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Bei ca. 95% der chronisch myeloischen Leukämie (CML) und 20-30% der akuten lymphatischen Leukämie (ALL) des Erwachsenen liegt eine reziproke Chromosomentranslokation t(9;22)(q34;q11) vor, in deren Rahmen das BCR (Breakpoint Cluster Region) Gen auf Chromosom 22 mit dem ABL (Abelson-Leukämie-Virus) Gen auf Chromosom 9 fusioniert. Auf Chromosom 22 gibt es zwei verschiedene Bruchpunkte, die somit zur Bildung von unterschiedlichen Fusionsgenen führen. Bei der CML findet man den sogenannten „großen“ Bruchpunkt (M-bcr), während bei der Ph+ ALL der sogenannte „kleine“ Bruchpunkt (m-bcr) vorkommt. Das hybride Fusionsgen auf Chromosom 22q+ (Philadelphia-Chromosom) kodiert für das jeweilige BCR/ABL Protein, während das Fusionsgen auf Chromosom 9q+ für das reziproke ABL/BCR Protein kodiert. Das ABL-Protein ist eine Nicht-Rezeptor Tyrosinkinase, die eine wichtige Rolle in der Signaltransduktion und der Regulation des Zellwachstums spielt. Im BCR/ABL Fusionsprotein wird die Kinase-Aktivität von ABL, die im Normalfall streng reguliert ist, durch die Fusion mit BCR konstitutiv aktiv. Dadurch kommt es zur Deregulierung intrazellulärer Signalwege, welche die maligne Transformation hämatopoetischer Zellen verursacht. Eine zielgerichtete Inhibierung von BCR/ABL mittels ABL-Kinase-Inhibitoren induziert Apoptose in BCR/ABL transformierten Zellen, was eine komplette Remission im größten Teil Ph+ Leukämie Patienten zur Folge hat.
Na+/H+ antiporters are integral membrane proteins that are present in almost every cell and in every kingdom of life. They are essential for the regulation of intracellular pH-value, Na+-concentration and cell volume. These secondary active transporters exchange sodium ions against protons via an alternating access mechanism, which is not understood in full detail. Na+/H+ antiporters show distinct species-specific transport characteristics and regulatory properties that correlate with respective physiological functions. Here we present the characterization of the Na+/H+ antiporter NhaA from Salmonella enterica serovar Thyphimurium LT2, the causing agent of food-born human gastroenteritis and typhoid like infections. The recombinant antiporter was functional in vivo and in vitro. Expression of its gene complemented the Na+-sensitive phenotype of an E. coli strain that lacks the main Na+/H+ antiporters. Purified to homogeneity, the antiporter was a dimer in solution as accurately determined by size-exclusion chromatography combined with multi-angle laser-light scattering and refractive index monitoring. The purified antiporter was fully capable of electrogenic Na+(Li+)/H+-antiport when reconstituted in proteoliposomes and assayed by solid-supported membrane-based electrophysiological measurements. Transport activity was inhibited by 2-aminoperimidine. The recorded negative currents were in agreement with a 1Na+(Li+)/2H+ stoichiometry. Transport activity was low at pH 7 and up-regulation above this pH value was accompanied by a nearly 10-fold decrease of KmNa (16 mM at pH 8.5) supporting a competitive substrate binding mechanism. K+ does not affect Na+ affinity or transport of substrate cations, indicating that selectivity of the antiport arises from the substrate binding step. In contrast to homologous E. coli NhaA, transport activity remains high at pH values above 8.5. The antiporter from S. Typhimurium is a promising candidate for combined structural and functional studies to contribute to the elucidation of the mechanism of pH-dependent Na+/H+ antiporters and to provide insights in the molecular basis of species-specific growth and survival strategies.
Colors and odors are associated; for instance, people typically match the smell of strawberries to the color pink or red. These associations are forms of crossmodal correspondences. Recently, there has been discussion about the extent to which these correspondences arise for structural reasons (i.e., an inherent mapping between color and odor), statistical reasons (i.e., covariance in experience), and/or semantically-mediated reasons (i.e., stemming from language). The present study probed this question by testing color-odor correspondences in 6 different cultural groups (Dutch, Netherlands-residing-Chinese, German, Malay, Malaysian-Chinese, and US residents), using the same set of 14 odors and asking participants to make congruent and incongruent color choices for each odor. We found consistent patterns in color choices for each odor within each culture, showing that participants were making non-random color-odor matches. We used representational dissimilarity analysis to probe for variations in the patterns of color-odor associations across cultures; we found that US and German participants had the most similar patterns of associations, followed by German and Malay participants. The largest group differences were between Malay and Netherlands-resident Chinese participants and between Dutch and Malaysian-Chinese participants. We conclude that culture plays a role in color-odor crossmodal associations, which likely arise, at least in part, through experience.
ND3, ND1 and 39kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I
(2014)
An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I+III2+IV (S1) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.
Memory Concerns, Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment
(2014)
Background: Concerns about worsening memory (“memory concerns”; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI).
Methods: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models.
Results: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33–4.89), lower memory performance (HR = 0.63, 95%CI: 0.56–0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18–3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment.
Conclusions: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.
Background: Dengue fever (DF) is the most rapidly spreading mosquito-borne viral disease in the world. In this decade it has expanded to new countries and from urban to rural areas. Nepal was regarded DF free until 2004. Since then dengue virus (DENV) has rapidly expanded its range even in mountain regions of Nepal, and major outbreaks occurred in 2006 and 2010. However, no data on the local knowledge, attitude and practice (KAP) of DF in Nepal exist although such information is required for prevention and control measures.
Methods: We conducted a community based cross-sectional survey in five districts of central Nepal between September 2011 and February 2012. We collected information on the socio-demographic characteristics of the participants and their knowledge, attitude and practice regarding DF using a structured questionnaire. We then statistically compared highland and lowland communities to identify possible causes of observed differences.
