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Natural products (NPs) from microorganisms have been important sources for discovering new therapeutic and chemical entities. While their corresponding biosynthetic gene clusters (BGCs) can be easily identified by gene-sequence-similarity-based bioinformatics strategies, the actual access to these NPs for structure elucidation and bioactivity testing remains difficult. Deletion of the gene encoding the RNA chaperone, Hfq, results in strains losing the production of most NPs. By exchanging the native promoter of a desired BGC against an inducible promoter in Δhfq mutants, almost exclusive production of the corresponding NP from the targeted BGC in Photorhabdus, Xenorhabdus and Pseudomonas was observed including the production of several new NPs derived from previously uncharacterized non-ribosomal peptide synthetases (NRPS). This easyPACId approach (easy Promoter Activated Compound Identification) facilitates NP identification due to low interference from other NPs. Moreover, it allows direct bioactivity testing of supernatants containing secreted NPs, without laborious purification.
Ausgangspunkt ist die Beobachtung, dass sich empirisch eine inklusive Schule oftmals als eine differenzierte und differenzierende Schule darstellt. Dies bezieht sich etwa auf die Ausdifferenzierung der ‚heterogenen Lehrgruppe‘. Im zeitgemäßen inklusiven Unterricht sind allgemein- und sonderpädagogische Lehrkräfte ebenso wie Schulbegleitungen anwesend. Auch Sozialpädagog*innen und Therapeut*innen gehören vermehrt zum Schulalltag.
Vorliegende Studien dokumentieren, dass die Gestaltung inklusiver Schulen bzw. von inklusivem Unterricht von nicht intendierten Effekten und Widerständigkeiten der Akteur*innen begleitet ist. Im Beitrag werden – basierend auf der ProFiS-Studie – zwei Herausforderungen von inklusiven Schulen in den Mittelpunkt gerückt. Zum einen wird auf das Spannungsfeld von Professionalisierung und Deprofessionalisierung eingegangen. Zum anderen stellt das Verhältnis von Kategorisierung und Dekategorisierung eine Herausforderung dar. Beide Relationen sind als Spannungsverhältnisse untereinander und zueinander zu denken, die sich nicht ‚einfach‘ in eine Richtung auflösen lassen, sondern die in ihrer Widersprüchlichkeit gerade konstitutiv für die Praxis ‚inklusiver Schulen‘ wirken. Zentrale Frage des Beitrags ist, wie dieses komplexe Spannungsverhältnis der wechselseitigen Bezogenheit de/kategorisierender und de/professionalisierender Prozesse in professionellen Aktivitäten hervorgebracht wird.
Background: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
Methods: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.
Results: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
Conclusions: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/− irinotecan in stage II/III colorectal cancer.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Pendants les années 1997 et 1998, un groupe des chercheurs de SFB 268 a effectué, dans la région de l’Atakora, des recherches botaniques, ethnologiques et géographiques concernant l’histoire du peuplement. Les travaux étaient concentrés sur la partie ouest de la région, c’est-à-dire le triangle Boukombé, Natitingou, Toucountouna. En résultat, il est possible aujourd’hui de faire une chronologie relative à l’histoire du peuplement dans cette région. En contraire, il manque toujours une chronologie absolue, pour cela il faut encore des recherches approfondies. Pourtant nous allons proposer, dans le cours de cette contribution, des hypothèses montrant le cadre, dans lequel une périodisation peut être possible.
Accurate spectroscopy of highly-charged high-Z ions in a storage ring is demonstrated to be feasible by the use of specially adapted crystal optics. The method has been applied for the measurement of the 1s Lamb shift in hydrogen-like gold (Au+78) in a storage ring through spectroscopy of the Lyman x-rays. This measurement represents the first result obtained for a high-Z element using high-resolution wavelength-dispersive spectroscopy in the hard x-ray regime, paving the way for sensitivity to higher- order QED effects.
