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We show the absence of an instability of homogeneous (chiral) condensates against spatially inhomogeneous perturbations for various (2+1)-dimensional four-fermion and Yukawa models. All models are studied at nonzero baryon chemical potential, while some of them are also subjected to chiral and isospin chemical potential. The considered theories contain up to 16 Lorentz-(pseudo)scalar fermionic interaction channels. We prove the stability of homogeneous condensates by analyzing the bosonic two-point function, which can be expressed in a purely analytical form at zero temperature. Our analysis is presented in a general manner for all of the different discussed models. We argue that the absence of an inhomogeneous chiral phase (where the chiral condensate is spatially nonuniform) follows from this lack of instability. Furthermore, the existence of a moat regime, where the bosonic wave-function renormalization is negative, in these models is ruled out.
Mücke, Marcus Maximilian ; Mücke, Victoria Therese ; Peiffer, Kai-Henrik ; Sarrazin, Christoph ; Zeuzem, Stefan ; Berger, Annemarie ; Vermehren, Johannes
Background: Patients with chronic hepatitis C virus (HCV) infection and active or previous hepatitis B virus (HBV) are at risk of HBV reactivation (HBV-R) during direct-acting antiviral (DAA) therapy. Recent reports suggest that HBV-R may even occur several months after completion of DAA therapy. The aim of this study was to assess the risk of HBV-R in patients with resolved HBV after successful DAA therapy during long-term follow-up (FU).
Methods: Among 848 patients treated for chronic HCV, all patients with resolved HBV and long-term FU data were eligible for inclusion. Patients were HBV DNA/hepatitis B surface antigen (HBsAg)–negative at the end of therapy (EOT) and were followed for up to 52 weeks thereafter. Patients underwent regular alanine transaminase (ALT) testing, and additional HBV DNA/HBsAg testing was performed at FU week 12, end of FU, and in case of an ALT increase above the upper limit of normal (>ULN).
Results: A total of 108 patients were followed up for a mean (range) of 41.5 (24–52) weeks after EOT. None of the patients experienced reverse HBsAg seroconversion or reappearance of HBV DNA. One patient received a liver transplantation; 1 patient was diagnosed with de novo hepatocellular carcinoma, and 2 patients died. Eighteen patients (16.7%) had increased ALT levels (grade 0/1). Of those, the majority were male (72.2%) and significantly more patients had cirrhosis (66.7% vs 36.2%, P = .015) or received ribavirin as part of their treatment regimen (86.7% vs 46.8%, P = .041). None of these were associated with HBV-R.
Conclusions: Our results indicate that the risk of HBV-R in patients with resolved HBV treated with DAAs for HCV is low during long-term follow-up.
Background: Plant hormones are well known regulators which balance plant responses to abiotic and biotic stresses. We investigated the role of abscisic acid (ABA) in resistance of barley (Hordeum vulgare L.) against the plant pathogenic fungus Magnaporthe oryzae.
Results: Exogenous application of ABA prior to inoculation with M. oryzae led to more disease symptoms on barley leaves. This result contrasted the finding that ABA application enhances resistance of barley against the powdery mildew fungus. Microscopic analysis identified diminished penetration resistance as cause for enhanced susceptibility. Consistently, the barley mutant Az34, impaired in ABA biosynthesis, was less susceptible to infection by M. oryzae and displayed elevated penetration resistance as compared to the isogenic wild type cultivar Steptoe. Chemical complementation of Az34 mutant plants by exogenous application of ABA re-established disease severity to the wild type level. The role of ABA in susceptibility of barley against M. oryzae was corroborated by showing that ABA application led to increased disease severity in all barley cultivars under investigation except for the most susceptible cultivar Pallas. Interestingly, endogenous ABA concentrations did not significantly change after infection of barley with M. oryzae.
Conclusion: Our results revealed that elevated ABA levels led to a higher disease severity on barley leaves to M. oryzae. This supports earlier reports on the role of ABA in enhancing susceptibility of rice to the same pathogen and thereby demonstrates a host plant-independent function of this phytohormone in pathogenicity of monocotyledonous plants against M. oryzae.
The theoretical IR-frequencies of sulphurdifluoride are computed from force constants, which are evaluated by means of molecules with S-F-bonds: ν1 = 795 ± 10cm-1, ν2 = 430± 5cm-1, ν3= 830 ± 10cm-1.
Die Mühlen des Rechts mahlen langsam, aber gerecht. Zu dieser Abwandlung eines berühmten Sprichworts mag derjenige greifen, wer das jüngste Urteil des Bundesverwaltungsgerichts zum Versammlungsrecht liest. Am 25.10.2017 entschied das Bundesverwaltungsgericht über den Tornado-Einsatz vom G8-Gipfel in Heiligendamm – über zehn Jahre, nachdem die damaligen Bundessprecher*innen der GRÜNEN JUGEND Jan Philipp Albrecht und Paula Riester gegen den Einsatz geklagt hatten. Gerade weil sich die staatliche Praxis im Umgang mit Versammlungen in jüngster Zeit immer stärker militarisiert und zugleich präventiv ausgerichtet hat, kommt dem leider in der Öffentlichkeit nicht hinreichend rezipierten Urteil (Pressemitteilung des BVerwG zu 6 C 45.16) eine grundsätzliche Bedeutung zu. ...
Abrupt climate changes of the last deglaciation detected in a Western Mediterranean forest record
(2010)
Abrupt changes in Western Mediterranean climate during the last deglaciation (20 to 6 cal ka BP) are detected in marine core MD95-2043 (Alboran Sea) through the investigation of high-resolution pollen data and pollen-based climate reconstructions by the modern analogue technique (MAT) for annual precipitation (Pann) and mean temperatures of the coldest and warmest months (MTCO and MTWA). Changes in temperate Mediterranean forest development and composition and MAT reconstructions indicate major climatic shifts with parallel temperature and precipitation changes at the onsets of Heinrich stadial 1 (equivalent to the Oldest Dryas), the Bölling-Allerød (BA), and the Younger Dryas (YD). Multi-centennial-scale oscillations in forest development occurred throughout the BA, YD, and early Holocene. Shifts in vegetation composition and (Pann reconstructions indicate that forest declines occurred during dry, and generally cool, episodes centred at 14.0, 13.3, 12.9, 11.8, 10.7, 10.1, 9.2, 8.3 and 7.4 cal ka BP. The forest record also suggests multiple, low-amplitude Preboreal (PB) climate oscillations, and a marked increase in moisture availability for forest development at the end of the PB at 10.6 cal ka BP. Dry atmospheric conditions in the Western Mediterranean occurred in phase with Lateglacial events of high-latitude cooling including GI-1d (Older Dryas), GI-1b (Intra-Allerød Cold Period) and GS-1 (YD), and during Holocene events associated with high-latitude cooling, meltwater pulses and N. Atlantic ice-rafting. A possible climatic mechanism for the recurrence of dry intervals and an opposed regional precipitation pattern with respect to Western-central Europe relates to the dynamics of the westerlies and the prevalence of atmospheric blocking highs. Comparison of radiocarbon and ice-core ages for well-defined climatic transitions in the forest record suggests possible enhancement of marine reservoir ages in the Alboran Sea by 200 years (surface water age 600 years) during the Lateglacial.
Abrupt climate changes of the last deglaciation detected in a western Mediterranean forest record
(2009)
Abrupt changes in Western Mediterranean climate during the last deglaciation (20 to 6 cal ka BP) are detected in marine core MD95-2043 (Alboran Sea) through the investigation of high-resolution pollen data and pollen-based climate reconstructions by the modern analogue technique (MAT) for annual precipitation (Pann) and mean temperatures of the coldest and warmest months (MTCO and MTWA). Changes in temperate Mediterranean forest development and composition and MAT reconstructions indicate major climatic shifts with parallel temperature and precipitation changes at the onsets of Heinrich stadial 1 (equivalent to the Oldest Dryas), the Bölling-Allerød (BA), and the Younger Dryas (YD). Multi-centennial-scale oscillations in forest development occurred throughout the BA, YD, and early Holocene. Shifts in vegetation composition and (Pann reconstructions indicate that forest declines occurred during dry, and generally cool, episodes centred at 14.0, 13.3, 12.9, 11.8, 10.7, 10.1, 9.2, 8.3 and 7.4 cal ka BP. The forest record also suggests multiple, low-amplitude Preboreal (PB) climate oscillations, and a marked increase in moisture availability for forest development at the end of the PB at 10.6 cal ka BP. Dry atmospheric conditions in the Western Mediterranean occurred in phase with Lateglacial events of high-latitude cooling including GI-1d (Older Dryas), GI-1b (Intra-Allerød Cold Period) and GS-1 (YD), and during Holocene events associated with high-latitude cooling, meltwater pulses and N. Atlantic ice-rafting. A possible climatic mechanism for the recurrence of dry intervals and an opposed regional precipitation pattern with respect to Western-central Europe relates to the dynamics of the westerlies and the prevalence of atmospheric blocking highs. Comparison of radiocarbon and ice-core ages for well-defined climatic transitions in the forest record suggests possible enhancement of marine reservoir ages in the Alboran Sea by 200 years (surface water age 600 years) during the Lateglacial.
The association of Schlen k’s hydrocarbon was studied by means of osmometric and magnetic measurements. The mixed chain-ring-association can be explained satisfactorily assuming that two different dimers and four monomer species participate in the equilibria, including a monomeric diamagnetic ring. The equilibria existing between the different species are discussed. For the equilibria between the monomer and dimer species, which can be detected in solutions of normal viscosity by means of ESR-measurements, the unexpected values of ΔH=0 for the enthalpie of association and ΔS= +19.7 e. u. for the entropie of association were found.
Edwin Thanarajah, Sharmili ; Han, Cheol E. ; Rotarska-Jagiela, Anna ; Singer, Wolf ; Deichmann, Ralf ; Maurer, Konrad ; Kaiser, Marcus ; Uhlhaas, Peter J.
The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal–frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.
O texto se ocupa com a questão da interpretação da obra de Jean-Jacques Rousseau, em particular com suas referências sobre a dependência constitutiva em relação aos outros. Vista negativamente na crítica da cultura, mas positivamente nos esboços de um contrato social, o lugar dessa dependência constitutiva da confirmação e estima por parte dos outros está vinculada ao significado dado ao “amor próprio” nos diferentes textos; mas ela abre a possibilidade de interpretar Rousseau como um teórico do reconhecimento. O autor acompanha Rousseau em seu desenvolvimento teórico até o ponto em que ele se tornou consciente das exigências de uma forma sociocontratual, igualitária do reconhecimento mútuo, para depois expor a enorme influência que a ideia bipolar de Rousseau a respeito do reconhecimento social exerceu sobre a teoria social da modernidade: em sua variante negativa, a profunda necessidade dos seres humanos de sobrepujar os respectivos cossujeitos no grau de estima social, reinterpretada por Kant como sendo a força motriz do progresso cultural e social, e em sua variante positiva, o respeito mútuo entre iguais, desenvolvido por Fichte e Hegel na direção de uma teoria do reconhecimento relacionada ao direito e à moralidade. No final, Honneth discute o ceticismo com que Rousseau sempre viu a dependência de outros contida no “amor próprio”, deixando sem solução definitiva a tensão entre a ideia estoica de uma independência pessoal de toda avaliação alheia e a ideia intersubjetivista de uma profunda dependência do outro. (Resumo do editor).
Bögemann, Martin ; Khaksar, Sara ; Bera, Guillaume ; Birtle, Alison ; Dopchie, Catherine ; Dourthe, Louis-Marie ; Everaert, Els ; Hatzinger, Martin ; Hercher, Dirko ; Hilgers, Werner ; Matus, Geoffrey ; Garcia Alvarez, Laura ; Antoni, Laurent ; Lukac, Martin ; Pissart, Geneviève ; Robinson, Paul ; Elliott, Tony
Background: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.
Methods: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.
Results: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).
Conclusions: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.
Modest Byamungu, Robert ; Schleuning, Matthias ; Ferger, Stefan W. ; Helbig-Bonitz, Maria ; Hemp, Andreas ; Neu, Alexander ; Vogeler, Anna ; Böhning-Gaese, Katrin ; Tschapka, Marco ; Albrecht, Jörg
Aim: The identification of the mechanisms determining spatial variation in biological diversity along elevational gradients is a central objective in ecology and biogeography. Here, we disentangle the direct and indirect effects of abiotic drivers (climatic conditions, and land use) and biotic drivers (vegetation structure and food resources) on functional diversity and composition of bird and bat assemblages along a tropical elevational gradient. Location: Southern slopes of Mt. Kilimanjaro, Tanzania, East Africa. Methods: We counted birds and recorded bat sonotypes on 58 plots distributed in near-natural and anthropogenically modified habitats from 700 to 4,600 m above sea level. For the recorded taxa, we compiled functional traits related to movement, foraging and body size from museum specimens and databases. Further, we recorded mean annual temperature, precipitation, vegetation complexity as well as the number of fruits, flowers, and insect biomass as measures of resource availability on each study site. Results: Using path analyses, we found similar responses of bird and bat functional diversity to the variation in abiotic and biotic drivers along the elevational gradient. In contrast, the functional composition of both taxa showed distinct responses to abiotic and biotic drivers. For both groups, direct temperature effects were most important, followed by resource availability, precipitation and vegetation complexity. Main Conclusions: Our findings indicate that physiological and metabolic constraints imposed by temperature and resource availability determine the functional diversity of bird and bat assemblages, whereas the composition of individual functional traits is driven by taxon-specific processes. Our study illustrates that distinct filtering mechanisms can result in similar patterns of functional diversity along broad environmental gradients. Such differences need to be taken into account when it comes to conserving the functional diversity of flying vertebrates on tropical mountains.
Fiebig, Jens ; Stefánsson, Andri ; Ricci, Andrea ; Tassi, Franco ; Viveiros, Fatima ; Silva, Catarina ; Lopez, Taryn ; Schreiber, Christoph ; Hofmann, Sven ; Mountain, Bruce W.
Abiotic formation of n-alkane hydrocarbons has been postulated to occur within Earth's crust. Apparent evidence was primarily based on uncommon carbon and hydrogen isotope distribution patterns that set methane and its higher chain homologues apart from biotic isotopic compositions associated with microbial production and closed system thermal degradation of organic matter. Here, we present the first global investigation of the carbon and hydrogen isotopic compositions of n-alkanes in volcanic-hydrothermal fluids hosted by basaltic, andesitic, trachytic and rhyolitic rocks. We show that the bulk isotopic compositions of these gases follow trends that are characteristic of high temperature, open system degradation of organic matter. In sediment-free systems, organic matter is supplied by surface waters (seawater, meteoric water) circulating through the reservoir rocks. Our data set strongly implies that thermal degradation of organic matter is able to satisfy isotopic criteria previously classified as being indicative of abiogenesis. Further considering the ubiquitous presence of surface waters in Earth’s crust, abiotic hydrocarbon occurrences might have been significantly overestimated.
Background: Stem cell therapy is considered as a promising alternative to treat intervertebral disc degeneration (IDD). Extensive work had been done on identifying and comparing different types of candidate stem cells, both in vivo and in vitro. However, few studies have shed light on degenerative nucleus pulposus cells (NPCs), especially their biological behavior under the influence of exogenous stem cells, specifically the gene expression and regulation pattern. In the present study, we aimed to determine messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), which are differentially expressed during the co-culturing process with adipose-derived mesenchymal stem cells (ASCs) and to explore the involved signaling pathways and the regulatory networks.
Methods: We compared degenerative NPCs co-cultured with ASCs with those cultured solely using lncRNA-mRNA microarray analysis. Based on these data, we investigated the significantly regulated signaling pathways based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Moreover, 23 micro RNAs (miRNAs), which were demonstrated to be involved in IDD were chosen; we investigated their theoretic regulatory importance associated with our microarray data.
Results: We found 632 lncRNAs and 1682 mRNAs were differentially expressed out of a total of 40,716 probes. We then confirmed the microarray data by real-time PCR. Furthermore, we demonstrated 197 upregulated, and 373 downregulated Gene Ontology terms and 176 significantly enriched pathways, such as the mitogen-activated protein kinase (MAPK) pathway. Also, a signal-net was constructed to reveal the interplay among differentially expressed genes. Meanwhile, a mRNA-lncRNA co-expression network was constructed for the significantly changed mRNAs and lncRNAs. Also, the competing endogenous RNA (ceRNA) network was built.
Conclusion: Our results present the first comprehensive identification of differentially expressed lncRNAs and mRNAs of degenerative NPCs, altered by co-culturing with ASCs, and outline the gene expression regulation pattern. These may provide valuable information for better understanding of stem cell therapy and potential candidate biomarkers for IDD treatment.
Aberrant neurophysiological signaling associated with speech impairments in Parkinson’s disease
(2023)
Wiesman, Alex I. ; Donhauser, Peter W. ; Degroot, Clotilde ; Diab, Sabrina ; Kousaie, Shanna ; Fon, Edward A. ; Klein, Denise ; Baillet, Sylvain
Difficulty producing intelligible speech is a debilitating symptom of Parkinson’s disease (PD). Yet, both the robust evaluation of speech impairments and the identification of the affected brain systems are challenging. Using task-free magnetoencephalography, we examine the spectral and spatial definitions of the functional neuropathology underlying reduced speech quality in patients with PD using a new approach to characterize speech impairments and a novel brain-imaging marker. We found that the interactive scoring of speech impairments in PD (N = 59) is reliable across non-expert raters, and better related to the hallmark motor and cognitive impairments of PD than automatically-extracted acoustical features. By relating these speech impairment ratings to neurophysiological deviations from healthy adults (N = 65), we show that articulation impairments in patients with PD are associated with aberrant activity in the left inferior frontal cortex, and that functional connectivity of this region with somatomotor cortices mediates the influence of cognitive decline on speech deficits.
Aberrant epigenetic regulators control expansion of human CD34+ hematopoietic stem/progenitor cells
(2013)
Faridi, Farnaz ; Ponnusamy, Kanagaraju ; Quagliano-Lo Coco, Isabell ; Chen-Wichmann, Linping ; Grez, Manuel ; Henschler, Reinhard ; Wichmann, Christian
Transcription is a tightly regulated process ensuring the proper expression of numerous genes regulating all aspects of cellular behavior. Transcription factors regulate multiple genes including other transcription factors that together control a highly complex gene network. The transcriptional machinery can be “hijacked” by oncogenic transcription factors, thereby leading to malignant cell transformation. Oncogenic transcription factors manipulate a variety of epigenetic control mechanisms to fulfill gene regulatory and cell transforming functions. These factors assemble epigenetic regulators at target gene promoter sequences, thereby disturbing physiological gene expression patterns. Retroviral vector technology and the availability of “healthy” human hematopoietic CD34+ progenitor cells enable the generation of pre-leukemic cell models for the analysis of aberrant human hematopoietic progenitor cell expansion mediated by leukemogenic transcription factors. This review summarizes recent findings regarding the mechanism by which leukemogenic gene products control human hematopoietic CD34+ progenitor cell expansion by disrupting the normal epigenetic program.
Dvorak, Jannis ; Hilke, Marietheres ; Trettin, Marco ; Wenzler, Sofia Maria ; Hagen, Marleen ; Ghirmai, Naddy ; Müller, Maximilian ; Kraft, Dominik ; Reif, Andreas ; Oertel-Knöchel, Viola
Introduction: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC.
Methods: We collected resting‐state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age‐ and gender‐matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level.
Results: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
Conclusion: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Gleichungen mit mehreren Unbekannten zu lösen, üben Schüler schon in der Mittelstufe. Für die einen ist es eine spannende mathematische Knobelei, für die anderen eher Quälerei. Doch den wenigsten ist bewusst, wie viele Leben dadurch jeden Tag gerettet werden. Die moderne medizinische Bildgebung beruht darauf, sehr viele Gleichungen nach sehr vielen Unbekannten aufzulösen.
Background: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.
Results: The tozasertib concentration that reduces cell viability by 50 % (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3ABCG2 cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3ABCG2 cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.
Conclusions: Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
Löschmann, Nadine ; Michaelis, Martin ; Rothweiler, Florian ; Voges, Yvonne ; Balónová, Barbora ; Blight, Barry A. ; Cinatl, Jindrich
The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.
Alten, Rieke ; Burkhardt, Harald ; Feist, Eugen ; Krüger, Klaus ; Rech, Hans Jürgen ; Rubbert-Roth, Andrea ; Voll, Reinhard ; Elbez, Yedid ; Rauch, Christiane
Background: Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce.
Methods: In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire—Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials.
Results: Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were –0.54 vs –0.44 (ATTAIN), –0.43 vs –0.43 (ASSURE), and –0.39 vs –0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE).
Conclusions: Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX.
Kurz, Alexander ; May, Caroline ; Schmidt, Oliver ; Müller, Thorsten ; Stephan, Christian ; Meyer, Helmut E. ; Gispert, Suzana ; Auburger, Georg ; Marcus, Katrin
Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
Electronic supplementary material: The online version of this article (doi:10.1007/s00702-011-0717-3) contains supplementary material, which is available to authorized users.
Ong, Yu Ting ; Andrade, Jorge ; Armbruster, Max ; Shi, Chenyue ; Castro, Marco ; Costa, Ana S. H. ; Sugino, Toshiya ; Eelen, Guy ; Zimmermann, Barbara ; Wilhelm, Kerstin ; Lim, Joseph ; Watanabe, Shuichi ; Günther, Stefan ; Schneider, Andre ; Zanconato, Francesca ; Kaulich, Manuel ; Pan, Duojia ; Braun, Thomas ; Gerhardt, Holger ; Efeyan, Alejo ; Carmeliet, Peter ; Piccolo, Stefano ; Grosso, Ana Rita ; Potente, Michael
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs—elicited by the loss of Rag GTPases—inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Groneberg, Jan David Alexander ; Rolle, Stefan ; Bendels, Michael Hans Karl ; Klingelhöfer, Doris ; Schöffel, Norman ; Bauer, Jan ; Brüggmann, Dörthe
Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
Klingelhöfer, Doris ; Zhu, Yun ; Braun, Markus ; Brüggmann, Dörthe ; Schöffel, Norman ; Groneberg, Jan David Alexander
Background: Esophageal cancer (EC) is one of the deadliest cancers worldwide. The contemporary strong increase of the adenocarcinomas in Western countries and the high mortality rates require the intensification of prospective multinational studies.
Methods: Therefore, this global health issue has been chosen for the bibliometric review of the global publication output. As source for meta and citation data, the Web of Science has been used and Density Equalizing Maps were applied for visualization.
Results: 17,387 articles on EC could be identified. The years with publication and citation maxima correspond to the appearance of the most prolific articles. China is the most publishing country, followed by Japan and the USA. Germany and the UK ranked 4th and 5th. The analysis of the ratios articles and socio-economic parameters emphasizes the leading position of the Scandinavian countries and Japan. Here, the high-income countries come out on top. The high incidence regions are mainly represented by Chinese and Japanese research. The association of the publication output and the overall research funding could be shown.
Conclusions: A strengthened international network increasingly consisting of the scientifically best positioned countries as well as more of the high incidence countries worldwide is mandatory for future research. The findings deliver scientists, clinicians and decision makers backgrounds for future decisions all over the world.
A world dataset on the geographic distributions of Solenidae razor clams (Mollusca: Bivalvia)
(2019)
Background: Using this dataset, we examined the global geographical distributions of Solenidae species in relation to their endemicity, species richness and latitudinal ranges and then predicted their distributions under future climate change using species distribution modelling techniques (Saeedi et al. 2016a, Saeedi et al. 2016b). We found that the global latitudinal species richness in Solenidae is bi-modal, dipping at the equator most likely derived by high sea surface temperature (Saeedi et al. 2016b). We also found that most of the Solenidae species will shift their distribution ranges polewards due to global warming (Saeedi et al. 2016a). We also provided a comprehensive review of the taxon to test whether the latitudinal gradient in species richness was uni-modal with a peak in the tropics or northern hemisphere or asymmetric and bimodal as proposed previously (Chaudhary et al. 2016).
New information: This paper presents an integrated global geographic distribution dataset for 77 Solenidae taxa, including 3,034 geographic distribution records. This dataset was compiled after a careful data-collection and cleaning procedure over four years. Data were collected using field sampling, literature and from open-access databases. Then all the records went through quality control procedures such as validating the taxonomy of the species by examining and re-identifying the specimens in museum collections and using taxonomic and geographic data quality control tools in the World Register of Marine Species (WoRMS) and the r-OBIS package (Provoost and Bosch 2017). This dataset can thus be further used for taxonomical and biogeographical studies of Solenidae.
Baader, Anna ; Kiani, Behnaz ; Brunkhorst-Kanaan, Nathalie ; Kittel-Schneider, Sarah ; Reif, Andreas ; Grimm, Oliver
New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium’s motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test’s hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended.
Current deep learning methods are regarded as favorable if they empirically perform well on dedicated test sets. This mentality is seamlessly reflected in the resurfacing area of continual learning, where consecutively arriving data is investigated. The core challenge is framed as protecting previously acquired representations from being catastrophically forgotten. However, comparison of individual methods is nevertheless performed in isolation from the real world by monitoring accumulated benchmark test set performance. The closed world assumption remains predominant, i.e. models are evaluated on data that is guaranteed to originate from the same distribution as used for training. This poses a massive challenge as neural networks are well known to provide overconfident false predictions on unknown and corrupted instances. In this work we critically survey the literature and argue that notable lessons from open set recognition, identifying unknown examples outside of the observed set, and the adjacent field of active learning, querying data to maximize the expected performance gain, are frequently overlooked in the deep learning era. Hence, we propose a consolidated view to bridge continual learning, active learning and open set recognition in deep neural networks. Finally, the established synergies are supported empirically, showing joint improvement in alleviating catastrophic forgetting, querying data, selecting task orders, while exhibiting robust open world application.
Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.
Os danos no processo formativo, decorrentes da hegemonia da indústria cultural, são investigados há algum tempo por pesquisadores das áreas de filosofia, psicologia, sociologia e história da educação. De forma geral, concluiu-se que não há uma relação de causa e efeito entre a indústria cultural e a produção de consciências reificadas. Porém, é preciso compreender de que modo o consumidor dos produtos da indústria cultural se esforça para permanecer na condição de objeto, ao invés de ser sujeito de suas ações. Tem-se como objetivo, neste artigo, refletir sobre a produção e propagação deste impulso conformista. Para tanto, parte-se do seguinte pressuposto: a chave para o entendimento das nuances desse impulso se encontra na análise das transformações históricas da relação entre a indústria cultural e a educação pela dureza.
We present a compact and versatile cryofocusing–thermodesorption unit, which we developed for quantitative analysis of halogenated trace gases in ambient air. Possible applications include aircraft-based in situ measurements, in situ monitoring and laboratory operation for the analysis of flask samples. Analytes are trapped on adsorptive material cooled by a Stirling cooler to low temperatures (e.g. −80 °C) and subsequently desorbed by rapid heating of the adsorptive material (e.g. +200 °C). The set-up involves neither the exchange of adsorption tubes nor any further condensation or refocusing steps. No moving parts are used that would require vacuum insulation. This allows for a simple and robust design. Reliable operation is ensured by the Stirling cooler, which neither contains a liquid refrigerant nor requires refilling a cryogen. At the same time, it allows for significantly lower adsorption temperatures compared to commonly used Peltier elements. We use gas chromatography – mass spectrometry (GC–MS) for separation and detection of the preconcentrated analytes after splitless injection. A substance boiling point range of approximately −80 to +150 °C and a substance mixing ratio range of less than 1 ppt (pmol mol−1) to more than 500 ppt in preconcentrated sample volumes of 0.1 to 10 L of ambient air is covered, depending on the application and its analytical demands. We present the instrumental design of the preconcentration unit and demonstrate capabilities and performance through the examination of analyte breakthrough during adsorption, repeatability of desorption and analyte residues in blank tests. Examples of application are taken from the analysis of flask samples collected at Mace Head Atmospheric Research Station in Ireland using our laboratory GC–MS instruments and by data obtained during a research flight with our in situ aircraft instrument GhOST-MS (Gas chromatograph for the Observation of Tracers – coupled with a Mass Spectrometer).
We present a compact and versatile cryofocusing– thermodesorption unit, which we developed for quantitative analysis of halogenated trace gases in ambient air. Possible applications include aircraft-based in situ measurements, in situ monitoring and laboratory operation for the analysis of flask samples. Analytes are trapped on adsorptive material cooled by a Stirling cooler to low temperatures (e.g. -80°C) and subsequently desorbed by rapid heating of the adsorptive material (e.g. 200°C). The set-up involves neither the exchange of adsorption tubes nor any further condensation or refocusing steps. No moving parts are used that would require vacuum insulation. This allows for a simple and robust design. Reliable operation is ensured by the Stirling cooler, which neither contains a liquid refrigerant nor requires refilling a cryogen. At the same time, it allows for significantly lower adsorption temperatures compared to commonly used Peltier elements. We use gas chromatography – mass spectrometry (GC–MS) for separation and detection of the preconcentrated analytes after splitless injection. A substance boiling point range of approximately -80 to +150°C and a substance mixing ratio range of less than 1 ppt (pmol mol−1)to more than 500 ppt in preconcentrated sample volumes of 0.1 to 10 L of ambient air is covered, depending on the application and its analytical demands. We present the instrumental design of the preconcentration unit and demonstrate capabilities and performance through the examination of analyte breakthrough during adsorption, repeatability of desorption and analyte residues in blank tests. Examples of application are taken from the analysis of flask samples collected at Mace Head Atmospheric Research Station in Ireland using our laboratory GC–MS instruments and by data obtained during a research flight with our in situ aircraft instrument GhOSTMS (Gas chromatograph for the Observation of Tracers – coupled with a Mass Spectrometer).
Dohrmann, Frank ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Holzmann, Romain ; Kählitz, Philipp K. ; Kämpfer, Burkhard ; Morinière, Emilie ; Pachmayer, Yvonne C. ; Ramstein, Béatrice ; Salabura, Piotr ; Stroth, Joachim ; Trebacz, Radoslaw ; Wiele, Jacques van de ; Wüstenfeld, Jörn
We have developed a versatile software package for the simulation of di-electron production in pp and dp collisions at moderate beam kinetic energies (1-2GeV). Particular attention has been paid to incorporate different descriptions of the Dalitz decay Δ rightarrow Ne + e - via a common interface. In addition, suitable parameterizations for the virtual bremsstrahlung process NN rightarrow NNe + e - based on one-boson exchange models have been implemented. Such simulation tools with high flexibility of the framework are important for the interpretation of the di-electron data taken with the HADES spectrometer and demonstrates the wide applicability within the field of nuclear and hadronic physics.
During CNS development and adult neurogenesis, immature neurons travel from the germinal zones towards their final destination using cellular substrates for their migration. Classically, radial glia and neuronal axons have been shown to act as physical scaffolds to support neuroblast locomotion in processes known as gliophilic and neurophilic migration, respectively (Hatten, 1999; Marin and Rubenstein, 2003; Rakic, 2003). In adulthood, long distance neuronal migration occurs in a glial-independent manner since radial glia cells differentiate into astrocytes after birth. A series of studies highlight a novel mode of neuronal migration that uses blood vessels as scaffolds, the so-called vasophilic migration. This migration mode allows neuroblast navigation in physiological and also pathological conditions, such as neuronal precursor migration after ischemic stroke or cerebral invasion of glioma tumor cells. Here we review the current knowledge about how vessels pave the path for migrating neurons and how trophic factors derived by glio-vascular structures guide neuronal migration both during physiological as well as pathological processes
When mapping eye-movement behavior to the visual information presented to an observer, Areas of Interest (AOIs) are commonly employed. For static stimuli (screen without moving elements), this requires that one AOI set is constructed for each stimulus, a possibility in most eye-tracker manufacturers' software. For moving stimuli (screens with moving elements), however, it is often a time-consuming process, as AOIs have to be constructed for each video frame. A popular use-case for such moving AOIs is to study gaze behavior to moving faces. Although it is technically possible to construct AOIs automatically, the standard in this field is still manual AOI construction. This is likely due to the fact that automatic AOI-construction methods are (1) technically complex, or (2) not effective enough for empirical research. To aid researchers in this field, we present and validate a method that automatically achieves AOI construction for videos containing a face. The fully-automatic method uses an open-source toolbox for facial landmark detection, and a Voronoi-based AOI-construction method. We compared the position of AOIs obtained using our new method, and the eye-tracking measures derived from it, to a recently published semi-automatic method. The differences between the two methods were negligible. The presented method is therefore both effective (as effective as previous methods), and efficient; no researcher time is needed for AOI construction. The software is freely available from https://osf.io/zgmch/.
Diploid transgenic organisms are either hemi- or homozygous. Genetic assays are, therefore, required to identify the genotype. Our AGameOfClones vector concept uses two clearly distinguishable transformation markers embedded in interweaved, but incompatible Lox site pairs. Cre-mediated recombination leads to hemizygous individuals that carry only one marker. In the following generation, heterozygous descendants are identified by the presence of both markers and produce homozygous progeny that are selected by the lack of one marker. We prove our concept in Tribolium castaneum by systematically creating multiple functional homozygous transgenic lines suitable for long-term fluorescence live imaging. Our approach saves resources and simplifies transgenic organism handling. Since the concept relies on the universal Cre-Lox system, it is expected to work in all diploid model organisms, for example, insects, zebrafish, rodents and plants. With appropriate adaptions, it can be used in knock-out assays to preselect homozygous individuals and thus minimize the number of wasted animals.
Kardos, Peter ; Vogelmeier, Claus F. ; Worth, Heinrich ; Buhl, Roland ; Lossi, Nadine S. ; Mailänder, Claudia ; Criée, Carl-Peter
Introduction: DACCORD is an observational, non-interventional study being conducted in German primary and secondary care centres. The study aims to describe the impact of disease (including exacerbations) and treatments over 2 years on ‘real-life’ patients with chronic obstructive pulmonary disease (COPD).
Materials and methods: Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years and, on recruitment, were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and randomised clinical trial participation. Exacerbations data were collected every 3 months. COPD medication, COPD Assessment Test (CAT) and forced expiratory volume in 1 s (FEV1) were recorded at baseline and after 1 and 2 years.
Results: A total of 6122 patients were recruited, 3137 (51.2%) of whom completed the 2-year visit. The mean age of these patients was 65.6 years, 59% were male, 69% had mild or moderate airflow limitation, and their mean COPD Assessment Test (CAT) total score was 20.3. Overall, there was a trend towards decreasing COPD exacerbation rates over the 2-year follow-up period, with rates of 0.390 during Year 1 and 0.347 during Year 2. Rates were lower in patients with no exacerbation during the 6 months prior to entry (0.263 and 0.251 during Years 1 and 2, respectively), with 51.6% of patients having no exacerbation during the 6 months prior to entry and over the 2-year follow-up. Approximately 50% of the overall population experienced a clinically relevant improvement from baseline in CAT total score at Year 1 and 2. When assessed by treatment class (or classes), persistence to medication was high (77.8% in Year 1 and 71.4% in Year 2).
Conclusions: Overall, the 2-year follow-up data from DACCORD suggest that for most patients with COPD exacerbations are a rare event. For the majority of patients, the focus should be on managing symptoms, and the impact that these symptoms have on their daily lives. Even for those patients who do exacerbate, although prevention of exacerbations is an important factor, management of symptoms should be a key consideration. DACCORD also suggests that COPD disease progression is not inevitable – providing patients are receiving pharmacological treatment.
Schwalb, Christian H. ; Grimm, Christina ; Baranowski, Markus ; Sachser, Roland ; Porrati, Fabrizio ; Reith, Heiko ; Das, Pintu ; Müller, Jens ; Völklein, Friedemann ; Kaya, Alexander ; Huth, Michael
This paper introduces a new methodology for the fabrication of strain-sensor elements for MEMS and NEMS applications based on the tunneling effect in nano-granular metals. The strain-sensor elements are prepared by the maskless lithography technique of focused electron-beam-induced deposition (FEBID) employing the precursor trimethylmethylcyclopentadienyl platinum [MeCpPt(Me)3]. We use a cantilever-based deflection technique to determine the sensitivity (gauge factor) of the sensor element. We find that its sensitivity depends on the electrical conductivity and can be continuously tuned, either by the thickness of the deposit or by electron-beam irradiation leading to a distinct maximum in the sensitivity. This maximum finds a theoretical rationale in recent advances in the understanding of electronic charge transport in nano-granular metals.
