Sentiment analysis of European bonds 2016 - 2018

We revisit the discussion of market sentiment in European sovereign bonds using a correlation analysis toolkit based on influence networks and hierarchical clustering. We focus on three case studies of political interest. In the case of the 2016 Brexit referendum, the market showed negative correlations between core and periphery only in the week before the referendum. Before the French presidential elections in 2017, the French bond spread widened together with the estimated Le Pen election probability, but the position of French bonds in the correlation blocks did not weaken. In summer 2018, during the budget negotiations within the new Italian coalition, the Italian bonds reacted very sensitively to changing political messages but did not show contagion risk to Spain or Portugal for several months. The situation changed during the week from October 22 to 26, as a spillover pattern of negative sentiment also to the other peripheral countries emerged

A quality assurance phantom for electronic portal imaging devices

Electronic portal imaging device (EPID) plays an important role in radiation therapy portal imaging, geometric and dosimetric verification. Consistent image quality and stable radiation response is necessary for proper utilization that requires routine quality assurance (QA). A commercial ‘EPID QC’ phantom weighing 3.8 kg with a dimension of 25 × 25 × 4.8 cm3 is used for EPID QA. This device has five essential tools to measure the geometric accuracy, signal‐to‐noise ratio (SNR), dose linearity, and the low‐ and the high‐contrast resolutions. It is aligned with beam divergence to measure the imaging and geometric parameters in both X and Y directions, and can be used as a baseline check for routine QA. The low‐contrast tool consists of a series of holes with various diameters and depths in an aluminum slab, very similar to the Las Vegas phantom. The high‐resolution contrast tool provides the modulation transfer function (MTF) in both the x‐ and y‐dimensions to measure the focal spot of linear accelerator that is important for imaging and small field dosimetry. The device is tested in different institutions with various amorphous silicon imagers including Elekta, Siemens and Varian units. Images of the QA phantom were acquired at 95.2 cm source‐skin‐distance (SSD) in the range 1–15 MU for a 26 × 26 cm2 field and phantom surface is set normal to the beam direction when gantry is at 0° and 90°. The epidSoft is a software program provided with the EPID QA phantom for analysis of the data. The preliminary results using the phantom on the tested EPID showed very good low‐contrast resolution and high resolution, and an MTF (0.5) in the range of 0.3–0.4 lp/mm. All imagers also exhibit satisfactory geometric accuracy, dose linearity and SNR, and are independent of MU and spatial orientations. The epidSoft maintains an image analysis record and provides a graph of the temporal variations in imaging parameters. In conclusion, this device is simple to use and provides testing on basic and advanced imaging parameters for daily QA on any imager used in clinical practice

DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression.

The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders

"Lebenswerte" Straße in resilienten urbanen Quartieren: Projektergebnisse eines Teilprojektes im Gesamtprojekt "Eckpunkte für die Umsetzung einer Landesstrategie zur Klimaanpassung aus wissenschaftlicher Sicht"

Urbane Räume sehen sich verschiedenen ökologischen, sozialen und ökonomischen Herausforderungen gegenüber, für deren Bewältigung es unter anderem neue bzw. veränderte Handlungs- und Planungsansätze bedarf. Der Klimawandel mit seinen räumlich wirksamen Folgewirkungen ist eine der zentralen ökologischen Herausforderungen des 21. Jahrhunderts. Städte sind dabei sowohl Verursacher des Klimawandels als auch Betroffene. Sie sind Wohnort, Heimat, Arbeits- und Produktionsstätte. Durch ihre hohe Bevölkerungsdichte und durch die Agglomeration ökonomischen Kapitals sind Städte aber auch stark durch Extremereignisse wie Starkniederschläge und Hitzeperioden gefährdet. Grüne Infrastrukturen können daher nicht nur eine Strategie sein, um sich gegen die Klimawandelfolgen anzupassen, sondern bieten gleichzeitig das Potenzial für neue Lebensräume, um so das Artensterben zu mindern bzw. zu stoppen. Die vorliegende Konzeptstudie widmet sich der Frage, wie Straßen im Sinne des genannten Zieldreiecks weiterentwickelt und gestaltet werden können, d.h. wie eine Transformation urbaner Quartiersstraßen hin zu "lebenswerten" Stadt- und Straßenräumen erfolgen kann

Solving unsolved rare neurological diseases—a Solve-RD viewpoint

Funding Information: Funding The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (Grant Numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (Grant Numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. The study was further funded by the Federal Ministry of Education and Research, Germany, through the TreatHSP network (01GM1905 to RS and LS), the National Institute of Neurological Diseases and Stroke (R01NS072248 to SZ and RS), the European Joint Program on Rare Diseases-EJP-RD COFUND-EJP N° 825575 through funding for the PROSPAX consortium (441409627 to MS, RS and BvW). CW was supported by the PATE program of the Medical Faculty, University of Tübingen. CEE received support from the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund. Authors on this paper are members of the European Reference Network for Rare Neurological Diseases (ERN-RND, Project ID 739510). Funding Information: Conflict of interest HG receives/has received research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Bundesministerium für Gesundheit (BMG) and the European Union (EU). He has received consulting fees from Roche. He has received a speaker honorarium from Takeda. The authors declare no competing interests.Peer reviewe

Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts

Brain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre- mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families

Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C>T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with frontotemporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement