Bottom-up fabrication of FeSb2 nanowires on crystalline GaAs substrates with ion-induced pre-patterning

In recent decades, nanostructuring has become one of the most important techniques to design and engineer functional materials. The properties of nanostructured materials are influenced by the interplay of its instrinsic bulk properties and the properties of its surface - the relative importance of the latter being enhanced by the increased surface-to-volume ratio in nanostructures. For instance, nanostructuring of a thermoelectric material can reduce the thermal conductivity while maintaining constant electrical conductivity and the Seebeck coefficient, which would improve the thermoelectric properties. For that reason, this study investigated the possibility of preparing nanowires of iron antimonide (FeSb2), a thermoelectric material, on single-crystalline gallium arsenide GaAs (001) substrates with ion-induced surface nanoscale pre-patterning and characterized the structure of the prepared FeSb2 nanowires. The GaAs (001) substrates were pre-patterned using 1 keV Ar+ ion irradiation. By using an ion source with a broad, unfocused ion beam at normal incidence, the patterned area can be scaled to nearly any size. The self-organized surface morphology is formed by reverse epitaxy and is characterized by almost perfectly parallel-aligned ripples at the nanometer scale. For the fabrication of FeSb2 nanowires, iron and antimony were successively deposited on the pre-patterned GaAs substrates at grazing incidence and then annealed. They were characterized using transmission electron microscopy (TEM), in particular high-resolution TEM imaging for structure analysis and spectrum imaging analysis based on energy-dispersive X-ray spectroscopy for element characterization. With the presented fabrication method, FeSb2 nanowires were produced successfully on GaAs(001) substrates with an ion-induced nanopatterned surface. The nanowires have a polycristalline structure and a cross-sectional area which is scalable up to 22 × 22 nm2. Due to the high order nanostructures on the GaAs substrate, the nanowires have a length of several micrometer. This bottom-up nanofabrication process based on ion-induced patterning can be a viable alternative to top-down procedures regarding to efficiency and costs

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague

[Significance] The bacterium Yersinia pestis has caused numerous historically documented outbreaks of plague and research using ancient DNA could demonstrate that it already affected human populations during the Neolithic. However, the pathogen’s genetic diversity, geographic spread, and transmission dynamics during this early period of Y. pestis evolution are largely unexplored. Here, we describe a set of ancient plague genomes up to 5,000 y old from across Eurasia. Our data demonstrate that two genetically distinct forms of Y. pestis evolved in parallel and were both distributed across vast geographic distances, potentially occupying different ecological niches. Interpreted within the archeological context, our results suggest that the spread of plague during this period was linked to increased human mobility and intensification of animal husbandry.The bacterial pathogen Yersinia pestis gave rise to devastating outbreaks throughout human history, and ancient DNA evidence has shown it afflicted human populations as far back as the Neolithic. Y. pestis genomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to its emergence from a Yersinia pseudotuberculosis-like progenitor; however, the number of reconstructed LNBA genomes are too few to explore its diversity during this critical period of development. Here, we present 17 Y. pestis genomes dating to 5,000 to 2,500 y BP from a wide geographic expanse across Eurasia. This increased dataset enabled us to explore correlations between temporal, geographical, and genetic distance. Our results suggest a nonflea-adapted and potentially extinct single lineage that persisted over millennia without significant parallel diversification, accompanied by rapid dispersal across continents throughout this period, a trend not observed in other pathogens for which ancient genomes are available. A stepwise pattern of gene loss provides further clues on its early evolution and potential adaptation. We also discover the presence of the flea-adapted form of Y. pestis in Bronze Age Iberia, previously only identified in in the Caucasus and the Volga regions, suggesting a much wider geographic spread of this form of Y. pestis. Together, these data reveal the dynamic nature of plague’s formative years in terms of its early evolution and ecology.This study was funded by the Max Planck Society, Max Planck Harvard Research Center for the Archaeoscience of the Ancient Mediterranean and the European Research Council under the European Union’s Horizon 2020 research and innovation program under Grant Agreement 771234 – PALEoRIDER (to W.H.), 856453 – HistoGenes (to J.K.), and 834616 – ARCHCAUCASUS (to S.H.). The Heidelberg Academy of Science financed the genetic and archeological research on human individuals from the Augsburg region within the project WIN Kolleg: “Times of Upheaval: Changes of Society and Landscape at the Beginning of the Bronze Age. M.E. was supported by the award “Praemium Academiae” of the Czech Academy of Sciences. M.D. was supported by the project RVO 67985912 of the Institute of Archaeology of the Czech Academy of Sciences, Prague. I.O. was supported by the Ramón y Cajal grant from Ministerio de Ciencia e Innovación, Spanish Government (RYC2019-027909-I). A. H€ubner was supported by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (EXC 2051 – Project-ID 390713860). J.F.-E. and J.A.M.-A. were supported by the Diputación Foral de Alava, IT 1223-19, Gobierno Vasco. A. Buzhilova was supported by the Center of Information Technologies and Systems (CITIS), Moscow, Russia 121041500329-0. L. M., L.B.D., and E. Khussainova were supported by the Grant AP08856654, Ministry of Education and Science of the Republic of Kazakhstan. A. Beisenov was supported by the Grant AP08857177, Ministry of Education and Science of the Republic of Kazakhstan.Peer reviewe

Role of Origin recognition complex subunit 1 (Orc1) in neuronal cell death after combined oxygen glucose deprivation - a cell culture model for ischemic stroke

Der origin recognition complex ORC, bestehend aus den Untereinheiten ORC1-ORC6, leitet als Prä-Initiationskomplex in proliferierenden Zellen die Synthese-Phase der DNA ein (S-Phase). Die Assemblierung von ORC1 an den Kernkomplex - bestehend aus ORC2-5 - wird zellzyklusabhängig reguliert. ORC1 gilt als regulatorische Untereinheit des Komplexes und vermittelt dessen Bindung zum Chromatin. Somit ist es essentiell für die Initiation der S-Phase. Orc1 selbst wird zellzyklusabhängig durch die Transkriptionsfaktoren der E2F- Familie reguliert. In differenzierten Neuronen wird Orc1 im Gegensatz zu den Untereinheiten Orc2-6 unter physiologischen Bedingungen sehr gering exprimiert. Der reprimierende Transkriptionsfaktor E2F4 scheint in solchen maturen Nervenzellen unter anderem durch eine Zellteilungsblockade eine Funktion in der Aufrechterhaltung des differenzierten Status zu haben. Neurone werden daher als post-mitotisch bezeichnet. Unter pathophysiologischen Bedingungen wie z.B. nach zerebraler Ischämie/Hypoxie hat ein aberranter Zellzykluseintritt den neuronalen Zelltod zur Folge. In dieser Arbeit wurde die Rolle von ORC1 und dessen transkriptionelle Regulation durch den E2F4-Repressorkomplex im Kontext des neuronalen Zelltodes im Zellkulturmodell für die zerebrale Ischämie untersucht. In Zellkultur (in vitro) wurde der Schaden durch einen transienten Sauerstoff- und Glukoseentzug (oxygen glucose deprivation: OGD) modelliert. Orc1 wurde nach OGD in Neuronen transkriptionell aktiviert. Dabei war die Regulation abhängig von einem Verlust des reprimierenden Transkriptionsfaktors E2F4 am Orc1 Promotor. Wurde die Orc1 Expression nach kombinierten Sauerstoff- und Glukoseentzug durch lentiviral vermittelte RNA Interferenz mit Orc1 in Neuronen gehemmt, schützte dies vor neuronalem Zelltod. ORC1 ist als Schlüsselprotein und dessen Regulation durch den reprimierenden Transkriptionsfaktor E2F4 als ein molekularer Mechanismus zur Initiation neuronalen Zelltods nach OGD identifiziert worden.In proliferating cells the origin recognition complex ORC, that is comprised of the subunits ORC1-ORC6, serves as a pre-initiation complex to induce DNA synthesis (S-phase). ORC1 assembly to the ORC core complex (subunits ORC2-5) regulates the ORC in a cell cycle dependent manner. ORC1 assembly is required to mediate binding to chromatin and is the rate limiting step for the initiation of S-phase. Orc1 is identified as a target gene of the cell cycle controlling E2F transcription factor family. ORC1 is virtually absent in mature neurons under physiological conditions in contrast to the constitutively expressed subunits ORC2-6. The repressive transcriptionfactor E2F4 seems to take part in the inhibition of cell cycle progression and maintains the differentiated state of neurons. Thus, neurons are entitled post-mitotic. Aberrant cell cycle reentry after brain ischemia or other pathophysiological conditions is implicated in neuronal cell death. In this study the role of ORC1 and its regulation by the repressive E2F4 complex in neuronal cell death after brain ischemia is explored. Orc1 was transcriptionally upregulated after hypoxic damage, which was induced by combined oxygen glucose deprivation (OGD) of mouse primary cortical neurons. Orc1 was regulated by the repressive transcriptionfactor E2F4. Inhibition of Orc1 de novo transcription by neuronal-specific RNA interference with Orc1 protected neurons against cell death induced by OGD. This study identified ORC1 as a novel rate limiting factor und its regulation through E2F4 as a molecular mechanism involved in neuronal cell death after oxygen glucose deprivation

