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- Frankfurt Institute for Advanced Studies (FIAS) (1577)
- Biowissenschaften (1525)
- Center for Financial Studies (CFS) (1481)
- Informatik (1381)
- Biochemie und Chemie (1081)
- Sustainable Architecture for Finance in Europe (SAFE) (1059)
- House of Finance (HoF) (703)
Coercion or privatization? Crisis and planned economies in the debates of the early Frankfurt School
(2023)
The 1930s–1940s underwent profound structural economic and political turmoil following the collapse of the nineteenth century liberal market economies. The intellectual debates of the time were dominated by the question of whether Marx’s theory of the tendency of rate of profit to fall was true, or what consequence could be imagined in the survival of capitalist societies. Placed in the middle of such debates was also the reorganization of national productions into war economies. By means of reconstructive analysis, the paper provides a critical overview of the debates that took place within the circle of the Frankfurt School during those years. It also advances an interpretive thesis suggesting that remedies to capitalist crises of the time turned state powers into privatized, illiberal coercive entities. Coercion and privatization reinforced each other. This general tendency is well illustrated by the famous Pollock-Neumann debate. These intellectuals expressed views not only intended to shed light on the historical period of time, but also to formulate long-term considerations on the authoritarian trends embedded in our contemporary democracies. Through historical reconstruction, the paper’s aim is to identify a long-term structural thread of transformation starting from the transformation of the German economy in 1930s and touching upon post Second World War problems of states’ restructuring along privatization/coercion divides.
Polyunsaturated fatty acids (PUFAs) play essential roles in mediating inflammation and its resolution. PUFA metabolites generated by the cytochrome P450 (CYP) - soluble epoxide hydrolase (sEH) axis are known to regulate macrophage activation/polarization but little is known about their role in the resolution of inflammation. Monocytes were isolated from murine bone marrow or human peripheral blood and differentiated to naïve macrophages (M0). Thereafter cells were polarized using LPS and IFNγ (M1), IL-4 (M2a), or TGFβ1 (M2c). Gene expression was analyzed by RNA sequencing, RT-qPCR and Western blotting. Phagocytosis of zymosan and oxo-LDL were also assessed in vitro. Zymosan-induced peritonitis combined with immune cell profiling was used to evaluate the resolution of inflammation in vivo. The expression of sEH was comparable in M0, M1 and M2a macrophages but markedly elevated in M2c polarized cells. The increase in sEH expression elicited by TGFβ relied on the TGFβ receptor ALK5 and the phosphorylation of SMAD2, which was able to bind to the sEH promoter. In macrophages lacking sEH, M2c polarization was incomplete and characterized by lower levels of pro-resolving phagocytosis associated receptors (Tlr2 and Mrc1), as well as higher levels of the pro-inflammatory markers; Nlrp3, IL-1β and TNFα. Fitting with the failure to upregulate phagocytosis associated receptors, the uptake of zymosan and ox-LDL was less efficient in M2c macrophages from sEH-/- mice. The latter animals also demonstrated a retarded resolution of inflammation (zymosan-induced peritonitis) in vivo with fewer resident macrophages and recruited macrophages. PUFA profile analysis indicated decreased sEH substrates e.g., 11, 12-EET, as well as increased sEH products e.g., 11, 12-DHET, indicating an increased sEH activity in M2c macrophages. Taken together, our data indicates that sEH expression is required for the effective M2c polarization of macrophages and thus the resolution of inflammation.
New U–Pb ages of detrital and igneous zircons of the Uppermost Unit of Crete shed light on its provenance and on Eohellenic to Eoalpine imprints in the eastern Mediterranean. The detrital zircons of all nappes show Variscan ages and are characterized by a Minoan-type age spectrum, which is typical for the NE margin of Gondwana. Parts of the metasedimentary rocks are unexpectedly young. Their detrital zircon ages continue via the Permian until the Late Triassic, Middle Jurassic and Early Cretaceous. The high-grade metamorphic rocks of the Asterousia crystalline complex are likely equivalents of the low-grade metamorphic trench and fore-arc deposits of the Vatos nappe pointing to Late Cretaceous slab roll back. The presence of both late Permian detrital zircons and Late Cretaceous arc-type granitoids suggest that the Uppermost Unit of Crete is derived from the late Permian/Late Cretaceous magmatic belt situated north of the Sava–Vardar–Izmir–Ankara Suture in the Strandja–Rhodope area. To achieve their recent position on Crete, the nappes had to travel more than 500 km. The traveling path is well tracked by rocks of the Upper Cycladic Unit, which are similar to those of the Uppermost Unit of Crete. The large displacement of the Cretan nappes was controlled not only by nappe transport, but probably also by dextral strike–slip along the North Anatolian Fault Zone and related counterclockwise rotation of the Anatolian block since the Eocene.
This thesis investigates the structure of the translocase of the outer membrane (TOM) complex in mitochondria, focusing on the TOM holo complex through single-particle electron cryo-microscopy (cryoEM) complemented by mass spectrometry and computational structure prediction. Mitochondria, crucial for energy production in eukaryotic cells, import most of their proteins from the cytoplasm. These proteins enter through the TOM complex, which in its core form consists of a membrane-embedded homodimer of Tom40 pores, two Tom22 cytoplasmic receptors, and six small TOM stabilizing subunits (Tom7, Tom6, and Tom5). The holo complex includes two additional subunits, Tom70 and Tom20, whose stoichiometry and positioning are less understood due to their easy dissociation during isolation of the complex. CryoEM analysis revealed the high-resolution structure of the Neurospora crassa TOM core complex at 3.3 Å, containing all core subunits, and the presence of a central phospholipid causing the Tom40 dimer to tilt to 20°. Furthermore, a 4 Å resolution map indicated the binding of a precursor protein as it transitions through the translocation barrel. Finally, at 6-7 Å resolution, the structure of the TOM holo complex highlighted Tom20's flexibility as it interacts with the core complex, emphasizing its role in protein translocation. This work provides significant insights into the architecture and functioning of the TOM complex, contributing to the understanding of mitochondrial protein import mechanisms.
Highlights
• Solidification and cooling of an intruded dyke or sill within the middle or shallow crust generate stresses of order 200 MPa, which relax on time scales of a few years to million years.
• Stresses may exceed the brittle strength forming tensile fractures.
• Combined with the pressure gradient within the over-pressurized felsic melts, this explains the migration of felsic contact melt into shrinkage cracks (Sederholm-type veins).
Abstract
Rapid emplacement of a mafic dyke or sill at mid-crustal depth heats and possibly melts the felsic wall rock followed by solidification. Associated volume changes generate stresses, possibly enforcing brittle failure and melt migration. We model the evolution of melting, solidification, temperature, and stress including visco-elastic relaxation in 1D - dykes or -sills using realistic rock rheologies of the Weschnitz pluton (Odenwald). For deep emplacement (Case 1, 15.3 km) extensive contact melting of the wall rock occurs, for shallow emplacement (Case 2, 10 km) it is negligible. The stresses are zero at high melt fractions, but increase during solidification and cooling: The intrusion orthogonal stress is always zero. The intrusion parallel stress σ‖ within the intrusion is tensile (O(200 MPa)). It relaxes on a time scale between a few years (Case 1) and 0.6 m.y. (Case 2). Within the wall rock σ‖ is compressive during heating, but becomes tensile under solidification and cooling. Wall rock stresses relax on a time scale of months to 100 years. A Deborah number is defined based on viscous to thermal relaxation allowing generalization of our results. Adding lithostatic stresses, the total stresses of Case 1 remain below the brittle strength, while for Case 2 they may exceed it. Adding the lithostatic pressure to the melt pressure, the effective stresses exceed the brittle strength and intrusion orthogonal tensile fractures are predicted. Combined with the pressure gradient within the over-pressurized felsic melts generated in the wall rock, this explains the migration of felsic contact melt into shrinkage cracks of the mafic sill in the Weschnitz pluton.
This work focused on the biosynthesis and characterization of esterified lipid mediators. Lipid mediators were generally thought to exert their effects as free molecules, and their esterification was regarded as a storage mechanism. However, more recent studies indicate that esterified lipid mediators are a distinct class of mediators. When this thesis started back in 2017, the idea of esterified lipids as a new class of mediators was relatively new so that respective compounds were either quite expensive or not commercially available at all. Therefore, a biosynthetic approach had to be established first to enable the study of the new lipid mediator class. Within the cell, esterified lipids are produced by activation and subsequent incorporation of polyunsaturated fatty acids. These steps are enzymatically catalyzed by members of the acyl-CoA synthetase family and the lysophosphatidylcholine acyltransferase family, respectively. Therefore, the enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 2 (LPCAT2) were selected for a biosynthetic approach due to their broad substrate acceptance.
In a first attempt, recombinant protein expression in E. coli was studied. While the expression and purification of C-terminally His6x-tagged ACSL4 resulted in a pure and active protein, the expression of LPCAT2 turned out quite troublesome. Although several expression and purification parameters were varied, including purification tags, buffer compositions, and chromatography strategies, successful purification of LPCAT2 was not achieved.
Instead, a second approach was studied. This time, stably transfected cells overexpressing ACSL4 and/or LPCAT2 were generated from the human embryonal kidney (HEK) 293T cell line. Stably transfected cell lines were characterized on protein level and regarding their oxylipin profile. After confirming the overexpression and functionality of the enzymes, lipoxygenases (LOs) were co-expressed in a doxycycline-inducible manner to prevent premature cell death due to increased oxidative stress. As a result, LO product formation was enhanced and enabled the investigation of specific oxylipins. Since increased lipid peroxidation is also a key component of the ferroptosis cell death mechanisms, cell lines were investigated towards their cell viability. Indeed, expression of ACSL4 and/or LPCAT2 promoted cell death when treated with the ferroptosis inducers erastin or RSL3, even in the absence of LO expression. Furthermore, analysis by laser scanning confocal microscopy revealed that the localization of 15-LO1 was altered in the presence of LPCAT2, similar to treatment with RSL3 in vector control cells.
In conclusion, a stable overexpression system of ACSL4 and/or LPCAT2 was successfully established in HEK293T cells, which enabled the synthesis and characterization of esterified oxylipins. Interestingly, characterization of the cell lines revealed a correlation with the cell death mechanism ferroptosis. Although the expression of ACSL4 has already been reported as a biomarker for ferroptosis, this is the first time that a potential connection of LPCAT2 with ferroptosis was demonstrated. As a result, this may provide new therapeutic options for ferroptosis-related pathologies such as neurodegeneration, autoimmune diseases, or tumorigenesis.
Highlights
• It is important to distinguish acute provoked seizures due to autoimmune encephalitis from chronic unprovoked seizures due to autoimmune-associated epilepsy.
• Currently it is hardly possible in an individual AIE/ALE/RE patient to separate acute provoked seizures from chronic unprovoked seizures due to limitations in determining seizure outcomes, unclear time courses, potential causal interactions between both seizure origins, compartmentalized immune-inflammation, and a lack of licensed drugs to reliably resolve immune-inflammation in the brain parenchyma.
• This makes it hard to decide when to terminate ASMs and to counsel the individual patient regarding driving abilities and other behavioral restrictions and recommendations.
• Studies are urgently needed to define clinical and paraclinical biomarkers in a hypothesis-free, data-driven approach reliably predicting (or not) the development of AAE and the cognitive and behavioral outcome in the due course of an individual patient´s disease.
• These studies should be experimentally validated in suitable animal models.
Abstract
The current International League Against Epilepsy (ILAE) definition and classification guidelines for the first time introduced the category of immune-mediated focal epilepsy in addition to structural, genetic, infectious, and metabolic aetiologies. Moreover, the ILAE Autoimmunity and Inflammation Taskforce recently provided a conceptual framework for the distinction between acute “provoked” seizures in the acute phase of autoimmune encephalitis from chronic “unprovoked” seizures due to autoimmune-associated epilepsy. The first category predominately applies to those autoimmune encephalitis patients with autoantibodies against cell surface neural antigens, in whom autoantibodies are assumed to exert a direct ictogenic effect without overt structural damage. These patients do not exhibit enduring predisposition to seizures after the “acute phase” encephalitis, and thus do not fulfil the definition of epilepsy. The second category applies to those autoimmune encephalitis patients with autoantibodies against intracellular neural antigens and Rasmussen's encephalitis, in whom T cells are assumed to cause epileptogenic effects through immune-inflammation and overt structural damage. These patients do exhibit enduring predisposition to seizures after the “acute phase” of encephalitis and thus fulfil the definition of epilepsy. AAE may result from both, ongoing brain autoimmunity and associated structural brain damage according to the current ILAE definition and classification guideline. We here discuss the shortcomings and defaults of this concept and suggest an unbiased translationally validated and data-driven approach to predict in an individual encephalitis patient the propensity to develop (or not) AAE and the cognitive and behavioural outcome.
Despite antagonizing attempts from the tobacco industry, passive inhalation of tobacco smoke is known to be cancerogenic and toxic to human health for decades. Nonetheless, millions of non-smoking adults and children are still victims of second-hand smoke. Accumulation of particulate matter (PM) in confined spaces such as the car are particularly harmful due to high concentrations. We here aimed to analyze the specific effects of ventilation conditions in the setting of a car. By the use of the measuring platform TAPaC (tobacco-associated particulate matter emissions inside a car cabin), 3R4F reference cigarettes, Marlboro red, and Marlboro gold were smoked in a car interior with a volume of 3.709 m3. Seven different ventilation conditions (C1–C7) were analyzed. Under C1, all windows were closed. Under C2–C7, the car ventilation was turned on power level 2/4 with the air directed towards the windshield. Only the passenger side window was opened, where an outer placed fan could create an airstream speed of 15.9–17.4 km/h at one meter distance to simulate a driving car. C2: Window 10 cm opened. C3: Window 10 cm opened with the fan turned on. C4: Window half-opened. C5: Window half-opened with the fan turned on. C6: Window fully opened. C7: Window fully opened with the fan turned on. Cigarettes were remotely smoked by an automatic environmental tobacco smoke emitter and a cigarette smoking device. Depending on the ventilation condition the cigarettes emitted different mean PM concentrations after 10 min under condition C1 (PM10: 1272–1697 µg/m3, PM2.5: 1253–1659 µg/m3, PM1: 964–1263 µg/m3) under C2, C4, and C6 (PM10: 68.7–196.2 µg/m3, PM2.5: 68.2–194.7 µg/m3, PM1: 66.1–183.8 µg/m3) C3, C5, and C7 (PM10: 73.7–139 µg/m3, PM2.5: 72–137.9 µg/m3, PM1:68.9–131.9 µg/m3). Vehicle ventilation is insufficient to protect passengers from toxic second-hand smoke completely. Brand-specific variations of tobacco ingredients and mixtures markedly influence PM emissions under ventilation conditions. The most efficient ventilation mode to reduce PM exposure was achieved by opening the passenger´s window 10 cm and turning the onboard ventilation on power level 2/4. In-vehicle smoking should be banned to preserve innocent risk groups (e.g., children) from harm.
Two new species of Perinereis with single bar-shaped paragnaths on area VI (Group 1) from the rocky shores of Mumbai, Maharashtra, India, are described with barely (Subgroup 1A) or largely (Subgroup 1B) expanded proximal region of dorsal ligule in posterior parapodia. Perinereis malabarensis sp. nov. can be distinguished from the morphologically similar 1B species P. euiini Park & Kim, 2017 by the paragnath count in area I, the laterally isolated paragnaths in area III, and the length of the dorsal cirrus and dorsal ligule. Additionally, P. misrai sp. nov. is more similar to 1A species P. falsovariegata Monro, 1933 and P. villalobosi Rioja, 1947, but differs by the paragnath count in areas III–V and VII–VIII, the isolated paragnaths in area III, and the number of rows in the anterior band of areas VII–VIII. The morphological characters of the current 44 species within Perinereis G1 are compared, and an identification key to the species belonging to this group is also provided.
The taxonomic status of recently described Isophya taxa from Serbia (Tettigoniidae, Phaneropterinae)
(2024)
Ivković, Slobodan ; Dey, Lara-Sophie ; Horvat, Laslo ; Iorgu, Ionuț Ștefan ; Buzzetti, Filippo Maria ; Hochkirch, Axel
During recent decades, increasing research of the taxonomy of the genus Isophya resulted in taxonomic descriptions of several new species. The delimitation of these species is mainly based on oscillographic song analysis of the male song in combination with morphological characters, such as the shape of male cerci, tegmina and ovipositor. In the present paper, we used an integrative taxonomic approach in order to resolve the status of four recently described Isophya taxa from Serbia. Based on our molecular and bioacoustic analyses, all analyzed taxa belong to a single species: Isophya modestior. The majority of the morphological characters used to differentiate the taxa showed strong intra- and interpopulational variability, proving that describing new species within the genus Isophya should not rely on morphological characters alone, but needs to consider bioacoustic analyses as the main tool and a larger series of specimens.
A collection of 1149 otoliths of the Ypresian and Ypresian–Lutetian transition (early Eocene) from 18 sites across five states in the eastern and southern regions of the USA was analyzed. In total, 33 otolith-based taxa are documented, of which 27 are identified at the species level. Nine of these are introduced as new species: “Conger” biaculeatus sp. nov., Bauzaia gibbosa sp. nov., Ampheristus brevicaudatus sp. nov., Symmetrosulcus virginicus sp. nov., Neobythites longesulcatus sp. nov., “Neobythites” pamunkeyensis sp. nov., “Neobythites” stringeri sp. nov., Waitakia dorsogibbosa sp. nov., and “Haemulon” ypresiensis sp. nov. The assemblages are distinct when compared to their younger Eocene counterparts in America. This distinction is primarily characterized by the high proportion of the newly introduced species or exclusive Ypresian species. Additionally, we highlight the presence of 10 amphi-Atlantic species originally described in European deposits. Significantly, the composition of the otolith collection supports the interpretation of a shallow-water environment for the sampled sites during the Ypresian. This ecological setting appears to persist into the subsequent middle and late Eocene within the same geographic region.
Sparse sensor networks for Lamb wave-based structural health monitoring (SHM) can detect defects in plate-like structures. However, the limited number of sensor positions provides little information to characterize the unknown scatterer. This can be achieved by full wavefield analysis e.g. using Laser Doppler vibrometry measurements.
This paper proposes deconvolution processing that enhances the acoustic wavefield interpretation by increasing the temporal resolution of the underlying ultrasound signals. Applying this preprocessor to the whole wavefield allows improved non-destructive assessment of the defect. This approach is verified experimentally through a case study on an isotropic aluminum plate with four cracks.
The article presents the results of numerical and experimental investigations of guided wave propagation in aluminum plates with variable thickness. The shapes of plate surfaces have been specially designed and manufactured using a CNC milling machine. The shapes of the plates were defined by sinusoidal functions varying in phase shift, which forced the changes in thickness variability alongside the propagation path. The main aim of the study is to analyze the wave propagation characteristics caused by non-uniform thickness. In the first step, the influence of thickness variability on the time course of propagating waves has been analyzed theoretically. The study proves that the wave propagation signals can be determined based on knowledge about the statistical description of the specimen geometry. The histograms of thickness distribution together with the a priori knowledge of the dispersion curves were used to develop an iterative procedure assuming that the signal from the previous step becomes the excitation in the next step. Such an approach allowed for taking into account the complex geometry of the plate and rejecting the assumption about the constant average thickness alongside the propagation path. In consequence, it was possible to predict correctly the signal time course, as well as the time of flight and number of propagating wave modes in specimens with variable thickness. It is demonstrated that theoretical signals predicted in this way coincide well with numerical and experimental results. Moreover, the novel procedure allowed for the correct prediction of the occurrence of higher-order modes.
The topic of the article is the status of translation and homophony in philosophy, psychoanalysis and philology. The article focuses on the question of how translation is carried out using the basic principle of equivalence of meaning by homophony and what effects this can produce. The analysis of two case studies by Freud and Lacan shows that homophonic transfer from one language to another can be extremely productive for the subjective traversal of a phantasm. It is then shown that this is not, however, of purely subjective interest. Werner Hamacher has sketched the future of philology starting from such homophonic translations; Lacan has tried to advance to another theory of language through homophonic formations.
Hunfeld, Klaus-Peter ; Allwinn, Regina ; Albert, Sabine ; Schumm-Draeger, Petra-Maria ; Brade, Volker ; Doerr, Hans Wilhelm
Das Virus der Frühsommermeningoenzephalitis (FSME) und Borrelia burgdorferi als Erreger der Lyme-Borreliose sind die klinischbedeutsamsten durch Zecken übertragenen Infektionserreger in Europa. Der vorliegende Fall beschreibt eine serologisch gesicherte. Doppelinfektion mit dem FSME-Virus und Borellia burgdorferi bei einer 69jährigen deutschen Patientin nach einem Zeckenstich in einem österreichischen Endemiegebiet. Klinisch bestand zum Zeitpunkt der Krankenhausaufnahme eine ausgeprägte Somnolenz und ein hochgradiges Doppelbildsehen. Ein passive Immunisierung gegen FSME war postexpositionell erfolgt, konnte eine Infektion jedoch nicht verhindern. Eine Doppelinfektion durch beide Erreger wurde durch den serologischen Nachweis von spezifischen IgG und IgM Antikörpern gegen das FSME-Virus und im weiteren Verlauf auch gegen Borrelia burgdorferi im ELISA beziehungsweise im rekombinanten Immunoblot gesichert. Obwohl Doppelinfektionen durch die beiden genannten Erregerselten sind, sollten sie bei zeckenübertragenen Erkrankungen mit untypischem Verlauf in der Differentialdiagnose berücksichtigt werden.
Brauchitsch, Sophie von ; Strzelczyk, Adam ; Rosenow, Felix ; Neuhaus, Elisabeth ; Dubinski, Daniel ; Steinbach, Joachim Peter ; Voss, Martin
Purpose: Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings.
Methods: This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period.
Results: Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients.
Conclusion: In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported.
Hundley, William Gregory ; Bluemke, David A. ; Bogaert, Jan ; Flamm, Scott D. ; Fontana, Marianna ; Friedrich, Matthias ; Große-Wortmann, Lars ; Karamitsos, Theodoros D. ; Kramer, Christopher M. ; Kwong, Raymond Y. ; McConnell, Michael ; Nagel, Eike ; Neubauer, Stefan ; Nijveldt, Robin ; Pennell, Dudley J. ; Petersen, Steffen Erhard ; Raman, Subha V. ; Rossum, Albert C. van
This paper shows that support for climate action is high across survey participants from all EU countries in three dimensions: (1) Participants are willing to contribute personally to combating climate change, (2) they approve of pro-climate social norms, and (3) they demand government action. In addition, there is a significant perception gap where individuals underestimate others' willingness to contribute to climate action by over 10 percentage points, influencing their own willingness to act. Policymakers should recognize the broad support for climate action among European citizens and communicate this effectively to counteract the vocal minority opposed to it.
In recent decades, biodiversity has declined significantly, threatening ecosystem services that are vital to society and the economy. Despite the growing recognition of biodiversity risks, the private sector response remains limited, leaving a significant financing gap. The paper therefore describes market-based solutions to bridge the financing gap, which can follow a risk assessment approach and an impact-oriented perspective. Key obstacles to mobilising private capital for biodiversity conservation are related to pricing biodiversity due to its local dimension, the lack of standardized metrics for valuation and still insufficient data reporting by companies hindering informed investment decisions. Financing biodiversity projects poses another challenge, mainly due to a mismatch between investor needs and available projects, for example in terms of project timeframes and their additionality.
The development of China’s exports – is there a decoupling from the EU and the United States?
(2024)
Some observers warn that a high level of economic dependence on China could negatively affect the economic resilience of Western economies and therefore recommend reducing such dependence by gradually decoupling from China. On the other hand, industry leaders emphasise the economic importance of China and warn against any kind of trade conflicts.
Against this background, we briefly analyse the development of China’s export strategy. We find that the export intensity of the Chinese economy is diminishing and that exports are becoming more diversified overall. In addition, the relative importance of the United States and the European Union as export markets has been reduced, indicating a gradual decoupling of China from Western economies. Conversely, we find that exports to China have become more important, both for the EU and the United States. Although the figures remain at a non-critical level, Europe’s export activities could be more diversified as well.
How does the design of debt repayment schedules affect household borrowing? To answer this question, we exploit a Swedish policy reform that eliminated interest-only mortgages for loan-to-value ratios above 50%. We document substantial bunching at the threshold, leading to 5% lower borrowing. Wealthy borrowers drive the results, challenging credit constraints as the primary explanation. We develop a model to evaluate the mechanisms driving household behavior and find that much of the effect comes from households experiencing ongoing flow disutility to amortization payments. Our results indicate that mortgage contracts with low initial payments substantially increase household borrowing and lifetime interest costs.
We educate investors with significant dividend holdings about the benefits of dividend reinvestment and the costs of misperceiving dividends as additional, free income. The intervention increases planned dividend reinvestment in survey responses. Using trading records, we observe a corresponding causal increase in dividend reinvestment in the field of roughly 50 cents for every euro received. This holds relative to their prior behavior and a placebo sample. Investors who learned the most from the intervention update their trading by the largest extent. The results suggest the free dividends fallacy is a significant source of dividend demand. Our study demonstrates that simple, targeted, and focused educational interventions can affect investment behavior.
Inflation and trading
(2024)
We study how investors respond to inflation combining a customized survey experiment with trading data at a time of historically high inflation. Investors' beliefs about the stock return-inflation relation are very heterogeneous in the cross section and on average too optimistic. Moreover, many investors appear unaware of inflation-hedging strategies despite being otherwise well-informed about inflation and asset returns. Consequently, whereas exogenous shifts in inflation expectations do not impact return expectations, information on past returns during periods of high inflation leads to negative updating about the perceived stock-return impact of inflation, which feeds into return expectations and subsequent actual trading behavior.
This paper contributes a multivariate forecasting comparison between structural models and Machine-Learning-based tools. Specifically, a fully connected feed forward non-linear autoregressive neural network (ANN) is contrasted to a well established dynamic stochastic general equilibrium (DSGE) model, a Bayesian vector autoregression (BVAR) using optimized priors as well as Greenbook and SPF forecasts. Model estimation and forecasting is based on an expanding window scheme using quarterly U.S. real-time data (1964Q2:2020Q3) for 8 macroeconomic time series (GDP, inflation, federal funds rate, spread, consumption, investment, wage, hours worked), allowing for up to 8 quarter ahead forecasts. The results show that the BVAR improves forecasts compared to the DSGE model, however there is evidence for an overall improvement of predictions when relying on ANN, or including them in a weighted average. Especially, ANN-based inflation forecasts improve other predictions by up to 50%. These results indicate that nonlinear data-driven ANNs are a useful method when it comes to macroeconomic forecasting.
Central bank intervention in the form of quantitative easing (QE) during times of low interest rates is a controversial topic. The author introduces a novel approach to study the effectiveness of such unconventional measures. Using U.S. data on six key financial and macroeconomic variables between 1990 and 2015, the economy is estimated by artificial neural networks. Historical counterfactual analyses show that real effects are less pronounced than yield effects.
Disentangling the effects of the individual asset purchase programs, impulse response functions provide evidence for QE being less effective the more the crisis is overcome. The peak effects of all QE interventions during the Financial Crisis only amounts to 1.3 pp for GDP growth and 0.6 pp for inflation respectively. Hence, the time as well as the volume of the interventions should be deliberated.
