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Our ability to select relevant information from the environment is limited by the resolution of attention – i.e., the minimum size of the region that can be selected. Neural mechanisms that underlie this limit and its development are not yet understood. Functional magnetic resonance imaging (fMRI) was performed during an object tracking task in 7- and 11-year-old children, and in young adults. Object tracking activated canonical fronto-parietal attention systems and motion-sensitive area MT in children as young as 7 years. Object tracking performance improved with age, together with stronger recruitment of parietal attention areas and a shift from low-level to higher-level visual areas. Increasing the required resolution of spatial attention – which was implemented by varying the distance between target and distractors in the object tracking task – led to activation increases in fronto-insular cortex, medial frontal cortex including anterior cingulate cortex (ACC) and supplementary motor area, superior colliculi, and thalamus. This core circuitry for attentional precision was recruited by all age groups, but ACC showed an age-related activation reduction. Our results suggest that age-related improvements in selective visual attention and in the resolution of attention are characterized by an increased use of more functionally specialized brain regions during the course of development.
The social construction of technological stasis : the stagnating data structure in OpenStreetMap
(2018)
The article aims for examining the ‘technological stasis’ of the data structure in OpenStreetMap – the successful global collaborative geodata project devoted to ‘create and distribute free geographic data for the world’. Digital structures are strongly influenced by continuing stagnation. This technological stasis – the lack of change in technology – influences data in various ways, as demonstrated by the intensive discussion of the issue by computer scientists and software engineers. However, existing research describing stagnating software is often technic centred and fuzzy, while critical research is barely considering issues of technological stasis in the digital context at all. Therefore, this paper aims for enriching this body of knowledge in order to shed light on aging data structures. I reframe technological stasis with a social-constructivist perspective – using the approach of Social Construction of Technology – especially with the concept of technological frames. Based on the case example of OpenStreetMap, my findings suggest that the data structure – and its stasis – is the outcome of competing understandings and perspectives, shaped by power asymmetries. Although the data structure did not significantly change for more than 10 years, I demonstrate that this is not because of a lack of motivation, nor technological difficulties of carrying out such changes. The technological stasis is rather rooted in the dominant position of few project members who are able to change the software design; it is their perception of the project that defines how data should be stored and what features are dispensable.
Auf Knopfdruck geht es sekundenschnell in die Tiefe. Als sich die Aufzugstür drei Stockwerke unter der Erde öffnet, tauchen im Licht von Neonröhren unendlich lang erscheinende Regale auf. Viele sind vollgestellt mit Büchern. Andere warten darauf, dass sich ihre Reihen noch füllen. Etwa 2,7 Millionen Bände lagern in unterirdischen Magazinen der Universitätsbibliothek (UB) Johann Christian Senckenberg am Campus Bockenheim. Der Name UB umfasst zum einen die Zentralbibliothek (ZB) am Campus Bockenheim, zum anderen die fünf Bereichsbibliotheken Naturwissenschaften, Recht und Wirtschaft, Sozialwissenschaften und Psychologie, Geisteswissenschaften sowie Medizin.
Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized by a progressive degeneration of the dorsal vagal nucleus and midbrain dopaminergic neurons together with an imbalance of many other neurotransmitters. Mutations in α-synuclein (SNCA), a protein modulating SNARE complex-dependent neurotransmission, trigger dominantly inherited PD variants and sporadic cases of PD. The A53T SNCA missense mutation is associated with an autosomal dominant early-onset familial PD. To test whether this missense mutation affects the circadian system, we analyzed the spontaneous locomotor behavior of non-transgenic wildtype mice and transgenic mice overexpressing mutant human A53T α-synuclein (A53T). The mice were subjected to entrained- and free-running conditions as well as to experimental jet lag. Furthermore, the vesicular glutamate transporter 2 (VGLUT2) in the suprachiasmatic nucleus (SCN) was analyzed by immunohistochemistry. Free-running circadian rhythm and, thus, circadian rhythm generation, were not affected in A53T mice. A53T mice entrained to the light–dark cycle, however, with an advanced phase angle of 2.65 ± 0.5 h before lights off. Moreover, re-entrainment after experimental jet lag was impaired in A53T mice. Finally, VGLUT2 immunoreaction was reduced in the SCN of A53T mice. These data suggest an impaired light entrainment of the circadian system in A53T mice.
