ablation magnitude.
Results: Relative nodular uptake in relation to total thyroidal uptake decreased after one session of HIFU in all cases. Median 99mTc-MIBI uptake reduction was 35.5% (ranging from 11% to 57%; p < 0.1), while 99mTc-pertechnetate scintigraphy showed a median uptake reduction of 27% (range 10% to 44%; p < 0.1). No major complications were observed.
Conclusions: HIFU appears to be safe and is an easy to perform means of thermal ablation. This study shows that HIFU treatment in thyroidal nodules can be evaluated by scintigraphic means shortly after the intervention. Due to small sample size, the exact magnitude of HIFU ablation efficiency in thyroidal nodules remains a value to beassessed in a larger study.
Background: The current taxonomy of the African giraffe (Giraffa camelopardalis) is primarily based on pelage pattern and geographic distribution, and nine subspecies are currently recognized. Although genetic studies have been conducted, their resolution is low, mainly due to limited sampling. Detailed knowledge about the genetic variation and phylogeography of the South African giraffe (G. c. giraffa) and the Angolan giraffe (G. c. angolensis) is lacking. We investigate genetic variation among giraffe matrilines by increased sampling, with a focus on giraffe key areas in southern Africa.
Results: The 1,562 nucleotides long mitochondrial DNA dataset (cytochrome b and partial control region) comprises 138 parsimony informative sites among 161 giraffe individuals from eight populations. We additionally included two okapis as an outgroup. The analyses of the maternally inherited sequences reveal a deep divergence between northern and southern giraffe populations in Africa, and a general pattern of distinct matrilineal clades corresponding to their geographic distribution. Divergence time estimates among giraffe populations place the deepest splits at several hundred thousand years ago.
Conclusions: Our increased sampling in southern Africa suggests that the distribution ranges of the Angolan and South African giraffe need to be redefined. Knowledge about the phylogeography and genetic variation of these two maternal lineages is crucial for the development of appropriate management strategies.
Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.
Background: Malaria is still a priority public health problem of Nepal where about 84% of the population are at risk. The aim of this paper is to highlight the past and present malaria situation in this country and its challenges for long-term malaria elimination strategies.
Methods: Malariometric indicator data of Nepal recorded through routine surveillance of health facilities for the years between 1963 and 2012 were compiled. Trends and differences in malaria indicator data were analysed.
Results: The trend of confirmed malaria cases in Nepal between 1963 and 2012 shows fluctuation, with a peak in 1985 when the number exceeded 42,321, representing the highest malaria case-load ever recorded in Nepal. This was followed by a steep declining trend of malaria with some major outbreaks. Nepal has made significant progress in controlling malaria transmission over the past decade: total confirmed malaria cases declined by 84% (12,750 in 2002 vs 2,092 in 2012), and there was only one reported death in 2012. Based on the evaluation of the National Malaria Control Programme in 2010, Nepal recently adopted a long-term malaria elimination strategy for the years 2011–2026 with the ambitious vision of a malaria-free Nepal by 2026. However, there has been an increasing trend of Plasmodium falciparum and imported malaria proportions in the last decade. Furthermore, the analysis of malariometric indicators of 31 malaria-risk districts between 2004 and 2012 shows a statistically significant reduction in the incidence of confirmed malaria and of Plasmodium vivax, but not in the incidence of P. falciparum and clinically suspected malaria.
Conclusions: Based on the achievements the country has made over the last decade, Nepal is preparing to move towards malaria elimination by 2026. However, considerable challenges lie ahead. These include especially, the need to improve access to diagnostic facilities to confirm clinically suspected cases and their treatment, the development of resistance in parasites and vectors, climate change, and increasing numbers of imported cases from a porous border with India. Therefore, caution is needed before the country embarks towards malaria elimination.
Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1).
Methods/Design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments.
Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients.
Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia
(2014)
Background: Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death.
Methods: We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm−/−).
Results: ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm−/− mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed.
Conclusions: Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.
Antigenic and 3D structural characterization of soluble X4 and hybrid X4-R5 HIV-1 Env trimers
(2014)
Background: HIV-1 is decorated with trimeric glycoprotein spikes that enable infection by engaging CD4 and a chemokine coreceptor, either CCR5 or CXCR4. The variable loop 3 (V3) of the HIV-1 envelope protein (Env) is the main determinant for coreceptor usage. The predominant CCR5 using (R5) HIV-1 Env has been intensively studied in function and structure, whereas the trimeric architecture of the less frequent, but more cytopathic CXCR4 using (X4) HIV-1 Env is largely unknown, as are the consequences of sequence changes in and near V3 on antigenicity and trimeric Env structure.
Results: Soluble trimeric gp140 Env constructs were used as immunogenic mimics of the native spikes to analyze their antigenic properties in the context of their overall 3D structure. We generated soluble, uncleaved, gp140 trimers from a prototypic T-cell line-adapted (TCLA) X4 HIV-1 strain (NL4-3) and a hybrid (NL4-3/ADA), in which the V3 spanning region was substituted with that from the primary R5 isolate ADA. Compared to an ADA (R5) gp140, the NL4-3 (X4) construct revealed an overall higher antibody accessibility, which was most pronounced for the CD4 binding site (CD4bs), but also observed for mAbs against CD4 induced (CD4i) epitopes and gp41 mAbs. V3 mAbs showed significant binding differences to the three constructs, which were refined by SPR analysis. Of interest, the NL4-3/ADA construct with the hybrid NL4-3/ADA CD4bs showed impaired CD4 and CD4bs mAb reactivity despite the presence of the essential elements of the CD4bs epitope. We obtained 3D reconstructions of the NL4-3 and the NL4-3/ADA gp140 trimers via electron microscopy and single particle analysis, which indicates that both constructs inherit a propeller-like architecture. The first 3D reconstruction of an Env construct from an X4 TCLA HIV-1 strain reveals an open conformation, in contrast to recently published more closed structures from R5 Env. Exchanging the X4 V3 spanning region for that of R5 ADA did not alter the open Env architecture as deduced from its very similar 3D reconstruction.
Conclusions: 3D EM analysis showed an apparent open trimer configuration of X4 NL4-3 gp140 that is not modified by exchanging the V3 spanning region for R5 ADA.
Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.
Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes and cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease.
Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV1(%) 77) were examined. Sequence analysis was performed for genes encoding GAP junction protein alpha 1 (GJA1/connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminescence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts.
Results: DNA analysis was performed in 35 patients. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) predicts an amino acid substitution (GTA → valine, ATA → isoleucine) as well as the fourth SNP (rs1764391: CCC→proline, TCC→serine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p=0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p=0.041) than those showing heterozygosity (G/A). In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p=0.07) was worse.
Conclusion: SNP rs41266431 seems a promising candidate for further investigations, suggesting GJA4 a potential disease modifying gene.
DNA methylation reader MECP2 : cell type- and differentiation stage-specific protein distribution
(2014)
Background: Methyl-CpG binding protein 2 (MECP2) is a protein that specifically binds methylated DNA, thus regulating transcription and chromatin organization. Mutations in the gene have been identified as the principal cause of Rett syndrome, a severe neurological disorder. Although the role of MECP2 has been extensively studied in nervous tissues, still very little is known about its function and cell type specific distribution in other tissues.
Results: Using immunostaining on tissue cryosections, we characterized the distribution of MECP2 in 60 cell types of 16 mouse neuronal and non-neuronal tissues. We show that MECP2 is expressed at a very high level in all retinal neurons except rod photoreceptors. The onset of its expression during retina development coincides with massive synapse formation. In contrast to astroglia, retinal microglial cells lack MECP2, similar to microglia in the brain, cerebellum, and spinal cord. MECP2 is also present in almost all non-neural cell types, with the exception of intestinal epithelial cells, erythropoietic cells, and hair matrix keratinocytes. Our study demonstrates the role of MECP2 as a marker of the differentiated state in all studied cells other than oocytes and spermatogenic cells. MECP2-deficient male (Mecp2−/y) mice show no apparent defects in the morphology and development of the retina. The nuclear architecture of retinal neurons is also unaffected as the degree of chromocenter fusion and the distribution of major histone modifications do not differ between Mecp2−/y and Mecp2wt mice. Surprisingly, the absence of MECP2 is not compensated by other methyl-CpG binding proteins. On the contrary, their mRNA levels were downregulated in Mecp2−/y mice.
Conclusions: MECP2 is almost universally expressed in all studied cell types with few exceptions, including microglia. MECP2 deficiency does not change the nuclear architecture and epigenetic landscape of retinal cells despite the missing compensatory expression of other methyl-CpG binding proteins. Furthermore, retinal development and morphology are also preserved in Mecp2-null mice. Our study reveals the significance of MECP2 function in cell differentiation and sets the basis for future investigations in this direction.