Pericytes are capillary-associated mural cells involved in the maintenance and the stability of the vascular network. This thesis aims to investigate the role of pericytes in the heart in the context of ageing and disease. We highlight the malignant effects of the remodelling in the heart and stress the focus on the role of cardiac pericytes in this context. We show that ageing reduces pericyte coverage and that myocardial infarction (MI) causes an activation of these cells. Single-nuclei and single-cell RNA sequencing analysis of murine hearts further revealed that the expression of the Regulator of G-protein signalling 5 (Rgs5) is reduced in cardiac pericytes both in ageing and transiently at day 1 and day 3 after MI. The loss of RGS5 in pericytes drives an entropic state of these mural cells characterized by morphological changes, excessive extracellular deposition and enhanced Gaq mediated GPCR signalling. The deletion of RGS5 in pericytes causes cardiac systolic dysfunction, induces myocardial fibrosis, and drives the activation of cardiac fibroblasts in a TGFb-dependent manner. In conclusion, our results describe the importance of pericytes maintaining cardiac homeostasis, identify RGS5 as a key regulator of this process and propose pericytes as crucial mediators of cardiac fibrosis and possible therapeutic targets to prevent cardiovascular disease.
The article investigates the results obtained from numerical simulations and experimental tests concerning the propagation of guided waves in corroded steel plates. Developing innovative methodologies for assessing corrosion-induced degradation is crucial for accurately diagnosing offshore and ship structures exposed to harsh environmental conditions. The main aim of the research is to analyze how surface irregularities affect wave propagation characteristics. An investigation was conducted for antisymmetric fundamental mode A0. Specifically, the study examines the asymmetrical wavefronts generated by nonuniform thickness in damaged specimens. Initially, numerical analysis explores the impact of thickness variation on wave field symmetry. Corroded plates with varying levels of degradation are modeled using the random fields approach, with degradation levels ranging from 0 % to 60 %. Subsequently, the research investigates how the standard deviation of thickness distribution (from 5 % to 20 % of the initial thickness) and excitation frequency (from 50 to 150 kHz) influence recorded signals and the shape of reconstructed wavefronts. Each scenario compares wavefront symmetry levels estimated using rotational and bilateral symmetry degrees as indicative parameters. The numerical simulations are complemented by experimental tests conducted on plates with three different degradation levels. The results demonstrate the efficacy of the proposed wave field analysis approach for assessing structural integrity, as evidenced by the agreement between numerical predictions and experimental observations.
Settelmeier, Stephan ; Kessler, Lukas ; Varasteh, Zohreh ; Mahabadi, Amir Abbas ; Michel, Christian Lars ; Papathanasiou, Maria ; Laschinsky, Christina ; Rischpler, Christoph ; Fendler, Wolfgang P. ; Schlosser, Thomas Wilfried ; Umutlu, Lale ; Herrmann, Ken ; Rassaf, Tienush ; Kersting, David
Prieto García, Cristian ; Hartmann, Oliver ; Reissland, Michaela ; Braun, Fabian ; Bozkurt, Süleyman ; Pahor, Nikolett ; Fuß, Carmina Teresa ; Schirbel, Andreas ; Schülein, Christina ; Buchberger, Alexander ; Calzado Canale, Marco A. ; Rosenfeldt, Mathias ; Đikić, Ivan ; Münch, Christian ; Diefenbacher, Markus Elmar
Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R-, BRAFV600E- or PI3KH1047R-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.
Anders, Björn ; Anders, Malte ; Kreuzer, Matthias ; Zinn, Sebastian ; Fricker, Lukas Rufus ; Maier, Christoph ; Wolters, Miriam ; Köhm, Michaela ; Behrens, Frank ; Walter, Carmen
Background and objectives: Our study aimed at examining the long-time inflammatory effects of rheumatoid arthritis (RA) as chronic immune-mediated disease on pain sensation and neuropathy development compared to healthy subjects (HS).
Methods: We used the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain and Electroencephalography (EEG)–based contact heat evoked potentials (CHEPs) before and after topical capsaicin application. We recruited 16 RA patients in remission or low disease activity state (mean age: 59.38 years [± 10.18]) and 16 healthy subjects (mean age: 56.69 years [± 8.92]).
Results: The application of capsaicin cream on the thigh provoked a stronger effect in HS for both mechanical and heat pain thresholds (MPT and HPT, resp.), according to the area under the receiver operation characteristic (AUROC) (HS: HPT: 0.8965, MPT: 0.7402; RA: HPT: 0.7012, MPT: 0.6113). We observed contrary effects regarding changes in CHEPs (HS: g*max = − 0.65; RA patients: g*max = 0.72).
Conclusion: As the overall effect of topical capsaicin application was higher in HS for QST, we suggest the existence of a sensitization of TRPV1 channels in RA patients caused by long-time chronical inflammation, despite a lack of clinical signs of inflammation due to adequate treatment. The effect in CHEPs probably uncovers neuropathic symptoms. The effect of topical capsaicin on HPTs and CHEPs can act as a marker for the extent of sensitization and the development of neuropathic symptoms. Further studies are needed to prove if our proposed method can act as a marker for the success of anti-inflammatory treatment.
Willems, Sabine ; Marschner, Julian ; Kilu, Whitney ; Faudone, Giuseppe ; Busch, Romy ; Duensing-Kropp, Silke ; Heering, Jan Peter ; Merk, Daniel
The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies. Simvastatin as example exhibits anti-inflammatory effects in astrocytes, which are abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1-silenced cells reveals strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induces several neuroprotective mechanisms via Nurr1 involving changes in inflammatory, metabolic and cell cycle gene expression. Further in vitro evaluation confirms reduced inflammatory response, improved glucose metabolism, and cell cycle inhibition of simvastatin-treated neuronal cells. These findings suggest Nurr1 involvement in the well-documented but mechanistically elusive neuroprotection by statins.
Ri, Keiken ; Weng, Tsai-Hsuan ; Claveras Cabezudo, Ainara ; Jösting, Wiebke ; Zhang, Yu ; Bazzone, Andre ; Leong, Nancy C. P. ; Welsch, Sonja ; Doty, Raymond T. ; Gursu, Gonca ; Lim, Tiffany Jia Ying ; Schmidt, Sarah Luise ; Abkowitz, Janis L. ; Hummer, Gerhard ; Wu, Di ; Nguyen, Long N. ; Safarian, Schara
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2,3,4,5,6,7. Earlier studies concluded that FLVCR1 may function as a haem exporter8,9,10,11,12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14,15,16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation–π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.
In natural environments, background noise can degrade the integrity of acoustic signals, posing a problem for animals that rely on their vocalizations for communication and navigation. A simple behavioral strategy to combat acoustic interference would be to restrict call emissions to periods of low-amplitude or no noise. Using audio playback and computational tools for the automated detection of over 2.5 million vocalizations from groups of freely vocalizing bats, we show that bats (Carollia perspicillata) can dynamically adapt the timing of their calls to avoid acoustic jamming in both predictably and unpredictably patterned noise. This study demonstrates that bats spontaneously seek out temporal windows of opportunity for vocalizing in acoustically crowded environments, providing a mechanism for efficient echolocation and communication in cluttered acoustic landscapes.
Forest wildflowers bloom earlier as Europe warms: lessons from herbaria and spatial modelling
(2022)
Today plants often flower earlier due to climate warming. Herbarium specimens are excellent witnesses of such long-term changes. However, the magnitude of phenological shifts may vary geographically, and the data are often clustered. Therefore, large-scale analyses of herbarium data are prone to pseudoreplication and geographical biases.
We studied over 6000 herbarium specimens of 20 spring-flowering forest understory herbs from Europe to understand how their phenology had changed during the last century. We estimated phenology trends with or without taking spatial autocorrelation into account.
On average plants now flowered over 6 d earlier than at the beginning of the last century. These changes were strongly associated with warmer spring temperatures. Flowering time advanced 3.6 d per 1°C warming. Spatial modelling showed that, in some parts of Europe, plants flowered earlier or later than expected. Without accounting for this, the estimates of phenological shifts were biased and model fits were poor.
Our study indicates that forest wildflowers in Europe strongly advanced their phenology in response to climate change. However, these phenological shifts differ geographically. This shows that it is crucial to combine the analysis of herbarium data with spatial modelling when testing for long-term phenology trends across large spatial scales.
Fischer, Thomas ; Hartmann, Oliver ; Reissland, Michaela ; Prieto-Garcia, Cristian ; Klann, Kevin ; Pahor, Nikolett ; Schülein, Christina ; Baluapuri, Apoorva ; Polat, Bülent ; Abazari, Arya ; Gerhard-Hartmann, Elena Maria ; Kopp, Hans-Georg ; Eßmann, Frank ; Rosenfeldt, Mathias Tillmann ; Münch, Christian ; Flentje, Michael ; Diefenbacher, Markus Elmar
Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
In natural environments, background noise can degrade the integrity of acoustic signals, posing a problem for animals that rely on their vocalizations for communication and navigation. A simple behavioral strategy to combat acoustic interference would be to restrict call emissions to periods of low-amplitude or no noise. Using audio playback and computational tools for the automated detection of over 2.5 million vocalizations from groups of freely vocalizing bats, we show that bats (Carollia perspicillata) can dynamically adapt the timing of their calls to avoid acoustic jamming in both predictably and unpredictably patterned noise. This study demonstrates that bats spontaneously seek out temporal windows of opportunity for vocalizing in acoustically crowded environments, providing a mechanism for efficient echolocation and communication in cluttered acoustic landscapes.
One Sentence Summary Bats avoid acoustic interference by rapidly adjusting the timing of vocalizations to the temporal pattern of varying noise.
In natural environments, background noise can degrade the integrity of acoustic signals, posing a problem for animals that rely on their vocalizations for communication and navigation. A simple behavioral strategy to combat acoustic interference would be to restrict call emissions to periods of low-amplitude or no noise. Using audio playback and computational tools for the automated detection of over 2.5 million vocalizations from groups of freely vocalizing bats, we show that bats (Carollia perspicillata) can dynamically adapt the timing of their calls to avoid acoustic jamming in both predictably and unpredictably patterned noise. This study demonstrates that bats spontaneously seek out temporal windows of opportunity for vocalizing in acoustically crowded environments, providing a mechanism for efficient echolocation and communication in cluttered acoustic landscapes.
One Sentence Summary: Bats avoid acoustic interference by rapidly adjusting the timing of vocalizations to the temporal pattern of varying noise.
Ri, Keiken ; Weng, Tsai-Hsuan ; Claveras Cabezudo, Ainara ; Jösting, Wiebke ; Yu, Zhang ; Bazzone, Andre ; Leong, Nancy C. P. ; Welsch, Sonja ; Doty, Raymond T. ; Gursu, Gonca ; Lim, Tiffany Jia Ying ; Luise Schmidt, Sarah ; Abkowitz, Janis L. ; Hummer, Gerhard ; Wu, Di ; Nguyen, Long N. ; Safarian, Schara
Human feline leukemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN, and Fowler syndrome2–7. Earlier studies concluded that FLVCR1 may function as a putative heme exporter8–12, while FLVCR2 was suggested to act as a heme importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14–17. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across human plasma membranes, utilizing a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unraveled the coordination chemistry underlying their substrate interactions. Within the binding pocket of both transporters, we identify fully conserved tryptophan and tyrosine residues holding a central role in the formation of cation-π interactions, essential for choline and ethanolamine selectivity. Our findings not only clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhancing our comprehension of disease-associated mutations that interfere with these vital processes, but also shed light on the conformational dynamics of these MFS-type proteins during the transport cycle.
Metabolic differences between symbiont subpopulations in the deep-sea tubeworm Riftia pachyptila
(2020)
Hinzke, Tjorven ; Kleiner, Manuel ; Meister, Mareike ; Schlüter, Rabea ; Hentschker, Christian ; Pané-Farré, Jan ; Hildebrandt, Petra ; Felbeck, Horst ; Sievert, Stefan M. ; Bonn, Florian ; Völker, Uwe ; Becher, Dörte ; Schweder, Thomas ; Markert, Stephanie
The hydrothermal vent tube worm Riftia pachyptila lives in intimate symbiosis with intracellular sulfur-oxidizing gammaproteobacteria. Although the symbiont population consists of a single 16S rRNA phylotype, bacteria in the same host animal exhibit a remarkable degree of metabolic diversity: They simultaneously utilize two carbon fixation pathways and various energy sources and electron acceptors. Whether these multiple metabolic routes are employed in the same symbiont cells, or rather in distinct symbiont subpopulations, was unclear. As Riftia symbionts vary considerably in cell size and shape, we enriched individual symbiont cell sizes by density gradient centrifugation in order to test whether symbiont cells of different sizes show different metabolic profiles. Metaproteomic analysis and statistical evaluation using clustering and random forests, supported by microscopy and flow cytometry, strongly suggest that Riftia symbiont cells of different sizes represent metabolically dissimilar stages of a physiological differentiation process: Small symbionts actively divide and may establish cellular symbiont-host interaction, as indicated by highest abundance of the cell division key protein FtsZ and highly abundant chaperones and porins in this initial phase. Large symbionts, on the other hand, apparently do not divide, but still replicate DNA, leading to DNA endoreduplication. Highest abundance of enzymes for CO2 fixation, carbon storage and biosynthesis in large symbionts indicates that in this late differentiation stage the symbiont’s metabolism is efficiently geared towards the production of organic material. We propose that this division of labor between smaller and larger symbionts benefits the productivity of the symbiosis as a whole.
Korinthenberg, Rudolf ; Bast, Thomas ; Haberlandt, Edda ; Stephani, Ulrich ; Strzelczyk, Adam ; Rücker, Gerta
We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52–0.67) and 0.56 (95% CI 0.43–0.68). The relapse rate was high (PP 0.33, 95% CI 0.27–0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and “symptomatic” etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48–0.89) or corticosteroids (PP 0.72, 95% CI 0.54–0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02–0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.
Key points
* Systematic review resulting in low to moderately solid evidence on the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroid treatment in children with epilepsy other than infantile spasms.
* Meta-analysis based on aggregate data from 2 controlled prospective, 5 uncontrolled prospective, and 31 retrospective studies.
* Pooled data showing a seizure response in 60% and electroencephalography (EEG) response in 56% of patients, with no major differences between drugs. However, 30%–40% of patients relapse after the cessation of treatment.
* The most frequent adverse effects are obesity and Cushing's syndrome, occurring in 70% of patients under continuous treatment for some weeks, but in less than 10% undergoing pulsed, intermittent regimens.
* More prospective, randomized-controlled studies are needed to improve the level of evidence and define the optimal doses and treatment duration.
Mann, Leonhard ; Rosenow, Felix ; Strzelczyk, Adam ; Hattingen, Elke ; Willems, Laurent M. ; Harter, Patrick Nikolaus ; Weber, Katharina ; Mann, Catrin
Background: Epilepsy surgery is an established treatment for drug-resistant focal epilepsy (DRFE) that results in seizure freedom in about 60% of patients. Correctly identifying an epileptogenic lesion in magnetic resonance imaging (MRI) is challenging but highly relevant since it improves the likelihood of being referred for presurgical diagnosis. The epileptogenic lesion’s etiology directly relates to the surgical intervention’s indication and outcome. Therefore, it is vital to correctly identify epileptogenic lesions and their etiology presurgically.
Methods: We compared the final histopathological diagnoses of all patients with DRFE undergoing epilepsy surgery at our center between 2015 and 2021 with their MRI diagnoses before and after presurgical diagnosis at our epilepsy center, including MRI evaluations by expert epilepsy neuroradiologists. Additionally, we analyzed the outcome of different subgroups.
Results: This study included 132 patients. The discordance between histopathology and MRI diagnoses significantly decreased from 61.3% for non-expert MRI evaluations (NEMRIs) to 22.1% for epilepsy center MRI evaluations (ECMRIs; p < 0.0001). The MRI-sensitivity improved significantly from 68.6% for NEMRIs to 97.7% for ECMRIs (p < 0.0001). Identifying focal cortical dysplasia (FCD) and amygdala dysplasia was the most challenging for both subgroups. 65.5% of patients with negative NEMRI were seizure-free 12 months postoperatively, no patient with negative ECMRI achieved seizure-freedom. The mean duration of epilepsy until surgical intervention was 13.6 years in patients with an initial negative NEMRI and 9.5 years in patients with a recognized lesion in NEMRI.
Conclusions: This study provides evidence that for patients with DRFE—especially those with initial negative findings in a non-expert MRI—an early consultation at an epilepsy center, including an ECMRI, is important for identifying candidates for epilepsy surgery. NEMRI-negative findings preoperatively do not preclude seizure freedom postoperatively. Therefore, patients with DRFE that remain MRI-negative after initial NEMRI should be referred to an epilepsy center for presurgical evaluation. Nonreferral based on NEMRI negativity may harm such patients and delay surgical intervention. However, ECMRI-negative patients have a reduced chance of becoming seizure-free after epilepsy surgery. Further improvements in MRI technique and evaluation are needed and should be directed towards improving sensitivity for FCDs and amygdala dysplasias.
Background: Patients with epilepsy often require a specialized treatment, which may differ because of the responsibility of the federal states for healthcare policy in Germany.
Objective: State-specific differences in healthcare structures based on inpatient hospital cases of epilepsy patients between 2000 and 2020 in relation to specialized treatment offers.
Material and methods: The inpatient hospital cases of the German federal states were evaluated using the Friedman test and time series trend analysis. A state-specific inpatient undertreatment or overtreatment of inpatient hospital cases outside the registered state was analyzed by comparing residence-related and treatment site-related case numbers with a threshold of ±5%.
Results: After age adjustment, significantly more inpatient cases were found in the “new states” compared to the “old states” (p < 0.001); the highest number of cases nationwide was found in Saarland with 224.8 ± 11.5 cases per 100,000 inhabitants. The trend analysis showed an increase in cases until the end of 2016 with a trend reversal from 2017 and a further significant decrease in hospital cases in the COVID year 2020. A relative inpatient undertreatment was shown for Brandenburg, Lower Saxony, Rhineland-Palatinate, Saxony-Anhalt, Schleswig-Holstein and Thuringia. Additional, possibly compensatory, inpatient care was found for all city states (Hamburg, Bremen and Berlin) and Baden-Wuerttemberg. In federal states with a relative inpatient undertreatment and/or high inpatient hospital case numbers, there was often a lower availability of specialized epilepsy centers, specialized outpatient clinics and epilepsy outpatient clinics.
Conclusion: In Germany there are state-specific differences in the structure of care, with higher inpatient hospital care in the “new states” and Saarland. In addition, there were federal states with disproportionately higher treatment of patients not registered in this federal state. A potential influencing factor may be the availability of centers with specialized treatment for epilepsy patients.
The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs.
Tuberous sclerosis complex (TSC) is a rare genetic disease that is, besides cutaneous and visceral organ manifestations, typically associated with a severe, usually drug refractory epilepsy at a very early stage of the disease. Due to its direct effect on the mTOR signaling pathway dysregulated by TSC and its synergistic effects on other organ manifestations, the rapamycin derivative everolimus (EVE) is increasingly being used. The aim of this systematic review is to evaluate the efficacy, safety and tolerability of EVE in patients with TSC-associated, refractory epilepsy.
Vovchenko, Volodymyr ; Brandt, Bastian Benjamin ; Cuteri, Francesca ; Endrődi, Gergely ; Hajkarim, Fazlollah ; Schaffner-Bielich, Jürgen
We investigate the possible formation of a Bose-Einstein condensed phase of pions in the early Universe at nonvanishing values of lepton flavor asymmetries. A hadron resonance gas model with pion interactions, based on first-principle lattice QCD simulations at nonzero isospin density, is used to evaluate cosmic trajectories at various values of electron, muon, and tau lepton asymmetries that satisfy the available constraints on the total lepton asymmetry. The cosmic trajectory can pass through the pion condensed phase if the combined electron and muon asymmetry is sufficiently large: |le+lμ|≳0.1, with little sensitivity to the difference le−lμ between the individual flavor asymmetries. Future constraints on the values of the individual lepton flavor asymmetries will thus be able to either confirm or rule out the condensation of pions during the cosmic QCD epoch. We demonstrate that the pion condensed phase leaves an imprint both on the spectrum of primordial gravitational waves and on the mass distribution of primordial black holes at the QCD scale, e.g., the black hole binary of recent LIGO event GW190521 can be formed in that phase.
Ablikim, Medina ; Achasov, Mikhail N. ; Adlarson, Patrik ; Ahmed, Samer ; Albrecht, Malte ; Aliberti, Riccardo ; Amoroso, Antonio ; An, Q. ; Bai, X. H. ; Bai, Y. ; Bakina, Olga ; Baldini Ferroli, Rinaldo ; Balossino, Ilaria ; Ban, Yong ; Begzsuren, Khurelbaatar ; Berger, Niklaus ; Bertani, Monica ; Bettoni, Diego ; Bianchi, Fabrizio ; Biernat, Jacek ; Bloms, Johannes ; Bortone, Alberto ; Boyko, Igor R. ; Briere, Roy A. ; Cai, H. ; Cai, X. ; Calcaterra, Alessandro ; Cao, G. F. ; Cao, N. ; Çetin, Serkant Ali ; Chang, Jinfan ; Chang, W. L. ; Chelkov, Gueorgui A. ; Chen, D. Y. ; Chen, G. ; Chen, Hesheng ; Chen, M. L. ; Chen, S. J. ; Chen, X. R. ; Chen, Yuanbo ; Chen, Z. J. ; Cheng, W. S. ; Cibinetto, Gianluigi ; Cossio, Fabio ; Cui, X. F. ; Dai, Hongliang ; Dai, Xinchen ; Dbeyssi, Alaa ; Boer, Remco E. de ; Dedovich, Dmitri V. ; Deng, Ziyan ; Denig, Achim ; Denysenko, Igor ; Destefanis, Marco Giovanni Maria ; De Mori, Francesca ; Ding, Y. ; Dong, C. ; Dong, J. ; Dong, Liaoyuan ; Dong, Mingyi ; Dong, X. ; Du, Shuxian ; Fang, J. ; Fang, Shuangshi ; Fang, Y. ; Farinelli, Riccardo ; Fava, Luciano ; Feldbauer, Florian ; Felici, Giulietto ; Feng, C. Q. ; Fritsch, Miriam ; Fu, Chengdong ; Gao, Y. ; Gao, Y. ; Gao, Y. ; Gao, Y. G. ; Garzia, I. ; Gersabeck, Evelina ; Gilman, A. ; Goetzen, Klaus ; Gong, L. ; Gong, Wenxuan ; Gradl, Wolfgang ; Greco, M. ; Gu, L. M. ; Gu, Minhao ; Gu, S. ; Gu, Y. T. ; Guan, C. Y. ; Guo, Aiqiang ; Guo, L. B. ; Guo, R. P. ; Guo, Yuping ; Guskov, Alexey ; Han, T. T. ; Hao, Xiqing ; Harris, F. A. ; Hüsken, Nils ; He, K. L. ; Heinsius, Fritz-Herbert ; Heinz, C. H. ; Held, T. ; Heng, Yuekun ; Herold, Christoph ; Himmelreich, Mathilde ; Holtmann, Tobias ; Hou, Y. R. ; Hou, Zhilong ; Hu, Haiming ; Hu, J. F. ; Hu, T. ; Hu, Y. ; Huang, G. S. ; Huang, L. Q. ; Huang, X. T. ; Huang, Y. P. ; Huang, Z. ; Hussain, Tahir ; Ikegami Andersson, Walter ; Imoehl, William ; Irshad, M. ; Jaeger, S. ; Janchiv, S. ; Ji, Quan ; Ji, Qingping ; Ji, X. B. ; Ji, X. L. ; Jiang, H. B. ; Jiang, Xiaoshan ; Jiao, J. B. ; Jiao, Z. ; Jin, Shan ; Jin, Y. ; Johansson, Tord ; Kalantar-Nayestanaki, Nasser ; Kang, X. S. ; Kappert, Rosa ; Kavatsyuk, Myroslav O. ; Ke, B. C. ; Keshk, I. K. ; Khoukaz, Alfons ; Kiese, P. ; Kiuchi, R. ; Kliemt, Ralf ; Koch, L. ; Kolcu, Onur Bugra ; Kopf, Bertram ; Kuemmel, M. ; Küßner, Meike ; Kupsc, Andrzej ; Kurth, M. G. ; Kühn, Wolfgang ; Lane, John Jake ; Lange, Jens Sören ; Larin, Paul ; Lavania, Anita ; Lavezzi, Lia ; Lei, Z. H. ; Leithoff, H. ; Lellmann, Max ; Lenz, Thomas ; Li, C. ; Li, C. H. ; Li, Cheng ; Li, D. M. ; Li, F. ; Li, G. ; Li, H. ; Li, H. ; Li, Haibo ; Li, H. J. ; Li, J. L. ; Li, J. Q. ; Li, Ke ; Li, L. K. ; Li, Lei ; Li, P. L. ; Li, P. R. ; Li, S. Y. ; Li, Weidong ; Li, Weiguo ; Li, X. H. ; Li, X. L. ; Li, Z. Y. ; Liang, H. ; Liang, H. ; Liang, H. ; Liang, Y. F. ; Liang, Y. T. ; Liao, L. Z. ; Libby, J. ; Lin, C. X. ; Liu, B. J. ; Liu, C. X. ; Liu, D. ; Liu, Fu-Hu ; Liu, Fang ; Liu, Feng ; Liu, H. B. ; Liu, H. M. ; Liu, Huanhuan ; Liu, Huihui ; Liu, J. B. ; Liu, J. Y. ; Liu, K. ; Liu, K. Y. ; Liu, Ke ; Liu, L. ; Liu, M. H. ; Liu, Q. ; Liu, S. B. ; Liu, Shuai ; Liu, T. ; Liu, W. M. ; Liu, X. ; Liu, Y. B. ; Liu, Zhen-An ; Liu, Z. Q. ; Lou, Xinchou ; Lu, F. X. ; Lu, H. J. ; Lu, J. D. ; Lu, Junguang ; Lu, X. L. ; Lu, Y. ; Lu, Yunpeng ; Luo, Chenglin ; Luo, M. X. ; Luo, P. W. ; Luo, T. ; Luo, X. L. ; Lusso, S. ; Lyu, Xiao-Rui ; Ma, Fengcai ; Ma, H. L. ; Ma, Lianliang ; Ma, M. M. ; Ma, Qiumei ; Ma, R. Q. ; Ma, R. T. ; Ma, X. X. ; Ma, Xiaoyan ; Maas, Frank E. ; Maggiora, Marco ; Maldaner, Stephan ; Malde, Sneha ; Mangoni, Alessio ; Mao, Yajun ; Mao, Zepu ; Marcello, Simonetta ; Meng, Z. X. ; Messchendorp, Johannes Gerhardus ; Mezzadri, Giulio ; Min, T. J. ; Mitchell, Ryan Edward ; Mo, Xiaohu ; Mo, Y. J. ; Muchnoi, Nikolai Yu. ; Muramatsu, H. ; Nakhoul, Simon ; Nefedov, Yury ; Nerling, Frank ; Nikolaev, Ivan Borisovich ; Ning, Z. ; Nisar, Shabana ; Olsen, Stephen L. ; Ouyang, Qun ; Pacetti, Simone ; Pan, X. ; Pan, Y. ; Pathak, A. ; Patteri, P. ; Pelizäus, Marc ; Peng, H. P. ; Peters, Klaus ; Pettersson, J. ; Ping, J. L. ; Ping, R. G. ; Pitka, A. ; Poling, Ronald ; Prasad, Vindhyawasini ; Qi, H. ; Qi, H. R. ; Qi, K. H. ; Qi, Ming ; Qi, T. Y. ; Qi, T. Y. ; Qian, S. ; Qian, W. B. ; Qian, Z. ; Qiao, Congfeng ; Qin, L. Q. ; Qin, X. S. ; Qin, Zhonghua ; Qiu, Jinfa ; Qu, S. Q. ; Ravindran, Krishnakumar ; Redmer, Christoph Florian ; Rivetti, Angelo ; Rodin, Viktor ; Da Rocha Rolo, Manuel Dionisio ; Rong, Gang ; Rosner, Christoph ; Rump, Marcel Andre ; Sang, H. S. ; Sarantsev, Andrei V. ; Schelhaas, Yasemin ; Schnier, Claudius ; Schönning, Karin ; Scodeggio, Marco ; Shan, D. C. ; Shan, Wei ; Shan, Xinyu ; Shao, M. ; Shen, C. P. ; Shen, P. X. ; Shen, X. Y. ; Shi, H. C. ; Shi, R. S. ; Shi, X. ; Shi, X. D. ; Song, J. J. ; Song, W. M. ; Song, Y. X. ; Sosio, Stefano ; Spataro, Stefano ; Su, K. X. ; Sui, F. F. ; Sun, Gongxing ; Sun, H. K. ; Sun, J. F. ; Sun, L. ; Sun, S. S. ; Sun, T. ; Sun, W. Y. ; Sun, X. ; Sun, Y. J. ; Sun, Y. K. ; Sun, Y. Z. ; Sun, Z. T. ; Tan, Y. H. ; Tan, Y. X. ; Tang, C. J. ; Tang, G. Y. ; Tang, J. ; Teng, J. X. ; Thoren, Viktor ; Uman, Ismail ; Wang, B. ; Wang, C. W. ; Wang, D. Y. ; Wang, H. P. ; Wang, K. ; Wang, L. L. ; Wang, M. ; Wang, M. Z. ; Wang, Meng ; Wang, W. H. ; Wang, W. P. ; Wang, X. ; Wang, X. F. ; Wang, X. L. ; Wang, Y. ; Wang, Y. ; Wang, Y. D. ; Wang, Y. F. ; Wang, Y. Q. ; Wang, Z. ; Wang, Z. Y. ; Wang, Ziyi ; Wang, Zongyuan ; Wei, D. H. ; Weidenkaff, P. ; Weidner, Frederik ; Wen, Shuopin ; White, D. J. ; Wiedner, Ulrich ; Wilkinson, G. ; Wolke, Magnus ; Wollenberg, Leonard ; Wu, J. F. ; Wu, L. H. ; Wu, L. J. ; Wu, X. ; Wu, Z. ; Xia, L. ; Xiao, H. ; Xiao, S. Y. ; Xiao, Zhenjun ; Xie, X. H. ; Xie, Y. G. ; Xie, Y. H. ; Xing, T. Y. ; Xu, Guofa ; Xu, J. J. ; Xu, Q. J. ; Xu, W. ; Xu, Xinping ; Xu, Y. C. ; Yan, F. ; Yan, L. ; Yan, L. ; Yan, W. B. ; Yan, W. C. ; Yan, Xu ; Yang, H. J. ; Yang, Hongxun ; Yang, L. ; Yang, S. L. ; Yang, Y. H. ; Yang, Yongxu ; Yang, Yifan ; Yang, Zhi ; Ye, M. ; Ye, Minghan ; Yin, J. H. ; You, Z. Y. ; Yu, Boxiang ; Yu, C. X. ; Yu, G. ; Yu, J. S. ; Yu, T. ; Yuan, Chang-Zheng ; Yuan, L. ; Yuan, W. ; Yuan, X. Q. ; Yuan, Y. ; Yuan, Z. Y. ; Yue, C. X. ; Yuncu, A. ; Zafar, A. A. ; Zeng, Y. ; Zhang, B. X. ; Zhang, Guangyi ; Zhang, H. ; Zhang, H. H. ; Zhang, H. H. ; Zhang, Hongyu ; Zhang, J. J. ; Zhang, J. L. ; Zhang, J. Q. ; Zhang, J. W. ; Zhang, Jianyong ; Zhang, J. Z. ; Zhang, Jianyu ; Zhang, Jiawei ; Zhang, Lei ; Zhang, S. ; Zhang, S. F. ; Zhang, X. D. ; Zhang, X. Y. ; Zhang, Y. ; Zhang, Y. H. ; Zhang, Y. T. ; Zhang, Yan ; Zhang, Yao ; Zhang, Yi ; Zhang, Z. H. ; Zhang, Z. Y. ; Zhao, G. ; Zhao, J. ; Zhao, J. Y. ; Zhao, J. Z. ; Zhao, Lei ; Zhao, Ling ; Zhao, Ming-Gang ; Zhao, Q. ; Zhao, Shujun ; Zhao, Yubin ; Zhao, Y. X. ; Zhao, Zhengguo ; Zhemchugov, Alexey ; Zheng, B. ; Zheng, Jianping ; Zheng, Y. ; Zheng, Y. H. ; Zhong, B. ; Zhong, C. ; Zhou, L. P. ; Zhou, Q. ; Zhou, X. ; Zhou, X. K. ; Zhou, X. R. ; Zhu, A. N. ; Zhu, J. ; Zhu, K. ; Zhu, Kejun ; Zhu, S. H. ; Zhu, W. J. ; Zhu, Y. C. ; Zhu, Zian ; Zou, B. S. ; Zou, Jiaheng
The Born cross sections and effective form factors for process 𝑒+𝑒−→Ξ−¯Ξ+ are measured at eight center-of-mass energies between 2.644 and 3.080 GeV, using a total integrated luminosity of 363.9 pb−1 𝑒+𝑒− collision data collected with the BESIII detector at BEPCII. After performing a fit to the Born cross section of 𝑒+𝑒−→Ξ−¯Ξ+, no significant threshold effect is observed.
Schubert-Bast, Susanne ; Kaur, Moninder ; Jöres, Lars ; Foskett, Nadia ; Roebling, Robert ; Strzelczyk, Adam
The present study aims to report the currently available epidemiology of focal onset seizures in children aged >1 month to 4 years with the help of a literature review. The terms ‘seizure*’ OR ‘epilepsy’ combined with pediatric and epidemiology terms were used to search Embase, PubMed, and Web of Science up to November 16, 2021. Due to the scarcity of epidemiology data on focal onset seizures, the incidence and prevalence were estimated using the proportion of focal onset seizures in epilepsy patients from the most recently published articles. The estimated annual incidence per 100,000 children of focal onset seizures in children of 0–4 years of age ranged from 25.1 (95 % confidence interval [CI] 18.9–32.7) in the United Kingdom to 111.8 in the United States. The estimated period prevalence of focal onset seizures in children 0–4 years of age ranged from 0.15 % (99 % CI 0.13–0.18) in Canada to 0.61 % in the United States. Neurodevelopmental outcomes and psychiatric disorders were the most commonly reported comorbidities in children with epilepsy of age 0–4 years. Presence of focal onset seizures in children with different epilepsy syndromes needs to be thoroughly considered in the treatment planning of this population of interest.
Bauer, Kristina ; Rosenow, Felix ; Knake, Susanne ; Willems, Laurent M. ; Kämppi, Leena ; Strzelczyk, Adam
Background: Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses.
Methods: In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection.
Results: We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients.
Conclusions: This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.
Strzelczyk, Adam ; Schubert-Bast, Susanne ; Simon, Andreas ; Wyatt, Geoffrey ; Holland, Rowena ; Rosenow, Felix
Highlights
• German patients with LGS identified using most specific algorithm to date.
• Prevalence of probable LGS with epilepsy diagnosis before age 6 was 6.5 per 100,000.
• High healthcare costs of €22,787 PPY; mostly due to inpatient and home nursing care.
• Costs were greater in patients prescribed rescue medications.
• Over 10 years, LGS patients had significant mortality vs. controls (2.88 vs. 0.01%).
Abstract
Objective: This retrospective study examined patients with probable Lennox-Gastaut syndrome (LGS) identified from German healthcare data.
Methods: This 10-year study (2007–2016) assessed healthcare insurance claims information from the Vilua Healthcare research database. A selection algorithm considering diagnoses and drug prescriptions identified patients with probable LGS. To increase the sensitivity of the identification algorithm, two populations were defined: all patients with probable LGS (broadly defined) and only those with a documented epilepsy diagnosis before 6 years of age (narrowly defined). This specific criterion was used as LGS typically has a peak seizure onset between age 3 and 5 years. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, hospitalization rate and length of stay (LOS), medication use, and mortality.
Results: In the final year of the study, 545 patients with broadly defined probable LGS (mean [range] age: 31.4 [2–89] years; male: 53%) were identified. Using the narrowly defined probable LGS definition, the number of patients was reduced to 102 (mean [range] age: 7.4 [2–14] years; male: 52%). Prevalence of broadly defined and narrowly defined probable LGS was 39.2 and 6.5 per 100,000 people. During the 10-year study, 208 patients with narrowly defined probable LGS were identified and followed up for 1379 patient-years. The mean annual cost of healthcare was €22,787 per patient-year (PPY); greatest costs were attributable to inpatient care (33%), home nursing care (13%), and medication (10%). Mean annual healthcare costs were significantly greater for those with prescribed rescue medication (45% of patient-years) versus those without (€33,872 vs. €13,785 PPY, p < 0.001). Mean (standard deviation [SD]) annual hospitalization rate was 1.6 (2.0) PPY with mean (SD) annual LOS of 22.7 (46.0) days. Annual hospitalization rate was significantly greater in those who were prescribed rescue medication versus those who were not (2.2 [2.3] vs. 1.1 [1.6] PPY, p < 0.001). The mean (SD) number of different medications prescribed was 11.3 (7.3) PPY and 33.8 (17.0) over the entire observable time per patient (OET); antiepileptic drugs only accounted for 2.1 (1.1) of the medications prescribed PPY and 3.8 (2.0) OET. Over the 10-year study period, mortality in patients with narrowly defined probable LGS was significantly higher than the matched control population (six events [2.88%] vs. one event [0.01%], p < 0.001).
Conclusion: Annual healthcare costs incurred by patients with probable LGS in Germany were substantial, and mostly attributable to inpatient care, home nursing care, and medication. Patients prescribed with rescue medication incurred significantly greater costs than those who were not. Patients with narrowly defined probable LGS had a higher mortality rate versus control populations.
Schubert-Bast, Susanne ; Kay, Lara ; Simon, Andreas ; Wyatt, Geoffrey ; Holland, Rowena ; Rosenow, Felix ; Strzelczyk, Adam
Highlights
• Prevalence of probable DS identified from German healthcare data: 4.7 per 100,000.
• Healthcare costs: €11,048 per patient-year, mostly inpatient care 47%, medication 26%.
• Costs and hospitalizations greater in patients with rescue medication than without.
• Mean (SD) of 5.0 (2.5) different ASMs prescribed per patient over study period.
• Patients with probable DS had significantly higher mortality risk vs. controls (11.88% vs. 1.19%).
Abstract
Objective: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data.
Methods: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality.
Results: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3–82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001).
Conclusion: Probable DS is associated with substantial healthcare costs in Germany.
How the brain evolved remains a mystery. The goal of this thesis is to understand the fundamental processes that are behind the evolutionary history of the brain. Amniotes appeared 320 million years ago with the transition from water to land. This early group bifurcated into sauropsids (reptiles and birds) and synapsids (mammals). Amniote brains evolved separately and display obvious structural and functional differences. Although those differences reflect brain diversification, all amniote brains share a common ancestor and their brains show multiple derived similarities: equivalent structures, networks, circuits and cell types have been preserved during millions of years. Finding these differences and similarities will help us understand brain historical evolution and function. Studying brain evolution can be approached from various levels, including brain structure, circuits, cell types, and genes. We propose a focus on cell types for a more comprehensive understanding of brain evolution. Neurons are the basic building blocks and the most diverse cell types in the brain. Their evolution reflects changes in the developmental processes that produce them, which in turn may shape the neural circuits they belong to. However, there is currently a lack of a unified criteria for studying the homology of connectivity and development between neurons. A neuron’s transcriptome is a molecular representation of its identity, connectivity, and developmental/evolutionary history. Hence the comparison of neuronal transcriptomes within and across species is a new and transformative development in the study of brain evolution. As an alternative, comparing neuronal transcriptomes across different species can provide insights into the evolution of the brain. We propose that comparing transcriptomes can be a way to fill this gap and unify these criteria. In previous studies, published in Science (Tosches et al., 2018) and Nature (Norimoto et al., 2020), we leveraged scRNAseq in reptiles to re-evaluate the origins and evolution of the mammalian cerebral cortex and claustrum. Motivated by the success of this approach, in this thesis we have now expanded single-cell profiling to the entire brain of a lizard species, the Australian dragon Pogona vitticeps, with a special focus in thalamus and prethalamus of. This approach allowed us to study the evolution of neuron types in amniotes. Therefore, we aimed to build a multilevel atlas of the lizard brain based on histology and transcriptomic and compare it to an equal mouse dataset (Zeisel et al., 2018).
Our atlas reveals a general structure that is consistent with that for other amniote brains, allowing us to make a direct comparison between lizard and mouse, despite their evolutionary divergence 320 million years ago. Through our analysis of the transcriptomes present in various neuron types, we have uncovered a core of conserved classes and discovered a fascinating dichotomy of new and conserved neuron types throughout the brain. This research challenges the traditional notion that certain brain regions are more conserved than others.
Our research also has uncovered the evolutionary history of the lizard thalamus and prethalamus by comparing them to homologous brain regions of the mouse. This pioneering research sheds new light on our understanding of the evolutionary history of the lizard brain. We propose a new classification of the lizard thalamic nuclei based on
transcriptomics. Our research revealed that the thalamic neuron types in lizards can be grouped into two large, conserved categories from the medial to lateral thalamus. These categories are encoded by a common set of effector genes, linking theories based on connectivity and molecular studies of these areas. In our data we have seen that there is a conservation of the medial-lateral transcriptomic axis in mouse and lizard, this conservation was most likely already present in the common ancestor. Although there is a shared medial-lateral axis, a deeper study of the thalamic cell types has allowed us to see the existence of a partial diversification of the thalamic population, specifically in the sensory-related lateral thalamus; in opposition, the medial thalamic nuclei neuron-types have been preserved.
On the other hand, the comparison with the mammalian prethalamus allowed us to confirm that the lizard ventromedial thalamic neuron types are homologous to mouse reticular thalamic neuron types (Díaz et al., 1994), even if they do not express the classical Reticular thalamic nucleus (RTn) marker PV/pvalb. We also discovered that there has been a simplification in the mammalian prethalamic neuron types in favor of an increase in the number of Interneurons (IN) types within their thalamus. We suggest that the loss of GABAergic neuronal types in the mammalian prethalamus is linked to the need for a more efficient control of the thalamo-pallial communication in mammals, while in lizards, where thalamo-pallial communication is probably simpler, the diversity prethalamus presents a higher diversity.
Biological membranes serve as physical barriers in cells and organelles, enabling the maintenance of chemical or ionic gradients that are essential for triggering various integral, peripheral, or lipid-anchored membrane proteins, necessary for their life-essential functions. The study of membrane proteins has unique challenges due to their hydrophobic nature, limited expression levels, and inherent flexibility. Single-particle analysis (SPA) enables the determination of high-resolution three-dimensional structures using minimal amounts of specimen without the need for crystallization. Additionally, cryogenic electron tomography (cryo-ET) and subtomogram averaging (StA) offer the ability to study membrane protein complexes, cellular architecture, and molecular interactions while preserving close-to-life conditions. With ongoing improvements in cryo-EM technologies, obtaining high-resolution structures of membrane proteins in vitro can allow people to understand their mechanisms and functions, and to facilitate the design and optimization of new therapeutic agents. Furthermore, there has been significant growth in the structural characterization of membrane proteins in situ, as studying biomolecules within their physiological context is an ultimate goal in structural biology for a comprehensive understanding of molecular networks in cells.
Due to the amphipathic nature of membrane proteins, their production, purification, and isolation pose significant challenges compared to soluble proteins. To maintain the membrane protein fold in an aqueous buffer after disrupting lipid membranes, the use of detergents, amphipols, lipid nanodiscs, saposin-lipoprotein (salipro), styrene-maleic acid co-polymer lipid particles (SMALPS) is common and often essential. A limitation of the membrane-mimetic systems is the absence of an actual lipid bilayer environment. To address this issue, membrane proteins can be reconstituted into liposomes, and this closed membrane environment closely mimics the physiological conditions of the proteins. The use of liposomes for structure determination is expected to significantly expand in the in vitro study of membrane proteins and membrane-associated proteins, particularly for capturing transient complexes in specific functional states.
Resolving the structures of membrane proteins in their native cellular context is considered the ideal approach for understanding their functions and associated molecular networks. While single-particle cryo-EM can achieve higher resolution than subtomogram averaging, it often requires at least partial purification of the target molecules from their native environment inside cells and tissues. By combining averaging tools on subvolumes obtained through cryo-ET, structures can currently be determined at resolutions of 10-30 Å. With ongoing advancements and refinements in cryo-ET methodologies, routine high-resolution structure determination in situ is poised to become a valuable tool for both structural and cell biologists in the long run, and the field holds great promise for further expanding our understanding of cellular structures and processes at the molecular level.
The main aim of this thesis is to further our knowledge of the structure and function of a small prokaryotic voltage-gated sodium ion channel, NaChBac in liposomes, and a large knob complex found on the surface of Plasmodium falciparum-infected human erythrocyte by cryo-ET and StA.
Chapter 2 presents the first StA map of the 120-kDa NaChBac embedded in liposomes under a resting membrane potential at a modest resolution of 16 Å. The approach presented in this study, which can be widely applied to cryo-EM analysis of membrane proteins, with a specific focus on membrane proteins with small soluble domains, lays the foundation for cryo-ET and StA of integral or peripheral membrane proteins whose functions are affected by transmembrane electrochemical gradients and/or membrane curvatures. Chapter 3 shows the first cryo-EM structure of the supramolecular knob complex in P. falciparum-infected human erythrocyte. While a previous study provided an overall architectural view of knobs using negative stain tomography, the in situ structure bridges this gap, guiding future investigations into the molecular composition and the role of these native knobs in Plasmodium infection and immunity.
This thesis opens up several promising lines for future studies of membrane proteins in vitro and in situ, where other membrane proteins can be studied in physiologically relevant environments. Already with the present generation of cryo-EM hardware and software, this thesis represents pioneering research in the field of membrane protein structural biology.
Klein, Joachim ; Nolden, Mark ; Sanders, Steven L. ; Kirchner, Jay ; Weil, P. Anthony ; Melcher, Karsten
An important goal is to identify the direct activation domain (AD)-interacting components of the transcriptional machinery within the context of native complexes. Toward this end, we first demonstrate that the multisubunit TFIID, SAGA, mediator, and Swi/Snf coactivator complexes from transcriptionally competent whole-cell yeast extracts were all capable of specifically interacting with the prototypic acidic ADs of Gal4 and VP16. We then used hexahistidine tags as genetically introduced activation domain-localized cross-linking receptors. In combination with immunological reagents against all subunits of TFIID and SAGA, we systematically identified the direct AD-interacting subunits within the AD-TFIID and AD-SAGA coactivator complexes enriched from whole-cell extracts and confirmed these results using purified TFIID and partially purified SAGA. Both ADs directly cross-linked to TBP and to a subset of TFIID and SAGA subunits that carry histone-fold motifs.
Mnemonic but not contextual feedback signals defy dedifferentiation in the aging early visual cortex
(2024)
Perception is an intricate interplay between feedforward visual input and internally generated feedback signals that comprise concurrent contextual and time-distant mnemonic (episodic and semantic) information. Yet, an unresolved question is how the composition of feedback signals changes across the lifespan and to what extent feedback signals undergo age-related dedifferentiation, that is, a decline in neural specificity. Previous research on this topic has focused on feedforward perceptual representation and episodic memory reinstatement, suggesting reduced fidelity of neural representations at the item and category levels. In this fMRI study, we combined an occlusion paradigm that filters feedforward input to the visual cortex and multivariate analysis techniques to investigate the information content in cortical feedback, focusing on age-related differences in its composition. We further asked to what extent differentiation in feedback signals (in the occluded region) is correlated to differentiation in feedforward signals. Comparing younger (18–30 years) and older female and male adults (65–75 years), we found that contextual but not mnemonic feedback was prone to age-related dedifferentiation. Semantic feedback signals were even better differentiated in older adults, highlighting the growing importance of generalized knowledge across ages. We also found that differentiation in feedforward signals was correlated with differentiation in episodic but not semantic feedback signals. Our results provide evidence for age-related adjustments in the composition of feedback signals and underscore the importance of examining dedifferentiation in aging for both feedforward and feedback processing.
Generating predictions about environmental regularities, relying on these predictions, and updating these predictions when there is a violation from incoming sensory evidence are considered crucial functions of our cognitive system for being adaptive in the future. The violation of a prediction can result in a prediction error (PE) which affects subsequent memory processing. In our preregistered studies, we examined the effects of different levels of PE on episodic memory. Participants were asked to generate predictions about the associations between sequentially presented cue-target pairs, which were violated later with individual items in three PE levels, namely low, medium, and high PE. Hereafter, participants were asked to provide old/new judgments on the items with confidence ratings, and to retrieve the paired cues. Our results indicated a better recognition memory for low PE than medium and high PE levels, suggesting a memory congruency effect. On the other hand, there was no evidence of memory benefit for high PE level. Together, these novel and coherent findings strongly suggest that high PE does not guarantee better memory.
A remarkable part of children’ s development and education happens in educational institutions. Acoustic environments in these institutions are usually highly complex and noisy, hence it is demanding to identify relevant target speakers and to ignore irrelevant sounds. Previous research has analyzed auditory selective attention in adults, both in dichotic and binaural listening environments. Until now, there is little knowledge of auditory selective attention in children. In the present work, the original paradigm was adapted by using a task suited for children which included child-oriented elements. Further, the subject’s anthropometric sizes were considered for an aurally-accurate reproduction of the acoustic scene. Twenty-four adults and twenty-four children participated in an experiment on auditory selective attention. Noise and noise-free conditions and various target-distractor distributions in the room were analyzed among others. The result of this experiment revealed significant differences between adults and children, especially in the way auditory attention was influenced by noise.
Schommartz, Iryna ; Lembcke, Philip F. ; Pupillo, Francesco ; Schuetz, Henriette ; Wald de Chamorro, Nina ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
Highlights
• Short- and long-delay memory consolidation is less robust in children than in young adults.
• Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions.
• Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
• Brain profiles differ between children and young adults.
Abstract
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to memory consolidation processes. The present study examined memory consolidation of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory retention rate were related to structural brain measures. Our results showed that children, in comparison to young adults, retained correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal head and subfield structures in the body was found to be associated with variation in short-delay memory retention. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), hippocampal head, and selective hippocampal subfield structures (CA1–2 and subiculum) was associated with variation in long-delay memory retention. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
Schommartz, Iryna ; Lembcke, Philip F. ; Pupillo, Francesco ; Schuetz, Henriette ; Wald de Chamorro, Nina ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
RESEARCH HIGHLIGHTS
* Short- and long-delay memory consolidation is less robust in children than in young adults
* Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions
* Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
* Brain profiles differ between children and young adults.
Schommartz, Iryna ; Lembcke, Philip F. ; Schuetz, Henriette ; Wald de Chamorro, Nina ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
RESEARCH HIGHLIGHTS
Short- and long-delay memory consolidation is less robust in children than in young adults
* Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions
* Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
* Brain profiles differ between children and young adults.
Childhood is a period when memory consolidation and knowledge base undergo rapid changes. The present study examined short-delay (overnight) and long-delay (after a 2-week period) consolidation of new information either congruent or incongruent with prior knowledge in typically developing 6- to 8-year-old children (n = 32), 9- to 11-year-old children (n = 33), and 18- to 30-year-old young adults (YA; n = 39). Both memory accessibility (cued recall of objects) and precision (precision of object placement) of initially well-learned object–scene pairs were measured. Our results showed that overnight, memory accessibility declined similarly in all age groups; memory precision improved more in younger children (YC) compared to older children (OC) and even declined in YA. After a 2-week period, both memory accessibility and precision became worse. Specifically, while age groups showed similar decline in memory accessibility, precision decline was less in YC than in OC and YA. The accessibility and precision of congruent and incongruent information changed similarly with consolidation in all age groups. Taken together, our results showed that, for initially well-learned information, YC have robust memory consolidation, despite their overall lower mnemonic performance compared to OC and YA, which is potentially crucial for stable and precise knowledge accumulation early on in development.
Preparing auditory task switching in a task with overlapping and non-overlapping response sets
(2023)
We used a variant of cued auditory task switching to investigate task preparation and its relation to response-set overlap. Previous studies found increased interference with overlapping response sets across tasks relative to non-overlapping motor response sets. In the present experiments, participants classified either pitch or loudness of a simple tone as low or high, hence, both tasks were constructed around common underlying integrated semantic categories ranging from low to high. Manual responses overlapped in both category and modality for both tasks in Experiment 1A, whereas each task was related to a specific response category and response modality (manual vs. vocal) in Experiment 1B. Focusing on the manual responses in both experiments, the data showed that non-overlapping response sets (Experiment 1B) resulted in a decreased congruency effect, suggesting reduced response-based crosstalk and thus better task shielding, but at the same time switch costs were increased, suggesting less efficient switching between task sets. Moreover, varying preparation time (cue-stimulus interval, CSI) showed that long CSI led to better performance overall. Our results thus suggest that when non-overlapping response sets share common semantic categories across tasks, there is no general benefit over overlapping response sets.
The role of response set overlap for flexibility and cognitive control in auditory multitasking
(2022)
Highlights
• We introduced a new variant of auditory task-switching.
• Motor response set overlap was varied systematically across two experiments.
• Switch costs and congruency effects were similar for manual and vocal responses.
• Switch costs were not reduced with reduced motor response set overlap.
• We dissociated effects of motor response modality from motor response set overlap.
Abstract
We developed a new variant of auditory task-switching in order to systematically investigate shifting and cognitive control in auditory task-switching and their relation to motor response overlap in a comprehensive way. In two experiments, participants classified either pitch or loudness of a simple tone as either low or high, hence, both tasks were constructed around a common underlying dimension ranging from low to high. In Experiment 1, response sets overlapped in both category and motor modality (both manual), whereas each task was related to a specific response category and motor response modality (manual vs. vocal) in Experiment 2. The data revealed reliable switch costs that were, contrary to our expectations, not reduced with reduced response set overlap. In addition, we found reliable congruency effects and their sequential modulation in both experiments with manual as well as vocal responses, and in the absence of competing motor activation (i.e., without motor response overlap). Congruency effects after auditory task switches were smaller when response sets did not overlap. Our data thus provides an important empirical generalization of known effects to auditory stimuli as well as with both manual and vocal responses. In addition, we demonstrated that reduced congruency effects after switches for non-overlapping response sets were due to the extent of overlap between different response sets in task-switching.
Strzelczyk, Adam ; Knake, Susanne ; Holtkamp, Martin ; Schulze-Bonhage, Andreas ; Lemke, Johannes ; Spiczak Brzezinski, Sarah von ; Berkenfeld, Ralf ; Rosenow, Felix ; Brandt, Christian ; Schmitt, Friedhelm C.
The Board of Directors of the German Society of Epileptology and the committee on epilepsy and syncope of the German Society of Neurology have reviewed the current data on vaccination to prevent coronavirus disease 2019 (COVID-19) and vaccination prioritization in people with epilepsy and provide a summary and recommendations.
100 Jahre Dieter Janz
(2020)
The 20 April 2020 marks the centenary of Dieter Janz’s birth. This issue of Zeitschrift für Epileptologie is published in his honor with the aim of tracing the work of Dieter Janz over the last five decades and summarizing new findings on the Janz syndrome (Juvenile Myoclonic Epilepsy), which is named after him.
The paper presents the findings of two recent books on the financial history of the Frankfurt School: Jeanette Erazo-Heufelder, Der argentinische Krösus: Kleine Wirtschaftsgeschichte der Frankfurter Schule, 2017, and Bertus Mulder, Sophie Louisa Kwaak und das Kapital der Unternehmerfamilie Weil. Ein Beitrag zur Wirtschaftsgeschichte der Frankfurter Schule, 2021 (Dutch original 2015). In contrast to the “court histories” of the school, the two authors tell the story of the money that brought the school to life and secured its existence throughout a turbulent period of history. At the center of the books are individuals who have been sidelined until now or even completely ignored by the literature on the Frankfurt School: on the one hand, Felix Weil, who founded and financed the Institute of Social Research and, on the other hand, Erich A. Nadel and Sophie L. Kwaak, two employees of the holding company who managed the accounts of the Weil family and the Institute’s foundations and were responsible for protecting the assets from being seized by Nazis. The books’ thick descriptions induced the author of the present paper to consider an alternative perspective on the Frankfurt School by contemplating Max Horkheimer and Friedrich Pollock as playing confidential games with Weil and others.
Background: The Association of the Scientific Medical Societies in Germany (AWMF) clinical practice guideline on cochlear implant (CI) treatment, which was updated in 2020, defined the entire process of CI care for the first time. In the present study, the feasibility and results of very early rehabilitation were examined.
Materials and methods: The intervention group (IG) comprised 54 patients in whom rehabilitation was initiated within 14 (maximally 28) days after implantation. Patients with a significantly longer waiting time were included in the control group (CG, n = 21). In addition to the start and duration of rehabilitation, the speech intelligibility achieved with CI was recorded at different timepoints within a 12-month period. In addition, questionnaires were used to assess the effort of fitting the CI processor and the patients’ satisfaction with the outcome as well as the timing of the start of rehabilitation.
Results: Median waiting time between implantation and start of rehabilitation was 14 days in the IG and 106 days in the CG; 92.6% of IG patients were able to start rehabilitation within 14 days. The effect of rehabilitation in the IG was 35 and in the CG 25 percentage points (Freiburg monosyllabic test). After 6 and 12 months of CI use, both groups showed comparable results in the test condition in quiet (IG/CG 6 months: 70%/70%; 12 months: 70%/60%, Freiburg monosyllabic test) and in noise (IG/CG 6 months: −1.1 dB SNR/–0.85 dB SNR; 12 months: −0.65 dB SNR/+0.3 dB SNR, Oldenburg sentence test). Hearing quality assessment scores collected by SSQ (Speech, Spatial and Qualities of Hearing Scale) questionnaire showed better scores in the IG at 6 months, which converged to CG scores at 12 months. The IG was significantly more satisfied with the timing of the start of rehab than the CG. All other data obtained from questionnaires showed no differences between the two groups.
Conclusion: A very early start of inpatient rehabilitation after cochlear implantation was successfully implemented. The rehabilitation was completed within 7 weeks of CI surgery. Comparison of speech recognition test results before and after rehabilitation showed a significant improvement. A clear rehabilitation effect can therefore be demonstrated. Inclusion of CI rehabilitation in the German catalog of follow-up treatments is thus scientifically justified and therefore strongly recommended.
Fusco, Claudia Mariateresa ; Desch, Kristina ; Dörrbaum, Aline Ricarda ; Wang, Mantian ; Staab, Anja ; Chan, Ivy C. W. ; Vail, Eleanor ; Villeri, Veronica ; Langer, Julian D. ; Schuman, Erin M.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs rapidly associated with translating ribosomes in the cytoplasm and that this incorporation was independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (following oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing neuronal synapses a rapid means to regulate local protein synthesis.
Fusco, Claudia Mariateresa ; Desch, Kristina ; Dörrbaum, Aline Ricarda ; Wang, Mantian ; Staab, Anja ; Chan, Ivy C.W. ; Vail, Eleanor ; Villeri, Veronica ; Langer, Julian D. ; Schuman, Erin M.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs quickly associated with translating ribosomes in the cytoplasm and that this incorporation is independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (in response to oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing remote neuronal synapses a rapid solution to the relatively slow and energy-demanding requirement of nuclear ribosome biogenesis.
Dörrbaum, Aline Ricarda ; Alvarez-Castelao, Beatriz ; Nassim-Assir, Belquis ; Langer, Julian David ; Schuman, Erin M.
Protein turnover, the net result of protein synthesis and degradation, enables cells to remodel their proteomes in response to internal and external cues. Previously, we analyzed protein turnover rates in cultured brain cells under basal neuronal activity and found that protein turnover is influenced by subcellular localization, protein function, complex association, cell type of origin, and by the cellular environment (Dörrbaum et al., 2018). Here, we advanced our experimental approach to quantify changes in protein synthesis and degradation, as well as the resulting changes in protein turnover or abundance in rat primary hippocampal cultures during homeostatic scaling. Our data demonstrate that a large fraction of the neuronal proteome shows changes in protein synthesis and/or degradation during homeostatic up- and down-scaling. More than half of the quantified synaptic proteins were regulated, including pre- as well as postsynaptic proteins with diverse molecular functions.
Silva, Daniela Santos Martins ; Olivier, Renan da Silva ; Queiroz, Larissa Lima de ; Pereira, Marcelo Ribeiro ; Boscardin, Jardel ; D’Angelis, Guilherme Rabelo
The genus Legua Walker, 1870 comprises only two known species from Central America and Brazil, with a notable scarcity of collected specimens. Herein, we provide a new contribution to our knowledge of the distribution of Legua rosea Amédégnato and Poulain, 1986 (Romaleinae: Leguini), that has a restricted distribution in Brazil, based on entomological collection data and social media information. Our records emphasize the importance of natural history collections and new tools for biodiversity studies.
ZooBank registration. urn:lsid:zoobank.org:pub:17E0802B-A389-4983-AC74-21B51197F557
A new species of Paranthrene Hübner (Lepidoptera: Sesiidae) from the northern midwest United States
(2024)
A clearwing moth species, Paranthrene sogaardi Taft and Smith, 2024, new species, is described from Michigan and Minnesota. The recognition of this new species is based on a phylogeny estimated from mitochondrial cytochrome oxidase I and wingless DNA sequences of 25 specimens representing all Paranthrene Hübner species including individuals from various locations. Paranthrene sogaardi new species was monophyletic and differed from Paranthrene tabaniformis Rottenburg, 1775 by a mean of 7.6% COI pairwise “p” distance, coloration, and genitalic morphology.
ZooBank registration. urn:lsid:zoobank.org:pub:8B9ED6CE-4DEB-4CB2-9235-3CA593F4D9DB
Hurd (1952) separated Pepsis cerberus Lucas from P. elegans Lepeletier (Hymenoptera: Pompilidae: Pepsinae: Pepsini) based on external morphology and biogeography. Vardy (2005) synonymized the familiar and historically well-documented P. cerberus and P. elegans, combining these Nearctic taxa with several Neotropical variants in an extremely broad definition of P. menechma Lepeletier. In doing so, Vardy (2005) breached the principle of nomenclatural stability. He ignored the prevailing usage and clearly violated articles 23.2, 23.3 and 23.9.1.2 of the ICZN (1999). Morphological differences, ecological divergence, and narrow sympatric geographic distribution of P. cerberus and P. elegans contradict Vardy (2005) and justify full species status (Kurczewski 2023a). Furthermore, we propose the removal of the two species from the P. menechma list of synonyms and recommend full species reinstatement as Pepsis cerberus, restored status and Pepsis elegans, restored status. Pepsis menechma becomes a senior synonym of P. elegans. Morphometric re-examination and statistical analysis of P. cerberus and P. elegans structural features strongly support their reinstatement. Quantitative measurement of 10 parasitoid-related morphological characteristics of the females revealed the two species differ significantly in frons width/head width, head length/head width, vertex length/head width, vertex length/head length, flagellomere 1 length/flagellomere 1 width, forewing length/mesosoma width, and hind tibial inner spur length/hind basitarsus length. Pepsis cerberus and P. elegans females are structurally and statistically similar in gena-postgena corner radius, fore femur width/mesosoma width, and number of hind tibial serrations.
ZooBank registation. urn:lsid:zoobank.org:pub:D22EC64F-7C55-4071-9290-4661CA377B24
The geographic distributions of three large wasps, Sphecius speciosus (Drury), Stictia carolina Fabricius and Stizus brevipennis Walsh (Hymenoptera: Crabronidae), occurring in Arkansas are defined using museum specimens and three internet-based data platforms. The internet-based data platforms generally provided more county location records than museum records. Using data from internet sources for easily identified species can better serve to illustrate the known distributions for some species thus making for a powerful tool elucidating distributional patterns and conservation planning.
ZooBank registration. urn:lsid:zoobank.org:pub:DCAE9192-1765-40CD-952B-0A094F413991
Corrections and additions to the Hydnocerina (Coleoptera: Cleridae: Clerinae: Hydnocerini) of Mexico
(2024)
Corrections, additions and remarks are made with respect to the recent checklist of the Cleridae (Coleoptera) of Mexico (Araujo-Castillo et al. 2024). Current valid names, synonymies, clarifications of taxonomic problems, and omitted taxa are reviewed. This work is intended to serve as a supplement to the “Hydnocerinae” section of the checklist.
ZooBank registration. urn:lsid:zoobank.org:pub:EF3E45B5-6EA6-41AB-B92F-DB4ABF9D8215
The exclusively New World velvet ant genus Timulla Ashmead, 1899 (Hymenoptera: Mutillidae: Mutillinae: Trogaspidiini) contains 180 species and ten subspecies. Most of these species are known from a single sex, and the validity of the subspecies has not been evaluated since their original description in 1937 and 1938. The Timulla fauna of the United States of America includes thirty species and eight subspecies, and the fauna of Canada includes three species. The faunas of these two countries were critically studied with the following results. Out of the eight total subspecies, seven were found to be structurally identical to and sympatric with the nominate subspecies. The subspecific differences were limited to cuticle and/or setal coloration in males and intergrades between them were found in several cases. With the senior synonym listed first, seven subspecies-level synonymies are proposed, which include: Timulla barbigera (Bradley, 1916) = T. barbigera rohweri Mickel, 1937, new synonym; T. dubitata (Smith, 1855) = T. dubitata fugitiva Mickel, 1937, new synonym; T. hollensis (Melander, 1903) = T. hollensis melanderi Mickel, 1937, new synonym; T. ocellaria Mickel, 1937 = T. ocellaria rufidorsa Mickel, 1937, new synonym; T. suspensa (Gerstaecker, 1874) = T. suspensa jonesi Mickel, 1937, new synonym, = T. suspensa sonora Mickel, 1937, new synonym; T. vagans (Fabricius, 1798) = T. vagans rufinota Mickel, 1937, new synonym. The final remaining subspecies, Timulla navasota coahuila Krombein, 1951, is raised to a full species, Timulla coahuila Krombein, 1951, new status, based on its unique female morphology. Also, four new sex associations are proposed, which include: Timulla barbata (Fox, 1899) = T. wileyae Mickel, 1937, new synonym; T. euterpe (Blake, 1879) = T. compressicornis Mickel, 1937, new synonym; T. neobule Mickel, 1937 = T. nicholi Mickel, 1937, new synonym; T. subhyalina Mickel, 1937 = T. dubitatiformis Mickel, 1937, new synonym. The former species, T. dubitatiformis, which was previously known only from females, is here recognized as being a morphologically-conservative complex of species; its synonymy with T. subhyalina effectively associates the remaining male-based members of the Timulla ocellaria species-group with it as well, which includes Timulla hollensis (Melander, 1903), T. kansana Mickel, 1937, T. ocellaria Mickel, 1937, T. rufosignata (Bradley, 1916), T. sayi (Blake, 1871), T. subhyalina Mickel, 1937, and T. tolerata Mickel, 1937. Further, two species-level synonymies are proposed, which include: Timulla dubitata (Smith, 1855) = T. murcia Mickel, 1938, new synonym; T. vagans (Fabricius, 1798) = T. huntleyensis Mickel, 1937, new synonym. Finally, Timulla cyllene (Cameron, 1894) is newly recorded in the United States of America from the state of Arizona.
ZooBank registration. urn:lsid:zoobank.org:pub:891E0C92-B8BF-4487-84D4-42EB2254AF4A
Schommartz, Iryna ; Lembcke, Philip F. ; Ortiz-Tudela, Javier ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
Memory consolidation tends to be less robust in childhood than adulthood. However, little is known about the corresponding functional differences in the developing brain that may underlie age-related differences in retention of memories over time. This study examined system-level memory consolidation of object-scene associations after learning (immediate delay), one night of sleep (short delay), as well as two weeks (long delay) in 5-to-7-year-old children (n = 49) and in young adults (n = 39), as a reference group with mature consolidation systems. Particularly, we characterized how functional neural activation and reinstatement of neural patterns change over time, assessed by functional magnetic resonance imaging combined with representational similarity analysis (RSA). Our results showed that memory consolidation in children was less robust and strong (i.e., more forgetting) compared to young adults. Contrasting correctly retained remote versus recent memories across time delay, children showed less upregulation in posterior parahippocampal gyrus, lateral occipital cortex, and cerebellum than adults. In addition, both children and adults showed decrease in scene-specific neural reinstatement over time, indicating time-related decay of detailed differentiated memories. At the same time, we observed more generic gist-like neural reinstatement in medial-temporal and prefrontal brain regions uniquely in children, indicating qualitative difference in memory trace in children. Taken together, 5-to-7-year-old children, compared to young adults, show less robust memory consolidation, possibly due to difficulties in engaging in differentiated neural reinstatement in neocortical mnemonic regions during retrieval of remote memories, coupled with relying more on gist-like generic neural reinstatement.