Principal findings: Out of 589 individuals interviewed, 77% had heard of DF. Only 12% of the sample had good knowledge of DF. Those living in the lowlands were five times more likely to possess good knowledge than highlanders (P<0.001). Despite low knowledge levels, 83% of the people had good attitude and 37% reported good practice. We found a significantly positive correlation among knowledge, attitude and practice (P<0.001). Among the socio-demographic variables, the education level of the participants was an independent predictor of practice level (P<0.05), and education level and interaction between the sex and age group of the participants were independent predictors of attitude level (P<0.05).
Conclusion: Despite the rapid expansion of DENV in Nepal, the knowledge of people about DF was very low. Therefore, massive awareness programmes are urgently required to protect the health of people from DF and to limit its further spread in this country.
The pharmacokinetic properties and tolerability of a triamcinolone acetonide poloxamer 407 hydrogel for intratympanic application were investigated in a guinea pig model. Evaluation of in vivo release kinetics showed very high initial perilymph drug levels, with clinically relevant levels present for a minimum of 10 days. Assessment of auditory brainstem response thresholds showed a minimal, delayed and transient threshold shift, which was apparent on day 3 and resolved by day 10. No relevant histological changes of the middle and inner ear structures were noted, and hair cell counts showed no significant differences between treated and untreated ears. Thus, the triamcinolone-acetonide-loaded poloxamer 407 hydrogel is an effective vehicle for sustained high-dose inner ear glucocorticoid delivery.
In this study prepared for the ECON Committee of the European Parliament, Gellings, Jungbluth and Langenbucher present a graphic overview on core legislation in the area of economic and financial services in Europe. The mapping overview can serve as background for further deliberations. The study covers legislation in force, proposals and other relevant provisions in fourteen policy areas, i.e. banking, securities markets and investment firms, market infrastructure, insurance and occupational pensions, payment services, consumer protection in financial services, the European System of Financial Supervision, European Monetary Union, Euro bills and Coins and statistics, competition, taxation, commerce and company law, accounting and auditing.
This paper contributes to the ongoing debate on the relationship between austerity measures and economic growth. We propose a general equilibrium model where (i) agents have recursive preferences; (ii) economic growth is endogenously driven by investments in R&D; (iii) the government is committed to a zero-deficit policy and finances public expenditures by means of a combination of labor taxes and R&D taxes. We find that austerity measures that rely on reducing resources available to the R&D sector depress economic growth both in the short- and long-run. High debt EU members are currently implementing austerity measures based on higher taxes and/or lower investments in the R&D sector. This casts some doubts on the real ability of these countries to grow over the next years.
The implications of delegating fiscal decision making power to sub-national governments has become an area of significant interest over the past two decades, in the expectation that these reforms will lead to better and more efficient provision of public goods and services. The move towards decentralization has, however, not been homogeneously implemented on the revenue and expenditure side: decentralization has materialized more substantially on the latter than on the former, creating "vertical fiscal imbalances". These imbalances measure the extent to which sub-national governments’ expenditures are financed through their own revenues. This mismatch between own revenues and expenditures may have negative consequences for public finances performance, for example by softening the budget constraint of sub-national governments. Using a large sample of countries covering a long time period from the IMF’s Government Finance Statistics Yearbook, this paper is the first to examine the effects of vertical fiscal imbalances on fiscal performance through the accumulation of government debt. Our findings suggest that vertical fiscal imbalances are indeed relevant in explaining government debt accumulation, and call for a degree of caution when promoting fiscal decentralization.
We develop a model of managerial compensation structure and asset risk choice. The model provides predictions about how inside debt features affect the relation between credit spreads and compensation components. First, inside debt reduces credit spreads only if it is unsecured. Second, inside debt exerts important indirect effects on the role of equity incentives: When inside debt is large and unsecured, equity incentives increase credit spreads; When inside debt is small or secured, this effect is weakened or reversed. We test our model on a sample of U.S. public firms with traded CDS contracts, finding evidence supportive of our predictions. To alleviate endogeneity concerns, we also show that our results are robust to using an instrumental variable approach.
We develop a model of managerial compensation structure and asset risk choice. The model provides predictions about how inside debt features affect the relation between credit spreads and compensation components. First, inside debt reduces credit spreads only if it is unsecured. Second, inside debt exerts important indirect effects on the role of equity incentives: When inside debt is large and unsecured, equity incentives increase credit spreads; When inside debt is small or secured, this effect is weakened or reversed. We test our model on a sample of U.S. public firms with traded CDS contracts, finding evidence supportive of our predictions. To alleviate endogeneity concerns, we also show that our results are robust to using an instrumental variable approach.
The Eurozone fiscal crisis has created pressure for institutional harmonization, but skeptics argue that cultural predispositions can prevent convergence in behavior. Our paper derives a robust cultural classification of European countries and utilizes unique data on natives and immigrants to Sweden. Classification based on genetic distance or on Hofstede’s cultural dimensions fails to identify a single ‘southern’ culture but points to a ‘northern’ culture. Significant differences in financial behavior are found across cultural groups, controlling for household characteristics. Financial behavior tends to converge with longer exposure to common institutions, but is slowed down by longer exposure to original institutions.
This is a chapter for a forthcoming volume Oxford Handbook of Financial Regulation (Oxford University Press 2014) (eds. Eilís Ferran, Niamh Moloney, and Jennifer Payne). It provides an overview of EU financial regulation from the first banking directive up until its most recent developments in the aftermath of the financial crisis, focusing on the multiple layers of multi-level governance and their characteristic conceptual difficulties. Therefore the paper discusses the need to accommodate cross-border capital flows following from the EU internal market and the resulting regulatory strategies. This includes a brief overview of the principle of home country control and the ensuing Financial Services Action Plan. Dealing with the accommodation of cross-border capital flows and their regulation necessarily require an orchestration of the underlying supervisory structures, which is therefore also discussed. In the aftermath of the financial crisis of 2007-09 an additional aspect of necessary orchestration has emerged, that is the need to control systemic risk. Specific attention is paid to microprudential supervision by the newly established European Supervisory Authorities and macroprudential supervision in the European Banking Union, the latter’s underlying drivers and the accompanying Single Supervisory Mechanism, including the SSM’s institutional framework as well as the consideration of its rationales and the Single Resolution Mechanism closely linked to it.
Mathematical modeling of Arabidopsis thaliana with focus on network decomposition and reduction
(2014)
Systems biology has become an important research field during the last decade. It focusses on the understanding of the systems which emit the measured data. An important part of this research field is the network analysis, investigating biological networks. An essential point of the inspection of these network models is their validation, i.e., the successful comparison of predicted properties to measured data. Here especially Petri nets have shown their usefulness as modeling technique, coming with sound analysis methods and an intuitive representation of biological network data.
A very important tool for network validation is the analysis of the Transition-invariants (TI), which represent possible steady-state pathways, and the investigation of the liveness property. The computational complexity of the determination of both, TI and liveness property, often hamper their investigation.
To investigate this issue, a metabolic network model is created. It describes the core metabolism of Arabidopsis thaliana, and it is solely based on data from the literature. The model is too complex to determine the TI and the liveness property.
Several strategies are followed to enable an analysis and validation of the network. A network decomposition is utilized in two different ways: manually, motivated by idea to preserve the integrity of biological pathways, and automatically, motivated by the idea to minimize the number of crossing edges. As a decomposition may not be preserving important properties like the coveredness, a network reduction approach is suggested, which is mathematically proven to conserve these important properties. To deal with the large amount of data coming from the TI analysis, new organizational structures are proposed. The liveness property is investigated by reducing the complexity of the calculation method and adapting it to biological networks.
The results obtained by these approaches suggest a valid network model. In conclusion, the proposed approaches and strategies can be used in combination to allow the validation and analysis of highly complex biological networks.
Cancer is a disease characterized by uncontrolled cell growth and the capacity to disseminate to distant organs. The properties of cancers are caused by genetic and epigenetic alterations when compared to their normal counterparts. Genetic mutations occur in oncogenes and tumor suppressor genes and are the initial drivers of cellular transformation (Lengauer et al., 1998; Vogelstein and Kinzler, 2004). In addition, epigenetic alterations, which influence the expression of oncogenes and tumor suppressor genes independently from sequence alterations, are also involved in the transformation process (Esteller and Herman, 2001; Sharma et al., 2010). Genetic alterations and epigenetic regulatory signals cooperate in tumor etiology. Glioblastoma multiforme (GBM) is a frequent and aggressive malignant brain tumor in humans. The median survival of GBM patients is about 15 months after diagnosis. Like in other cancers, genetic and epigenetic alterations can be detected in GBM. Genetic alterations in GBM affect cell growth, apoptosis, angiogenesis, and invasion; however, epigenetic alterations in GBM also affect the expression of oncogenes or tumor suppresser genes that increase tumor malignancy (Nagarajan and Costello, 2009).
Reprogramming is a cellular process in which somatic cells can be induced to assume the properties of less differentiated stem cells. This process can be mediated through epigenetic modifications of the genome of somatic cells by the action of four defined transcription factors (Oct4, Sox2, Klf4 and Myc) or by the action of the miR 302/367 cluster (Anokye-Danso et al., 2011; Takahashi and Yamanaka, 2006; Takahashi et al., 2007) and result in the generation of induced pluripotent stem cells (iPS cells). Reprogramming of somatic cells by the miR 302/367 cluster can generate nontumorigenic iPS cells through the inhibition of the epithelial to mesenchymal transition (EMT), cell cycle regulatory genes and epigenetic modifiers (Lin and Ying, 2013).
A grammar of Pite Saami
(2014)
Pite Saami is a highly endangered Western Saami language in the Uralic language family currently spoken by a few individuals in Swedish Lapland. This grammar is the first extensive book-length treatment of a Saami language written in English. While focussing on the morphophonology of the main word classes nouns, adjectives and verbs, it also deals with other linguistic structures such as prosody, phonology, phrase types and clauses. Furthermore, it provides an introduction to the language and its speakers, and an outline of a preliminary Pite Saami orthography. An extensive annotated spoken-language corpus collected over the course of five years forms the empirical foundation for this description, and each example includes a specific reference to the corpus in order to facilitate verification of claims made on the data. Descriptions are presented for a general linguistics audience and without attempting to support a specific theoretical approach, but this book should be equally useful for scholars of Uralic linguistics, typologists, and even learners of Pite Saami.
We consider a class of nonautonomous nonlinear competitive parabolic systems on bounded radial domains under Neumann or Dirichlet boundary conditions. We show that, if the initial profiles satisfy a reflection inequality with respect to a hyperplane, then bounded positive solutions are asymptotically (in time) foliated Schwarz symmetric with respect to antipodal points. Additionally, a related result for (positive and sign changing solutions) of scalar equations with Neumann or Dirichlet boundary conditions is given. The asymptotic shape of solutions to cooperative systems is also discussed.
What happened in Cyprus? The economic consequences of the last communist government in Europe
(2014)
This paper reviews developments in the Cypriot economy following the introduction of the euro on 1 January 2008 and leading to the economic collapse of the island five years later. The main cause of the collapse is identified with the election of a communist government in February 2008, within two months of the introduction of the euro, and its subsequent choices for action and inaction on economic policy matters. The government allowed a rapid deterioration of public finances, and despite repeated warnings, damaged the country's creditworthiness and lost market access in May 2011. The destruction of the island's largest power station in July 2011 subsequently threw the economy into recession. Together with the intensification of the euro area crisis in the summer and fall of 2011, these events weakened the banking system which was vulnerable due to its exposure in Greece. Rather than deal with its fiscal crisis, the government secured a loan from the Russian government that allowed it to postpone action until after the February 2013 election. Rather than protect the banking system, losses were imposed on banks and a campaign against them was coordinated and used as a platform by the communist party for the February 2013 election. The strategy succeeded in delaying resolution of the crisis and avoiding short-term political cost for the communist party before the election, but also in precipitating a catastrophe right after the election.
So-called medicanes (Mediterranean hurricanes) are meso-scale, marine, and warm-core Mediterranean cyclones that exhibit some similarities to tropical cyclones. The strong cyclonic winds associated with medicanes threaten the highly populated coastal areas around the Mediterranean basin. To reduce the risk of casualties and overall negative impacts, it is important to improve the understanding of medicanes with the use of numerical models. In this study, we employ an atmospheric limited-area model (COSMO-CLM) coupled with a one-dimensional ocean model (1-D NEMO-MED12) to simulate medicanes. The aim of this study is to assess the robustness of the coupled model in simulating these extreme events. For this purpose, 11 historical medicane events are simulated using the atmosphere-only model, COSMO-CLM, and coupled model, with different setups (horizontal atmospheric grid-spacings of 0.44°, 0.22°, and 0.08°; with/without spectral nudging, and an ocean grid-spacing of 1/12°). The results show that at high-resolution, the coupled model is able to not only simulate most of medicane events but also improve the track length, core temperature, and wind speed of simulated medicanes compared to the atmosphere-only simulations. The results suggest that the coupled model is more proficient for systemic and detailed studies of historical medicane events, and that this model can be an effective tool for future projections.
Background: The aim of this study was to compare outcome of patients with previous cardiac surgery undergoing transapical aortic valve implantation (Redo-TAVI) to those undergoing classic aortic valve replacement (Redo-AVR) by using propensity analysis.
Methods: From January 2005 through May 2012, 52 high-risk patients underwent Redo-TAVI using a pericardial xenograft fixed within a stainless steel, balloon-expandable stent (Edwards SAPIEN™). During the same period of time 167 patients underwent classic Redo-AVR. Logistic regression analysis was used to identify covariates among 11 baseline patient variables including the type of initial surgery. Using the significant regression coefficients, each patient’s propensity score was calculated, allowing selectively matched subgroups of 40 patients each. Initial surgery included coronary artery bypass grafting in 30 patients, aortic valve replacement in 7 patients and mitral valve reconstruction in 3 patients in each group. Follow-up was 4 ± 2 years and was 100% complete.
Results: Postoperative chest tube drainage (163 ± 214 vs. 562 ± 332 ml/24 h, p = 0.02) and incidence of early permanent neurologic deficit (0 vs. 13%, p = 0.04) was lower in patients with Redo-TAVI and there was a trend towards improved 30-day survival (p = 0.06). Also we detected a decreased ventilation time (p = 0.04) and lower transfusion rate of allogenic blood products (p ≤ 0.05) in the Redo-TAVI group. At late follow up differences regarding incidence of major adverse events, including death and permanent neurologic deficits (25% vs. 43%, p = 0.01) statistically supported early postoperative findings.
Conclusion: The encouraging results regarding early and long-term outcomes following TAVI in patients with previous cardiac surgery show, that this evolving approach may be particularly beneficial in this patient cohort.
The role of RNA interference in the developmental separation of blood and lymphatic vasculature
(2014)
Background: Dicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development.
Methods: In order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells.
Results: We show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature.
Conclusion: Thus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature.
The recent approval by the US Food and Drug Administration of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA), often associated with vitreomacular traction (VMT) and macular hole (MH), has brought new attention to the field of pharmacologic vitreolysis. The need for an enzyme to split the vitreomacular interface, which is formed by a strong adhesive interaction between the posterior vitreous cortex and the internal limiting membrane, historically stems from pediatric eye surgery. This review summarizes the different anatomic classifications of posterior vitreous detachment or anomalous posterior vitreous detachment and puts these in the context of clinical pathologies commonly observed in clinical practice of the vitreoretinal specialist, such as MH, VMT, age-related macular degeneration, and diabetic macular edema. We revisit the outcome of the Phase II studies that indicated ocriplasmin was a safe and effective treatment for selected cases of symptomatic VMA and MH. Release of VMA at day 28 was achieved by 26.5% of patients in the ocriplasmin group versus 10.1% in the placebo group (P<0.001). Interestingly, for MHs, the numbers were more remarkable. Predictive factors for successful ocriplasmin treatment were identified for VMT (VMA diameter smaller than 1,500 µm) and MH (smaller than 250 µm). In comparison with the highly predictable outcome after vitrectomy, the general success rate of ocriplasmin not under clinical trial conditions has not fully met expectations and needs to be proven in real-world clinical settings. The ocriplasmin data will be compared in the future with observational data on spontaneous VMA release, will help retina specialists make more accurate predictions, and will improve outcome rates.
On January 29, 2014, EU Commissioner Barnier published a draft law proposing a ban for proprietary trading by big banks in Europe. In this opinion piece, published in a German newspaper on 30 January, 2014, Jan Pieter Krahnen, who was a member of the Liikanen Commission, argues that the proposal could prove to be effective in preventing systemic risk.
