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More than 70 human adenoviruses with type-dependent pathogenicity have been identified but biological information about the majority of these virus types is scarce. Here we employed multiple sequence alignments and structural information to predict receptor usage for the development of an adenoviral vector with novel biological features. We report the generation of a cloned adenovirus based on human adenovirus type 17 (HAdV17) with high sequence homology to the well characterized human adenovirus type 37 (HAdV37) that causes epidemic keratoconjunctivitis (EKC). Our study revealed that human CD46 (CD46) is involved in cell entry of HAdV17. Moreover, we found that HAdV17 infects endothelial cells (EC) in vitro including primary cells at higher efficiencies compared to the commonly used human adenovirus type 5 (HAdV5). Using a human CD46 transgenic mouse model, we observed that HAdV17 displays a broad tropism in vivo after systemic injection and that it transduces ECs in this mouse model. We conclude that the HAdV17-based vector may provide a novel platform for gene therapy.
Purpose: Collaborative care is effective in improving symptoms of patients with depression. The aims of this study were to characterize symptom trajectories in patients with major depression during one year of collaborative care and to explore associations between baseline characteristics and symptom trajectories.
Methods: We conducted a cluster-randomized controlled trial in primary care. The collaborative care intervention comprised case management and behavioral activation. We used the Patient Health Questionnaire-9 (PHQ-9) to assess symptom severity as the primary outcome. Statistical analyses comprised latent growth mixture modeling and a hierarchical binary logistic regression model.
Results: We included 74 practices and 626 patients (310 intervention and 316 control recipients) at baseline. Based on a minimum of 12 measurement points for each intervention recipient, we identified two latent trajectories, which we labeled "fast improvers" (60.5%) and "slow improvers" (39.5%). At all measurements after baseline, "fast improvers" presented higher PHQ mean values than "slow improvers". At baseline, "fast improvers" presented fewer physical conditions, higher health-related quality of life, and had made fewer suicide attempts in their history.
Conclusions: A notable proportion of 39.5% of patients improved only "slowly" and probably needed more intense treatment. The third follow-up in month two could well be a sensible time to adjust treatment to support "slow improvers".
The mechanisms of transfer of crustal material from the subducting slab to the overlying mantle wedge are still debated. Mélange rocks, formed by mixing of sediments, oceanic crust, and ultramafics along the slab-mantle interface, are predicted to ascend as diapirs from the slab-top and transfer their compositional signatures to the source region of arc magmas. However, the compositions of melts that result from the interaction of mélanges with a peridotite wedge remain unknown. Here we present experimental evidence that melting of peridotite hybridized by mélanges produces melts that carry the major and trace element abundances observed in natural arc magmas. We propose that differences in nature and relative contributions of mélanges hybridizing the mantle produce a range of primary arc magmas, from tholeiitic to calc-alkaline. Thus, assimilation of mélanges into the wedge may play a key role in transferring subduction signatures from the slab to the source of arc magmas.
Introduction: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe.
Methods: A cross‐sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV‐positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign‐born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men.
Results: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post‐migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three‐quarters of people on antiretrovirals had an HIV viral load <50 copies/mL.
Conclusions: Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention.
Himalopsyche Banks, 1940 (Trichoptera, Rhyacophilidae) is a genus of caddisflies inhabiting mountain and alpine environments in Central and East Asia and the Nearctic. Of 53 known species, only five species have been described previously in the aquatic larval stage. We perform life stage association using three strategies (GMYC, PTP, and reciprocal monophyly) based on fragments of two molecular markers: the nuclear CAD, and the mitochondrial COI gene. A total of 525 individuals from across the range of Himalopsyche (Himalayas, Hengduan Shan, Tian Shan, South East Asia, Japan, and western North America) was analysed and 32 operational taxonomic units (OTUs) in our dataset delimited. Four distinct larval types of Himalopsyche are uncovered, and these are defined as the phryganea type, japonica type, tibetana type, and gigantea type and a comparative morphological characterisation of the larval types is presented. The larval types differ in a number of traits, most prominently in their gill configuration, as well as in other features such as setal configuration of the pronotum and presence/absence of accessory hooks of the anal prolegs.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Die forensische Entomologie nutzt nekrophage Insekten, hauptsächlich Dipteren und ihre juvenilen Stadien, zur Schätzung der minimalen Leichenliegezeit. Dem liegt zugrunde, dass nekrophage Dipteren binnen Minuten nach dem Todeseintritt potentiell in der Lage sind, einen Leichnam zu detektieren und zu besiedeln. Das anschließende Wachstum und die Entwicklung der juvenilen Stadien erfolgt als Funktion von der Art und der Umgebungstemperatur.
Mit Hilfe von Laborstudien konnten bislang für einige forensisch relevante Fliegenarten Entwicklungsdaten erhoben werden, die eine Altersbestimmung der sich an einem Leichnam entwickelnden Larven und Puppen erlauben und so eine Schätzung der minimalen Leichenliegezeit ermöglichen. Als Nährsubstrat für Laborstudien werden tierische Gewebe verwendet. Eine Übertragbarkeit der Daten auf humanes Gewebe wurde aber bislang nicht verifiziert. In der vorliegenden Arbeit wurde das larvale Wachstum und die juvenile Entwicklungsgeschwindigkeit der forensisch relevanten Schmeißfliege Calliphora vicina (Diptera: Calliphoridae) auf humanem Muskelgewebe untersucht und mit dem Wachstum auf Schweineleber, magerem Schweinemuskelfleisch und Schweinehackfleisch verglichen. Die auf humanem Gewebe heranwachsenden Individuen waren mit bis zu 3,5 mm signifikant länger als die Individuen, die sich auf Leber und dem mageren Schweinemuskelfleisch entwickelten. Bei der Verwendung von Hackfleisch vom Schwein zeigte sich kein Unterschied. Darauf basierend wird die Empfehlung ausgesprochen, für zukünftige Entwicklungsstudien Schweinehackfleisch als Ersatz für humanes Gewebe zu verwenden.
Zahlreiche Anleitungen zur Asservierung forensisch-entomologischer Spuren empfehlen das Sammeln getrennt nach Körperregionen eines Leichnams. Dies soll eine mögliche gewebespezifische Entwicklungsrate berücksichtigen. Das für die vorliegende Arbeit durchgeführte systematische Absammeln von Fliegenlarven von 51 Leichnamen getrennt nach Körperregionen zeigte keine artspezifischen Präferenzen für bestimmte Gewebe oder Körperregionen. Das Artenspektrum entsprach größtenteils dem aufgrund von Studien an Schweinekadavern zu erwartendem Artenspektrum für Deutschland und Mitteleuropa. Insgesamt konnten 15 Schmeißfliegenarten nachgewiesen werden, von denen in der Regel mehrere gleichzeitig an einem Leichnam zu finden waren. Dies zeigt, dass ein Faktor wie interspezifische Konkurrenz in Zukunft mehr Beachtung in der Forschung erhalten sollte.
Bislang wurde in der forensischen Entomologie die minimale Leichenliegezeit durch die Untersuchung juveniler Stadien von Fliegen eingegrenzt. Eine eventuell mögliche Ausweitung dieses Zeitfensters könnte durch eine Altersbestimmung der adulten Fliegen oder der leeren Puparien gelingen. Der Nachweis, dass die dafür untersuchten Fliegen bzw. Puparien tatsächlich von dem fraglichen Leichnam stammen, war bislang nicht möglich. Die forensische relevante Schmeißfliege Lucilia sericata wurde in der vorliegenden Arbeit auf humanem Gewebe und Gewebe von elf weiteren Tierarten großgezogen. Durch die Analyse stabiler Kohlen- und Stickstoffisotope konnte ein von diesen elf Tierarten abgrenzbares humanes Isotopenprofil sowohl für die adulten Fliegen von L. sericata, als auch für ihre leeren Puparien detektiert werden. Dieses Profil spiegelte die Nahrungszusammensetzung der Wirte wider.