Schommartz, Iryna ; Lembcke, Philip F. ; Ortiz-Tudela, Javier ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
Memory consolidation tends to be less robust in childhood than adulthood. However, little is known about the corresponding functional differences in the developing brain that may underlie age-related differences in retention of memories over time. This study examined system-level memory consolidation of object-scene associations after learning (immediate delay), one night of sleep (short delay), as well as two weeks (long delay) in 5-to-7-year-old children (n = 49) and in young adults (n = 39), as a reference group with mature consolidation systems. Particularly, we characterized how functional neural activation and reinstatement of neural patterns change over time, assessed by functional magnetic resonance imaging combined with representational (dis)similarity analysis (RSA). Our results showed that memory consolidation in children was less robust (i.e., more forgetting) compared to young adults. For correctly retained remote memories, young adults showed increased neural activation from short to long delay in neocortical (parietal, prefrontal and occipital) and cerebellar brain regions, while children showed increased neural activation in prefrontal and decrease in neural activity in parietal brain regions over time. In addition, there was an overall attenuated scene-specific memory reinstatement of neural patterns in children compared to young adults. At the same time, we observed category-based reinstatement in medial-temporal, neocortical (prefrontal and parietal), and cerebellar brain regions only in children. Taken together, 5-to-7-year-old children, compared to young adults, show less robust memory consolidation, possibly due to difficulties in engaging in differentiated neural reinstatement in neocortical mnemonic regions during retrieval of remote memories, coupled with relying more on gist-like, category-based neural reinstatement.
Key, Jana ; Gispert, Suzana ; Koepf, Gabriele ; Steinhoff-Wagner, Julia ; Reichlmeir, Marina ; Auburger, Georg
Mitochondrial matrix peptidase CLPP is crucial during cell stress. Its loss causes Perrault syndrome type 3 (PRLTS3) with infertility, neurodegeneration and growth deficit. Its target proteins are disaggregated by CLPX, which also regulates heme biosynthesis via unfolding ALAS enzyme, providing access of pyridoxal-5’-phosphate (PLP). Despite efforts in diverse organisms with multiple techniques, CLPXP substrates remain controversial. Here, avoiding recombinant overexpression, we employed complexomics in mitochondria from three mouse tissues to identify endogenous targets. CLPP absence caused accumulation and dispersion of CLPX-VWA8 as AAA+ unfoldases, and of PLPBP. Similar changes and CLPX-VWA8 comigration were evident for mitoribosomal central protuberance clusters, translation factors like GFM1-HARS2, RNA granule components LRPPRC-SLIRP, and enzymes OAT-ALDH18A1. Mitochondrially translated proteins in testis showed reductions to <30% for MTCO1-3, misassembly of complex-IV supercomplex, and accumulated metal-binding assembly factors COX15-SFXN4. Indeed, heavy metal levels were increased for iron, molybdenum, cobalt and manganese. RT-qPCR showed compensatory downregulation only for Clpx mRNA, most accumulated proteins appeared transcriptionally upregulated. Immunoblots validated VWA8, MRPL38, MRPL18, GFM1 and OAT accumulation. Coimmunoprecipitation confirmed CLPX binding to MRPL38, GFM1 and OAT, so excess CLPX and PLP may affect their activity. Our data elucidate mechanistically the mitochondrial translation fidelity deficits, which underlie progressive hearing impairment in PRLTS3.
Köppke, Julia ; Keller, Luise-Elektra ; Stuck, Michelle ; Arnow, Nicolas Dominik ; Bannert, Norbert ; Döllinger, Jörg ; Cingöz, Oya
Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
Köppke, Julia ; Keller, Luise-Elektra ; Stuck, Michelle ; Arnow, Nicolas Dominik ; Bannert, Norbert ; Döllinger, Jörg ; Cingöz, Oya
Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
Köppke, Julia ; Keller, Luise-Elektra ; Stuck, Michelle ; Arnow, Nicolas Dominik ; Bannert, Norbert ; Cingöz, Oya
Viruses that carry a positive-sense, single-stranded RNA translate their genomes after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to express proteins. Here we show through various biochemical methods that HIV-1 genomes are translated after entry, in case of minimal or full-length genomes, envelopes using different cellular entry pathways and in diverse cell types. Our findings challenge the dogma that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
Alvarez-Castelao, Beatriz ; TomDieck, Susanne ; Fusco, Claudia Mariateresa ; Donlin-Asp, Paul ; Perez, Julio D ; Schuman, Erin M.
We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2α, surprisingly mediated by eIF2α kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2α phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for neuronal HRI that senses and responds to compromised function of the proteasome to restore proteostasis.
The nine genera of Malagasy spittlebug are revised, with the addition of new characters, facilitating the identification of the species. Nesaulax Jacobi, 1917, is synonymized with Amberana Distant, 1908, leading to a new combination for Amberana vittipennis (Bergroth, 1894). A new endemic genus Soulierana Bucher & Bouteille gen. nov. is proposed for two species originally placed in Literna Stål, 1866, based on morphological characters of the head, tegmina and male genitalia. Also, three new species are described in this genus: Soulierana bigidea Bucher gen. et sp. nov., Soulierana claudinae Bouteille gen. et sp. nov. and Soulierana kelymena Le Cesne gen. et sp. nov. Pictures of species and drawings of the male genitalia for all genera, with the exception of Rhinaulax Amyot & Serville, 1843, Alluaudensia Lallemand, 1920 and Literna, are included. An identification key is available in both a dichotomous format and an interactive format (Xper3).
Systematics of the Sierra Nevada endemic earwig: Eulithinus analis (Forficulidae, Dermaptera)
(2024)
Puerta-Rodríguez, Leticia ; Jurado-Angulo, Pilar ; Jiménez-Ruiz, Yolanda ; Rosas-Ramos, Natalia ; García-París, Mario
Since the description of Eulithinus analis (Rambur, 1838) the taxonomic position of this Sierra Nevada endemic earwig has been controversial. It has been subdivided in different taxa, assigned to various genera or transferred to different subfamilies. With the aim of clarifying its systematics, we performed a mitochondrial phylogeographic analysis using specimens from different localities of Sierra Nevada representing the diverse phenotypes treated as differentiated taxa until now, and a phylogenetic analysis including representatives of apparently distant, but morphologically close, relatives. The phylogenetic and phylogeographic results obtained using mitochondrial (cytb, cox1) and nuclear (ITS2) markers and the study of morphological characters, indicate that the Sierra Nevada Mountain Range harbors a single species of the genus Eulithinus. Based on these molecular data, the morphological characters used to date in the internal taxonomy of this group of earwigs, especially size and shape of the cerci, lack diagnostic validity and show a large inter- and intra-populational variability. These results imply the synonymy of Eulithinus montanus (Steinmann, 1981) with Eulithinus analis (Rambur, 1838) syn. nov. and the reconsideration of Eulithinus analis outside the subfamily Allodahliinae. We established the synonymy between Eulithinus analis (Rambur, 1838) and Forficula brevis Rambur, 1838 syn. nov., a name that must be removed from the synonymy of Forficula decipiens Gené, 1832.
A comparison of different APTT-reagents, heparin-sensitivity and detection of mild coagulopathies
(1992)
The activated partial thromboplastin time (aPTT) is widely used to detect coagulation abnormalities or to monitor heparin treatment.
Many commercial aPTT-reagents are available which contain different phospholipid reagents and activators. In the present study 3 aPTT-reagents (aPTT-D, Instrumentation Laboratory, Neothromtin, Behring, PTTa, Boehringer) were compared using a computerized centrifugal analyzer. One aPTT-reagent (Pathromtin, Behring) was tested on a semiautomated coagulometer. Instrument precision was evaluated using aPTT-D as reagent.
Comparative tests were performed on plasma samples of 40 healthy donors, 3 patients with mild von Willebrand's disease (vWd), W patients with heaemophilia or subhaemophilia A, 1 patient with subhaemophilia A and vWd, 8 patients treated with subcutaneous injection of unfractionated heparin (UFH) and 14 patients treated with subcutaneous injection of a low molecular weight heparin (LMWH).
aPTT-D was the most sensitive reagent to detect mild vWd while Pathromtin detected none of these defects. In patients with heamophilia A and subhaemophilia A aPTT-D, Neothromtin and PTTa detected the abnormality in nearly all tested samples while Pathromtin was less sensitive.
Patients treated with subcutaneously applied UFH or LMWH often had a prolonged aPTTt especially when aPTT-D and Neothromtin were used as reagents.
Background: Hundreds of West African healthcare workers (HCW) have become ill with Ebola virus disease (EVD) and died during the recent outbreak. The occurrence of occupational infections in laboratories could be due to the lack of use of personal protective equipment, the failure to implement specific regulations about the use of equipment and how to work with hazardous materials. Our study attempted to assess the information as well as training level of HCW of a German high level isolation unit and their concern over an occupationally acquired EVD.
Methods: During the recent Ebola virus outbreak a survey was conducted among HCWs, using an anonymous questionnaire.
Results: Although 70% of our total study population stated that they have all the information needed to care for Ebola patients, only 18.2% of laboratory workers and 29.4% of the HCW of the virology department felt sufficiently trained. The HCW rated the Internet (64.3%) and the daily press (54.3%) as the most important sources of information. Medical literature (45.7%) and official institutions (40.4%) were rated less often.
Conclusions: Formulated pointedly, the HCW turned to popular science to get the information they need to feel safe. Further in house training regarding practical skills and reference to scientific literature would be a better solution to ensure workplace safety.
Herpes simplex virus type 2 (HSV-2) is the main cause of herpes genitalis, a recurrent sexually transmitted disease. By the use of routine Serologie methods (complement fixation test, enzyme immunoassay), virus carriers are difficult to identify because of strong antibody cross reactions with antigens of HSV-1 which is ubiquitously spread throughout the population. We introduce a microtechnique Western blot system loaded with HSV-1 and HSV-2 type-specific and common antigens on separated nitrocellulose strips. By the simultaneous evaluation of Immunologie reactions with both strips, the occurrence of HSV-2 specific antibodies can be sensitively detected in serum specimens containing antibodies to HSV-1. A total of 158 serum specimens were analyzed and the results obtained by Western blot were compared to those of a screening ELISA and virus isolation performed with smears of herpes lesions.
An agreement of 97.9 % was assessed between Western blot and virus isolation to detect an HSV-1 and HSV-2 infection. Less specific serologic results were produced by the screening ELISA on HSV-2 antibodies which correlated in 85.4 % (41/48) with virus isolation and typing. Concerning HSV-2 antibody testing, Western blot and ELISA showed an overall agreement in 89.8 % of the sera investigated.
As shown by our data, the HSV type specific Western blot proved to be a specific, reproducible and standardized technique. It can be utilized for both sero-epidemiological surveys and determination of the HSV immune status.
[Abstract] Occurrence of hepatitis B virus (HBV) reactivation following kidney transplantation
(2004)
Activated blood coagulation factor (F) XIII (FXIIIa), a transglutaminase comprised of two A and two B subunits in a tetrameric structure (A2B2) of 320 kd, has a central role in the haemostatic system by cross-linking fibrin monomers in the final step of blood coagulation, thus stabilizing the fibrin clot and increasing its resistance to fibrinolysis. In addition, FXIIIa is implicated in the cross-linking of several other proteins, such as a-2-antiplasmin, fibronectin, and collagen. The impact of genetic variations of FXIII in thrombotic disorders has not been studied until recently, when a common polymorphism was described as a new candidate genetic factor influencing the risk of thrombotic diseases. This polymorphism results from a G to T transition in codon 34 of exon 2 of the catalytic FXIII A-subunit gene, leading to the substitution of leucine for valine (FXHIVal34Leu) close to the thrombin activation site. Genotype at this polymorphism is closely related to FXIII fibrin cross-linking activity, and FXIIILeu is associated with increased thrombin activation of FXIII with associated changes in fibrin structure. Initially, FXIII Val34Leu was shown to be significantly less common in British patients with a history of myocardial infarction than in controls, suggesting for the first time a new role for FXIII in a polygenic thrombotic disease. In addition to its proposed protective effect against thrombotic heart diseases, the Leu34 allele has also been correlated with protection against venous thromboembolism and thrombotic cerebral artery occlusion, whereas it seems to confer an increased risk for intracerebral haemorrhage. Because this genetic variation is associated with a higher activity of the enzyme, the mechanism accounting for the putative anti-thrombotic effect of FXIII Val34Leu is not well understood. However, it has been hypothesized that increased rates of FXIII activation could lead to ineffective cross-linking, or that the kinetics of the cross-linking reactions may be disrupted because of the effects of FXIIIa on other proteins. Previous s'tudies have demonstrated that the FXIII Val34Leu polymorphism is highly prevalent in ^[[200~several Caucasian populations, with reported Leu34 allele frequencies of around 0.25, whereas it is less prevalent in populations of African and Asian origin. The known significant ethnic heterogeneity linked to the FXIII Val34Leu polymorphism is of relevance when analyzing its role in vascular diseases. In summary, published studies indicate that blood coagulation FXIII is involved in the multifactorial pathogenesis of vascular diseases and suggest a contribution of FXIII Val34Leu in determining the risk of myocardial infarction, stroke and venous thromboembolism.
Highly sensitive qualitative and quantitative automatednucleic acid amplification tests (NATs) that are commercially available for the detection of hepatitis B virus (HBV)infection have been developed only in the last few years.The potential indications for HBV NATs are: follow-up ofchronic hepatitis B, therapy and antiviral resistance monitoring, determination of infectivity and transmission risk,detection of occult (HBsAg-negative and HBV DNA-positive) infection and mutant virus which may escape serologic diagnosis, blood donor screening, and resolution ofunusual or discordant serologic constellations. Although NATs are now widely implemented in the routine diagnosis of clinical laboratories, there are several importantissues which need to be further investigated. Standardisation of NATs used for the monitoring of antiviral therapyand follow-up of chronic infection is still lacking, and theclinical significance of HBV DNA levels needs to be clarified. The influence of genetic variability in terms of genotype variation has been poorly investigated so far.Although there are highly sensitive automated NATs forblood donor screening available, their implementation is still subject to discussion and certain countries rejectedHBV DNA testing for blood donation for reasons of poor cost-effectiveness.