Frenzel, Svenja B. ; Junker, Nina Mareen ; Avanzi, Lorenzo ; Bolatov, Aidos ; Haslam, S. Alexander ; Häusser, Jan ; Kark, Ronit ; Meyer, Ines ; Mojzisch, Andreas ; Monzani, Lucas ; Reicher, Stephen ; Samekin, Adil ; Schury, Valerie A. ; Steffens, Niklas K. ; Sultanova, Liliya ; Van Dijk, Dina ; Zyl, Llewellyn Ellardus van ; Dick, Rolf van
The COVID-19 pandemic has triggered health-related anxiety in ways that undermine peoples’ mental and physical health. Contextual factors such as living in a high-risk area might further increase the risk of health deterioration. Based on the Social Identity Approach, we argue that social identities can not only be local that are characterized by social interactions, but also be global that are characterized by a symbolic sense of togetherness and that both of these can be a basis for health. In line with these ideas, we tested how identification with one’s family and with humankind relates to stress and physical symptoms while experiencing health-related anxiety and being exposed to contextual risk factors. We tested our assumptions in a representative sample (N = 974) two-wave survey study with a 4-week time lag. The results show that anxiety at Time 1 was positively related to stress and physical symptoms at Time 2. Feeling exposed to risk factors related to lower physical health, but was unrelated to stress. Family identification and identification with humankind were both negatively associated with subsequent stress and family identification was negatively associated with subsequent physical symptoms. These findings suggest that for social identities to be beneficial for mental health, they can be embodied as well as symbolic.
The RNA cleaving catalyst tris(2-aminobenzimidazole) when attached to the 5’ terminus of oligonucleotides cuts complementary RNA strands in a highly site-specific manner. Conjugation was previously achieved by the acylation of an amino linker by an active ester of the catalyst. However, this procedure was low yielding and not reliable. Here, a phosphoramidite building block is described that can be coupled to oligonucleotides by manual solid phase synthesis in total yields around 85%. Based on this chemistry, we have now studied the impact of LNA (locked nucleic acids) nucleotides on the rates and the site-specificities of RNA cleaving conjugates. The highest reaction rates and the most precise cuts can be expected when the catalyst is attached to a strong 5’ closing base pair and when the oligonucleotide contains several LNA units that are equally distributed in the strand. However, when placed in the 5’ position, LNA building blocks tend to diminish the specificity of RNA cleavage.
Heitel, Pascal ; Faudone, Giuseppe ; Helmstädter, Moritz ; Schmidt, Jurema ; Kaiser, Astrid ; Tjaden, Amelie ; Schröder, Martin ; Müller, Susanne ; Schierle, Simone ; Pollinger, Julius Carl ; Merk, Daniel
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
A new polymorph of the title compound, [Pd2(C8H18P)2(C8H19P)2], has been found. It belongs to the triclinic P-1 space group, whereas the known form [Leoni, Sommovigo, Pasquali, Sabatino & Braga (1992 [triangle]), J. Organomet. Chem. 423, 263–270] crystallizes in the monoclinic C2/c space group. The title compound features a dinuclear palladium complex with a planar central Pd2(μ-P)2 core (r.m.s. deviation = 0.003 Å). The Pd—Pd distance of 2.5988 (5) Å is within the range of a PdI—PdI bond. The molecules of both polymorphs are located on a crystallographic centre of inversion. The molecular conformations of the two polymorphs are essentially identical. The crystal packing patterns, on the other hand, are slightly different.
A toolbox for the generation of chemical probes for Baculovirus IAP Repeat containing proteins
(2022)
Schwalm, Martin P. ; Berger, Lena Marie ; Meuter, Maximilian N. ; Vasta, James D. ; Corona, Cesear R. ; Röhm, Sandra ; Berger, Benedict-Tilman ; Farges, Frederic ; Beinert, Sebastian M. ; Preuß, Franziska Friederike ; Morasch, Viktoria ; Rogov, Vladimir V. ; Mathea, Sebastian ; Saxena, Krishna ; Robers, Matthew B. ; Müller, Susanne ; Knapp, Stefan
E3 ligases constitute a large and diverse family of proteins that play a central role in regulating protein homeostasis by recruiting substrate proteins via recruitment domains to the proteasomal degradation machinery. Small molecules can either inhibit, modulate or hijack E3 function. The latter class of small molecules led to the development of selective protein degraders, such as PROTACs (PROteolysis TArgeting Chimeras), that recruit protein targets to the ubiquitin system leading to a new class of pharmacologically active drugs and to new therapeutic options. Recent efforts have focused on the E3 family of Baculovirus IAP Repeat (BIR) domains that comprise a structurally conserved but diverse 70 amino acid long protein interaction domain. In the human proteome, 16 BIR domains have been identified, among them promising drug targets such as the Inhibitors of Apoptosis (IAP) family, that typically contain three BIR domains (BIR1, BIR2, and BIR3). To date, this target area lacks assay tools that would allow comprehensive evaluation of inhibitor selectivity. As a consequence, the selectivity of current BIR domain targeting inhibitors is unknown. To this end, we developed assays that allow determination of inhibitor selectivity in vitro as well as in cellulo. Using this toolbox, we have characterized available BIR domain inhibitors. The characterized chemical starting points and selectivity data will be the basis for the generation of new chemical probes for IAP proteins with well-characterized mode of action and provide the basis for future drug discovery efforts and the development of PROTACs and molecular glues.
Spahn, Christoph Klaus ; Glaesmann, Mathilda ; Grimm, Jonathan B. ; Ayala, Anthony X. ; Lavis, Luke D. ; Heilemann, Mike
Maintenance of the bacterial homeostasis initially emanates from interactions between proteins and the bacterial nucleoid. Investigating their spatial correlation requires high spatial resolution, especially in tiny, highly confined and crowded bacterial cells. Here, we present super-resolution microscopy using a palette of fluorescent labels that bind transiently to either the membrane or the nucleoid of fixed E. coli cells. The presented labels are easily applicable, versatile and allow long-term single-molecule super-resolution imaging independent of photobleaching. The different spectral properties allow for multiplexed imaging in combination with other localisation-based super-resolution imaging techniques. As examples for applications, we demonstrate correlated super-resolution imaging of the bacterial nucleoid with the position of genetic loci, of nascent DNA in correlation to the entire nucleoid, and of the nucleoid of metabolically arrested cells. We furthermore show that DNA- and membrane-targeting labels can be combined with photoactivatable fluorescent proteins and visualise the nano-scale distribution of RNA polymerase relative to the nucleoid in drug-treated E. coli cells.
With a growing Muslim population, many European countries need to integrate Muslims into their societies. One aspect that can hinder successful integration are substantial differences in human values. This is because such values are consequential for attitudes as well as behavior. We compare basic human values between Muslim immigrants and non-Muslim natives in four European countries with distinct immigration histories and integration politics: Belgium, France, Germany, and Sweden. For most insightful comparisons, we contrast values of Muslim immigrants with those of Christian natives as well as those of non-religious natives. We employ data of more than 50,000 individuals based on the first eight waves of the European Social Survey. Our findings reveal significant differences in value priorities between Muslims, Christians and non-religious individuals in all four countries. Amongst other things, Muslim immigrants score particularly high in conservation values (security and tradition/conformity). At the same time, they also score higher in self-transcendence values (benevolence as well as universalism). While many of these findings are in line with theory and previous research, the higher score in universalism is unexpected. A potential explanation is the combination of religious traditionalism and discrimination experiences. In other words, religious traditions are associated with more conservative views, but being subject to marginalization can still result in an appreciation of equal opportunities. We find only limited support for differences in hedonism. Religiosity correlates with values of tradition/conformity for Muslim immigrants as well as for Christian natives. Thus, accounting for religiosity renders differences in these values between Muslims and other groups statistically insignificant. While most of these findings hold in all countries, differences are most pronounced in Sweden and lower in the other three countries, which is also true after accounting for differences in socio-economic status and religiosity between the three groups. This suggests that a combination of a country's history of diversity and national integration policies either encourages the convergence of values or leads to a solidification of value differences between groups. We discuss these political and social implications of our findings.
Trübutschek, Darinka ; Marti, Sebastien ; Ojeda, Andrés ; King, Jean-Rémi ; Mi, Yuanyuan ; Tsodyks, Misha ; Dehaene, Stanislas
Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we investigate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after several seconds. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non-conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of ‘activity-silent’ working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds.
Some physical and chemical properties of the cancerostat cyclophosphamide (generic name: ENDOXAN) and its basic constituents H3PO4 and nor-N-mustard have been calculated with the help of a modified CNDO/S-method. The spectroscopic data of the H3PO4 , which is the starting-point for a corresponding calculation of cyclophosphamide, has been studied by taking account of the 3 d electron of the phosphorus. Nor-N-mustard is a very reactive compound, characterized by the ability to split off chloride ions and to act as an alkylating agent. The binding of the nor-N-mustard to the cyclic phosphate ester (cyclophosphamide) modifies the chemical reactivity of the mustard group in an essential way, and the 3d electron of the phosphorus plays an important role with respect to the excitability of the C -Cl bonds. Cyclophosphamide must be metabolized in a suitable way to develop the same alkylating activity as the nor-N-mustard. The computation of the excited states of cyclophosphamide revealed a similar term scheme as it was found by Clar in the case of the carcinogenic polycyclic hydrocarbons.
O texto tenta, num primeiro passo, mostrar que a textura intrínseca da justiça não consiste em bens distribuíveis, mas em relações sociais comumente aceitas que são constituídas por práticas perpassadas de conteúdo moral. Nessas práticas podem ser encontradas aquelas que definem o que significa tratar uma outra pessoa de forma razoável ou justa. Se este ponto de partida é convincente, então algumas consequências metodológicas sobre o conceito de justiça tem que ser tiradas e que são apresentados na segunda etapa: ao invés de construir um procedimento normativo que nos permite deduzir o conteúdo de justiça, temos de começar pela reconstrução das práticas sociais que nos informam sobre o respeito à justiça. O resultado será, tal como indicado em uma terceira etapa, a pluralização do nosso conceito de justiça, que inclui tanto princípios relevantes da justiça como há formas de relações sociais geralmente aceitas e apreciadas.
The temporal development of macroobservables is described within a correlation-functionformalism. The results are exact for a certain class of initial ensembles. The same problem is discussed with the help of the linear-response-formalism. The results agree under certain conditions which should be fulfilled for macroobservables.
A teoria do reconhecimento social de Axel Honneth aplicado no direito previdenciário brasileiro
(2016)
O reconhecimento é uma categoria muito utilizada para debater sobre a questão da identidade e da diferença, portanto sua relevância torna-se necessária no âmbito jurídico. A questão proposta é: Quais as formas e eficiência de reconhecimento no campo social e familiar no direito previdenciário? O objetivo deste artigo é, portanto, trazer a discussão o processo de reconhecimento social e a influência de sua estrutura cultural e toda complexidade de fatores. A pesquisa é teórica sistêmica que se dá pela abordagem sociológica, tanto conceitual quanto empírica dos sistemas jurídico.
Vinculada à tradição da Escola de Frankfurt (Horkheimer, Adorno, Habermas), a teoria de reconhecimento (Honneth) tem grande repercussão nas ciências sociais, pois propõe um novo tipo de fundamentação ética com vistas ao projeto de uma sociedade solidária e justa. Na pedagogia, porém,sua recepção é ainda modesta. O ensaio objetiva mudar a situação, querendo mostrar a importância da contribuição de Honneth para a práxis educativa. Primeiro, são apresentados alguns tópicos centrais da teoria. Depois, os conflitos entre as diretrizes ético-morais no trabalho profissional servem de exemplo para mostrar como a teoria de reconhecimento recorda aos pedagogos a necessidade de refletirem sobre o processo pedagógico como campo de experiência essencialmente social para os envolvidos.
Based on a meta-analysis, Redick and Lindsey (2013) found that complex span and n-back tasks show an average correlation of r = 0.20, and concluded that "complex span and n-back tasks cannot be used interchangeably as working memory measures in research applications" (p. 1102). Here, we comment on this conclusion from a psychometric perspective. In addition to construct variance, performance on a test contains measurement error, task-specific variance, and paradigm-specific variance. Hence, low correlations among dissimilar indicators do not provide strong evidence for the existence, or absence, of a construct common to both indicators. One way to arrive at such evidence is to fit hierarchical latent factors that model task-specific, paradigm-specific, and construct variance. We report analyses for 101 younger and 103 older adults who worked on nine different working memory tasks. The data are consistent with a hierarchical model of working memory, according to which both complex span and n-back tasks are valid indicators of working memory. The working memory factor predicts 71% of the variance in a factor of reasoning among younger adults (83% for among older adults). When the working memory factor was restricted to any possible triplet of working memory tasks, the correlation between working memory and reasoning was inversely related to the average magnitude of the correlations among the indicators, indicating that more highly intercorrelated indicators may provide poorer coverage of the construct space. We stress the need to go beyond specific tasks and paradigms when studying higher-order cognitive constructs, such as working memory.
Promyelocytic leukemia nuclear bodies (PML NBs) are multi-protein assemblies representing distinct sub-nuclear structures. As phase-separated molecular condensates, PML NBs exhibit liquid droplet-like consistency. A key organizer of the assembly and dynamics of PML NBs is the ubiquitin-like SUMO modification system. SUMO is covalently attached to PML and other core components of PML NBs thereby exhibiting a glue-like function by providing multivalent interactions with proteins containing SUMO interacting motifs (SIMs). PML NBs serve as the catalytic center for nuclear SUMOylation and SUMO-SIM interactions are essential for protein assembly within these structures. Importantly, however, formation of SUMO chains on PML and other PML NB-associated proteins triggers ubiquitylation and proteasomal degradation which coincide with disruption of these nuclear condensates. To date, a plethora of nuclear activities such as transcriptional and post-transcriptional regulation of gene expression, apoptosis, senescence, cell cycle control, DNA damage response, and DNA replication have been associated with PML NBs. Not surprisingly, therefore, SUMO-dependent PML NB integrity has been implicated in regulating many physiological processes including tumor suppression, metabolism, drug-resistance, development, cellular stemness, and anti-pathogen immune response. The interplay between PML NBs and viral infection is multifaceted. As a part of the cellular antiviral defense strategy, PML NB components are crucial restriction factors for many viruses and a mutual positive correlation has been found to exist between PML NBs and the interferon response. Viruses, in turn, have developed counterstrategies for disarming PML NB associated immune defense measures. On the other end of the spectrum, certain viruses are known to usurp specific PML NB components for successful replication and disruption of these sub-nuclear foci has recently been linked to the stimulation rather than curtailment of antiviral gene repertoire. Importantly, the ability of invading virions to manipulate the host SUMO modification machinery is essential for this interplay between PML NB integrity and viruses. Moreover, compelling evidence is emerging in favor of bacterial pathogens to negotiate with the SUMO system thereby modulating PML NB-directed intrinsic and innate immunity. In the current context, we will present an updated account of the dynamic intricacies between cellular PML NBs as the nuclear SUMO modification hotspots and immune regulatory mechanisms in response to viral and bacterial pathogens.
A tale of two seasons: The link between seasonal migration and climatic niches in passerine birds
(2020)
The question of whether migratory birds track a specific climatic niche by seasonal movements has important implications for understanding the evolution of migration, the factors affecting species' distributions, and the responses of migrants to climate change. Despite much research, previous studies of bird migration have produced mixed results. However, whether migrants track climate is only one half of the question, the other being why residents remain in the same geographic range year-round. We provide a literature overview and test the hypothesis of seasonal niche tracking by evaluating seasonal climatic niche overlap across 437 migratory and resident species from eight clades of passerine birds. Seasonal climatic niches were based on a new global dataset of breeding and nonbreeding ranges. Overlap between climatic niches was quantified using ordination methods. We compared niche overlap of migratory species to two null expectations, (a) a scenario in which they do not migrate and (b) in comparison with the overlap experienced by closely related resident species, while controlling for breeding location and range size. Partly in accordance with the hypothesis of niche tracking, we found that the overlap of breeding versus nonbreeding climatic conditions in migratory species was greater than the overlap they would experience if they did not migrate. However, this was only true for migrants breeding outside the tropics and only relative to the overlap species would experience if they stayed in the breeding range year-round. In contrast to the hypothesis of niche tracking, migratory species experienced lower seasonal climatic niche overlap than resident species, with significant differences between tropical and nontropical species. Our study suggests that in seasonal nontropical environments migration away from the breeding range may serve to avoid seasonally harsh climate; however, different factors may drive seasonal movements in the climatically more stable tropical regions.
Introduction: To date, several meta-analyses clearly demonstrated that resistance and plyometric training are effective to improve physical fitness in children and adolescents. However, a methodological limitation of meta-analyses is that they synthesize results from different studies and hence ignore important differences across studies (i.e., mixing apples and oranges). Therefore, we aimed at examining comparative intervention studies that assessed the effects of age, sex, maturation, and resistance or plyometric training descriptors (e.g., training intensity, volume etc.) on measures of physical fitness while holding other variables constant.
Methods: To identify relevant studies, we systematically searched multiple electronic databases (e.g., PubMed) from inception to March 2018. We included resistance and plyometric training studies in healthy young athletes and non-athletes aged 6 to 18 years that investigated the effects of moderator variables (e.g., age, maturity, sex, etc.) on components of physical fitness (i.e., muscle strength and power).
Results: Our systematic literature search revealed a total of 75 eligible resistance and plyometric training studies, including 5,138 participants. Mean duration of resistance and plyometric training programs amounted to 8.9 ± 3.6 weeks and 7.1±1.4 weeks, respectively. Our findings showed that maturation affects plyometric and resistance training outcomes differently, with the former eliciting greater adaptations pre-peak height velocity (PHV) and the latter around- and post-PHV. Sex has no major impact on resistance training related outcomes (e.g., maximal strength, 10 repetition maximum). In terms of plyometric training, around-PHV boys appear to respond with larger performance improvements (e.g., jump height, jump distance) compared with girls. Different types of resistance training (e.g., body weight, free weights) are effective in improving measures of muscle strength (e.g., maximum voluntary contraction) in untrained children and adolescents. Effects of plyometric training in untrained youth primarily follow the principle of training specificity. Despite the fact that only 6 out of 75 comparative studies investigated resistance or plyometric training in trained individuals, positive effects were reported in all 6 studies (e.g., maximum strength and vertical jump height, respectively).
Conclusions: The present review article identified research gaps (e.g., training descriptors, modern alternative training modalities) that should be addressed in future comparative studies.
A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC)
(2020)
Zöllner, Johann Philipp ; Franz, David Neal ; Hertzberg, Christoph ; Nabbout, Rima ; Rosenow, Felix ; Sauter, Matthias ; Schubert-Bast, Susanne ; Wiemer-Kruel, Adelheid ; Strzelczyk, Adam
Objective: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs.
Methods: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included.
Results: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years.
Conclusions: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.
The assessment of knee or hip joint loading by external joint moments is mainly used to draw conclusions on clinical decision making. However, the correlation between internal and external loads has not been systematically analyzed. This systematic review aims, therefore, to clarify the relationship between external and internal joint loading measures during gait. A systematic database search was performed to identify appropriate studies for inclusion. In total, 4,554 articles were identified, while 17 articles were finally included in data extraction. External joint loading parameters were calculated using the inverse dynamics approach and internal joint loading parameters by musculoskeletal modeling or instrumented prosthesis. It was found that the medial and total knee joint contact forces as well as hip joint contact forces in the first half of stance can be well predicted using external joint moments in the frontal plane, which is further improved by including the sagittal joint moment. Worse correlations were found for the peak in the second half of stance as well as for internal lateral knee joint contact forces. The estimation of external joint moments is useful for a general statement about the peak in the first half of stance or for the maximal loading. Nevertheless, when investigating diseases as valgus malalignment, the estimation of lateral knee joint contact forces is necessary for clinical decision making because external joint moments could not predict the lateral knee joint loading sufficient enough. Dependent on the clinical question, either estimating the external joint moments by inverse dynamics or internal joint contact forces by musculoskeletal modeling should be used.
Ottomana, Angela Maria ; Presta, Martina ; O'Leary, Aet ; Sullivan, Mairéad ; Pisa, Edoardo ; Laviola, Giovanni ; Glennon, Jeffrey C. ; Zoratto, Francesca ; Slattery, David A. ; Macrì, Simone
Highlights
• Hyperglycaemia, in rodents, is consistently associated with cognitive impairments.
• The strength of this association is supported by the heterogeneity of the studies.
• The study of the role of insulin on cognition is mainly limited to spatial memory.
• Preclinical studies on the role of insulin signalling on cognition are male biased.
Abstract
Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer’s disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia – as a proxy of insulin-related metabolic dysfunctions – and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.
Ottomana, Angela Maria ; Presta, Martina ; O'Leary, Aet ; Sullivan, Mairéad ; Pisa, Edoardo ; Laviola, Giovanni ; Glennon, Jeffrey C. ; Zoratto, Francesca ; Slattery, David A. ; Macrì, Simone
Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer’s disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia – as a proxy of insulin-related metabolic dysfunctions – and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.
Demographic change is supposed to be the most important indirect driver for changing biodiversity. In this article, a systematic review of 148 studies was conducted to examine the scientific evidence for this relationship and to identify potential gaps in research. We explored the spatial distribution of studies, the categories addressed with respect to biodiversity and demographic change, and the ways in which their relationships were conceptualised (spatially and temporally) and valued. The majority of studies were carried out in Africa, Europe and North America. Our analysis confirms the trend that demographic phenomena were mostly found to negatively influence biodiversity. However, a considerable number of studies also point towards impacts that were context dependent, either positive or negative under certain circumstances. In addition to that we identified significant gaps in research. In particular, there is a lack of addressing (1) other demographic aspects such as population decline, age structure or gender differences, (2) spatial variability of, e.g. human population growth, (3) long-term effects of demographic processes, and (4) the context dependency (e.g. regulations/law enforcement, type of human activities, and choice of scale or proxy). We conclude there is evidence that the relationship between biodiversity and demographic change is much more complex than expected and so far represented in research. Thus, we call for a social–ecological biodiversity research that particularly focusses on the functional relation between biodiversity and human activities, namely the different types, context, and interdependent dynamics (spatial and temporal) of this complex relation.
In a year marked by challenging market dynamics, the importance of ESG investments remains unwavering. But the wave of ESG regulations and requests generates a demand for more scalable ways to collect and analyze ESG data. The rise of AI could mark a turning point in an industry heavily burdened by reporting requirements, and unlock the true potential of ESG for businesses and investors alike.
In this survey paper, we present a multiscale post-processing method in exploration. Based on a physically relevant mollifier technique involving the elasto-oscillatory Cauchy–Navier equation, we mathematically describe the extractable information within 3D geological models obtained by migration as is commonly used for geophysical exploration purposes. More explicitly, the developed multiscale approach extracts and visualizes structural features inherently available in signature bands of certain geological formations such as aquifers, salt domes etc. by specifying suitable wavelet bands.
Many cellular processes are regulated via pH, and maintaining the pH of different organelles is crucial for cell survival. A pH-sensitive GFP variant, the so-called pHluorin, has proven to be a valuable tool to study the pH of the cytosol, mitochondria and other organelles in vivo. We found that the fluorescence intensity of Endoplasmic Reticulum (ER)-targeted pHluorin in the yeast Saccharomyces cerevisiae was very low and barely showed pH sensitivity, probably due to misfolding in the oxidative environment of the ER. We therefore developed a superfolder variant of pHluorin which enabled us to monitor pH changes in the ER and the cytosol of S. cerevisiae in vivo. The superfolder pHluorin variant is likely to be functional in cells of different organisms as well as in additional compartments that originate from the secretory pathway like the Golgi apparatus and pre-vacuolar compartments, and therefore has a broad range of possible future applications.
Barth, Winfried ; Aulenbacher, Kurt ; Basten, Markus ; Dziuba, Florian ; Gettmann, Viktor ; Miski-Oglu, Maksym ; Podlech, Holger ; Yaramyshev, Stepan
Recently the Universal Linear Accelerator (UNILAC) serves as a powerful high duty factor (25%) heavy ion beam accelerator for the ambitious experiment program at GSI. Beam time availability for SHE (Super Heavy Element)-research will be decreased due to the limitation of the UNILAC providing Uranium beams with an extremely high peak current for FAIR simultaneously. To keep the GSI-SHE program competitive on a high level and even beyond, a standalone superconducting continuous wave (100% duty factor) LINAC in combination with the upgraded GSI High Charge State injector is envisaged. In preparation for this, the first LINAC section (financed by HIM and GSI) will be tested with beam in 2017, demonstrating the future experimental capabilities. Further on the construction of an extended cryo module comprising two shorter Crossbar-H cavities is foreseen to test until end of 2017. As a final R&D step towards an entire LINAC three advanced cryo modules, each comprising two CH cavities, should be built until 2019, serving for first user experiments at the Coulomb barrier.
This paper explores the many interesting implications for oscillator design, with optimized phase-noise performance, deriving from a newly proposed model based on the concept of oscillator conjugacy. For the case of 2-D (planar) oscillators, the model prominently predicts that only circuits producing a perfectly symmetric steady-state can have zero amplitude-to-phase (AM-PM) noise conversion, a so-called zero-state. Simulations on standard industry oscillator circuits verify all model predictions and, however, also show that these circuit classes cannot attain zero-states except in special limit-cases which are not practically relevant. Guided by the newly acquired design rules, we describe the synthesis of a novel 2-D reduced-order LC oscillator circuit which achieves several zero-states while operating at realistic output power levels. The potential future application of this developed theoretical framework for implementation of numerical algorithms aimed at optimizing oscillator phase-noise performance is briefly discussed.
Schuhmacher, Bianca ; Rengstl, Benjamin ; Döring, Claudia ; Bein, Julia ; Newrzela, Sebastian ; Brunnberg, Uta ; Kvasnicka, Hans Michael ; Vornanen, Martine ; Küppers, Ralf ; Hansmann, Martin-Leo ; Hartmann, Sylvia
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.
Highlights
• Gender cues are defined differently across languages.
• We propose a new refined and standardized definition of gender transparency.
• Gender transparency is quantifiable with values that match theoretical expectations.
• We present the first quantitative method to measure the gender transparency of languages.
Abstract
Languages can express grammatical gender through different ortho-phonological regularities present in nouns (e.g., the cues “-o” and “-a” for the masculine and the feminine respectively in Italian, Portuguese, or Spanish). The term “gender transparency” was coined to describe these regularities (Bates et al., 1995). In gendered languages, we can hence distinguish between transparent nouns, i.e., those displaying form regularities; opaque nouns, i.e., those with ambiguous endings; and irregular nouns, i.e., those that display the typical form regularities but are associated with the opposite gender. Following a descriptive analysis of such regularities, languages have been recently classified according to their degree of gender transparency, which seems relevant in regard to gender acquisition and processing. Yet, there are certain inconsistencies in determining which languages are overall transparent and which are opaque. In particular, it is not clear whether some other complex regularities such as derivational suffixes are also “transparent” cues for gender, what really constitutes an “opaque” noun, or which role orthography and morphology have in transparency. Given the existing inconsistencies in classifying languages as transparent or opaque, this work introduces a proposal to assess gender transparency systematically. Our methodology adapts the standardized factors proposed by Audring (2019) to analyse the relative complexity of gender systems. Such factors are adapted to gender transparency on the basis of the literature on gender acquisition and processing. To support the feasibility of such a proposal, the concepts have been instantiated in a quantitative model to obtain for the first time an objective measure of gender transparency using European Portuguese and Dutch as instances of target languages. Our results coincide with the theoretically expected outcome: European Portuguese obtains a high value of gender transparency while Dutch obtains a moderately low one. Future adaptations of this model to the gender systems of other languages could allow the continuum of gender transparency to sustain robust predictions in studies on gender processing and acquisition.
Pittner, Stefan ; Merold, Veronika ; Anders, Sven ; Lohner, Larissa ; Amendt, Jens ; Klinger, Miriam ; Hausmann, Roland ; Kißling, Steffen ; Monticelli, Fabio Carlo ; Geissenberger, Janine ; Zissler, Angela ; Steinbacher, Peter
The analysis of postmortem protein degradation has become of large interest for the estimation of the postmortem interval (PMI). Although several techniques have been published in recent years, protein degradation-based techniques still largely did not exceed basic research stages. Reasons include impractical and complex sampling procedures, as well as highly variable protocols in the literature, making it difficult to compare results. Following a three-step procedure, this study aimed to establish an easily replicable standardized procedure for sampling and processing, and further investigated the reliability and limitations for routine application. Initially, sampling and processing were optimized using a rat animal model. In a second step, the possible influences of sample handling and storage on postmortem protein degradation dynamics were assessed on a specifically developed human extracorporeal degradation model. Finally, the practical application was simulated by the collection of tissue in three European forensic institutes and an international transfer to our forensic laboratory, where the samples were processed and analyzed according to the established protocol.
Lucaciu, Alexandra ; Kuhn, Hannah ; Trautmann, Sandra ; Ferreirós Bouzas, Nerea ; Steinmetz, Helmuth ; Pfeilschifter, Josef ; Brunkhorst, Robert ; Pfeilschifter, Waltraud ; Subburayalu, Julien ; Vutukuri, Rajkumar
Emerging evidence suggests a complex relationship between sphingosine 1-phosphate (S1P) signaling and stroke. Here, we show the kinetics of S1P in the acute phase of ischemic stroke and highlight accompanying changes in immune cells and S1P receptors (S1PR). Using a C57BL/6 mouse model of middle cerebral artery occlusion (MCAO), we assessed S1P concentrations in the brain, plasma, and spleen. We found a steep S1P gradient from the spleen towards the brain. Results obtained by qPCR suggested that cells expressing the S1PR type 1 (S1P1+) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (TH) and regulatory T (TREG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1PR expression patterns in the brain after MCAO. This study provides insight that the S1P-S1PR axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1PR+ TH and TREG cells. Further insights by which means the S1P-S1PR-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.
After a short introduction into traditional image transform coding, multirate systems and multiscale signal coding the paper focuses on the subject of image encoding by a neural network. Taking also noise into account a network model is proposed which not only learns the optimal localized basis functions for the transform but also learns to implement a whitening filter by multi-resolution encoding. A simulation showing the multi-resolution capabilitys concludes the contribution.
Helling, Bianca ; König, Martin ; Dälken, Benjamin ; Engling, Andre ; Krömer, Wolfgang ; Heim, Katharina ; Wallmeier, Holger ; Haas, Jürgen ; Wildemann, Brigitte ; Fritz, Brigitte ; Jonuleit, Helmut ; Kubach, Jan ; Dingermann, Theodor ; Radeke, Heinfried H. ; Osterroth, Frank ; Uherek, Christoph ; Czeloth, Niklas ; Schüttrumpf, Jörg
CD4+CD25+ regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.
Kaluza, Antonia J. ; Aydin, Anna Lisa ; Cordes, Berrit L. ; Ebers, Gianna ; Fuchs, Albert ; Konietzny, Christiane ; Dick, Rolf van ; Baumann, Ulrich
Taking blood via venipuncture is part of the necessary surveillance before and after liver transplantation. The spectrum of response from children and their parents is variable, ranging from a short and limited aversion to paralyzing phobia. The aim of this retrospective, cross-sectional study was to determine the level of anxiety amongst children during venipuncture, to compare the anxiety reported by children and parents, and to identify the factors affecting the children’s and parents’ anxiety in order to develop therapeutic strategies. In total, 147 children (aged 0–17 years, 78 female) and their parents completed questionnaires. Statistical analysis was performed using qualitative and quantitative methods. Results showed that the majority of children reported anxiety and pain during venipuncture. Younger children had more anxiety (self-reported or assessed by parents). Children and parental reports of anxiety were highly correlated. However, the child’s anxiety was often reported as higher by parents than by the children themselves. The child’s general anxiety as well as the parents’ perceived stress from surgical interventions (but not the number of surgical interventions) prompted parental report of child anxiety. For children, the main stressors that correlated with anxiety and pain were factors during the blood collection itself (e.g., feeling the puncture, seeing the syringe). Parental anxiety was mainly related to circumstances before the blood collection (e.g., approaching the clinic, sitting in the waiting room). The main stressors mentioned by parents were the child’s discomfort and their inability to calm the child. Results indicate that the children’s fear of factors during the blood collection, along with the parents’ perceived stress and helplessness as well as their anticipatory anxiety are important starting points for facilitating the drawing of blood from children before and after liver transplantation, thereby supporting a better disease course in the future.
Small RNAs have been implicated in numerous cellular processes, including effects on chromatin structure and the repression of transposons. We describe the generation of a small RNA response at DNA ends in Drosophila that is analogous to the recently reported double-strand break (DSB)-induced RNAs or Dicer- and Drosha-dependent small RNAs in Arabidopsis and vertebrates. Active transcription in the vicinity of the break amplifies this small RNA response, demonstrating that the normal messenger RNA contributes to the endogenous small interfering RNAs precursor. The double-stranded RNA precursor forms with an antisense transcript that initiates at the DNA break. Breaks are thus sites of transcription initiation, a novel aspect of the cellular DSB response. This response is specific to a double-strand break since nicked DNA structures do not trigger small RNA production. The small RNAs are generated independently of the exact end structure (blunt, 3′- or 5′-overhang), can repress homologous sequences in trans and may therefore—in addition to putative roles in repair—exert a quality control function by clearing potentially truncated messages from genes in the vicinity of the break.
Riva, Antonella ; Morazzoni, Paolo ; Artaria, Christian ; Allegrini, Pietro ; Meins, Jürgen ; Savio, Daniele ; Appendino, Giovanni ; Schubert-Zsilavecz, Manfred ; Abdel Tawab, Mona
Background: The oral administration of the gum resin extracts of Indian frankincense (Boswellia serrata Roxb. ex Colebr) results in very low plasma concentrations of boswellic acids (BAs), being far below the pharmacologically active concentrations required in vitro for anti-inflammatory activity. For that reason the use of Indian frankincense in clinical practice and pharmaceutical development has substantially lagged behind. Recently the application of new formulation technologies resulted in a formulation of frankincense extract with lecithin, which revealed improved absorption and tissue penetration of BAs in a rodent study, leading for the first time to plasma concentrations of BAs in the range of their anti-inflammatory activity.
Purpose: In order to verify these encouraging results in humans, the absorption of a standardized Boswellia serrata extract (BE) and its lecithin formulation (CSP) was comparatively investigated in healthy volunteers.
Study design: According to a randomized cross-over design with two treatments, two sequences and two periods, 12 volunteers alternatively received the lecithin-formulated Boswellia extract (CSP) or the non-formulated Boswellia extract (BE) at a dosage of 2 × 250 mg capsules.
Methods: The plasma concentrations of the six major BAs (KBA, AKBA, βBA, αBA, AβBA, AαBA) were determined using LC/MS.
Results: With the exception of KBA, a significantly higher (both in terms of weight-to-weight and molar comparison) and quicker absorption of BAs from the lecithin formulation was observed, leading to Cmax in the range required for the interaction with their molecular targets.
Conclusion: These findings pave the way to further studies evaluating the clinical potential of BAs, and verify the beneficial effect of lecithin formulation to improve the absorption of poorly soluble phytochemicals.
Karimova, Madina ; Baker, Oliver ; Camgoz, Aylin ; Naumann, Ronald ; Buchholz, Frank ; Anastassiadis, Konstantinos
Site-specific recombinases (SSR) are utilized as important genome engineering tools to precisely modify the genome of mice and other model organisms. Reporter mice that mark cells that at any given time had expressed the enzyme are frequently used for lineage tracing and to characterize newly generated mice expressing a recombinase from a chosen promoter. With increasing sophistication of genome alteration strategies, the demand for novel SSR systems that efficiently and specifically recombine their targets is rising and several SSR-systems are now used in combination to address complex biological questions in vivo. Generation of reporter mice for each one of these recombinases is cumbersome and increases the number of mouse lines that need to be maintained in animal facilities. Here we present a multi-reporter mouse line for loci-of-recombination (X) (MuX) that streamlines the characterization of mice expressing prominent recombinases. MuX mice constitutively express nuclear green fluorescent protein after recombination by either Cre, Flp, Dre or Vika recombinase, rationalizing the number of animal lines that need to be maintained. We also pioneer the use of the Vika/vox system in mice, illustrating its high efficacy and specificity, thereby facilitating future designs of sophisticated recombinase-based in vivo genome engineering strategies.
Sharma, Sunny ; David Hartmann, Johannes ; Watzinger, Peter ; Klepper, Arvid ; Peifer, Christian ; Kötter, Peter ; Lafontaine, Denis L. J. ; Entian, Karl-Dieter
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Hutten, Nadia R. P. W. ; Kuypers, Kim P. C. ; Wel, Janelle van ; Theunissen, Eef L. ; Tönnes, Stefan W. ; Verkes, Robbert Jan ; Ramaekers, Johannes G.
Background: Prospective memory is the ability to recall intended actions or events at the right time or in the right context. While cannabis is known to impair prospective memory, the acute effect of cocaine is unknown. In addition, it is not clear whether changes in prospective memory represent specific alterations in memory processing or result from more general effects on cognition that spread across multiple domains such as arousal and attention.
Aims: The main objective of the study was, therefore, to determine whether drug-induced changes in prospective memory are memory specific or associated with more general drug-induced changes in attention and arousal.
Methods: A placebo-controlled, three-way, cross-over study including 15 regular poly-drug users was set up to test the influence of oral cocaine (300 mg) and vaporised cannabis (300+150 ‘booster’ µg/kg bodyweight) on an event-based prospective memory task. Attentional performance was assessed using a divided attention task and subjective arousal was assessed with the Profile of Mood States questionnaire.
Results: Results showed that cocaine enhanced prospective memory, attention and arousal. Mean performance of prospective memory and attention, as well as levels of arousal were lowest during treatment with cannabis as compared with placebo and cocaine as evinced by a significantly increased trend across treatment conditions. Prospective memory performance was only weakly positively associated to measures of attention and arousal.
Conclusion: Together, these results indicate that cocaine enhancement of prospective memory performance cannot be fully explained by parallel changes in arousal and attention levels, and is likely to represent a direct change in the neural network underlying prospective memory.
Riessen, Reimer ; Behmenburg, Melanie ; Blumenstock, Gunnar ; Guenon, Doris ; Enkel, Sigrid ; Schäfer, Richard ; Haap, Michael
Introduction: Aim of this study was to reduce blood loss caused by diagnostic blood sampling and to minimize the development of anemia in a high-risk group of mechanically ventilated medical intensive care patients. We therefore implemented a “blood-saving bundle” (BSB) combining a closed-loop arterial blood sampling system, smaller sampling tubes, reduced frequency of blood drawings, and reduced sample numbers.
Methods: The study included all patients from our medical ICU who were ventilated for more than 72 hours. Exclusion criteria were: acute or chronic anemia on admission, bleeding episode(s) during the ICU stay, or end-of-life therapy. The BSB was introduced in 2009 with training and educational support. Patients treated in 2008, before the introduction of the BSB, served as a control group (n = 41, 617 observation days), and were compared with patients treated in 2010 after the introduction of the BSB (BSB group, n = 50, 559 observation days). Primary endpoints were blood loss per day, and development of anemia. Secondary endpoints were numbers of blood transfusions, number of days on mechanical ventilation, and length of the ICU stay.
Results: Mean blood loss per ICU day was decreased from 43.3 ml (95% CI: 41.2 to 45.3 ml) in the controls to 15.0 ml (14.3 to 15.7 ml) in the BSB group (P < 0.001). The introduction of a closed-loop arterial blood sampling system was the major contributor to this effect. Mean hemoglobin concentrations showed no significant differences in both groups during the ICU stay. Hemoglobin values <9 g/dl, however, were recorded in 21.2% of observation days in the controls versus 15.4% in the BSB group (P = 0.01). Units of transfused red blood cells per 100 observation days decreased from 7 to 2.3 (P < 0.001). The mean number of ventilation days was 7.1 days (6.1 to 8.3 days) in the controls and 7.5 days (6.6 to 8.5 days) in the BSB group (P = NS). In total, patients in the BSB group stayed in ICU for a mean of 9.9 days (8.6 to 11.3 days), compared to a mean ICU stay of 13.0 days (10.9 to 15.4 days) in the control group (P = 0.014). Due to the longitudinal study design, however, we cannot exclude uncontrolled confounders affecting the transfusion frequency and mean ICU stay.
Conclusion: Our BSB could be easily implemented and was able to reduce diagnostic blood loss.
Specifying accurate informative prior distributions is a question of carefully selecting studies that comprise the body of comparable background knowledge. Psychological research, however, consists of studies that are being conducted under different circumstances, with different samples and varying instruments. Thus, results of previous studies are heterogeneous, and not all available results can and should contribute equally to an informative prior distribution. This implies a necessary weighting of background information based on the similarity of the previous studies to the focal study at hand. Current approaches to account for heterogeneity by weighting informative prior distributions, such as the power prior and the meta-analytic predictive prior are either not easily accessible or incomplete. To complicate matters further, in the context of Bayesian multiple regression models there are no methods available for quantifying the similarity of a given body of background knowledge to the focal study at hand. Consequently, the purpose of this study is threefold. We first present a novel method to combine the aforementioned sources of heterogeneity in the similarity measure ω. This method is based on a combination of a propensity-score approach to assess the similarity of samples with random- and mixed-effects meta-analytic models to quantify the heterogeneity in outcomes and study characteristics. Second, we show how to use the similarity measure ω as a weight for informative prior distributions for the substantial parameters (regression coefficients) in Bayesian multiple regression models. Third, we investigate the performance and the behavior of the similarity-weighted informative prior distribution in a comprehensive simulation study, where it is compared to the normalized power prior and the meta-analytic predictive prior. The similarity measure ω and the similarity-weighted informative prior distribution as the primary results of this study provide applied researchers with means to specify accurate informative prior distributions.
We present an immersed boundary method for the solution of elliptic interface problems with discontinuous coefficients which provides a second-order approximation of the solution. The proposed method can be categorised as an extended or enriched finite element method. In contrast to other extended FEM approaches, the new shape functions get projected in order to satisfy the Kronecker-delta property with respect to the interface. The resulting combination of projection and restriction was already derived in Höllbacher and Wittum (TBA, 2019a) for application to particulate flows. The crucial benefits are the preservation of the symmetry and positive definiteness of the continuous bilinear operator. Besides, no additional stabilisation terms are necessary. Furthermore, since our enrichment can be interpreted as adaptive mesh refinement, the standard integration schemes can be applied on the cut elements. Finally, small cut elements do not impair the condition of the scheme and we propose a simple procedure to ensure good conditioning independent of the location of the interface. The stability and convergence of the solution will be proven and the numerical tests demonstrate optimal order of convergence.
Forrester, Alison ; De Leonibus, Chiara ; Grumati, Paolo ; Fasana, Elisa ; Piemontese, Marilina ; Staiano, Leopoldo ; Fregno, Ilaria ; Raimondi, Andrea ; Marazza, Alessandro ; Bruno, Gemma ; Iavazzo, Maria ; Intartaglia, Daniela ; Seczynska, Marta ; Anken, Eelco van ; Conte, Ivan ; De Matteis, Maria Antonietta ; Đikić, Ivan ; Molinari, Maurizio ; Settembre, Carmine
Autophagy is a cytosolic quality control process that recognizes substrates through receptor‐mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR‐Cas9 or knockout‐mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER‐resident lectin chaperone Calnexin (CANX) and the ER‐phagy receptor FAM134B are required for autophagy‐mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co‐receptor that recognizes ER luminal misfolded procollagens and interacts with the ER‐phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane‐associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome‐resistant misfolded clients from the ER.
We explore the parameter space of the two-flavor thermal quark–meson model and its Polyakov loop-extended version under the influence of a constant external magnetic field B. We investigate the behavior of the pseudo critical temperature for chiral symmetry breaking taking into account the likely dependence of two parameters on the magnetic field: the Yukawa quark–meson coupling and the parameter T0 of the Polyakov loop potential. Under the constraints that magnetic catalysis is realized at zero temperature and the chiral transition at B=0 is a crossover, we find that the quark–meson model leads to thermal magnetic catalysis for the whole allowed parameter space, in contrast to the present picture stemming from lattice QCD.
Bramsen, Jesper B. ; Pakula, Malgorzata M. ; Hansen, Thomas B. ; Bus, Claus ; Langkjær, Niels ; Odadžić, Dalibor ; Smicius, Romualdas ; Wengel, Suzy L. ; Chattopadhyaya, Jyoti ; Engels, Joachim W. ; Herdewijn, Piet ; Wengel, Jesper ; Kjems, Jørgen
Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2–8 of either siRNA strand counting from the 5'-end) and complementary sequences in the 3'UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA–target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low.
This study presents a method for adjusting long-term climate data records (CDRs) for the integrated use with near-real-time data using the example of surface incoming solar irradiance (SIS). Recently, a 23-year long (1983–2005) continuous SIS CDR has been generated based on the visible channel (0.45–1 μm) of the MVIRI radiometers onboard the geostationary Meteosat First Generation Platform. The CDR is available from the EUMETSAT Satellite Application Facility on Climate Monitoring (CM SAF). Here, it is assessed whether a homogeneous extension of the SIS CDR to the present is possible with operationally generated surface radiation data provided by CM SAF using the SEVIRI and GERB instruments onboard the Meteosat Second Generation satellites. Three extended CM SAF SIS CDR versions consisting of MVIRI-derived SIS (1983–2005) and three different SIS products derived from the SEVIRI and GERB instruments onboard the MSG satellites (2006 onwards) were tested. A procedure to detect shift inhomogeneities in the extended data record (1983–present) was applied that combines the Standard Normal Homogeneity Test (SNHT) and a penalized maximal T-test with visual inspection. Shift detection was done by comparing the SIS time series with the ground stations mean, in accordance with statistical significance. Several stations of the Baseline Surface Radiation Network (BSRN) and about 50 stations of the Global Energy Balance Archive (GEBA) over Europe were used as the ground-based reference. The analysis indicates several breaks in the data record between 1987 and 1994 probably due to artefacts in the raw data and instrument failures. After 2005 the MVIRI radiometer was replaced by the narrow-band SEVIRI and the broadband GERB radiometers and a new retrieval algorithm was applied. This induces significant challenges for the homogenisation across the satellite generations. Homogenisation is performed by applying a mean-shift correction depending on the shift size of any segment between two break points to the last segment (2006–present). Corrections are applied to the most significant breaks that can be related to satellite changes. This study focuses on the European region, but the methods can be generalized to other regions. To account for seasonal dependence of the mean-shifts the correction was performed independently for each calendar month. In comparison to the ground-based reference the homogenised data record shows an improvement over the original data record in terms of anomaly correlation and bias. In general the method can also be applied for the adjustment of satellite datasets addressing other variables to bridge the gap between CDRs and near-real-time data.
Holzgreve, Fabian Christian ; Fräulin, Laura ; Betz, Werner ; Erbe, Christina ; Wanke, Eileen M. ; Brüggmann, Dörthe ; Nienhaus, Albert ; Groneberg, Jan David Alexander ; Maurer-Grubinger, Christian ; Ohlendorf, Daniela Maren
Background: In general, the prevalence of work-related musculoskeletal disorders (WMSD) in dentistry is high, and dental assistants (DA) are even more affected than dentists (D). Furthermore, differentiations between the fields of dental specialization (e.g., general dentistry, endodontology, oral and maxillofacial surgery, or orthodontics) are rare. Therefore, this study aims to investigate the ergonomic risk of the aforementioned four fields of dental specialization for D and DA on the one hand, and to compare the ergonomic risk of D and DA within each individual field of dental specialization. Methods: In total, 60 dentists (33 male/27 female) and 60 dental assistants (11 male/49 female) volunteered in this study. The sample was composed of 15 dentists and 15 dental assistants from each of the dental field, in order to represent the fields of dental specialization. In a laboratory setting, all tasks were recorded using an inertial motion capture system. The kinematic data were applied to an automated version of the Rapid Upper Limb Assessment (RULA). Results: The results revealed significantly reduced ergonomic risks in endodontology and orthodontics compared to oral and maxillofacial surgery and general dentistry in DAs, while orthodontics showed a significantly reduced ergonomic risk compared to general dentistry in Ds. Further differences between the fields of dental specialization were found in the right wrist, right lower arm, and left lower arm in DAs and in the neck, right wrist, right lower arm, and left wrist in Ds. The differences between Ds and DAs within a specialist discipline were rather small. Discussion: Independent of whether one works as a D or DA, the percentage of time spent working in higher risk scores is reduced in endodontologists, and especially in orthodontics, compared to general dentists or oral and maxillofacial surgeons. In order to counteract the development of WMSD, early intervention should be made. Consequently, ergonomic training or strength training is recommended.