Bei Autismus-Spektrum-Störungen (ASS) handelt es sich um genetisch komplexe Störungen mit hoher Erblichkeit. Als zugrundeliegender Pathomechanismus von ASS werden unter anderem Veränderungen der neuronalen Entwicklung diskutiert. Der Phänotyp von ASS ist definiert durch Einschränkungen in der sozialen Interaktion und Kommunikation sowie repetitives und stereotypes Verhalten. Genkopiepolymorphismen (englisch „copy number variations“/CNVs), also Deletionen oder Duplikationen einer chromosomalen Region, wurden wiederholt in Probanden mit ASS identifiziert. Hierbei ist in ASS die Region 16p11.2 mit am häufigsten von CNVs betroffen. Einige Gene aus diesem chromosomalen Abschnitt wurden bereits funktionell charakterisiert. Dennoch können die Befunde der bisherigen Einzelgenstudien nicht alle Aspekte erklären, die durch 16p11.2 CNVs hervorgerufen werden. Ziel dieser Studie war es daher, ein weiteres neuronal assoziiertes Kandidatengen dieser Region zu identifizieren und im Anschluss funktionell im Kontext der neuronalen Differenzierung zu charakterisieren.
Das SH-SY5Y Neuroblastom-Zellmodell wurde auf Transkriptom- und morphologischer Ebene auf seine Eignung als Modell für neuronale Differenzierung untersucht und bestätigt. Eine Analyse der Expressionen aller Gene der 16p11.2-Region zeigte, dass das Gen Quinolinat-Phosphoribosyltransferase (QPRT) eine vergleichsweise hohe Expression mit der stärksten und robustesten Regulierung über die Zeit aufwies. Eine de novo Deletion der 16p11.2-Region wurde in einem Patienten im Vergleich zu seinen Eltern validiert. In Patienten-spezifischen lymphoblastoiden Zelllinien derselben Familie konnten wir eine Gendosis-abhängige Expression von QPRT auf RNA-Ebene bestätigen. In SH-SY5Y-Zellen korrelierte die Expression von QPRT signifikant mit der Entwicklung von Neuriten während der Differenzierung. Um QPRT funktionell zu charakterisieren, benutzten wir drei verschiedene Methoden zur Reduktion der QPRT-Gendosis: (i) knock down (KD) durch siRNA, (ii) chemische Inhibition durch Phthalsäure und (iii) knock out (KO) über CRISPR/Cas9-Geneditierung. Eine Reduktion von QPRT durch siRNA führte zu einer schwachen Veränderung der neuronalen Morphologie differenzierter SH-SY5Y-Zellen. Die chemische Inhibition sowie der genetische KO von QPRT waren letal für differenzierende aber nicht für proliferierende Zellen. Eine Metabolitenanalyse zeigte keine Veränderungen des QPRT-assoziierten Tryptophanstoffwechsels. Gene, welche auf Transkriptomebene im Vergleich zwischen KO- und Kontrollzellen differenziell reguliert vorlagen, waren häufig an Prozessen der neuronalen Entwicklung sowie an der Bildung, Stabilität und Funktion synaptischer Strukturen beteiligt. Die Liste differenziell regulierter Gene enthielt außerdem überdurchschnittlich viele ASS-Risikogene und ko-regulierte Gengruppen waren assoziiert mit der Entwicklung des dorsolateralen präfrontalen Cortex, des Hippocampus sowie der Amygdala.
In dieser Studie zeigten wir einen kausalen Zusammenhang zwischen QPRT und der neuronalen Differenzierung in vitro sowie einen Einfluss von QPRT auf die Regulation von ASS-assoziierten Genen und Gen-Netzwerken. Funktionell standen diese Gene im Kontext mit synaptischen Vorgängen, welche durch Veränderungen zu einem Exzitations-Inhibitions-Ungleichgewicht und letztendlich zum Zelltod von Neuronen führen können. Unsere Ergebnisse heben in Summe die wichtige Rolle von QPRT in der Krankheitsentstehung von ASS, insbesondere in Trägern einer 16p11.2 Deletion, hervor.
Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an in vitro model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored in vitro by culturing MOVAS under calcifying conditions. Both, in vitro and in vivo, autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic Tunica media, but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. Vice versa, rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification in vitro and in vivo. Rapamycin reduced Runx2 transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and Sm22α transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
Background: Scientifically evaluated cognitive intervention programs are essential to meet the demands of our increasingly aging society. Currently, one of the “hottest” topics in the field is the improvement of working memory function and its potential impact on overall cognition. The present study evaluated the efficacy of WOME (WOrking MEmory), a theory-based working memory training program, in a double-blind, placebo-controlled, and randomized controlled trial (www.drks.de, DRKS00013162).
Methods: N = 60 healthy older adults were allocated to (1) the WOME intervention, (2) an active low-level intervention, or (3) a passive control group. Overall, the intervention groups practiced twelve sessions of 45 min within 4 weeks of their respective training. Transfer effects were measured via an extensive battery of neuropsychological tests and questionnaires both pre-/post-training and at a 3-month follow-up.
Results: WOME led to a significant improvement in working memory function, demonstrated on a non-trained near transfer task and on two different composite scores with moderate to large effect sizes. In addition, we found some indication of relevant impact on everyday life. The effects were short-term rather than stable, being substantially diminished at follow-up with only little evidence suggesting long-term maintenance. No transfer effects on other cognitive functions were observed.
Conclusion: WOME is an appropriate and efficient intervention specifically targeting the working memory system in healthy older adults.
Trial Registration: German Clinical Trials Register (DRKS), Identifier: DRKS00013162.
Nucleation and growth of aerosol particles from atmospheric vapors constitutes a major source of global cloud condensation nuclei (CCN). The fraction of newly formed particles that reaches CCN sizes is highly sensitive to particle growth rates, especially for particle sizes <10 nm, where coagulation losses to larger aerosol particles are greatest. Recent results show that some oxidation products from biogenic volatile organic compounds are major contributors to particle formation and initial growth. However, whether oxidized organics contribute to particle growth over the broad span of tropospheric temperatures remains an open question, and quantitative mass balance for organic growth has yet to be demonstrated at any temperature. Here, in experiments performed under atmospheric conditions in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN), we show that rapid growth of organic particles occurs over the range from −25 ∘C to 25 ∘C. The lower extent of autoxidation at reduced temperatures is compensated by the decreased volatility of all oxidized molecules. This is confirmed by particle-phase composition measurements, showing enhanced uptake of relatively less oxygenated products at cold temperatures. We can reproduce the measured growth rates using an aerosol growth model based entirely on the experimentally measured gas-phase spectra of oxidized organic molecules obtained from two complementary mass spectrometers. We show that the growth rates are sensitive to particle curvature, explaining widespread atmospheric observations that particle growth rates increase in the single-digit-nanometer size range. Our results demonstrate that organic vapors can contribute to particle growth over a wide range of tropospheric temperatures from molecular cluster sizes onward.
Pretubulysin (PT), a biosynthetic precursor of the myxobacterial compound tubulysin D, was recently identified as a novel microtubule-targeting agent (MTA) causing microtubule destabilization. MTAs are the most frequently used chemotherapeutic drugs. They are well studied regarding their direct cytotoxic effects against various tumors as well as for their anti-angiogenic and vascular-disrupting action addressing endothelial cells of the tumor vasculature. However, the impact of MTAs on endothelial cells of the non-tumor vasculature has been largely neglected, although tumor cell interactions with the healthy endothelium play a crucial role in the process of cancer metastasis. Besides their use as potent anti-cancer drugs, some MTAs such as colchicine are traditionally used or recommended for the therapy of inflammatory diseases. Here, too, the role of endothelial cells has been largely neglected, although the endothelium is crucially involved in regulating the process of inflammation.
In the present study, the impact of PT on tumor-endothelial cell interactions was therefore analyzed in vitro to gain insights into the mechanism underlying its anti-metastatic effect that was recently confirmed in vivo. In the second part of this work, the influence of PT and other MTAs, namely the microtubule-destabilizing compounds vincristine (VIN) and colchicine (COL) and the microtubule-stabilizing drug paclitaxel (PAC), on leukocyte-endothelial cell interactions was investigated in vitro and in vivo (only PT). It is important to mention that in all in vitro experiments solely endothelial cells and not tumor cells or leukocytes were treated with the MTAs to strictly focus on the role of the endothelium in the action of these compounds.
The impact of PT on tumor-endothelial cell interactions was analyzed in vitro by cell adhesion and transendothelial migration assays as well as immunocytochemistry using the breast cancer cell line MDA-MB-231 and primary human umbilical vein endothelial cells (HUVECs). The treatment of HUVECs with PT increased the adhesion of MDA cells onto the endothelial monolayer, whereas their transendothelial migration was reduced by the compound. Thereafter, the influence of PT on the endothelial cell adhesion molecules (CAMs) E-selectin, N-cadherin, ICAM-1, VCAM-1 and galectin-3 and on the CXCL12/CXCR4 chemokine system was examined, since they might be involved in the PT-triggered tumor cell adhesion. Interestingly, although PT induced the upregulation of ICAM-1, VCAM-1, N-cadherin and CXCL12, cell adhesion assays using neutralizing antibodies or the CXCL12 inhibitor AMD3100 revealed that all these molecules were dispensable for the PT-evoked tumor cell adhesion. As PT induces the formation of interendothelial gaps and MDA cells might adhere onto components of the underlying extracellular matrix (ECM), the precise location of MDA cells attached to the PT-treated endothelial monolayer was investigated. Instead of a direct interaction between tumor and endothelial cells, this work showed that MDA cells preferred to adhere to the ECM component collagen that was exposed within PT-triggered endothelial gaps. Both the PT-evoked increase in tumor cell adhesion onto and the decrease in trans-endothelial migration were completely abolished when β1-integrins were blocked on MDA cells. Similar results were obtained when endothelial cells were treated with VIN and COL but not PAC, indicating that the observed effects of PT depend on its microtubule-destabilizing activity.
The impact of PT, VIN, COL and PAC on leukocyte-endothelial cell interactions was analyzed in vivo (only PT) by intravital microscopy of the mouse cremaster muscle and in vitro by cell adhesion assays using the monocyte-like cell line THP-1 and TNFα-activated human dermal microvascular endothelial cells (HMEC-1). While PT did not affect the rolling of leukocytes on the endothelium, their firm adhesion onto and transmigration through the activated endothelium was reduced by PT in vivo. In accordance, the treatment of HMEC-1 with PT, VIN and COL decreased the TNFα-induced adhesion of THP-1 cells onto the endothelial monolayer, whereas PAC had no influence on this process. Thereafter, the influence of PT, VIN, COL and PAC on endothelial ICAM-1 and VCAM-1 was examined, since these molecules are substantially involved in the firm adhesion of leukocytes onto the endothelium. The cell surface protein expression of ICAM-1 and VCAM-1 was reduced by PT, VIN and COL in activated endothelial cells, whereas PAC did only slightly affect the TNFα-induced upregulation of VCAM-1. As the pro-inflammatory transcription factor NFκB plays a crucial role in the TNFα-induced expression of these CAMs, the impact of the MTAs on the NFκB promotor activity was investigated. While PT, VIN and COL decreased the activation of NFκB in activated endothelial cells, PAC did not affect this process. However, in contrast to the strong effects regarding the cell surface protein expression of ICAM-1 and VCAM-1, the effects of PT, VIN and COL on the NFκB activity was rather low. Thus, the used MTAs might also affect other relevant signaling pathways and/or the intracellular transport of CAMs might be influenced by the impact of the MTAs on the microtubule network.
Taken together, the current study provides – at least in part – an explanation for the anti-metastatic potential of PT and gives first insights into the use of PT and VIN as anti-inflammatory drugs. Moreover, this work highlights the endothelium as an attractive target for the development of new anti-cancer and anti-inflammatory drugs.
An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources – randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) – underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Photolabile protecting groups (PPGs, cages, photocages) are molecules which can block the activity of a functional group and be removed by irradiation of light of an appropriate wavelength. One of the goals of this work was to design new photolabile protecting groups, based on a literature known one. The far-UV absorbing diethylamino benzyl (DEAMb) photocage, developed by Wang et al., was selected as structural basis for this work. In order to trigger the uncaging reaction with longer wavelengths (≥365 nm), thus allowing also biological applications, its structure was optimized. This was done by elongating the π-orbital conjugation using biphenyl derivatives instead of a single aromatic moiety. The photocage was loaded with glutamic acid as the leaving group.
The highest bathochromic shift was shown by compounds, which had the smallest sterical hindrance imposed on the second aromatic ring. The absorption spectrum was more redshifted if the second aromatic ring contained an electron withdrawing group. However, the stronger the substituents electron withdrawing strength was, the lower the uncaging quantum yield was. It was rationalized, that this is due to a decreased excited state electron density at the benzylic carbon of the DEAMb core which is necessary to trigger bond dissociation. This has been confirmed using TDDFT (time-dependent density functional theory) computations done by Jan von Cosel, Konstantin Falahati and Carsten Hamerla (from the group of Irene Burghardt). The best uncaging quantum yield was 42% for m-phenyl substituted DEAMb, while if a strong electron withdrawing group was present (nitro group), there was no photoactivity at all.
In order to achieve a better π-orbital conjugation of the non-coplanar biphenyl derivatives, a C-C bond was introduced between the benzylic carbon and the second aromatic ring. The resulting planar compounds belong to the fluorene class. The computational data predicted the photochemical meta effect to some extent to be preserved in these molecules. A set of fluorene derivatives was synthesized and photochemically characterized. The molar absorption coefficients of all prepared fluorene derivatives were higher than for any of the biphenyl derivatives. Quantum yields of the acetate release ranged between 3-42%, thus being as good as the best glutamic acid releasing biphenyl compounds. The highest uncaging cross section of the acetate release from the prepared fluorene derivatives was above 5000 M^-1 cm^-1. This value proves the high potential of the new fluorene based photocages developed in this work. Furthermore, release of hydroxide ion from fluorenol could be shown along with generation of, presumably, fluorenyl cation. These intriguing results paves a way for further exploration of fluorene based photocages for the release of bad leaving groups.
The second part of this work describes the custom synthesis of 13C labeled compounds for the VIPER (VIbrationally Promoted Electronic Resonance) project. In the VIPER pulse sequence, a molecule is vibrationally excited by a narrow band IR-pump pulse. The following Vis-pump pulse will promote the vibrationally pre-excited molecules to an electronically excited state. This Vis-pump pulse is offresonant for the not vibrationally pre-selected species and only resonant with the molecules, which are already pre-excited by the IR-pump pulse. Since the IR absorption bands usually are well resolved, a selective excitation of one molecule in an ensemble of similar ones is possible in the IR frequency range. Isotopologues and isotopomers are an extreme case of molecules which are near identical and differ only by isotopic composition or position. As a result in solution and at room temperature they have an identical UV-Vis absorption spectrum but different IR spectrum. This allows vibrational excitation of only one isotopologue (or isotopomer).
Isotopic labels were introduced in known photocages: 7-diethylamino coumarin (DEACM) and para-hydroxy phenacyl (pHP). The position for isotopic label incorporation in these molecules was guided by computations done by Jan von Cosel and Carsten Neumann. To allow control of the photoreactions in an ultrafast timescale, an IR active leaving group was used. The uncaging behavior of the prepared molecules in steady state was tested using chromatography (HPLC) and spectroscopy (1H NMR, FTIR and UV-Vis). The VIPER experiments were performed by Daniela Kern-Michler, Carsten Neumann, Nicole Mielke and Luuk van Wilderen (from the group of Jens Bredenbeck). A selective uncaging of only the vibrationally pre-excited molecules could be achieved.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Background: The city of Wrocław in Poland represents one of Central Europeans oldest capitals of science with numerous Nobel laureates. Due to a long history of political suppressions with Nazi Germany and Communism from 1933 until 1989, its scientific community was suppressed for more than half a century.
Methods: The present study assessed scientific activities in the field of social and neighbouring sciences using density equalizing mapping. On the basis of the NewQIS (New Quality and Quantity Indices in Science) platform and the Social Sciences Citation Index (SSCI) of the Web of Science database, a total of 1787 articles originating from Wrocław were identified between 1966 and 2017.
Results: In total, 549 research collaborations of Wrocław with 96 different countries were present (30.7%). Among the 107 research areas the highest activity was found for the field of Business and Economics with n = 272 articles (average citation rate (AVR) of 12.54), followed by Psychology (n = 252 articles, AVR = 9.06), Psychiatry (n = 205 articles, AVR = 4.74) and Public, Environmental and Occupational Health (n = 145 articles, AVR = 7.96). The highest AVR was found for Operations Research (25.36 with n = 87 articles). Density equalizing mapping procedures revealed a global pattern of social sciences research collaborations with scientists from Germany, the UK and the US as the primary cooperating partner of Wrocław. The different countries had major differences in the area of research collaborations.
Conclusions: This is the first study that depicts the global network of Wrocław scientific activities in the field of social sciences. The exorbitant increase in research activity from 2006 onwards can lead to the assumption that Wrocław social sciences encounter a fruitful future.
Martin Luthers theologische Idee der Unterscheidung von Gnade/Evangelium und Gesetz/Vernunft, Glauben/Unglauben und Werk, schränkte die Zweiwertigkeitslogik des Aristoteles auf die Gestaltung der Existenz ein und erwies ihre Ungültigkeit für die Erfassung des Grundes der Existenz. Während Luther die dialektische Struktur der Beziehung von Gestaltung und Grund der Existenz in der Form der o.g. Vorstellung zum Ausdruck brachte, hat G.W.F. Hegel sie auf den Begriff gebracht und damit Luthers Theologie in die Philosophie transformiert.
Determining the cell fate and the distribution of mesenchymal stromal/stem cells (MSCs) after transplantation are essential parts of characterizing the mechanisms of action and biosafety profile of stem cell therapy. Many recent studies have shown that MSCs migrate into injured tissues, but are only detectable at extremely low frequencies. We investigated the cell fate of MSCs after transplantation in an acute kidney injury (AKI) mouse model using in vivo bioluminescence imaging (BLI) and subsequent verification of cell migration using quantitative real-time polymerase chain reaction (qRT-PCR). The AKI was induced by a single injection of cisplatin (8 or 12 mg/kg). One day later, adipose-derived mesenchymal stromal/stem cells isolated from luciferase transgenic mice (Luc+-mASCs, 5 × 105) were intravenously transplanted. Migration kinetics of the cells was monitored using BLI on day 1, 3, and 6, and finally via quantitative real-time PCR at the endpoint on day 6. Using BLI, infused Luc+-mASCs could only be detected in the lungs, but not in the kidneys. In contrast, PCR endpoint analysis revealed that Luc-specific mRNA could be detected in injured renal tissue; compared to the control group, the induction was 2.2-fold higher for the 8 mg/kg cisplatin group (p < 0.05), respectively 6.1-fold for the 12 mg/kg cisplatin group (p < 0.001). In conclusion, our study demonstrated that Luc-based real-time PCR rather than BLI is likely to be a better tool for cell tracking after transplantation in models such as cisplatin-induced AKI.
This paper argues that the introduction of the Banking Recovery and Resolution Directive (BRRD) improved market discipline in the European bank market for unsecured debt. The different impact of the BRRD on bank bonds provides a quasi-natural experiment that allows to study the effect of the BRRD within banks using a difference-in-difference approach. Identification is based on the fact that (otherwise identical) bonds of a given bank maturing before 2016 are explicitly protected from BRRD bail-in. The empirical results are consistent with the hypothesis that debt holders actively monitor banks and that the BRRD diminished bail-out expectations. Bank bonds subject to BRRD bail-in carry a 10 basis points bail-in premium in terms of the yield spread. While there is some evidence that the bail-in premium is more pronounced for non-GSIB banks and banks domiciled in peripheral European countries, weak capitalization is the main driver.
Subduction zone magmas are more oxidised on eruption than those at mid-ocean ridges. This is attributed either to oxidising components, derived from subducted lithosphere (slab) and added to the mantle wedge, or to oxidation processes occurring during magma ascent via differentiation. Here we provide direct evidence for contributions of oxidising slab agents to melts trapped in the sub-arc mantle. Measurements of sulfur (S) valence state in sub-arc mantle peridotites identify sulfate, both as crystalline anhydrite (CaSO4) and dissolved SO42− in spinel-hosted glass (formerly melt) inclusions. Copper-rich sulfide precipitates in the inclusions and increased Fe3+/∑Fe in spinel record a S6+–Fe2+ redox coupling during melt percolation through the sub-arc mantle. Sulfate-rich glass inclusions exhibit high U/Th, Pb/Ce, Sr/Nd and δ34S (+ 7 to + 11‰), indicating the involvement of dehydration products of serpentinised slab rocks in their parental melt sources. These observations provide a link between liberated slab components and oxidised arc magmas.