Die vorliegende Arbeit erhebt Daten zur Entwicklung einer forensisch relevanten Schmeißfliegenart auf humanem Gewebe, belegt das bislang lediglich am tierischen Modell erhobene Schmeißfliegeninventar als für menschliche Leichen relevant und hinterfragt die gewebespezifische Asservierungsempfehlung als ein akademisches Artefakt. Auf dieser Basis konnten Empfehlungen für die Weiterzucht fallrelevanter entomologischer Spuren ausgesprochen werden, die gerichtsverwertbar sind und die Verwendung von tierischem Gewebe oder Tierkadaver in der forensisch-entomologischen Forschung legitimieren. Die Analyse stabiler Isotope legt darüber hinaus einen neuen, innovativen Grundstein für die routinemäßige Spurenzuordnung älterer Entwicklungsstadien und ist damit Vorreiter auf dem Gebiet der forensischen Entomologie.
The interaction between the T4 bacteriophage gp37 adhesin and the bacterial lipopolysaccharide (LPS) is a well-studied system, however, the affinity and strength of the interaction haven’t been analyzed so far. Here, we use atomic force microscopy to determine the strength of the interaction between the adhesin and its receptor, namely LPS taken from a wild strain of E. coli B. As negative controls we used LPSs of E. coli O111:B and Hafnia alvei. To study the interaction an AFM tip modified with the gp37 adhesin was used to scan surfaces of mica covered with one of the three different LPSs. Using the correlation between the surface topography images and the tip-surface interaction we could verify the binding between the specific LPS and the tip in contrast to the very weak interaction between the tip and the non-binding LPSs. Using force spectroscopy we could then measure the binding strength by pulling on the AFM tip until it lifted off from the surface. The force necessary to break the interaction between gp37 and LPS from E. coli B, LPS from E. coli O111:B and LPS from H. alvei were measured to be 70 ± 29 pN, 46 ± 13 pN and 45 ± 14 pN, respectively. The latter values are likely partially due to non-specific interaction between the gp37 and the solid surface, as LPS from E. coli O111:B and LPS from H. alvei have been shown to not bind to gp37, which is confirmed by the low correlation between binding and topography for these samples.
The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.
Die vorliegende Arbeit beschäftigt sich mit dem Thema Stemmatologie, d.h. primär der Rekonstruktion der Kopiergeschichte handschriftlich fixierter Dokumente. Zentrales Objekt der Stemmatologie ist das Stemma, eine visuelle Darstellung der Kopiergeschichte, welche i.d.R. graphtheoretisch als Baum bzw. gerichteter azyklischer Graph vorliegt, wobei die Knoten Textzeugen (d.s. die Textvarianten) darstellen während die Kanten für einzelne Kopierprozesse stehen. Im Mittelpunkt des Wissenschaftszweiges steht die Frage des Autorenoriginals (falls ein einziges solches existiert haben sollte) und die Frage der Rekonstruktion seines Textes. Das Stemma selbst ist ein Mittel zu diesem Hauptzweck (Cameron 1987). Der durch für manuelle Kopierprozesse kennzeichnende Abweichungen zunehmend abgewandelte Originaltext ist meist nicht direkt überliefert. Ziel der Arbeit ist es, die semi-automatische Stemmatologie umfassend zu beschreiben und durch Tools und analytische Verfahren weiterzuentwickeln. Der erste Teil der Arbeit beschreibt die Geschichte der computer-assistierten Stemmatologie inkl. ihrer klassischen Vorläufer und mündet in der Vorstellung eines einfachen Tools zur dynamischen graphischen Darstellung von Stemmata. Ein Exkurs zum philologischen Leitphänomen Lectio difficilior erörtert dessen mögliche psycholinguistische Ursachen im schnelleren lexikalischen Zugriff auf hochfrequente Lexeme. Im zweiten Teil wird daraufhin die existenziellste aller stemmatologischen Debatten, initiiert durch Joseph Bédier, mit mathematischen Argumenten auf Basis eines von Paul Maas 1937 vorgeschlagenen stemmatischen Models beleuchtet. Des Weiteren simuliert der Autor in diesem Kapitel Stemmata, um den potenziellen Einfluss der Distribution an Kopierhäufigkeiten pro Manuskript abzuschätzen.
Im nächsten Teil stellt der Autor ein eigens erstelltes Korpus in persischer Sprache vor, welches ebenso wie 3 der bekannten artifiziellen Korpora (Parzival, Notre Besoin, Heinrichi) qualitativ untersucht wird. Schließlich wird mit der Multi Modal Distance eine Methode zur Stemmagenerierung angewandt, welche auf externen Daten psycholinguistisch determinierter Buchstabenverwechslungswahrscheinlichkeiten beruht. Im letzten Teil arbeitet der Autor mit minimalen Spannbäumen zur Stemmaerzeugung, wobei eine vergleichende Studie zu 4 Methoden der Distanzmatrixgenerierung mit 4 Methoden zur Stemmaerzeugung durchgeführt, evaluiert und diskutiert wird.
We propose a spatiotemporal approach for modeling risk spillovers using time-varying proximity matrices based on observable financial networks and introduce a new bilateral specification. We study covariance stationarity and identification of the model, and analyze consistency and asymptotic normality of the quasi-maximum-likelihood estimator. We show how to isolate risk channels and we discuss how to compute target exposure able to reduce system variance. An empirical analysis on Euro-area cross-country holdings shows that Italy and Ireland are key players in spreading risk, France and Portugal are the major risk receivers, and we uncover Spain's non-trivial role as risk middleman.
We show that bond purchases undertaken in the context of quantitative easing efforts by the European Central Bank created a large mispricing between the market for German and Italian government bonds and their respective futures contracts. On top of the direct effect the buying pressure exerted on bond prices, we show three indirect effects through which the scarcity of bonds, resulting from the asset purchases, drove a wedge between the futures contracts and the underlying bonds: the deterioration of bond market liquidity, the increased bond specialness on the repurchase agreement market, and the greater uncertainty about bond availability as collateral.
We study the role of various trader types in providing liquidity in spot and futures markets based on complete order-book and transactions data as well as cross-market trader identifiers from the National Stock Exchange of India for a single large stock. During normal times, short-term traders who carry little inventory overnight are the primary intermediaries in both spot and futures markets, and changes in futures prices Granger-cause changes in spot prices. However, during two days of fast crashes, Granger-causality ran both ways. Both crashes were due to large-scale selling by foreign institutional investors in the spot market. Buying by short-term traders and cross-market traders was insufficient to stop the crashes. Mutual funds, patient traders with better trade-execution quality who were initially slow to move in, eventually bought sufficient quantities leading to price recovery in both markets. Our findings suggest that market stability requires the presence of well-capitalized standby liquidity providers.
An important assumption underlying the designation of some insurers as systemically important is that their overlapping portfolio holdings can result in common selling. We measure the overlap in holdings using cosine similarity, and show that insurers with more similar portfolios have larger subsequent common sales. This relationship can be magnified for some insurers when they are regulatory capital constrained or markets are under stress. When faced with an exogenous liquidity shock, insurers with greater portfolio similarity have even larger common sales that impact prices. Our measure can be used by regulators to predict which institutions may contribute most to financial instability through the asset liquidation channel of risk transmission.
This paper investigates inertia within and across banks in retail deposit markets using detailed panel data on consumer choices and account characteristics. In a structural choice model, I find that costs of inertia are around one third higher for switching accounts across compared to switching within banks. Observable proxies of bank-level switching costs (number and type of additional financial products) explain most of this cost premium, while online banking usage reduces inertia. Consistent with theory, I provide evidence that banks incorporate inertia in their pricing as older accounts pay lower rates than comparable newer accounts. Counterfactual policies reducing inertia shift market share to more competitive smaller banks, but only eliminating inertia within banks already results in high potential gains in consumer surplus. This suggests that facilitating bank switching alone might be insufficient to improve consumer choices.