A role of the Qв binding protein in the mechanism of cyanobacterial adaptation to light intensity?
(1986)
Growth of the unicellular blue-green alga Anacystis nidulans in media containing sublethal concentrations of DCMU-type inhibitors of photosynthetic electron transport in strong white light gave rise to shade type appearance in this organism, as characterized by an increased ratio of phycocyanin to chlorophyll and reduced ratios, both, of carotenoids to chlorophyll and of total chlorophyll to P700. Shade type in Anacystis was caused neither by phenolic inhibitors tested nor by those known to bind to the cytochrome b6/f-complex. Surprisingly enough, the molar ratio of phycocyanin to chlorophyll in artificially shade adapted Anacystis1 grown in strong white light in the presence of 10-6 м atrazine, was found to increase with temperature for a given light intensity and with light intensity for a given temperature.
Mutants of Anaeystis with a reduced binding capacity for DCMU-type herbicides due to an amino acid exchange in the 32 kDa Qв-binding polypeptide, also called D-1 protein, were ob- served to show shade type appearance in strong light, to respond very little to changes in light intensity and to show a reduced capability to further change their appearance to shade type by binding of competitors of Ob to the 32 kDa polypeptide.
In Anaeystis a concentration of atrazine (10-7 м), ten times lower than the one causing the highest rate of shade adaptation (10-6 м), was shown to induce an optimum in cell density, which in turn resulted in an optimum in light-dependent O2 evolution. Both factors together might be responsible for the so-called greening effect observed in higher plants treated with sublethal concentrations of DCMU-type inhibitors of photosynthetic electron transport.
Swart, Laura E. ; Koekman, Cornelis Arnold ; Seinen, Cor W. ; Issa, Hasan ; Rasouli, Milad ; Schiffelers, Raymond Michel ; Heidenreich, Olaf Torben
Targeted delivery of nucleic acids is gaining momentum due to improved efficacy, selectivity, increased circulation time and enhanced tissue retention in target cells. Using nucleic acid-based therapies previously undruggable targets have proven now to be amenable for treatment. Currently, several methods for preparing targeted or labelled delivery vehicles for nucleic acids are based on liposomal formulations. Lipid nanoparticles (LNPs) are structurally different from liposomes and these methods should therefore be evaluated before being translated to siRNA LNPs preparation protocols. Here, we describe a robust and facile method for the preparation of targeted or fluorescently labelled siRNA LNPs. Using a copper free strain-promoted azide-alkyne cycloaddition (SPAAC) we demonstrate that post-insertion of ligand-lipid conjugates into preformed LNPs is superior to direct-surface modification because it preserves the physicochemical parameters of the LNPs. We found that the time point of solvent removal by dialysis is critical and affects the hydrodynamic diameter of the LNPs; post-insertion after dialysis shows the smallest increase in hydrodynamic diameter and polydispersity index (PDI). The post-insertion of ligand-lipid conjugates also proceeded with rapid kinetics and high efficacy over a wide temperature range. Using this optimised protocol, we generated siRNA LNPs containing both targeting and fluorescent tracking ligands allowing us to monitor siRNA LNP uptake kinetics in dependence of the targeting ligand. In aggregate, we describe a robust approach for the generation of targeted and labelled siRNA LNPs that allows their controlled and facile decoration with ligand combinations.
A risk based assessment approach for chemical mixtures from wastewater treatment plant effluents
(2022)
Finckh, Saskia ; Beckers, Liza-Marie ; Busch, Wibke ; Carmona, Eric ; Dulio, Valeria ; Kramer, Lena ; Krauss, Martin ; Posthuma, Leo ; Schulze, Tobias ; Slootweg, Jaap ; Ohe, Peter Carsten von der ; Brack, Werner
In this study, 56 effluent samples from 52 European wastewater treatment plants (WWTPs) were investigated for the occurrence of 499 emerging chemicals (ECs) and their associated potential risks to the environment. The two main objectives were (i) to extend our knowledge on chemicals occurring in treated wastewater, and (ii) to identify and prioritize compounds of concern based on three different risk assessment approaches for the identification of consensus mixture risk drivers of concern. Approaches include (i) PNEC and EQS-based regulatory risk quotients (RQs), (ii) species sensitivity distribution (SSD)-based hazard units (HUs) and (iii) toxic units (TUs) for three biological quality elements (BQEs) algae, crustacean, and fish.
For this purpose, solid-phase extracts were analysed with wide-scope chemical target screening via liquid chromatography high-resolution mass spectrometry (LC-HRMS), resulting in 366 detected compounds, with concentrations ranging from < 1 ng/L to > 100 µg/L. The detected chemicals were categorized with respect to critical information relevant for risk assessment and management prioritization including: (1) frequency of occurrence, (2) measured concentrations, (3) use groups, (4) persistence & bioaccumulation, and (5) modes of action. A comprehensive assessment using RQ, HU and TU indicated exceedance of risk thresholds for the majority of effluents with RQ being the most sensitive metric. In total, 299 out of the 366 compounds were identified as mixture risk contributors in one of the approaches, while 32 chemicals were established as consensus mixture risk contributors of high concern, including a high percentage (66%) of pesticides and biocides. For samples which have passed an advanced treatment using ozonation or activated carbon (AC), consistently much lower risks were estimated.
Molecular phylogenetic studies of Moraea Mill. and the inclusion of Barnardiella Goldblatt, Galaxia Thunb., Gynandriris Parl., Hexaglottis Vent., Homeria Vent. and Roggeveldia Goldblatt in the genus have rendered the existing infrageneric classification, dating from 1976, in need of substantial revision. In particular, subg. Moraea and subg. Vieusseuxia have been shown to be paraphyletic. We propose a new infrageneric classification, based, as far as current data permit, on phylogenetic principles. Monophyletic subgenera and sections are circumscribed based on molecular phylogenies alone or in combination with morphological considerations. We recognize 11 subgenera, 15 sections and three series, arranged as follows in phylogenetic sequence: Plumarieae; Visciramosae (with sect. Multifoliae and sect. Visciramosae); Moraea (with sect. Moraea and sect. Polyphyllae); Galaxia (with ser. Unguiculatae, ser. Eurystigma and ser. Galaxia); Monocephalae; Acaules; Polyanthes (with sect. Serpentinae, sect. Deserticola, sect. Hexaglottis, sect. Gynandriris, sect. Polyanthes and sect. Pseudospicatae); Grandifl orae; Vieusseuxia (with sect. Integres, sect. Vieusseuxia and sect. Villosae); and Homeria (with sect. Stipanthera, sect. Flexuosae, sect. Homeria and sect. Conantherae). Most are moderately to well circumscribed at the morphological level either by floral or vegetative characters, except subg. Moraea, which includes a small number of unspecialized species apparently not linked by any apomorphic features. With over 27 new species described in the past 25 years and another 60 transferred to the genus, Moraea now includes 214 species. We provide a full taxonomic synopsis of the genus.
Orientation: Publishing methodologically sound, empirically based studies in reputable accredited scientific journals are essential in order to advance knowledge and evidence-based practice in the field of industrial and organisational psychology.
Research purpose: The purpose of the research was to conduct a broad content analysis of the articles published in the South African Journal of Industrial Psychology (SAJIP) between 2004 and 2013. The study aimed to provide a descriptive overview of the most frequent content themes,published authors and institutions, research approaches, strategies, designs and analysis techniques, software packages and sample sizes in industrial and organisational (I-O) psychology utilised in the publications.
Motivation for study: The periodic analyses of published content in scholarly journals provide an index of the extent to which the publications reflect the scope of practice in a given discipline and broaden insight into the direction and relevance of research published in a journal.
Research design, approach and method: A broad systematic content analysis was conducted of 342 documented articles published in the SAJIP between 2004 and 2013. Descriptive data(frequencies and percentages) were used to report the findings.
Main findings: The publishing pattern of the SAJIP appeared to correspond with its focus and scope. Manuscripts utilising mostly cross-sectional quantitative correlational research designs with large samples (n > 201) were published in the SAJIP. The University of Johannesburg and Professor Sebastiaan (Ian) Rothmann were the largest contributors to publications between 2004 and 2013. Organisational psychology and psychometrics were the most prominent domains in I-O psychology research. Data were predominantly processed utilising SPSS.
Practical implications: The insights derived from the findings can be employed to plan future research initiatives in the field of I-O psychology.
Contribution/value-add: The findings provide valuable insight into the current status of the foci of I-O psychology research as published in the SAJIP between 2004 and 2013 and the contribution made by the SAJIP to advancing knowledge and evidence-based practice in I-O psychology.
The relativistic method of moments is one of the most successful approaches to extract second order viscous hydrodynamics from a kinetic underlying background. The equations can be systematically improved to higher order, and they have already shown a fast convergence to the kinetic results. In order to generalize the method we introduced long range effects in the form of effective (medium dependent) masses and gauge (coherent) fields. The most straightforward generalization of the hydrodynamic expansion is problematic at higher order. Instead of introducing an additional set of approximations, we propose to rewrite the series in terms of moments resumming the contributions of infinite non-hydrodynamics modes. The resulting equations are are consistent with hydrodynamics and well defined at all order. We tested the new approximation against the exact solutions of the Maxwell-Boltzmann-Vlasov equations in (0 + 1)-dimensions, finding a fast and stable convergence to the exact results.
Bohus, Martin ; Schmahl, Christian ; Fydrich, Thomas ; Steil, Regina ; Müller-Engelmann, Meike ; Herzog, Julia ; Ludäscher, Petra ; Kleindienst, Nikolaus ; Priebe, Kathlen
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
Fundamental rights protection, once a side show, has become important for the EU, as proved by the newfound treaty recognition of the EU fundamental rights charter (CFREU), and the upcoming accession to the European Convention on Human Rights (ECHR). At the same time the fundamental rights situation in a considerable number of Member States is an increasing cause for concern. This has mostly been illustrated with reference to minorities and asylum seekers. However, recent reports of organizations like the Council of Europe, the OSCE and various NGOs have also highlighted serious problems with regard to media freedom, such as overt political influence, media concentration, disproportionate sanctions on journalists, misuse of counter-terrorism legislation against the press, deficient protection of journalistic sources and failure to investigate violence against reporters. ...
A reply to my critics
(2021)
It is a real pleasure to reply to so many thoughtful and probing responses to my book. In what follows, I will focus on six key themes that emerge across the various pieces. Some of them call into question core commitments of my theory, and in those cases I will try to show what might be said in its defence. Quite a number of the critics, however, present what we might call expansionist arguments: though they endorse some of the arguments I make, that is – or pick up some of its key concepts – they seek to push them in new and interesting directions. I will suggest that many of those arguments look likely to be successful, though I will also express caution about one or two of them. I doubt, however, that I will be the final judge of their success. Early on in the book I express the hope that it might provide a set of conceptual tools capable of advancing discussions about resource justice more broadly, even for scholars who reject my own idiosyncratic approach. Having made that gambit, I cannot now claim to have a monopoly on the use of the tools in question. Witnessing the use that others have already made of them has been a refreshing and rewarding experience.
A remark on the bank cases
(2021)
Since their formulation by Keith DeRose (1992), the so-called bank cases have played a major role in the discussion about whether knowledge depends on practical factors. According to the proponents of pragmatic encroachment, the proper conclusion to be drawn from the bank cases and similar examples is that knowledge of a proposition p does not supervene on one’s evidence for or against p. In my view, this conclusion is ill-founded. The reason is that the bank cases and similar examples suffer from an ambiguity concerning the known proposition — an ambiguity that has so far been overlooked. When this ambiguity is made explicit, it becomes clear that the conclusion does not follow.
We show how nonlocal boundary conditions of Robin type can be encoded in the pointwise expression of the fractional operator. Notably, the fractional Laplacian of functions satisfying homogeneous nonlocal Neumann conditions can be expressed as a regional operator with a kernel having logarithmic behaviour at the boundary.