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An automated NMR chemical shift assignment algorithm was developed using multi-objective optimization techniques. The problem is modeled as a combinatorial optimization problem and its objective parameters are defined separately in different score functions. Some of the heuristic approaches of evolutionary optimization are employed in this problem model. Both, a conventional genetic algorithm and multi-objective methods, i.e., the non-dominated sorting genetic algorithms II and III (NSGA2 and NSGA3), are applied to the problem. The multi-objective approaches consider each objective parameter separately, whereas the genetic algorithm followed a conventional way, where all objectives are combined in one score function. Several improvement steps and repetitions on these algorithms are performed and their combinations are also created as a hyper-heuristic approach to the problem. Additionally, a hill-climbing algorithm is also applied after the evolutionary algorithm steps. The algorithms are tested on several different datasets with a set of 11 commonly used spectra. The test results showed that our algorithm could assign both sidechain and backbone atoms fully automatically without any manual interactions. Our approaches could provide around a 65% success rate and could assign some of the atoms that could not be assigned by other methods.
An accurate measurement of the 140Ce(n,γ) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the 140Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in 140Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the 140Ce Maxwellian-averaged cross-section.
Transcatheter left atrial appendage occlusion (LAAO) is non-inferior to vitamin K antagonists (VKAs) in preventing thromboembolic events in atrial fibrillation (AF). Non-vitamin K antagonists (NOACs) have an improved safety profile over VKAs; however, evidence regarding their effect on cardiovascular and neurological outcomes relative to LAAO is limited. Up-to-date randomized trials or propensity-score-matched data comparing LAAO vs. NOACs in high-risk patients with AF were pooled in our study. A total of 2849 AF patients (LAAO: 1368, NOACs: 1481, mean age: 75 ± 7.5 yrs, 63.5% male) were enrolled. The mean CHA2DS2-VASc score was 4.3 ± 1.7, and the mean HAS-BLED score was 3.4 ± 1.2. The baseline characteristics were comparable between the two groups. In the LAAO group, the success rate of device implantation was 98.8%. During a mean follow-up of 2 years, as compared with NOACs, LAAO was associated with a significant reduction of ISTH major bleeding (p = 0.0002). There were no significant differences in terms of ischemic stroke (p = 0.61), ischemic stroke/thromboembolism (p = 0.63), ISTH major and clinically relevant minor bleeding (p = 0.73), cardiovascular death (p = 0.63), and all-cause mortality (p = 0.71). There was a trend toward reduction of combined major cardiovascular and neurological endpoints in the LAAO group (OR: 0.84, 95% CI: 0.64–1.11, p = 0.12). In conclusion, for high-risk AF patients, LAAO is associated with a significant reduction of ISTH major bleeding without increased ischemic events, as compared to “contemporary NOACs”. The present data show the superior role of LAAO over NOACs among high-risk AF patients in terms of reduction of major bleeding; however, more randomized controlled trials are warranted.
Simple Summary: The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma.
Abstract: A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
In this roadmap article, we have focused on the most recent advances in terahertz (THz) imaging with particular attention paid to the optimization and miniaturization of the THz imaging systems. Such systems entail enhanced functionality, reduced power consumption, and increased convenience, thus being geared toward the implementation of THz imaging systems in real operational conditions. The article will touch upon the advanced solid-state-based THz imaging systems, including room temperature THz sensors and arrays, as well as their on-chip integration with diffractive THz optical components. We will cover the current-state of compact room temperature THz emission sources, both optolectronic and electrically driven; particular emphasis is attributed to the beam-forming role in THz imaging, THz holography and spatial filtering, THz nano-imaging, and computational imaging. A number of advanced THz techniques, such as light-field THz imaging, homodyne spectroscopy, and phase sensitive spectrometry, THz modulated continuous wave imaging, room temperature THz frequency combs, and passive THz imaging, as well as the use of artificial intelligence in THz data processing and optics development, will be reviewed. This roadmap presents a structured snapshot of current advances in THz imaging as of 2021 and provides an opinion on contemporary scientific and technological challenges in this field, as well as extrapolations of possible further evolution in THz imaging.
Presolar grains and their isotopic compositions provide valuable constraints to AGB star nucleosynthesis. However, there is a sample of O- and Al-rich dust, known as group 2 oxide grains, whose origin is difficult to address. On the one hand, the 17O/16O isotopic ratios shown by those grains are similar to the ones observed in low-mass red giant stars. On the other hand, their large 18O depletion and 26Al enrichment are challenging to account for. Two different classes of AGB stars have been proposed as progenitors of this kind of stellar dust: intermediate mass AGBs with hot bottom burning, or low mass AGBs where deep mixing is at play. Our models of low-mass AGB stars with a bottom-up deep mixing are shown to be likely progenitors of group 2 grains, reproducing together the 17O/16O, 18O/16O and 26Al/27Al values found in those grains and being less sensitive to nuclear physics inputs than our intermediate-mass models with hot bottom burning.
Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
This essay explores the problem of legitimation crises in deliberative systems. For some time now, theorists of deliberative democracy have started to embrace a “systemic approach.” But if deliberative democracy is to be understood in the context of a system of multiple moving parts, then we must confront the possibility that that system’s dynamics may admit of breakdowns, contradictions, and tendencies toward crisis. Yet such crisis potentials remain largely unexplored in deliberative theory. The present article works toward rectifying this lacuna, using the 2016 Brexit and Trump votes as examples of a particular kind of “legitimation crisis” that results in a sequence of failures in the deliberative system. Drawing on recent work of Rainer Forst, I identify this particular kind of legitimation crisis as a “justification crisis.”
The strengths use scale: psychometric properties, longitudinal invariance and criterion validity
(2021)
Strengths use is an essential personal resource to consider when designing higher-educational programs and interventions. Strengths use is associated with positive outcomes for both the student (e.g., study engagement) and the university (e.g., academic throughput/performance). The Strengths Use Scale (SUS) has become a popular psychometric instrument to measure strengths use in educational settings, yet its use has been subjected to limited psychometric scrutiny outside of the U.S. Further, its longitudinal stability has not yet been established. Given the wide use of this instrument, the goals of this study were to investigate (a) longitudinal factorial validity and the internal consistency of the scale, (b) its equivalence over time, and (c) criterion validity through its relationship with study engagement over time. Data were gathered at two-time points, 3 months apart, from a sample of students in the Netherlands (n = 360). Longitudinal confirmatory factor analyses showed support for a two-factor model for overall strengths use, comprised of Affinity for Strengths and Strengths Use Behaviors. The SUS demonstrated high levels of internal consistency at both the lower- and upper bound limits at both time points. Further, strict longitudinal measurement invariance was established, which confirmed the instrument's temporal stability. Finally, criterion validity was established through relating strengths use to study engagement at different time stamps. These findings support the use of the SUS in practice to measure strengths use and to track the effectiveness of strengths use interventions within the higher education sector.
Research has contended youth is an "invention" of the 18th century. This thesis does not contest the fact that youth was already known and accepted as a stage in life even earlier. Certain basic anthropological patterns of youthfulness, for example nonchalance, instability, recklessness, exaggeration, bashfulness looking forward to the future and the ability to make friends have been rhetorically implied, repeated and cited as a matter of course since the time of Aristoteies. The pointed thesis that the concept of youth only arose in the 18th century accentuates that youth as an autonomous way of life is a characteristic of the Modern Age.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.
The aim of this study was to evaluate whether recurrent carpal tunnel syndrome (CTS) after complete and sufficient division of the transverse ligament really exists. Another goal was to analyze the underlying reasons for recurrent CTS operated on in our department. Over an observation period of eleven years, 156 patients underwent surgical intervention due to CTS. The records of each patient were analyzed with respect to baseline data (age, gender, affected hand), as were clinical signs and symptoms pre- and postoperatively. To assess long-term results, standardized telephone interviews were performed using a structured questionnaire in which the patients were questioned about persisting symptoms, if any. Of the 156 patients, 128 underwent first surgical intervention due to CTS in our department. In long-term follow-up, two-thirds of these patients had no symptoms at all; one-third of the patients described mild persisting numbness. None of the patients experienced a recurrence of CTS. The 28 patients who received their first operation outside of our department were operated on for recurrent CTS. The cause of recurrence was incomplete division of the distal part of the transverse carpal ligament in all cases. The results suggest that recurrent CTS after complete and sufficient division of the transverse ligament is very unlikely.
Background: Dentists (Ds) and dental assistants (DAs) have a high lifetime prevalence of musculoskeletal disorders (MSDs). In this context, it is assumed that they have an increased intake of substances such as pain medication. Currently, there exist no data on the use of medication among Ds and DAs with MSDs in Germany. Methods: The online questionnaire (i.e., the Nordic Questionnaire) analysed the medical therapies used by 389 Ds (240 f/149 m) and 406 DAs (401 f/5 m) to treat their MSDs. Results: Ds (28.3–11.5%) and DAs (29.4–10.3%) with MSDs took medication depending on the affected body region. A trend between the Ds and DAs in the intake of drug therapy and the frequency was found for the neck region (Ds: 21.1%, DAs: 28.7%). A single medication was taken most frequently (Ds: 60.0–33.3%, DAs: 71.4–27.3%). The frequency of use varied greatly for both occupational groups depending on the region affected. Conclusion: Ds and DAs perceived the need for medical therapies because of their MSDs. Painkillers such as ibuprofen and systemic diclofenac were the medications most frequently taken by both occupational groups. The intake of pain killers, most notably for the neck, should prevent sick leave.
Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
The new class of microbial rhodopsins, called xenorhodopsins (XeRs),[1] extends the versatility of this family by inward H+ pumps.[2–4] These pumps are an alternative optogenetic tool to the light-gated ion channels (e.g. ChR1,2), because the activation of electrically excitable cells by XeRs is independent from the surrounding physiological conditions. In this work we functionally and spectroscopically characterized XeR from Nanosalina (NsXeR).[1] The photodynamic behavior of NsXeR was investigated on the ps to s time scale elucidating the formation of the J and K and a previously unknown long-lived intermediate. The pH dependent kinetics reveal that alkalization of the surrounding medium accelerates the photocycle and the pump turnover. In patch-clamp experiments the blue-light illumination of NsXeR in the M state shows a potential-dependent vectoriality of the photocurrent transients, suggesting a variable accessibility of reprotonation of the retinal Schiff base. Insights on the kinetically independent switching mechanism could furthermore be obtained by mutational studies on the putative intracellular H+ acceptor D220.
Photoactivatable compounds for example photoswitches or photolabile protecting groups (PPGs, photocages) for spatiotemporal light control, play a crucial role in different areas of research. For each application, parameters such as the absorption spectrum, solubility in the respective media and/or photochemical quantum yields for several competing processes need to be optimized. The design of new photochemical tools therefore remains an important task. In this study, we exploited the concept of excited-state-aromaticity, first described by N. Colin Baird in 1971, to investigate a new class of photocages, based on cyclic, ground-state-antiaromatic systems. Several thio- and nitrogen-functionalized compounds were synthesized, photochemically characterized and further optimized, supported by quantum chemical calculations. After choosing the optimal scaffold, which shows an excellent uncaging quantum yield of 28 %, we achieved a bathochromic shift of over 100 nm, resulting in a robust, well accessible, visible light absorbing, compact new photocage with a clean photoreaction and a high quantum product (ϵ⋅Φ) of 893 M−1 cm−1 at 405 nm.
We show that the COVID-19 pandemic triggered a surge in the elasticity of non-financial corporate to sovereign credit default swaps in core EU countries, characterized by strong fiscal capacity. For peripheral countries with lower budgetary slackness, the pandemic had essentially no impact on such elasticity. This evidence is consistent with the disaster-induced repricing of government support, which we model through a rare-disaster asset pricing framework with bailout guarantees and defaultable public debt. The model implies that risk-adjusted guarantees in the core were 2.6 times those in the periphery, suggesting that fiscal capacity buffers provide relief to firms’ financing costs.
We analyze the impact of decreases in available lending resources on quantitative and qualita- tive dimensions of firms’ patenting activities. We thereby make use of the European Banking Authority?s capital exercise to carve out the causal effect of bank lending on firm innovation. In order to do so we combine various datasets to derive information on firms’ financials, their patenting behaviors, as well as their relationships with their lenders. Building on this self- generated dataset, we provide support for the “less finance, less innovation” view. At the same time, we show that lower available financial resources for firms lead to improvement in the qualitative dimensions of their patents. Hence, we carve out a “less finance, less but better innovation” pattern.
We investigate the differential effect of the COVID-19 shock to the stock market shock on the share prices of firms with different levels of ESG (Environmental, Social and Governance) scores. Thereby, we analyse whether and to what extent better ESG ratings provided insurance for investors in the stocks of those firms during this shock. We focus our analysis on the European market in which ESG investment plays a particularly important role. Using a broad sample of listed firms we provide mixed evidence. On the one hand, we show that immediately after the start of the shock firms with a higher ESG score outperformed their peers. On the other hand, this effect faded less than six weeks later. Given the quick recovery of the market our finding supports the idea that ESG stocks provide limited insurance in severe crises.
Predictions of oil prices reaching $100 per barrel during the winter of 2021/22 have raised fears of persistently high inflation and rising inflation expectations for years to come. We show that these concerns have been overstated. A $100 oil scenario of the type discussed by many observers, would only briefly raise monthly headline inflation, before fading rather quickly. However, the short-run effects on headline inflation would be sizable. For example, on a yearover- year basis, headline PCE inflation would increase by 1.8 percentage points at the end of 2021 under this scenario, and by 0.4 percentage points at the end of 2022. In contrast, the impact on measures of core inflation such as trimmed mean PCE inflation is only 0.4 and 0.3 percentage points in 2021 and 2022, respectively. These estimates already account for any increases in inflation expectations under the scenario. The peak response of the 1-year household inflation expectation would be 1.2 percentage points, while that of the 5-year expectation would be 0.2 percentage points.
Retail investors pay over twice as much attention to local companies than non-local ones, based on Google searches. News volume and volatility amplify this attention gap. Attention appears causally related to perceived proximity: first, acquisition by a nonlocal company is associated with less attention by locals, and more by nonlocals close to the acquirer; second, COVID-19 travel restrictions correlate with a drop in relative attention to nonlocal companies, especially in locations with fewer fights after the outbreak. Finally, local attention predicts volatility, bid-ask spreads and nonlocal attention, not viceversa. These findings are consistent with local investors having an information-processing advantage.
Careers in finance
(2021)
The finance wage premium since the 1990s has arguably lured talent away from other industries. However, the allocation of talent is likely to respond to differences in career paths, not in wages at a given date. We use resume data to reconstruct the careers of 11,255 professionals in finance, high-tech and services from 1980 to 2017, and find that careers mostly develop within sectors. Careers in asset management feature higher and steeper pay profiles than those of employees in banking, insurance and non-finance, yet this career premium cannot be explained by higher risk. Labor market entry responds positively to career premia in asset management and high-tech, and these sectors are regarded as substitutes by potential entrants, consistently with high-tech competing with asset management in attracting talent.
Using the pandemic as a laboratory, we show that asset markets assign a time- varying price to firms' disaster risk exposure. In 2020 the cross-section of realized and expected stock returns reflected firms' different exposure to the pandemic, as measured by their vulnerability to social distancing. Realized and expected return differentials initially widened and then narrowed, but disaster exposure still commanded a risk premium in December 2020. When inferred from market outcomes, resilience correlates not only with social distancing, but also with cash and environmental ratings. However, vulnerability to social distancing is the only characteristic that identifies persistently scarred firms.
We investigate whether government credit guarantee schemes, extensively used at the onset of the Covid-19 pandemic, led to substitution of non-guaranteed with guaranteed credit rather than fully adding to the supply of lending. We study this issue using a unique euro-area credit register data, matched with supervisory bank data, and establish two main findings. First, guaranteed loans were mostly extended to small but comparatively creditworthy firms in sectors severely affected by the pandemic, borrowing from large, liquid and well-capitalized banks. Second, guaranteed loans partially substitute pre-existing non-guaranteed debt. For firms borrowing from multiple banks, the substitution mainly arises from the lending behavior of the bank extending guaranteed loans. Substitution was highest for funding granted to riskier and smaller firms in sectors more affected by the pandemic, and borrowing from larger and stronger banks. Overall, the evidence indicates that government guarantees contributed to the continued extension of credit to relatively creditworthy firms hit by the pandemic, but also benefited banks’ balance sheets to some extent.
The collection of cephalopods from eight sampling horizons within the Olenidsletta Member, Valhallfonna Formation, Floian–Dapingian, from Profilstranda and nearby Profilbekken, Ny Friesland, Spitsbergen, resulted in the detection of 31 species, 20 genera, and 12 families from the Ellesmerocerida, Endocerida, Riocerida, Dissidocerida, Orthocerida, Tarphycerida, and Oncocerida. Of these, five genera (Ethanoceras gen. nov., Hinlopoceras gen. nov., Nyfrieslandoceras gen. nov., Olenidslettoceras gen. nov., Svalbardoceras gen. nov.) and 19 species (Bactroceras fluvii sp. nov., Buttsoceras buldrebreenense sp. nov., Cycloplectoceras hinlopense sp. nov., Cyclostomiceras profilstrandense sp. nov., Deltoceras beluga sp. nov., Eosomichelinoceras borealis sp. nov., Ethanoceras solitudines gen. et sp. nov., Hemichoanella occulta sp. nov., Hinlopoceras tempestatis gen. et sp. nov., H. venti gen. et sp. nov., Lawrenceoceras ebenus sp. nov., L. larus sp. nov., Litoceras profilbekkenense sp. nov., Nyfrieslandoceras bassleroceroides gen. et sp. nov., Olenidslettoceras farmi gen. et sp. nov., Protocycloceras minor sp. nov., Proterocameroceras valhallfonnense sp. nov., Svalbardoceras sterna gen. et sp. nov., S. skua gen. et sp. nov.) are new. The diagnoses of the Cyptendoceratidae, Bactroceratidae and of Deltoceras Hyatt, 1894 are emended. Well preserved early growth stages in several species are remarkable. Turnover between the sampling horizons and between sampling intervals is high. The differences in composition, diversity and evenness of the assemblages are interpreted as reflecting changing depth and oxygenation depositional bottom conditions. The co-occurrence of endemic and cosmopolitan species is interpreted as resulting from a high vertical niche differentiation and from eustatically generated lateral shifts of facies zones. Based on calculations of phragmocone implosion depths, depositional depths of 50–130 m are plausible for the Olenidsletta Member, supporting independent evidence from biomarker signatures. Several cephalopod species of the Olenidsletta Member represent odd mosaics of morphological features of previously known cephalopods which cannot be unambiguously assigned to one of the existing cephalopod higher taxa. Results from a cladistic analysis shed new light on the early evolution of the Oncocerida and Orthocerida.
The European Journal of Taxonomy (EJT) is a decade-old journal dedicated to the taxonomy of living and fossil eukaryotes. Launched in 2011, the EJT published exactly 900 articles (31 778 pages) from 2011 to 2021. The journal has been processed in its entirety by Plazi, liberating the data therein, depositing it into TreatmentBank, Biodiversity Literature Repository and disseminating it to partners, including the Global Biodiversity Information Facility (GBIF) using a combination of a highly automated workflow, quality control tools, and human curation. The dissemination of original research along with the ability to use and reuse data as freely as possible is the key to innovation, opening the corpus of known published biodiversity knowledge, and furthering advances in science. This paper aims to discuss the advantages and limitations of retro-conversion and to showcase the potential analyses of the data published in EJT and made findable, accessible, interoperable and reusable (FAIR) by Plazi. Among others, taxonomic and geographic coverage, geographical distribution of authors, citation of previous works and treatments, timespan between the publication and treatments with their cited works are discussed. Manually counted data were compared with the automated process, the latter being analysed and discussed. Creating FAIR data from a publication results in an average multiplication factor of 166 for additional access through the taxonomic treatments, figures and material citations citing the original publication in TreatmentBank, the Biodiversity Literature Repository and the Global Biodiversity Information Facility. Despite the advances in processing, liberating data remains cumbersome and has its limitations which lead us to conclude that the future of scientific publishing involves semantically enhanced publications.
The new class of microbial rhodopsins, called xenorhodopsins (XeRs),[1] extends the versatility of this family by inward H+ pumps.[2–4] These pumps are an alternative optogenetic tool to the light-gated ion channels (e.g. ChR1,2), because the activation of electrically excitable cells by XeRs is independent from the surrounding physiological conditions. In this work we functionally and spectroscopically characterized XeR from Nanosalina (NsXeR).[1] The photodynamic behavior of NsXeR was investigated on the ps to s time scale elucidating the formation of the J and K and a previously unknown long-lived intermediate. The pH dependent kinetics reveal that alkalization of the surrounding medium accelerates the photocycle and the pump turnover. In patch-clamp experiments the blue-light illumination of NsXeR in the M state shows a potential-dependent vectoriality of the photocurrent transients, suggesting a variable accessibility of reprotonation of the retinal Schiff base. Insights on the kinetically independent switching mechanism could furthermore be obtained by mutational studies on the putative intracellular H+ acceptor D220.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Key Points: Seventy-eight patients with Dravet syndrome were treated with FFA at multiple centers within the CUP in Germany; FFA had a good retention rate over a sustained period; 85% of patients remained on treatment with FFA for a median duration of 255.5 days; FFA was associated with clinically meaningful reductions in total and convulsive seizures, seizure days per month, and episodes of status epilepticus; FFA was associated with reductions in the number or dose of concomitant antiseizure medications in 68% of patients; FFA was well tolerated, with the main adverse events being somnolence (36%), decreased appetite (22%), and ataxia (8%).
The development of photosynthesis was a highlight in the progression of bacteria. In addition to the photosystems with their structural proteins, the photosynthesis apparatus consists of different cofactors including essential carotenoids. Thus, the evolution of the carotenoid pathways in relation to the functionality of the resulting structures in photosynthesis is the focus of this review. Analysis of carotenoid pathway genes indicates early evolutionary roots in prokaryotes. The pathway complexity leading to a multitude of structures is a result of gene acquisition, including their functional modifications, emergence of novel genes and gene exchange between species. Along with the progression of photosynthesis, carotenoid pathways coevolved with photosynthesis according to their advancing functionality. Cyanobacteria, with their oxygenic photosynthesis, became a landmark for evolutionary events including carotenogenesis. Concurrent with endosymbiosis, the cyanobacterial carotenoid pathways were inherited into algal plastids. In the lineage leading to Chlorophyta and plants, carotenoids evolved to their prominent role in protection and regulation of light energy input as constituents of a highly efficient light-harvesting complex.
Chondrules are thought to play a crucial role in planet formation, but the mechanisms leading to their formation are still a matter of unresolved discussion. So far, experiments designed to understand chondrule formation conditions have been carried out only under the influence of terrestrial gravity. In order to introduce more realistic conditions, we developed a chondrule formation experiment, which was carried out at long-term microgravity aboard the International Space Station. In this experiment, freely levitating forsterite (Mg2SiO4) dust particles were exposed to electric arc discharges, thus simulating chondrule formation via nebular lightning. The arc discharges were able to melt single dust particles completely, which then crystallized with very high cooling rates of >105 K h−1. The crystals in the spherules show a crystallographic preferred orientation of the [010] axes perpendicular to the spherule surface, similar to the preferred orientation observed in some natural chondrules. This microstructure is probably the result of crystallization under microgravity conditions. Furthermore, the spherules interacted with the surrounding gas during crystallization. We show that this type of experiment is able to form spherules, which show some similarities with the morphology of chondrules despite very short heating pulses and high cooling rates.
Redirection of the transcription factor SP1 to AT rich binding sites by a synthetic adaptor molecule
(2021)
The ubiquitous transcription factor SP1 binds to a GC rich consensus sequence. Here we describe an adaptor molecule that mediates binding of SP1 to a non-cognate DNA site rich in AT. The adaptor is comprised of a Dervan-type hairpin polyamide with high affinity to an AT rich hexamer duplex. It also carries a 27mer DNA that contains the SP1 consensus sequence. The synthesis and purification of the polyamide-DNA conjugate is reported. Pulldown experiments and western blot analysis demonstrate adaptor mediated binding of SP1 to the hexamer duplex TTGTTA.
Photoactivatable compounds for example photoswitches or photolabile protecting groups (PPGs, photocages) for spatiotemporal light control, play a crucial role in different areas of research. For each application, parameters such as the absorption spectrum, solubility in the respective media and/or photochemical quantum yields for several competing processes need to be optimized. The design of new photochemical tools therefore remains an important task. In this study, we exploited the concept of excited-state-aromaticity, first described by N. Colin Baird in 1971, to investigate a new class of photocages, based on cyclic, ground-state-antiaromatic systems. Several thio- and nitrogen-functionalized compounds were synthesized, photochemically characterized and further optimized, supported by quantum chemical calculations. After choosing the optimal scaffold, which shows an excellent uncaging quantum yield of 28 %, we achieved a bathochromic shift of over 100 nm, resulting in a robust, well accessible, visible light absorbing, compact new photocage with a clean photoreaction and a high quantum product (ϵ⋅Φ) of 893 M−1 cm−1 at 405 nm.
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.
Two species, namely Russula adwanitekae A.Ghosh, K.Das & Buyck sp. nov. and Russula purpureozonata K.Das, A.Ghosh & Buyck sp. nov. are proposed herein as new mushroom taxa from the Indian Himalaya based on their morphological features and ITS-based phylogenetic inferences. Both species belong to the crown clade of Russula subgenus Russula but with affinities to different subsections, viz. subsect. Laricinae Romagn. and subsect. Decolorantes Maire, respectively. Russula adwanitekae sp. nov. was collected in mixed temperate forests where it is most likely associated with conifers. It is distinct from several similarly looking, small, mild species with dark spore print and reddish lilac, orchid purple or greyish to deep magenta colored pileus in subsect. Laricinae by its sequence data (nrITS) or geographic distribution. Russula purpureozonata sp. nov. associates with Abies densa Griff., and possesses all typical features of Decolorantes, viz. the amyloid suprahilar spot on the spores, presence of pileogloeocystidia, the reddening then blackening context, equal lamellae and colored spore print. It reminds of North American R. californiensis Burl. and R. magna Beardslee under the microscope but has distinctly smaller spores and differs further in the unique coloration and concentrically zonated pileus margin. Macro- and micromorphological features are illustrated for both species. Their habitats, distributions and relationships with allied species are discussed.
This paper is the conclusion of the “Spaghetti Project” aiming to revise French species of Terebellidae sensu lato (s.l.) belonging to the five families: Polycirridae, Telothelepodidae, Terebellidae sensu stricto (s.s.), Thelepodidae and Trichobranchidae. During this project, 41 species were observed, 31 of them new for science: eight species of Polycirridae, eleven species of Terebellidae s.s., three species of Thelepodidae and nine species of Trichobranchidae. We provide a comprehensive key for all European species of terebellids with a focus on the important diagnostic characters for each family. Finally, we discuss issues on taxonomy, biodiversity and cryptic and pseudo-cryptic species of polychaetes in European waters, based on results obtained during this project.
The problem of unconstrained or constrained optimization occurs in many branches of mathematics and various fields of application. It is, however, an NP-hard problem in general. In this thesis, we examine an approximation approach based on the class of SAGE exponentials, which are nonnegative exponential sums. We examine this SAGE-cone, its geometry, and generalizations. The thesis consists of three main parts:
1. In the first part, we focus purely on the cone of sums of globally nonnegative exponential sums with at most one negative term, the SAGE-cone. We ex- amine the duality theory, extreme rays of the cone, and provide two efficient optimization approaches over the SAGE-cone and its dual.
2. In the second part, we introduce and study the so-called S-cone, which pro- vides a uniform framework for SAGE exponentials and SONC polynomials. In particular, we focus on second-order representations of the S-cone and its dual using extremality results from the first part.
3. In the third and last part of this thesis, we turn towards examining the con- ditional SAGE-cone. We develop a notion of sublinear circuits leading to new duality results and a partial characterization of extremality. In the case of poly- hedral constraint sets, this examination is simplified and allows us to classify sublinear circuits and extremality for some cases completely. For constraint sets with certain conditions such as sets with symmetries, conic, or polyhedral sets, various optimization and representation results from the unconstrained setting can be applied to the constrained case.
My PhD work employed genetic and pharmacological manipulations, coupled with highresolution live imaging, to understand intercellular communications during zebrafish cardiovascular development. The heart is the first organ to form, and it is composed of several tissues, among which interactions are crucial. I identified two important interactions between muscular and non-muscular tissues in poorly characterized contexts, and the molecules required for the signalling. First, I discovered an important cellular and molecular crosstalk orchestrating the development of the cardiac outflow tract (i.e., the aortic root in mammals).
Endothelial-derived TGF-beta signalling controls the generation of the local extracellular matrix (ECM). The ECM in turn affects endothelial proliferation as well as smooth muscle cell organization (Boezio et al, 2020; Bensimon-Brito*, Boezio* et al, 2020). In my second project, I investigated the crosstalk between the epicardial layer and the myocardial wall. By generating epicardial-impairment models, I identified a novel role for the epicardium in regulating cardiomyocyte volume during heart development (Boezio et al, 2021). Ultimately, this research contributed to our understanding of how paracrine signalling controls the multicellular interactions integral to organogenesis.
Die Bildung von Blutgefäßen ist essentiell für die Entwicklung und Homöostase von Wirbeltieren und die Endothelzellspezifikation ist ein wichtiger erster Schritt in diesem Prozess. Das früheste bekannte Ereignis bei der Endothelzellspezifikation im Zebrafisch ist die Expression des bHLH-PAS-Transkriptionsfaktor-Gens npas4l. Ich habe eine transgene V5-Linie zum Nachweis des markierten Npas4l auf Proteinebene und eine Gal4-VP16-Reporterlinie zur Visualisierung und Verfolgung von npas4l exprimierenden Zellen in vivo generiert. Beide Linien können bereits in frühen Entwicklungsstadien nachgewiesen werden und komplementieren auch starke npas4l-Mutanten Allele. Um npas4l Reporter exprimierende Zellen in npas4l Mutanten zu verfolgen, habe ich anschließend eine mutierte Variante der Gal4-Reporterlinie erzeugt. Diese Mutante trägt eine Insertion in der Region, die die DNA-Bindedomäne kodiert. Dadurch stört sie die Npas4l-Funktion, aber nicht die Reporterexpression. Dieses mutierte Reporterallel komplementiert nicht die npas4l-Mutanten und zeigt einen starken Phänotyp, was darauf hindeutet, dass es sich um ein funktionelles Nullallel handelt. Phänotypische Analysen zeigten, dass npas4l-Reporter positive Zellen in npas4l-Mutanten nicht spezifizieren oder zur Mittelachse wandern. Stattdessen tragen sie zu den vom intermediären Mesoderm abgeleiteten pronephrischen Tubuli und dem vom paraxialen Mesoderm abgeleiteten Skelettmuskel bei. Ich habe diese Phänotypen durch Einzelzell-RNAseq an den npas4l-Reporter positiven Zellen in npas4l+/- und npas4l-/- Embryonen bestätigt. Zusammen erklären diese beiden alternativen Zellschicksale den Großteil der beobachteten Veränderungen zwischen den Genotypen. Npas4l ist dafür bekannt die Expression der drei Transkriptionsfaktorgene etsrp, tal1 und lmo2 zu fördern. Ich stellte die Hypothese auf, dass das Fehlen jedes dieser Transkriptionsfaktoren in npas4l-Mutanten verschiedene Aspekte des npas4l-Phänotyps verursacht. Daher habe ich Mutantenlinien für alle drei Gene generiert und sie sowohl in vaskulären Reporterlinien als auch im npas4l-Reporterhintergrund analysiert. Die Daten legen nahe, dass verschiedene Gene unterschiedliche Prozesse während der frühen Endothelentwicklung regulieren. In npas4l-/- und etsrp-/- Embryonen differenzieren npas4l-Reporter exprimierende Zellen nicht zu Endothelzellen und tragen stattdessen zur Skelettmuskelzellpopulation bei. In npas4l-/- und tal1-/- Embryonen können npas4l-Reporter exprimierende Zellen nicht migrieren und tragen stattdessen zu der Bildung der pronephrischen Tubuli bei. Um die Beziehung zwischen diesen Faktoren besser zu verstehen, habe ich getestet, ob die Injektion von etsrp-, tal1- oder lmo2-mRNA verschiedene Aspekte des npas4l-Phänotyps retten würde. npas4l-, etsrp- und tal1-Mutanten zeigen alle schwere vaskuläre Phänotypen. Einige Endothelzellen und vaskuläre Strukturen bleiben jedoch in jeder Mutante erhalten. Der Phänotyp ist am stärksten in npas4l-/- Embryonen, aber selbst in diesen Embryonen können einige fli1a-positive Endothelzellen in der Schwanzregion beobachtet werden. Es war unklar, ob sich diese Population von Endothelzellen unabhängig von der Npas4l-, Tal1- und Etsrp-Funktion entwickelt oder als Folge einer restlichen tal1- oder etsrp-Expression unabhängig von Npas4l. Um diese Frage zu untersuchen, habe ich Doppelmutanten generiert und nach dem Vorhandensein von fli1a-positiven Endothelzellen in diesen Mutanten gesucht. Während fli1a-positive Endothelzellen in npas4l-/- und npas4l-/-;tal1-/- Embryonen deutlich vorhanden sind, können keine solchen Zellen in npas4l-/-;etsrp-/- oder etsrp-/-;tal1-/- Embryonen beobachtet werden. Diese Daten deuten darauf hin, dass sich im Zebrafisch keine Endothelzellen entwickeln können, wenn zugleich npas4l und etsrp oder etsrp und tal1 gestört sind. Während der Verlust von etsrp zu stärkeren Defekten in npas4l-Mutanten führt, gibt es keinen zusätzlichen Phänotyp, der durch den Verlust von tal1verursacht wird, was darauf hindeutet, dass die Expression von etsrp, aber nicht die von tal1, unabhängig von Npas4l auftreten kann. Diese Idee wird durch die Beobachtung unterstützt, dass etsrp, aber nicht tal1-Expression in den meisten fli1a-exprimierenden Zellen in npas4l-/- Embryonen beobachtet wird. Dennoch wird der Großteil -Expression durch Npas4l reguliert. tal1-mRNA-Injektionen reichten aus, um eine Wildtyp-ähnliche vaskuläre Musterbildung im Bauchbereich der npas4l-/- Embryonen wiederherzustellen, einschließlich der Rettung sowohl der Zellmigration als auch der Differenzierung. Da Npas4l mehrere unterschiedliche transkriptionelle Effektoren hat, war eine so starke Rettung durch nur einen dieser Effektoren unerwartet. In den geretteten Mutanten wurde die bilaterale Population von npas4l-Reporter-positiven pronephrischen Tubuluszellen nicht entdeckt, aber die Anzahl der ektopischen npas4l-Reporter exprimierenden Muskelzellen war im Vergleich zu nicht injizierten npas4l-Mutanten gleichbleibend.
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It is increasingly recognized that neuroscience has not delivered the revolutionary clinical possibilities for psychiatry that had been promised. Explanations differ, however: some proponents emphasize the divide between biopsychosocial psychiatry and mechanistic neurology. Others rely on further basic experimental neuroscience as only the most elementary level of explanation will allow us to fully understand and treat mental disorders. From a clinical-neuropsychological perspective, I shall argue that both views are mistaken. Diagnosis and treatment of neurological diseases demands a biopsychosocial perspective similar to psychiatry. Acknowledging this might help to bring both disciplines together and improve clinical outcome.
Multi-view microscopy techniques are used to increase the resolution along the optical axis for 3D imaging. Without this, the resolution is insufficient to resolve subcellular events. In addition, parts of the images of opaque specimens are often highly degraded or masked. Both problems motivate scientists to record the same specimen from multiple directions. The images, then have to be digitally fused into a single high-quality image. Selective-plane illumination microscopy has proven to be a powerful imaging technique due to its unsurpassed acquisition speed and gentle optical sectioning. However, even in the case of multi view imaging techniques that illuminate and image the sample from multiple directions, light scattering inside tissues often severely impairs image contrast.
Here we show that for c-elegans embryos multi view registration can be achieved based on segmented nuclei. However, segmentation of nuclei in high density distribution like c-elegans embryo is challenging. We propose a method which uses 3D Mexican hat filter for preprocessing and 3D Gaussian curvature for the post-processing step to separate nuclei. We used this method successfully on 3 data sets of c-elegans embryos in 3 different views. The result of segmentation outperforms previous methods. Moreover, we provide a simple GUI for manual correction and adjusting the parameters for different data.
We then proposed a method that combines point and voxel registration for an accurate multi view reg- istration of c-elegans embryo, which does not need any special experimental preparation. We demonstrate the performance of our approach on data acquired from fixed embryos of c-elegans worms. This multi step approach is successfully evaluated by comparison to different methods and also by using synthetic data. The proposed method could overcome the typically low resolution along the optical axis and enable stitching to- gether the different parts of the embryo available through the different views. A tool for running the code and analyzing the results is developed.
Neurons are cells with a highly complex morphology; their dendritic arbor spans up to thousands of micrometers. This extended arbor poses a challenge for the logistics of neuronal processes: mRNA, proteins, and organelles have to be transported to dendrites, hundreds of micrometers away from the soma. This thesis aims to calculate the minimum number of proteins needed to populate the dendritic trees for different scenarios.
In chapter 2, I analyzed the ability of different mechanisms to populate the dendritic arbor. I started from the solution of the diffusion equation in Sec. 2.1, then I included the contribution of active transport in Sec. 2.2 and showed how it could have either the effect of increasing the effective diffusion coefficient or of introducing a bias in the diffusion process. In Sec. 2.3 I studied the spatial distribution of locally synthesized protein, accordingly with actively and passively transported mRNA. In Sec. 2.5, I derived the boundary condition for branches showing a qualitatively different behavior of surface and cytoplasmic proteins induced by the medium’s dimensionality in which they diffuse.
In chapter 3, I introduced the concept of protein requirement, defined as the minimum number of proteins that the neuron needs to produce to provide at least one protein to each micrometer of the dendritic arbor. In Sec. 3.1, I derived the protein requirement for diffusive proteins for somatic translation and constant translation in the dendritic arbor. In Sec. 3.2, I analyzed numerically the protein requirement in the case of actively transported protein synthesized in the soma, and, in Sec. 3.3, in the case of actively transported proteins synthesized in the dendritic arbor. In Sec. 3.4, I analyzed the protein requirement of protein synthesized in the dendrite accordingly with the distribution of mRNA described in Sec. 3.3 and 3.2. In Sec. 3.5, I derived the protein requirement for a single branch and purely diffusive proteins.
In chapter 4, I analyzed the relation between the radii of the three afferent dendrites in a branch, their length, and the diffusion length of a protein. In Sec. 4.1 I derived the optimal ratio between the radii of the daughter dendrites that minimizes the protein requirement. In Sec. 4.3 I introduced the 3/2− Rall Rule and in Sec. 4.5 its generalization. Finally, I used those rules to estimate the fraction of proteins diffusing away from and toward the soma.
In chapter 5, I analyzed the radii distribution for three categories of neurons: cultured hippocampal neurons in Sec. 5.1, stomatogastric ganglia neuron in Sec. 5.2, and 3DEM reconstructed prefrontal pyramidal neurons in Sec. 5.3. For each of these three classes, I analyzed the distribution of radii, Rall exponents, and the probability ratio. For most of them, I found that the probability of a protein diffusing away from the soma is higher for surface proteins than for cytoplasmic ones. I quantified this with a parameter called surface bias.
In Chapter 6, I analyzed the fluorescent ratio imaged by our collaborators Anne-Sophie Hafner, for a surface protein, GFP::Nlg, and a soluble one, GFP, in cultured hippocampal neurons, and I compared the fluorescent ratio with the probability ratio obtained in 5.1, finding that they are in good agreement.
In chapter 7, I compared the real dendritic morphologies imaged by one of our collaborators Ali Karimi with the optimal branching rule obtained in Sec. 4.1 and I calculated the cost for not having optimal branching radii.
Finally, in Chapter 8, I used the knowledge of the branching statistics gathered in 5.3 to simulate the protein profile on three different classes of neurons: pyramidal neurons, granule neuron, and Purkinje neurons. I compared the protein profile for surface and cytoplasmic neurons for each morphology for two different values of the diffusion length: λ = 109µm and λ = 473µm, both for optimized radii and symmetrical radii. I showed how the radii optimization reduces the protein requirement of a factor 10 4 for pyramidal neurons.
Sampling of remote inland aquatic habitats in South Africa has constantly been yielding novel endemic freshwater crab species (Potamonautes MacLeay,1838). During the present study, we report on the discovery and description of two new freshwater crab species (Potamonautes baziya sp. nov., and P. mariepskoppie sp. nov.) from Afrotemperate forested mountain regions in the Eastern Cape and Mpumalanga provinces of South Africa, respectively. Phylogenetic evidence derived from DNA sequence data of three partial mitochondrial loci (12S rRNA, 16S rRNA and cytochrome oxidase subunit one, COI) corroborates the evolutionary distinction of the two novel species. In addition, morphological and ecological data for the two new species further delineate their evolutionary distinction from congeneric sister species. A comparison of the taxonomically important gonopods 1 and 2 and carapace features among the sister species and other known freshwater crabs of South Africa was further used to provide evidence for the distinction of the two novel species. The discovery of two new species suggest that remote mountainous areas or unsampled regions in South Africa likely harbor several novel species, reiterating a call to document aquatic inland biodiversity in forested and mountainous regions of the country.
Diese Arbeit ist ein detaillierter Bericht über die Forschungsaktivitäten, die ich während meiner Promotion am Max-Planck-Institut für Biophysik durchgeführt habe. Mit dem Aufkommen der direkten Elektronendetektoren erlebte die Transmissionselektronenmikroskopie von gefrorenen hydratisierten Proben (Kryo-EM) einen epochalen Wandel, die sogenannte “Auflösungsrevolution”. Ab den 2010er Jahren ermöglichte die Kommerzialisierung der ersten direkten Detektoren die Erforschung biologischer Phänomene in beispiellosem Detail und machte Kryo-EM zu einer der leistungsstärksten (und gefragtesten) Forschungsmethoden in den Biowissenschaften. Meine Forschung konzentrierte sich auf die Verwendung der Elektronen-Kryotomographie, um zwei herausfordernde Ziele zu erreichen. Das erste bestand darin, die Denaturierung von Proteinen an der Luft-Wasser-Grenzfläche zu untersuchen, und das zweite die molekulare Landschaft eines lichtempfindlichen Chloroplastenvorläufers, des Etioplasten, zu beschreiben. Um die Relevanz, Herausforderungen und Auswirkungen meiner Arbeit zu vermitteln, habe ich diese Arbeit in drei Kapitel unterteilt.
Kapitel eins enthält eine Einführung in die Transmission-Elektronenmikroskopie.
Nach einer kurzen Zusammenfassung der historischen Meilensteine in der Disziplin beschreibe ich die wesentlichen Komponenten des TEM und deren Funktionsweise. Hier lege ich besonderen Wert auf die Struktur elektromagnetischer Linsensysteme, wie sie den Weg der Elektronen beim Durchlaufen der Säule beeinflussen und wie Bilder entstehen. Der hardwarebezogene Teil der Einführung wird durch eine vereinfachte Beschreibung der Elektronendetektoren abgeschlossen, in der ich die revolutionären Aspekte der direkten Elektronendetektoren, mit der Struktur und Funktion von CCD-Detektoren (Charge Coupled Device detector) vergleiche. Als nächstes konzentriere ich mich auf die theoretischen Prinzipien der Bilderzeugung. Um die Hauptphänomene im Zusammenhang mit der Bildqualität in TEM hervorzuheben, stelle ich grundlegende Konzepte wie den Einfluss von Elektronenenergie und optischen Aberrationen vor, gefolgt von einer ausführlicheren Beschreibung des Ursprungs von Kontrast und Rauschen. Der Unterabschnitt schließt mit einigen Überlegungen darüber, wie - und vor allem wie effizient - Detektoren kontinuierliche Elektronenwellen in diskrete Bereiche (Pixel) abtasten. Der folgende Unterabschnitt ist der Erfassung und Verarbeitung tomografischer Daten gewidmet. Hier gebe ich eine vereinfachte Beschreibung, wie Kippserien mit dem Mikroskop erfasst werden und wie die Rohdaten zu einer dreidimensionalen Darstellung der Probe verarbeitet werden. Der Einfluss der Neigungsgeometrie und der Dosisverteilung auf die Rekonstruktionsqualität wird ebenfalls diskutiert. Der zweite Teil des Unterabschnitts befasst sich mit der Strukturbestimmung durch Subtomogramm-Mittelung und der Errechnung der Auflösung von Kryo-EM-Rekonstruktion. Zuletzt schließe ich das Kapitel mit einer Beschreibung der Vorbereitung biologischer Proben für die Kryo-EM-Bildgebung mit einigen abschließenden Bemerkungen zur Dynamik und den Grenzen der Vitrifizierung ab.
Kapitel zwei folgt dem Thema der Kryo-Präparation biologischer Proben mit der Untersuchung der Denaturierung von Proteinen an der Luft-Wasser-Grenzfläche.
Im Einführungsabschnitt skizziere ich die wichtigsten Aspekte dieses Phänomens. Frühe Experimente zum Verhalten von Proteinen in Lösung zeigten ihre Neigung, aus der Lösung zu ihrer Grenzfläche mit der Atmosphäre zu diffundieren. Hier bilden sie meist unlösliche Schichten denaturierter Fibrillen Es wurde vorgeschlagen, dass die Korrelation zwischen Proteindenaturierung und Kontakt mit der Grenzfläche auf einen allmählichen Entfaltungsprozess zurückzuführen ist, bei dem Tausende von Wechselwirkungen pro Sekunde zu einer immer größeren strukturellen Schädigung führen würden. Ein direkter Beweis für diesen Mechanismus wurde jedoch nie dokumentiert. Um einen tieferen Einblick in die Dynamik an der Luft-Wasser-Grenzfläche zu erhalten, sammelte ich Kryotomogramme vitrifizierter Präparate der Fettsäuresynthase (FAS, Fatty Acid Synthase) aus Hefe. Im ersten Unterabschnitt der Ergebnisse beschreibe ich, wie die biochemische und Negativkontrastierung-TEM-Analyse von FAS-Fraktionen zeigte, dass der Komplex während des gesamten Reinigungsverfahrens intakt und katalytisch aktiv blieb. Nach der Vitrifizierung ergab die Einzelpartikelanalyse jedoch, dass 90% aller Komplexe stark beschädigt waren. Die tomographische Rekonstruktion derselben Proben zeigte, dass alle FAS-Komplexe an die Luft-Wasser-Grenzfläche gebunden waren. Die Seite des Moleküls, die der Grenzfläche ausgesetzt war, schien abgeflacht zu sein, während die Seite, in der wässrigen Phase, ihre native Struktur beibehielt. Die Mittelung der Subtomogramme bestätigte, dass eine Seite von fast 90% der Partikel stark beschädigt war. Durch den Vergleich der Ausrichtung dieser beschädigten Seite mit der Position eines Rechenmodells der Luft-Wasser-Grenzfläche konnte ich nachweisen, dass sie perfekt übereinstimmen, was den ersten direkten Beweis dafür liefert, dass die Wechselwirkung mit der Luft-Wasser-Grenzfläche die lokale Denaturierung großer Proteinkomplexe herbeiführt.
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The US Tax Cuts and Jobs Act (TCJA) led to a drastic reduction in the corporate tax and improved the treatment of C corporations compared to S corporations. We study the differential effect of the TCJA on these types of corporations using key economic variables of US banks, such as the number of employees, average salaries and benefits, profit/loss before taxes, and net income. Our analysis suggests that the TCJA increased the net-of-tax profits of C corporation banks compared to S corporations and, to a lesser extent, their pre-tax profits. At the same time, the reform triggered no significantly differential effect on the employment and average wages.
Historically Central Bank Independence (CBI) was anything but the norm. CBI seems to contradict core principles of democracy. Most economists were also against CBI. After the Great Inflation of the 1970ies many empirical studies demonstrated that there is a strong negative correlation between the degree of CBI and the rate of inflation. In 1990 most major countries had endowed their central bank with the status of independence. Overburdening with elevated expectations and additional competences are threatening the reputation of central banks and undermining the case for CBI.