In recent years European financial regulation has experienced a tremendous reorientation with respect to the shadow banking system, which manifested first and foremost in its reframing as market-based finance. Initially identified as a source of systemic risk certain initiatives did not only fall much behind the envisaged changes but all to the contrary have been substantially modified in a way that they now aim at revitalizing these activities. The reorientation of European regulatory agency on shadow banking post-crisis, from curtailing it to facilitating resilient market-based finance, has been a cause for irritation by academic observers, dismissed by some as mere rebranding or taken as a sign of regulatory capture. All to the contrary, this paper documents the central role of regulatory agency in shadow banking’s reconfiguration. It does so by analyzing the European initiatives concerning the regulation of Asset-Backed Commercial Paper (ABCP) and another prime example of shadow banking, Money Market Mutual Funds (MMFs). Based on documentary analysis and expert interviews we trace the way the recently published EU frameworks for MMFs and ABCP have been designed (in particular the STS, CRR and MMF regulation in 2017). Furthermore, we show how they have been transformed in such a way that their final versions allow to re-establish the shadow banking chain linking MMFs, the ABCP market and arguably the regular banking system. This transformation is driven by a new form of pro-active European regulatory agency which aims at creating a regulatory infrastructure able to sustain the orderly flow of real economy debt. Far from being captured by the industry, they did so consciously and in cooperation with private actors in order to maintain a channel for credit creation outside of bank credit, a task made more complicated by the rushed politicized final negotiations coupled with technical complexity. This paper thereby contributes to a new strand of literature, seeing the creation and reconfiguration of the shadow banking system as characterized by the active and conscious role of state actors.
We propose a unified framework to measure the effects of different reforms of the pension system on retirement ages and macroeconomic indicators in the face of demographic change. A rich overlapping generations (OLG) model is built and endogenous retirement decisions are explicitly modeled within a public pension system. Heterogeneity with respect to consumption preferences, wage profiles, and survival rates is embedded in the model. Besides the expected direct effects of these reforms on the behavior of households, we observe that feedback effects do occur. Results suggest that individual retirement decisions are strongly influenced by numerous incentives produced by the pension system and macroeconomic variables, such as the statutory eligibility age, adjustment rates, the presence of a replacement rate, and interest rates. Those decisions, in turn, have several impacts on the macro-economy which can create feedback cycles working through equilibrium effects on interest rates and wages. Taken together, these reform scenarios have strong implications for the sustainability of pension systems. Because of the rich nature of our unified model framework, we are able to rank the reform proposals according to several individual and macroeconomic measures, thereby providing important support for policy recommendations on pension systems.
The paper investigates the determinants of the idiosyncratic volatility puzzle by allowing linkages across asset returns. The first contribution of the paper is to show that portfolios sorted by increasing indegree computed on the network based on Granger causality test have lower expected returns, not related to idiosyncratic volatility. Secondly, empirical evidence indicates that stocks with higher idiosyncratic volatility have the lower exposition on the indegree risk factor.
We examine how a firms' investment behavior affects the investment of a neighboring firm. Economic theory yields ambiguous predictions regarding the direction of firm peer effects and consistent with earlier work, we find that firms display similar investment behavior within an area using OLS analysis. Exploiting time-variation in the rise of U.S. states' corporate income taxes and utilizing heterogeneity in firms' exposure to increases in corporate income tax rates, we identify the causal impact of local firms' investments. Using this as an instrumental variable in a 2SLS estimation, we find that an increases in local firms' investment reduces the investment of a local peer firm. This effect is more pronounced if local competition among firms is stronger and supports theories that firm investments are strategic substitutes due to competition.
We use minutes from 17,000 financial advisory sessions and corresponding client portfolio data to study how active client involvement affects advisor recommendations and portfolio outcomes. We find that advisors confronted with acquiescent clients stick to their standards and recommend expensive but well diversified mutual fund portfolios. However, if clients take an active role in the meetings, advisors deviate markedly from their standards, resulting in poorer portfolio diversification and lower Sharpe ratios. Our findings that advisors cater to client requests parallel the phenomenon of doctors prescribing antibiotics to insistent patients even if inappropriate, and imply that pandering diminishes the quality of advice.