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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.
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.
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).
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.
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.
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)
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)
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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)
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.
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.
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.