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Der Beitrag stellt am Beispiel der dritten Phase der Lehrer:innenbildung den Professionalisierungsansatz vor, der in dem Forschungs- und Entwicklungsprojekt „Reflexion, Leistung und Inklusion“ (ReLInk) konzipiert und in Fortbildungsworkshops für Lehrkräfte der Sekundarstufe I erprobt wurde. Nach einer Projektdarstellung (Abschnitt 1) werden ausgewählte Ergebnisse der im Rahmen von ReLInk durchgeführten qualitativen Studie vorgestellt (Abschnitt 2). Diese Ergebnisse bildeten den Ausgangspunkt für die Entwicklung kasuistischer Materialien für die Aus- und Fortbildung von (angehenden) Lehrkräften. Für die Gestaltung der Fortbildungsworkshops stellte die Arbeit mit der Methode der sequenzanalytischen praxisreflexiven Kasuistik den Kern des Professionalisierungsansatzes von ReLInk dar. Die Materialien stehen online in einem Open-Access-Themenheft zur Verfügung (Abschnitt 3). Hierzu werden Erfahrungen aus den Workshops und Ergebnisse einer qualitativen Evaluation dieses Ansatzes präsentiert (Abschnitt 4). Am Ende werden anschließende Fragen sowohl für die Professionalisierung sowie für die Forschung aufgeworfen (Abschnitt 5).
The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+ vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.
The decays J/ψ→ηΣ+Σ¯− and ψ(3686)→ηΣ+Σ¯− are observed for the first time, using (10087±44)×106 J/ψ and (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector at the BEPCII collider. We determine the branching fractions of these two decays to be B(J/ψ→ηΣ+Σ¯−)=(6.34±0.21±0.37)×10−5 and B(ψ(3686)→ηΣ+Σ¯−)=(9.59±2.37±0.61)×10−6, where the first uncertainties are statistical and the second are systematic. The ratio of these two branching fractions is determined to be B(ψ(3686)→ηΣ+Σ¯−)B(J/ψ→ηΣ+Σ¯−)=(15.1±3.8)%, which is in agreement with the "12\% rule."
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 19 fb−1 collected with the BESIII detector at the BEPCII collider, we search for the production of deuterons and antideuterons via e+e−→ppπ−d¯+c.c. for the first time at center-of-mass energies between 4.13 and 4.70 GeV. No significant signal is observed and the upper limit of the e+e−→ppπ−d¯+c.c. cross section is determined to be from 9.0 to 145 fb depending on the center-of-mass energy at the 90% confidence level.
Using 𝑒+𝑒− collision data corresponding to an integrated luminosity of 7.33 fb−1 recorded by the BESIII detector at center-of-mass energies between 4.128 and 4.226 GeV, we present an analysis of the decay 𝐷+𝑠→𝜋+𝜋−𝑒+𝜈𝑒, where the 𝐷+𝑠 is produced via the process 𝑒+𝑒−→𝐷*±𝑠𝐷∓𝑠. We observe the 𝑓0(980) in the 𝜋+𝜋− system and the branching fraction of the decay 𝐷+𝑠→𝑓0(980)𝑒+𝜈𝑒 with 𝑓0(980)→𝜋+𝜋− measured to be (1.72±0.13stat±0.10syst)×10−3, where the uncertainties are statistical and systematic, respectively. The dynamics of the 𝐷+𝑠→𝑓0(980)𝑒+𝜈𝑒 decay are studied with the simple pole parametrization of the hadronic form factor and the Flatté formula describing the 𝑓0(980) in the differential decay rate, and the product of the form factor 𝑓𝑓0+(0) and the 𝑐→𝑠 Cabibbo-Kobayashi-Maskawa matrix element |𝑉𝑐𝑠| is determined for the first time to be 𝑓𝑓0+(0)|𝑉𝑐𝑠|=0.504±0.017stat±0.035syst. Furthermore, the decay 𝐷+
𝑠→𝑓0(500)𝑒+𝜈𝑒 is searched for the first time but no signal is found. The upper limit on the branching fraction of 𝐷+𝑠→𝑓0(500)𝑒+𝜈𝑒, 𝑓0(500)→𝜋+𝜋− decay is set to be 3.3×10−4 at 90% confidence level.
Using a data sample corresponding to an integrated luminosity of 10.9 fb−1 collected at center-of-mass energies from 4.16 to 4.34 GeV with the BESIII detector, we search for the decay χc1(3872)→π+π−χc1 in the radiative production e+e−→γχc1(3872). No significant signal is observed, and the ratio for the branching fraction of χc1(3872)→π+π−χc1 to χc1(3872)→π+π−J/ψ is measured as R≡B[χc1(3872)→π+π−χc1]B[χc1(3872)→π+π−J/ψ]<0.18 at 90% confidence level. The upper limit on the product of the cross section σ[e+e−→γχc1(3872)] and the branching fraction B[χc1(3872)→π+π−χc1] at each center-of-mass energy is also given. These measurements favor the non-conventional charmonium nature of the χc1(3872) state.
A narrow structure in the pΛ¯ system near the mass threshold, named as X(2085), is observed in the process e+e−→pK−Λ¯ with a statistical significance greater than 20σ. Its spin and parity are determined for the first time to be JP=1+ in an amplitude analysis, with statistical significance greater than 5σ over other quantum numbers. The pole positions of X(2085) are measured to be Mpole=(2086±4±6)~MeV and Γpole=(56±5±16) MeV, where the first uncertainties are statistical and the second ones are systematic. The analysis is based on the study of the process e+e−→pK−Λ¯ and uses the data samples collected with the BESIII detector at the center-of-mass energies s√=4.008, 4.178, 4.226, 4.258, 4.416, and 4.682 GeV with a total integrated luminosity of 8.35 fb−1.
Based on a sample of 448.1×106 ψ(3686) events collected with the BESIII detector, a study of ψ(3686)→ΛΛ¯π0 and ψ(3686)→ΛΛ¯η is performed. Evidence of the isospin-violating decay ψ(3686)→ΛΛ¯π0 is found for the first time with a statistical significance of 3.7σ, the branching fraction B(ψ(3686)→ΛΛ¯π0) is measured to be (1.42±0.39±0.59)×10−6, and its corresponding upper limit is determined to be 2.47×10−6 at 90\% confidence level. A partial wave analysis of ψ(3686)→ΛΛ¯η shows that the peak around Λη invariant mass threshold favors a Λ∗ resonance with mass and width in agreement with the Λ(1670). The branching fraction of the ψ(3686)→ΛΛ¯η is measured to be (2.34±0.18±0.52)×10−5. The first uncertainties are statistical and the second are systematic.
Based on e+e− collision data corresponding to an integrated luminosity of 4.5 fb−1 collected at the center-of-mass energies between 4.600 and 4.699 GeV with the BESIII detector at BEPCII, the absolute branching fraction of the inclusive decay Λ+c→n+X, where X refers to any possible final state particles, is measured. The absolute branching fraction is determined to be B(Λ+c→n+X)=(32.4±0.7±1.5)%, where the first uncertainty is statistical and the second systematic. Assuming CP symmetry, the measurement indicates that about one-fourth of Λ+c (Λ¯−c) decay modes with a neutron (an anti-neutron) in the final state have not been observed.
Based on e+e− collision data corresponding to an integrated luminosity of 4.5 fb−1 collected at the center-of-mass energies between 4.600 and 4.699 Gev with the BESIII detector at BEPCII, the absolute branching fraction of the inclusive decay Λ¯−c→n¯+X, where X refers to any possible final state particles, is measured. The absolute branching fraction is determined to be B(Λ¯−c→n¯+X)=(33.5±0.7±1.2)%, where the first uncertainty is statistical and the second systematic. Neglecting the effect of CP violation, the measurement indicates that about one-fourth of Λ+c decay modes with a neutron in the final state have not been observed.