Immunotherapy of cancer utilizes dendritic cells (DCs) for antigen presentation and the induction of tumor-specific immune responses. However, the therapeutic induction of anti-tumor immunity is limited by tumor escape mechanisms. In this study, immortalized dendritic D2SC/1 cells were transduced with a mutated version of the p53 tumor suppressor gene, p53M234I, or p53C132F/E168G, which are overexpressed in MethA fibrosarcoma tumor cells. In addition, D2SC/1 cells were fused with MethA tumor cells to generate a vaccine that potentially expresses a large repertoire of tumor-antigens. Cellular vaccines were transplanted onto Balb/c mice and MethA tumor growth and anti-tumor immune responses were examined in vaccinated animals. D2SC/1-p53M234I and D2SC/1-p53C132F/E168G cells induced strong therapeutic and protective MethA tumor immunity upon transplantation in Balb/c mice. However, in a fraction of immunized mice MethA tumor growth resumed after an extended latency period. Analysis of these tumors indicated loss of p53 expression. Mice, pre-treated with fusion hybrids generated from D2SC/1 and MethA tumor cells, suppressed MethA tumor growth and averted adaptive immune escape. Polyclonal B-cell responses directed against various MethA tumor proteins could be detected in the sera of D2SC/1-MethA inoculated mice. Athymic nude mice and Balb/c mice depleted of CD4(+) or CD8(+) T-cells were not protected against MethA tumor cell growth after immunization with D2SC/1-MethA hybrids. Our results highlight a potential drawback of cancer immunotherapy by demonstrating that the induction of a specific anti-tumor response favors the acquisition of tumor phenotypes promoting immune evasion. In contrast, the application of DC/tumor cell fusion hybrids prevents adaptive immune escape by a T-cell dependent mechanism and provides a simple strategy for personalized anti-cancer treatment without the need of selectively priming the host immune system.
FLRTs are broadly expressed proteins with the unique property of acting as homophilic cell adhesion molecules and as heterophilic repulsive ligands of Unc5/Netrin receptors. How these functions direct cell behavior and the molecular mechanisms involved remain largely unclear. Here we use X-ray crystallography to reveal the distinct structural bases for FLRT-mediated cell adhesion and repulsion in neurons. We apply this knowledge to elucidate FLRT functions during cortical development. We show that FLRTs regulate both the radial migration of pyramidal neurons, as well as their tangential spread. Mechanistically, radial migration is controlled by repulsive FLRT2-Unc5D interactions, while spatial organization in the tangential axis involves adhesive FLRT-FLRT interactions. Further, we show that the fundamental mechanisms of FLRT adhesion and repulsion are conserved between neurons and vascular endothelial cells. Our results reveal FLRTs as powerful guidance factors with structurally encoded repulsive and adhesive surfaces.
Cryo-electron tomography provides a snapshot of the cellular proteome. With template matching, the spatial positions of various macromolecular complexes within their native cellular context can be detected. However, the growing awareness of the reference bias introduced by the cross-correlation based approaches, and more importantly the lack of a reliable confidence measurement in the selection of these macromolecular complexes, has restricted the use of these applications. Here we propose a heuristic, in which the reference bias is measured in real space in an analogous way to the R-free value in X-ray crystallography. We measure the reference bias within the mask used to outline the area of the template, and do not modify the template itself. The heuristic works by splitting the mask into a working and a testing area in a volume ratio of 9:1. While the working area is used during the calculation of the cross-correlation function, the information from both areas is explored to calculate the M-free score. We show using artificial data, that the M-free score gives a reliable measure for the reference bias. The heuristic can be applied in template matching and in sub-tomogram averaging. We further test the applicability of the heuristic in tomograms of purified macromolecules, and tomograms of whole Mycoplasma cells.
The genus Casmaria H. Adams & A. Adams, 1853 (family Cassidae) is widespread in the tropical Indo-Pacific and has been documented from some Atlantic localities as well. Two Casmaria species, C. erinaceus (Linnaeus, 1758) and C. ponderosa (Gmelin, 1791), are common in Indo-Pacific shallow-water sandy bottom communities and are characterized by high morphological variability; both species encompass multiple, often sympatric forms of uncertain status. In the present study we carry out a phylogenetic analysis of some Philippine Casmaria morphs and demonstrate that one of the distinctive morphs earlier assigned to Casmaria ponderosa is in fact a different species, which we describe as Casmaria boblehmani sp. nov. The smooth form of Casmaria ponderosa, C. ponderosa ponderosa, and the solid nodulose form, widely called “form nodulosa” despite being strikingly different in shell morphology, are shown to be conspecific. Studied specimens of these two morphs even from different localities share the same haplotype of the CO1 gene. In light of these new data on the morphological variability of Casmaria species, we discuss criteria of species delimitation in the genus Casmaria and possible affinities of Casmaria boblehmani sp. nov. within the genus.
Correlative microscopy incorporates the specificity of fluorescent protein labeling into high-resolution electron micrographs. Several approaches exist for correlative microscopy, most of which have used the green fluorescent protein (GFP) as the label for light microscopy. Here we use chemical tagging and synthetic fluorophores instead, in order to achieve protein-specific labeling, and to perform multicolor imaging. We show that synthetic fluorophores preserve their post-embedding fluorescence in the presence of uranyl acetate. Post-embedding fluorescence is of such quality that the specimen can be prepared with identical protocols for scanning electron microscopy (SEM) and transmission electron microscopy (TEM); this is particularly valuable when singular or otherwise difficult samples are examined. We show that synthetic fluorophores give bright, well-resolved signals in super-resolution light microscopy, enabling us to superimpose light microscopic images with a precision of up to 25 nm in the x-y plane on electron micrographs. To exemplify the preservation quality of our new method we visualize the molecular arrangement of cadherins in adherens junctions of mouse epithelial cells.
Physical Biology is a field of life sciences dealing with the extraction of quantitative data from biophysical or molecular biological experiments with different levels of complexity. Such data are further used as parameters for mathematical models of the biological system. These models allow to predict reactions on external stimuli by describing the relevant molecular interactions and are therefore used for example to generate a deeper comprehension of complex human diseases. An essential technique in biophysical research on human diseases is fluorescence microscopy. This is a constantly developed toolbox comprising a large number of specific labeling strategies, as well as a broad spectrum of fluorescent probes. It is further minimal invasive and therefore suitable for measurements in living cells or organisms. The sensitivity of modern photo-detectors even allows for the detection of a single fluorescent probe with an accuracy of approximately 10 nm.
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The model-prediction was further verified by two color SMLM experiments. In this work the development and application of imaging-systems are described which provide quantitative data with single-molecule resolution for systems biological model approaches with a low degree of abstractness. In the near future, the impact of mathematical models in the research field of complex human diseases will increase. The predictions of these models will be more exact, the more detailed and accurate the input parameters will become. This work gives an impression of how quantitative data obtained by SMLM may serve as input parameters for mathematical models at the single-cell level.
Dinteria : Nr. 34, 2014
(2014)
Bacteria have adapted their NhaA Na(+)/H(+) exchangers responsible for salt homeostasis to their different habitats. We present an electrophysiological and kinetic analysis of NhaA from Helicobacter pylori and compare it to the previously investigated exchangers from Escherichia coli and Salmonella typhimurium. Properties of all three transporters are described by a simple model using a single binding site for H(+) and Na(+). We show that H.pylori NhaA only has a small acidic shift of its pH-dependent activity profile compared to the other transporters and discuss why a more drastic change in its pH activity profile is not physiologically required.
Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand–survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.
We examine the relationship between household wealth and self-control. Although self-control has been linked to consumption and financial behavior, its measurement remains an open issue. We employ a definition of self-control failure that follows literature in psychology, suggesting that three factors can render self-control defective: lack of planning, lack of monitoring, and lack of commitment to pre-set plans. Our measure combines those three ingredients and can be computed using a standard representative survey. We find that self-control failure is strongly associated with different household net wealth measures and with self-assessed financial distress.
How special are they? - Targeting systemic risk by regulating shadow banking : (October 5, 2014)
(2014)
This essay argues that at least some of the financial stability concerns associated with shadow banking can be addressed by an approach to financial regulation that imports its functional foundations more vigorously into the interpretation and implementation of existing rules. It shows that the general policy goals of prudential banking regulation remain constant over time despite dramatic transformations in the financial and technological landscape. Moreover, these overarching policy goals also legitimize intervention in the shadow banking sector. On these grounds, this essay encourages a more normative construction of available rules that potentially limits both the scope for regulatory arbitrage and the need for ever more rapid updates and a constant increase in the complexity of the regulatory framework. By tying the regulatory treatment of financial innovation closely to existing prudential rules and their underlying policy rationales, the proposed approach potentially ends the socially wasteful race between hare and tortoise that signifies the relation between regulators and a highly dynamic industry. In doing so it does not generally hamper market participants’ efficient discoveries where disintermediation proves socially beneficial. Instead, it only weeds-out rent-seeking circumventions of existing rules and standards.
Previous research has documented strong peer effects in risk taking, but little is known about how such social influences affect market outcomes. The consequences of social interactions are hard to isolate in financial data, and theoretically it is not clear whether peer effects should increase or decrease risk sharing. We design an experimental asset market with multiple risky assets and study how exogenous variation in real-time information about the portfolios of peer group members affects aggregate and individual risk taking. We find that peer information ameliorates under-diversification that occurs in a market without such information. One reason is that peer information increases risk aversion and induces a concern for relative income position that may reduce or amplify risk taking, depending on whether the context highlights the most or least successful trader. Thus, contrary to conventional wisdom, we show that social interactions may help to reduce earnings volatility in financial markets, and we discuss implications for institutional design.
This paper contrasts the recent European initiatives on regulating corporate groups with alternative approaches to the phenomenon. In doing so it pays particular regard to the German codified law on corporate groups as the polar opposite to the piecemeal approach favored by E.U. legislation.
It finds that the European Commission’s proposal to submit (significant) related party transactions to enhanced transparency, outside fairness review, and ex ante shareholder approval is both flawed in its design and based on contestable assumptions on informed voting of institutional investors. In particular, the contemplated exemption for transactions with wholly owned subsidiaries allows controlling shareholders to circumvent the rule extensively. Moreover, vesting voting rights with (institutional) investors will not lead to the informed assessment that is hoped for, because these investors will rationally abstain from active monitoring and rely on proxy advisory firms instead whose competency to analyze non-routine significant related party transactions is questionable.
The paper further delineates that the proposed recognition of an overriding interest of the group requires strong counterbalances to adequately protect minority shareholders and creditors. Hence, if the Commission choses to go down this route it might end up with a comprehensive regulation that is akin to the unpopular Ninth Company Law Directive in spirit, though not in content. The latter prediction is corroborated by the pertinent parts of the proposal for a European Model Company Act.
Research results confirm the existence of various forms of international tax planning by multinational firms. Prominent examples for firms employing tax avoidance strategies are Amazon, Google and Starbucks. Increasing availability of administrative data for Europe has enabled researchers to study behavioural responses of European multinationals to taxation. The present paper summarizes what we can learn from these recent studies in general and about German multinationals in particular.
SAFE Professor Michalis Haliassos was a member of the National Council for Research and Technology (ESET) established by the Government of Greece for the period 2010-2013. The council, consisting of eleven scientists from a range of disciplines, has now published their communiqué "National Strategic Framework for Research and Innovation 2014 -2020".
To promote the advancement of research, technology and innovation in Greece, the strategic plan proposed by the authors seeks to identify areas of existing research strength and excellence that can be further advanced to become engines for progress and growth in Greece, as well as flaws inherent to the present system. The authors stress the need to address current constraints to growth, which include the declining education system; the confusion and weaknesses of R&D governance and management; the discontinuities and inefficiencies of resource allocation and investment; the lack of adaptation to clearly-defined national priorities; and the inadequate opportunities and funding for high-quality research and development to flourish. They stress the need for prioritisation and efficient allocation; stability of the policy frame; predictability of planning; provision of opportunity; recognition of excellence; and responsiveness to current and future needs.
9.01 This chapter outlines the development of Contingent Convertible Securities (CoCos) for financial institutions from their theoretical origins to their current form under the European Union’s Fourth Capital Requirements Directive framework and its Bank Recovery and Resolution Directive and examines the effect the framework and the directive have had on their design and ability to fulfill the ends for which they were initially conceived. It examines this from two viewpoints: the policy goals CoCos are meant to achieve and the corporate law issues raised by the requirements of CRD IV. On the policy side we conclude that CRD IV and the RRD have significantly limited the amount of CoCos a financial institution is likely to issue, but expanded their possible forms by including write-down as well as convertible structures and narrowed the differences between them and pure regulatory bail-in structures, thus calling into question whether they are truly ‘going concern’ rather than ‘gone concern’ capital. On the company law side we conclude that a number of issues, in particular the limits on an authorization of management to issue CoCos and shares, the scope of the shareholders’ right of pre-emption, the concept of dilution and the distinction between contributions in cash and in kind merit closer attention than they appear to have received in the current discussion on CoCos.
How special are they? - Targeting systemic risk by regulating shadow banking : (October 5, 2014)
(2014)
This essay argues that at least some of the financial stability concerns associated with shadow banking can be addressed by an approach to financial regulation that imports its functional foundations more vigorously into the interpretation and implementation of existing rules. It shows that the general policy goals of prudential banking regulation remain constant over time despite dramatic transformations in the financial and technological landscape. Moreover, these overarching policy goals also legitimize intervention in the shadow banking sector. On these grounds, this essay encourages a more normative construction of available rules that potentially limits both the scope for regulatory arbitrage and the need for ever more rapid updates and a constant increase in the complexity of the regulatory framework. By tying the regulatory treatment of financial innovation closely to existing prudential rules and their underlying policy rationales, the proposed approach potentially ends the socially wasteful race between hare and tortoise that signifies the relation between regulators and a highly dynamic industry. In doing so it does not generally hamper market participants’ efficient discoveries where disintermediation proves socially beneficial. Instead, it only weeds-out rent-seeking circumventions of existing rules and standards.
Chronic ethanol abuse is known to increase susceptibility to infections after injury, in part, by modification of macrophage function. Several intracellular signalling mechanisms are involved in the initiation of inflammatory responses, including the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the systemic and hepatic effect of chronic ethanol feeding on in vivo activation of NF-κB in NF-κB(EGFP) reporter gene mice. Specifically, the study focused on Kupffer cell proinflammatory cytokines IL-6 and TNF-α and activation of NF-κB after chronic ethanol feeding followed by in vitro stimulation with lipopolysaccharide (LPS). We found that chronic ethanol upregulated NF-κB activation and increased hepatic and systemic proinflammatory cytokine levels. Similarly, LPS-stimulated IL-1 β release from whole blood was significantly enhanced in ethanol-fed mice. However, LPS significantly increased IL-6 and TNF-α levels. These results demonstrate that chronic ethanol feeding can improve the responsiveness of macrophage LPS-stimulated IL-6 and TNF-α production and indicate that this effect may result from ethanol-induced alterations in intracellular signalling through NF-κB. Furthermore, LPS and TNF-α stimulated the gene expression of different inflammatory mediators, in part, in a NF-κB-dependent manner.
Advertising arbitrage
(2014)
Speculators often advertise arbitrage opportunities in order to persuade other investors and thus accelerate the correction of mispricing. We show that in order to minimize the risk and the cost of arbitrage an investor who identifies several mispriced assets optimally advertises only one of them, and overweights it in his portfolio; a risk-neutral arbitrageur invests only in this asset. The choice of the asset to be advertised depends not only on mispricing but also on its "advertisability" and accuracy of future news about it. When several arbitrageurs identify the same arbitrage opportunities, their decisions are strategic complements: they invest in the same asset and advertise it. Then, multiple equilibria may arise, some of which inefficient: arbitrageurs may correct small mispricings while failing to eliminate large ones. Finally, prices react more strongly to the ads of arbitrageurs with a successful track record, and reputation-building induces high-skill arbitrageurs to advertise more than others.
Has economic research been helpful in dealing with the financial crises of the early 2000s? On the whole, the answer is negative, although there are bright spots. Economists have largely failed to predict both crises, largely because most of them were not analytically equipped to understand them, in spite of their recurrence in the last 25 years. In the pre-crisis period, however, there have been important exceptions – theoretical and empirical strands of research that largely laid out the basis for our current thinking about financial crises. Since 2008, a flurry of new studies offered several different interpretations of the US crisis: to some extent, they point to potentially complementary factors, but disagree on their relative importance, and therefore on policy recommendations. Research on the euro debt crisis has so far been much more limited: even Europe-based researchers – including CEPR ones – have often directed their attention more to the US crisis than to that occurring on their doorstep. In terms of impact on policy and regulatory reform, the record is uneven. On the one hand, the swift and massive liquidity provision by central banks in the wake of both crises is, at least partly, to be credited to previous research on the role of central banks as lenders of last resort in crises and on the real effects of bank lending and monetary policy. On the other hand, economists have had limited impact on the reform of prudential and security market regulation. In part, this is due to their neglect of important regulatory choices, which policy-makers are therefore left to take without the guidance of academic research-based analysis.
Consumption-based asset pricing with rare disaster risk : a simulated method of moments approach
(2014)
The rare disaster hypothesis suggests that the extraordinarily high postwar U.S. equity premium resulted because investors ex ante demanded compensation for unlikely but calamitous risks that they happened not to incur. Although convincing in theory, empirical tests of the rare disaster explanation are scarce. We estimate a disaster-including consumption-based asset pricing model (CBM) using a combination of the simulated method of moments and bootstrapping. We consider several methodological alternatives that differ in the moment matches and the way to account for disasters in the simulated consumption growth and return series. Whichever specification is used, the estimated preference parameters are of an economically plausible size, and the estimation precision is much higher than in previous studies that use the canonical CBM. Our results thus provide empirical support for the rare disaster hypothesis, and help reconcile the nexus between real economy and financial markets implied by the consumption-based asset pricing paradigm.
The long-run consumption risk (LRR) model is a promising approach to resolve prominent asset pricing puzzles. The simulated method of moments (SMM) provides a natural framework to estimate its deep parameters, but caveats concern model solubility and weak identification. We propose a two-step estimation strategy that combines GMM and SMM, and for which we elicit informative macroeconomic and financial moment matches from the LRR model structure. In particular, we exploit the persistent serial correlation of consumption and dividend growth and the equilibrium conditions for market return and risk-free rate, as well as the model-implied predictability of the risk-free rate. We match analytical moments when possible and simulated moments when necessary and determine the crucial factors required for both identification and reasonable estimation precision. A simulation study – the first in the context of long-run risk modeling – delineates the pitfalls associated with SMM estimation of a non-linear dynamic asset pricing model. Our study provides a blueprint for successful estimation of the LRR model.
he predictive likelihood is of particular relevance in a Bayesian setting when the purpose is to rank models in a forecast comparison exercise. This paper discusses how the predictive likelihood can be estimated for any subset of the observable variables in linear Gaussian state-space models with Bayesian methods, and proposes to utilize a missing observations consistent Kalman filter in the process of achieving this objective. As an empirical application, we analyze euro area data and compare the density forecast performance of a DSGE model to DSGE-VARs and reduced-form linear Gaussian models.
We propose a new estimator for the spot covariance matrix of a multi-dimensional continuous semi-martingale log asset price process which is subject to noise and non-synchronous observations. The estimator is constructed based on a local average of block-wise parametric spectral covariance estimates. The latter originate from a local method of moments (LMM) which recently has been introduced by Bibinger et al. (2014). We extend the LMM estimator to allow for autocorrelated noise and propose a method to adaptively infer the autocorrelations from the data. We prove the consistency and asymptotic normality of the proposed spot covariance estimator. Based on extensive simulations we provide empirical guidance on the optimal implementation of the estimator and apply it to high-frequency data of a cross-section of NASDAQ blue chip stocks. Employing the estimator to estimate spot covariances, correlations and betas in normal but also extreme-event periods yields novel insights into intraday covariance and correlation dynamics. We show that intraday (co-)variations (i) follow underlying periodicity patterns, (ii) reveal substantial intraday variability associated with (co-)variation risk, (iii) are strongly serially correlated, and (iv) can increase strongly and nearly instantaneously if new information arrives.
This paper studies the use of performance pricing (PP) provisions in debt contracts and compares accounting-based with rating-based pricing designs. We find that rating-based provisions are used by volatile-growth borrowers and allow for stronger spread increases over the credit period. Accounting-based provisions are employed by opaque-growth borrowers and stipulate stronger spread reductions. Further, a higher spread-increase potential in rating-based contracts lowers the spread at the loan’s inception and improves the borrower’s performance later on. In contrast, a higher spread-decrease potential in accounting-based contracts lowers the initial spread and raises the borrower’s leverage afterwards. The evidence indicates that rating-based contracts are indeed employed for different reasons than accounting-based contracts: the former to signal a borrower’s quality, the latter to mitigate investment inefficiencies.
This paper examines the effect of imperfect labor market competition on the efficiency of compensation schemes in a setting with moral hazard, private information and risk-averse agents. Two vertically differentiated firrms compete for agents by offering contracts with fixed and variable payments. Vertical differentiation between firms leads to endogenous, type-dependent exit options for agents. In contrast to screening models with perfect competition, we find that existence of equilibria does not depend on whether the least-cost separating allocation is interim efficient. Rather, vertical differentiation allows the inferior firm to offer (cross-)subsidizing fixed payments even above the interim efficient level. We further show that the efficiency of variable pay depends on the degree of competition for agents: For small degrees of competition, low-ability agents are under-incentivized and exert too little effort. For large degrees of competition, high-ability agents are over-incentivized and bear too much risk. For intermediate degrees of competition, however, contracts are second-best despite private information.
We analyze the differential impact of domestic and foreign monetary policy on the local supply of bank credit in domestic and foreign currencies. We analyze a novel, supervisory dataset from Hungary that records all bank lending to firms including its currency denomination. Accounting for time-varying firm-specific heterogeneity in loan demand, we find that a lower domestic interest rate expands the supply of credit in the domestic but not in the foreign currency. A lower foreign interest rate on the other hand expands lending by lowly versus highly capitalized banks relatively more in the foreign than in the domestic currency.
In this paper we argue that very high marginal labor income tax rates are an effective tool for social insurance even when households have preferences with high labor supply elasticity, make dynamic savings decisions, and policies have general equilibrium effects. To make this point we construct a large scale Overlapping Generations Model with uninsurable labor productivity risk, show that it has a wealth distribution that matches the data well, and then use it to characterize fiscal policies that achieve a desired degree of redistribution in society. We find that marginal tax rates on the top 1% of the earnings distribution of close to 90% are optimal. We document that this result is robust to plausible variation in the labor supply elasticity and holds regardless of whether social welfare is measured at the steady state only or includes transitional generations.
What would be the economic effects of the UK leaving the European Union on living standards of British people? We focus on the effects of trade on welfare net of lower fiscal transfers to the EU. We use a standard quantitative static general equilibrium trade model with multiple sectors, countries and intermediates, as in Costinot and Rodriguez-Clare (2013). Static losses range between 1.13% and 3.09% of GDP, depending on the assumptions used in our counterfactual scenarios. Including dynamic effects could more than double such losses.
We use data from the 2009 Internet Survey of the Health and Retirement Study to examine the consumption impact of wealth shocks and unemployment during the Great Recession in the US. We find that many households experienced large capital losses in housing and in their financial portfolios, and that a non-trivial fraction of respondents have lost their job. As a consequence of these shocks, many households reduced substantially their expenditures. We estimate that the marginal propensities to consume with respect to housing and financial wealth are 1 and 3.3 percentage points, respectively. In addition, those who became unemployed reduced spending by 10 percent. We also distinguish the effect of perceived transitory and permanent wealth shocks, splitting the sample between households who think that the stock market is likely to recover in a year’s time, and those who do not. In line with the predictions of standard models of intertemporal choice, we find that the latter group adjusted much more than the former its spending in response to financial wealth shocks.
This chapter discusses whether and how 'new quantitative trade models' (NQTMs) can be fruitfully applied to quantify the welfare effects of trade liberalization, thus shedding light on the trade-related effects of further European integration. On the one hand, it argues that NQTMs have indeed the potential of being used to supplement traditional 'computable general equilibrium' (CGE) analysis thanks to their tight connection between theory and data, appealing micro-theoretical foundations, and enhanced attention to the estimation of structural parameters. On the other hand, further work is still needed in order to fully exploit such potential.
Especially in developing countries credit constraints are often perceived as one of the most important market frictions constraining firm innovation and growth. Huge amounts of public money are being devoted to the removal of such constraints but their effectiveness is still subject to an intense policy debate. This paper contributes to this debate by analysing the effects of the Brazilian Development Bank (BNDES) loans. It finds that, before receiving BNDES support, granted firms are indeed more credit constrained than comparable non-granted firms. It also finds that BNDES support allows granted firms to achieve the same level of performance as similar non-granted firms that are not credit constrained. However, it does not allow granted firms to outperform similar non-granted ones.
We develop a model of an order-driven exchange competing for order flow with off-exchange trading mechanisms. Liquidity suppliers face a trade-off between benefits and costs of order exposure. If they display trading intentions, they attract additional trade demand. We show, in equilibrium, hiding trade intentions can induce mis-coordination between liquidity supply and demand, generate excess price fluctuations and harm price efficiency. Econometric high-frequency analysis based on unique data on hidden orders from NASDAQ reveals strong empirical support for these predictions: We find abnormal reactions in prices and order flow after periods of high excess-supply of hidden liquidity.
We propose a framework for estimating network-driven time-varying systemic risk contributions that is applicable to a high-dimensional financial system. Tail risk dependencies and contributions are estimated based on a penalized two-stage fixed-effects quantile approach, which explicitly links bank interconnectedness to systemic risk contributions. The framework is applied to a system of 51 large European banks and 17 sovereigns through the period 2006 to 2013, utilizing both equity and CDS prices. We provide new evidence on how banking sector fragmentation and sovereign-bank linkages evolved over the European sovereign debt crisis and how it is reflected in network statistics and systemic risk measures. Illustrating the usefulness of the framework as a monitoring tool, we provide indication for the fragmentation of the European financial system having peaked and that recovery has started.
Examining event-related potential (ERP) correlates of decision bias in recognition memory judgments
(2014)
Memory judgments can be based on accurate memory information or on decision bias (the tendency to report that an event is part of episodic memory when one is in fact unsure). Event related potentials (ERP) correlates are important research tools for elucidating the dynamics underlying memory judgments but so far have been established only for investigations of accurate old/new discrimination. To identify the ERP correlates of bias, and observe how these interact with ERP correlates of memory, we conducted three experiments that manipulated decision bias within participants via instructions during recognition memory tests while their ERPs were recorded. In Experiment 1, the bias manipulation was performed between blocks of trials (automatized bias) and compared to trial-by-trial shifts of bias in accord with an external cue (flexibly controlled bias). In Experiment 2, the bias manipulation was performed at two different levels of accurate old/new discrimination as the memory strength of old (studied) items was varied. In Experiment 3, the bias manipulation was added to another, bottom-up driven manipulation of bias induced via familiarity. In the first two Experiments, and in the low familiarity condition of Experiment 3, we found evidence of an early frontocentral ERP component at 320 ms poststimulus (the FN320) that was sensitive to the manipulation of bias via instruction, with more negative amplitudes indexing more liberal bias. By contrast, later during the trial (500–700 ms poststimulus), bias effects interacted with old/new effects across all three experiments. Results suggest that the decision criterion is typically activated early during recognition memory trials, and is integrated with retrieved memory signals and task-specific processing demands later during the trial. More generally, the findings demonstrate how ERPs can help to specify the dynamics of recognition memory processes under top-down and bottom-up controlled retrieval conditions.
Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.
Methods: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6–12).
Results: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).
Conclusions: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.
Higher N170 amplitudes to words and to faces were recently reported for faster readers of German. Since the shallow German orthography allows phonological recoding of single letters, the reported speed advantages might have their origin in especially well-developed visual processing skills of faster readers. In contrast to German, adult readers of Hebrew are forced to process letter chunks up to whole words. This dependence on more complex visual processing might have created ceiling effects for this skill. Therefore, the current study examined whether also in the deep Hebrew orthography visual processing skills as reflected by N170 amplitudes explain reading speed differences. Forty university students, native speakers of Hebrew without reading impairments, accomplished a lexical decision task (i.e., deciding whether a visually presented stimulus represents a real or a pseudo word) and a face decision task (i.e., deciding whether a face was presented complete or with missing facial features) while their electroencephalogram was recorded from 64 scalp positions. In both tasks stronger event related potentials (ERPs) were observed for faster readers in time windows at about 200 ms. Unlike in previous studies, ERP waveforms in relevant time windows did not correspond to N170 scalp topographies. The results support the notion of visual processing ability as an orthography independent marker of reading proficiency, which advances our understanding about regular and impaired reading development.
MicroRNAs are key modulators at molecular level in different biological processes, including determination of cell fate and differentiation. Herein, microRNA expression profiling experiments were performed on syngeneic cardiac (CStC) and bone marrow (BMStC) mesenchymal stromal cells cultured in standard growth medium and then in vitro exposed to adipogenic, osteogenic, cardiomyogenic and endothelial differentiation media. Analysis identified a tissue-specific microRNA signature composed of 16 microRNAs that univocally discriminated cell type of origin and that were completely unaffected by in vitro differentiation media: 4 microRNAs were over-expressed in cardiac stromal cells, and 12 were overexpressed or present only in bone marrow stromal cells. Further, results revealed microRNA subsets specifically modulated by each differentiation medium, irrespective of the cell type of origin, and a subset of 7 microRNAs that were down-regulated by all media with respect to growth medium. Finally, we identified 16 microRNAs that were differentially modulated by the media when comparing the two tissues of origin. The existence of a tissue-specific microRNA signature surviving to any differentiation stimuli, strongly support the role if microRNAs determining cell identity related to tissue origin. Moreover, we identified microRNA subsets modulated by different culture conditions in a tissue-specific manner, pointing out their importance during differentiation processes.
Background: Rapidly increasing temperatures in the mountain region of Nepal and recent reports of dengue fever and lymphatic filariasis cases from mountainous areas of central Nepal prompted us to study the spatio-temporal distribution of the vectors of these two diseases along an altitudinal transect in central Nepal.
Methodology/Principal Findings: We conducted a longitudinal study in four distinct physiographical regions of central Nepal from September 2011 to February 2012. We used BG-Sentinel and CDC light traps to capture adult mosquitoes. We found the geographical distribution of the dengue virus vectors Aedes aegypti and Aedes albopictus along our study transect to extend up to 1,310 m altitude in the Middle Mountain region (Kathmandu). The distribution of the lymphatic filariasis vector Culex quinquefasciatus extended up to at least 2,100 m in the High Mountain region (Dhunche). Statistical analysis showed a significant effect of the physiographical region and month of collection on the abundance of A. aegypti and C. quinquefasciatus only. BG-Sentinel traps captured significantly higher numbers of A. aegypti than CDC light traps. The meteorological factors temperature, rainfall and relative humidity had significant effects on the mean number of A. aegypti per BG-Sentinel trap. Temperature and relative humidity were significant predictors of the number of C. quinquefasciatus per CDC light trap. Dengue fever and lymphatic filariasis cases had previously been reported from all vector positive areas except Dhunche which was free of known lymphatic filariasis cases.
Conclusions/Significance: We conclude that dengue virus vectors have already established stable populations up to the Middle Mountains of Nepal, supporting previous studies, and report for the first time the distribution of lymphatic filariasis vectors up to the High Mountain region of this country. The findings of our study should contribute to a better planning and scaling-up of mosquito-borne disease control programmes in the mountainous areas of Nepal.
Objectives: Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated.
Methods: Hind-limb ischemia was induced in 10–12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery.
Results: Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent.
Conclusions: Low energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium.
Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.
Plexins are widely expressed transmembrane proteins that mediate the cellular effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still poorly understood. Here we show that signalling via B-family plexins leading to the activation of the small GTPase RhoA requires activation of the IκB kinase (IKK)-complex. In contrast, plexin-B-dependent regulation of R-Ras activity is not affected by IKK activity. This regulation of plexin signalling depends on the kinase activity of the IKK-complex, but is independent of NF-κB activation. We confirm that the IKK-complex is active in tumour cells and osteoblasts, and we demonstrate that plexin-B-dependent tumour cell invasiveness and regulation of osteoblast differentiation require an active IKK-complex. This study identifies a novel, NF-κB-independent function of the IKK-complex and shows that IKK directs plexin-B signalling to the activation of RhoA.
Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.
Background: Low Emission Zones (LEZs) are areas where the most polluting vehicles are restricted from entering. The effectiveness of LEZs to lower ambient exposures is under debate. This study focused on LEZs that restricted cars of Euro 1 standard without appropriate retrofitting systems from entering and estimated LEZ effects on NO2, NO, and NOx ( = NO2+NO).
Methods: Continuous half-hour and diffuse sampler 4-week average NO2, NO, and NOx concentrations measured inside and outside LEZs in 17 German cities of 6 federal states (2005–2009) were analysed as matched quadruplets (two pairs of simultaneously measured index values inside LEZ and reference values outside LEZ, one pair measured before and one after introducing LEZs with time differences that equal multiples of 364 days) by multiple linear and log-linear fixed-effects regression modelling (covariables: e.g., wind velocity, amount of precipitation, height of inversion base, school holidays, truck-free periods). Additionally, the continuous half-hour data was collapsed into 4-week averages and pooled with the diffuse sampler data to perform joint analysis.
Results: More than 3,000,000 quadruplets of continuous measurements (half-hour averages) were identified at 38 index and 45 reference stations. Pooling with diffuse sampler data from 15 index and 10 reference stations lead to more than 4,000 quadruplets for joint analyses of 4-week averages. Mean LEZ effects on NO2, NO, and NOx concentrations (reductions) were estimated to be at most −2 µg/m3 (or −4%). The 4-week averages of NO2 concentrations at index stations after LEZ introduction were 55 µg/m3 (median and mean values) or 82 µg/m3 (95th percentile).
Conclusions: This is the first study investigating comprehensively the effectiveness of LEZs to reduce NO2, NO, and NOx concentrations controlling for most relevant potential confounders. Our analyses indicate that there is a statistically significant, but rather small reduction of NO2, NO, and NOx concentrations associated with LEZs.
The genetic treatment of neurodegenerative diseases still remains a challenging task since many approaches fail to deliver the therapeutic material in relevant concentrations into the brain. As viral vectors comprise the risk of immune and inflammatory responses, human serum albumin (HSA) nanoparticles were found to represent a safer and more convenient alternative. Their ability to cross the blood-brain barrier (BBB) and deliver drugs into the brain in order to enhance gene-based therapy has been previously demonstrated. The present study deals with the development of pGL3-PEI-coated HSA nanoparticles and subsequent in vitro testing in cerebellar granular and HeLa cells. The luciferase control vector pGL3 was chosen as reporter plasmid encoding for the firefly luciferase protein, linear polyethylenimine (22 kDa) as endosomolytic agent for enhancing the cells’ transfection. Studies on particle characteristics, their cellular uptake into aforementioned cell lines and on subcellular localisation, and transfection efficiency in the cerebellar cells proved the feasibility of nanoparticle-based gene delivery.
Introduction: Electrical impedance tomography (EIT) is an emerging clinical tool for monitoring ventilation distribution in mechanically ventilated patients, for which many image reconstruction algorithms have been suggested. We propose an experimental framework to assess such algorithms with respect to their ability to correctly represent well-defined physiological changes. We defined a set of clinically relevant ventilation conditions and induced them experimentally in 8 pigs by controlling three ventilator settings (tidal volume, positive end-expiratory pressure and the fraction of inspired oxygen). In this way, large and discrete shifts in global and regional lung air content were elicited.
Methods: We use the framework to compare twelve 2D EIT reconstruction algorithms, including backprojection (the original and still most frequently used algorithm), GREIT (a more recent consensus algorithm for lung imaging), truncated singular value decomposition (TSVD), several variants of the one-step Gauss-Newton approach and two iterative algorithms. We consider the effects of using a 3D finite element model, assuming non-uniform background conductivity, noise modeling, reconstructing for electrode movement, total variation (TV) reconstruction, robust error norms, smoothing priors, and using difference vs. normalized difference data.
Results and Conclusions: Our results indicate that, while variation in appearance of images reconstructed from the same data is not negligible, clinically relevant parameters do not vary considerably among the advanced algorithms. Among the analysed algorithms, several advanced algorithms perform well, while some others are significantly worse. Given its vintage and ad-hoc formulation backprojection works surprisingly well, supporting the validity of previous studies in lung EIT.
Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness.
Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ~506 ms with notched T waves). Parents were I° cousins – both heterozygous for the mutation and clinically unremarkable (QTc ~447 ms, father and ~396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q.
Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.
Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.
Intensive land use is a driving force for biodiversity decline in many ecosystems. In semi-natural grasslands, land-use activities such as mowing, grazing and fertilization affect the diversity of plants and arthropods, but the combined effects of different drivers and the chain of effects are largely unknown. In this study we used structural equation modelling to analyse how the arthropod communities in managed grasslands respond to land use and whether these responses are mediated through changes in resource diversity or resource quantity (biomass). Plants were considered resources for herbivores which themselves were considered resources for predators. Plant and arthropod (herbivores and predators) communities were sampled on 141 meadows, pastures and mown pastures within three regions in Germany in 2008 and 2009. Increasing land-use intensity generally increased plant biomass and decreased plant diversity, mainly through increasing fertilization. Herbivore diversity decreased together with plant diversity but showed no response to changes in plant biomass. Hence, land-use effects on herbivore diversity were mediated through resource diversity rather than quantity. Land-use effects on predator diversity were mediated by both herbivore diversity (resource diversity) and herbivore quantity (herbivore biomass), but indirect effects through resource quantity were stronger. Our findings highlight the importance of assessing both direct and indirect effects of land-use intensity and mode on different trophic levels. In addition to the overall effects, there were subtle differences between the different regions, pointing to the importance of regional land-use specificities. Our study underlines the commonly observed strong effect of grassland land use on biodiversity. It also highlights that mechanistic approaches help us to understand how different land-use modes affect biodiversity.
Species distributed across vast continental areas and across major biomes provide unique model systems for studies of biotic diversification, yet also constitute daunting financial, logistic and political challenges for data collection across such regions. The tree frog Dendropsophus minutus (Anura: Hylidae) is a nominal species, continentally distributed in South America, that may represent a complex of multiple species, each with a more limited distribution. To understand the spatial pattern of molecular diversity throughout the range of this species complex, we obtained DNA sequence data from two mitochondrial genes, cytochrome oxidase I (COI) and the 16S rhibosomal gene (16S) for 407 samples of D. minutus and closely related species distributed across eleven countries, effectively comprising the entire range of the group. We performed phylogenetic and spatially explicit phylogeographic analyses to assess the genetic structure of lineages and infer ancestral areas. We found 43 statistically supported, deep mitochondrial lineages, several of which may represent currently unrecognized distinct species. One major clade, containing 25 divergent lineages, includes samples from the type locality of D. minutus. We defined that clade as the D. minutus complex. The remaining lineages together with the D. minutus complex constitute the D. minutus species group. Historical analyses support an Amazonian origin for the D. minutus species group with a subsequent dispersal to eastern Brazil where the D. minutus complex originated. According to our dataset, a total of eight mtDNA lineages have ranges >100,000 km2. One of them occupies an area of almost one million km2 encompassing multiple biomes. Our results, at a spatial scale and resolution unprecedented for a Neotropical vertebrate, confirm that widespread amphibian species occur in lowland South America, yet at the same time a large proportion of cryptic diversity still remains to be discovered.
Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.
Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
The cyanogenic diglucoside amygdalin, derived from Rosaceae kernels, is employed by many patients as an alternative anti-cancer treatment. However, whether amygdalin indeed acts as an anti-tumor agent is not clear. Metastasis blocking properties of amygdalin on bladder cancer cell lines was, therefore, investigated. Amygdalin (10 mg/ml) was applied to UMUC-3, TCCSUP or RT112 bladder cancer cells for 24 h or for 2 weeks. Tumor cell adhesion to vascular endothelium or to immobilized collagen as well as tumor cell migration was examined. Effects of drug treatment on integrin α and β subtypes, on integrin-linked kinase (ILK) and total and activated focal adhesion kinase (FAK) were also determined. Integrin knock-down was carried out to evaluate integrin influence on migration and adhesion. A 24 h or 2 week amygdalin application distinctly reduced tumor cell adhesion and migration of UMUC-3 and RT112 cells. TCCSUP adhesion was also reduced, but migration was elevated under amygdalin. Integrin subtype expression was significantly and specifically altered by amygdalin depending on the cell line. ILK was moderately, and activated FAK strongly, lost in all tumor cell lines in the presence of amygdalin. Knock down of β1 integrin caused a significant decrease in both adhesion and migration of UMUC-3 cells, but a significant increase in TCCSUP adhesion. Knock down of β4 integrin caused a significant decrease in migration of RT112 cells. Since the different actions of amygdalin on the different cell lines was mirrored by β1 or β4 knock down, it is postulated that amygdalin influences adhesion and migratory properties of bladder cancer cells by modulating β1 or β4 integrin expression. The amygdalin induced increase in TCCSUP migratory behavior indicates that any anti-tumor benefits from amygdalin (seen with the other two cell lines) may depend upon the cancer cell type.
Myofacial Pain is the most common form of temporomandibular disorders (TMD), affecting principally women in reproductive age. The etiology of TMD is still controversial. Currently a multifactorial theory has received a great support among the scientific community. This theory draws attention to the interaction of psychological, neuromuscular and oral pathogenic factors. Objectives: to describe the possible etiological factors of the Myofacial Pain; and to evaluate the effectiveness of the current treatments for Myofacial Pain. Materials and methods: a narrative review of the etiological factors and epidemiological data of Myofacial Pain introduces this work. Thereafter the author presents five systematic reviews of RCTs which have been published during the last thirteen years (1999-2012) for the use of acupuncture, low level laser therapy, drugs, physiotherapeutical interventions, splint therapy, and psychosocial interventions in the treatment of Myofacial Pain. Moreover, the author reports a systematic review and meta-analysis of all the available literature of two modern approaches for the treatment of Myofacial Pain. A comparison between the “usual treatment” based on splint therapy and psychosocial interventions was conducted. Results: the author did not find sufficient evidence to support therapies based on one single intervention. However, the condition of the patients with myofacial pain could be treated more effectively with combined treatments. After comparing “usual treatment” with psychosocial interventions, the author observed a tendency of the latter to improve psychological outcomes, whereas the first one was slightly more effective to enhance clinical functional outcomes. In general, a high level of heterogeneity was observed among the included studies of the different systematic reviews. The quality of the studies is susceptible to be improved. Clinical implications: the author proposes core outcomes to be implemented within the research on myofacial pain in particular and temporomandibular disorders in general, in order to enable scientifical comparisons between different therapies.
Objective: Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients.
Methods: Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors.
Results: From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).
Conclusions: AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.
This study included 30 patients with diagnosed rheumatoid arthritis (RA) and 30 test subjects without RA (control group). The objective of the study was to examine both groups for the presence of temporomandibular disorders (TMD) and morphological changes of the temporomandibular joint (TMJ). All individuals were examined using a systematic detailed clinical TMD examination as well as magnetic resonance imaging (MRI). The clinical TMD examination yielded significant differences between the RA patients and the control group concerning crepitus of the TMJ, and palpation tenderness of the masticatory muscles as well as the unassisted mandibular opening. The evaluation of the MRI images for the RA group showed significantly more frequent deformations of the condyle, osteophyte formations and erosions in the condylar compacta, and degenerative changes in the spongiosa. Increased intra-articular accumulation of synovial liquid and signs of inflammatory changes of the spongiosa were only found in the RA group. Statistical analysis showed a significant correlation between crepitus and specific osteoarthrotic changes (MRI), respectively, and between crepitus and a complete anterior disk displacement without reduction (MRI). The duration of the RA disease correlated neither with the anamnestic and clinical dysfunction index by Helkimo nor with RA-specific MRI findings.
Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons
(2014)
Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca2+ channel activity, internal Ca2+, and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca2+ channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca2+ channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca2+ channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.
5-Lipoxygenase (5LO) is a key enzyme in biosynthesis of leukotrienes (LTs), lipid mediators of inflammation. To study the roles of the 5LO accessory proteins coactosin-like protein (CLP) and 5LO-activating protein (FLAP), we knocked down these proteins in human monocytic cells. Our results show that expression of CLP was required for full cellular 5LO activity when cells were activated with Ca2+ ionophore, as well as with a physiological stimulus (lipopolysaccharide followed by N-formylmethionyl-leucyl-phenylalanine). During LT biosynthesis in stimulated cells, 5LO typically translocates to the nuclear membrane. This redistribution, from cytosolic to perinuclear, was clearly compromised in both CLP- and FLAP-deficient cells. Our results suggest that the CLP–5LO interaction may be a target for reduced LT production.
Background: It is well accepted that medical faculty teaching staff require an understanding of educational theory and pedagogical methods for effective medical teaching. The purpose of this study was to evaluate the effectiveness of a 5-day teaching education program.
Methods: An open prospective interventional study using quantitative and qualitative instruments was performed, covering all four levels of the Kirkpatrick model: Evaluation of 1) "Reaction" on a professional and emotional level using standardized questionnaires; 2) "Learning" applying a multiple choice test; 3) "Behavior" by self-, peer-, and expert assessment of teaching sessions with semistructured interviews; and 4) "Results" from student evaluations.
Results: Our data indicate the success of the educational intervention at all observed levels. 1) Reaction: The participants showed a high acceptance of the instructional content. 2) Learning: There was a significant increase in knowledge (P<0.001) as deduced from a pre-post multiple-choice questionnaire, which was retained at 6 months (P<0.001). 3) Behavior: Peer-, self-, and expert-assessment indicated a transfer of learning into teaching performance. Semistructured interviews reflected a higher level of professionalism in medical teaching by the participants. 4) Results: Teaching performance ratings improved in students' evaluations.
Conclusions: Our results demonstrate the success of a 5-day education program in embedding knowledge and skills to improve performance of medical educators. This multimethodological approach, using both qualitative and quantitative measures, may serve as a model to evaluate effectiveness of comparable interventions in other settings.
Background: A discontinuous dose response relationship is a major characteristic of the anti-inflammatory effects of low-dose X-irradiation therapy. Although recent data indicate an involvement of a variety of molecular mechanisms in these characteristics, the impact of reactive oxygen species (ROS) production to give rise or contribute to these phenomena in endothelial cells (EC) remains elusive.
Material and methods: HUVEC derived immortalized EA.hy926 cells were stimulated by tumor necrosis factor-α (TNF-α, 20 ng/ml) 4 h before irradiation with doses ranging from 0.3 to 1 Gy. To analyse DNA repair capacity, phospho-histone H2AX foci were assayed at 1 h, 4 h and 24 h after irradiation. ROS production and superoxide dismutase (SOD) activity were analysed by fluorometric 2',7'-dichlorodihydrofluorescein-diacetate (H2DCFDA) and colorimetric assays. A functional impact of ROS on γH2AX production was analysed by treatment with the scavenger N-acetyl-L-cysteine (NAC).
Results: Irrespective of stimulation by TNF-α, EA.hy926 cells revealed a linear dose response characteristic of γH2AX foci detection at 1 h and 4 h after irradiation. By contrast, we observed a discontinuity in residual γH2AX foci detection at 24 h after irradiation with locally elevated values following a 0.5 Gy exposure that was abolished by inhibition of ROS by NAC. Moreover, SOD protein expression was significantly decreased at doses of 0.5 Gy and 0.7 Gy concomitant with a reduced SOD activity.
Conclusion: These data implicate a non-linear regulation of ROS production and SOD activity in EA.hy926 EC following irradiation with doses < 1 Gy that may contribute to a discontinuous dose-response relationship of residual γH2AX foci detection.
Our focus is the identification, characterisation and functional analysis of different MLL fusions. In general, MLL fusion proteins are encoded by large cDNA cassettes that are difficult to transduce into haematopoietic stem cells. This is due to the size limitations of the packaging process of those vector-encoded RNAs into retro- or lentiviral particles. Here, we present our efforts in establishing a universal vector system to analyse different MLL fusions. The universal cloning system was embedded into the backbone of the Sleeping Beauty transposable element. This transposon has no size limitation and displays no integration preference, thereby avoiding the integration into active genes or their promoter regions. We utilised this novel system to test different MLL fusion alleles (MLL-NEBL, NEBL-MLL, MLL-LASP1, LASP1-MLL, MLL-MAML2, MAML2-MLL, MLL-SMAP1 and SMAP1-MLL) in appropriate cell lines. Stable cell lines were analysed for their growth behaviour, focus formation and colony formation capacity and ectopic Hoxa gene transcription. Our results show that only 1/4 tested direct MLL fusions, but 3/4 tested reciprocal MLL fusions exhibit oncogenic functions. From these pilot experiments, we conclude that a systematic analysis of more MLL fusions will result in a more differentiated picture about the oncogenic capacity of distinct MLL fusions.
Futures markets are a potentially valuable source of information about market expectations. Exploiting this information has proved difficult in practice, because the presence of a time-varying risk premium often renders the futures price a poor measure of the market expectation of the price of the underlying asset. Even though the expectation in principle may be recovered by adjusting the futures price by the estimated risk premium, a common problem in applied work is that there are as many measures of market expectations as there are estimates of the risk premium. We propose a general solution to this problem that allows us to uniquely pin down the best possible estimate of the market expectation for any set of risk premium estimates. We illustrate this approach by solving the long-standing problem of how to recover the market expectation of the price of crude oil. We provide a new measure of oil price expectations that is considerably more accurate than the alternatives and more economically plausible. We discuss implications of our analysis for the estimation of economic models of energy-intensive durables, for the debate on speculation in oil markets, and for oil price forecasting.
While distribution conflicts over natural resources were central to the debates on a New International Economic Order, during the last decades the specific distribution conflicts surrounding natural resource exploitation no longer have been at the core of international law. In this paper I trace the developments in the relationship between international law and resource distribution conflicts. I first argue that the New International Economic Order favored the political resolution of distribution conflicts over natural resources and envisaged international distribution conflicts to be addressed by the political organs of international institutions within legal procedures Second, I show how the NIEO was surpassed by a different order that relied largely on the market as a distribution mechanism for raw materials and how international institutions and international law played a crucial role in the establishment of this order by promoting the privatization of natural resource exploitation and protecting foreign direct investment and trade. With reference to the copper industry in Zambia I thirdly illustrate how international investment law, and more broadly international economic law, is shaping (and affecting the resolution of) not only distribution conflicts between, but also within States. I conclude with a call for a renewed focus on an international law of resource conflicts to allow for their political resolution given the countermoves we can observe with respect to international investment law and the persistence of (violent) conflicts over natural resource exploitation within States.
Background: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
Methods: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Results: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
Conclusions: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
Background: While the use of plastic materials has generated huge societal benefits, the "plastic age" comes with downsides: One issue of emerging concern is the accumulation of plastics in the aquatic environment. Here, so-called microplastics (MP), fragments smaller than 5 mm, are of special concern because they can be ingested throughout the food web more readily than larger particles. Focusing on freshwater MP, we briefly review the state of the science to identify gaps of knowledge and deduce research needs.
State of the science: Environmental scientists started investigating marine (micro)plastics in the early 2000s. Today, a wealth of studies demonstrates that MP have ubiquitously permeated the marine ecosystem, including the polar regions and the deep sea. MP ingestion has been documented for an increasing number of marine species. However, to date, only few studies investigate their biological effects. The majority of marine plastics are considered to originate from land-based sources, including surface waters. Although they may be important transport pathways of MP, data from freshwater ecosystems is scarce. So far, only few studies provide evidence for the presence of MP in rivers and lakes. Data on MP uptake by freshwater invertebrates and fish is very limited.
Knowledge gaps: While the research on marine MP is more advanced, there are immense gaps of knowledge regarding freshwater MP. Data on their abundance is fragmentary for large and absent for small surface waters. Likewise, relevant sources and the environmental fate remain to be investigated. Data on the biological effects of MP in freshwater species is completely lacking. The accumulation of other freshwater contaminants on MP is of special interest because ingestion might increase the chemical exposure. Again, data is unavailable on this important issue.
Conclusions: MP represent freshwater contaminants of emerging concern. However, to assess the environmental risk associated with MP, comprehensive data on their abundance, fate, sources, and biological effects in freshwater ecosystems are needed. Establishing such data critically depends on a collaborative effort by environmental scientists from diverse disciplines (chemistry, hydrology, ecotoxicology, etc.) and, unsurprisingly, on the allocation of sufficient public funding.
Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall.
Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8–9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2, and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
Currently, little is known about how synesthesia develops and which aspects of synesthesia can be acquired through a learning process. We review the increasing evidence for the role of semantic representations in the induction of synesthesia, and argue for the thesis that synesthetic abilities are developed and modified by semantic mechanisms. That is, in certain people semantic mechanisms associate concepts with perception-like experiences—and this association occurs in an extraordinary way. This phenomenon can be referred to as “higher” synesthesia or ideasthesia. The present analysis suggests that synesthesia develops during childhood and is being enriched further throughout the synesthetes’ lifetime; for example, the already existing concurrents may be adopted by novel inducers or new concurrents may be formed. For a deeper understanding of the origin and nature of synesthesia we propose to focus future research on two aspects: (i) the similarities between synesthesia and ordinary phenomenal experiences based on concepts; and (ii) the tight entanglement of perception, cognition and the conceptualization of the world. Importantly, an explanation of how biological systems get to generate experiences, synesthetic or not, may have to involve an explanation of how semantic networks are formed in general and what their role is in the ability to be aware of the surrounding world.
In this paper, we investigate how the introduction of complex, model-based capital regulation affected credit risk of financial institutions. Model-based regulation was meant to enhance the stability of the financial sector by making capital charges more sensitive to risk. Exploiting the staggered introduction of the model-based approach in Germany and the richness of our loan-level data set, we show that (1) internal risk estimates employed for regulatory purposes systematically underpredict actual default rates by 0.5 to 1 percentage points; (2) both default rates and loss rates are higher for loans that were originated under the model-based approach, while corresponding risk-weights are significantly lower; and (3) interest rates are higher for loans originated under the model-based approach, suggesting that banks were aware of the higher risk associated with these loans and priced them accordingly. Further, we document that large banks benefited from the reform as they experienced a reduction in capital charges and consequently expanded their lending at the expense of smaller banks that did not introduce the model-based approach. Counter to the stated objectives, the introduction of complex regulation adversely affected the credit risk of financial institutions. Overall, our results highlight the pitfalls of complex regulation and suggest that simpler rules may increase the efficacy of financial regulation.
The recent decline in euro area inflation has triggered new calls for additional monetary stimulus by the ECB in order to counter the threat of a self‐reinforcing deflation and recession spiral. This note reviews the available evidence on inflation expectations, output gaps and other factors driving current inflation through the lens of the Phillips curve. It also draws a comparison to the Japanese experience with deflation in the late 1990s and the evidence from Japan concerning the outputinflation nexus at low trend inflation. The note concludes from this evidence that the risk of a selfreinforcing deflation remains very small. Thus, the ECB best await the impact of the long‐term refinancing operations decided in June that have the potential to induce substantial monetary accommodation once implemented for the first time in September.
This essay reviews a cornerstone of the European Banking Union project, the resolution of systemically important banks. The focus is on the inherent conflict between a possible intervention by resolution authorities, conditional on a crisis situation, and effective prevention prior to a crisis. Moreover, the paper discusses the rules for bail-in debt and conversion rules for different layers of debt. Finally, some organizational requirements to achieve effective resolution results will be analyzed.
Channelrhodopsin-1 from Chlamydomonas augustae (CaChR1) is a light-activated cation channel, which is a promising optogenetic tool. We show by resonance Raman spectroscopy and retinal extraction followed by high pressure liquid chromatography (HPLC) that the isomeric ratio of all-trans to 13-cis of solubilized channelrhodopsin-1 is with 70:30 identical to channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2). Critical frequency shifts in the retinal vibrations are identified in the Raman spectrum upon transition to the open (conductive P2(380)) state. Fourier transform infrared spectroscopy (FTIR) spectra indicate different structures of the open states in the two channelrhodopsins as reflected by the amide I bands and the protonation pattern of acidic amino acids.
The subatomic world is governed by the strong interactions of quarks and gluons, described by Quantum Chromodynamics (QCD). Quarks experience confinement into colour-less objects, i.e. they can not be observed as free particles. Under extreme conditions such as high temperature or high density, this constraint softens and a transition to a phase where quarks and gluons are quasi-free particles (Quark-Gluon-Plasma) can occur. This environment resembles the conditions prevailing during the early stages of the universe shortly after the Big Bang.
The phase diagram of QCD is under investigation in current and future collider experiments, for example at the Large Hadron Collider (LHC) or at the Facility for Antiproton and Ion Research (FAIR). Due to the strength of the strong interactions in the energy regime of interest, analytic methods can not be applied rigorously. The only tool to study QCD from first principles is given by simulations of its discretised version, Lattice QCD (LQCD).
These simulations are in the high-performance computing area, hence, the numerical aspects of LQCD are a vital part in this field of research. In recent years, Graphic Processing Units (GPUs) have been incorporated in these simulations as they are a standard tool for general purpose calculations today.
In the course of this thesis, the LQCD application cl2qcd has been developed, which allows for simulations on GPUs as well as on traditional CPUs, as it is based on OpenCL. cl2qcd constitutes the first application for Wilson type fermions in OpenCL.
It provides excellent performance and has been applied in physics studies presented in this thesis. The investigation of the QCD phase diagram is hampered by the notorious sign-problem, which restricts current simulation algorithms to small values of the chemical potential.
Theoretically, studying unphysical parameter ranges allows for constraints on the phase diagram. Of utmost importance is the clarification of the order of the finite temperature transition in the Nf=2 chiral limit at zero chemical potential. It is not known if it is of first or second order. To this end, simulations utilising Twisted Mass Wilson fermions aiming at the chiral limit are presented in this thesis.
Another possibility is the investigation of QCD at purely imaginary chemical potential. In this region, QCD is known to posses a rich phase structure, which can be used to constrain the phase diagram of QCD at real chemical potential and to clarify the nature of the Nf=2 chiral limit. This phase structure is studied within this thesis, in particular the nature of the Roberge-Weiss endpoint is mapped out using Wilson fermions.