The investigated haloarchaeal species, Halobacterium salinarum, Haloferax mediterranei, and H. volcanii, have all been shown to be polyploid. They contain several replicons that have independent copy number regulation, and most have a higher copy number during exponential growth phase than in stationary phase. The possible evolutionary advantages of polyploidy for haloarchaea, most of which have experimental support for at least one species, are discussed. These advantages include a low mutation rate and high resistance toward X-ray irradiation and desiccation, which depend on homologous recombination. For H. volcanii, it has been shown that gene conversion operates in the absence of selection, which leads to the equalization of genome copies. On the other hand, selective forces might lead to heterozygous cells, which have been verified in the laboratory. Additional advantages of polyploidy are survival over geological times in halite deposits as well as at extreme conditions on earth and at simulated Mars conditions. Recently, it was found that H. volcanii uses genomic DNA as genetic material and as a storage polymer for phosphate. In the absence of phosphate, H. volcanii dramatically decreases its genome copy number, thereby enabling cell multiplication, but diminishing the genetic advantages of polyploidy. Stable storage of phosphate is proposed as an alternative driving force for the emergence of DNA in early evolution. Several additional potential advantages of polyploidy are discussed that have not been addressed experimentally for haloarchaea. An outlook summarizes selected current trends and possible future developments.
A multiple filter test for the detection of rate changes in renewal processes with varying variance
(2014)
The thesis provides novel procedures in the statistical field of change point detection in time series.
Motivated by a variety of neuronal spike train patterns, a broad stochastic point process model is introduced. This model features points in time (change points), where the associated event rate changes. For purposes of change point detection, filtered derivative processes (MOSUM) are studied. Functional limit theorems for the filtered derivative processes are derived. These results are used to support novel procedures for change point detection; in particular, multiple filters (bandwidths) are applied simultaneously in oder to detect change points in different time scales.
Panel Sample Selection ModelsThe empirical evidence currently available in the literature regarding the effects of a country's IMF program participation on its output growth is rather inconclusive. In this paper we propose and estimate a panel data sample selection model featuring state dependence. As in this model the output growth effects of program participation can be conditional on the realization of a state variable (conditional pooling), our framework may reconcile previous empirical evidence based on models without state-dependent effects. We find that the effects of IMF program participation on output growth vary systematically with an index reflecting a country's institutional record, and that output growth effects of program participation are significantly positive only if the program participation is coupled with sufficient improvement of the institutional record.
Although oil price shocks have long been viewed as one of the leading candidates for explaining U.S. recessions, surprisingly little is known about the extent to which oil price shocks explain recessions. We provide the first formal analysis of this question with special attention to the possible role of net oil price increases in amplifying the transmission of oil price shocks. We quantify the conditional recessionary effect of oil price shocks in the net oil price increase model for all episodes of net oil price increases since the mid-1970s. Compared to the linear model, the cumulative effect of oil price shocks over course of the next two years is much larger in the net oil price increase model. For example, oil price shocks explain a 3% cumulative reduction in U.S. real GDP in the late 1970s and early 1980s and a 5% cumulative reduction during the financial crisis. An obvious concern is that some of these estimates are an artifact of net oil price increases being correlated with other variables that explain recessions. We show that the explanatory power of oil price shocks largely persists even after augmenting the nonlinear model with a measure of credit supply conditions, of the monetary policy stance and of consumer confidence. There is evidence, however, that the conditional fit of the net oil price increase model is worse on average than the fit of the corresponding linear model, suggesting much smaller cumulative effects of oil price shocks for these episodes of at most 1%.
Efforts to control bank risk address the wrong problem in the wrong way. They presume that the financial crisis was caused by CEOs who failed to supervise risk-taking employees. The responses focus on executive pay, believing that executives will bring non-executives into line—using incentives to manage risk-taking—once their own pay is regulated. What they overlook is the effect on non-executive pay of the competition for talent. Even if executive pay is regulated, and executives act in the bank’s best interests, they will still be trapped into providing incentives that encourage risk-taking by non-executives due to the negative externality that arises from that competition. Greater risk-taking can increase short-term profits and, in turn, the amount a non-executive receives, potentially at the expense of long-term bank value. Non-executives, therefore, have an incentive to incur significant risk upfront so long as they can depart for a new employer before any losses materialize. The result is an upward spiral in compensation—reducing an executive’s ability to set non-executive pay and the ability of any one bank to adjust compensation to reflect risk-taking and long-term outcomes. New regulation must address the tension between compensation and competition. Regulators should take account of the effect of competition on market-wide levels of pay, including by non-banks who compete for talent. The ability of non-executives to jump from a bank employer to another financial firm should also be limited. In addition, banks should be required to include a long-term equity component in non-executive pay, with subsequent employers being restricted from compensating a new employee for any losses she incurs related to her prior work.
We examine trust and trustworthiness of individuals with varying professional preferences and experiences. Our subjects study business and economics in Frankfurt, the financial center of Germany and continental Europe. In the trust game, subjects with a high interest in working in the financial industry return 25 percent less than subjects with a low interest. We find no evidence that the extent of professional experience in the financial industry has a negative impact on trustworthiness. We also do not find any evidence that the financial industry screens out less trustworthy individuals in the hiring process. In a prediction game that is strategically equivalent to the trust game, the amount sent by first-movers was significantly smaller when the second-mover indicated a high interest in working in finance. These results suggest that the financial industry attracts less trustworthy individuals, which may contribute to the current lack of trust in its employees.
In the wake of the Global Financial Crisis that started in 2007, policymakers were forced to respond quickly and forcefully to a recession caused not by short-term factors, but rather by an over-accumulation of debt by sovereigns, banks, and households: a so-called “balance sheet recession.” Though the nature of the crisis was understood relatively early on, policy prescriptions for how to deal with its consequences have continued to diverge. This paper gives a short overview of the prescriptions, the remaining challenges and key lessons for monetary policy.
n a contribution prepared for the Athens Symposium on “Banking Union, Monetary Policy and Economic Growth”, Otmar Issing describes forward guidance by central banks as the culmination of the idea of guiding expectations by pure communication. In practice, he argues, forward guidance has proved a misguided idea. What is presented as state of the art monetary policy is an example of pretence of knowledge. Forward guidance tries to give the impression of a kind of rule-based monetary policy. De facto, however, it is an overambitious discretionary approach which, to be successful, would need much more (or rather better) information than is currently available. In Issing's view, communication must be clear and honest about the limits of monetary policy in a world of uncertainty.
Results of an Odonata survey carried out in the peatlands of Central Kalimantan, Indonesia, in 2012
(2014)
The results of a survey of Odonata (dragonflies and damselflies) in the peat lands of Central Kalimantan, Indonesia, in 2012 are presented. Fifty four species of Odonata found in the area in June-July 2012 are listed, along with brief notes and the locations in which they were found. Of the species found, twelve had not been recorded in Central Kalimantan previously, and of these at least four are completely new to science. Six species, originally described from Central Kalimantan and not recorded any- where since 1953, were rediscovered. At least sixteen of the species found during the survey are considered to be of conservation concern. The discovery of at least four new species to science in a relatively short survey indicates a high probability of occurrence of many more species that are awaiting discovery, and that many un-discovered species may be lost or highly threatened because of the rapid demise of peat swamp forest habitats. A checklist of the Odonata known from Central Kalimantan is provided in an appendix.
The human endothelin receptors, ETA and ETB, are two members of the G-protein coupled receptors family (GPCRs) and they are key players in cardiovascular regulation. The characterization of their functionality in vitro has been limited by the possibility to obtain high quality samples using conventional expression systems. The Cell-Free expression system is an alternative technique for the production of membrane protein as well as GPCRs and can overcome some of the limitations that are commonly encountered using an in vivo approach. Cell-Free expression protocols for the two receptors ETA and ETB have been optimized by implementing post- and co-translational association to lipid bilayers. The efficiency of the reconstitution or association to liposomes and nanodiscs has systematically been studied and the ligand binding properties of the two receptors have been analyzed using a set of different complementary techniques. In several different conditions a high affinity binding of the peptide ligand ET-1 to both endothelin receptors could be obtained and the highest activity values were detected in sample prepared using a co-translational approach in presence of nanodiscs. Furthermore, the characteristic differential binding pattern of selected agonists and antagonists to the two receptors was confirmed. In samples obtained from several Cell-Free expression conditions, two intrinsic properties of the functionally folded ETB receptor, such as the proteolytic processing based on conformational recognition as well as the formation of SDS-resistant complexes with the peptide ligand ET-1, were detected. ETA and ETB are able to induce in vivo the activation of hetrotrimeric G proteins upon stimulation with an agonist, leading to the dissociation of the heterotrimeric complex and the exchange of GDP to GTP in the Galpha subunit. The Cell-Free expression system was chosen for the production of two G alpha subunit, Galpha s and Galpha q. Soluble expression of the two proteins was achieved and the production of active Galpha s was confirmed using fluorescent as well as radioactive assays. In conclusion, the obtained results document a new process for the production of ligand binding competent endothelin receptors, as well as Galpha proteins, using a Cell-Free expression system. The combination of this expression system and the nanodiscs technology appears to be a promising tool for the further characterization of membrane proteins as well as GPCRs.
We investigate the relationship between anchoring and the emergence of bubbles in experimental asset markets. We show that setting a visual anchor at the fundamental value (FV) in the first period only is sufficient to eliminate or to significantly reduce bubbles in laboratory asset markets. If no FV-anchor is set, bubble-crash patterns emerge. Our results indicate that bubbles in laboratory environments are primarily sparked in the first period. If prices are initiated around the FV, they stay close to the FV over the entire trading horizon. Our insights can be related to initial public offerings and the interaction between prices set on pre-opening markets and subsequent intra-day price dynamics.
he observed hump-shaped life-cycle pattern in individuals' consumption cannot be explained by the classical consumption-savings model. We explicitly solve a model with utility of both consumption and leisure and with educational decisions affecting future wages. We show optimal consumption is hump shaped and determine the peak age. The hump results from consumption and leisure being substitutes and from the implicit price of leisure being decreasing over time; more leisure means less education, which lowers future wages, and the present value of foregone wages decreases with age. Consumption is hump shaped whether the wage is hump shaped or increasing over life.
This paper provides a systematic analysis of individual attitudes towards ambiguity, based on laboratory experiments. The design of the analysis allows to capture individual behavior across various levels of ambiguity, ranging from low to high. Attitudes towards risk and attitudes towards ambiguity are disentangled, providing pure measures of ambiguity aversion. Ambiguity aversion is captured in several ways, i.e. as a discount factor net of a risk premium, and as an estimated parameter in a generalized utility function. We find that ambiguity aversion varies across individuals, and with the level of ambiguity, being most prominent for intermediate levels. Around one third of subjects show no aversion, one third show maximum aversion, and one third show intermediate levels of ambiguity aversion, while there is almost no ambiguity seeking. While most theoretical work on ambiguity builds on maxmin expected utility, our results provide evidence that MEU does not adequately capture individual attitudes towards ambiguity for the majority of individuals. Instead, our results support models that allow for intermediate levels of ambiguity aversion. Moreover, we find risk aversion to be statistically unrelated to ambiguity aversion on average. Taken together, the results support the view that ambiguity is an important and distinct argument in decision making under uncertainty.
Mohammad Arkoun (٭1928, Algeria; †2010, Paris) was an influential Muslim intellectual and particularly concerned with - amongst a profound spectrum of scholarly interests – reforming the academic study of Islamic societies. Trained at the University of Algiers (Faculty of Philology) he ventured off to lecture Arab language and literature at the Sorbonne. His engagement with philosophy and sociology led in 1968 to his PhD at the Sorbonne through a work on Ibn Miskawayh’s ethics...
This exploration into Arkoun’s stances on the Quran looks onto the genesis of the Quran, the notion of the Quran as the ‘deliverer of truth’, and with that, its significane for the ‘being in the world’ of Muslim societies. I will also point out some crucial difficulties in the study of Arkoun’s views on the Quran as well as their implications for the study of Islamic cultures.
The Crusade movement is one of the most important occurrences of medieval history. It took place throughout two centuries in the Levant and affected both Muslims and Crusaders and in turn changed the way in which West and East related to one another. When the Crusaders took control of the Holy Land and many Islamic cities in the Levant, they transferred their feudal European system there. They established four main fiefdoms or lordships, Jerusalem, Edessa, Antioch and Tripoli. In addition, there were another twelve secondary fiefdoms, of which Tibnīn was one. Tibnīn was called “Toron” by the Crusaders. Once the Crusaders had captured Tibnīn, they began building its fortified castle, from which the fief of Tibnīn gained its importance throughout the period of the Crusades.
This paper traces the military role of Tibnīn and its rulers in the Latin East against the Muslims until 1187/ 583. Tibnīn played a key role in overcoming the Muslims in Tyre and controlled it in 1124. It also played a vital role in the conflict between Damascus and the Kingdom of Jerusalem. Tibnīn participated in defending Antioch, Banyas, Hebron and Transjordan several times. Furthermore, its soldiers and Knights joined the army of the Kingdom of Jerusalem to capture Ascalon in 1153, and joined the campaigns of Amaury I, King of Jerusalem, against Egypt from 1164 to1169. The military situation of Tibnīn under the rule of the royal house until its fall to the Muslims in 1187/ 583 will be studied as well.
The Crusade movement is one of the most important occurrences of medieval history. It took place throughout two centuries in the Levant and affected both Muslims and Crusaders and in turn changed the way in which West and East related to one another.1 When the Crusaders took control of the Holy Land and many Islamic cities in the Levant, they transferred their feudal European system there. They established four main fiefdoms or lordships, Jerusalem, Edessa, Antioch and Tripoli. In addition, there were another twelve secondary fiefdoms,2 of which Tibnīn was one. Tibnīn was called “Toron” by the Crusaders. Once the Crusaders had captured Tibnīn, they began building its fortified castle, from which the fief of Tibnīn gained its importance throughout the period of the Crusades.
This paper traces the military role of Tibnīn and its rulers in the Latin East against the Muslims until 1187/ 583. Tibnīn played a key role in overcoming the Muslims in Tyre and controlled it in 1124. It also played a vital role in the conflict between Damascus and the Kingdom of Jerusalem. Tibnīn participated in defending Antioch, Banyas, Hebron and Transjordan several times. Furthermore, its soldiers and Knights joined the army of the Kingdom of Jerusalem to capture Ascalon in 1153, and joined the campaigns of Amaury I, King of Jerusalem, against Egypt from 1164 to1169. The military situation of Tibnīn under the rule of the royal house until its fall to the Muslims in 1187/ 583 will be studied as well.
In this essay, one of the most serious problems highlighted with respect to contemporary Iranians, who are mostly known as Shi‘ite-Perso (Shi‘ite-Persian) citizens of Iran, and what their view toward abusing wine and opium is. On one hand, the wealthy Persian literature is full of poems, narrations and notes with reference to wine and opium, while on the other hand, many parts of Shi‘ite-Islamic thought deem wine unclean and illegal, and abusing opium is forbidden except under certain [hard-fulfilling] conditions. Hereby, in this essay the aim is to express why the question “are drinking wine and abusing opium known as addiction or literal culture?” is suspended throughout the young Iranian generation. In this regard, the standpoints of Persian poets and Iranian religious figures towards wine and opium will be considered.
Motivated by the question whether sound and expressive applicative similarities for program calculi with should-convergence exist, this paper investigates expressive applicative similarities for the untyped call-by-value lambda-calculus extended with McCarthy's ambiguous choice operator amb. Soundness of the applicative similarities w.r.t. contextual equivalence based on may-and should-convergence is proved by adapting Howe's method to should-convergence. As usual for nondeterministic calculi, similarity is not complete w.r.t. contextual equivalence which requires a rather complex counter example as a witness. Also the call-by-value lambda-calculus with the weaker nondeterministic construct erratic choice is analyzed and sound applicative similarities are provided. This justifies the expectation that also for more expressive and call-by-need higher-order calculi there are sound and powerful similarities for should-convergence.
The pi-calculus is a well-analyzed model for mobile processes and mobile computations.
While a lot of other process and lambda calculi that are core languages of higher-order concurrent and/or functional programming languages use a contextual semantics observing the termination behavior of programs in all program contexts, traditional program equivalences in the pi-calculus are bisimulations and barbed testing equivalences, which observe the communication capabilities of processes under reduction and in contexts.
There is a distance between these two approaches to program equivalence which makes it hard to compare the pi-calculus with other languages. In this paper we contribute to bridging this gap by investigating a contextual semantics of the synchronous pi-calculus with replication and without sums.
To transfer contextual equivalence to the pi-calculus we add a process Stop as constant which indicates success and is used as the base to define and analyze the contextual equivalence which observes may- and should-convergence of processes.
We show as a main result that contextual equivalence in the pi-calculus with Stop conservatively extends barbed testing equivalence in the (Stop-free) pi-calculus. This implies that results on contextual equivalence can be directly transferred to the (Stop-free) pi-calculus with barbed testing equivalence.
We analyze the contextual ordering, prove some nontrivial process equivalences, and provide proof tools for showing contextual equivalences. Among them are a context lemma, and new notions of sound applicative similarities for may- and should-convergence.
The Paddys River Wetlands in the New South Wales Southern Highlands, southwest of Sydney, are characterised by several watercourses with associated swamps (fens), some of which, on Forestry Corporation of NSW land, have been the focus for removal of Pinus radiata wildings by the Penrose Swamps Conservation Group. In this study we map a population of Eucalyptus aquatica trees in one of these swamps perched above Paddys River (latitude 34.65575o S, longitude 150.21831o E; 600 m elevation). Eucalyptus aquatica is geographically restricted to the Paddys River area and is listed as a threatened species at state and national levels. New findings on the physical characteristics of the swamp in relation to the bedrock geology, stream geomorphology, peat development and the main native plant species, are presented. The occurrence of clumps of Eucalyptus aquatica appears to be independent of the type or thickness of the growing substrate. Rather it is suggested that a continuous supply of water and the shelter afforded by the narrow valley may be key factors determining the distribution of the trees at the study site. An on-going programme of research is underway to study other occurrences of Eucalyptus aquatica.
The Queensland Herbarium Regional Ecosystem Survey and Mapping (QHRESM) program has contributed almost 90000 (89389) specimens to the Queensland Herbarium in Brisbane accounting for 28% of the specimens added to the Herbarium between 1970 and 2011. These specimens have been collected across all bioregions and vegetation communities in Queensland in a systematic sampling program driven by the requirement to sample comprehensively all vegetation communities. The QHRESM’s Queensland Herbarium (BRI) specimens represent more than 79% of the native, and 73% of the naturalised vascular flora of Queensland, as well as making valuable contributions to the bryophytes, lichens and liverworts collections. The data and specimens collected enhance our ability to assess local, state and continental-scale plant diversity, and will be used by botanists, ecologists, governments, business and the public for long into the future.
Natural vegetation of freely draining beach sand ridges in the valley of the Upper Myall River on the lower North Coast of NSW is sclerophyllous open forest or woodland. Based on previous experience on the nearby Eurunderee area, the vegetation on the sand ridges was classified into three types. These were mapped using aerial photographs and field observation. In transects, each 50 m long, the presence of species was scored in 10, 5 X 5 m quadrats. 48 such transects were used sampling all three types of vegetation on the sand ridges and also vegetation in periodically waterlogged sites adjacent to the ridges. Data from the transects, subjected to an ordination using principal components analysis, revealed clear separation between vegetation of the ridges and that of periodically waterlogged sites. In the ordination, vegetation of the ridges formed a continuum with the three types occupying characteristic parts of the continuum, reflecting their respective distributions on sands with different geomorphological histories. The most grassy, tallest forest, termed Dry Sclerophyll Forest (DSF) is on sands either recently disturbed or deposited (Holocene) or closely overlying other substrates. Banksia serrata occurs in DSF. The least grassy, most sclerophyllous, lowest forest or woodland, termed Dry Heath Forest (DHF), occurs on sands apparently little disturbed since they were laid down in the Pleistocene. Banksia aemula occurs in DHF. An intermediate forest, in which Banksia aemula and Banksia serrata occur together, Intermediate Dry Forest (IDF), is most widely found on the sand mass close to Bombah Broadwater. This sand is postulated to have been reworked during the last Glacial Period. In short, the vegetation of these sand ridges largely varies with time since they were laid down or last disturbed in a major way. Preliminary observations indicate the degree of podsolization of their soils is similarly related to this variation in time.
Lysimachia mauritiana Lam. (family Primulaceae), a small short-lived herb native to India, Indian and Pacific Ocean islands, and coastal east Asia, is described as a new naturalised record from the eastern suburbs of Sydney, New South Wales, Australia. It was first recorded in 1981 near Coogee, and grows in exposed rock crevices and seepages on the seacoast, very similar to its natural habitat overseas. Lysimachia mauritiana is known to have been cultivated in the area in 1961 in a home garden, which is the likely source of this introduction; it appears to be spreading locally as a weed.
Vegetation of Little Bora Nature Conservation Trust Agreement, North Western Slopes, New South Wales
(2014)
The vegetation of the Little Bora Nature Conservation Trust Agreement property (560 ha in area), 8 km south east of Bingara (lat 29° 55’S long 150° 37’) in the Gwydir Shire and within the Nandewar Bioregion is described. Eight vegetation communities are defined based on flexible UPGMA analysis of cover-abundance scores of all vascular plant taxa. These communities are mapped based on ground truthing, ADS40 imagery interpretation, topography and substrate. Communities described are: 1) Melaleuca bracteata – Eucalyptus melanophloia – Eucalyptus camaldulensis Woodland, 2) Callitris glaucophylla – Eucalyptus melanophloia – Eucalyptus albens Woodland, 3) Callitris glaucophylla – Eucalyptus melanophloia – Brachychiton populneus Woodland, 4) Eucalyptus albens Woodland, 5) Eucalyptus caleyi – Eucalyptus albens – Callitris glaucophylla Woodland, 6) Callitris glaucophylla – Eucalyptus melanophloia – Eucalyptus albens Woodland, 7) Austrostipa verticillata – Austrostipa scabra Derived Grassland, 8) Eucalyptus melliodora – Eucalyptus dealbata Woodland. A total of 232 vascular plant taxa were found of which 14% were considered exotic in origin. 66 ha of listed threatened communities were mapped along with populations of a currently listed Extinct plant (TSC Act) Dodonaea stenophylla.
A population of 700 Blandfordia cunninghamii Lindl. (family Blandfordiaceae) plants in the Blue Mountains, 100 km west of Sydney, New South Wales was monitored over a period of seven years, during which a part of the population area was burnt in a Hazard Reduction Burn (HRB). The survey measured flowering of Blandfordia cunninghamii in both the burnt and unburnt areas. In part of the unburnt area flowering (in December) was strongly correlated with previous September rainfall, but in another unburnt area there was no flowering at all over the seven years. An enhanced flowering response after fire was found in the burnt area and the diminution of this enhanced response in subsequent years was found to be logarithmic (taking into account potential rainfall effects). No recruitment of juvenile plants after fire was observed. 87% of seeds of Blandfordia cunninghamii were found to be germinable. Slow juvenile growth of Blandfordia cunninghamii in the field was measured over seven years. Seed was collected for two major seedbanks, the NSW Plantbank at the Australian Botanic Garden, Mt Annan and the Millennium Seedbank at Kew in the United Kingdom.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.