The decentralized enforcement of European law: national court decisions on EU directives with and without preliminary reference submissions

<p>This article contributes to the study of the preliminary reference procedure and the literature on the decentralized enforcement of European Union (EU) law through national courts. Drawing on the ‘compliance pull’ explanation for why national courts submit preliminary references to the Court of Justice of the European Union (ECJ), it suggests that a greater need to clarify ‘the validity and interpretation’ of one act compared to another is associated with variation in Article 267 submissions. Drawing on a sample of 1,300 national court decisions on EU directives with variation in Article 267 Treaty on the Functioning of the European Union (TFEU) submissions, this article finds that disputes relating to directives leaving more room for manoeuvre in implementation (‘delegation’) and relating to more complex regulatory issues (‘information intensity’) are more likely to be referred to the ECJ for interpretation. It argues that neglecting the ‘compliance pull’ explanations has consequences for how we conceptualize ‘decentralized enforcement’.</p

Differing Time Courses of Reward-Related Attentional Processing: An EEG Source-Space Analysis

Since our environment typically contains more information than can be processed at any one time due to the limited capacity of our visual system, we are bound to differentiate between relevant and irrelevant information. This process, termed attentional selection, is usually categorized into bottom-up and top-down processes. However, recent research suggests reward might also be an important factor in guiding attention. Monetary reward can bias attentional selection in favor of task-relevant targets and reduce the efficiency of visual search when a reward-associated, but task-irrelevant distractor is present. This study is the first to investigate reward-related target and distractor processing in an additional singleton task using neurophysiological measures and source space analysis. Based on previous studies, we hypothesized that source space analysis would find enhanced neural activity in regions of the value-based attention network, such as the visual cortex and the anterior cingulate. Additionally, we went further and explored the time courses of the underlying attentional mechanisms. Our neurophysiological results showed that rewarding distractors led to a stronger attentional capture. In line with this, we found that reward-associated distractors (compared with reward-associated targets) enhanced activation in frontal regions, indicating the involvement of top-down control processes. As hypothesized, source space analysis demonstrated that reward-related targets and reward-related distractors elicited activation in regions of the value-based attention network. However, these activations showed time-dependent differences, indicating that the neural mechanisms underlying reward biasing might be different for task-relevant and task-irrelevant stimuli

Activation of the Mitochondrial Apoptotic Signaling Platform during Rubella Virus Infection

Mitochondria- as well as p53-based signaling pathways are central for the execution of the intrinsic apoptotic cascade. Their contribution to rubella virus (RV)-induced apoptosis was addressed through time-specific evaluation of characteristic parameters such as permeabilization of the mitochondrial membrane and subsequent release of the pro-apoptotic proteins apoptosis-inducing factor (AIF) and cytochrome c from mitochondria. Additionally, expression and localization pattern of p53 and selected members of the multifunctional and stress-inducible cyclophilin family were examined. The application of pifithrin μ as an inhibitor of p53 shuttling to mitochondria reduced RV-induced cell death to an extent similar to that of the broad spectrum caspase inhibitor z-VAD-fmk (benzyloxycarbonyl-V-A-D-(OMe)-fmk). However, RV progeny generation was not altered. This indicates that, despite an increased survival rate of its cellular host, induction of apoptosis neither supports nor restricts RV replication. Moreover, some of the examined apoptotic markers were affected in a strain-specific manner and differed between the cell culture-adapted strains: Therien and the HPV77 vaccine on the one hand, and a clinical isolate on the other. In summary, the results presented indicate that the transcription-independent mitochondrial p53 program contributes to RV-induced apoptosis

Disentangling magnetic order on nanostructured surfaces

We present a synchrotron-based x-ray scattering technique which allows disentangling magnetic propertiesof heterogeneous systems with nanopatterned surfaces. This technique combines the nanometer-range spatialresolution of surface morphology features provided by grazing incidence small angle x-ray scattering and thehigh sensitivity of nuclear resonant scattering to magnetic order. A single experiment thus allows attributingmagnetic properties to structural features of the sample; chemical and structural properties may be correlatedanalogously. We demonstrate how this technique shows the correlation between structural growth and evolutionof magnetic properties for the case of a remarkable magnetization reversal in a structurally and magneticallynanopatterned sample system

Abolishing Dopamine D2long/D3 Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2 Receptor Agonists

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H2 receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D2-like receptors (especially to the D3R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H1–4 and D2long/3 receptors. This study revealed a couple of selective candidates (among others 31 and 47), and the most promising ones were screened at several off-target receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H2- and D2long/3-receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies